Pathology of Heart Disease in the Fetus, Infant and Child: Autopsy, Surgical and Molecular Pathology [1 ed.] 1107116287, 9781107116283

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Pathology of Heart Disease in the Fetus, Infant and Child: Autopsy, Surgical and Molecular Pathology [1 ed.]
 1107116287, 9781107116283

Table of contents :
Cover
Pathology of Heart Disease in
the Fetus, Infant and Child:

Autopsy, Surgical and Molecular Pathology
Copyright
Dedication
Contents
Preface
1 The Anatomy of the Normal Heart
2 Examination of the Heart
3 Development of the Heart
4 Congenital Heart Disease (I)
5 Congenital Heart Disease (II)
6 Ischaemia and Infarction
7 Cardiomyopathy
8 Inflammation of the Myocardium,
Endocardium and Aorta
9 The Coronary Arteries
10 Metabolic and Storage Disease
11 Pericardium
12 Fetal Cardiovascular Disease
13 Tumours
14 Heart Transplantation
15 Sudden Cardiac Death in the Young
Index

Citation preview

Pathology of Heart Disease in the Fetus, Infant and Child

Pathology of Heart Disease in the Fetus, Infant and Child Autopsy, Surgical and Molecular Pathology Michael T. Ashworth Great Ormond Street Hospital for Children

University Printing House, Cambridge CB2 8BS, United Kingdom One Liberty Plaza, 20th Floor, New York, NY 10006, USA 477 Williamstown Road, Port Melbourne, VIC 3207, Australia 314–321, 3rd Floor, Plot 3, Splendor Forum, Jasola District Centre, New Delhi – 110025, India 79 Anson Road, #06–04/06, Singapore 079906 Cambridge University Press is part of the University of Cambridge. It furthers the University’s mission by disseminating knowledge in the pursuit of education, learning, and research at the highest international levels of excellence. www.cambridge.org Information on this title: www.cambridge.org/9781107116283 DOI: 10.1017/9781316337073 © Michael T. Ashworth 2019 This publication is in copyright. Subject to statutory exception and to the provisions of relevant collective licensing agreements, no reproduction of any part may take place without the written permission of Cambridge University Press. First published 2019 Printed in Singapore by Markono Print Media Pte Ltd. A catalogue record for this publication is available from the British Library. Library of Congress Cataloging-in-Publication Data Names: Ashworth, Michael T., 1956– author. Title: Pathology of heart disease in the fetus, infant and child : autopsy, surgical and molecular pathology / Michael T. Ashworth. Description: Cambridge, United Kingdom ; New York, NY, USA : Cambridge University Press, 2019. | Includes bibliographical references and index. Identifiers: LCCN 2019005631 | ISBN 9781107116283 (hardback) Subjects: | MESH: Heart Diseases–pathology | Infant | Fetus | Child | Case Reports Classification: LCC RJ421 | NLM WS 295 | DDC 618.92/12–dc23 LC record available at https://lccn.loc.gov/2019005631 ISBN 978-1-107-11628-3 Hardback Cambridge University Press has no responsibility for the persistence or accuracy of URLs for external or third-party internet websites referred to in this publication and does not guarantee that any content on such websites is, or will remain, accurate or appropriate.

............................................................................. Every effort has been made in preparing this book to provide accurate and up-to-date information that is in accord with accepted standards and practice at the time of publication. Although case histories are drawn from actual cases, every effort has been made to disguise the identities of the individuals involved. Nevertheless, the authors, editors, and publishers can make no warranties that the information contained herein is totally free from error, not least because clinical standards are constantly changing through research and regulation. The authors, editors, and publishers therefore disclaim all liability for direct or consequential damages resulting from the use of material contained in this book. Readers are strongly advised to pay careful attention to information provided by the manufacturer of any drugs or equipment that they plan to use.

For my sister, Anne.

Contents Preface 1

2

3

4

The 1.1 1.2 1.3 1.4 1.5

xi

Anatomy of the Normal Heart Introduction 1 Anatomy 1 Histology 18 Electron Microscopy 25 Weights and Measures 28

4.10 Transposition of the Great Arteries 4.11 Common Arterial Trunk (Truncus Arteriosus) 109

1

Examination of the Heart 33 2.1 Introduction 33 2.2 Dissection 33 2.3 Sequential Segmental Analysis 36 2.4 Simulated Echocardiographic Views 2.5 Histology 40 2.6 Photography 50

5

Congenital Heart Disease (II) 118 5.1 Double Inlet Ventricle 118 5.2 Double Outlet Ventricle 120 5.3 Abnormalities of the Pulmonary Veins 121 5.4 Ebstein’s Malformation 124 5.5 Tricuspid Atresia 125 5.6 Other Abnormalities of the Tricuspid Valve 126 5.7 Uhl’s Anomaly 127 5.8 Atrial Isomerism 128 5.9 Structural Abnormalities of the Coronary Arteries 131 5.10 Other Abnormalities 131 5.11 Anomalies of the Venous Duct (Ductus Venosus) 134 5.12 Pulmonary Vascular Disease in Congenital Heart Disease 138 5.13 Surgical Operations for Congenital Heart Disease 145 5.14 Assessment of the Operated Heart 150

6

Ischaemia and Infarction 155 6.1 Introduction 155 6.2 Macroscopic Appearance 155 6.3 Microscopic Appearance 158

7

Cardiomyopathy 164 7.1 Introduction 164 7.2 Hypertrophic Cardiomyopathy 164 7.3 Other Cardiomyopathies with a Hypertrophic Phenotype 168 7.4 Dilated Cardiomyopathy 170 7.5 Restrictive Cardiomyopathy 173 7.6 Eosinophilic Endomyocardial Disease 175 7.7 Mitochondrial Cardiomyopathy 176 7.8 Arrhythmogenic Cardiomyopathy 177 7.9 Non-Compaction of the Ventricular Myocardium 179 7.10 Histiocytoid Cardiomyopathy 181 7.11 Other Forms of Cardiomyopathy 182

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Development of the Heart 53 3.1 Introduction 53 3.2 Brief Recap of Relevant Early Human Embryonic Development 53 3.3 Brief Summary of Heart Development 54 3.4 Early Development 54 3.5 Looping of the Heart Tube 57 3.6 Development of the Chambers and Septation 58 3.7 Pericardium 66 3.8 Coronary Arteries 66 3.9 Conduction Tissue 66 3.10 Arterial System 66 3.11 Venous System 68 3.12 The Fetal Circulation and Changes at Birth 70 Congenital Heart Disease (I) 75 4.1 Introduction 75 4.2 Ventricular Septal Defect (VSD) 75 4.3 Atrioventricular Septal Defect (AVSD) 78 4.4 Atrial Septal Defect (ASD) 82 4.5 Abnormalities of the Arterial Duct 83 4.6 Coarctation of the Aorta 86 4.7 Pulmonary Stenosis and Atresia, Including Tetralogy of Fallot 86 4.8 Aortic Stenosis 92 4.9 Hypoplastic Left Heart 96

100

vii

Table of Contents

8

Inflammation of the Myocardium, Endocardium and Aorta 187 8.1 Introduction 187 8.2 Myocarditis 187 8.3 Systemic Inflammatory Diseases with Heart Involvement 194 8.4 Aortitis 197 8.5 Endocarditis 199

9

The Coronary Arteries 203 9.1 Introduction 203 9.2 Normal Structure 203 9.3 Common Normal Variants of the Coronary Arteries 203 9.4 Abnormal Variations in the Epicardial Distribution of the Coronary Arteries in the Normally Formed Heart 206 9.5 Coronary Artery Fistula 206 9.6 Coronary Artery Hypoplasia and Atresia 209 9.7 Variations in the Epicardial Coronary Arteries in Congenital Heart Disease 209 9.8 Vasculitis Including Kawasaki Disease 211 9.9 Eosinophilic Granulomatosis with Polyangiitis (Formerly Churg–Strauss Syndrome) 214 9.10 Thrombosis and Embolism 215 9.11 Fibromuscular Dysplasia 216 9.12 Segmental Arterial Mediolysis 217 9.13 Idiopathic Arterial Calcification 217

10 Metabolic and Storage Disease 221 10.1 Introduction 221 10.2 Glycogen Storage Disorders 221 10.3 Lysosomal Storage Disorders 227 10.4 Mucopolysaccharidosis 229 10.5 Disorders of Fatty Acid Metabolism 230 10.6 Congenital Disorders of Glycosylation 235 10.7 Disorders of Iron Metabolism 236 10.8 Organic Acidaemias and Disorders of Amino Acid Metabolism 237 11 Pericardium 243 11.1 Introduction 243 11.2 Congenital Defects of the Pericardium 11.3 Cysts and Diverticula 244 11.4 Heterotopia 244 11.5 Effusions and Tamponade 244 11.6 Epicardial Haemorrhage 245 11.7 Haemopericardium 245 11.8 Pneumopericardium 245 11.9 Pericarditis 246 11.10 Post-pericardiotomy Syndrome 249 11.11 Constrictive Pericarditis 249 11.12 Pericardial Tumours 249

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243

12 Fetal Cardiovascular Disease 252 12.1 Introduction 252 12.2 The Normal Fetal Heart 252 12.3 Fetal Hydrops 253 12.4 Syndromes with Heart Malformations 255 12.5 Structural Heart Disease in the Fetus 262 12.6 Fetal Cardiomyopathy 262 12.7 Fetal Myocarditis 263 12.8 Fetal Arrhythmia 266 12.9 Fetal Tumours 272 12.10 Twin–Twin Transfusion Syndrome 274 12.11 Conjoined Twins 274 13 Tumours 283 13.1 Introduction 283 13.2 Rhabdomyoma 283 13.3 Fibroma 284 13.4 Teratoma 285 13.5 Myxoma 287 13.6 Vascular Tumours 288 13.7 Cystic Tumour of the Atrioventricular Node 289 13.8 Inflammatory Myofibroblastic Tumour 13.9 Juvenile Xanthogranuloma 290 13.10 Histiocytoid Cardiomyopathy 292 13.11 Lipoma and Other Fatty Lesions 292 13.12 Primary Malignant Tumours 293 13.13 Secondary Tumours 294 13.14 Pseudoneoplasms 294 14 Heart 14.1 14.2 14.3 14.4 14.5 14.6 14.7 14.8 14.9 14.10 14.11 14.12 14.13 14.14 14.15

289

Transplantation 300 Introduction 300 Assessment of the Explanted Heart 300 The Pathology of the Implanted Heart 311 Post-Transplant Endomyocardial Biopsy 313 Allograft Rejection and Graft Dysfunction (Both Acute and Chronic) 313 Specimen Handling 314 Artefacts and Variants of Normal 314 Acute Cellular Rejection 314 Antibody-Mediated Rejection 317 Post-Transplant Lymphoproliferative Disorder 319 Post-Transplant Infection of the Myocardium 319 Chronic Allograft Vasculopathy 320 Recurrent Disease in the Transplanted Heart 321 Failure of the Cardiac Graft and Its Removal at a Second Transplant Operation 322 Post-Mortem in the Transplanted Heart 322

Table of Contents

15 Sudden Cardiac Death in the Young 327 15.1 Introduction 327 15.2 Investigation 327 15.3 Congenital Heart Disease 327 15.4 Coronary Artery Origin Abnormalities 15.5 Cardiomyopathy 330 15.6 Aortic Dissection 333 15.7 Myocarditis 333 15.8 Metabolic Disease 334 15.9 Heart Rhythm Disorders 337

15.10 15.11 15.12 15.13 329

Index

Sudden Infant Death Syndrome 337 Tumours 339 Commotio Cordis 339 Other Rare Causes of Sudden Cardiac Death 339

342

ix

Preface

There are many books that deal with the pathology of congenital heart disease. Many books treat the pathology of noncongenital heart disease, but few do so from a paediatric perspective. I have read many of them and used them extensively over the years, but there is no single source where one can turn when faced with problems in the interpretation of the pathology of heart disease in the fetus and child. This book is an attempt to address this and to offer, primarily to the practising pathologist, a guide to the pathology of these disorders. There has been an explosion of knowledge about heart disease since I began medical practice. Newer imaging methods have revolutionized its understanding. The pathology that I practised as a young consultant is no longer practicable. Soon, I suspect, most investigation of congenital heart disease, in death as in life, will be by means of imaging. The traditional cardiac pathologist will no longer practise in the fashion he or she once did. We belong to a profession whose horizons are changing, but before they do, I wish to make available the wealth of cases that I have seen over the years and the likes of which may not be seen in quite the same way again, but which are still valuable in understanding childhood heart disease.

I wish to express my thanks to the people who have helped this book come about. Firstly to Dr Jean Keeling who many years ago suggested I write a monograph on cardiac pathology, and to my late lamented colleague Dr Marian Malone at whose suggestion I began this particular work four years ago and who put me in touch with Cambridge University Press. My thanks to Professor Jem Berry who first encouraged me in paediatric cardiac pathology, and to Dr Audrey Smith who guided my first steps on that road. To my current Consultant colleagues at Great Ormond St Hospital, Neil Sebire, Liina Palm, Sam Levine and Thivya Sekar who have indulged my interest, and to my many pathology colleagues in the United Kingdom and abroad who have generously referred me cases over the years that have increased my understanding, even if I have not always increased theirs, I am grateful. To my clinical colleagues too numerous to list by name in cardiac surgery, cardiology and radiology in Bristol, Liverpool and London who have given of their time and experience, my heartfelt thanks. Finally, in completing this work I can do no better than echo the words of the unknown ancient author of 2 Maccabees: If it is well told and to the point, that is what I myself desired: if it is poorly done and mediocre, that was the best I could do. (2 Mac 15:38)

xi

Chapter

1

The Anatomy of the Normal Heart

1.1 Introduction Self-evidently, before tackling an abnormal heart, knowledge of normal cardiac anatomy and histology is useful. This chapter examines the structure of the normal heart at the gross, microscopic and ultrastructural levels. Chapter 2 gives details of dissection of the heart and includes a detailed description of sequential segmental analysis. Chapter 3 describes the formation of the normal heart.

layer of pericardium is adherent to the diaphragm, sternum and costal cartilages. The bilateral symmetry of the pulmonary veins combined with asymmetrical arrangement of the caval veins (lying on the right side, and not the left) means that there is a blind invagination of pericardium behind the left atrium between the right pulmonary veins and the inferior caval vein – the oblique sinus of the pericardium (Figure 1.4). A transverse sinus runs from side to side posterior to the aorta and pulmonary trunk and anterior to the bodies of both atria (Figure 1.5).

A Brief Note on Terminology As is now common practice in the United Kingdom, I have anglicised many anatomical terms. Thus, for example, I have used the terms “superior caval vein” rather than “superior vena cava” and “arterial duct” rather than “ductus arteriosus”. I have, however, baulked at the use of such neologisms as “atriums” and “septums”, preferring the original, shorter and infinitely more elegant Latin plurals “atria” and “septa”. I fully accept that there is, thus, inconsistency, but it is, at least, consistent inconsistency. The point of language is to communicate information and I do not believe that the terms I have employed in any way impair that communication.

1.2 Anatomy 1.2.1 Situation The heart sits in the mediastinum, more on the left side than the right. Inferiorly it rests on the central part of the diaphragm and superiorly the aortic arch rises almost to the neck (Figures 1.1 and 1.2). Posteriorly, there is the descending thoracic aorta, oesophagus and vertebral column, and anteriorly, the thymus and sternum. The lungs lie on either side, and their anterior extensions interpose between the heart and the anterior chest wall.

1.2.2 Pericardium The heart is anchored by its attached structures (caval and pulmonary veins and the aorta and pulmonary trunk) and is surrounded by a dense fibrous covering – the pericardium. The pericardium encloses the heart and great vessels but is reflected off the anchoring structures (Figure 1.3). Externally, the parietal

Figure 1.1 Normal heart. A post-mortem in a neonate. The chest has been opened and the sternum removed by cutting through the costal cartilages. The heart is enclosed in the pericardium. Above is the thymus, below the diaphragm separates it from the liver. The pleural cavities are open, and the lungs are visible.

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1: The Anatomy of the Normal Heart

Figure 1.2 Normal heart after removal of the thymus and pericardium. The greater part of the ventricular mass visible in this view is the right ventricle. The right atrial appendage lies above, and above this again the superior caval vein. The pulmonary artery arises from the right ventricle, and the aorta is just visible behind it. The left atrial appendage is just visible to the left of the arterial pedicle.

Figure 1.4 Oblique sinus of the pericardium. The heart viewed from behind. One pair of forceps grabs the cut edge of the parietal pericardium. Another pair is inserted into the oblique sinus. The right margin is formed by the pericardial attachment between the inferior caval vein and right pulmonary veins, and the superior blind end is closed by the attachment of pericardium between the upper pulmonary veins.

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Figure 1.3 Diagram of attachments of pericardium. The sites of attachment are coloured red. The pericardial cavity encloses the most proximal parts of the superior and inferior caval veins and the pulmonary veins, and also the most proximal parts of the aorta and pulmonary trunk and proximal part of the arterial duct.

Figure 1.5 Transverse sinus of pericardium. The heart is viewed from the right side. A pair of forceps has been inserted from the left side between the arterial pedicle and the atria. The tip can be seen emerging on the right side between the junction of the superior caval vein and right atrium posteriorly and the aorta anteriorly. The cut edge of the pericardial reflection is seen above.

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1: The Anatomy of the Normal Heart

A small triangular fold of the pericardium is reflected from the left pulmonary artery to the left upper pulmonary vein – the fold of the left caval vein (vestigial fold of Marshall) (Figure 1.6). It contains a fibrous strand, called the ligament of the left caval vein, that is a remnant of the left common cardinal vein (left duct of Cuvier) and that extends downwards in front of the root of the left lung to the back of the left atrium where it is continuous with the oblique vein of the left atrium. The fold frequently forms the anterior wall of a small blind recess, the mouth of which is directed to the left. In the undissected state connective tissue joins the aorta and pulmonary trunk, and there is no cavity between them. The pulmonary end of the arterial duct lies within the pericardial cavity; its distal part is outwith the pericardium. The pericardium is not essential to life, nor the efficient working of the heart, which operates

adequately even when the pericardium is removed. The phrenic nerves descend on the outer lateral aspects of the pericardial sac, one on each side.

Figure 1.6 Fold of Marshall. The heart viewed from the left side and displaced by forceps to the right to display the left pulmonary artery and the left pulmonary veins. A fold of pericardium runs from the inferior surface of the left pulmonary artery to the upper border of the left upper pulmonary vein. This is the vestigial fold of Marshall, and it is continuous with the oblique vein of the left atrium (not visible in this picture). The transverse sinus of the pericardium lies anterior to the fold. Posterior to it is a blind-ending recess of the pericardial cavity.

Figure 1.7 The right heart dissected to show the septal structures. The parts of the right atrium shown lie between the orifices of the superior and inferior caval veins. Visible are the interatrial septum, including oval fossa, vestibule of the tricuspid valve, and coronary sinus orifice. In this view only the origin (just above the oval fossa) and insertion (from the junction with the inferior caval vein, eustachian valve, and above the coronary sinus) of the terminal crest are seen, and the muscular trabeculations and appendage are not included. This part of the atrium derives from the sinus venosus and is smooth walled.

1.2.3 The Right and Left Atrium The right atrium comprises three components: a smoothwalled venous component; an atrial appendage; a vestibule supporting the tricuspid valve. 1. The venous component lies between the orifices of the superior and inferior caval veins, encompasses the orifice of the coronary sinus and is smooth walled (Figure 1.7). Embryologically it derives from the sinus venosus and is separated from the atrial appendage externally by the terminal groove and internally by the terminal crest (crista terminalis) (Figure 1.8). The terminal crest originates on the right atrial aspect of the interatrial septum and passes anterior to the mouth of the superior caval vein onto the lateral wall of the atrium and extends downwards to pass anterior to the orifice of the inferior caval vein where it is continuous with the eustachian valve. 2. The right atrial appendage is triangular in shape and has a broad junction with the atrium (Figure 1.9). It contains multiple parallel trabeculations – pectinate muscles – that extend around the greater part of the orifice of the tricuspid valve and are limited by the terminal crest (Figure 1.8). Externally, the junction of the crest of the appendage with the superior caval vein marks the site of the sinoatrial node (Figure 1.10). 3. The vestibule supports the tricuspid valve, and it is smooth. Situated in the vestibule, between the orifice of the coronary sinus, the attachment of the tricuspid valve and the membranous septum (see Section 1.2.7), lies the

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1: The Anatomy of the Normal Heart

atrioventricular (AV) node. The bundle of His exits the node anteriorly to penetrate the membranous septum and divide astride the crest of the muscular interventricular septum giving rise to the right and left bundle branches. The interatrial septum is smaller than it appears. The true septum comprises only the oval fossa with its rim (Figure 1.11). The remainder of the party wall with the left atrium is formed by infolding of both atrial walls with a sandwich of extracardiac adipose tissue (Figure 1.12). The oval fossa is closed by a flap valve. About 20% of the population have a valve that is

Figure 1.8 Terminal crest. The right atrium in a simulated four-chamber view of the heart. The interatrial septum runs diagonally across the field. A little beneath it, and separated from it by the orifice of the superior caval vein (not seen in this view), is the terminal crest – a solid rounded bar of atrial muscle that runs from superior to inferior delimiting the atrial appendage, and from which muscular trabeculations arise at right angles and extend to the vestibule of the tricuspid valve.

Figure 1.10 The sinoatrial node lies at the junction of the superior caval vein and the crest of the right atrial appendage.

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Figure 1.9 Right atrial appendage. Viewed from the outside. The right atrial appendage is roughly pyramidal in shape, has a broad junction with the right atrium and contains parallel muscular trabeculations that extends into the body of the atrium around the vestibule of the tricuspid valve.

Figure 1.11 Oval fossa. The right atrium and right ventricle have been opened, and the heart is viewed from the right side. The opened orifice of the inferior caval vein is to the left midfield and the unopened orifice of the superior caval vein to the upper midfield. Lying between them is the oval depression of the oval fossa. Its rim is smooth and the flap valve completely closed. Beneath it, the orifice of the coronary sinus can be seen.

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1: The Anatomy of the Normal Heart

Figure 1.12 Infolding of atrial septum. (A) A post-mortem heart from a case of idiopathic dilated cardiomyopathy showing the interatrial septum cut vertically through the oval fossa. The rim of the fossa is muscular, but the remainder of the apparent septum is formed of infolding of extracardiac fibrous and adipose tissue. Note also the extension of muscular trabeculations around the right atrioventricular junction while the left is smooth. (B) The histological section shows more clearly the infolding of fibrous tissue between the two atrial walls, especially superiorly. The right atrium is on the left of the field and the left atrium to the right.

Figure 1.13 The right atrium and ventricle have been opened and are viewed from the right side. The opened right atrial appendage is on top. Beneath this is the slightly distorted orifice of the superior caval vein. Beneath this again is the oval fossa. There is persistence of the oval foramen with the flap valve not closing the defect anterosuperiorly.

probe patent at its anterosuperior margin (sometimes termed persistent foramen ovale (PFO)) (Fig 1.13). The right atrium contains a eustachian valve of variable prominence (Figure 1.7) – a relic of the structure that in fetal life directed the venous duct (ductus venosus) blood from the inferior caval vein through the oval foramen. In some instances, the valve is a thick muscular ridge. The coronary sinus may be guarded by a thin membrane: the thebesian valve. The valve is usually attached at the postero-inferior margin and is variably fenestrated (Figure 1.14). The area between the orifices of the inferior caval vein and the coronary sinus is termed the sinus septum and is traversed by the tendon of Todaro. Between the eustachian valve and the attachment of the septal leaflet of the tricuspid valve is an area known by electrophysiologists as the isthmus. It contains a pouch-like area beneath the orifice of the coronary sinus termed the subthebesian recess [1]. A Chiari network may be present (Figure 1.15). This is a netlike structure in the right atrium connected to the terminal crest or atrial septum and to the eustachian or thebesian valve.

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1: The Anatomy of the Normal Heart

Figure 1.14 Eustachian and thebesian valves. (A) The right atrium and ventricle have been opened and are viewed from the right side. The oval fossa is at the top of the picture. The eustachian valve runs obliquely from bottom left to upper centre. Towards its upper extent is the oval fossa with a slight ridge of tissue postero-interiorly forming the thebesian valve. The valve is very variable in morphology, if it is present at all. (B) In a different heart viewed from the same vantage point, the eustachian valve has been grasped and pulled taut. It can be appreciated how it acts as a baffle to direct blood to the oval fossa. The coronary sinus shows a fenestrated thebesian valve.

Usually it is highly fenestrated, but may be more solid and resemble a spinnaker sail, causing obstruction to forwards flow of venous blood across the tricuspid valve [2]. It represents the remains of the right venous valve of the sinus venosus [3]. Remnants of the left valve of the sinus venosus may be seen as lacelike structures or cords resembling tendinous cords (chordae tendineae) attached to the right side of the atrial septum in the region of the oval fossa (Figure 1.16) [4]. The left atrium is usually smaller than the right and receives the pulmonary veins. The junction between the two is marked externally by a shallow groove running vertically between the superior caval vein and the right pulmonary veins – Waterston’s groove (Figure 1.17). Usually there are four: two on the right – one superior and one inferior – and two on the left – one superior and one inferior – but the number can vary. The left side of the oval fossa is generally corrugated and rougher than on the right (Figure 1.18). The endocardium of the left atrium is thicker than that of the right atrium, the thickening being caused by fibroelastic tissue. This should not be mistaken for a pathological change. The left atrial appendage is quite distinct from the right. It is long and tubular and has a narrow junction with the atrium and characteristically has a hooked extremity. Pectinate muscles are confined to the appendage and do not extend onto the atrial wall, nor around the orifice of the mitral valve (Figure 1.19). The coronary sinus runs in the posterior wall of the left atrium at the level of the atrioventricular junction. If there is a persistent left superior caval vein, the sinus is correspondingly larger and may bulge into the left atrium. Figure 1.15 Chiari network. Termination of pregnancy at 18 weeks’ gestation for hypoplastic right heart. The right atrium has been opened looking towards the interatrial septum. A filigreed diaphanous structure partly covers the oval fossa extending from the terminal crest down towards the eustachian and thebesian valves. The right heart structures were small but otherwise unremarkable. It is unknown whether this Chiari network was the cause of right heart hypoplasia by obstructing the tricuspid orifice.

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1.2.4 The Ventricles The left ventricle is the thicker walled of the two ventricles and is ellipsoid in shape. The right ventricle is wrapped around its rightward aspect, thus giving it a more complex

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1: The Anatomy of the Normal Heart

Figure 1.16 Remnants of left valve of sinus venosus. The oval fossa viewed from the right atrium. The eustachian valve is grasped by forceps. The lower border of the oval fossa is buttressed by a trabecular network of fibrous cords that represent the incompletely fused remnants of the left valve of the embryonic sinus venosus.

Figure 1.17 Waterston’s groove. The heart viewed from behind. Running superiorly from the inferior caval vein to the superior caval vein is a shallow groove marking the junction between the right and left atrium – Waterston’s groove.

Figure 1.18 Left side oval fossa. The left atrium has been opened to display the left side of the interatrial septum. The mitral valve leaflets are apparent to the lower right. Note the opaque thick pale endocardium characteristic of the left atrium. This is especially evident on the cut edge of the wall at the upper right of the field where the endocardium occupies nearly one-third of the thickness of the atrial wall. No distinct oval structure can be recognised on the left side of the septum. Instead the attachments of the flap valve of the oval fossa are evident as a rugose area in the centre of the field.

shape (Figure 1.20). From the point of view of descriptive anatomy, the ventricles have three components: an inlet, comprising the atrioventricular valve and its supporting structures; an outlet supporting the arterial valve; and an apical trabecular component linking the two (Figure 1.21). It is important to keep in mind that the components on the right and left side are not perfectly aligned. This apical trabecular component is the most constant and most characteristic feature of the ventricles. On the right side, the septal aspect of the apex shows thick

muscle bundles termed trabeculations (trabeculae) that have a roughly parallel orientation along the long axis of the septum. The most prominent of these, the septomarginal trabeculation (trabecula septomarginalis), extends nearly the full length of the septum. Shaped like the letter Y, its stem extends from the apex upwards, its anterior limb extends in the outflow tract to the pulmonary valve and its posterior limb extends backwards, supporting the medial papillary muscle of the tricuspid valve (Figure 1.22). There is considerable normal variation in the posterior limb – in some cases it extends posterior to the membranous septum and in others anterior [5]. The septomarginal trabeculation is usually incorporated into the muscle of the septum analogous to an engaged pillar or pilaster, but may occasionally, at least in the fetus, be a largely freestanding structure (Figure 1.23). On the left side of the septum the trabeculations are fine and typically have an interwoven appearance, and the outflow tract shows a smooth septal surface (Figure 1.24).

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1: The Anatomy of the Normal Heart

Figure 1.19 Left atrial appendage. Explanted heart from a 14-year-old boy with idiopathic dilated cardiomyopathy, cut in a four-chamber view and viewed from behind. The orifice of the right atrial appendage is on the right side and shows extension of the muscular trabeculations from the appendage around the atrioventricular junction. By contrast, on the left side, the junction of the appendage and atrium is narrow and the trabeculations are confined to the appendage, the remainder of the atrial wall being smooth.

Figure 1.21 Components of septal aspect of right ventricle. The heart has been dissected to demonstrate the right-sided aspect of the interventricular septum. The tricuspid valve together with its tension apparatus (tendinous cords and papillary muscles) occupies the inlet component. Distal to it is the apical trabecular component where the muscular trabeculations are chunky and roughly parallel to one another. The outlet component lies superior to the papillary muscles of the tricuspid valve and is largely smooth. The septomarginal trabeculation occupies much of this component.

1.2.5 Atrioventricular Valves The right-sided atrioventricular valve, the tricuspid valve, as its name indicates, has three leaflets: septal, anterosuperior and inferior. All three leaflets are anchored by tendinous cords (chordae tendineae) to papillary muscle groups situated at the leaflet commissures. The septal leaflet is also attached by cords directly to the septum (Figure 1.25). Its medial papillary muscle (muscle of Lancisi) is small and arises from the

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Figure 1.20 Right ventricle wrapping around left. A short-axis dissection of the heart viewed from the apical aspect. The left ventricle is roughly elliptical in cross section and is at the lower aspect of the picture. The anterior leaflet of the mitral valve occupies much of its cavity. The right ventricle is wrapped around the left and extends from the left of the picture, where the right atrium and tricuspid valve are seen to the right, where it disappears up towards the pulmonary valve. Occupying the “hinge” region is the supraventricular crest. The bulge upwards in the interventricular septum at the site of insertion of the supraventricular crest into the septum represents the stem of the septomarginal trabeculation. The anterior limb of the septomarginal trabeculation extends upwards into the right ventricular outflow tract. The posterior limb is obscured by anterior and septal leaflets of the tricuspid valve. The commissure of the valve is supported by the medial papillary muscle attached to the posterior limb.

Figure 1.22 Septomarginal trabeculation. The same dissection as in Fig 1.21 rotated forwards to demonstrate the right ventricular outflow tract. The Y-shape of the septomarginal trabeculation can be readily appreciated with the anterior limb of the Y extending up to the pulmonary valve. Inserted between the limbs of the Y is the supraventricular crest, which separates the pulmonary valve from the tricuspid valve and which forms the posterior wall of the subpulmonary infundibulum. Externally, the right coronary artery travels along the upper border of the supraventricular crest. Note the spiral configuration of the aorta and pulmonary artery relative to each other.

posterior limb of the septomarginal trabeculation (Figure 1.20). Frequently there are associated small accessory papillary muscles variably located around the muscle of Lancisi [5]. The anterosuperior leaflet is the largest of the three leaflets of

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1: The Anatomy of the Normal Heart

Figure 1.23 Free-standing septomarginal trabeculation. A fetus of 24 weeks’ gestation with hypoplastic left heart. The dissection of the right side of the interventricular septum shows a septomarginal trabeculation that is largely free standing. Pins have been inserted between the stem of the trabeculation and the septum to demonstrate the lack of attachment.

Figure 1.24 Septal aspect of left ventricle. The left ventricle has been opened along its lateral margin and splayed to demonstrate the structures on the left aspect of the interventricular septum. The inlet component is occupied by the mitral valve leaflets, their attached tendinous cords and papillary muscles. The apical component shows fine trabeculations with a criss-cross configuration. The outlet component is smooth.

the tricuspid valve and its anterior papillary muscle is prominent. The inferior leaflet is less conspicuous, as are its papillary muscles. The left atrioventricular valve – the mitral valve – comprises two leaflets: a large rectangular, anterior (or aortic) leaflet, and a mural leaflet, which is attached to about twothirds of the atrioventricular junction (Figure 1.26). Two large papillary muscle groups, termed anterolateral and posteromedial, support the commissures of the leaflets. The anterior leaflet is attached to the interventricular septum only on its postero-inferior aspect; the left ventricular outflow tract is interposed between the ventricular aspect of the leaflet and the septum. Thus, there is fibrous continuity via a subaortic fibrous curtain between the anterior mitral leaflet and the noncoronary cusp and part of the left coronary cusp of the aortic valves (Figure 1.27). The two lateral margins of this area of fibrous continuity show fibrous thickening, the so-called right and left fibrous trigones, the right fibrous trigone being in continuity with the membranous septum and the left fibrous trigone anchoring the fibrous curtain to the muscular septum.

In a small percentage of normal hearts a small band of muscle separates mitral and aortic valves [6]. The attachment of the mitral valve to the left side of the interventricular septum is higher than the attachment of the tricuspid valve to the right side of the septum, a feature termed offsetting, and easily detected on echocardiography and useful for identifying the ventricles (Figure 1.28). This means that there is an area between the two attachment sites where there is a potential communication between the left ventricle and the right atrium – the so-called atrioventricular septum. Especially in the neonate, small blood-filled cysts may be present on the leaflets of the atrioventricular valves (see Section 1.3.4 for more detailed discussion). Yellow thickenings may be seen on the anterior leaflet of the mitral valve even at a young age (Figure 1.27) [7].

1.2.6 Interventricular Septum The septum between the two ventricles is predominantly muscular and usually of a similar thickness to the rest of the left

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1: The Anatomy of the Normal Heart

Figure 1.25 Tricuspid valve. A heart opened to display the tricuspid valve. The septal leaflet, as its name implies, is attached to the spetum and shows short cord-like attachments to it. The medial papillary muscle is a small structure at the top centre of the field. The inferior leaflet has been cut through to open the heart. Nonetheless, its papillary muscle is visible towards the bottom centre. The anterosuperior leaflet is the largest and occupies the upper right field. Its papillary muscle is just visible.

Figure 1.27 Subaortic fibrous curtain. The left ventricular outflow tract has been opened and the anterosuperior leaflet of the mitral valve retracted to the right of the field. The proximal aorta, aortic valve and septal aspect of the left ventricular outflow are visible. The cut passes through the left coronary cusp of the aortic valve. The two intact leaflets are the right coronary leaflet to the left of the field and the non-coronary leaflet in the centre. In the fibrous triangle between the right and non-coronary cusps lies the membranous septum. The mitral valve is in fibrous continuity with the non-coronary cusp and part of the left coronary cusp – the so-called subaortic fibrous curtain. That part of the fibrous curtain adjacent to the membranous septum is thickened as the right fibrous trigone. The left fibrous trigone attaches to the muscular interventricular septum. Note that even though this child was only five years old at the time of death, there are fatty streaks in the fibrous curtain.

ventricular wall. The right ventricular aspect has already been discussed in detail above. The left ventricular aspect has a finely trabeculated apical aspect. The upper part of the left side

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Figure 1.26 Mitral valve. The mitral valve has been opened between the lateral junction of the anterior leaflet (to the left of the field) and the mural leaflet. The posteromedial papillary muscle group occupies the centre of the field and the anterolateral group has been divided with components on the extreme right and left of the lower part of the field. Note that the anterosuperior leaflet is attached to about only one-third of the valve circumference but has a greater depth. Thus, when closed, the anterosuperior leaflet occupies the greater part of the cross sectional area of the orifice and is encompassed on three sides by the mural leaflet.

Figure 1.28 Tricuspid–mitral offsetting. Heart cut in a simulated fourchamber view. The anterosuperior leaflet of the mitral valve is attached to the septum at a higher level than the septal leaflet of the tricuspid valve. The area of the septum lying between the two attachments is the atrioventricular septum.

of the interventricular septum is usually smooth and forms the left ventricular outflow tract (Figure 1.24). In this area and immediately beneath the aortic valve there is a small fibrous area situated between the right and non-coronary cusps of the aortic valve and extending beneath the non-coronary cusp, where the septum is very thin and completely fibrous – the membranous septum (Figure 1.29). This can be dramatically demonstrated by transillumination (Figure 1.30). On the right

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1: The Anatomy of the Normal Heart

Figure 1.29 Membranous septum. A close-up view of the left ventricular outflow tract. The anterosuperior leaflet of the mitral valve has been bisected to expose the septal aspect of the outflow tract. On the left upper part of the picture the right coronary cusp of the aortic valve is visible with the orifice of the right coronary artery. The non-coronary cusp lies beside it towards the mitral valve. In the triangle formed by the ventricular attachments of these two cusps and the crest of the muscular interventricular septum lies the membranous septum. The right fibrous trigone lies beside it, representing the thickened right end of the subaortic fibrous curtain.

Figure 1.30 Membranous septum. The left ventricular outflow tract opened in the same manner as in Figure 1.29 and transilluminated from the right side. This demonstrates the thin membranous septum that is roughly triangular in shape and occupies the triangle between the ventricular attachments of the right and non-coronary cusps of the aortic valve.

Figure 1.31 Relationship of the septal leaflet of the tricuspid valve to the membranous septum. The heart is viewed from the right side – the endocardium of the right atrium is stripped and the leaflets of the tricuspid valve cut close to their attachments to the atrioventricular junction. The right atrium occupies the left and upper parts of the field and the right ventricle the lower and right parts. The atrioventicular junction runs diagonally from upper right to lower left. At the very centre of the field the membranous septum can be seen as a pale grey triangular area. It is crossed by the attachment of the tricuspid valve leafet such that a small part lies above the valve (to the left in this picture). This is the membranous atrioventricular septum.

Figure 1.32 Membranous septum in trisomy 21. A heart from a child with trisomy 21 viewed from the right side. The membranous septum is in the centre of the field, and the commissure of the septal and anterior leaflets is deficient, exposing a large membranous septum.

side, the attachment of the septal leaflet of the tricuspid valve runs diagonally across this membranous septum (Figure 1.31). The membranous septum may be abnormally large in cases of trisomy 21 (Figure 1.32) [8]. The exact anatomy of the muscle bundles in the normal heart has not been conclusively proven. At least in the fetal heart the arrangement has been described as “a set of geodesics

arranged over nested toroids” and has been likened to a set of distorted pretzels or sets of two doughnuts side by side, the interventricular septum corresponding to the junction of the two doughnuts [9]. The right ventricle contributes more to the distortion because of the separation of tricuspid and pulmonary valve (Figure 1.33).

1.2.7 Cardiac Conduction System There are two main recognisable components to the human cardiac conduction system: the sinoatrial node and the atrioventricular conduction axis [10]. It is still debated as to

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1: The Anatomy of the Normal Heart Figure 1.33 Orientation of muscle bundles of the ventricles. A female infant born at term who died very shortly afterwards from pulmonary hypoplasia. The heart is viewed from posteriorly. The orientation of the superficial muscle bundles in the ventricular myocardium is evident on the epicardial surface. The orientation is oblique but slightly different in its axis in both ventricles and dips in towards the interventricular septum.

whether anatomically distinct specialised conduction pathways exist in the right atrium linking the two [11, 12]. The sinoatrial node is roughly triangular in outline and lies on the epicardial surface of the heart at the junction of the superior caval vein with the crest of the right atrial appendage, sometimes in front of the junction, sometimes behind and, at times, astride it. It is not visible macroscopically (Figure 1.10) and requires histological examination for its assessment. The AV node is also roughly triangular in shape and sits at the lower part of the interatrial septum in the triangle of Koch. The borders of this triangle are the atrioventricular junction, the mouth of the coronary sinus and the tendon of Todaro – a fibrous subendocardial prolongation of the eustachian valve that inserts into the membranous septum (Figure 1.34). The non-branching bundle of His emerges from the node, penetrates the membranous septum and divides astride the crest of the muscular interventricular septum to give a fan-shaped left bundle branch and a rather more discrete right bundle branch. The left bundle branch lies, for the most part, immediately beneath the endocardium of the left ventricular outflow tract, by contrast, the right bundle branch dives into the myocardium of the right side of the interventricular septum and travels towards the apex in that location [13]. The structure is dealt with in more detail in Section 1.3.5.

1.2.8 Arterial Valves The pulmonary artery arises from the right ventricle, and the aorta from the left. The aortic valve sits in the centre of the base of the heart and is wedged between the tricuspid and mitral valves (the axes of both atrioventricular valves being at an angle of approximately 45 degrees to the anteroposterior

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Figure 1.34 Triangle of Koch. Same heart as in Figure 1.31, but before removal of endocardium and valve leaflets The commissure of the septal and anterosuperior leaflets of the tricuspid valve lies adjacent to the centre of the field marking the position of the membranous septum. The orifice of the coronary sinys is visible to the left and immediately above it a fold of tissue representing the eustachian valve. The prolongation of the fold towards the membranous septum Is the tendon of Todaro. The triangle of Koch is delimited by the mouth of the coronary sinus, the tendon of Todaro and the septal attachment of the tricuspid valve. Within it lies the AV node. If one views Figure 1.31, it is evident that the node is not visible to the naked eye.

axis of the heart) (Figure 1.35). The pulmonary valve sits anteriorly and to the left of the aortic valve and at an angle of approximately 45 degrees to it. Both arterial valves have three cusps with associated commissures (Figure 1.36). Each valve cusp has a semicircular attachment to the ventriculoarterial junction with the convex aspect on the ventricular side. The free edges meet at the commissures on the arterial aspect. The pocket thus formed between each cusp and the arterial

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1: The Anatomy of the Normal Heart

Figure 1.35 Dissection of heart to demonstrate the relations of the great arteries. The heart is viewed from above with the posterior aspect at the upper part of the field and the anterior aspect on the lower part. The right ventricle is to the left of the field and the left ventricle to the right. The aorta sits in the centre of the base of the heart and the pulmonary trunk is anterior to it and to the left. The aorta is wedged between the two atrioventricular valves. The axes of the two great arteries are at an angel of approximately 45 degrees to each other. It can be appreciated that the commissure of the two valvar cusps in the anterior aorta abuts the commissure of the two posterior cusps in the pulmonary trunk. The origins of the coronary arteries from the facing sinuses of the aortic valve are also evident, as is the way that the right ventricle is wrapped around the anterior aspect of the left.

wall is termed a sinus. The artery at the site of the valve bulges outward slightly such that when the valve is fully open, the cusps fill the recess and do not impair the forwards flow of blood from the ventricle to the artery. The line of apposition of the cusps when the valve is closed lies not at the free edges of the cusps but a little way below this. The area between the free edge and the line of apposition is called the lunula. A small nodular area of thickening is present in the centre of the free edge of each cusp – the nodule of Arantius (Figure 1.37). The commissure of two of the cusps of the pulmonary valve is contiguous with the commissure of two of the cusps of the aortic valve to produce facing sinuses in each valve (Figure 1.35). The two facing sinuses of the aortic valve give rise to the coronary arteries. The pulmonary valve is supported by a complete muscular infundibulum (Figure 1.22); the aortic valve, by contrast, has a rim supported only partly by muscle and partly by the fibrous continuity between the left coronary and non-coronary leaflets of the aortic valve and the anterior leaflet of the mitral valve (Figure 1.26). A muscle bundle, the “anterolateral muscle bundle of Moulaert”, is conspicuous in about 40% of hearts (Figure 1.38) [14]. The aorta and pulmonary trunk have a spiral relationship to each other – the pulmonary trunk extending backwards and to the right and the aorta slightly forwards and to the left (Figure 1.39). In the fetus and neonate the arterial duct is a direct continuation of the pulmonary trunk to the descending thoracic aorta with a narrow angle between its superior surface and the aortic arch (Figure 1.40). Later growth of the pulmonary

Figure 1.36 Normal pulmonary valve. The right ventricular outflow tract has been opened to expose the pulmonary valve. The circumference of the valve contains three cusps that have a semicircular attachment to the ventriculoarterial junction. They are attached such that the lower part of the sinus of each overlies myocardium while the upper part of the sinus overlies arterial wall. Similarly, on the ventricular aspect of each cusp, part of the triangular space between the cusps overlies arterial wall and the remainder overlies myocardium. The aortic valve where it is attached to the ventricular wall has a similar arrangement. The free edges of the cusps also have a semicircular profile when viewed from the arterial side. When closed, the three cusps come together to give a triradiate appearance. The line of apposition of the cusps is not in fact at the free edge but slightly lower on the cusp.

Figure 1.37 Semilunar valve cusp morphology. Excised aortic valve cusps. Each is semilunar in shape. The free edge shows a slight nodular thickening in its mid part – the nodule of Arantius. Between the free edge of the cusps and the line of apposition, the valvar tissue is thin and, frequently, as here, fenestrated.

artery and aorta causes the angle between the duct and the aorta to approach at more of a right angle (Figure 1.41).

1.2.9 Coronary Arteries The coronary arteries arise from the right- and left-facing sinuses of the aortic valve. Although Anderson and co-workers

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1: The Anatomy of the Normal Heart

Figure 1.38 Anterolateral muscle bundle of Moulaert. Left ventricular outflow tract opened by bisecting the anterosuperior leaflet of the mitral valve. The cut end of the mitral valve is grasped in the forceps. Extending from the area of the left fibrous trigone, a prominent muscle bundle descends between the septum and the ventricular wall. This feature is said to occur in up to 40% of normal hearts, but its prominence is very variable. While it has the potential to narrow the outflow tract, of itself it does not cause problems.

Figure 1.39 Spiral relation of aorta and pulmonary artery. Normal fetal heart at 22 weeks’ gestation. The rightward spiral of aorta and pulmonary artery around each other is well seen.

Figure 1.40 Neonatal arterial duct in a one-day-old infant. The arterial duct is evident as an upwards continuation of the pulmonary artery. It joins the inferior aspect of the aortic arch at an acute angle.

have urged the naming of the sinuses as 1 and 2 (as viewed from a hypothetical observer sitting in the non-coronary sinus and observing the sinus at their right hand as number 1 and that at their left hand as number 2), this is at variance with their otherwise stated preference for avoidance of alphanumerical systems of classification [15]. They arise from within the valve sinus and below, or sometimes at the level of the sinotubular junction. The left artery arises from the left-facing sinus, and there is usually only one orifice. The right artery arises from the right-facing sinus. In up to 50% of normal hearts there is a second, smaller orifice giving rise to an

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Figure 1.41 Post-neonatal arterial duct. The angle of entry of the arterial ligament into the pulmonary arterial wall is greater than in the neonate.

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1: The Anatomy of the Normal Heart

Figure 1.42 Multiple right coronary artery orifices. The left ventricular outflow and aortic valve opened to demonstrate the coronary artery orifices. To the left of the field the left coronary artery arises via a single orifice from the left sinus of Valsalva. In the centre the right coronary artery arteries from the right sinus of Valsalva . There are three orifices. The main orifice is towards the commissure with the non-coronary cusp. Two smaller orifices are visible towards the centre of the sinus, representing the orifices of infundibular branches.

infundibular (conus) artery (Figure 1.42) [16]. The orifices are usually in the central part of the sinus, but they may be located close to the commissures. The epicardial course of the coronary arteries is in the atrioventricular grooves and the interventricular grooves. In about 90% of subjects the posterior (inferior) interventricular coronary artery takes origin from the right coronary artery – so-called right-dominance (Figure 1.43). In most of the remainder the posterior interventricular artery has its origin for the left circumflex artery, socalled left dominance (Figure 1.44). In a small number of cases there are posterior interventricular arteries arising from both right and left circulations, the so-called balanced pattern (Figure 1.45). An exceptionally rare occurrence is the origin of the left coronary artery from the posterior sinus [17]. The right coronary artery emerges directly from the aorta into the adipose tissue of the right atrioventricular groove and overlies the supraventricular crest. It courses in the groove around the tricuspid valve to supply the inferior surface of the heart. If the infundibular artery does not arise directly from the sinus, it forms one of the first branches of the right coronary artery after its exit from the aorta. The sinoatrial node branch is also an early branch in about 50% of cases (in the remainder, this artery arises from the early part of the course of the left circumflex artery) (Figure 1.46). The next major branch of the right coronary artery is the marginal branch running towards the apex on the acute margin of the heart. In those hearts with right-dominance, the posterior interventricular artery from the right coronary artery supplies the inferior wall of the left ventricle and the posteromedial papillary muscle of the mitral valve.

Figure 1.43 Right dominant coronary circulation. The normal heart viewed from its diaphragmatic surface. The right coronary artery can be seen at the top centre of the field as it courses in the right atrioventricular groove from the anterior surface of the heart. Adjacent to the inferior caval vein it gives off a posterior descending artery that travels towards the apex, together with the middle cardiac vein. The circumflex artery is seen at the bottom of the field in the left atrioventricular groove as it terminates in a branch running obliquely over the diaphragmatic surface towards the apex. The posterior vein of the left ventricle runs from the atrioventricular groove towards the apex equidistant from the two arteries.

The left coronary artery has a short undivided course following its exit from the aorta. It divides to the left of the pulmonary artery to form anterior descending (interventricular) and circumflex branches. In about one-third of individuals a third vessel arises at this branching point, called the first diagonal branch (or intermediate artery) that courses obliquely over the anterolateral wall of the left ventricle (Figure 1.47). The anterior descending artery gives off diagonal branches supplying the obtuse margin of the heart. It also gives off perforating branches into the interventricular septum. In many cases the left anterior descending coronary artery has a short intramyocardial course before re-emerging onto the epicardium (Figure 1.48). The circumflex artery has a variable course depending on whether or not there is right-dominance. The artery to the AV node arises from the dominant coronary artery at the crux of the heart (junction of the interatrial and atrioventricular grooves inferiorly) (Figure 1.49) [18].

1.2.10 Cardiac Veins The veins of the heart are usually ignored by pathologists, seen, if seen at all, as a minor inconvenience in dissecting the coronary arteries. There has been renewed interest in their anatomy of late because of their usefulness in cardiac catheterisation and electrophysiological studies [19]. Most of the cardiac venous return is via epicardial veins to the coronary sinus (Figure 1.50) [20]. The major named veins are: 1. The great cardiac vein. It originates at the cardiac apex and ascends on the anterior surface of the epicardium in the

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Figure 1.45 Balanced coronary circulation. An explanted heart from a tenyear-old girl viewed from behind following dissection of the coronary arteries. The right coronary artery and the left circumflex artery both reach the crux of the heart where they both supply a descending artery.

Figure 1.44 Left-dominance coronary artery. The heart is viewed from below and behind. In the upper centre of the fields is the right atrial appendage with the inferior caval vein orifice to its left. The left atrial appendage is visible in the left centre. The atrioventricular groove runs horizontally in the field and within it, from the left side, is the circumflex artery. The artery turns and descends towards the apex at the crux of the heart, forming the posterior interventricular artery.

anterior interventricular groove to reach the left atrioventricular sulcus where it turns leftwards and travels around the obtuse margin of the heart where it is continuous with the coronary sinus, the entry of the vein of Marshall marking the junction. Its major tributary is the left (obtuse) marginal vein, which is present in over 80% of people. 2. The middle cardiac vein, which runs in the posterior interventricular groove and enters the coronary sinus near its orifice. In the majority of hearts with right coronary artery dominance, it is in close proximity to the right coronary artery. 3. The small cardiac vein, sometimes referred to as the right cardiac vein, which runs in the right atrioventricular groove and joins the coronary sinus near its orifice.

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Figure 1.46 Proximal right coronary artery. Heart viewed from anteriorly. The pulmonary infundibulum is retracted to the left to expose the origin of the right coronary artery from the aorta. At least five branches run from the artery to the right of the field, supplying the anterior right ventricular wall and pulmonary infundibulum. A large branch runs between the right atrial appendage and the aorta, ascending on the medial aspect of the right atrium towards the junction with the superior caval vein. This is the artery to the sinoatrial node.

4. The posterior vein of the left ventricle, which runs on the left ventricle’s diaphragmatic surface to the left of the middle cardiac vein. It is only identifiable in about 50% of hearts. 5. The oblique vein of the left atrium, which is a remnant of the left superior caval vein and may persist. It runs obliquely along the posterior aspect of the left atrium and joins the coronary sinus, marking its junction with the great cardiac vein. 6. The right (acute) marginal vein may open directly into the right atrium or sometimes into the small cardiac vein. There is considerable crossing of veins over arteries and arteries over veins at the obtuse margin of the heart (circumflex

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1: The Anatomy of the Normal Heart

Figure 1.47 Left coronary artery and intermediate branch. The heart is viewed from the left anterior position. The left coronary artery has been dissected from its origin from the aorta. The pulmonary trunk has been drawn forwards and to the right to expose the full course of the artery. The short main stem divides into three. Superiorly the circumflex artery runs in the left atrioventricular groove beneath the left atrial appendage. The anterior descending artery crosses the field obliquely to the lower right field. Between these two arteries a third artery arises – the intermediate artery.

Figure 1.49 Atrioventricular nodal artery. Heart viewed from inferiorly following dissection of the coronary arteries. There is right dominant circulation with the right coronary artery supplying the posterior interventricular artery. From the point where the right coronary artery leaves the atrioventricular groove to descend in the interventricular groove arises a smaller branch that enters the myocardium at the crux – the artery to the AV node. This artery usually arises from the dominant artery. The vessel forming the third side of a vascular triangle in this dissection is the middle cardiac vein that ascends to enter the coronary sinus to the left of the atrioventricular nodal artery.

artery) and at the crux (right coronary artery) [21]. The veins contain valves. The most prominent is the thebesian valve at the mouth of the coronary sinus (Figure 1.13). Within the coronary sinus at its junction with the great cardiac vein and oblique vein of the left atrium (vein of Marshall) is another named valve – the valve of Vieussens. The coronary sinus has a sleeve of myocardium from the left atrium.

Figure 1.48 Intramyocardial course of left anterior interventricular artery. A six-day-old infant with pulmonary atresia. The epicardial surface of the left ventricle shows very distended veins. In addition, there is a short segment of the left anterior descending artery that is not present on the surface but dips into the myocardium before resurfacing further distally. This is of no significance.

Figure 1.50 Cardiac veins. The posterior atrioventricular junction in this heart has been dissected to demonstrate the cardiac veins. The coronary sinus occupies the greater part of the posterior atrioventricular junction. Branches on the epicardium of atria and ventricles join it.

For a review of the literature on cardiac veins, see reference [20]. Several veins do not drain to the coronary sinus; the anterior cardiac veins run over the front of the right ventricle and open directly into the right atrium crossing over the course of the right coronary artery in the right atrioventricular groove. In up to a quarter of cases they may merge to form a common trunk before entering the right atrium [21]. The right ventricle and both atria are drained by these veins. Small veins in the atrial, and sometimes the ventricular, walls may open directly into the adjacent cavity. The epicardial veins drain the external two-thirds of the myocardium. The inner one-third is drained by veins directly into the luminal chambers. These are termed thebesian veins [19].

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1.3 Histology 1.3.1 Pericardium The pericardium consists of a layer of collagenous fibrous tissue with blood vessels. The surface facing the pericardial cavity is lined by a single layer of mesothelial cells. Focally there may be epicardial extra-medullary haematopoiesis around the origins of the great arteries and coronary arteries (Figure 1.51). Brown fat can occur in the epicardium even into the teen years. Epicardial fat extends into the apparent interatrial septum. Fat cells are also present along the course of the intramyocardial coronary arteries and may be prominent, particularly on the right side (Figure 1.52).

Figure 1.51 Extramedullary haemopoiesis of epicardium. Sudden death aged 1 month. The epicardial surface of the heart shows a small focus of extramedullary haemopoiesis. Erythroblasts and myeloblasts are present admixed with the epicardial fat.

Figure 1.53 Fetal myocardium. Section of myocardium of a fetus of 20 weeks' gestation. The myocytes are thin and closely packed and the nuclei appear crowded. The nuclei are relatively hyperchromatic and the cytoplasm slightly vacuolated.

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1.3.2 Myocardium The myocardium is made up of individual myocytes. Cardiomyocytes account for about 80% of the volume of the heart, but as a proportion of cells present they represent only about 30% [22], the remainder being composed of endothelial cells, fibroblasts and smooth muscle cells [23]. The myocardium has the structure of a modified blood vessel with the individual myocytes arranged tangentially and, in some cases, obliquely in the wall but with distinct anatomical units. The general orientation of the myocytes varies at different depths within the myocardium [24]. Histologically, the fetal myocardium appears more vacuolated than its adult counterpart (Figure 1.53). Mitotic figures may be seen up to the time of birth and probably also for a short while thereafter in the neonatal period (Figure 1.54).

Figure 1.52 Fat in the right ventricular myocardium. Adolescent female who died of non-cardiac causes. A section from close to the right ventricular apex showing extensive fatty infiltration, almost to the endocardium. Critically, there is no associated fibrosis.

Figure 1.54 Mitotic figures in myocardium. Ventricular myocardium in an 18week fetus. In the centre of the field is a mitotic figure within a myocyte. Such mitotic figures can be found in normal hearts up to term and in post-neonatal diseased hearts where they may represent failure of the normal switching off mechanism.

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1: The Anatomy of the Normal Heart

Figure 1.55 Anitschkow cells. Female infant born at 29 weeks’ gestation with dilated cardiomyopathy and hydrops. She died aged 3 days. In a high-power view of the ventricular myocardium, at least five myocyte nuclei are visible that show clearing of the nucleus and a longitudinal bar of dark chromatin. Several nuclei are cut in their short axis where the chomatin is visible as a central bullseye.

Figure 1.56 Lipofuscin myocytes (child). Among the numerous mitochondria present there is a rounded structure composed of granular osmiophilic material with included small lipid droplets. This is the characteristic feature of lipofuscin. Although not obvious in this example, lipofuscin is membrane bound in lysosomes (Figure courtesy of Mr G. Anderson, Clinical Electron-microscopist, Great Ormond Street Hospital, London).

Figure 1.57 Nerves in a normal heart. A section from the right ventricular myocardium of a four-year-old stained with antibody S100. Between the myocytes there are numerous fine nerve twigs, many associated with small vessels. There are also numerous fine nerve fibres in the endocardium.

Figure 1.58 Capillaries of the heart. Section of normal myocardium stained with antibody to CD34 to demonstrate the density of the capillary network within the myocardium.

Myocyte nuclei may show Anitschkow nuclear features [25]. This consists of a central solid bar of chromatin in longitudinally cut nuclei with surrounding clear nucleoplasm (Figure 1.55). In cross section these nuclei have an owl-eye appearance. Similar nuclear features may be present also in interstitial cells (including macrophages) and Schwann cells, and in valvar stromal cells [26]. The phenotype seems largely confined to the heart in the fetus and infant, although occasional foci of such nuclei may be seen in the larynx. The significance if any of this change is unknown. Neonatal cardiac myocytes do not contain lipofuscin pigment; this first becomes recognisable on light microscopy at about nine years of age [27], although it may be seen on electron microscopy earlier (Figure 1.56).

In contrast to skeletal muscle, which is composed of very long fibres that result from the progressive fusion of hundreds of cells during embryogenesis, and in which each cell is supplied by a nerve fibre and contracts individually in response to stimulation through its own neuromuscular junction, the cardiac myocytes form a syncytium linked by intercalated discs. Nerve fibres, especially of the autonomic variety, are found throughout the heart (Figure 1.57), but they do not serve the purpose of stimulating the muscle cells to contract. Rather, they seem to regulate the overall activity of the heart. The normal myocardium is an extremely vascular structure and staining for endothelial cells reveals just how vascular it is (Figure 1.58).

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1: The Anatomy of the Normal Heart

Figure 1.59 Right atrial myocardium. There are deep recesses in the wall where the myocardium is excluded and the endocardium rests on the epicardium.

Figure 1.60 Myocardium around pulmonary veins. Myocardium in adventitia of pulmonary veins. Sixteen-month-old female with DiGeorge syndrome. Sudden death.

Figure 1.61 Megakaryocytes. High-power view of the myocardium from a patient who had dilated cardiomyopathy. There is intense capillary congestion with many of the capillaries containing erythrocytes. In the centre of the field a large irregular nucleus is present within a distended capillary. This represents a megakaryocyte nucleus.

Figure 1.62 Mast cells in a normal heart. High-power view of the myocardium shows an area of fibrous tissue that contains mast cells. The cells have rounded nuclei that are eccentric and show coarse chromatin; the cytoplasm is opaque and pinkish purple. At least three mast cells are present in this field.

The myocardium of the right atrium is composed of muscular trabeculations. Between the trabeculations the wall can be quite thin and, in places, the endocardium rests directly on the pericardium without intervention of cardiac muscle (Figure 1.59). Small amounts of atrial myocardium may extend into the pulmonary veins external to the muscular media (Figure 1.60) [28]. Megakaryocytes, or at least their nuclei, may occasionally be seen within capillaries in the myocardium (Figure 1.61). It has long been known that they occur in adult myocardium in about 16% of cases of traumatic sudden death and in 45% of cases of hospital deaths [29]. Mast cells are a component of the interstitium of the normal myocardium. Their numbers are increased in

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myocarditis and dilated cardiomyopathy and, indeed, in any condition that induces an increase in cardiac fibrous tissue (Figure 1.62) [30].

1.3.3 Endocardium The endocardial layer of the left atrium is thicker than that of the right (Figure 1.63). The epicardium and endocardium come very close together in the atrial appendages and between the pectinate muscles (Figure 1.59); in the neonate, fluid under pressure in central lines may leak into the pericardial space in these areas. The atrial endocardium, and sometimes the ventricular endocardium, contains smooth muscle cells (Figure 1.64), and sometimes these can be quite prominent.

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1: The Anatomy of the Normal Heart

Figure 1.63 Endocardium of left atrium. A Masson’s trichrome stained section of normal left atrium showing the thick endocardium of this chamber. It should not be mistaken for a pathological process.

Figure 1.64 Smooth muscle atrial endocardium. A case of hypertrophic cardiomyopathy. This section of the left atrium endocardium shows a continuous sheet of smooth muscle cells within the thickened endocardium.

Figure 1.65 Histology flap valve of oval fossa. This specimen is from a heart explanted from a neonate with cardiomyopathy and is stained with Elastic vanGieson. The right atrium is above, and the left below the flap valve consists of an irregular layer of fibroelastic tissue in which there are discontinuous bundles of myocardium. The point of attachment to the left atrium is seen to the right upper part of the field. On the right atrial side of the valve there is deposition of laminar elastic tissue over the attachment point.

Figure 1.66 Prichard’s structures. A two-month old-girl with a structurally normal heart who died of sepsis. A high-power section through the flap valve of the oval fossa shows small clusters of cells with dark nuclei and scanty cytoplasm. These represent endothelial structures commonly seen in this area – so-called Prichard’s structures.

The interatrial septum, more particularly the flap valve of the oval fossa, is a muscular structure (Figure 1.65). In the endocardium on both right and left sides there are clusters of cells with hyperchromatic nuclei resembling multinucleate cells [31]. These cell clusters have received little attention in the literature but appear to be of endothelial origin [32] (Figure 1.66). The endocardium has a limited repertoire of response to injury, and this response usually assumes the form of fibroelastic thickening. The intimal surfaces of the valves, which are essentially endocardium, also exhibit a similar response to injury, and a similar reaction is seen in the intima of the great

arteries. Thus, in endocardial fibroelastosis, in valvar stenosis and damage, and in the intimal proliferation in response to vessel injury or in the intima of grafts, a very similar picture is seen of layered fibroelastic thickening with variable cellularity. The younger the tissue, the more likely it is to be cellular. Inflammatory cells, while they may occasionally be found, are not a prominent component of the response.

1.3.4 Valves The atrioventricular and arterial (semilunar) valves have a similar histological structure. The atrioventricular valves are slightly thicker than the arterial valves and the left-sided valves

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Figure 1.67 Histology of normal atrioventricular valve.

Figure 1.68 Histology of normal ventriculoarterial (semilunar) valve.

slightly thicker than the right-sided ones [33]. They have a dense collagenous layer – the fibrosa that extends from the base to the free edge with the collagen bundles circumferentially arranged. In the arterial valves there is a layer termed the ventricularis and in the atrioventricular valves an equivalent layer termed the atrialis composed of radially oriented elastic fibres lying beneath the endocardium. The ventricularis/atrialis does not extend to the free edge of the valve. In the atrioventricular valves the fibrosa lies on the ventricular aspect, while in the arterial valves the fibrosa is on the arterial aspect. This permits orientation even of excised valvar leaflets – the side of the valve exposed to the higher cavity pressure (the ventricular aspect of the AV valves and the arterial aspect of the arterial valves). Lying between these two layers is the spongiosa composed predominantly of proteoglycans (Figures 1.67 and 1.68). The spongiosa does not extend to the free edge of the valve leaflet. Covering the surface of the valve is a thin layer of endothelium. The valves are more cellular in the child than in the adult and may be rather myxoid, but should not be nodular. If nodular and myxoid, then they are considered dysplastic (Figure 1.69). Calcification may occur in degenerate valves, and cartilage is reported in some and sometimes even woven bone [34]. Blood cysts (Figure 1.70) are a very frequent finding. These are rounded nodules filled with blood, usually on the atrioventricular valves, although they may sometimes be seen on the arterial valves. They lie near the line of closure on the atrial aspect of the atrioventricular valves or towards the base of the ventricular aspect of the arterial valves. Histologically, they are rounded, blood-filled spaces lined by endothelium [35]. They may be multilocular and are frequently multiple (Figure 1.71). They may measure up to 3 mm in diameter, but many are smaller. There may be haemosiderin in the surrounding valvar stroma. They usually disappear by about six months of age. They may, however, persist and form giant blood cysts [36].

Figure 1.69 Dysplastic valve. Excised dysplastic mitral valve leaflets from a 10year-old with Robinow’s syndrome. The leaflets are thickened and nodular, and the chordae are thickened and partly fused.

There is no consensus as to their origin, and multiple hypotheses have been proposed to explain their development: • They are formed during valve development as a result of blood trapped in crevices that later seal off. • They are the result of haematomas secondary to the occlusion of small vascular branches of end arteries. • They result from metaplastic change in the tissue that comes from primitive pericardial mesothelium. • They represent ectatic or dilated blood vessels in the valve. • They are simple angiomas. They are of no significance except in the very rare instances where they develop into giant cysts and obstruct the flow of blood [37].

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1: The Anatomy of the Normal Heart

Figure 1.70 (A) Blood cyst atrioventricular valve. Eight-week-old male infant. The left side of normal heart opened to show blood cysts on the mitral valve. The cysts are visible as black nodules adjacent to the free edges of the mural leaflet of the valve. A secundum atrial septal defect is also visible. (B) Blood cyst semilunar valve. A small blood cyst is present on the ventricular aspect of one of the cusps of the pulmonary valve. A pair of forceps has been inserted into the sinus to distend the cusp, which shows a partially blood-filled cyst protruding from the ventricular aspect adjacent to the point of attachment to the ventricle.

Figure 1.71 Blood cyst – microscopic appearance. Three-week-old female infant. The sections show an atrioventricular valve with a blood cyst protruding from the atrial surface. The cyst is lined by flattened endothelial cells, contains fresh blood and there is a compressed thin fibrous wall.

1.3.5 Conduction Tissue The sinoatrial node, the pacemaker of the heart, is situated at the junction of the superior caval vein and the crest of the right atrial appendage. In approximately 10% of individuals the node straddles the apex of the junction and extends into the interatrial groove [38]. It lies beneath the epicardium. Histologically, it comprises a triangular area of myocardium, the constituent cells of which are smaller than the surrounding “working” atrial myocardium, but which at the periphery of the node intermix with the atrial myocardium (Figure 1.72A). A very helpful marker of its site is the central large sinoatrial nodal artery [10]. There is also a close association with

branches of the vagus nerve. With increasing age, there is increase in interstitial fibrous tissue. The nodal cells stain positively for smooth muscle actin, in contrast to the surrounding myocardium and the cells of the AV node, which are negative (Figure 1.72B). The AV node is situated in the right atrium in the triangle of Koch, above the atrioventricular junction and lying between the mouth of the coronary sinus and the membranous septum. Histologically it is a pyramidal area of myocytes lying beneath the endocardium and a thin layer of atrial myocardium and abutting the fibrous tissue of the central fibrous body (the membranous septum and the rightward extension of the mitral aortic fibrous continuity) (Figure 1.73). Transitional cells connect it to the atrial working myocardium. Tissue from the node extends as the bundle of His superiorly into this fibrous tissue, which insulates it from the myocardium. Within the membranous septum it lies on the apex of the muscular component of the interventricular septum and branches to give left and right bundle branches (Figure 1.74). The left branches lie immediately beneath the endocardium of the left ventricular outflow tract and consist of several thin bands of tissue that fan out beneath the endocardium to connect with the Purkinje cells. The right bundle branch, by contrast, remains as a single cord of cells and lies deep within the myocardium of the septomarginal trabeculation before entering the moderator band and reaching the parietal wall of the right ventricle.

1.3.6 Coronary Arteries The coronary arteries have the structure of muscular systemic arteries with a well-developed muscular tunica media separated from a thin tunica intima by a well-developed internal elastic lamina. The outer aspect of the tunica media is separated from the tunica adventitia by an incomplete layer of

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1: The Anatomy of the Normal Heart

Figure 1.72 Histology of normal sinoatrial node. (A) The sections show normal sinoatrial node. The epicardial surface is present in the left-hand corner. The node is present as a flat and triangular structure composed of small pale cells centred on the large artery in the centre of the field. It extends almost to the endocardial surface of the atrium in the bottom right-hand corner of the picture. It contains rather more interstitial collagen (stained red) than the surrounding working myocardium. (B) Sinoatrial node from a case of sudden childhood death stained with antibody to smooth muscle actin. There is strong staining of the smooth muscle of the central nodal artery. The cells of the node are dispersed around the artery and show cytoplasmic positivity in contrast to the negative cells of the working myocardium.

elastic tissue (Figure 1.75). The origins of the coronary arteries from the aorta show a short segment where the arterial wall structure is a hybrid of muscular and elastic artery (Figure 1.76). At the origins there is often a small amount of intimal thickening, and small areas of intimal thickening with some disruption of the underlying internal elastic lamina are present even in late fetal life. During the first few months of life the epicardial arteries develop irregular intimal thickenings, most pronounced in the left anterior descending artery and at the branch points. These fibrous thickenings contain elastic fibres and cells [39, 40]. They become relatively less conspicuous with the growth in size of the vessels (Figure 1.77). A more detailed discussion of coronary artery histology and its variants is given in Chapter 9.

1.3.7 Cardiac Veins The cardiac veins have the structure of normal systemic veins (Figure 1.78). The intima is thin and consists of endothelium only. An internal elastic lamina is not readily discernible. The media is not well developed and contains muscle cells, elastic fibres and collagen, but without the orderly arrangement of the arterial wall. It is a thin layer. The adventitia contains abundant collagen and elastic fibres.

1.3.8 Cardiac Lymphatics There are three lymphatic plexuses in the ventricular myocardium [41], one in the epicardium and one in the endocardium connected by an intramyocardial plexus. The endocardial plexus drains through the myocardium to the epicardial plexus that drains via lymphatics accompanying the major epicardial

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arteries (Figure 1.79). The atria appear to have only an epicardial plexus. Lymphatics are present in the valves.

1.3.9 Aorta, Pulmonary Arteries and Arterial Duct The aorta and pulmonary trunk are both elastic arteries. They show a thick tunica media composed of concentrically arranged sheets of elastic tissue with smooth muscle between them. In histological sections these sheets appear as elastic laminae. The internal elastic lamina is well developed. Internal to it lies the tunica intima that comprises only endothelium lying on the internal elastic lamina. The external elastic lamina is not well formed. The tunica adventitia comprises collagenous fibrous tissue and fine elastic fibres. It contains nerves and small blood vessels and lymphatics. The pulmonary trunk changes its elastic laminae, which before birth are continuous, similar to those in the aorta. In the pulmonary trunk and its main branches the elastic fibres are fragmented, but the smaller elastic pulmonary arteries show continuous laminae (Figure 1.80). Smooth muscle cells lie between the elastic laminae, and the endothelial layer rests on the internal elastic lamina. The arterial duct is a muscular artery that lies between the two elastic arteries: the aorta and pulmonary trunk. The duct has a thick muscular media. In the third trimester its tunica intima develops swellings that contain smooth muscle cells and abundant glycosaminoglycans (mucopolysaccharide) (Figure 1.81). These increase in size and project into the lumen, and the smooth muscle of the media begins to develop pools of glycosaminoglycans also. At birth there is contraction of the arterial duct with apposition of the intimal cushions occluding the lumen. The media becomes fibrotic and eventually calcifies.

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1: The Anatomy of the Normal Heart

Figure 1.74 Histology of branching bundle of His. Figure 1.73 Histology of normal AV node. A section through the atrioventricular junction to demonstrate the AV node. The right atrium is to the left and the left atrium to the right. The upper part of the field shows the myocardium of the interatrial septum and the lower part of the field shows the crest of the interventricular septum. A tongue of atrial myocardium descends from the left atrial aspect towards the hinge point to the mitral valve. The node is a triangular area of myocardium identified by the presence of the nodal artery and the relatively small size of the constituent myocytes.

1.3.10 Nerves Autonomic nerves serve not to cause contraction of the heart muscle, but rather to regulate overall activity.

1.4 Electron Microscopy The myocytes are cylindrical, about 15 μm in diameter and have an outer plasma membrane with associated basal lamina together forming the sarcolemma. The cytoplasm contains the usual organelles – mitochondria, lysosomes, Golgi and endoplasmic reticulum (termed sarcoplasmic reticulum in the myocyte) – but the most striking feature is the presence of multiple longitudinally arranged contractile elements, the myofibrils (between 300 and 700 per cell) (Figure 1.82). Each of these myofibrils is composed of subsidiary myofilaments (approximately 200–1000 per myofibril), which contain a myosin

filament surrounded by six actin filaments [42]. Within the myofibril the functional unit is the sarcomere, composed of actin and myosin filaments bounded at their ends by Z-bands. Actin filaments from contiguous sarcomeres insert into the Zband, which serves as an anchoring point for the filaments during contraction (Figure 1.83). Within the myocytes there are invaginations of the plasma membranes and associated basal lamina forming transverse tubules entering the cells. These come into close contact with the sarcoplasmic reticulum. The sarcoplasmic reticulum forms a branching system of tubules within the sarcoplasm that is more or less parallel to the microfilaments and has points of contact with the T system and the sarcolemma. Adjacent myocytes are connected in a step-like fashion by intercalated discs. The sarcomeres are composed of I-bands formed by thin filaments, A-bands formed by thick filaments and M-bands formed by transversely oriented protein cross bridges that connect adjacent thick filaments and Z-bands composed of finely filamentous electron-dense material. Transversely oriented filaments connect adjacent myofibrils to the nuclear membranes and to the sarcolemma. Nuclei are centrally located and composed of the inner and outer nuclear membranes and nucleoli. The nuclear membrane contains pores.

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1: The Anatomy of the Normal Heart

Figure 1.75 Histology of normal epicardial coronary artery. Sudden death case in a five-year-old.

Figure 1.76 Origin of coronary artery from aorta. It can be appreciated that the first couple of millimetres of the vessel wall has an elastic structure similar to that of the aorta.

Figure 1.77 Intimal thickening of neonatal coronary arteries.

The atrial myocardium contains dense core bodies [43] that store the myocytokines atrial natriuretic peptide and brain natriuretic peptide. Non-myelinated nerves are present in the myocardium, especially adjacent to the node in the right atrium. Lipid droplets and membrane-bound glycogen are present. Mitochondria are found in three separate locations within the myocyte: 1. Beneath the sarcolemma 2. Between the filaments 3. Perinuclearly It is thought that they carry out separate functions – energy generation largely for contraction, with ion channel regulation and with transcription respectively [44]. Gap junctions are clusters of channels that span the cell membrane and directly link the cytoplasm of contiguous cells

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Figure 1.78 Histology of normal cardiac vein. Section of an epicardial vein situated over the anterior aspect of the interventricular septum stained with Elastic vanGieson. Note the paucity of muscle in the wall and the presence of a valve at the junction with the branch emerging from the myocardium.

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1: The Anatomy of the Normal Heart

permitting direct intercellular communication. In the heart, gap junctions also mediate electrical coupling between myocytes. In the heart, gap junctions vary greatly in size, some containing tens of thousands of channels and others fewer than ten. The gap junctions are organised together with two types of adhesion junction – fasciae adherentes junctions and desmosomes – at the intercalated discs (Figure 1.84) [45]. The intercalated disc has a characteristic irregular, step-like structure, specialised for the task of integrating cell-to-cell electro-mechanical function. Fasciae adherentes junctions, which transmit mechanical force from cell to cell, are situated in the vertical “steps” of the disc, linking up the myofibrils of

Figure 1.79 Cardiac lymphatic histology. A section through the right ventricular myocardium of a four-year-old – stained with antibody D2–40. This highlights the endothelium of small lymphatic vessels in the superficial myocardium.

adjacent cells in series. Desmosomes, often likened to “press studs” between cells, form attachment sites for the desmin cytoskeleton, and are found predominantly in the intervening horizontal portions of the disc. Most of the gap junctions are also found in these horizontal segments, often with larger junctional plaques at the disc periphery. Each channel in a gap junction comprises a pair of abutting hemichannels, termed connexons, one contributed by each of the apposed cell membranes. The connexon spans the full depth of the membrane and is composed of six connexin molecules. Twenty-one different connexin types have been identified, and the specific connexin type or mix of types within the connexon permits differentiation of the functional properties of the channel. Cardiac myocytes express three principal connexins: connexin40 (Cx40), Connexin43 (Cx43) and Connexin45 (Cx45). Connexin43 predominates and shows co-expression with Cx40 and/or Cx45. The pattern of expression is specific for the working (contractile) myocardium of atria, ventricles and the specialised conduction tissue [46]. In the working myocytes of the ventricle Cx43-containing gap junctions predominate. In the atrial myocardium gap junctions are organised in less well demarcated intercalated discs and contain both Cx43 and Cx40. In both ventricular and atrial human myocardium, Cx45 is detected in low quantities, with higher levels in the atria than the ventricles. The myocytes of the conduction system differ from the working myocardium in their connexin expression profiles. Myocytes of the sinoatrial and AV nodes characteristically have small, dispersed gap junctions composed of Cx45. Distal to the bundle of His, the conduction system myocytes coexpress Cx40. Cx43 becomes more abundant in the more distal parts of the system, and Cx45 is expressed continuously from the AV node to the ends of the Purkinje fibres.

Figure 1.80 Aorta and pulmonary artery. The pulmonary artery (A) and the aorta (B) from the same infant heart, stained with Elastic vanGieson (EvG) and photographed at the same magnification. The elastic fibres in the pulmonary artery are finer and shorter than those in the aorta.

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1: The Anatomy of the Normal Heart

Figure 1.81 Arterial duct at term. A section through part of the wall of the duct at term, stained with Elastic vanGieson. The tunica media contains muscle and is pale. There are intimal cushions that contain abundant elastic tissue. The duct is contracted.

Figure 1.83 EM of sarcomere. A higher power view shows bundles of myofilaments with intervening mitochondria (Figure courtesy of Mr G. Anderson, Clinical Electron-Microscopist, GOSH).

1.5 Weights and Measures It is possible to record many measurements of the heart. The simplest, and probably the most useful, is the weight. The organ is weighed following evacuation of all blood and blood clot. The heart weight is a reflection of the weight of the myocardium and gives in turn a measure of ventricular myocardial bulk. The heart size, and hence weight, increases in a more or less linear fashion throughout gestation and continues to grow throughout childhood to adulthood. Standard tables have been available for over half a century giving weights for normal hearts for children and adults [47– 50] (Table 1.1). These have been supplemented by tables for

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Figure 1.82 Electron microscopy (EM) of myofilaments showing the ultrastructure of longitudinally arranged myocytes. The parallel arrangement of the myofilaments within the myocytes gives the characteristic banded appearance of the myocyte. The mitochondria are arranged running longitudinally between the bundles of myofilaments (Figure courtesy of Mr G. Anderson, Clinical Electron-Microscopist, GOSH).

Figure 1.84 EM of intercalated discs. An intercalated disc is seen at the left of the picture consisting of stepped desmosomes visible as dark parallel lines with a pale intervening line. Multiple rounded mitochondria are also seen. A sinuous cell membrane is seen at the top of the field (Figure courtesy of Mr G. Anderson, Clinical Electron-Microscopist, GOSH).

the third and second trimester fetus [51, 52]. Tables have also been produced of weights of fetal organs that have been formalin-fixed [53]. Ranges have been produced with centiles, and many centres have sought to establish local ranges to reflect their local populations [54] (Table 1.2). Given the recent rise in body weight among adults, new tables have been prepared to reflect this increase [55]. Body surface area shows a strong relationship to left ventricular mass [56], at least in adults. Other measurements that may be useful include ventricular wall thickness. This usually entails measuring the thickness of

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1: The Anatomy of the Normal Heart Table 1.1 Heart measurements related to age and length, males

Body Age

Heart

Weight

Length

Weight

(g)

(cm)

(g)

Thickness (cm) Lv

Rv

Valve circumferences (cm) Tricuspid

Pulmonic

Mitral

Aortic

Gestational age 5 mo

312

22.7

4.6

0.20

0.20

1.3

0.8

1.2

0.9

6 mo

729

30.6

6.2

0.28

0.20

2.3

1.2

2.0

1.0

7 mo

1145

36.2

9.8

0.35

0.26

2.4

1.4

2.2

1.3

8 mo

1778

40.6

14.0

0.39

0.28

3.1

1.8

2.6

1.6

9 mo

2420

45.0

18.0

0.42

0.30

3.4

2.0

2.9

1.8

3171

49.3

23.0

0.46

0.32

3.8

2.2

3.2

2.0

1 mo

51.4

23.0

0.59

0.26

3.8

2.3

3.3

2.1

2 mo

54.0

27.0

0.60

0.29

4.2

2.5

3.4

2.3

3 mo

57.7

30.0

0.64

0.25

4.4

2.7

3.6

2.6

4 mo

60.4

31.0

0.65

0.23

4.7

2.7

3.8

2.6

5 mo

62.0

35.0

0.68

0.26

4.8

2.9

4.1

2.7

6 mo

64.2

40.0

0.74

0.26

5.0

3.1

4.2

2.8

7 mo

66.7

43.0

0.76

0.28

5.0

3.1

4.2

2.9

8 mo

68.2

44.0

0.76

0.27

5.2

3.2

4.4

3.2

9 mo

69.4

45.0

0.74

0.24

5.4

3.2

4.5

3.0

10 mo

69.7

46.0

0.75

0.26

5.4

3.4

4.5

3.3

11 mo

70.5

48.0

0.73

0.25

5.5

3.3

4.6

3.2

12 mo

73.8

50.0

0.79

0.28

5.5

3.5

4.7

3.3

13–18 mo

78.0

54.0

0.80

0.27

5.8

3.5

4.7

3.4

19–24 mo

84.0

60.0

0.80

0.26

6.2

3.7

5.0

3.5

3 yr

90.0

72.0

0.79

0.27

6.8

4.0

5.5

3.9

4 yr

101.0

88.0

0.86

0.24

7.3

4.5

6.1

4.2

5 yr

109.0

94.0

0.86

0.25

7.5

4.5

6.2

4.4

6 yr

114.0

105.0

0.86

0.24

7.8

4.4

6.1

4.3

7 yr

121.0

110.0

0.92

0.27

7.9

4.7

6.5

4.4

8 yr

127.0

119.0

0.94

0.25

8.3

4.8

6.8

4.7

9 yr

132.0

138.0

1.00

0.28

8.6

4.9

7.2

4.7

10 yr

138.0

150.0

0.98

0.28

8.8

5.2

7.4

4.9

11 yr

144.0

154.0

1.00

0.26

9.6

5.2

7.3

4.9

12 yr

149.0

169.0

1.00

0.25

9.5

5.5

7.8

5.4

13 yr

155.0

212.0

1.03

0.28

10.3

6.2

7.9

5.6

14 yr

159.0

219.0

1.04

0.26

10.6

6.2

8.4

5.8

15 yr

163.0

224.0

1.05

0.27

10.8

6.3

8.3

5.9

Post-natal age 0–1 wk

Lv, left ventricular; Rv, right ventricular. Schultz & Giordano. Arch Pathol 74: 464–471,1962. [47].

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1: The Anatomy of the Normal Heart Table 1.2 Heart weight infants. BMC Clin Pathol. 2014; 14: 18 (Ref 53)

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1: The Anatomy of the Normal Heart

the myocardium of the free wall of the left and right ventricles and of the interventricular septum. This can vary depending on where it is measured, but it has been standardised for echocardiographic and other radiological investigation and it is possible to reproduce this at autopsy. A single measurement is probably not very useful. The size of valves may be measured with a set of obturators that are introduced into the valve orifice. Alternatively, length and breadth of the orifice may be measured in the unopened valve (or diameter in the case of valves with a circular profile). Additionally, the valve circumference may be measured in the

References 1.

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Cabrera JA, Sanchez-Quintana D, Ho SY, Medina A, Anderson RH. The architecture of the atrial musculature between the orifice of the inferior caval vein and the tricuspid valve: the anatomy of the isthmus. J Cardiovasc Electrophysiol 1998; 9: 1186–1195. Jones RN, Niles NR. Spinnaker formation of sinus venosus valve. Circulation 1968; 38: 468–473.

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Doucette J, Knoblich R. Persistent right valve of the sinus venosus. Arch Pathol 1963; 75: 105–112.

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Arey JB. Embryology of the heart and great vessels. In Cardiovascular Pathology in Infants and Children. Philadelphia: WB Saunders; 1984, p. 25.

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Restivo A, Smith A, Wilkinson JL, Anderson RH. The medial papillary muscle complex and its related septomarginal trabeculation. A normal anatomical study on human hearts. J Anat 1989; 163: 231–243. Rosenquist GC, Clark EB, Sweeney LJ, McAllister HA. The normal spectrum of mitral and aortic valve discontinuity. Circulation.1976; 54: 298–301.

opened valve. Standard tables are available for these measurements in children of varying age [48, 51]. Other measurements that may be useful in individual cases include the maximum diameter of the atria or ventricular chambers where these structures are dilated or contracted. And, of course, the measurements for abnormal features, for example septal defects, should be recorded. Given the increasing popularity of post-mortem imaging, it is useful to bear in mind that there is evidence that the measurements of heart wall thickness in post-mortem CT are higher than those in ante-mortem CT of the same hearts [57].

in the paediatric age group. Diagn Histopathol 1981; 4: 3–15. 11. Blom NA, Gittenberger-de Groot AC, DeRuiter MC et al. Development of the cardiac conduction tissue in human embryos using HNK-1 antigen expression: possible relevance for understanding of abnormal atrial automaticity. Circulation. 1999; 99: 800–806. 12. Anderson RH, Ho SY, Smith A, Becker AE. The internodal atrial myocardium. Anat Rec 1981; 201: 75–82. 13. James TN. Cardiac conduction system: fetal and postnatal development. Am J Cardiol 1970; 25: 213–226. 14. Moulaert AJ, Oppenheimer-Dekker A. Anterolateral muscle bundle of the left ventricle, bulboventricular flange and subaortic stenosis. Am J Cardiol 1976; 37: 78–81. 15. Anderson RH. Surgical anatomy of the coronary circulation. In Wilcox BR, Cook AC, Anderson RH (eds) Surgical Anatomy of the Heart, 3rd edn. Cambridge: Cambridge University Press; 2004, pp. 84–85.

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Pomerance A. Atheroma of the mitral valve. J. Atheroscler Res 1967; 7: 151–160.

16. Schlesinger MJ, Zoll PM, Wessler S. The conus artery: a third coronary artery. Am Heart J 1949; 38: 823–826.

8.

Rosenquist GC, Sweeny LJ, Amsel J et al. Enlargement of the membranous ventricular septum: an internal stigma of Down’s syndrome. J Pediatr 1974; 85: 490–493.

17. Garg A, Ogilvie BC, McLeod AA. Anomalous origin of the left coronary artery from the non-coronary sinus of Valsalva. Heart 2000; 84: 136.

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Jouk PS, Usson Y, Michalowicz G, Grossi L. Three-dimensional cartography of the pattern of the myofibres in the second trimester fetal human heart. Anat Embryol 2000; 202: 103–118.

10. Anderson RH, Ho SY, Smith A et al. Study of the cardiac conduction tissues

18. Spicer DE, Henderson DJ, Chaudhry B, Mohun TJ, Anderson RH. The anatomy and development of normal and abnormal coronary arteries. Cardiol Young 2015; 25: 1493–1503. 19. von Lüdinghausen M. The venous drainage of the human myocardium. Adv Anat Embryol Cell Biol 2003; 168: I–VIII, 1–104.

20. Loukas M, Bilinsky S, Bilinsky E, elSedfy A, Anderson RH. Cardiac veins: a review of the literature. Clin Anat 2009; 22: 129–145. 21. Ho SY, Sanchez-Quintana D, Becker AE. A review of the coronary venous system: a road less travelled. Heart Rhythm 2004; 1: 107–112. 22. Zhou P, Pu WT. Recounting cardiac cellular composition. Circ Res 2016; 118: 368–370. 23. Pinto AR, Ilinykh A, Ivey MJ et al. Revisiting cardiac cellular composition. Circ Res 2016; 118: 400–409. 24. Anderson RH, Smerup M, SanchezQuintana D, Loukas M, Lunkenheimer PP. The three-dimensional arrangement of myocytes in the ventricular walls. Clin Anat 2009; 22: 64–76. 25. Stephens WE, Zuccollo JM. Anitschkow myocytes or cardiac histiocytes in human hearts. Pathology 1999; 31: 98–101. 26. Favara BE, Moores H. Anitschkow nuclear structure: a study of pediatric hearts. Pediatr Pathol 1987; 7: 151–164. 27. Goyal VK. Early appearance and rate of lipofuscin pigment accumulation in human myocardium. Exp Geront 1981; 16: 219–222. 28. Douglas YL, Jongbloed MR, Gittenberger-de Groot AC et al. Histology of vascular myocardial wall of left atrial body after pulmonary venous incorporation. Am J Cardiol 2006; 97: 662–670. 29. Smith EB, Butcher J. The incidence, distribution and significance of megakaryocytes in normal and diseased human tissues. Blood 1952; 7: 214–224. 30. Levick SP, Meléndez GC, Plante E et al. Cardiac mast cells: the centrepiece in

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1: The Anatomy of the Normal Heart

adverse myocardial remodelling. Cardiovasc Res 2011; 89(1): 2–19. 31. Acebo E, Val-Bernal JF, Gómez-Román JJ. Prichard’s structures of the fossa ovalis are not histogenetically related to cardiac myxoma. Histopathology 2001; 39: 529–535. 32. Val-Bernal JF, Martino M, Mayorga M, Garijo MF. Prichard’s structures of the fossa ovalis are age-related phenomena composed of nonreplicating endothelial cells: the cardiac equivalent of cutaneous senile angioma. APMIS 2007; 115: 1234–1240. 33. Hinton RB, Yutzey KE. Heart valve structure in development and disease. Annu Rev Physiol 2011; 73: 29–46. 34. Mirzaie M, Schultz M, Schwartz P, Coulibaly M, Schöndube F. Evidence of woven bone formation in heart valve disease. Ann Thorac Cardiovasc Surg 2003; 9: 163–169. 35. Zimmerman KG, Paplanus SH, Dong S, Nagle RB. Congenital blood cysts of the heart valves. Hum Pathol 1983; 14: 699–703. 36. Gallucci V, Stritoni P, Fasoli G, Thiene G. Giant blood cyst of tricuspid valve. Successful excision in an infant. Br Heart J 1976; 38: 990–992. 37. Cook AC, Fagg NLK, Sharland GK. Large blood cyst causing severe left ventricular obstruction in a fetus. Cardiol Young 1996; 6: 171–173. 38. Anderson KR, Ho SY, Anderson RH. Location and vascular supply of sinus node in human heart. Br Heart J 1979; 41: 28–32. 39. Pesonen E. Extrinsic and intrinsic factors relating to intimal thickening in children. Acta Paediatr Suppl 2004; 446: 43–47.

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40. DeSa DJ. Coronary artery ruptures in stillbirths Pediatr Dev Pathol 2002; 5: 605. 41. Loukas M, Abel M, Tubbs RS et al. The cardiac lymphatic system. Clin Anat 2011; 24: 684–691. 42. Sommer JR, Waugh RA. Ultrastructure of heart muscle. Environ Health Perspect 1978; 26: 159–167. 43. Chiba A, Watanabe-Takano H, Miyazaki T, Mochizuki N. Cardiomyokines from the heart. Cell Mol Life Sci 2018; 75: 1349–1362. 44. Hoppel CL, Tandler B, Fujioka H, Riva A. Dynamic organization of mitochondria in human heart and in myocardial disease. Int J Biochem Cell Biol 2009; 41: 1949–1956. 45. Severs NJ, Bruce AF, Dupont E, Rothery S. Remodelling of gap junctions and connexin expression in diseased myocardium. Cardiovasc Res 2008; 80: 9–19. 46. Desplantez T. Cardiac Cx43, Cx40 and Cx45 co-assembling: involvement of connexins epitopes in formation of hemichannels and Gap junction channels. BMC Cell Biol 2017; 18: 3. 47. Schulz DM, Giordano DA, Schulz DH. Weights of organs of fetuses and infants. Arch Pathol 1962; 74: 244–250. 48. Rowlatt UF, Rimoldi HJA, Lev M. The quantitative anatomy of the normal child’s heart. Pediatr Clin N Am 1963; 10: 499–588. 49. Eckner FAO, Brown BW, Davidson DL, Glagov S. Dimensions of normal human hearts. Arch Pathol Lab Med 1969; 88: 497–507. 50. Sholtz DG, Kitzman DW, Hagen PT, Ilstrup DM, Edwards WD. Age related changes in normal human hearts

during the first 10 decades of life. Part I (growth): a quantitative anatomic study of 200 specimens from subjects from birth to 19 years old. Mayo Clin Proc 1988; 63: 126. 51. Alvarez L, Aránega A, Saucedo R, Contreras JA. The quantitative anatomy of the normal human heart in fetal and perinatal life. Int J Cardiol 1987; 17: 57–72. 52. Hanson K, Sung CJ, Huang C et al. Reference values for second trimester fetal and neonatal organ weights and measurements. Ped Devel Pathol 2003; 6:160 – 167. 53. Guihard-Costa AM, Ménez F, Delezoide AL. Organ weights in human fetuses after formalin fixation: standards by gestational age and body weight. Pediatr Dev Pathol 2002; 5: 559–578. 54. Pryce JW, Bamber AR, Ashworth MT et al. Reference ranges for organ weights of infants at autopsy: results of >1,000 consecutive cases from a single centre. BMC Clin Pathol 2014; 14: 18. 55. Gaitskell K, Perera R, Soilleux EJ. Derivation of new reference tables for human heart weights in light of increasing body mass index. J Clin Pathol 2011; 64: 358–362. 56. Hees PS, Fleg JL, Lakatta EG, Shapiro EP. Left ventricular remodeling with age in normal men versus women: novel insights using three-dimensional magnetic resonance imaging. Am J Cardiol 2002; 90: 1231–1236. 57. Okuma H, Gonoi W, Ishida M et al. Heart wall is thicker on postmortem computed tomography than on antemortem [corrected] computed tomography: the first longitudinal study. PLoS ONE 2013; 8: e76026.

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Chapter

2

Examination of the Heart

2.1 Introduction Armed with knowledge of the structure of the normal heart we are now in a position to dissect the heart. Sequential segmental analysis is the tool used for assessing the components of the heart and how they relate to one another to form a coherent whole. However, before we can get there, we must take the heart apart. That is to say we must open it up to inspect its features so that individually they can be examined.

2.2 Dissection There is, in essence, no difference between hearts obtained at autopsy and those explanted during cardiac transplantation, any difference lying largely in the indications for their removal and in the usual absence of much of the atria in the explanted heart. A detailed discussion of examination of the explanted heart is given in Chapter 14. The spectrum of abnormality at post-mortem is of course much greater, ranging from the normal to any abnormality imaginable. At post-mortem, the heart is examined in situ and its position in the chest and the position of its apex noted. The pericardium is opened anteriorly and its contents, if any, noted. The vascular connections should be examined, particular care being given to the venous system, noting the presence of the innominate vein once the thymus has been removed and whether there is a persistent left superior caval vein. The pulmonary venous connection should be established. This can usually be done by lifting up the apex of the heart. The left pulmonary venous attachments will prevent the heart frombeing elevated far. The right pulmonary veins are more difficult to assess. The atrial appendages should be inspected to confirm usual situs, and the relation of the great vessels noted in relation to each other. The relative size of the ventricles and of the atria can also be noted. The site of the aortic arch should be recorded – whether to the right or to the left. The branching pattern should be inspected, taking particular care to confirm the origin of the right subclavian artery from the brachiocephalic artery – if not, a retro-oesophageal right subclavian artery could easily be missed. The arterial duct should be inspected by folding forward the left lung, and the size of the aortic isthmus and juxta-ductal area inspected – coarctation can very easily be missed if not specifically sought.

Ideally, and particularly where cardiac abnormality is known or suspected, the heart together with the lungs should be removed and fixed in formalin before further dissection. The tissues are easier to handle and retain their relationships better when fixed, and histological sampling is infinitely easier and more exact. This is not always possible, but even in cases where, for whatever reason, the heart cannot be retained, overnight fixation in 20% formalin will fix it sufficiently well for detailed examination and histological sampling. Following fixation, the soft tissues can be dissected from around the heart and lungs. This is tedious and not essential, but it does permit exact relationships to be inspected and recorded. Particular care is needed to avoid cutting small vessels, especially collateral vessels. Photographic records are essential. Increasingly, I also use video recording to permit demonstration. Once the lungs have been detached, a more detailed analysis of the heart can begin. The method of dissection depends on the nature of the abnormality to be demonstrated, but, to some extent, the methods are arbitrary and depend as much on personal preference as on scientific validation. Also, if the specimen is to be retained for further study, demonstration or research, the extent of dissection and removal of tissue must be correspondingly limited. There are multiple methods of opening the heart which in itself indicates that none is overwhelmingly superior to the others. My own prejudice in the uncomplicated case is to adopt the traditional method of following the flow of blood. The right atrium is opened by cutting from the inferior caval vein to the tip of the right atrial appendage. It is better not to open the superior caval vein: the superior caval junction with the right atrial appendage marks the site of the sinoatrial node, and cutting this area risks loss of landmarks should it become necessary to sample the node for histology. The superior caval vein should be probed, however, to ensure that it is not thrombosed. Opening from the inferior caval vein displays all the right atrial structures; there is a good view of the atrial septum, and the appendage and coronary sinus can easily be inspected. The tricuspid valve can be inspected from above before cutting down the lateral border of the right ventricle through the atrioventricular junction to the apex (Figure 2.1). A further cut from the apex to the pulmonary artery completes the opening of the right heart. This method does destroy the

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2: Examination of the Heart

Figure 2.1 Right heart opened in the line of the blood flow. The atrium was opened from inferior caval vein to the tip of the atrial appendage and the ventricle on its acute margin. The septal structures of the right atrium and right ventricle are well displayed by this technique. The tricuspid valve is also readily inspected.

Figure 2.2 The same heart viewed with the right ventricular outflow tract exposed by a cut from the ventricular apex to the pulmonary trunk. This view permits inspection of the free wall of the right ventricle, the subpulmonary infundibulum, the pulmonary valve and the proximal pulmonary artery.

Figure 2.3 The left heart exposed by opening the left atrium between the pulmonary veins and then cutting down to the left ventricular apex. The left atrium is well seen as is the mitral valve and its supporting structures.

Figure 2.4 The left ventricular outflow tract exposed by cutting through the anterior leaflet of the mitral valve. The two halves of the valve leaflet have been separated to demonstrate the structures of the outflow tract. This cut passes through the non-coronary cusp of the aortic valve, and the origins and epicardial course of the coronary arteries are not affected. It does, however, cut through the atrial wall to access the aorta.

continuity of the valves but allows close inspection of their constituent parts. The right ventricular aspect of the interventricular septum is exposed, as is the pulmonary infundibulum (Figure 2.2). The incision may be extended through the arterial duct into the aorta. Alternatively, the duct may be probed and sectioned transversely for histology. The left atrium is opened between the pulmonary veins, and the incision can be extended into the atrial appendage to give better visualisation of the chamber. The orifices of the pulmonary veins should be probed, because even in pulmonary vein stenosis the vessels may appear of good calibre externally. The left ventricle is opened by cutting down the free wall of the ventricle through the atrioventricular junction

34

to the apex (Figure 2.3). To expose the outflow tract, one of two approaches may be used, neither of which is without disadvantage. The aortic outflow can be exposed by cutting up through the aortic leaflet of the mitral valve. This destroys the integrity of the valve leaflet, but exposes the coronary arteries well and does not transect the proximal left coronary artery (Figure 2.4). Alternatively, the incision may be made through the anterior wall of the ventricle close to the septum leaving the anterior leaflet of the mitral valve intact but transecting the left coronary artery near its origin (Figure 2.5). The incision is extended along the length of the aortic arch on its

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2: Examination of the Heart

Figure 2.5 (A) The heart has been opened in similar fashion to Figure 2.3. (B) The cut can be seen to pass through the left coronary cusp close to the origin of the left coronary artery. The integrity of the anterior leaflet of the mitral valve and of the interatrial septum is preserved, and the fibrous curtain between mitral and aortic valves is seen.

Figure 2.6 Termination of pregnancy at 13 weeks for hypoplastic aortic arch. (A) The heart weighs 0.1 g and is close to the limits of comfortable dissection with the aid of a dissecting microscope. The ascending aorta and its branches are small. (B) The corresponding micro-CT shows the vascular anatomy because the iodine used to obtain tissue contrast attaches to blood cells and acts as a vascular contrast medium. It demonstrates the large calibre arterial duct and the thread-like aortic arch. The left common carotid artery and the left subclavian artery are also clearly outlined. The arterial duct is 0.5 mm in internal diameter (Micro-CT image courtesy of Dr O. Arthurs and Dr S. Shelmardine, Radiology Department, GOSH).

convex aspect to permit inspection of the junction of the arterial duct and aorta. The coronary artery ostia should be inspected carefully, and the arteries may be probed with a very fine probe. Their course on the epicardium should be noted and the artery supplying the posterior interventricular artery identified. It is rarely necessary to make transverse cuts every few millimetres, as in the adult. It can be advantageous to dissect the epicardial course of the coronary arteries and their major branches. The epicardial veins are especially difficult to dissect, particularly at the crux and at the junction of the anterior interventricular and atrioventricular grooves, where

arteries and veins cross each other in a random pattern, but their overall configuration can be checked by inspection. In addition, where there has been surgical intervention, it is necessary to define the surgical procedure, the presence of cannulae, lines and pacing wires, assist devices, conduits, grafts and valves. This approach works well in the neonatal and older heart, although marked ventricular hypertrophy can make internal inspection difficult. For smaller hearts and particularly for small macerated hearts with abnormality, formalin fixation of the heart is essential, followed by examination with some form

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2: Examination of the Heart

of magnification system. I prefer a dissecting microscope because of the clarity of detail and the range of magnification available. For embryos, especially those from ruptured ectopic pregnancies, embedding the embryo whole and serial sectioning has until now been the only sure way of thorough examination. The advent of microfocus CT holds promise that these very small specimens can now be examined in exquisite detail (Figure 2.6) [1].

2.3 Sequential Segmental Analysis The near-universally followed method of describing the heart relies upon sequential segmental analysis [2]. This system recognises the heart to comprise three sets of segments: • Atrial segments • Ventricular segments • Arterial segments

Figure 2.7 Situs inversus. A child with situs inversus and no other abnormality. The cardiac apex is directed to the right. The liver is left sided, as was the appendix.

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2: Examination of the Heart

The segments are identified by their most consistent feature. For the atria this is the morphology of their appendages; for the ventricles it is the morphology of the septal aspect of their apical trabecular component; and for the arterial trunks it is the branching pattern of the vessels. The atrial situs is determined, and, following identification of the segments, their morphology is noted and their connections to each other assessed. Associated abnormalities can then be described. For most hearts this can be done very quickly. With complex malformations, the system comes into its own.

2.3.3 Segmental Connections The connection of the segments is assessed at the atrioventricular level and at the ventriculoarterial level (Figure 2.10). The connection at either of these levels can be concordant, discordant or show absence of one of the connections. Additionally, at the atrioventricular level there may be ambiguous connection or double inlet to one ventricle; at the ventriculoarterial level there may be double outlet from one ventricle.

2.3.1 Situs Situs applies only to the atria; the atrial situs can be usual (situs solitus), reversed (situs inversus) or mirror image (isomerism). With usual atrial situs, there is a morphologically right atrium on the right side and a morphologically left atrium on the left side. In situs inversus, the morphologically left atrium is situated on the right side and the morphologically right atrium on the left side (Figure 2.7). In isomerism, both atria are of similar morphology, either both of right-sided morphology or both of left-sided morphology (Figure 2.8).

2.3.2 Topology A further feature that must be assessed is the topology of the ventricles. This refers to the left-handedness or righthandedness of a ventricle and is assessed by placing the palm of an imaginary hand of the interventricular septum with the thumb in the atrioventricular junction, the wrist at the ventricular apex and the fingers in the outflow tract [3]. For a normal right ventricle, only the right hand can be so placed. Thus, the right ventricle is said to have right-handed topology (Figure 2.9).

Figure 2.8 Isomerism of the atrial appendages. A fetus of 13 weeks with left atrial isomerism. There are bilateral morphologically left-sided atrial appendages (long and narrow with a hooked end). The heart is left sided with a left-directed apex. Cases of atrial isomerism usually have multiple other abnormalities. In this case they included: bilateral superior caval veins, double inlet left ventricle with common atrioventricular valve, rudimentary right ventricle with ventricular septal defect (VSD) and lacking an inlet, discordant ventriculoarterial connections with anterior aorta, right-sided stomach with multiple small spleens and intestinal malrotation.

Figure 2.9 Topology. The right hand is placed palm down on the right aspect of the interventricular septum with the thumb in the atrioventricular junction and the remaining fingers in the outflow tract. This indicates right-handed topology. It is not possible to do this with the left hand. Similarly, in the left ventricle, only the left hand can be so deployed. For most practical purposes it is not necessary to invoke topology, but in complex arrangements of ventricles and connections it becomes a very useful descriptor.

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2: Examination of the Heart

RA

LA

LA

RA

RV

LV

LV

RV

Usual atrial situs RA

RA

RV

Situs inversus

LV

RV

LA

RV

LV

LV

Right atrial isomerism

Le atrial isomerism

RA

LA

RA

LA LA

RV

LV

RV

LV

Absent Rt AV connecon RA

LV RV

Absent Le AV & VA connecon

RA

Absent Lt AV connecon RA

LA

LV

Double-inlet Right ventricle

RA

LA

LV

RV

LV

RV

LV

RA

LA

LV

LA

LA RV

RV

RV

RA

Double outlet right ventricle Double outlet le ventricle

Double-inlet Le ventricle

RA

LA

LA

RV RV

LV

Absent Le VA connecon Absent Le VA connecon (intact septum) (VSD)

RA RV

LA

LA

LA

RA

RA

LA

LV

LV TA

Absent Rt ventriculoarterial connection (with VSD) (A)

Absent Rt ventriculoarterial connection (with intact septum) (B)

Common arterial trunk

Figure 2.10 Sequential segmental analysis. AV, atrioventricular; LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle; TA, truncus arteriosus; VA, ventriculoarterial; VSD, ventricular septal defect.

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2: Examination of the Heart

2.3.4 Atrioventricular Connections 1. With concordant atrioventricular connection the morphologically right atrium is connected to the morphologically right ventricle and the morphologically left atrium to the morphologically left ventricle. This can occur with usual atrial arrangement or with situs inversus. 2. In discordant atrioventricular connection the morphologically right atrium is connected to the morphologically left ventricle and the morphologically left atrium to the morphologically right ventricle. This also can occur with either usual or inverted atrial arrangement. 3. Ambiguous connection relates to the atrioventricular connection in atrial isomerism, whether left or right. Clearly, one atrium is going to be connected to the right ventricle and one to the left, but since both atria are of the same morphology, the connection cannot be described as concordant or discordant and must, therefore, remain

ambiguous. This can occur where the ventricular topology is either right-handed or left-handed. 4. Both atria may connect to a single ventricle – so-called double inlet ventricle, in which case the other ventricle is usually small and connected to the dominant ventricle via a VSD. The atrial arrangement may be usual, inverted or isomeric (right or left). 5. There may be absence of either right or left atrioventricular connection. A further layer of complexity is added by the fact that the valves may override or straddle the interventricular septum.

2.3.5 Ventriculoarterial Connections 1. With concordant ventriculoarterial connections, the morphologically right ventricle is connected to the pulmonary trunk and the morphologically left ventricle is connected to the aorta.

Figure 2.11 Obtaining a simulated four-chamber cut of the heart. (A,B) The formalin-fixed heart (in this case an explanted heart with dilated cardiomyopathy) is stood on its apex. A pair of forceps is placed through each atrioventricular valve with their tips at the ventricular apices. These forceps serve as a guide for the knife. A long-bladed, sharp knife is then placed between the blades of both pair of forceps and the heart is cut from base to apex. (C) The resultant specimen is cut through the centre of each of the atrioventricular valves. It displays the relative sizes of the atria and ventricles.

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2: Examination of the Heart

heart is not recommended. The standard views that are easy to obtain are the four-chamber view, the long-axis view and the short-axis view. The four-chamber view is easy to obtain, cutting as it does from base to apex through the central parts of both atrioventricular valves. It is best to make an incision in the roof of the atria first. A pair of forceps can then be introduced through each of the atrioventricular junctions to the apex of the heart, and these are then used as guides for the knife cut (Figure 2.11). The four-chamber view is especially useful in displaying variations in ventricular or atrial size (Figure 2.12). It is my preferred cut of the heart in cardiomyopathy where it demonstrates relative chamber dimensions. The simulated long-axis view takes a bit more practice to obtain but essentially runs through the central parts of the mitral and aortic valves. It cuts through the right ventricular outflow tract, which remains as a muscular oval. Again, a cut is made first in the left atrium and in the aorta, and forceps are introduced (with care) through the aortic valve, and separately through the mitral valve, which are then used as guides for the knife cut (Figure 2.13). The long-axis view is particularly suited to demonstrating left-sided structures and is useful, for example, in aortic stenosis or any other form of left ventricular outflow obstruction (Figure 2.14). Most pathologists are already familiar with the short-axis view since that is the standard method of demonstrating ventricular hypertrophy (Figure 2.15) [4]. A refinement that may not be so familiar is a cut at a higher level demonstrating the features at the base of the heart (Figure 2.16).

2.4.1 Another Method for Opening and Sampling the Post-Mortem Heart Figure 2.11 (cont.)

2. In discordant ventriculoarterial connections, the aorta arises from the right ventricle and the pulmonary trunk from the left ventricle. 3. There may be double outlet from one ventricle, both great arteries arising from that chamber with absent arterial outlet from the remaining chamber. 4. Finally, there may be a single outlet from the heart. This group encompasses not only a common arterial trunk (truncus arteriosus), but also either pulmonary artery or aorta when the other artery is atretic and cannot be identified to connect to the heart.

2.4 Simulated Echocardiographic Views In clinical practice it is now unusual to receive a heart that has not undergone some form of imaging, such that the cardiac defect is already known or suspected. It is, therefore, worth considering cutting the heart in one of the standard echocardiographic planes following fixation, better to demonstrate the particular abnormality. Attempting to do so in the unfixed

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Donnelly has proposed a method of opening and sampling the neonatal heart looking for evidence of hypoxic\ischaemic damage [5]. The heart is opened in the fresh state and then fixed before sampling for histology. The aorta and pulmonary trunk are first transected above the level of the coronary arteries. The next cut is from the inferior caval vein to the tip of the right atrial appendage, the cut being extended through the supraventricular crest, leaving the pulmonary valve intact, and down the anterior wall of the right ventricle adjacent to the interventricular septum. The left atrium is opened from between the pulmonary veins to the tip of the left atrial appendage, the cut being extended across the left ventricular outflow and through the anterior leaflet of the mitral valve. The cut is then curved towards the septum and down to the left ventricular apex. According to the authors, this method permits, in particular, sampling of the papillary muscles of the atrioventricular valves to determine if there is evidence of hypoxic damage.

2.5 Histology 2.5.1 Sampling for Histology If no macroscopic abnormality is seen on dissection of the heart, then a reasonable sampling for histology would include

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2: Examination of the Heart

Figure 2.12 Examples of hearts cut in a simulated four-chamber view. (A) Dilated cardiomyopathy. The dilated left atrium and ventricle are readily appreciated, together with the endocardial fibrosis in both. (B) Hypertrophic cardiomyopathy. The gross thickening of the left ventricular wall and interventricular septum is evident. The lead of an implantable cardioverter defibrillator is visible in the right atrium. (C) Restrictive cardiomyopathy. This specimen is viewed from behind, so the right ventricle is on the right of the picture. The marked atrial dilatation characteristic of restrictive cardiomyopathy is present. (D) Idiopathic pulmonary arterial hypertension. The disproportionate right ventricular hypertrophy is visible, the right ventricular wall thickness in places exceeding that of the left.

right and left atrioventricular junctions to include papillary muscles, a transverse section through the mid-point of the interventricular septum to include left and right free wall attachments, and a vertical block to include the membranous septum and atrioventricular conduction axis (Figure 2.17). It is, of course, possible to process a full cross section of the fetal

and infant heart in a large block (megablock). Even in larger hearts this is useful for specific parts of the heart and permits more rapid scanning of abnormalities while retaining anatomical relationships (Figure 2.18). As regards staining, haematoxylin and eosin (H&E) is essential. Masson’s trichrome stain is very useful for assessing

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2: Examination of the Heart

Figure 2.13 Obtaining a simulated long-axis cut of the heart. (A) The formalinfixed heart is stood on its apex. The aorta has been transected in its ascending part and the roof of the left atrium has been incised. Forceps are introduced through the aortic valve and through the mitral valves to the left ventricular apex and their blades are aligned. (B) A sharp long-bladed knife is introduced between the blades of the forceps, and the heart is cut from base to apex, using the forceps as guides. (C) The heart thus cut, the left-sided structures (the left atrium, left ventricle and aorta) are seen at a glance. The interventricular septum is plainly visible, and the right ventricular outflow tract is a muscular oval to the top of the field.

internal myocyte architecture and for myocyte necrosis. Elastic vanGieson is a must for arteries veins, pericardium and endocardium. Most cases can be dealt with using these stains, but occasionally other methods are needed, e.g. periodic acid– Schiff (PAS), Congo red, Gram, Grocott, and immunohistochemistry. Table 2.1 lists microscopic features of the heart and their significance, and Table 2.2 lists immunohistochemical stains for the heart. This list of possible samples is applicable to the uncomplicated, post-mortem heart. The pathologist, however, may also be faced with samples from the heart or its related structures other than whole hearts. These may include endomyocardial biopsies, biopsies of aorta or valves, conduits and shunts, pericardium, and tumours. A good overview of the approach to the handling, processing and interpretation of such specimens has been prepared by the Society for Cardiovascular Pathology and the Association for European Cardiovascular Pathology [6]. As with all guidelines, the authors stress that they should be viewed as recommendations and not as mandatory requirements.

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2.5.2 Endomyocardial Biopsy For endomyocardial sampling a minimum of three pieces is suggested [7]. If more than three pieces are received, then consider freezing one and submitting for electron microscopy. If tissue was not originally submitted for electron microscopy processing and electron microscopy is desired, formalin-fixed tissue can be processed for electron microscopy, or paraffinembedded tissue can be reprocessed for electron microscopy. Tissue taken for immunofluorescence (IF) can be held and used when appropriate. Immunofluorescence can be useful for subtyping amyloid deposits and in the determination of cardiac non-amyloidotic immunoglobulin deposition disease [8, 9]. Multiple sections (three or more) should be stained with H&E at different levels through the biopsy (Figure 2.19). For diseases that have a patchy distribution (myocarditis, etc.), even further sectioning can be performed if the entity is not seen on the initial slides. Intervening sections between H&E stains should be used for histochemical or immunohistochemical staining [10]. The most commonly used histochemical and

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2: Examination of the Heart

Figure 2.14 Examples of pathology shown in simulated long-axis views of the heart. (A) Hypertrophic cardiomyopathy. The heart is viewed from behind. The forceps grasp the aortic wall. There is marked hypertrophy of the left ventricular myocardium. The bulging of the upper part of the interventricular septum into the left ventricular outflow tract can be seen. (B) Supravalvar aortic stenosis. There is a discrete hourglass narrowing of the aorta above the level of the aortic valve. The valvar tissue also appears dysplastic.

Figure 2.15 Short axis view of the heart. A standards transverse cut through the ventricles at mid-ventricular level.

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2: Examination of the Heart

Figure 2.16 Simulated short-axis view through the base of the heart. The specimen is viewed from above with the right border of the heart to the left of the picture and the anterior border to the bottom of the picture. At the centre of the base of the heart is the aortic valve with the left atrium behind it and the right ventricular outflow tract anterior to it. The entire sweep of the right side of the heart is included with right atrium, right atrioventricular junction, right ventricle, right ventricular outflow tract, and pulmonary valve and pulmonary artery all visible. The view especially well demonstrates the position of the membranous septum, the intimate connection of anterior mitral valve leaflet with the aortic valve and the different planes of the aortic and pulmonary valves.

Figure 2.17 Routine histology blocks. A neonatal heart sampled for histology. From right to left of the picture the samples are: left atrioventricular junction; • right atrioventricular junction; • transverse section of left ventricle at mid-ventricular level; • two vertical sections through the region of the AV node and membranous • septum.

immunohistochemical stains are listed in Table 2.2. Using 8μm-thick sections can enhance the sensitivity of Congo red staining for amyloid. The endomyocardial biopsy remains the gold standard in the assessment of transplant rejection [11]. The International Society for Heart and Lung Transplantation (ISHLT) scoring system (Revised 2005) should be employed [12]. Also assess for C4d and CD68, looking for antibody-mediated rejection [13].

2.5.3 Myectomy Tissue removed during surgical relief of subaortic obstruction on hypertrophic cardiomyopathy may be submitted for histopathological assessment [14]. The specimen consists of multiple fragments of muscle with a varying amount of overlying, sometimes thickened, endocardium (Figure 2.20). Sometimes it is removed for other indications [15]. All of the tissue should be processed and H&E, trichrome and EvG stains used for assessment. If the tissue is received fresh, it is worth considering freezing a piece for possible genetic analysis.

2.5.4 Apical Biopsy

Figure 2.18 Large histology block. A section from a large block into which a full section of the neonatal heart could be fitted. This is a case of pulmonary atresia with intact septum. Keeping the heart intact preserves the anatomical relationships. The right ventricular hypertrophy can be readily seen, as can the bulging of the interatrial septum to the left.

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Obtained at the time of insertion of ventricular assist device [16], this is usually done in the context of cardiomyopathy or myocarditis. It generally consists of a full transmural fragment of left (sometimes right) ventricular myocardium (Figure 2.21). A small sample should be frozen and stored, and can be used for DNA extraction or for PCR for viruses, if required. The tissue is then fixed and processed in full and treated as for the myectomy specimens.

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2: Examination of the Heart Table 2.1 Histological features of the paediatric heart and their significance

Feature

Significance

Myocyte vacuolation

Normal beneath the endocardium Present around areas of hypoxic damage May indicate storage disorder or mitochondrial disease if extensive

Cytoplasmic glycogen

Normal variable Excess with storage disorder Excess with hypertrophic cardiomyopathy

Cytoplasmic lipid

Small amounts normal Increased in sepsis Increased in stress Increased with hypoxia Increased in fatty acid oxidation disorders

Cytoplasmic lipofuscin

Normally not seen before age of about nine years May be seen on electron microscopy before this

Apoptosis

Myocardial injury Arrhythmogenic cardiomyopathy

Thrombosis

Disseminated intravascular coagulation Antiphospholipid syndrome

Necrosis

Hypoxic\ischaemic Toxic Contraction bands

Embolism

Megakaryocytes normally present Tumour emboli Foreign bodies from intravascular material Tumour emboli Bone marrow emboli in resuscitation

Giant mitochondria

Mitochondrial disease Possibly trisomy 21

Vessel dysplasia

Normal in papillary muscles Seen around areas of fibrosis Hypertrophic cardiomyopathy Fibromuscular dysplasia

Vasculitis

Kawasaki disease Transplant rejection Mycotic aneurysm Polyarteritis nodosa

Calcification

Common in neonatal injury Frequent in maternal lupus Coronaries in idiopathic arterial calcification Fetal trisomy

Infiltration

Amyloid very rare in children

Epicardium Mesothelial hyperplasia

Pericarditis

Fibrosis

Old pericarditis Old surgery

Haemorrhage

Asphyxia Surgery Trauma

Extramedullary haemopoiesis

Normal in fetus around coronary arteries Around areas of myocardial necrosis

Inflammation

Pericarditis Surgery

Myocardium Myocyte hypertrophy

Myocyte disarray

Fibrosis

Cardiomyopathy: Hypertrophic, dilated, restrictive Pressure overload Volume overload Right ventricle in pulmonary arterial hypertension Normal around septum and in right ventricular trabeculations Hypertrophic cardiomyopathy Noonan’s syndrome In congenital heart disease In certain metabolic diseases Healing infarct Toxic Maternal lupus Scleroderma Dilated cardiomyopathy Myocarditis

Atrophy Fatty change

Inflammation

Giant cells

Normal around arteries Common in right ventricle Arrhythmogenic right ventricular cardiomyopathy (ARVC) Stressor effect Myocarditis Around infarcts Sarcoidosis Giant cell myocarditis Foreign bodies

Anitschow cells

Normal in neonatal period Rheumatic fever

Mitotic figures in myocytes

Probably normal in the first few months of life Mitogenic cardiomyopathy

Endocardium Hyperplasia Haemorrhage

Ischaemia Disseminated intravascular coagulation Sepsis

Inflammation

Bacterial endocarditis Transplant rejection

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2: Examination of the Heart Table 2.1 (cont.)

2.5.5 Cardiac Tumours

Feature

Significance

Thrombosis

Overlying infarcts

Tumour Necrosis Fibroelastosis

Dilated cardiomyopathy Eosinophilic disease Hypertrophic cardiomyopathy (impact) Jet lesion Around VSD

Valves Cartilage and bone Myxoid change

Valvar dysplasia

As with all tumours, these, ideally, are received fresh so that samples for cytogenetic or molecular testing may be taken. Once this tissue is obtained, it can be described, then formalin fixed and processed. H&E and connective tissue stains are done and other stains used, usually those involving immunohistochemistry as indicated by the preliminary findings on H&E.

2.5.6 Atrial Appendages Atrial appendages are rarely removed and submitted for histology in children. In adults the myocardium in resected atrial appendages frequently displays profound myocyte hypertrophy and vacuolisation, and interstitial fibrosis [6].

Table 2.2 Immunohistochemical staining of the normal and pathological heart

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Antibody

Normal staining

Pathological staining

Reference

Desmin

Myocyte cytoplasm. Smooth muscle of vessel walls

DCM inclusions Reduced in DCM

[22]

Smooth muscle actin

Muscle of blood vessels Expressed in myocardium in fetal heart Cells of normal sinoatrial node

HMB45

None

Focally in rhabdomyoma

[25]

Calretinin

Autonomic ganglia in the epicardium

Myxoma cells

[26]

S100

Nerves

Plakoglobin

Intercalated discs

Absent in ARVC

[27]

Myoglobin

Myocyte cytoplasm

Rhabdomyoma

[28]

Myosin

Myocyte cytoplasm

Rhabdomyoma Myxoma

Dystrophin

Myocyte sarcolemma

Absent in dystrophinopathies

Transthyretin

Not seen in normal heart

Amyloidosis

Serum amyloid P

Not seen in normal heart

Amyloidosis

Kappa light chain

Not seen in normal heart

Amyloidosis

Lambda light chain

Not seen in normal heart

Amyloidosis

Amyloid AA protein

Not seen in normal heart

Amyloidosis

Glut-1

Patchy myocyte cytoplasmic Erythrocytes

Infantile haemangioma

D2–40

Lymphatic endothelium

Lymphangioma

CD34

Endocardium Endothelium of blood vessels

Haemangioma endothelium

CD45

Normal transient population of leucocytes

Myocarditis

CD3

T-lymphocytes

Myocarditis PTLD Lymphoma

[23, 24]

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2: Examination of the Heart Table 2.2 (cont.)

Antibody

Normal staining

Pathological staining

CD21

B-lymphocytes

Myocarditis PTLD Lymphoma

HLA-DR

Scanty endothelial

Endothelial cells and myocytes in myocarditis and DCM

NSE

Nerves

Connexin 40

Atrial myocytes

[30]

Connexin 43

Ventricular and atrial myocytes

[30]

Connexin 45

Conduction system

[30]

C4d

[29]

Myocyte necrosis Antibody-mediated rejection

[31] [32]

CD56

Intercalated discs NK cells

Adjacent to fibrosis

CD68

Interstitial macrophages

Myocarditis GCM (some) Antibody-mediated rejection (intravascular)

CD61

Reference

Small thrombi

[33]

ARVC, arrhythmogenic right ventricular cardiomyopathy; DCM, dilated cardiomyopathy; GCM, giant cell myocarditis; NK cells, natural killer cells; PTLD, posttransplant lymphoproliferative–proliferative disorder.

Figure 2.19 Endomyocardial biopsy histology. A low-power histological section of an endomyocardial biopsy stained with H&E. This size is fairly typical of those received in routine practice.

2.5.7 Aorta Samples of aorta may be removed during aortic valve surgery or aneurysm correction with a query as to whether there is evidence of connective tissue disease or inflammation [17]. Usually only a small piece is received (Figure 2.22). Sometimes a small sample of aortic wall is removed during coarctation repair, and the interest in these cases is whether there are remains of ductal tissue in the specimen. The samples should

Figure 2.20 Myectomy specimen. A section from a myectomy specimen stained with Masson’s trichrome, for obstructive hypertrophic cardiomyopathy. The endocardial surface is uppermost and displays fibrous thickening with prominent smooth muscle. There is some adipose tissue in the superficial myocardium in addition to mild interstitial fibrosis.

be formalin fixed, embedded so as to obtain a full thickness of the wall and stained with H&E, EVG and Alcian blue (AB) PAS. Multiple levels may need to be examined.

2.5.8 Vascular Grafts Vascular grafts may be biological or synthetic grafts. Pulmonary homografts are examples of biological materials

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2: Examination of the Heart

Figure 2.21 Apical core biopsy. A full-thickness plug of myocardium removed from the left ventricular apex at the time of insertion of a left ventricular assist device. The thickened, opaque endocardium from this case of dilated cardiomyopathy is readily appreciated.

Figure 2.22 Aortic wall biopsy. A two-year-old child with Williams syndrome and supravalvar aortic stenosis. The specimen is the resected supravalvar area of the aorta. It is viewed end-on and shows concentric luminal narrowing. This was confirmed on histology.

(PTFE; Gore-Tex)[19]. Synthetic grafts are used in aortic and large-diameter peripheral arterial bypass surgeries. Dacron is a type of polyester that comes in either woven or knitted form; it is frequently crimped for greater flexibility, and it may be straight tubular or branched. PTFE is made from fluorocarbon polymer sheets and has a smooth surface. It is available in many sizes and wall thicknesses. It is the preferred material for construction of extra-anatomic conduits. Any of these grafts may be removed because of occlusion, thrombosis, stenosis, infection or aneurysm. The excised graft should be measured and described paying particular attention to luminal integrity, the presence of thrombus or vegetations, and degenerative changes such as calcification. Photographic recording is especially useful. The materials can easily be cut and are amenable to histological sectioning. Care should be taken to try to remove any sutures in the histological blocks (Figures 2.25 and 2.26).

2.5.9 Native Valves

Figure 2.23 Homograft. Four-year-old with excision of homograft for infective endocarditis. One of the valve leaflets is seen in the picture with a fungating vegetation from its ventricular aspect.

(Figure 2.23). Decellularised bovine pericardium (CardioCell) may be used to patch aortic valve cusps [18] (Figure 2.24). Widely used synthetic grafts are made from polyethylene terephthalate (PET; Dacron) and polytetrafluoroethylene

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Diseased native valves are removed because of functional disturbance such as stenosis or regurgitation where the native tissue cannot successfully be repaired. The excised tissue may be dysplastic or show infiltration or degenerative changes or may show vegetations. The atrioventricular valve leaflets are usually removed with their associated chordae (Figure 2.27). The arterial valve leaflets are usually excised separately and come as semilunar pieces of variable thickness and regularity (Figure 2.28A,B). Subaortic membranes may also be submitted, usually as a semicircular piece of rubbery fibrous tissue (Figure 2.29). The specimens should be described and photographed and consideration given to tissue for microbiological culture or freezing for DNA extraction. Electron microscopy may also

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2: Examination of the Heart

Figure 2.24 CardioCell. An adolescent with removal of patches used previously to repair the aortic valve. (A) This is a semilunar piece of bovine pericardium that shows opaque white areas of fibrosis and irregular granular yellow areas of calcification towards the attachment line of the leaflet. (B) The histological section shows the patch visible as a quadrangular, slightly wavy horizontal area occupying the middle part of the section. It is overlain by fibrous tissue reaction on both sides. There is some fibrin over the left upper part of the patch. The left half of the patch is basophilic because of calcification.

Figure 2.25 Gore-Tex shunt. A histological section (H&E) through a shunt. The shunt wall has a reticular refractile appearance. There is eccentric non-occlusive intimal fibrous thickening.

Figure 2.26 Dacron. Histological section through the atrioventricular junction in a case of patched atrioventricular septal defect. The left ventricle is above and the right ventricle below; the interventricular septum is to the left of the picture and the interatrial septum and aorta to the right. The patch is visible as the sinous structure sutured to the right side of the interventricular and interatrial septa. There is considerable overlying endocardial fibrosis (EvG).

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2: Examination of the Heart

Figure 2.27 Resected atrioventricular valve. A boy with Frank ter Haar syndrome and severe mitral regurgitation. The excised anterior leaflet of the mitral valve shows opaque pale thickening and coarsening of the chordae tendineae. Histologically there was fibrosis.

Figure 2.29 Subaortic membrane. A child with neurofibromatosis and subaortic obstruction who underwent resection of a subaortic membrane. The membrane is actually a thick ridge of fibroelastic tissue, looking very much like valvar tissue.

Figure 2.28 Resected semilunar valve. (A) Resected cusps of a regurgitant aortic valve. The free edges of the cusps are thick and rolled. (B) A bicuspid and stenotic aortic valve showing thickening and fusion of the elements of the valve to form a rigid obstruction.

be considered, particularly if there is suspicion of metabolic disorder. A section should be taken longitudinally through the axis of the valve, usually at its widest point to include attachment and free edge in the same piece. The tissue may need to be decalcified before processing. Sections should be stained with H&E, EVG, AB/PAS, and then further stains may be employed depending on the clinical features and histological appearances.

2.6 Photography In an age when it is no longer feasible in many cases to retain hearts for demonstration purposes, macroscopic photography

50

is increasingly important. If one goes to the trouble of elaborate dissection to demonstrate abnormality, it is worth the little extra effort to photograph the specimen [20, 21]. If absolutely necessary, the specimen may be photographed fresh, but it is almost impossible to avoid a bloody background that distracts from the essential features. It is better to fix the specimen. A camera stand to avoid shake and permit longer exposure is useful, as is a source of artificial lighting. Many modern digital cameras, even mobile phones, give perfectly acceptable results, but purists still prefer an SLR camera. There is controversy as to whether a scale should be included. A photograph with and without a scale avoids falling foul of either party. Any clean

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2: Examination of the Heart

Figure 2.30 (A) A normal fetal chest photographed in ambient light. Note the light reflections on the glistening organ surfaces. (B) Immersing the fetus in a bowl of cold water permits the structures to be seen minus the glare.

background is acceptable. It should be capable of being cleaned easily. For a better-quality photograph, black velvet may be used. It avoids glare and reflection, and when viewed, the specimen appears to be floating in space. Small samples may be photographed under magnification in a dissecting microscope. Immersion in fluid, usually alcohol, gives a clearer picture without reflections or glare (Figure 2.30). The

References 1.

2.

3.

4.

5.

6.

Hutchinson JC, Arthurs OJ, Ashworth MT et al. Clinical utility of post-mortem microcomputed tomography of the fetal heart: diagnostic imaging vs macroscopic dissection. Ultrasound Obstet Gynecol 2016; 47: 58–64. Anderson RH, Ho SY. Sequential segmental analysis – description and categorization for the millennium. Cardiol Young 1997; 7: 98–116. Van Praagh R, David I, Gordon D, Wright GB, Van Praagh S. Ventricular diagnosis and designation. In Godlman M (ed.) Pediatric Cardiology, Vol 4. Edinburgh: Churchill Livingstone; 1981, pp. 153–168. Basso C, Burke M, Fornes P et al.; Association for European Cardiovascular Pathology. Guidelines for autopsy investigation of sudden cardiac death. Virchows Arch 2008; 452: 11–18. Donnelly WH, Hawkins H. Optimal examination of the normally formed perinatal heart. Hum Pathol 1987; 18: 55–60.

7.

specimen can be pinned out on card or a thin layer of plasticine to give a coloured background. If the heart is not retained, then a short video recording of the opened heart to demonstrate the usual features is very useful. The photographs employed in this book have all been taken using these techniques.

Stone JR, Basso C, Baandrup UT et al. Recommendations for processing cardiovascular surgical pathology specimens: a consensus statement from the Standards and Definitions Committee of the Society for Cardiovascular Pathology and the Association for European Cardiovascular Pathology. Cardiovasc Pathol 2012; 21: 2–16. Cunningham KS, Veinot JP, Butany J. An approach to endomyocardial biopsy interpretation. J Clin Pathol 2006; 59: 121–129.

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Collins AB, Smith RN, Stone JR. Classification of amyloid deposits in diagnostic cardiac specimens by immunofluorescence. Cardiovasc Pathol 2009; 18: 205–216.

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Toor AA, Ramdane BA, Joseph J et al. Cardiac nonamyloidotic immunoglobulin deposition disease. Mod Pathol 2006; 19: 233–237.

10. Leone O, Veinot JP, Angelini A et al. 2011 consensus statement on endomyocardial biopsy from the Association for European Cardiovascular Pathology and the

Society for Cardiovascular Pathology. Cardiovasc Pathol 2012; 21: 245–274. 11. Tan CD, Baldwin WM, Rodriguez ER. Update on cardiac transplantation pathology. Arch Pathol Lab Med 2007; 131: 1169–1191. 12. Stewart S, Winters GL, Fishbein MC, et al. Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection. J Heart Lung Transplant 2005; 24: 1710–1720. 13. Berry GJ, Burke MM, Andersen C et al. The 2103 International Society of Heart and Lung Transplantation Working Formulation for the standardization of nomenclature in the pathologic diagnosis of antibody-mediated rejection in heart transplantation. J Heart Lung Transplant 2013; 32: 1147–1162. 14. Lamke GT, Allen RD, Edwards WD, Tazelaar HD, Danielson GK. Surgical pathology of subaortic septal myectomy associated with hypertrophic cardiomyopathy. A study of 204 cases (1996–2000). Cardiovasc Pathol 2003; 12: 149–158.

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2: Examination of the Heart

15. Allen RD, Edwards WD, Tazelaar HD, Danielson GK. Surgical pathology of subaortic septal myectomy not associated with hypertrophic cardiomyopathy: a study of 98 cases (1996–2000). Cardiovasc Pathol 2003; 12: 207–215. 16. Cazes A, Van Huyen JPD, Fornes P et al. Mechanical ventricular assistance in heart failure: pathology of the cardiac apex removed during device implantation. Cardiovasc Pathol 2010; 19: 112–116. 17. Jain D, Dietz HC, Oswald GL, Maleszewski JJ, Halushka MK. Causes and histopathology of ascending aortic disease in children and young adults. Cardiovasc Pathol 2011; 20: 15–25. 18. Nordmeyer S, Murin P, Schulz A et al. Results of aortic valve repair using decellularized bovine pericardium in congenital surgery. Eur J Cardiothorac Surg 2018; 54: 986–992. 19. Kapadia MR, Popowich DA, Kibbe MR. Modified prosthetic vascular conduits. Circulation 2008; 17: 1873–1882. 20. Liepinsh E, Kuka J, Dambrova M. Troubleshooting digital macro photography for image acquisition and the analysis of biological samples. J Pharmacol Toxicol Methods 2013; 67: 98–106. 21. Rampy BA, Glassy EF. Pathology gross photography: the beginning of digital

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pathology. Clin Lab Med 2016; 36: 67–87. 22. Pawlak A, Gil RJ, Kulawik T et al. Type of desmin expression in cardiomyocytes – a good marker of heart failure development in idiopathic dilated cardiomyopathy. J Intern Med 2012; 272: 287–297. 23. Suurmeijer AJ, Clément S, Francesconi A et al. Alpha-actin isoform distribution in normal and failing human heart: a morphological, morphometric, and biochemical study. J Pathol 2003; 199: 387–397. 24. Orlandi A, Hao H, Ferlosio A et al. Alpha actin isoforms expression in human and rat adult cardiac conduction system. Differentiation 2009; 77: 360–368. 25. Weeks DA, Chase DR, Malott RL et al. HMB-45 staining in angiomyolipoma, cardiac rhabdomoma, other mesenchymal processes, and tuberous sclerosis-associated brain lesions. Int J Surg Pathol 1994; 1: 191–198. 26. Terracciano LM, Mhawech P, Suess K et al. Calretinin as a marker for cardiac myxoma. Diagnostic and histogenetic considerations. Am J Clin Pathol 2000; 114: 754–759. 27. Asimaki A, Tandri H, Huang H et al. A new diagnostic test for arrhythmogenic right ventricular

cardiomyopathy. N Eng J Med 2009; 360: 1075–1084. 28. Ordway GA, Garry DJ. Myoglobin: an essential hemoprotein in striated muscle. J Exp Biol 2004; 207: 3441–3446. 29. Noutsias M, Seeberg B, Schultheiss HP, Kühl U. Expression of cell adhesion molecules in dilated cardiomyopathy: evidence for endothelial activation in inflammatory cardiomyopathy. Circulation 1999; 99: 2124–2131. 30. Severs NJ, Bruce AF, Dupont E, Rothery S. Remodelling of gap junctions and connexin expression in diseased myocardium. Cardiovasc Res 2008; 80: 9–19. 31. Husain AN, Mirza KM, Fedson SE. Routine C4d immunohistochemistry in cardiac allografts: long-term outcomes. J Heart Lung Transplant 2017; 36: 1329–1335. 32. Nagao K, Sowa N, Inoue K et al. Myocardial expression level of neural cell adhesion molecule correlates with reduced left ventricular function in human cardiomyopathy. Circ Heart Fail 2014; 7: 351–358. 33. Burke AP, Mont E, Kolodgie F et al. Thrombotic thrombocytopenic purpura causing rapid unexpected death: value of CD61 immunohistochemical staining in diagnosis. Cardiovasc Pathol 2005; 14: 150–155.

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Chapter

3

Development of the Heart

Note on Nomenclature Human gene symbols are italicised, with all letters in uppercase (e.g. SHH for sonic hedgehog). Proteins have the same designation, but are not italicised, with all letters in uppercase (SHH). The same conventions are applied to chicken genes. Rodent gene symbols are italicised, with only the first letter in uppercase and the remaining letters in lowercase (Shh). Protein designations are the same as the gene symbol but are not italicised and all are upper case (SHH). Zebrafish gene symbols are italicised, with all letters in lowercase (shh). Protein designations are the same as the gene symbol but are not italicised; the first letter is in uppercase and the remaining letters are in lowercase (Shh) [1].

3.1 Introduction The technical and ethical difficulties inherent in the study of early human embryos have determined that much of the detail of the early development of the heart is based on studies in mouse and chick embryos [2]. With minor differences in venous anatomy, mouse heart development is substantially the same as in the human [3]. This large volume of animal embryo experiments has been supplemented by the morphological examination of early human embryos. This examination, historically, has entailed reconstruction of serial histological sections of early embryos, but use of techniques such as magnetic resonance imaging (MRI) and Episcopic Fluorescence Image Capture more recently has yielded much more detailed information [4]. Although the heart is an organ largely derived from mesoderm (with small contributions from ectodermally derived neural crest), it does not develop in isolation. It is intimately related to its neighbouring structures such as the pharynx (Figure 3.1). Heart development is both influenced by and influences these surrounding structures. It is therefore no surprise that defects in the heart may frequently be associated with defects in these adjacent structures. From its earliest stages the heart is a beating structure containing flowing liquid, and hence mechanical forces are also important in shaping its development [5].

Figure 3.1 Relation of the developing heart to surrounding structures. A saggital section of a mouse embryo at approximately 12.5 days, equivalent to a human embryonic age of approximately 40 days. The heart within the pericardial cavity is present in the centre of the field. Dorsal to it is the trachea with the pharynx visible dorsal to this. Dorsal to this again and not in the field is the spine and notochord. The pharynx lies cephalad and the liver caudad.

3.2 Brief Recap of Relevant Early Human Embryonic Development In the second week (days 7–14) post-fertilisation, the human embryo consists of a cellular, two-layered disc, one cell layer facing the amniotic cavity called the epiblast, and the other

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3: Development of the Heart

(facing the cavity of the yolk sac) called the hypoblast. During the third week the cells of the epiblast under the influence of BMP, FGF and WNT proliferate, migrate to the midline of the embryonic disc, where they are visible as the primitive streak, and there descend between the two cell layers and insinuate between them (a process known as gastrulation). The cells of the epiblast give rise to all three embryonic germ layers: those cells remaining in the epiblast constitute the embryonic ectoderm, other cells from the epiblast replace the cells of the hypoblast to form embryonic endoderm, and the insinuated cells between the ectoderm and endoderm constitute the embryonic mesoderm. Some of the mesenchymal cells coalesce in the midline to form the notochord, the structure that co-ordinates development of the axial nervous system and associated musculoskeletal structures. At the cranial end of the notochord is the prechordal plate where the endoderm and ectoderm are in contact (without interposed mesoderm) and which marks the site of the future mouth. The mesoderm on either side of the notochord is designated (with increasing distance from the midline) paraxial mesoderm, intermediate mesoderm and lateral mesoderm, the last extending to the edges of the embryonic disc. The paraxial mesoderm gives rise to the somites, which in turn give rise to the axial skeleton and its musculature. Spaces develop in the lateral mesoderm that gradually coalesce so that a cavity forms. The cavity will go on to form the pleural, pericardial and peritoneal cavities. The cavity thus formed divides the lateral mesoderm into two: the splanchnic (adjacent to the endoderm) and parietal or somatic (adjacent to the ectoderm) layers. The somatic mesoderm together with its associated ectoderm will form the embryonic body wall, whereas the splanchnic mesoderm will form the heart and intestine. Some mesenchymal cells that have entered the mesoderm from the primitive streak migrate cranially on each side of the notochordal process cranial to the prechordal plate. They fuse cranially to form the cardiogenic mesoderm of the primary heart field (cardiac crescent) and are segregated into the splanchnic layer of lateral plate mesoderm [6]. The notochord induces the overlying ectoderm to form the neural tube by a process of invagination. As the neural tube closes, some cells at its margins detach and lie between the neural tube and the overlying reconstituted ectoderm as the neural crest. A subpopulation of these cells contributes to cardiac development. During the fourth week the embryo folds, converting the disc to a complex three-dimensional structure. The main driver of this folding is differential growth of the parts of the disc, bringing the caudal cranial and lateral edges together in the ventral midline where the opposite sides fuse.

3.3 Brief Summary of Heart Development Within the cardiac crescent paired endothelium-lined tubes develop with their long axis in the long axis of the embryonic disc. These endothelium-lined tubes fuse in the midline to form a primitive heart tube. The inflow is caudal, a continuation of the primitive veins, and the outflow cranial and

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connected to the paired aortic arches. The surrounding mesoderm of the cardiac crescent differentiates to provide an investing sleeve of myocardium, both layers separated by extracellular matrix termed cardiac jelly. The pericardial cavity is present initially on the ventral surface, the heart tube being connected dorsally to the mesenchyme by the dorsal mesocardium. The primitive myocardium of this primary heart tube shows regular contractions by the third week. This heart tube elongates by addition of mesodermal cells at its two poles (and from the dorsal mesocardium until that structure involutes) and undergoes rightward looping. The atrial and ventricular chambers form by ballooning of the myocardium of the heart tube. Heart formation is completed with the development of valves, the conduction system and the formation of the coronary arteries by the ingrowth of extracardiac tissues derived from the neural crest, and from the pro-epicardium situated in the septum transversum [7]. We will now review this process in considerably more detail. Table 3.1 lists many of the major genes involved in heart development.

3.4 Early Development Traditionally and of necessity, embryology of the heart has concentrated on morphogenesis and its coordination, on growth and on cellular differentiation. However, there is a series of steps that occurs before these, and on which these later processes are critically dependent, and that is not visible to the morphologist. These steps include the specification of precursor cells, their migration to the organ-forming region and the specification of cell types within the developing organ.

3.4.1 The Heart Fields The term” heart field” describes a collection of mesodermal cells that contribute to the development of the heart. Two such fields are described, usually termed primary and secondary. The nomenclature is confusing and not all authors use the same terms for each. The fields change in position and with time [8]. In general, the primary heart field provides cells that form the primitive heart tube. The tube grows by addition of cells at its poles that are derived from the second heart field [9]. The first and second heart fields are temporally sequential [8]. The populations contributing to the heart are plastic, in that cells taken from a different location or developmental time point could contribute to the heart when placed in the appropriate location. This indicates that cellular environment is more important than the initial identity of the cells. The cells that will form the heart fields are initially located in two small areas, one on either side of the midline in the epiblast of the bilaminar embryonic disc, close to the cranial part of the primitive streak. The earliest known committed cardiac precursors express the T-box transcription factor Eomesodermin\Tbr2 (EOMES) [10]. EOMES activates another transcription factor MESP1. These progenitor cells migrate together through the primitive streak and form two plates of lateral mesoderm cells

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3: Development of the Heart Table 3.1 Major genes in human heart development

Gene

Location

Function

Defect

EOMES

3p24.1

The gene belongs to the TBR1 (T-box brain protein 1) subfamily of T-box genes sharing the common DNA-binding T-box domain. It is the earliest known specific gene for cardiomyocyte differentiation expressed during gastrulation. The gene encodes a protein transcription factor crucial for embryonic development of mesoderm and nervous system

Lack of the gene prevents development of the heart and is fatal

BMP

BMP1: 8p21.3 BMP2: 20p12.3

Drive myocardial specification and differentiation and negatively regulate FGF signalling. Bind and activate type 1 and 2 BMP receptors that result in phosphorylation of Smad1/5/8 proteins. Bmp signalling is inhibited by Smad 5 and 7

BMP1 mutation: osteogenesis imperfecta type XIII BMP2 mutation: short stature, facial dysmorphism, skeletal abnormalities and cardiac defects

MESP1

15q26.1

Mesoderm Posterior bHLH Transcription factor 1. Required for primitive mesodermal cells to leave the primitive streak and participate in formation of early heart tube

Early embryonic death Cardia bifida

ISL1

5q11.1

Regulates signalling pathways required to coordinate second heart field deployment and is essential for heart tube elongation

GATA4

8p23.1

Also required for testicular development

ASD-VSD, VSD ToF

MEF2C

5q14.3

MEF2C belongs to the myocyte enhancer factor-2 (MEF2) family of transcription factors. MEF2C plays a pivotal role in myogenesis, development of the anterior heart field, neural crest and craniofacial development, and neurogenesis

AD mental retardation

NKX2–5

5q35.1

Human equivalent of Drosphila tinman gene

Holt–Oram syndrome ASD with conduction defects ToF VSD

CX40 (GJA5)

1q21.2

Polymerise to form gap junctions for intercellular communication

Familial atrial fibrillation

CX43 (GJA1)

6q.22.31

Polymerise to form gap junctions for intercellular communication

HLH AVSD

NPPA (ANF)

1p36.22

Expression of ANF is one of the first markers of chamber formation

Atrial fibrillation

TBX2

17q23.2

Represses the chamber genetic programme and promotes cushion development in the AV canal and outflow tract

Mental retardation, multiple cardiac defects

TBX3

12q24.21

Represses the chamber genetic programme and promotes cushion development in the AV canal and outflow tract

TBX5

12q24.21

Promotes chamber myocardial development

Holt–Oram syndrome

TBX20

7p14.2

Promotes chamber myocardial development

Overexpression in ToF

FOXH1

8q24.3

FOXH1 protein binds SMAD2 and activates an activin response element via binding the DNA motif TGT(G/T)(T/G)ATT

TGA Multiple VSD

NOTCH

9q34.3

Local cell–cell signalling mechanism required for cardiac specification, progenitor cell differentiation, valve primordium formation and morphogenesis, ventricular trabeculation and compaction, and coronary vessel development

Aortic valve disease Alagille syndrome

WNT Canonical

Binding of ligand stabilises intracellular β-catenin, which translocates to the nucleus, binds TCF/LEF and activates transcription. Overexpression of Wnt3a and Wnt 8 causes cardiomyocyte inhibition

WNT Noncanonical

Non-canonical WNT signalling is mediated by intracellular calcium ions

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3: Development of the Heart Table 3.1 (cont.)

Gene

Location

Function

Defect

FGF8

10q24.32

Required during looping by positively regulating differentiation

Hypogonadism

FGF10

5p12

Required during looping by positively regulating differentiation

FGFR1

8p11.23

Required during looping by positively regulating differentiation

TGFβ1

19q13.2

Encodes TGFB, a multi-functional peptide that controls proliferation and differentiation in multiple cell types

Skeletal dysplasia Hypogonadism

ASD = atrial septal defect; VSD = ventricular septal defect; ToF = tetralogy of Fallot; AD = autosomal dominant; HLH = hypoplastic left heart; AVSD = atrioventricular septal defect; TGA = transposition of the great arteries.

positioned anteriorly. The general specification of a heart field (cardiogenic mesoderm) has already started during this cellular migration. The progenitor cells migrate such that the medial–lateral arrangement of these cells will become the cranial–caudal axis of a linear heart tube. With the formation of the embryonic coelom, they segregate to the splanchnic mesoderm. The cells of this cardiac mesoderm express the cardiac-specific genes NKX2.5 and GATA-4 [11]. They become specified for heart development by interaction with surrounding structures. The adjacent foregut endoderm is thought to provide inductive signals to begin myocardial differentiation [12] (Figure 3.2). The foregut endoderm also plays a mechanical role in assembly of the heart tube. The endoderm around the oropharyngeal membrane actively contracts and pulls the bilateral fields of cardiogenic mesoderm towards the midline, permitting them to form the fused heart tube [13]. The primitive heart tube initially functions not so much to support the embryonic circulation as to provide a scaffold into which the cells from the secondary heart field migrate prior to chamber morphogenesis. Secondary heart field cells are first located medial to the cardiac crescent, and subsequently reside in mesoderm underlying the pharynx before they are added to the heart. The contribution of this population of cardiac progenitors to the heart was demonstrated by studies of the LIM transcription factor Islet1 (Isl1) that is a marker of the second heart field [14], although its expression is much broader than just the secondary heart field. The cranial part of the secondary heart field – the anterior heart field – which is marked by Fgf10 expression [15] and a specific enhancer of the Mef2c gene [16], contributes to the formation of right ventricular and outflow tract myocardium [17, 18], whereas cells in the posterior second heart field [14] expressing Isl1, but not anterior heart field markers, contribute to atrial myocardium [19]; that is to say, they are added at the venous pole of the developing heart. Myocardial progenitors from the left or right sides of the posterior secondary heart field contribute to the corresponding side of the common atrium, indicating that most cells do not migrate or mix either within the forming heart or across the secondary heart field [19]. The secondary heart field is patterned along the anterior–posterior axis of the mouse

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embryo; however, a detailed understanding of the molecular regulatory pathways governing this process is lacking [20].

3.4.2 The Heart Tube Within the specified cardiac mesoderm anterior to the prechordal plate a primitive heart tube forms. The process begins when a plexus of endothelium-lined channels forms within the mesenchyme. These channels fuse to form bilateral endothelial tubes (Figure 3.3). Folding of the embryo brings these paired tubes together in the midline where they fuse to form a single endothelium-lined tube with a surrounding cuff of mesenchyme separated from it by extracellular matrix termed cardiac jelly. The unfused, paired inflow is caudal and the unfused, paired outflow is cranial. The tube is attached to the posterior body wall by dorsal mesocardium, while anteriorly it is surrounded by a cavity of the pericardium. Growth of the tube is by addition of mesodermal cells from the mesoderm of the inflow and outflow regions, and (until it breaks down) also the dorsal mesocardium. By folding of the embryo, the lateral parts of the cardiac mesoderm are brought together, forming the ventral part of the heart tube. The inner curvature of the cardiac crescent forms the dorsal side of the tube, and is contiguous with the dorsal mesocardium, the attachment of the heart to the body wall. The peripheral part of the cardiac crescent will eventually face the transverse septum and forms the venous pole of the heart, whereas the central part of the crescent, which forms the outflow tract, is contiguous with the pharyngeal mesenchyme [21]. The cardiac precursors are initially situated anterior (cranial) and lateral to the future mouth, but posterior (caudal) to the mesoderm that forms the transverse septum, which contributes to the formation of the diaphragm. During the process of folding the cardiac precursors end up between the mouth at the cranial side, the diaphragm at the caudal side and ventral to the foregut, as in the adult situation (Figure 3.4) [9]. This intimate association of the cardiac and facial region during development is a possible explanation for the high incidence of combined cardiac and facial malformations [9]. The growth of the linear heart is not by division of in situ myocytes, but by addition from without. When being added to the heart, the fate of these

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3: Development of the Heart Figure 3.2 Specification of the heart. A diagrammatic representation of some of the more important gene interactions in the early development of the heart.

Activation of cardiac transcription factors

+ Pharynx\foregut

-

BMP FGF

β-catenin/WNT +

Midline

WNT inhibitors

Activation of transcription factors NKX2.5 TBX5 GATA4 MEF2C SMARCD3 (BAF60C)

+ MESP1 Eomes

+ Second heart field ISL1 TBX1 FGF8 FGF10

cellular additions is not fixed. Their identity depends on their eventual location. The endocardium develops simultaneously with the myocardium and as a specialised endothelial cell type derived from the splanchnic mesoderm that via an unknown mechanism differs from the myocardial precursors [9].

3.4.3 Contraction The myocardium shows regular contractions by the third week. This indicates that the functional adaptations required for contraction, namely contractile proteins, sarcoplasmic reticulum and gap junctions, are already present in the myocardial cells of the primitive heart tube. It would appear that the initial contractions, at least in the chick embryo, are not

essential for tissue oxygen and nutrient supply, but have more to do with mechanical stimuli for further development of the heart [5]. Early blood flow in the embryo is dependent on the yolk sac and the development of the vitelline circulation. When the placental circulation becomes functional, both extraembryonic circulations send blood to the developing heart. Haemodynamic changes in the extraembryonic vitelline or placental circulations can alter normal heart development to induce cardiac abnormalities [22].

3.5 Looping of the Heart Tube Looping of the straight heart tube begins at around day 22 following activation of a gene cascade that determines

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3: Development of the Heart

Figure 3.3 Schematic drawing of a cross section of a trilaminar embryo before folding. The coelom is developing within the mesoderm, localising the paired heart tubes to the splanchnic mesoderm on the ventral aspect of the embryo. As the embryo folds, the lateral edges are brought into apposition, and the endoderm fuses to form the gut. The paired heart tubes are brought side by side and fuse in the midline ventral to the gut. The coelom forms the pericardial cavity. The ectoderm enfolds the other structures, and the amniotic cavity extends completely to surround the embryo.

right–left symmetry. These genes are already expressed in the cardiac mesoderm before formation of the heart tube and include the genes LEFTY, NODAL, and PITX2, of which PITX2 is the controlling gene [23, 24]. Looping is caused by elongation of the tube, fixed at its caudal and cranial ends, within the confines of the pericardial cavity [25]. This elongation results from addition of cells at each end from the secondary heart field, and by dissolution of the tethering dorsal mesocardium. During the early phase of looping the straight heart tube bends towards the ventral body wall and undergoes torsion around its central axis such that it acquires the configuration of a helix with a single counter-clockwise (left-handed) twist. This loop looks like the letter “C” when viewed in a frontal two-dimensional projection with the convexity of the “C” pointing to the right side of the embryo. The heart loop then acquires a more complex helical shape, which resembles the letter “S” as viewed in a frontal two-dimensional projection. The configuration of the “S-shaped” heart loop has been termed a “helical perversion” [26]. A helical perversion connects two helical segments of opposite handedness within the same helically coiled object (a two-handed helix). Applied to the embryonic heart, the two-handed helix consists of a caudal limb with a left-handed twist and a cranial limb with a righthanded twist. These two are connected by a curved loop convex to the right (Figure 3.5). Following the direction of blood flow, this heart loop configuration may be termed a “left–right-handed helix”. The direction of looping is not random but is controlled by genes not yet understood and not under the control of PITX2. It has been shown in a mechanical model that looping

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will occur to the right if the venous pole is moved to the left of the midline [27]. The looping causes the segments of the tube to be brought into close proximity on the inner curvature of the loop. This is absolutely essential for establishing the correct connections of the chambers. Actin polymerisationdriven myocardial cell shape changes have been found to contribute to the bending of the heart tube [28, 29]. The looped heart tube has unidirectional blood flow. This flow was originally thought to be peristaltic but is claimed to be more akin to a Liebau pump. Liebau pumping is the unidirectional flow obtained when a more or less elastic tube containing a fluid is periodically squeezed. It is pulsatile [30]. The developing atrioventricular cushions function as primitive valves to permit unidirectional flow of blood in the looped heart tube [31].

3.6 Development of the Chambers and Septation Septation of the ventricles occurs between 5 and 7.5 weeks of gestation. The atria and ventricles develop by ballooning growth from the heart tube, the atria from the dorsal aspect and the ventricles from the ventral aspect (Figure 3.6) [9]. In the atrial segment this growth is bilateral and in parallel, whereas in the ventricular segments it is unilateral and in sequence. Thus, in the atria it is possible to develop isomerism – it is impossible for this to occur in the ventricles. The ballooning myocardium shows trabeculations and does not have associated cardiac jelly between it and the endocardium with the result that histologically, the cardiac chambers are

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3: Development of the Heart Figure 3.4 A diagrammatic representation of the shift in position of the heart relative to the gut and liver. (A) A representation of a saggital section through the unfolded embryo at the beginning of the fourth week. The cardiogenic mesoderm lies cephalad to the oropharyngeal membrane with the septum transversum lying further cephalad again. (B) The box in A is expanded to show the detail. Note that the pericardial cavity at this stage is dorsal to the heart tube. Note also the close proximity of the endoderm of the foregut. (C) With the marked expansion of the neural plate the heart moves ventrally and caudad. (D) With further growth of the neural tissue the amniotic cavity extends further ventrally and caudally, and the developing heart now comes to lie caudad to the oropharyngeal membrane with the pericardial cavity ventrally. With lateral folding of the embryo the foregut develops, and the stalk of the yolk sac is constricted. The septum transversum in which the liver will develop now lies ventral and caudad to the heart. (E) Further folding brings the heart to its final position.

(A)

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3: Development of the Heart Figure 3.4 (cont.)

characterised by trabeculation and absence of cardiac jelly [9] (Figure 3.7). By this differential growth the cardiac jelly becomes confined to the atrioventricular junctions and outflow tracts (Figure 3.8). The endocardial cells of the atrioventricular canal and outflow tracts give rise to cells that populate the

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underlying cardiac jelly to form cardiac cushions that contribute to the septation of these regions. At the same time, the atria and ventricles develop myocardial trabeculations. The myocardium that forms the chambers shows specific gene expression (Anf, Cx40, Cx43) but does not show Tbx 2 and Tbx3

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3: Development of the Heart Figure 3.4 (cont.)

expression, which are repressors of the process and persist in the primitive myocardium of the primary heart tube [32]. Interestingly, the early markers of chamber formation Anf and Cx40 remain restricted to the original trabeculated myocardium, whereas the compact ventricular layer does not express these markers [33]. The initially formed atrial chamber myocardium only gives rise to the trabeculated, atrial appendages in the formed heart. All smooth-walled myocardium found in the fully grown heart is added later during development. How the left and right ventricles obtain their different morphology is not understood, albeit some differences between the left and the right ventricle in terms of gene expression are known. For instance, the cardiac transcription factor Tbx5 is expressed in a gradient tapering off towards the right ventricle [9]. Ventricular myocardial compaction is, thus, not a process by which trabeculated myocardium becomes compact, but primarily a process by which the myocardium at the epicardial side of the ventricular wall proliferates to form the compact layer. When the compact outer layer starts to form, proliferation in the ventricular trabeculations ceases [9]. There is a gradient of strain across the ventricular wall, greatest on the inner surface and least on the outer surface. There is a corresponding increase in myocyte proliferation in the outer compact layer of the myocardium than in the inner trabecular component [34]. The curvature of the heart depends on cell shape changes at the cellular level caused by a complex interplay of haemodynamic shear stress, contractive wall strain and electrical activity. NOTCH, ERBB and Ephrin play a role in trabeculation, whereas NOTCH, BMP and FGF play a role in compact myocardium development [35].

Initially, because the atrial segment is connected to the left ventricular segment, there is no direct connection with the right ventricle, but blood can flow from the atria to the right ventricle via the interventricular foramen (Figure 3.9). The atrial–right ventricular connection is established by growth of the ventricular inlet to the right. Likewise, the outlet is connected initially solely to the right ventricle, but by a similar differential growth, the outlet comes to overlie both ventricles. The ventricular septum grows from the apex of the heart loop between the left and right ventricular segments.

3.6.1 Atrial Septation The T-box transcription factor Tbx18 is required for the differentiation of the sinus horn myocardium from mesenchymal precursors, and its absence causes delayed formation and malformation of the sinus horns [36]. The atria incorporate the draining veins and form a pair of valves around the sinus venosus. Fusion of the anterior part of these valves creates the septum spurium, which contributes to closure of the atria. The primary atrial septum develops to the right of this and grows downwards towards the fused atrioventricular cushions, the gap between its free edge and the atrioventricular cushions being termed the ostium primum (Figure 3.10). The mesenchymal cap on the edge of the primary septum is continuous ventrally with the ventral atrioventricular cushion and dorsally with the dorsal mesenchymal protrusion and the dorsal atrioventricular cushion. The septum is thin and fibrous. An opening then forms in the primary septum – the ostium secundum – by fenestration before obliteration of the ostium primum by

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3: Development of the Heart

(A)

Figure 3.6 Ballooning of atria and ventricles. A schematic model of the heart at approximately 38 days. The outflow tract is to the left and the sinus venosus at the posterior aspect of the right atrium. The blue area outlines the original heart tube from the sinus venosus through the atrioventricular canal to the outflow. The atria balloon out from the tube, one on either side, but the ventricles balloon out in sequence, the left ventricle on the right of the picture and the right ventricle on the left of the picture. The supraventricular foramen is visible above the crest of the muscular interventricular septum. It is obvious that the interventricular septum is formed of the apposed walls of the ballooning right and left ventricles and represents an “outgrowth” of the heart rather than an “ingrowth” into the ventricles.

fusion of the septum primum and the atrioventricular cushions. The septum secundum then develops on the right side of the septum primum, beginning at day 41 by infolding of the muscular wall of the atrium. It is thicker and more muscular than the septum primum. It grows downwards and its anterior part fuses with the endocardial cushions, but a defect remains: the oval fossa. The ostium primum is actually beneath the free edge of the septum primum and is Figure 3.5 Looping of the heart. (A) A schematic drawing of the looping heart tube at approximately 26 days. The anterior wall of the pericardium has been cut away. The anterior part of the neural tube is visible above its superior aspect. At the inferior part of the field the two sinus horns fuse with the atrium. The heart tube then loops anticlockwise to the right. At the midline it then loops clockwise to result in an “S”-shaped tube. It exits the pericardium superiorly to

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enter the aortic sac. The two coils at the edge of the diagram illustrate the direction of looping. (B) A simplified model of the looping heart viewed from anteriorly and slightly to the left. The sinus horns are inferior and posterior and the aortic sac and dorsal aorta superior and anterior. The deep scores in the tube superiorly and inferiorly represent the approximate sites of the pericardial attachment.

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3: Development of the Heart

Figure 3.7 Ventricular trabeculation. A section from the ventricular apex of a mouse embryo at the same age as that above. The trabeculae contain myocytes and are covered with endocardial cells. At the pericardial surface there is a continuous layer of mesothelial cells and the underlying myocardium is compacted. Mitotic figures are visible in the compacted layer of myocardium. The compacted layer forms by addition of cells to the outer aspect of the myocardium rather than fusion (compaction) of the trabeculae.

obliterated when that edge fuses with the endocardial cushions at day 37. The sinus venosus is incorporated into the right atrium, the coronary sinus representing the left horn. The right valve of the sinus venosus disappears in its upper part, but the lower part becomes the valve of the inferior caval vein (eustachian valve) and the valve of the coronary sinus (thebesian valve). Occasionally remnants of the upper part of the valve it persist as thin thread attached to the right side of the septum and very occasionally a Chiari network (Figure 3.11). The left valve of the sinus venosus is incorporated into the the developing septum secundum. The pulmonary vein enters the left part of the atrium and is incorporated into it. The exact site of development of the pulmonary vein is still controversial [37]. The atrial appendages represent the original parts of the primitive atrium. The smooth-walled part of the right atrium develops from incorporation of the sinus venosus and is termed the sinus venarum. The smooth wall of the body of the left atrium results from incorporation of the pulmonary veins into the atrium.

3.6.2 The Interventricular Septum The greater part of the interventricular septum is caused by ballooning of the ventricular chambers, and the septum grows by a process of apposition beginning at day 26 (Figure 3.6). The crest of the interventricular septum expresses TBX3. The crest of the septum connects with the dorsal atrioventricular cushion. Overexpression of the microRNA, miR-1, plays a fundamental role in ventricular cardiomyocyte proliferation and prevents expansion of the ventricular myocardium [38]. Hand2 (a transcription factor that promotes ventricular cardiomyocyte expansion) is a target for miR-1.

Figure 3.8 Endocardial cushions. A section through the thorax of a mouse embryo at age 13.5 days, equivalent to a human embryo at 44 days. One of the atrioventricular valves and the aortic valve are seen and contain myxoid cellular tissue derived from the cardiac jelly. Elsewhere in the myocardium, the cardiac jelly is lost.

3.6.3 The Atrioventricular Junction During cardiac looping, TBX3 [39] and Notch1 [40] act to localise myocardial–endocardial signals to the atrioventricular and outflow tract regions. During looping the cardiac jelly is eliminated from much of the heart tube but persists at the site of the endocardial cushions at the atrioventricular junction [41] as well as in the outflow tract. A subset of endocardial cells lining the atrioventricular junction and the outflow tract transform into a mesenchymal phenotype and invade the cardiac jelly, a process termed endocardial to mesenchymal transformation [42]. This invasive, proliferating mesenchyme progressively remodels the matrix, and the resultant cellular masses, now called cushions, continue to grow and extend into the lumen. In the atrioventricular canal these form superiorly and inferiorly and fuse in the mid-line to create right and left atrioventricular orifices, differential growth of the right atrioventricular canal having brought the right atrium into contact with the right ventricle. Fusion of the cushions with the developing interventricular muscular septum and the atrial primary septum completes septation of the atrial and ventricular chambers. Lateral cushions develop in addition. The

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3: Development of the Heart

Figure 3.9 Chamber connections. (A) Schematic model of the heart as in Figure 3.6 but with the inclusion of the atrioventricular and outflow tract cushions (yellow). The mesenchymal cap of the free edge of the septum primum and the dorsal mesenchymal protrusion are also yellow. The two pale bands show the flow of blood from the atria during diastole. On the left side of the heart (right side of the picture), the flow is across the left aspect of the atrioventricular canal from left atrium to left ventricle. On the right side of the heart, flow is from the right atrium through the supraventricular foramen into the right ventricle. (B) During systole the flow is from right ventricle to outflow tract. From the left ventricle the flow is through the supraventricular foramen to the outflow tract.

cushions are originally acellular but endocardial to mesenchymal transformation, mediated by BMP through TGFβ and Notch produced by the myocardium of the atrioventricular junction, produces cells that populate the cushions [43]. This process begins at day 26. The lateral cushions also attract cells from the epicardium. The dorsal mesenchymal protrusion, also called the vestibular spine, is contiguous with the dorsal atrioventricular cushion and the mesenchymal cap of the primary atrial septum in the atria and is derived from extracardiac cells in the second heart field [44]. Maldevelopment causes atrioventricular septal defect (AVSD) and absence is seen in fetuses with Down syndrome [45]. Even before septation, laminar blood flow ensures separation of the right and left streams of blood. The primary foramen is that part of the primitive heart tube from which the ventricles balloon. It is sometimes referred to as the interventricular foramen but is not actually between the two ventricles, but rather above them

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at the inner curvature of the heart (Figure 3.6). Blood streams through this foramen from the right atrium to the right ventricle during diastole and from the left ventricle to the aorta in systole. Thus, this foramen becomes septated by the membranous septum at day 44. The atrioventricular canal develops ventral and dorsal cushions that separate the canal into right and left parts. The outflow tract is separated by two ridges called the septal and parietal outflow tract ridges. In the adult heart the membranous part of the ventricular septum is the remnant of the fused atrioventricular and outflow tract cushions. The atrioventricular valves develop from the two endocardial cushions. The septal leaflet of the tricuspid valve and the aortic leaflet of the mitral valve arise from fusion of the dorsal and ventral atrioventricular cushions on the right and left side, respectively [46]. The septal leaflet detaches from the myocardium by apoptosis. The mural leaflets of the two AV valves are

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3: Development of the Heart

Figure 3.10 Atrial septation. (A) Schematic model of the heart showing right and left atria and left ventricle with posterior atrioventricular cushion. The septum primum grows between the right and left atria. Its lower border grows towards the atrioventricular cushion, the gap between them forming the ostium primum. Its lower border is covered by a mesenchymal cap, not shown here. The lower border of the septum primum fuses with the atrioventricular cushion, thus obliterating the ostium primum. (B) By the time they fuse, however, fenestrations have appeared in the septum primum to permit right-to-left passage of blood in the atrium. These fenestrations coalesce as the ostium secundum. A second septum, the septum secundum grows to the right of the septum primum. (C) The septum secundum covers the ostium secundum, the septum primum forming the flap valve of the oval fossa. The left valve of the sinus venosus fuses with the septum secundum. The upper part of the right valve regresses, but the lower part forms the eustachian and thebesian valves.

formed from the lateral AV cushions. The ventricular space grows behind these mural leaflets. The semilunar valves form from the parietal and septal outflow tract cushions and two intercalated ridges (Figure 3.12). The parietal outflow tract cushion gives rise to the right aortic and pulmonary valve leaflets. The septal outflow tract cushion gives rise to the left aortic and pulmonary leaflets, and the right and left intercalated ridges give rise to the posterior aortic and anterior pulmonary leaflets. The cushion at the distal margin undergoes apoptosis to achieve a cusp. The atrioventricular and semilunar valves then mature by remodelling of their matrix.

3.6.4 Outflow Tract The outflow tract connects the developing ventricles and the aortic sac that is connected to the symmetrical pharyngeal arch

arteries. Septation starts at day 32 and occurs distally to proximally, and the cushions are disposed in a spiral fashion (Figure 3.13). The outflow tract myocardium becomes incorporated into the developing right ventricle. The outflow is connected via the aortic sac to arch arteries 3, 4 and 6. A protrusion of pharyngeal mesoderm – the aortopulmonary septum – grows into the aortic sac and connects distally to the spiralling outflow tract ridges. This separates the sixth and fourth pharyngeal arch artery. The outflow tracts have a complex origin, partly from the primary heart tube and partly from ingrowth of cells from two distinct sources: the cardiac neural crest and the secondary heart field. The complex interaction of all these tissues gives rise to the ventricular outflow tracts, the arterial valves and the intrapericardial parts of the aorta and pulmonary trunk [47]. Haemodynamic forces are thought to play a critical role in the remodelling of the aortic arches [48].

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3: Development of the Heart

Figure 3.11 Remnants of the right valve of sinus venosus. The right atrium opened to demonstrate the interatrial septum. The septal leaflet of the tricuspid valve is visible at the lower centre of the picture. On the left of the picture the orifice of the coronary sinus is visible, and it is partly guarded by a thebesian valve. The eustachian valve lies superior to it and from the eustachian valve fine fibrous threads extend towards the interatrial septum (Chiari network). The thebesian valve, eustachian valve and Chiari network are all remnants of the right valve of the sinus venosus. The left valve fuses with the oval fossa and usually is not discernible.

Figure 3.10 (cont.)

3.7 Pericardium

3.9 Conduction Tissue

The pericardium develops as a sac around the developing heart tube. Initially, the tube is connected to the posterior mediastinum by the dorsal mesocardium, but this breaks down, permitting the folding of the heart tube on which subsequent development is so critically dependent. The epicardium is derived from a transient structure called the proepicardial organ (PEO), a cluster of mesothelial progenitor cells located at the venous pole of the heart tube and derived from Nkx2.5expressing and Islet1-expressing secondary heart field precursors [49]. The cells of the PEO migrate onto the surface of the looping heart to envelop the myocardium (Figure 3.14). Some of these cells then undergo epicardial-to-mesenchymal transition and invade the underlying myocardium, where they differentiate into multiple cell types. Others remain on the surface of the heart and form the epicardium.

The conduction tissue develops from the myocardium of the primitive heart tube, being found in the transitional zones. Biomechanics play a critical role in induction and patterning of the cardiac conduction system [5]. The formation of an insulating fibrous and fatty tissue plane between atrial and ventricular myocardium occurs only after completion of septation, beginning at 7 weeks and largely complete by 12 weeks of development [52].

3.8 Coronary Arteries The coronary arteries and veins develop by both vasculogenesis (the formation of vessels in situ) and angiogenesis (the

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formation of new vessels by sprouting from existing vessels) from cells that grow over the myocardium from the proepicardium (Figure 3.15). Both the endothelium and the medial smooth muscle of the coronary arteries derive from this source. These vessels link up and grow to join with the aorta (Figure 3.12) [50]. Proepicardial progenitor cells expressing Sema3D-, Scx have the potential to differentiate into coronary endothelial cells. Other intracardiac cells that arise from the PEO include fibroblasts, coronary smooth muscle cells and possibly cardiomyocytes.

3.10 Arterial System The establishment of arterial and venous systems involves multiple molecular factors including morphogens (Hh), signalling molecules (Notch) and growth factors (VEGF) [53]. BMP signalling plays a pivotal role in vascular recruitment, patterning and remodelling. Notch signalling recruits vascular precursor cells to the dorsal aortae. Importantly, BMP ligands are broadly expressed throughout embryos, but the BMP signalling activation region is spatially defined by precisely regulated expression of BMP antagonists [54].

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3: Development of the Heart

Figure 3.12 Semilunar valves. A section through the aortic valve and aorta in a mouse embryo. Two cushions are evident in the lower aorta that are closely apposed. They are covered by endothelium and there is the beginnings of excavation between them and the aortic wall to form the valvar sinuses. Myocardium extends into the aorta almost to the distal extent of the valvar cushions. The orifice of the left coronary artery is visible, with the vessel lumen running through the aortic wall.

During folding of the embryo caused by massive expansion of the neural tube in the fourth week, the endocardial tubes are carried into the ventral thorax and the paired dorsal aortae attached to the cranial ends of the tubes are pulled ventrally to form a pair of dorso-ventral loops: the first aortic arches [55]. During the fourth and fifth weeks, four additional pairs of aortic arches develop in cranio–caudal succession connecting the aortic sac at the superior end of the cardiac outflow to the dorsal aortae (Figure 3.16). The paired dorsal aortae fuse below the level of the fourth thoracic segment. The dorsal aorta develops three sets of branches: 1. A series of ventral branches that supply the gut derivatives derived from a network of vitelline arteries 2. Lateral branches that supply retroperitoneal structures such as adrenals, kidneys and gonads 3. Dorsolateral intersegmental branches that penetrate between the somite derivatives The paired dorsal aortae become connected with the umbilical arteries.

Figure 3.13 Outflow tract. Sections through the embryonic human heart from a ruptured ectopic pregnancy at approximately 37 days of age to show the developing septation of the outflow tracts. (A) Approximate coronal section – the left ventricle is to the right and the interventricular foramen links the two ventricles. The arterial trunk is cut across and shows two major cushions (superior and inferior). Small cushions are visible in the lateral aspects. The cushions have not yet fused in the midline at this level. (B) A section from the same heart from a plane anterior to that in A. The outflow tract is seen to overlie the right ventricle; the outflow tract cushions are cut longitudinally and more superiorly are almost fused (From Suvarna SK (ed.) Cardiac Pathology: A Guide to Current Practice. London: Springer; 2013, with permission).

The first pair of aortic arches lies in the thickened mesenchyme of the first pair of pharyngeal arches on either side of the developing pharynx. Ventrally the aortic arch arteries arise for the aortic sac and extrapericardial expansion of the cranial end of the truncus arteriosus. Between days 26 and 29 aortic arches 2, 3, 4 and 6 develop by vasculogenesis and angiogenesis within the respective pharyngeal arches. Neuralcrest-derived ectomesenchymal cells are involved in normal development of the pharyngeal arches but do not themselves form blood vessels. The first two arches regress as the later arches form. On day 28 when the first arch is regressing, arches 3 and 4 appear. On day 29 the sixth arch appears, and the second arch disappears Arches 3, 4 and 6 give rise to the vessels of the head, neck and thorax (Table 3.2).

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3: Development of the Heart

Figure 3.15 Origin of the coronary arteries. A schematic drawing of the junction of the sinus venosus and right atrium. The sinus endothelium is shown in red, the atrial endocardium in green and the mesothelium of the pericardium in mauve. Some of the epicardial coronary arteries have originated from the endothelium of the sinus venosus, some from the endocardium of the atrium and a few from the pericardial cells.

Figure 3.14 Pericardium. A diagram showing the proepicardial organ in the septum transversum that populates the surface of the heart. It is thought that the fronds of the organ form physical bridges to the epicardial surface of the heart across which the cells migrate and spread over the epicardial surface.

The third arch becomes the common carotid and internal carotid artery. By day 35 the segments of dorsal aorta connecting arch 3 and 4 disappear leaving the third aortic arch to supply blood to the head. The fourth and sixth arches undergo asymmetrical remodelling to supply the upper extremities, dorsal aorta and lungs. The region of the aortic sac connected to the right fourth arch is modified to form the brachiocephalic artery. The left fourth arch becomes the aortic arch and most cranial part of the descending aorta. The right and left subclavian arteries derive from the seventh intersegmental arteries. The left sixth arch is the distal arterial duct.

3.11 Venous System There are three pairs of veins in embryos in the fifth week of development (Figure 3.17) [55].

3.11.1 Vitelline Veins Also known as omphalomesenteric veins, these paired veins carry blood from the yolk sac to the sinus venosus. Before joining the sinus medially, they break into a plexus around the duodenum and pass through the septum transversum. Hepatocytes growing into the septum induce the hepatic sinusoids. The

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proximal right vitelline vein persists as the hepatic part of the IVC, its distal part becomes the superior mesenteric vein and the anastomotic network around the duodenum becomes the portal vein. The proximal part of the left vitelline vein disappears.

3.11.2 Umbilical Veins Paired veins join the sinus lateral to the vitelline veins and medial to the cardinal veins. With growth of the liver, they form anastomoses with the hepatic sinusoids. The proximal parts of both right and left veins disappear, and the distal left umbilical vein persists and drains to the hepatic sinusoids. A direct anastomosis develops between the left umbilical vein and the proximal right vitelline vein – the venous duct (ductus venosus).

3.11.3 Cardinal Veins The paired common cardinal veins join the sinus most laterally and are formed by the confluence of anterior cardinal veins (draining the head) and posterior cardinal veins. From the fifth to the seventh week further veins form; the subcardinal veins draining mostly the kidneys, the supracardinal veins draining the body wall by the intercostal veins (following regression of the posterior cardinal veins), and the sacrocardinal veins draining the lower limbs.. Anastomoses develop between the right and left sides. The brachiocephalic vein is formed of the anastomosis between the two anterior cardinal veins. The SVC is formed from the proximal right anterior cardinal vein and the right common cardinal vein. The anastomosis between the two subcardinal veins becomes the left renal vein and the left subcardinal vein then regresses with its distal part becoming the left gonadal vein. The right subcardinal vein becomes the renal segment of the IVC, and it connects proximally with the

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3: Development of the Heart

Figure 3.16 Arterial system. (A) A model of the development of the paired aortic arches viewed from the front. The aortic sac is connected to the looped heart tube. Arising from the aortic sac from inferior to superior are the paired sixth, fourth and third arch arteries. The first and second arch arteries have involuted by the time the latter arches develop, and no fifth arch arteries ever develop. The arch arteries are connected to paired dorsal aortae that fuse distally posteriorly. Three pairs of systemic veins are shown in blue: from medial to lateral on each side they are the vitelline, umbilical and cardinal veins. (B) The model has been trimmed to show the final arterial configuration. The dorsal aortae disappear except for the left aorta caudad to the fourth arch and the vessels cephalad to the attachment of the third arches. The third arches become the proximal common carotid arteries and the dorsal aortae their more distal aspect. The fourth arches become the proximal parts of the subclavian artery and on the left side the aortic arch. The sixth arches become the pulmonary arteries and on the left side the arterial duct. Internal division of the aortic sac separates the pulmonary trunk for the aorta. The remaining vessels involute. There has also been considerable pruning of the venous system.

hepatic IVC derived from the right vitelline vein. The anastomosis between the sacrocardinal veins becomes the left common iliac vein. The right sacrocardinal vein becomes the sacrocardinal segment of the IVC. The azygos vein derives from the right supracardinal vein and part of the posterior cardinal vein. On the left side the supracardinal vein subtending the fourth to the seventh intercostal veins becomes the hemiazygos vein that drains to the azygos vein. Initially the veins draining to the heart are embedded in the mesenchyme at the venous pole of the heart. By expansion of the pericardial cavity the connecting veins become “excavated” from this mesenchyme. In this way the common cardinal veins, which are the confluence of the left and right superior and inferior cardinal veins, become incorporated within the

pericardial cavity. They acquire a sleeve of myocardium, and this confluence of the systemic veins is then called sinus venosus, or left and right sinus horns. Eventually both sinus horns connect to the right atrium [9]. Unlike the systemic venous connections, the pulmonary vein develops and connects to the heart after the formation of the initial heart tube and start of chamber formation. Mesenchyme dorsal to the heart differentiates into a vascular plexus surrounding the embryonic foregut. At day 28 the cranial component of this plexus connects as a solitary pulmonary vein to the heart through the dorsal mesocardium in the midline and cranial to the AV node. Although the pulmonary venous connection is a midline structure, the pulmonary vein will eventually connect to the left atrium, because the primary atrial septum

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3: Development of the Heart Table 3.2 Arterial derivatives of the embryonic aortic arches

Embryonic arch

Arterial derivative

Notes

1

Maxillary artery

2

Hyoid artery Stapedial artery

3

Common carotid artery First part internal carotid artery

Dorsal aorta gives rise to remainder of internal carotid

4

Proximal right subclavian artery Aortic arch between left common carotid and left subclavian arteries

Left subclavian artery derives from the seventh intersegmental artery

6

Branch pulmonary arteries and arterial duct

develops at the right side, causing the midline structures, including the pulmonary vein, to become incorporated into the morphologically left atrium. It is subsequent to its connection to the forming left atrium that the pulmonary vein and its bifurcations develop a sleeve of myocardium. The transcription factor PITX2c plays a crucial role in the differentiation of the pulmonary vein myocardium. Interestingly, it does so at the left and the right side. Therefore, this transcription factor seems not to function as a mere laterality marker [56]. During development, the muscularised pulmonary veins incorporate into the left atrium, up to their second bifurcation, resulting in four pulmonary orifices in the left human atrium. The pulmonary myocardial sleeves do not extend to a great extent upstream of the pulmonary orifices.

3.12 The Fetal Circulation and Changes at Birth 3.12.1 The Venous Duct and Oval Foramen In the fetus blood is oxygenated by the placenta and returned to the fetus through the umbilical vein, which joins the portal vein at the hepatic hilum (Figure 3.18). It supplies preferentially the left lobe of the liver and bypasses much of the liver by the venous duct (ductus venosus) to enter the inferior caval vein (Figure 3.19) [57]. The proportion of umbilical venous blood that passes through the venous duct varies markedly from 20% to 90%. Blood flow velocity in the venous duct is 65–75 cm/s, whereas abdominal caval vein flow velocity is approximately 16 cm/s. There is, thus, streaming of inferior caval blood flow as it enters the right atrium, the anterior stream being slower and with poor oxygen saturation derived from the abdominal inferior caval vein and right hepatic vein. The posterior stream originating in the venous duct is faster and has a much higher oxygen saturation. Blood from the venous duct is preferentially directed to the oval foramen by

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Figure 3.17 Venous system. Schematic representation of an embryo at the end of the fourth week. The arterial and venous systems are shown. The arteries and veins show bilateral symmetry, but for ease of viewing only one side is shown. The anterior cardinal vein drains the head and the posterior cardinal vein the body. They fuse to form the common cardinal vein before entering the sinus venosus lateral to the umbilical vein, which is in turn lateral to the vitelline vein. As the vitelline veins traverse the septum transversum they break into a plexus of vessels that will form the hepatic sinusoids.

the eustachian valve and by nature of its higher velocity, while the greater part of the more anteriorly placed blood stream derived from the inferior caval vein crosses the tricuspid valve. The deoxygenated superior caval blood is directed preferentially to the tricuspid valve and right ventricle, only about 5% crossing the oval foramen (Figure 3.18) [58].

3.12.2 Arterial Duct, Lungs and Systemic Circulation The right ventricle pumps blood into the pulmonary trunk. Because of the high pulmonary resistance, less than one-third

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3: Development of the Heart

Figure 3.18 Fetal circulation. Most of the oxygenated blood from the umbilical vein enters the ductus venosus and passes as a fast jet in the posterior aspect of the inferior caval vein to the right atrium where it is shunted by the eustachian valve to the oval foramen and left atrium, from where it is ejected from the left ventricle into the ascending aorta to supply the head and neck vessels. A small percentage crosses the aortic isthmus to the descending aorta. A fraction of the blood from the umbilical artery enters the portal venous system and from there enters the inferior caval vein via the hepatic veins, joining the superior caval venous return to cross the tricuspid valve to the right atrium. From there it is ejected via the pulmonary trunk and arterial duct to the descending aorta and through the umbilical arteries to the placenta for the cycle to begin all over again.

of the right ventricular output goes to the lungs and over two-thirds passes via the arterial duct to the descending aorta (75 ml/kg per min and 175 ml/kg per min, respectively, in the late-gestation fetus). The left atrium receives its blood from across the oval fossa and from the pulmonary veins. This blood flows across the mitral valve and is ejected by the left ventricle into the ascending aorta where it supplies preferentially the head and upper limbs. Only about one-quarter of the left ventricular output crosses the aortic isthmus to join the blood flowing through the arterial duct into the descending aorta. The ratio of right-to-left ventricular output is in the order of 1.2–1.3:1, equivalent to 200:250 ml/kg per min in the lategestation fetus.

Figure 3.19 Venous duct. A dissection of the liver in a fetus of 18 weeks’ gestation to demonstrate the venous duct. The umbilical vein is at the bottom left of the field and enters the confluence of the right and left portal veins within the substance of the liver. Running from the upper border of the left portal vein, the venous duct ascends through the hepatic parenchyma to enter the anterior aspect of the inferior caval vein.

Unlike the situation in the adult circulation, there is mixing of oxygenated and deoxygenated blood at several points in the fetal circulation: • in the liver • in the inferior caval vein • in the left atrium Streaming of blood partly prevents mixing by preferentially directing oxygenated blood through the oval fossa to the left heart and from there to the head, and by directing inferior and superior caval blood to the right ventricle and via the arterial duct to the descending aorta and from there via the umbilical arteries to the placenta [58]. In the fetus the arterial blood oxygen tension is 20–30 mmHg. Thus, fetal development occurs in an environment that is bordering on hypoxic when compared with the adult, and it takes very little for the fetus to become hypoxic [59].

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3.12.3 Post-Natal Adaptation At birth, the function of oxygenation of the blood, previously subserved by the placenta, is assumed by the fetal lungs. The first gasps of the newborn infant expand the lungs with air, with a reduction in pulmonary vascular resistance, a reduction that continues in the immediate post-partum weeks by remodelling of the pulmonary vascular bed. This drop in pulmonary vascular resistance has several effects. It causes redistribution in blood flow from the right ventricle. The blood ejected from the right ventricle now, instead of passing preferentially through the arterial duct, passes to the lungs. This increases pulmonary venous return to the left atrium with a subsequent rise in left atrial pressure. This rise in pressure pushes the flap valve of the oval fossa tight against the septum and seals the interatrial communication. The rise in arterial oxygen

Fetal Neonatal Med 2013; 18: 237–244.

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23. Harvey RP. Patterning of the vertebrate heart. Nat Rev Genet 2002; 3: 544–556. 24. Brown N, Anderson RH. Symmetry and laterality in the human heart: developmental implications. In Harvey RP, Rosenthal N (eds) Heart Development. London: Academic Press; 1999: pp. 447–461. 25. Taber LA, Voronov DA, Ramasubramanian A. The role of mechanical forces in the torsional component of cardiac looping. Ann NY Acad Sci 2010; 1188: 103–110. 26. Männer J. On the form problem of embryonic heart loops, its geometrical solutions, and a new biophysical concept of cardiac looping. Ann Anat 2013; 195: 312–323. 27. Bayraktar M, Männer J. Cardiac looping may be driven by compressive loads resulting from unequal growth of the heart and pericardial cavity. Observations on a physical simulation model. Front Physiol 2014; 5: 112. 28. Manasek FJ, Burnside MB, Waterman RE. Myocardial cell shape changes as a mechanism of embryonic heart looping. Dev Biol 1972; 29: 349–371. 29. Latacha KS, Remond MC, Ramasubramanian A et al. Role of actin polymerization in bending of the early heart tube. Dev Dyn 2005; 233: 1272–1286. 30. Manner J, Wessel A, Yelbuz TM. How does the tubular embryonic heart work? Looking for the physical mechanism generating unidirectional blood flow in the valveless embryonic heart tube. Dev Dyn 2010; 239: 1035–1046. 31. Butcher JT, McQuinn TC, Sedmera D, Turner D, Markwald RR. Transitions in early embryonic atrioventricular valvular function correspond with changes in cushion biomechanics that are predictable by tissue composition. Circ Res 2007; 100: 1503–1511. 32. Moorman AFM, Christoffels VM. Cardiac chamber formation: development, genes and evolution. Physiol Rev 2003; 83: 1223–1267. 33. Sizarov A, Ya J, de Boer BA et al. Formation of the building plan of the human heart: morphogenesis, growth, and differentiation. Circulation 2011; 123: 1125–1135.

34. Sedmera D, Thompson RP. Myocyte proliferation in the developing heart. Dev Dyn 2011; 240: 1322–1334. 35. Samsa LA, Yang B, Liu J. Embryonic cardiac chamber maturation: trabeculation, conduction, and cardiomyocyte proliferation. Am J Med Genet C Semin Med Genet 2013; 163C: 157–168. 36. Mommersteeg MT, Domínguez JN, Wiese C et al. The sinus venosus progenitors separate and diversify from the first and second heart fields early in development. Cardiovasc Res 2010; 87: 92–101. 37. Moorman A, Webb S, Brown NA, Lamers W, Anderson RH. Development of the heart: (1) formation of the cardiac chambers and arterial trunks. Heart 2003; 89: 806–814. 38. Zhao Y, Samal E, Srivastava D. Serum response factor regulates a musclespecific microRNA that targets Hand2 during cardiogenesis. Nature 2005; 436: 214–220. 39. Moorman AF, Soufan AT, Hagoort J, de Boer PA, Christoffels VM. Development of the building plan of the heart. Ann NY Acad Sci 2004; 1015: 171–181. 40. MacGrogan D, Luna-Zurita L, de la Pompa JL. Notch signaling in cardiac valve development and disease. Birth Defects Res A Clin Mol Teratol 2011; 91: 449–459. 41. Person AD, Klewer SE, Runyan RB. Cell biology of cardiac cushion development. Int Rev Cytol 2005; 243: 287–335. 42. Combs MD, Yutzey KE. Heart valve development: regulatory networks in development and disease. Circ Res 2009; 105: 408–421. 43. Luna-Zurita L, Prados B, Grego-Bessa J et al. Integration of a Notch-dependent mesenchymal gene program and Bmp2driven cell invasiveness regulates murine cardiac valve formation. J Clin Invest 2010; 120: 3493–3507. 44. Briggs LE, Kakarla J, Wessels A. The pathogenesis of atrial and atrioventricular septal defects with special emphasis on the role of the dorsal mesenchymal protrusion. Differentiation 2012; 84: 117–130.

45. Bloom NA, Ottenkamp J, Wenning AG, Gittenberger de Groot AC. Deficiency of the vestibular spine in atrioventricular septal defects in human fetuses with Down syndrome. Am J Cardiol 2003; 91: 180–184. 46. Hinton RB, Yutzey KE. Heart valve structure and function in development and disease. Annu Rev Physiol 2011; 73: 29–46. 47. Anderson RH, Mori S, Spicer DE, Brown NA, Mohun TJ. Development and morphology of the ventricular outflow tracts. World J Pediatr Congenit Heart Surg 2016; 7: 561–577. 48. Yashiro K, Shiratori H, Hamada H. Haemodynamics determined by a genetic programme govern asymmetric development of the aortic arch. Nature 2007; 450: 285–288. 49. van Wijk B, van den Berg G, Abu-Issa R et al. Epicardium and myocardium separate from a common precursor pool by crosstalk between bone morphogenetic protein- and fibroblast growth factor-signaling pathways. Circ Res 2009; 105: 431–434. 50. Pérez-Pomares JM, de la Pompa JL, Franco D et al. Congenital coronary artery anomalies: a bridge from embryology to anatomy and pathophysiology – a position statement of the development, anatomy, and pathology ESC Working Group. Cardiovasc Res 2016; 109: 204–216. 51. Katz TC, Singh MK, Degenhardt K, et al. Distinct compartments of the proepicardial organ give rise to coronary vascular endothelial cells. Dev Cell 2012; 22: 639–650. 52. Wessels A, Markman MWM, Vermeulen JLM et al. The development of the atrioventricular junction in the human heart. Circ Res 1996; 78: 10–117. 53. Swift MR, Weinstein BM. Arterialvenous specification during development. Circ Res 2009; 104: 576–588. 54. Garriock RJ, Mikawa T. Early arterial differentiation and patterning in the avian embryo model. Semin Cell Dev Biol 2011; 22: 985–992. 55. Larsen WJ. Human Embryology. Edinburgh: Churchill Livingstone; 1993, pp. 167–203.

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56. Mommersteeg MT, Christoffels VM, Anderson RH, Moorman AF. Atrial fibrillation: a developmental point of view. Heart Rhythm 2009; 6: 1818–1824. 57. Sinkovskaya E, Klassen A, Abuhamad A. A novel systematic approach to the evaluation of the fetal venous system.

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Semin Fetal Neonatal Med 2013; 18: 269–278. 58. Rudolph AM. The fetal circulation and postnatal adaptation. In Rudolph AM. Congenital Diseases of the heart: Clinical-Physiological Considerations. 2nd edn. Armonk: Futura Publishing Co; 2001, pp. 3–44.

59. Patterson AJ, Zhang L. Hypoxia and fetal heart development. Curr Mol Med 2010; 10: 653–666. 60. Kondo M, Itoh S, Kunikata T et al. Time of closure of ductus venosus in term and preterm neonates. Arch Dis Child Fetal Neonatal Ed. 2001; 85: F57–F59.

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Chapter

4

Congenital Heart Disease (I)

4.1 Introduction Although the term congenital heart disease is used synonymously with structural congenital heart disease, it should be borne in mind that other forms of heart disease lacking structural defects can also develop in utero and be present at birth: cardiomyopathy, rhythm disorders and myocardial infarction. These will be dealt with separately in subsequent chapters. Increasingly, structural heart disease is being identified in utero by ultrasonography and attempts have been made at in utero intervention. This subject is covered at more length in the chapter on heart disease in the fetus. But by no means is all congenital heart disease identified in utero. Presentation may be at any time in childhood, although the more severe forms present in the first days of life. Hypoplastic left heart, transposition and obstructed total anomalous pulmonary venous connection constitute medical emergencies in the neonate. Most forms of congenital heart disease are amenable to surgical correction or palliation. Operative mortality is low and children with simple defects can expect to live as long as their contemporaries [1]. However, children with more complex congenital heart disease are surviving in ever greater numbers into adulthood where they present a particular set of problems. The majority of cases of congenital heart disease involve anomalous positioning of the cardiac outflow tracts, impaired remodelling of the endocardial cushions into valve leaflets or abnormal remodelling of the aortic arches into great vessels. There are eight common lesions that together account for about 80% of all cases of structural congenital heart disease [2]. They

are listed in Table 4.1. The pathology of these defects will now be discussed in detail.

4.2 Ventricular Septal Defect (VSD) Closure of a VSD is the commonest surgical procedure for congenital heart disease in children in England, accounting for nearly one-quarter of all such operations [3].

Table 4.1 The eight commonest types of congenital heart disease

Ventricular septal defect Atrioventricular septal defect Atrial septal defect Patent arterial duct Coarctation of the aorta Pulmonary stenosis/atresia Aortic stenosis Transposition of the great arteries

Figure 4.1 Perimembranous VSD. A neonate with trisomy 21 who died shortly after birth. The left ventricle is viewed from the left and the mitral valve has been divided to display the left ventricular outflow tract. There is a large VSD beneath the aortic valve impinging on the membranous septum (which lies between the right and non-coronary cusps of the aortic valve). The right coronary cusp is the cusp viewed en face in this view. Chordal tissue of the tricuspid valve is visible through the defect.

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Figure 4.2 Muscular VSD. (A) Two-week-old male infant. In the centre of the interventricular septum (viewed from the left side) there is a large oval muscular VSD. (B) Viewed from the right side, the defect lies inferior to the septomarginal trabeculation at the junction of the inlet and apical parts of the septum.

As its name implies, a VSD is a defect in the interventricular septum, permitting direct flow of blood between the two ventricular cavities. Its clinical effect depends on its size and the presence of associated lesions. The defects are usually round or oval, and vary in size from a few millimetres to several centimetres [4]. There may be multiple defects. A VSD forms an integral part of many complex cardiac defects such as common arterial trunk, atrioventricular septal defect and tetralogy of Fallot. VSDs may also occur as an isolated lesion and such defects account for about half of the cases reported in surgical series. Two basic forms are described depending on their relation to the membranous interventricular septum: those involving the membranous septum, the so-called perimembranous VSD (Figure 4.1), and those in which muscle is interposed between the defect and the membranous septum, the so-called muscular VSD (Figure 4.2). Because the septal attachment of the tricuspid valve crosses the membranous septum and the mitral valve attachment on the left side is also related to the membranous septum, a perimembranous defect will, by definition, have fibrous continuity between the tricuspid and mitral valves through the defect (Figure 4.3). Muscular VSDs may occur in

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Figure 4.3 Fibrous continuity of mitral and tricuspid valves through a perimembranous VSD. Termination of pregnancy at 22 weeks’ gestation. At post-mortem: situs inversus (atrial, pulmonary, abdominal) with congenitally corrected transposition and VSD with pulmonary stenosis. There are associated bilateral superior caval veins and retro-oesophageal subclavian artery. The right atrium is connected to the left ventricle. There is a large, central, oval perimembranous VSD through which the mitral valve leaflets are seen to be in continuity with the tricuspid valve.

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Figure 4.4 The divisions of the interventricular septum. (A) A normal heart viewed from the right side following removal of the parietal walls of the right atrium and right ventricle. (B) Cartoon of the specimen showing divisions of the septum into inlet (orange), apical trabecular (green) and outlet (yellow) parts. The septomarginal trabeculation forms the boundary between inlet and outlet. The membranous septum is shown in Figure 4.4 B the membranous septum appears to be a yellow circle rather than red. SVC, superior caval vein; TSM, septomarginal trabeculation; TV, tricuspid valve; IVC, inferior caval vein; SVC, supraventricular crest.

any part of the interventricular septum and may be multiple. Because of associated ventricular hypertrophy, those occurring in the lower parts of the septum can be easily missed, even on close inspection of the heart, being hidden among the hypertrophied muscular trabeculations. Perimembranous and muscular VSDs can, and sometimes do, coexist in the same heart. The significance of the distinction of perimembranous and muscular VSDs lies in the intimate and superficial relation of the atrioventricular conduction tissue to the perimembranous VSD and its susceptibility to damage during surgical closure of the defect. It also has implications for its relation to the atrioventricular and arterial valves. VSDs may lie in the inlet, outlet or apical trabecular part of the ventricular septum when viewed from the right ventricle – the side most often approached by the surgeon at the time of surgical repair (Figure 4.4). It is important to recall that because the left ventricular outflow tract is wedged between the mitral and aortic valves, the inlet, outlet and apical components on the right side do not match exactly those on the left. Indeed, the right ventricular inlet is separated by the interventricular septum largely from the left ventricular outlet, and this can cause difficulty in ascribing a VSD to one of these components. VSDs may also be closely related to the arterial valves. Thus, the defects can be labelled inlet VSD, outlet VSD or subarterial VSD. A large perimembranous VSD extending into more than one component of the septum is termed a confluent VSD. Outlet perimembranous VSDs are usually associated with malalignment of the outlet septum [5]. Malalignment of the outlet septum occurs when the plane of the outlet septum, as seen in the cardiac short axis, is out of alignment with the rest of the muscular ventricular septum. Malalignment of the outlet septum can be present with

perimembranous, muscular or doubly committed and juxtaarterial defects [6]. A VSD occurring in the right ventricular outflow tract may permit fibrous continuity between the aortic and pulmonary valves. Such defects (which may be either muscular or perimembranous) are said to be doubly committed and juxtaarterial [7]. In the setting of a double outlet ventricle the outflow from the smaller ventricle will be dependent on the size of the VSD, and, if too small, the VSD is said to be restrictive. Small perimembranous VSDs are usually better appreciated by the pathologist from the left ventricular outflow tract; on the right side they may be obscured by the chordal and leaflet tissue of the tricuspid valve. Unless there is restricted outflow through the pulmonary valve, blood will tend to flow through the VSD from left to right ventricle because of the pressure gradient between the two, and the right ventricle will suffer volume overload. Ventricular septal defects, if small, may close spontaneously by fibrosis (Figure 4.5) [8], but tissue tags associated with VSDs may cause subvalvar obstruction. VSDs are also a site of predilection for infective endocarditis (Figure 4.6). The principles of closure of VSD are to achieve secure unobstructed separation of the systemic and pulmonary circulations avoiding damage to the conduction system and valves [9]. Small muscular VSDs are usually closed by pledgeted mattress sutures, but larger muscular VSD and perimembranous VSDs are patched with Gore-Tex, Dacron or pericardium. This is usually achieved via an atriotomy incision, but sometimes a ventriculotomy is required. Increasingly, they are being closed by endovascular devices (Figure 4.7) [10].

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Figure 4.5 Spontaneous closure of a VSD. (A) Four-year-old girl with trisomy 21 known to have had a perimembranous VSD that closed. The opened left ventricular outflow tract shows a mass of opaque fibrous tissue surrounding the membranous septum beneath the aortic valve at the site of the closed defect. Some endocardial fibrosis extends over the septum forming a mirror image of the anterior leaflet of the mitral valve. (B) A 13-year-old with known muscular VSD with spontaneous closure. A trabecular muscular VSD that has closed by fibrosis. A fibrous scar extends through the full thickness of the septum and is associated with fibrous tissue tags on the right ventricular aspect.

Examination of the heart with a patched VSD shows the patch usually attached to the right-handed side of the interventricular septum (Figure 4.8). Viewed from the left side this usually results in a recess at the site of the VSD (Figure 4.9). With time the patch and its accompanying pledgeted sutures becomes covered with a thick layer of fibroelastic tissue. It is unusual for the patch to calcify. Histologically a foreign body reaction is present at the margins of the patch with fibrosis in the surrounding myocardium (Figure 4.10). There may be small residual defects that the patch has not completely covered (Figure 4.11) or, rarely, there may be break down of part of the suture line (Figure 4.12). Very rarely, infective endocarditis develops.

4.3 Atrioventricular Septal Defect (AVSD) The basic abnormality in this defect is a common atrioventricular junction. This is in contrast to the separate right and left atrioventricular junctions present in the normal heart

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(Figure 4.13A) [11]. The common junction is guarded by a common valve (Figure 4.13B), but separate valvar orifices may be present. Because of the common junction, the aorta is displaced from its normal position (where it is wedged between the separate left and right atrioventricular junctions) to lie anterior to the common atrioventricular junction (Figure 4.14). The inferior aspect of the interatrial septum is not connected to the ventricular septum and is a free-standing structure, usually with a concave aspect; the upper border of the interventricular septum lies below the level of the atrioventricular junction and also has a concave aspect giving a so-called scooped-out appearance (Figure 4.15). The common valve has five leaflets: superior and inferior bridging leaflets that cross (bridge) the interventricular septum and that have papillary muscle attachments in both ventricles; on the left side there is a mural leaflet that is smaller than its normally occurring counterpart, and on the right, anterior and inferior leaflets (Figure 4.16). In practice, distinguishing the leaflets is not

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Figure 4.6 Infective endocarditis VSD. (A) Histological section through the interventricular septum in a child with a muscular VSD. The aortic outflow is to the left of the picture with the aortic valve at the top. There is endocardial fibrous thickening around the edges of the defect, and on the right ventricular aspect there are fibrinous vegetations. The blue haze seen extending into the lower right ventricular endocardium is caused by inflammatory cell infiltration. (B) A four-year-old girl who died of the effects of sepsis associated with bacterial endocarditis around a restrictive perimembranous VSD. There is dense endocardial thickening and puckering around the margins of the small VSD. Vegetations were not seen at post-mortem but they had previously been seen on echocardiography, and there had been a prolonged course of antibiotics.

always straightforward. The valvar tissue may be dysplastic and valvar regurgitation is common. The attachment of the superior bridging leaflet in the right ventricle is variable, ranging from attachment just to the right of the interventricular septum to attachment well within the right ventricle. This variability gives rise to the Rastelli classification of this defect [12]. Where the bridging leaflets float freely, being attached only at the atrioventricular junction and having no attachment to either interatrial or interventricular septum, or to each other, the defect is called a complete AVSD. In complete AVSD there is free communication of blood between both ventricles beneath the AV valve leaflets and between both atria above them (Figure 4.17). Where there is attachment of the bridging leaflet tissue to the crest of the interventricular septum or where a tongue of leaflet tissue joins the two leaflets over the interventricular septum, there is some restriction in the mixing of blood at the ventricular level and the defect is called a partial AVSD (Figure 4.18). Where the bridging leaflets are attached to the crest of the interventricular septum so as to obliterate the interventricular communication, the defect becomes, in effect, an interatrial communication and is the so-called ostium primum atrial septal

defect. That the ostium primum defect is, in reality, an atrioventricular septal defect is reflected in the features it shares with other forms of AVSD – the common AV junction (despite separate orifices), the unwedged aorta, the scooped-out interventricular septal crest and the vestige of the fused bridging leaflets in the misnamed “cleft” anterior leaflet of the mitral valve (Figure 4.19A). Cases also exist where the bridging leaflets are attached to the crest of the interatrial septum so as to obliterate the interatrial communication, and leave only an interventricular communication (Figure 4.19B). The defect is recognised as an AVSD by the same features as an ostium primum defect is recognised as an AVSD. In AVSD the relative sizes of both ventricles can vary, and there is often disproportion [13], and at the extreme end of this spectrum one can see a double inlet ventricle (Figure 4.20). AVSD can coexist with other forms of congenital heart disease, such as arterial valve obstruction or tetralogy of Fallot (Figure 4.21) [14]. AVSD is an almost universal finding in cases of right atrial isomerism and in about half of the cases of left atrial isomerism. AVSD is the characteristic cardiac defect occurring with trisomy 21. Because of the anterior displacement of the aorta in this defect, if the superior bridging

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Figure 4.8 Patched VSD right side. One-year-old girl with patched perimembranous VSD. The right ventricular outflow tract has been opened and the parietal wall retracted to expose the right side of the interventricular septum. A rounded patch with overlying endocardial fibrosis is visible between the tricuspid and pulmonary valves and abutting the membranous septum. The outlines of some of the sutures are still visible. The operation site is intact.

Figure 4.7 Endovascular closure of a VSD. A simulated long-axis cut of the heart to demonstrate two Amplatzer devices that have been used to close a large muscular VSD. They were placed at different times, and the device that has been longer in situ shows a covering of fibrous tissue.

leaflet is attached to the crest of the interventricular septum then the aortic outflow tract is lengthened and narrowed. While of itself not causing significant obstruction, it takes little additional obstruction, for example by valvar tissue tags, to cause clinical symptoms. Because the structures of the membranous septum are deficient or absent, the atrioventricular conduction tissue is abnormally sited. The AV node, instead of being located in the usual site of the triangle of Koch, is located more inferiorly in the so-called nodal triangle whose borders are the atrioventricular junction, the mouth of the coronary sinus and the postero-inferior leading edge of the atrial septum [15]. The bundle of His is unusually long, and travels on the crest of the interventricular septum before dividing. Presentation of AVSD is with cardiac failure. It presents in the first few weeks of life rather than the first days of life.

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Figure 4.9 Patched VSD left side. The left ventricular outflow tract is exposed in a heart with a patched perimembranous VSD. The defect is visible as an oval dark area beneath the aortic valve cusps. It is sealed by a patch applied to the right side of the septum leaving a shelf-like residual recess.

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Figure 4.10 Patched VSD histology. A histological section through a patched VSD. The patch material is pericardium. It shows dark pink staining because of its content of collagen, but because of pretreatment, it is completely acellular. At the right of the field it is slightly folded back on itself. Adjacent to this, some myocardium is visible. Multiple rounded holes are visible that represent sutures. This material does not cut well and must be removed before sectioning. At the left upper side of the picture there is a felt buttress, and it has elicited a foreign body inflammatory response. There is dense fibrous thickening of the endocardium over both sides of the patch, more so on the lower part of the picture.

Heart failure is exacerbated in the presence of coarctation, patent arterial duct, ventricular disproportion or valvar regurgitation. Cyanosis is usually not evident. The defect is treated by early operation with a one- or two-patch repair, with or without repair of the left side component of the AV valve (Figure 4.22) [16]. The operation accounts for approximately 9% of all cases of congenital heart disease surgery in children [3]. It may be necessary to replace the left-sided atrioventricular valve. In untreated cases, unless there is associated pulmonary stenosis, pulmonary hypertension develops rapidly, and plexiform lesions may be evident within the first year of life [17]. Examination of a repaired case of AVSD will show patching of the defect and suturing of the two septal components of the left atrioventricular valve. The patches are Dacron or pericardium and are amenable to histological examination. As with simple VSD, there is a foreign body reaction around the edges of the patch and growth of fibroelastic tissue over the right and left sides of it (Figure 4.23). Very rarely there may be a small defect of the atrioventricular membranous septum without a common atrioventricular junction, the so-called Gerbode defect. In this defect there is a small communication between the left ventricular outflow tract and the right atrium through (Figure 4.24) deficiency of the atrioventricular septum [18]. It may be congenital but may also be acquired following catheter intervention, endocarditis or myocardial infarction.

Figure 4.11 Residual defect after repair of a VSD. Ten-year-old with patched doubly committed VSD. The defect was patched some years before death. The picture shows the left ventricular outflow tract. The patch is visible as a concave depression beneath the aortic valve. A rounded, small, residual defect is visible at the superior margin of the patch with some irregularity of the endocardium around it.

Figure 4.12 Patched VSD dehiscence. Two-year-old with repair of tetralogy of Fallot. Death during a respiratory illness. The heart is cut in a simulated long axis view. The left ventricle is globular and dilated. Immediately beneath the aortic valve there is a patch. The patch has come away from the tissues at its upper border, and a large defect is now present.

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Figure 4.13 Atrioventricular junction in normal heart and AVSD. (A) A dissection of the heart to display the normal atrioventricular junctions. Much of the atrial walls and the atrial appendages have been removed. The two atrioventricular valves – the tricuspid on the right of the picture and the mitral on the left – have separate junctions with the ventricular mass. The long axes of the tricuspid and mitral valves are at almost 90 degrees to each other, forming a “V” into the fork of which the aortic valve sits snugly. (B) A heart with complete AVSD dissected to display the common atrioventricular junction and common atrioventricular valve. The atria have been removed and the heart is viewed from above. The leaflets of the common atrioventricular valve bridge over the septum. The crest of the interventricular septum is visible on the right-hand side of the field, and most of the ventricular cavity visible is that of the left ventricle.

Figure 4.14 AVSD with common junction and unwedging of aorta. The base of the heart viewed from above in a case of complete AVSD. The aorta is displaced anteriorly from its usual position between the atrioventricular valves. It now lies almost side by side with the pulmonary trunk.

4.4 Atrial Septal Defect (ASD) Most abnormal communications between the two atria occur at the site of the oval fossa. In about 10–20% of the general population there is probe patency of the interatrial septum at the anterosuperior part of the oval fossa [19, 20]. It is sometimes referred to as persistent foramen ovale. These individuals have a normal sized flap valve that is attached to the left side of the interatrial septum (Figure 4.25). Because under normal conditions the pressure of blood in the left atrium is higher

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than that in the right, the flap is pushed against the atrial septum and the potential communication remains closed. Deficiency of the flap valve of the oval fossa, usually in the anterosuperior aspect of the flap, is responsible for true ASDs (Figure 4.26A). Such defects are, by definition, ASDs of secundum type. Any ASD occurring outwith the oval fossa cannot be of secundum type. Secundum ASD is one of the commonest types of congenital heart disease [21] and accounts for 42% of heart defects in cases of trisomy 21 [22]. The defects may involve, when extreme, the entire oval fossa or merely a tiny part. The defect may be fenestrated with multiple small holes within the flap valve (Figure 4.26B). There may be slight surrounding endocardial fibroelastosis but usually no other consequence. The other types of ASD, with the exception of the ostium primum defect – which in reality is a form of AVSD (discussed above under AVSD) – are very rare: the coronary sinus defect [23] and the so-called sinus venosus defect [24] (Figure 4.27), which is usually associated with anomalous drainage of the right pulmonary veins through the defect into the right atrium and which accounts for 4–11% of ASDs [25]. ASD may, of course, occur in combination with any other cardiac defect and in some is essential for the continued wellbeing of the child. For example, in complete transposition of the great arteries with intact ventricular septum, if an ASD is not present, one has to be created artificially to permit mixing of both pulmonary and systemic circulations and ensure survival (Figure 4.28). Symptoms of isolated ASD in childhood are not usual, and even with large defects it is generally not until the third

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Figure 4.15 AVSD. A heart with complete atrioventricular septal defect dissected to show the septal structures and viewed from the right side (A) and from the left side (B). (A) The right atrium is above, the right ventricle below and the pulmonary valve anterosuperiorly. The arched lower border of the interatrial septum forms the superior margin of the AVSD. The lower margin is formed by the “scooped-out” crest to the atrioventricular septum that lies well below the plane of the atrioventricular junction. Superior (anterior) and inferior(posterior) bridging leaflets cross the crest of the interventricular septum from the right ventricle to the left ventricle. (B) Viewed from the left side, the lower border of the interatrial septum and crest of the interventricular septum are again clearly visible as are the bridging leaflets. The left ventricular outflow tract is displaced forward anterior to the superior bridging leaflet.

decade that symptoms begin to occur. Similarly, in isolated secundum ASD pulmonary arterial hypertension is very rare in childhood. If pulmonary arterial hypertension is present in a child with isolated ASD then complicating factors such as trisomy 21, where abnormal lung developments and upper airway obstruction may contribute [26], should be sought. The ASD may close spontaneously, with almost two-thirds showing closure or reduction in size over time, the major factor predicting closure being the initial size [27]. Elective closure either by surgery or transcatheter device is usually undertaken at age 4–6 years (Figure 4.29) [21]. Inherited ASD associated with conduction disturbance and NKX2–5 mutations is associated with an increased risk of sudden death [28].

4.5 Abnormalities of the Arterial Duct The arterial duct is a muscular artery interposed between the two elastic arteries (aorta and pulmonary trunk) [29]. It runs from the postero-superior aspect of the junction of the pulmonary trunk with the left pulmonary artery, upwards and slightly laterally and inserts into the medial aspect of the aorta just distal to and opposite the left subclavian artery (Figure 1.40). It develops from the embryonic sixth aortic arch. Variations in anatomy occur normally; some ducts are long and others short. There is also some variation in the angle of entry of the duct into the aorta, and some authors consider this of importance in ductal closure [30]. In the fetus the angle of entry of the duct to the aorta is acute but subsequent post-natal growth of the aorta converts the angle to nearly a right angle

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Figure 4.16 Bridging leaflets of AVSD. Heart with AVSD cut in a simulated four-chamber view and viewed from anteriorly. The AVSD lies between the lower border of the interatrial septum and the crest of the interventricular septum. The superior bridging leaflet is firmly attached to the crest of the interventricular septum. The superior and inferior bridging leaflets are separate and do not show connecting tissue; the crest of the septum can be seen in the gap between them.

(Figure 1.41). In the presence of a right-sided aortic arch the duct usually remains on the left side, taking origin from the left subclavian artery or the innominate artery.

4.5.1 Absence of the Arterial Duct In tetralogy of Fallot there is absence of the duct in approximately one-fifth of cases (Figure 4.30). Truncus arteriosus usually lacks an arterial duct. Cases of pulmonary atresia with VSD and major aortopulmonary collateral arteries also lack an arterial duct. Bilateral arterial ducts may also occur in some forms of interrupted aortic arch or with isolated left pulmonary artery.

Figure 4.17 Complete AVSD. The heart is viewed from the left side. The inferior bridging leaflet lies posteriorly and the superior bridging leaflet anteriorly. The superior bridging leaflet rides high above the crest of the interventricular septum and does not show attachments to it, thus leaving a wide interventricular communication beneath the valvar tissue. There is a large interatrial communication evident beneath the interatrial septum.

4.5.2 Normal Closure Having in the normal course of events become redundant at birth, the arterial duct closes by muscular contraction in the first 24 hours of extrauterine life; this is manifest as shortening and thickening of the duct. This approximates the intimal cushions that form in late fetal life, enhancing the closure and causes ischaemia of the muscle of the duct leading to fibrosis of the media. Over the following weeks permanent closure is achieved by mural fibrosis, and the duct is converted into a thick fibrous cord – the ligamentum arteriosum – that frequently calcifies [29]. Closure is usually complete by 3–4 weeks of age.

4.5.3 Premature Closure in Utero This is rare and may be associated with in utero right heart failure, fetal distress, hydrops or intrauterine death (31, 32).

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Figure 4.18 Partial AVSD. Heart cut in a simulated four-chamber view. The inferior bridging leaflet is attached by multiple fibrous cords to the crest of the interventricular septum leaving very little interventricular communication beneath the valve.

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Figure 4.19 (A) Ostium primum AVSD. Six-week old-male infant with ostium primum AVSD. The heart has been opened along the lateral aspect of the left atrium and ventricle and splayed to display the left side of the septal structures. There was a secundum atrial septal defect that is obscured by the atrial wall in this picture. The ostium primum defect is the large oval defect towards the middle of the field. In common with AVSD it lies beneath the lower border of the interatrial septum, the crest of the interventricular septum is scooped-out and the left atrioventricular valve displays fused superior and inferior bridging leaflets. The atrioventricular valve leaflets are firmly attached to the interventricular septum, and the only connection between the right and left sides of the heart is above the valve leaflets. (B) AVSD without interatrial communication. Heart cut in a simulated four-chamber view. There is situs inversus, and the heart is viewed from posteriorly. There is a large secundum ASD. There are separate atrioventricular orifices with the valvar tissue attached to the lower border of the interatrial septum. The interventricular septum is scooped-out with a large interventricular communication with bridging of the valve leaflets.

Figure 4.20 (A) AVSD and double inlet left ventricle. Four-chamber view of a heart with complete AVSD. There is disproportion in the size of the ventricles with the interventricular septum displaced to the right and the right ventricle being small. As a consequence, it can be seen that most of the right atrial connection is with the left ventricle rather than the right – double inlet left ventricle. (B) In this heart the situation is more extreme (From Suvarna SK (ed.) Cardiac Pathology: A Guide to Current Practice. London: Springer; 2013, with permission).

The duct is contracted and may still be probe patent. The presence of thrombosis assists greatly in making the diagnosis. Maternal ingestion of non-steroidal anti-inflammatory drugs is reported in some cases [33].

4.5.4 Persistent Patency of the Duct The duct remains functionally patent for the first few days of life in most premature infants [34]. Administration of

indomethacin – an inhibitor of prostaglandin synthesis – causes closure of the duct in most, but not all, cases, and a closed duct may reopen by poorly understood mechanisms [31]. Persistent patency of the duct is associated with the development of chronic lung disease in premature infants [35]. Persistent patency of the duct occurs in association with various forms of structural heart disease, its patency in some being essential to life. In the hybrid procedure for hypoplastic left heart the arterial duct is stented to maintain its patency

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trimester and postnatally, most cases are detected in the first two months of life [38]. Most cases are asymptomatic and resolve spontaneously and the true incidence may thus be commoner than reported. Cases have been associated with Marfan’s syndrome, Ehlers–Danlos syndrome, Smith–Lemi– Opitz syndrome, and trisomy 21 and 13 [38]. The size of the aneurysm varies with most cases being in the order of 0.8–2.4 cm in maximum diameter. Histologically, the findings are variable. Absence of intimal cushions in some cases and disorganisation of the medial elastic tissue in others have been reported [38]. A minority of cases may show luminal thrombus (Figure 4.34) and tears in the intima, or infection [39, 40]. Rupture with fatal tamponade may occur. A case of transient vocal cord paralysis by compression of the recurrent laryngeal nerve has been described [41].

4.6 Coarctation of the Aorta

Figure 4.21 AVSD and tetralogy of Fallot. This is the same heart as in Figure 4.17 but viewed from the right side. In addition to the AVSD, there is anomalous anterior insertion of the supraventricular crest giving muscular subpulmonary stenosis, the characteristic morphology of tetralogy of Fallot.

(Figure 4.31). Patent duct and peripheral pulmonary artery stenosis are the commonest cardiac manifestation of maternal rubella infection. The duct may be long or short. The pulmonary artery is wide and the aorta distal to the duct may be of larger diameter than the aortic isthmus proximal to the entry of the duct. In the premature infant treatment is medical, with surgery reserved for those in whom medical treatment is not possible or fails. Surgical closure is either by thoracotomy or videoassisted thorascopic surgery (Figure 4.32). In the nonpremature infant catheter closure is the treatment of choice (Figure 4.33) [36]. In the non-premature infant surgical closure is associated with fewer re-interventions as compared to catheter closure, albeit outcomes are similar [37]. A persistently patent arterial duct is at risk of development of infective endocarditis.

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Coarctation is a narrowing of the aorta, usually at the site of insertion of the arterial duct. The narrowing may be discrete or it may be accompanied by tubular hypoplasia of the aorta [42]. The normal aortic isthmus (that segment of the aortic arch between the left subclavian artery and the arterial duct) is normally narrower than the remainder of the aorta and may remain so well into post-natal life [43], particularly in the situation of prematurity and a persistent patent arterial duct. It is important not to mistake this normal appearance for tubular hypoplasia. The discrete lesion of coarctation is usually evident externally as a notch in the aortic arch wall (Figure 4.35), most prominently on its convex aspect opposite the ductal insertion; internally there is a shelf of tissue protruding into the lumen from the side of aortic wall opposite the site of insertion of the arterial duct. A degree of post-stenotic dilatation may be visible, but in infants it is usually not marked (Figure 4.36). Coarctation of the aorta may occur as an isolated lesion, or it may accompany other cardiovascular malformations, most notably VSD and left-sided obstructive lesions [44]. It is particularly common in Turner’s syndrome [45]. Histologically, a sling of ductal tissue extends around the aortic wall causing the narrowing. This is confirmed on phase contrast tomography [46]. Secondary intimal fibrous proliferation further narrows the lumen (Figure 4.37) [47]. Following resection of the affected segment, re-coarctation may occur if sufficient ductal tissue is left in the aortic wall [48]. Those with severe coarctation present in the first weeks of life with evidence of cardiac failure. They may present as a dilated cardiomyopathy beyond the first year of life [49].

4.5.5 Aneurysm of the Duct

4.7 Pulmonary Stenosis and Atresia, Including Tetralogy of Fallot

Symptomatic aneurysmal dilatation of the arterial duct is a rare occurrence that may be detected antenatally or postnatally. The antenatally detected cases develop in the third

Congenital atresia of the pulmonary valve may occur with an intact interventricular septum or may be coupled with a VSD. The two entities are distinct clinically and have distinct

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Figure 4.22 Two-patch repair of AVSD. (A) The heart is viewed from the right side following removal of the free walls of the right atrium and ventricle. There is puckering of the attachment of the atrioventricular valve to the atrioventricular junction. Suture lines for patches in the atrium and ventricle on either side of the valve are evident. The right ventricular wall shows mild thickening, and its endocardium is more fibrous than normal. A suture is also visible in the rim of the oval fossa, and a stent is also present in the fossa. (B) This heart is cut in a simulated four-chamber view. The cut edges of the two patches are visible with overlying fibrosis. It can be appreciated that both patches have been applied from the right side. There is now offsetting of the two atrioventricular valves. (C) Ostium primum patch viewed from the right atrium. The patch lies just above the atrioventricular valve and is away from the oval fossa.

pathological associations. There may be severe stenosis of the pulmonary valve instead of atresia, and, indeed, there is evidence from serial ultrasound scanning in utero that at least some cases of pulmonary atresia develop from pulmonary stenosis [50].

4.7.1 Pulmonary Atresia with Intact Interventricular Septum This lesion usually occurs as part of more complex malformations. As an isolated lesion, it is uncommon (1–4% cases of congenital heart disease) [51]. It almost always occurs with concordant atrioventricular and ventriculoarterial connections. Pathologically, it is characterised by patency of the oval foramen and of the arterial duct. The right atrium is dilated; the larger the right ventricle, the more dilated the right atrium. The right ventricle is usually small with a hypertrophied wall, but in those cases in which the tricuspid valve is not competent, the right ventricle may be of normal size. The degree of

ventricular hypertrophy may be so great as to obliterate the outlet and apical trabecular components of the right ventricle, leaving only an inlet component (Figure 4.38). The tricuspid valve is small, and there is associated Ebstein’s malformation in about 10% of cases. The tricuspid valve may even be absent. In those cases of unguarded tricuspid orifice and Ebstein’s malformation the right ventricle tends to be dilated (Figure 4.39). The pulmonary trunk is small but may be of normal size (it is rarely atretic), and the valve annulus is narrow. The pulmonary valve is imperforate, being convex towards the pulmonary trunk and showing three ridges radiating from a central fibrous button (Figure 4.40). The branch pulmonary arteries are thin-walled. The left ventricle is also hypertrophied. The ascending aorta is wide, and the normal narrowing of the isthmus is absent. The arterial duct is narrow and arises from the descending aorta with an acute inferior angle. A notable feature is the presence of right ventricularcoronary artery sinusoids. These are said to arise from

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Figure 4.23 Histological section of repaired AVSD. (A) Two-patch repair of complete AVSD. This section extends from the lower border of the interatrial septum (top right corner) to the crest of the interventricular septum (bottom left) and is stained with EvG. The interatrial component of the patch is of pericardium and is the bright red line extending from the interatrial septum to the atrioventricular valvar tissue. The ventricular component is of Dacron and is considerably smaller, and its upper border shows a fold at its upper margin. Note the considerable deposition of fibroelastic tissue over both patches. The operation was approximately 12 months before death. (B) Patch repair of primum AVSD. The interatrial septum is above and the interventricular septum below. Note both atrioventricular valves are connected to the crest of the septum. The patch is applied to the right side of the defect. Death occurred shortly after operation, and there is no deposition of fibrous tissue over the patch.

persistence of the normal ventricular-coronary communications in the embryo because of persistently elevated right ventricular pressure. However, there is at least one report of identification of ventricular-coronary artery sinusoids before the onset of pulmonary obstruction [52]. The sinusoids are readily demonstrable on echocardiography but are very difficult to demonstrate convincingly pathologically. They do, however, cause dramatic secondary changes in the affected coronary arteries. These arteries show greatly thickened muscular walls, intimal fibrous and elastic thickening, and adventitial elastic deposition (Figure 4.41A,B) [53]. Sometimes the epicardial coronary arteries may be two to three times their normal external diameter. On occasion, the affected coronary artery loses its communication with the aorta because of the intimal proliferation. The perfusion of the myocardium supplied by such an artery may then be crucially dependent on the elevated right ventricular pressure for retrograde perfusion. Histologically, the hypertrophied right ventricular myocardium shows myocyte disarray (Figure 4.42) [53]. If the right ventricle is of reasonable size, then ventricular decompression by radiofrequency puncture of the pulmonary valve (Figure 4.43) followed by balloon dilatation can be

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attempted and biventricular repair (with pulmonary homograft) carried out at a later date. If the right ventricle is too small, then univentricular repair with Fontan circulation is carried out. In utero balloon valvuloplasty has been undertaken in utero in an attempt to improve right ventricular growth (Figure 4.44) [54].

4.7.2 Pulmonary Stenosis with Intact Interventricular Septum Stenosis of the pulmonary valve is less common in the neonate than atresia. The morphology of the valve may be reminiscent of that in atresia but with a central lumen [55], or may comprise three cusps that are thickened and dysplastic (Figure 4.45). The severity of the stenosis depends on the pressure gradient across the right ventricular outflow tract: gradients of between 40 and 80 mmHg are considered moderate and above 80 mmHg are considered severe. Experimentally, the pulmonary artery must be constricted to one-third of its diameter to produce a significant pressure gradient. The right ventricle is hypertrophied, as is the right atrium because of the increased diastolic filling pressure. The pulmonary trunk is large and thin-walled because of post-stenotic dilatation. Some

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Figure 4.24 Gerbode defect. This is a defect of the atrioventricular septum between the left ventricle and the right atrium. The neonate had antenatally diagnosed pulmonary atresia with intact septum and died during cardiac catheterisation after birth. (A) The membranous septum between the right and non-coronary cusps of the aortic valve is large and bulges to the right with ragged margins . (B) Viewed from the right side, the bulging septum with defect is present in the right atrium above the septal leaflet of the tricuspid valve. No communication was seen antenatally and it is possible that cardiac catheterisation caused the abnormal septum to rupture.

4.7.3 Pulmonary Stenosis with VSD, Including Tetralogy of Fallot

Figure 4.25 Patent oval foramen (PFO). A neonatal death with pulmonary hypoplasia. The heart is viewed in a simulated four-chamber cut. The flap valve of the oval fossa on the left side of the interatrial septum is of adequate size but is displaced away from the rim of the oval fossa.

cases show a thickened tricuspid valve and jet lesions in the right atrium. Pulmonary stenosis may occur in Williams syndrome, in Noonan’s syndrome [56] or as a result of maternal rubella infection.

Tetralogy of Fallot refers to a group of four abnormalities occurring together: pulmonary stenosis, VSD, overriding aorta and right ventricular hypertrophy [57]. The basic defect is an abnormally anterior insertion of the ventriculoinfundibular fold into the anterior limb of the septomarginal trabeculation (Figure 4.46). (Normally the ventriculoinfundibular fold inserts between the limbs of the septomarginal trabeculation.) This leaves a VSD posteriorly and causes muscular narrowing of the right ventricular outflow tract. The aorta overrides the VSD and the presence of pulmonary stenosis leads eventually to right ventricular hypertrophy. About one-quarter of cases show a right-sided aortic arch, and there may be absence of the arterial duct. The aorta is usually large and the pulmonary artery small, but they may be of equal size. The pulmonary trunk and pulmonary arteries are thin-walled. The VSD is usually large and may extend to the membranous septum to become a perimembranous VSD. The degree of aortic override is also variable. If the degree of override is greater than 50%, the case is then, by convention, classified as double outlet right ventricle (Figure 4.47). While infundibular stenosis is present in all cases, there is variable valvar stenosis and approximately

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Figure 4.26 Atrial septal defect of secundum type. (A) The interatrial septum is viewed from the right atrium. The oval fossa is visible, and the flap valve is deficient superiorly giving an interatrial communication –ASD of secundum type. Inferiorly the eustachian valve separates the oval fossa from the coronary sinus. (From Khong TY & Malcolmson RDG (eds) Keeling’s Fetal and Neonatal Pathology. London: Springer; 2015, with permission.) (B) Oval fossa viewed from the right atrium in term neonate with common arterial trunk. The flap valve bulges into the right atrium. It shows multiple rounded fenestrations of variable size.

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Figure 4.27 Sinus venosus ASD. The septal structures of the heart viewed from the right side. A pulmonary artery band is in situ. The interatrial septum shows deficiency posteriorly, and the venous return from the right lung enters the right atrium astride the septum (forceps).

Figure 4.28 Atrial septostomy. A ten-year-old with myocarditis who underwent balloon atrial septostomy as part of extracorporeal life support. The left side of the atrial septum shows an irregular orifice with ragged margins.

20% of cases have pulmonary atresia (Figure 4.48). The valve may have one, two, three or even four cusps. The valve may be completely absent with associated aneurysmal dilatation of the pulmonary trunk and absence of the arterial duct (Figure 4.49) [58]. There may also be supravalvar stenosis. It must be emphasised that not all cases of pulmonary stenosis with VSD represent tetralogy of Fallot; only those (majority) of cases exhibiting the characteristic morphology of anomalous anterior insertion of the ventriculoinfundibular fold can be so designated. Because of the reduction in pulmonary blood flow and shunting of blood from the right ventricle to the aorta,

tetralogy of Fallot presents with cyanosis usually in the first few months of life. Sudden death may occur, even in operated cases [59]. The muscular pulmonary arteries within the lung show atrophy of their tunica media because of the reduced pulse pressure (Figure 4.50) [60]. Correction may be attempted in the neonatal period, but many would advocate operating later – by six months of age and before 12 months [61]. The aim of surgery is to close the VSD, relieve the right ventricular outflow tract obstruction and preserve myocardial function. If the pulmonary arteries are of sufficient size to accommodate the entire cardiac output, the VSD is closed and the pulmonary outflow tract enlarged either

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Figure 4.30 Absent arterial duct. Three-month old child with DiGeorge syndrome and tetralogy of Fallot. A view of the left hilum showing the pulmonary trunk, left pulmonary artery and left-sided aortic arch. There is no arterial duct in the expected site, and none was present elsewhere.

Figure 4.29 Patched secundum ASD. An infant with trisomy 21 who underwent closure of a secundum ASD with autologous pericardial patch at age two months and who died suddenly six months later. A section through the interatrial septum and upper interventricular septum stained with EvG. The patch has been applied from the right atrial aspect (left side of field). Note the thick layer of elastic tissue on both atrial aspects of the patch.

Figure 4.31 Stented arterial duct. The child had hypoplastic left heart and underwent a hybrid procedure with banding of the branch pulmonary arteries and stenting of the arterial duct. The opened duct shows the wire stent in situ, partly endothelialised and incorporated into the intima of the vessel.

Figure 4.32 Ligated arterial duct. A two-week-old child with AVSD and coarctation who underwent coarctation repair and banding of the pulmonary artery. The pulmonary artery band is visible as a broad loop around the pulmonary trunk tied with a green suture. There is blue Prolene suturing evident in the adventitia of the descending aorta. The arterial duct shows a metal clip and abundant black suture material.

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by resection of muscle or by a transannular patch or valved conduit (Figure 4.51). If the pulmonary arteries are too small, then a systemic–pulmonary shunt is required (Figure 4.52). Reoperation is frequently needed.

4.7.4 Pulmonary Atresia with Ventricular Septal Defect This is a quite distinct abnormality from pulmonary atresia with intact septum. This lesion does not show the diminutive and hypertrophied ventricle of pulmonary atresia with intact septum. The pulmonary trunk is usually atretic, being represented only by a thin thread-like cord and ends blindly on the ventricular muscle (Figure 4.53). The subpulmonary

infundibulum is very narrow and does not communicate with the pulmonary trunk. The branch pulmonary arteries may be of normal size and supplied by an arterial duct. The duct may be absent, in which case the lungs derive their blood supply exclusively from major aortopulmonary collateral arteries (MAPCAs) [62]. These vessels, muscular systemic arteries [63], some at least of which are hypertrophied bronchial arteries, arise from the aortic arch and descending aorta (Figure 4.54). Many cases represent tetralogy of Fallot with pulmonary valvar atresia and these are regarded as the severe end of the spectrum of tetralogy. If the branch pulmonary arteries are of adequate size, the condition is treated in the same manner as pulmonary stenosis and VSD. If there are MAPCAs, the blood supply of the lung must be unifocalised (Figure 4.55), either at the same time as definitive repair or as a staged preliminary step to it [64].

4.7.5 Absence of the Pulmonary Valve In this condition there is complete absence of the cusps of the pulmonary valve, or the valvar tissue is represented only by rudimentary excrescences at the site of the valve (Figure 4.49). It is usually associated with a VSD and may occur in the setting of tetralogy of Fallot. Characteristically there is dilatation of the pulmonary artery, sometimes to aneurysmal proportions (Figure 4.56), and the vessel wall may be disorganised and calcified. The bronchi are compressed, a change that begins in utero [65].

4.8 Aortic Stenosis Figure 4.33 Catheter closure of patent arterial duct. The pulmonary arterial end of an arterial duct some five months after catheter coil closure. An endothelialised loop of a coil can be seen protruding at the former ductal orifice.

Aortic stenosis is traditionally classified into three forms: subvalvar stenosis, valvar stenosis and supravalvar stenosis [66], although obstruction frequently occurs at more than one of these levels; valvar stenosis is the commonest form. Aortic stenosis may occur regardless of the ventriculoarterial connection.

Figure 4.34 Aneurysm of the arterial duct. A case of congenital diaphragmatic hernia. (A) There is a large tortuous arterial duct. (B) The opened specimen shows that it is thrombosed.

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Figure 4.35 Coarctation of the aorta. Viewed from the right side, the aorta shows a distinct notch on its convex aspect distal to the point of entry of the arterial duct (From Suvarna SK (ed.) Cardiac Pathology: A Guide to Current Practice. London: Springer; 2013, with permission).

Figure 4.36 Coarctation of the aorta. The same specimen as in Figure 4.35 opened to show the discrete narrowing of the aortic lumen distal to the ductal insertion. The duct was closed.

Figure 4.37 Coarctation of the aorta. Histological section of excised coarctation stained with EvG. The discrete fibroelastic shelf is readily appreciated. There is secondary intimal fibroelastic thickening associated with the narrowed area.

4.8.1 Valvar Stenosis This may occur as an isolated lesion or may be associated with other abnormalities such as mitral stenosis, aortic coarctation (Figure 4.57) or VSD. At its most extreme it merges with hypoplastic left heart syndrome. The valve orifice is usually narrow, and there is fusion and dysplasia of the valve cusps (Figure 4.58) [67]. A unicommissural valve is uncommon but causes severe aortic stenosis in early childhood. Macroscopically, a unicommissural valve consists of an apparent single leaflet with one functional commissure. Most cases, however, show vestigial raphe of the other commissures, with the functional commissure in the position between the putative left and

Figure 4.38 Pulmonary atresia with intact septum. The heart has been cut in a simulated four-chamber view. The right ventricle is small, not extending to the apex, but it is thick-walled and the cavity is almost obliterated. The right atrioventricular valve is patent but is much smaller than that on the left side. Thickened coronary arteries are visible over the epicardial surface of the right ventricle.

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Figure 4.39 Pulmonary atresia with intact septum and unguarded tricuspid orifice. In this case of pulmonary valvar atresia with intact interventricular septum there is an unguarded tricuspid orifice. The right atrium and right ventricle have been opened to display the cavities. Note the absence of any valvar tissue at the right atrioventricular junction. In contrast with Figure 4.38, the right ventricular cavity is dilated, and the wall is thin.

Figure 4.40 Pulmonary atresia with intact septum. The pulmonary trunk has been transected near the sinotubular junction, and the valve is viewed from above. The valve is small and imperforate and composed of three cusps that are thickened and rigid, and fused centrally to form a fibrous button with three radiations.

Figure 4.41 Pulmonary atresia with intact septum. (A) Heart from an infant aged 12 days who died suddenly on day after insertion of a Blalock–Taussig shunt for pulmonary atresia with intact septum. The heart is viewed from the front. The right ventricular apex is visible about halfway down the right border of the heart. There is congestion of the pericardium. The pulmonary trunk is narrow. The left coronary artery shows irregular thickening of its wall as it courses in the anterior interventricular groove. (B) A histological section of one of the thickened epicardial arteries showing thickening of all three coats – adventitia, media and intima, by concentric laminar fibrous and elastic tissue. In areas it is impossible to recognise the original arterial wall.

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Figure 4.42 Pulmonary atresia with intact septum. Histological section of the thickened right ventricular myocardium to demonstrate the florid myocyte disarray that is a common feature of this condition.

Figure 4.43 Pulmonary atresia with intact septum. Radiofrequency ablation of the imperforate valve. The valve is viewed from above through the pulmonary artery and shows the fenestrations made.

posterior sinuses [68]. A dysplastic valve may be associated with dysplastic pulmonary or other valves in so-called polyvalvar dysplasia (Figure 4.59) [69]. An X-linked form is associated with FLNA mutation [70]. Bicuspid aortic valve is one of the commonest congenital cardiovascular abnormalities and occurs in up to 2% of individuals. A subset is associated with NOTCH1 mutations [71]. Manifestations during childhood are uncommon, with development of aortic dilatation. Up to 5% go on to develop aortic dissection [72]. Isolated critical aortic stenosis is usually treated by balloon valvoplasty. Reoperation is frequently required, and if there is valvar regurgitation, valvar replacement with aortic homograft or pulmonary autograft may be required (Figure 4.60). Patients with severe aortic stenosis show left ventricular myocardial hypertrophy and fibrosis (endocardial thickening, subendocardial microscars with a decreasing endomyocardial to mid-myocardial fibrosis gradient and diffuse interstitial mid-myocardium fibrosis) (Figure 4.59C) [73].

4.8.2 Subvalvar Stenosis

Figure 4.44 In utero balloon dilatation of pulmonary valve. A fetus aged 22 weeks with severe pulmonary valvar stenosis who underwent balloon dilatation of the valve. The outflow tract was accidentally perforated, and the fetus died 24 hours later. Free walls of the right atrium and ventricle have been removed, and the specimen is viewed from the right. The right ventricle was slightly small compared to the left. The pulmonary artery is dilated and the pulmonary valve narrow, but patent. Immediately beneath the valve a tear is visible in the posterior infundibulum that is partly obscured by the valve leaflets.

Subvalvar stenosis may be caused by muscular obstruction as, for example, in hypertrophic cardiomyopathy, or by hypertrophy of an anomalous muscle bar or hypertrophied outlet septum in cases of double outlet ventricle (Figure 4.61). Secondary muscular hypertrophy with mild obstruction frequently accompanies valvar stenosis. Subvalvar obstruction may be caused by a subvalvar fibrous shelf that is attached to the muscular septum and extends onto the subaortic fibrous curtain. It rarely forms a complete subvalvar diaphragm (Figure 4.62) [74]. Subvalvar obstruction may also be caused by fibrous tissue tags, or atrioventricular valvar tissue associated with a VSD. Subvalvar obstruction can be surgically removed. Hypertrophied muscle may also be resected.

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Figure 4.45 Pulmonary valvar stenosis with intact septum. (A) Three-month old known to have moderate pulmonary stenosis who died suddenly. The opened right ventricular outflow tract shows a trileaflet pulmonary valve with nodularity and thickening of the leaflets. (B) The histological section of the valve shows dysplasia, with a thickened leaflet showing an excess of elastic and fibrous tissue.

Figure 4.46 Tetralogy of Fallot. The right-sided septal structures in tetralogy of Fallot viewed from the right side. The large overriding aorta is seen over the right ventricle with a VSD beneath it lying between the limbs of the septomarginal trabeculation. The supraventricular crest that would normally occupy this position is abnormally anteriorly inserted into the anterior limb of the septomarginal trabeculation, causing narrowing of the subpulmonary outflow.

4.8.3 Supravalvar Stenosis Supravalvar aortic stenosis is caused by irregular thickening of the aortic wall some 1–2 cm above the aortic valve (Figure 4.63) [75]. It is usually associated with Williams syndrome caused by microdeletion of chromosome 7q11.23 [76]. The deletion affects the elastin gene (ELN). Point mutations in ELN are responsible for autosomal dominant familial supravalvar aortic stenosis without other features of William syndrome [77]. The affected segment of ascending aorta has a

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Figure 4.47 Tetralogy of Fallot. In this example of tetralogy of Fallot the aorta takes origin largely from the right ventricle and the case is, thus, classified as double outlet right ventricle.

characteristic hourglass appearance (Figure 4.64) when viewed externally. The aortic wall is thickened by disorganised fibrous and elastic tissue (Figure 4.65). There is usually thickening and fibrosis of the coronary arteries [78], the arteries bearing a striking resemblance to those seen in pulmonary atresia with intact septum and ventriculocoronary artery communications. The left ventricle is hypertrophied. Repair of supravalvar aortic stenosis is undertaken with transvalvar gradients of 50 mmHg or more. Surgery involves resection of the hourglass constriction with patching with pericardium.

4.9 Hypoplastic Left Heart This is a group of abnormalities characterised by a small left ventricle unable to support the systemic circulation [79]. There are several morphological forms that may differ in their

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Figure 4.48 Tetralogy of Fallot. The aorta overrides the VSD in this example of tetralogy of Fallot. There is muscular obliteration of the right ventricular outflow tract. The pulmonary trunk ended blindly on the ventricular mass and there was no communication between it and the right ventricle.

Figure 4.50 Tetralogy of Fallot lung histology. A typical section from a case of unoperated tetralogy of Fallot. The muscular pulmonary artery accompanying the bronchiole is dilated and thin-walled. This appearance is due to lack of trophic effect of the usual variation on pulse pressure by pulmonary stenosis.

aetiology, but all involve obstruction to the inflow or the outflow of the left ventricle [80]. The commonest form has atresia of both mitral and aortic valves. In this case the left ventricle is a slit-like cavity without endocardial fibrosis (Figure 4.66). The remaining forms have at least one patent valve. There may be a mitral atresia with patent aortic valve, a subset having associated VSD (Figure 4.67). Or there are those cases with patent mitral valve but with either coarctation of the aorta or aortic valvar abnormalities (stenosis or atresia) (Figure 4.68). The usual case has a thread-like ascending aorta that is patent and supplies blood to the coronary arteries in a retrograde fashion (Figure 4.69). The mitral valve is usually small and dysplastic, in which case the ventricle shows marked endocardial fibroelastosis; if the mitral valve is atretic, there is no

Figure 4.49 Tetralogy of Fallot and absent pulmonary valve. This case of tetralogy of Fallot shows double outlet right ventricle. The narrowing of the right ventricular outflow is not severe. The pulmonary valve is largely absent being represented by a few dysplastic myxoid nodules at the valve location. The pulmonary trunk is greatly dilated, as is usual with absent pulmonary valve (From Khong TY & Malcolmson RDG (eds) Keeling’s Fetal and Neonatal Pathology. London: Springer; 2015, with permission).

endocardial fibroelastosis (Figure 4.70). The left atrium is small. The aortic valve is more usually atretic, but may be severely stenotic or dysplastic, in which case the ascending aorta is correspondingly larger. The interventricular septum is usually intact but there may be a VSD if there is mitral atresia. Externally, the coronary arteries delimit the hypoplastic left ventricle. The left ventricular myocardium is hypertrophic, and 80% of cases show myocyte disarray histologically. The appearances are analogous to the right heart in pulmonary atresia with intact septum, and, in some cases, ventriculocoronary artery communications can also be demonstrated [81, 82]. There may be fibrosis and calcification of the papillary muscles of the mitral valve (Figure 4.71) [81]. About two-thirds of cases show coarctation of the aorta [83]. There is undoubtedly a genetic component in some cases, but no single gene defect has been identified. Hypoplastic left heart most probably arises on the basis of reduced ventricular flow. This may affect filling pressure because of mitral stenosis with consequent reduction in myocardial strain. This leads to a decrease in ventricular growth normally driven by myocardial strain [84, 85]. The infant with hypoplastic left heart can survive while the oval foramen and arterial duct remains patent, permitting the systemic circulation to be supplied by the right ventricle. The treatment consists either of staged Norwood procedure or cardiac transplantation. Norwood stage 1 involves a systemicto-pulmonary artery shunt (modified Blalock–Taussig shunt or Sano shunt – RV-PA conduit) with Damus–Kaye–Stansel anastomosis and removal of the atrial septum (Figure 4.72). Stages 2 and 3 unload the single ventricle such that it only supports the systemic circulation. Stage 2 involves taking down the Blalock–Taussig shunt and creation of a bidirectional

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Figure 4.51 Operated tetralogy of Fallot. (A) Patched VSD. An area of dense stellate fibrosis over the endocardium marks the site of the patched VSD. (B) Transannular patch. The right ventricular outflow has been augmented by a patch anteriorly. The patch has been incised to demonstrate the anastomosis to the outflow of the right ventricle. The pulmonary valve is visible through the opening thus created. (C) A valved conduit connects an anterior ventriculotomy (bottom of field ) to the pulmonary trunk (top of field). An artificial patch completes the integrity of the lower part of the patch. The conduit shows dilatation with some separation of the valve cusps. There was calcification of the conduit wall.

Glenn shunt (Figure 4.73), and stage 3 involves completion of the Fontan circulation with connection of the inferior caval blood to the pulmonary circulation by either an intra-atrial baffle or an extra-atrial shunt. There is considerable mortality both while awaiting operation and in the interstage periods, most notably between stages 1 and 2 where it can be around

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10% [86]. The long-term results are reasonable, but cardiac transplantation is required in many cases. More recently, a so-called hybrid procedure has been employed whereby the arterial duct is stented and both pulmonary arteries are banded, and atrial septectomy or septostomy performed (Figure 4.74). The results have not borne out

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Figure 4.52 Tetralogy of Fallot. (A) The front view of the heart shows a small pulmonary trunk. A tie is present at the tip of the right atrial appendage. A right modified Blalock-Taussig shunt is in situ. The proximal end is just visible taking origin from the lateral aspect of the ascending aorta. (B) Viewed from above and behind the shunt is seen to be inserted into the right pulmonary artery.

Figure 4.53 Pulmonary atresia with VSD. (A) The external surface of the heart shows a thread-like pulmonary trunk that is skirted on either side by the coronary arteries. The trunk widens as it ascends to form the pulmonary artery confluence. A Blalock-Taussig shunt is inserted in the left pulmonary artery. (B) A histological section stained with EvG shows a patent, albeit very narrow, subpulmonary outflow. The valve is represented by a nodular mass projecting into the narrow proximal trunk.

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Figure 4.54 Pulmonary atresia with VSD; major aortopulmonary collateral arteries. A posterior view of the descending aorta in a case of pulmonary atresia with VSD shows numerous arteries running from the aorta to the pulmonary hilum to supply the lung.

Figure 4.55 Unifocalisation of MAPCAs. A child with pulmonary atresia and VSD with multiple aortopulmonary collaterals. Initially treated by Blalock– Taussig shunt with unifocalisation of the pulmonary arteries. Sudden death. The heart is viewed from behind with the aorta retracted to the upper left of the picture. In the centre the “pulmonary arteries” are seen. These were created by detaching the MAPCAs from the aorta and joining them end to end and augmenting the size of the vessels with a patch. A Blalock–Taussig shunt is anastomosed to the right side of this vessel. A further tortuous MAPCA arises from the descending aorta and supplied the right upper lobe.

earlier optimistic predictions, but the procedure may confer a survival advantage over the Norwood operation in infants with low birth weight [87].

4.10 Transposition of the Great Arteries 4.10.1 Complete Transposition In transposition the ventriculoarterial connections are discordant, the aorta arising from the morphologically right ventricle

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Figure 4.56 Absent pulmonary valve. (A) Pulmonary artery opened to demonstrate absence of pulmonary valvar tissue. The pulmonary trunk is dilated. (B) A case of in utero absence of pulmonary valve. There is aneurysmal dilatation of the confluence of the pulmonary arteries. The trachea and carina are visible above the pulmonary artery. Frequently there is airway compression by the distended vessels.

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There may be an ASD, which allows some mixing of systemic and pulmonary circulations. If an ASD does not exist, one must be created artificially to permit survival until an arterial switch operation can be performed (Figure 4.77). Complete transposition may be complicated by VSD (Figure 4.78) (approximately 20% of cases), pulmonary stenosis (~7% of cases) or coarctation (~7% of cases) [90]. Coarctation or interrupted aortic arch (Figure 4.79) are more frequent in the presence of subaortic (right ventricular outflow tract) obstruction. In complete transposition the atrioventricular conduction tissue is normally disposed. When a VSD is present, the components of the ventricular septum are frequently malaligned. The severity of this spectrum of abnormalities varies and at its more extreme end there is double outlet right ventricle with subpulmonary VSD – the so-called Taussig–Bing heart (Figure 4.80) [91]. In the absence of a VSD the baby appears normal at birth but becomes cyanosed on the first day of life and quickly becomes acidotic. In those cases, with VSD, breathlessness and cardiac failure develop within the first week of life; cyanosis is minimal. A balloon atrial septostomy (Rashkind) is usually performed if the interatrial communication is too small to permit adequate mixing of the circulations.

4.10.2 Arterial Switch Operation

Figure 4.57 Aortic stenosis and coarctation. A long-axis view of the heart and aorta showing mild valvar aortic stenosis (bicuspid valve) and mild narrowing of the aorta at the level of the arterial duct.

and the pulmonary artery from the morphologically left ventricle (Figure 4.75). In the most common occurrence of the abnormality (complete transposition) the atrioventricular connections are concordant; this may occur in the setting of usual atrial situs or with situs inversus. If the atrioventricular connection is also discordant, then the term congenitally corrected transposition is employed [88]. In the majority of cases of transposition the aorta and pulmonary trunk are usually of equal size, and the aorta lies anterior and to the right of the pulmonary artery (in the normal heart the aorta lies posterior and to the right of the pulmonary trunk), but the relationship can vary. The aorta has a complete muscular infundibulum and the pulmonary valve is in fibrous continuity with the mitral valve; the aorta and pulmonary trunk lack the usual spiral relation to each other (Figure 4.76). Instead they arise parallel within the pericardial sac. The coronary artery origins from the aorta are more variable than usual [89] and are discussed more fully in the chapter on the coronary arteries.

Optimal treatment of complete transposition is neonatal arterial switch where the pulmonary artery and the aorta are transected and switched to their correct ventricles (Figure 4.81). The coronary arteries are also switched, each with an attached button of surrounding arterial wall. This is the most critical aspect of the operation. Abnormal coronary anatomy sometimes complicates, but does not preclude, arterial switch operation. During the operation the aorta and pulmonary arteries are dissected and the arterial duct divided. The aorta is transected a few millimetres above the sinotubular junction and the pulmonary artery just proximal to its bifurcation. The coronary artery origins are dissected from the aorta with a surrounding button of aortic wall. In effect this includes most of the corresponding sinus of Valsalva. The coronary arteries with their attached button of arterial wall are now sewn into the pulmonary trunk (neo-aorta) above the sinotubular junction (Figure 4.82). The arteries are switched (Jatene manoeuvre)and sewn into their new location. Results are excellent [92]. Abnormal coronary artery anatomy increases the risk of mortality, with a six-fold increase in early mortality associated with the presence of an intramural coronary artery and a three-fold increase in mortality associated with a single coronary artery [93]. Other complicating factors are severe malalignment of the commissures of the great arteries, aortic arch obstruction, multiple VSDs, Taussig–Bing anatomy with subaortic obstruction, more than three weeks of age at operation, and weight at operation less

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Figure 4.58 Critical aortic stenosis. (A) Neonatal critical aortic stenosis. There is a bicuspid aortic valve that is thickened and narrowed. The left ventricular myocardium is thickened. (B) An infant with aortic stenosis. The valve consists of three cusps, but they are thickened and dysplastic. (C) Teenage boy with critical aortic stenosis who died suddenly. The heart shows concentric subendocardial interstitial and replacement fibrosis in the hypertrophied left ventricular myocardium (Masson’s trichrome stain).

than 2.5 kg [94]. Complications are unusual but include supravalvar pulmonary stenosis, neoaortic valve insufficiency and coronary ostial stenosis. Functional problems include reduced exercise capacity, diffuse coronary insufficiency [95], and neurodevelopmental defects, of which the true incidence and potential clinical implications are still unknown [96]. If arterial

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switch is delayed beyond the neonatal period, it can still be performed, but the left ventricle requires pre-conditioning with pulmonary artery band. In the presence of untreatable subaortic obstruction and intact septum, atrial redirection with right ventricular to pulmonary artery conduit may be undertaken.

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Figure 4.59 Polyvalvar dysplasia. An infant with polyvalvar dysplasia. The aortic valve shows thickened and slightly nodular cusps. The pulmonary valve is viewed from above and also shows thickened and myxoid valve cusps (From Suvarna SK (ed.) Cardiac Pathology: A Guide to Current Practice. London: Springer; 2013, with permission).

Figure 4.60 Aortic stenosis and aortic valve replacement. Cut in a long-axis view this heart shows left ventricular hypertrophy. The aortic valve shows a mechanical valve replacement.

Figure 4.61 Subvalvar aortic stenosis. (A) A case of hypertrophic cardiomyopathy with subaortic outlet obstruction caused by marked enlargement of the interventricular septum. (B) Post-myectomy for muscular subaortic obstruction. There is generalised thickening of the endocardium of the left ventricle. In the area of resection the endocardium is absent and a bare area of myocardium of the interventricular septum is visible. There was also a pulmonary homograft replacement of the aortic valve and a previous patched VSD.

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Figure 4.62 Subaortic fibrous shelf. (A) Subaortic fibrous ridge causing subaortic stenosis. There is fibrosis of the endocardium of the left ventricular outflow tract over the interventricular septum. Immediately below the valvar leaflets this is accentuated as a shelf-like projection. (B) Histological section of the left ventricular outflow. The pulmonary valve is cut in cross section at the top right. The left ventricle is to the bottom left and the aorta to the top middle. The anterior leaflet of the mitral valve descends to the bottom of the picture. Two cusps of the aortic valve are visible, and they appear unremarkable. Projecting into the lumen of the left ventricular outflow tract there is a fibrous ridge arising from the endocardium.

Figure 4.63 A long-axis view of the heart. There is hourglass constriction of the aorta just above the level of the aortic valve with severe narrowing of the lumen. The valve is thickened and stenotic.

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Figure 4.64 Supravalvar aortic stenosis. A case of supravalvar aortic stenosis viewed from the aorta looking at the aortic valve. The constriction of the aortic lumen above the valve is visible.

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Figure 4.65 Supravalvar aortic stenosis – histology. The aorta at the level of the supravalvar stenosis. The left-hand side of the field shows a normal arrangement of elastic laminae, but at the right there is separation and disorganisation of the fibrils.

Figure 4.66 Hypoplastic left heart. This explanted heart, cut in a simulated long-axis view, shows mitral and aortic atresia and a slit-like left ventricular cavity without endocardial fibrosis. The aorta is connected to the left ventricle only by a fibrous cord. Part of the pulmonary valve is included in the cut, and there is also a right ventriculotomy scar beneath it.

A small subgroup of patients exists with TGA and persistent pulmonary hypertension of the newborn who have an unusually poor outcome [97].

4.10.3 Atrial Switch Operations (Mustard and Senning)

Figure 4.67 Hypoplastic left heart with VSD. A fetus of 20 weeks’ gestation with hypoplasia of the mitral valve, a small bicuspid aortic valve and hypoplasia of the aortic arch. The left ventricle is small and non-apex forming. The left ventricle has been opened to display the septum. There is a perimembranous VSD beneath the aortic valve. Note the small size of the aorta compared to the pulmonary trunk. An inlet muscular VSD is also visible as a horizontal slit on the posterior aspect of the septum about mid-way down.

In the past, atrial switch, as opposed to arterial switch, operations have been performed for correction of transposition. These operations effectively create discordant atrioventricular connections. They employ baffles inserted into the atria to redirect the systemic venous return to the mitral valve and the pulmonary venous return to the tricuspid valve (Figures 4.83 and 4.84). The Senning operation employs autologous material, while the Mustard operation employs autologous and synthetic materials [98]. Because both involve extensive incisions and suturing in the atria, they are prone to atrial arrhythmias. Late mortality is of the order of 5%, and the commonest causes are sudden death and systemic ventricular dysfunction. Predictors of sudden death are the presence of

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Figure 4.68 Hypoplastic left heart. A neonate with mitral hypoplasia and aortic stenosis. The aortic valve is nodular and dysplastic, but patent. The left ventricular cavity is small and shows a thick layer of fibroelastic tissue in the endocardium (From Suvarna SK (ed.) Cardiac Pathology: A Guide to Current Practice. London: Springer; 2013, with permission).

Figure 4.70 Hypoplastic left heart – endocardial fibrosis. Five-week-old infant who died suddenly following stage 1 Norwood procedure. The heart is cut in a simulated four-chamber view. Both the left atrium and left ventricle are smaller than the corresponding chamber on the right. The mitral valve is patent, but small, and the left ventricle diminutive. The left ventricle shows an especially prominent layer of endocardial fibroelastic thickening.

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Figure 4.69 Hypoplastic left heart. This fetal heart (23 weeks) is viewed from the front. The ascending aorta is a thin thread compared to the pulmonary trunk. Internally there was mitral and aortic valvar hypoplasia.

Figure 4.71 Hypoplastic left heart – myocardial histology. Histological section of one of the papillary muscles of a hypoplastic mitral valve. There is extensive replacement fibrosis with multiple foci of dystrophic calcification.

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Figure 4.72 Hypoplastic left heart – Damus–Kaye–Stansel anastomosis. (A) One-year-old who died suddenly post stage 2 Norwood. The heart is viewed from the right side following removal of the free walls of the right atrium and right ventricle. The pulmonary trunk has been transected and connected to the ascending aorta, the latter having been augmented by a patch. The most proximal part of the aorta has not been opened but is identified by the origin of the right coronary artery on the epicardial surface of the supraventricular crest. (B) Further dissection reveals the proximal aorta anastomosed to the pulmonary trunk. The suture lines of the augmenting patch are just visible above the anastomosis.

symptoms and of atrial arrhythmias [99]. Less common, but significant, late complications are obstruction of the venous pathways and pulmonary arterial hypertension [100].

4.10.4 Rastelli Operation If a VSD is present with unresectable left ventricular outflow obstruction, then a Rastelli procedure may be undertaken. In this operation a patch is placed to direct blood from the left ventricle through the VSD to the aorta. The pulmonary valve is oversewn, and continuity is established between the right ventricle and the pulmonary artery by means of a valved conduit (Figure 4.85). As with all conduits, these conduits are subject to deterioration and obstruction over time. Figure 4.73 Hypoplastic left heart – bidirectional Glenn shunt. Stage 2 Norwood. There are dense fibrous adhesions over the heart because of previous surgery. The DKS anastomosis is not clearly seen. The superior caval vein is anastomosed to the right pulmonary artery near its junction with the left.

4.10.5 Congenitally Corrected Transposition As noted above, the term congenitally corrected transposition refers to discordant ventriculoarterial connections in the setting of discordant atrioventricular connections [86]. The

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Figure 4.74 Hypoplastic left heart – hybrid procedure. (A) In this heart a metal stent has been placed in the arterial duct between the pulmonary trunk below and the descending aorta above. One of the pulmonary artery bands is clearly visible – that on the left pulmonary artery. The separate views show the bands around the right pulmonary artery (B) and the left pulmonary artery (C).

vast majority of these hearts have associated cardiac malformations with most having abnormalities of the tricuspid valve, a VSD or subpulmonary obstruction (Figure 4.86). Some form of surgical intervention is usually required and depends on the

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precise abnormality, and ranges from systemic-to-pulmonary artery anastomosis to both atrial and arterial redirection or single-ventricle palliation [101]. Late cardiovascular complications are common.

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Figure 4.75 Transposition of the great arteries. Sudden unexpected death within minutes of a normal term delivery. At post-mortem there was transposition. Viewed from the front, the heart shows an anterior aorta and posterior pulmonary trunk with left-sided arch and arterial duct. The left coronary artery supplies the anterior interventricular artery. The posterior interventricular artery arose from the right coronary artery.

Figure 4.76 Transposition of the great arteries. Transposition identified on second day of life. Sudden deterioration and death before septostomy could be performed. The heart is cut in a simulated long-axis view and demonstrates the characteristic parallel arrangement of the great arteries. The aorta is anterior (to the left of the field) and arises from the right ventricle: only the valve is seen. The left ventricle gives rise to the pulmonary trunk. The arterial duct was closed.

Figure 4.77 Transposition of the great arteries – Rashkind septostomy. The interatrial septum and included oval fossa are viewed from the right atrium. The flap valve shows a horizontal tear along its length, the result of balloon septostomy.

4.11 Common Arterial Trunk (Truncus Arteriosus) This lesion is uncommon, accounting for only about 0.5% of all cases of structural congenital heart disease. A single arterial trunk arises from the base of the heart that gives rise to the pulmonary arteries, the systemic arteries and the coronary

arteries (Figure 4.87). Self-evidently, there is a subarterial VSD (Figure 4.88). The truncal valve may have three, two, four or even five leaflets and may be dysplastic (Figure 4.89). Variation in the origin of the pulmonary arteries from the trunk is the basis of the classification of this lesion [102]: type I shows a single pulmonary artery arising from the trunk, which then divides into right and left pulmonary arteries (Figure 4.90). In type II the pulmonary arteries arise separately, but very close together, from the trunk. In practice, it can be very difficult to distinguish between these two. In type III – the least common type –the origins of the pulmonary arteries from the trunk are widely spaced. If there is complete absence of the intrapericardial pulmonary arteries and the lungs are supplied by MAPCAs, the lesion is best designated as solitary arterial trunk, since there is no way of knowing whether had the pulmonary arteries been present they would have been connected to the trunk (common arterial trunk) or

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Figure 4.78 Transposition of the great arteries. A dissection of the outflow of a fetal heart with transposition. The interventricular septum is to the bottom of the picture. The left ventricle is to the left and the right ventricle to the right. The aorta (identified by the presence of a coronary artery orifice) arises from the right ventricle and the pulmonary trunk from the left ventricle. Note the parallel ascent to the great arteries. Beneath the origins of the great arteries, and separated from them by muscle, there is a muscular VSD.

Figure 4.80 Taussig–Bing heart. The heart is opened by removing the anterior wall of the right ventricle. Both great arteries arise from the right ventricle: the aorta arises anteriorly with a complete muscular infundibulum. There is subpulmonary VSD. In addition, there is muscular subpulmonary obstruction.

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Figure 4.79 Transposition of the great arteries – interrupted aortic arch. Neonatal transposition. The aorta arises anteriorly from the right ventricle and gives rise to the brachiocephalic and left common carotid arteries. The arch is then interrupted. The pulmonary trunk arises to the left and slightly posterior to the aorta and via the arterial duct gives rise to the left subclavian artery and descending aorta.

to the ventricular mass (pulmonary atresia with VSD) [103]. The arterial duct is usually, but not invariably, absent. There may be interruption of the aortic arch in such cases. The coronary artery origins and course are abnormal [104]. If the truncal valve is competent, there are few or no symptoms in the first couple of weeks of life. Falling pulmonary vascular resistance with consequent increased pulmonary blood flow leads to the development of breathlessness and heart failure. If the valve is incompetent, symptoms occur in the first days of life. Surgical correction is usually undertaken in the neonatal period. It involves closing the VSD in such a way as to direct the left ventricular blood to the trunk, detaching the pulmonary arteries from the trunks and connecting them via a conduit to the right ventricle, avoiding injury to the coronary arteries, and repair of the truncal valve (Figure 4.91).

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4: Congenital Heart Disease (I)

Figure 4.81 Arterial switch operation. (A) A close-up view of the operation site in the neo-aorta. The site of transection of the artery is visible as a horizontal line of suturing across the entire middle of the field. The coronary artery orifice with a surrounding cuff of arterial wall has been sutured into the vessel above the cusp of the valve. (B) The neo-pulmonary artery again shows the circumferential suture line. The defects in the vessel created by removal of the coronary artery buttons are closed with pericardium.

Figure 4.82 Transposition of the great arteries – coronary artery. A case of transposition in a neonate. The coronary arteries arose from the facing sinuses of the aortic valve; the right coronary artery gives rise to the anterior interventricular artery, a marginal branch supplying the right ventricle and the posterior interventricular artery. The left coronary artery gave rise to the left circumflex artery only. Variant patterns of coronary artery anatomy in transposition are more prevalent when the great arteries have a side-by-side arrangement than when the aorta is anterior.

Figure 4.83 Transposition – Mustard atrial switch operation. Explanted heart from a case of transposition that had undergone a Mustard operation. There is atrial situs solitus. There has been previous atrial switch operation connecting the inferior and superior caval veins posteriorly to the left atrioventricular valve and the pulmonary veins directed anteriorly towards the right atrioventricular valve. Note the thickened right ventricular wall.

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4: Congenital Heart Disease (I)

Figure 4.84 Transposition - Senning atrial switch operation. Sudden death in a patient 20 years after Senning operation for transposition. (A) The right side of the heart exposed by removal of its free wall. The aorta arises via a complete muscular infundibulum from the right ventricle – this is the systemic ventricle. The atrial mass has been reconfigured so that the pulmonary venous channel is behind the systemic venous channel and emerges above the tricuspid valve. The systemic venous component lies posterior to the plane of the picture. (B) A pair of forceps has been inserted into the IVC emerging from the SVC to demonstrate that the pulmonary venous channel runs behind the systemic channel, curving round at the right border of the heart, like a hockey stick, to reach the right atrioventricular junction. (C) The left side of the heart is dissected to show the pulmonary artery arising from the left ventricle – note the thinness of the wall. The systemic venous blood is directed to the left atrioventricular junction. Part of the pulmonary venous chamber is seen to the left of the picture above the pulmonary artery.

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Figure 4.85 Rastelli operation. Transposition with VSD and pulmonary stenosis. Rastelli operation in a child aged three and sudden death some 20 years later. (A) The right ventricle opened to display the septum. There is dense endocardial fibrosis over a patched VSD visible to the right of the septal leaflet of the tricuspid valve. Further to the right the suture line of the right ventricular conduit is visible. Pale flecks of calcification are seen around it. (B) From the left side the lower margins of the original VSD are readily appreciated. There is considerable surrounding endocardial fibrosis. The aorta has been committed to the left ventricle by a ventricular patch inserted horizontally in the right ventricle approximately 1.0 cm below the aortic valve and connecting the right ventricular aspect of the inferior margin of the VSD to the right ventricular parietal wall. This has created a recess below the aortic valve, the entrance to which is the margin of the previous VSD. The original pulmonary trunk was disconnected from the heart and anastomosed to the right ventricular conduit. Its original cardiac connection is visible as a rugose area separated by a thin fibrous septum from the upper posterior border of the VSD (upper right in this view).

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4: Congenital Heart Disease (I)

Figure 4.87 Common arterial trunk. A fetal heart with common arterial trunk. The pulmonary trunk arises from the common trunk above the level of the left atrial appendage.

Figure 4.86 Congenitally corrected transposition. Congenitally corrected transposition with pulmonary atresia and VSD treated with patch to the VSD and valved right-sided ventricle to pulmonary artery conduit. Sudden death aged ten years. (A) The right side of the heart. The right atrium is connected to a morphologically left ventricle. A heavily calcified valved conduit has been sewn into the anterior wall of the ventricle. (B) The left side of the heart shows the left atrium connected to a morphologically right ventricle that shows prominent hypertrophy. Arising via a complete muscular infundibulum is the aorta. A VSD with patch is not visible in either view because it lies in the inlet beneath the atrioventricular valve leaflets.

Figure 4.88 Common arterial trunk. A heart with common arterial trunk opened and viewed from the right side. The obligatory VSD lies immediately beneath the truncal valve. The trunk overrides the defect.

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Figure 4.90 Common arterial trunk. Common arterial trunk at 21 weeks’ gestation. The trunk is viewed from above. The pulmonary arteries arise from the posterior aspect very close together – type II trunk.

Figure 4.89 Common arterial trunk. Common arterial trunk at 23 weeks’ gestation. The right ventricle has been opened to display the ventricular outlet and subtruncal VSD. The truncal valve is well seen. In this instance it comprised three cusps that were thickened.

Figure 4.91 Common arterial trunk – surgical correction. A neonate with type II common arterial trunk. The pulmonary arteries have been disconnected from the trunk and connected to a conduit from the right ventricle (superior). The truncal valve was quadricuspid and was reduced to three cusps.

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86. Ghanayem NS, Allen KR, Tabbutt S et al.; Pediatric Heart Network Investigators. Interstage mortality after the Norwood procedure: results of the multicenter Single Ventricle Reconstruction trial. J Thorac Cardiovasc Surg 2012; 144: 896–906.

96. Dodge-Khatami A, Mavroudis C, Mavroudis CD, Jacobs JP. Past, present, and future of the arterial switch operation: historical review. Cardiol Young 2012; 22: 724–731.

87. Wilder TJ, McCrindle BW, Hickey EJ et al.; Congenital Heart Surgeons’ Society. Is a hybrid strategy a lower-risk alternative to stage-1 Norwood operation? J Thoracic Cardiovasc Surg 2017; 153: 163–172. 88. Allwork SP, Bentall HH, Becker AE et al. Congenitally corrected transposition of the great arteries: morphologic study of 32 cases. Am J Cardiol 1976; 38: 910–923. 89. Yacoub MH, Radley Smith R. Anatomy of the coronary arteries in transposition of the great arteries and methods of their transfer in anatomical correction. Thorax 1978; 33: 418–424. 90. Anderson RH, Henry GW, Becker AE. Morphologic aspects of complete transposition. Cardiol Young 1991; 1: 41. 91. Konstantinov IE. Taussig-Bing anomaly: from original description to the current era. Tex Heart Inst J 2009; 36: 580–585. 92. Fraser CD Jr. The neonatal arterial switch operation: technical pearls. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2017; 20: 38–42. 93. Pasquali SK, Hasselblad V, Li JS, Kong DF, Sanders SP. Coronary artery pattern and outcome of arterial switch operation for transposition of the great arteries: a meta-analysis. Circulation 2002; 106: 2575–2580. 94. Lacour-Gayet F. Complexity stratification of the arterial switch

97. Roofthooft MT, Bergman KA, Waterbolk TW et al. Persistent pulmonary hypertension of the newborn with transposition of the great arteries. Ann Thorac Surg 2007; 83: 1446–1450. 98. Warnes CA. Transposition of the great arteries. Circulation 2006; 114: 2699–2709. 99. Kammeraad JA, van Deurzen CH, Sreeram N et al. Predictors of sudden cardiac death after Mustard or Senning repair for transposition of the great arteries. J Am Coll Cardiol 2004; 44: 1095–1102. 100. Ebenroth ES, Hurwitz RA, Cordes TM. Late onset of pulmonary hypertension after successful Mustard surgery for dtransposition of the great arteries. Am J Cardiol 2000; 85: 127–130. 101. Kutty S, Danford DA, Diller GP, Tutarel O. Contemporary management and outcomes in congenitally corrected transposition of the great arteries. Heart 2018; 104: 1148–1155. 102. Collett RW, Edwards JE. Persistent truncus arteriosus: a classification according to anatomic types. Surg Clin N Amer 1949; 29: 1245–1270. 103. Crupi G, McCartney FJ, Anderson RH. Persistent truncus arteriosus. A study of 66 autopsy cases with special reference to definition and morphogenesis. Am J Cardiol 1977; 40: 569–578. 104. de la Cruz MV, Cayre R, Angelini P, Noriega-Ramos N, Sadowinski S. Coronary arteries in truncus arteriosus. Am J Cardiol 1990; 66: 1482–1486.

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5.1 Double Inlet Ventricle

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This term describes an atrioventricular connection (univentricular atrioventricular connection): both atria are connected to one ventricle, either a morphologically right or morphologically left ventricle – the dominant ventricle (Figure 5.1). The inlet may be via two separate valves or via a common valve. There may be straddling of one valve (Figure 5.2). The other

ventricle is usually rudimentary and connected to the dominant ventricle via a VSD. By definition the rudimentary ventricle lacks a connection with the atria but is connected to one of the great arteries. The term univentricular heart is sometimes even applied to these cases. Two ventricles, albeit one rudimentary, are present, but the heart is functionally univentricular [1].

Figure 5.1 Double inlet left ventricle (DILV). Heart sectioned in four-chamber view. There is a dominant left ventricle that occupies all the ventricular area. Both atrioventricular valves open into this ventricle. On the right of the field towards the atrioventricular junction the ventricular wall is thickened; this represents the posterior aspect of the rudimentary right ventricle. As is usual in DILV, the aorta arose from the rudimentary ventricle and there was subpulmonary stenosis.

Figure 5.2 Double inlet left ventricle: four-chamber view looking from posteriorly. The rudimentary right ventricle is to the left of the field with a restrictive VSD. The left atrioventricular valve straddles the VSD but is committed for most of its area to the dominant left ventricle. Pacing leads are visible on the left of the picture. This reflects the abnormalities of atrioventricular conduction frequent in double inlet left ventricle.

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Figure 5.3 An explanted heart with double inlet left ventricle cut to demonstrate the right atrioventricular junction, VSD, both ventricular cavities and both ventriculoarterial junctions. The pulmonary artery arises from the left ventricle and the aorta from the rudimentary right ventricle. The VSD is restrictive. There is a muscular outlet septum above the VSD and separating both arterial valves.

5.1.1 Double Inlet Left Ventricle This is the commoner of the two forms of double inlet ventricle [2]. The left ventricle is identified by the pattern of trabeculations on its apical septal surface. The rudimentary right ventricle is usually situated on the anterosuperior aspect of the ventricular mass and is delimited externally by the epicardial coronary arteries. In most cases, there is discordance of the ventriculoarterial connections, the pulmonary artery arising from the dominant left ventricle and the aorta from the rudimentary right ventricle (Figure 5.3). The VSD is usually restrictive (Figure 5.4), and there is coarctation of the aorta. There may be subpulmonary stenosis. The conduction tissue is abnormally located and the origins and epicardial distribution of the coronary arteries may be variable (Figure 5.5). There may be atrial isomerism. The term “Holmes’ heart” is applied if the ventriculoarterial connection is concordant.

5.1.2 Double Inlet Right Ventricle This malformation is very rare and extreme forms may show double inlet and double outlet from the dominant right ventricle (Figure 5.6). The rudimentary left ventricle lies posteroinferiorly in the ventricular mass. Very rarely no rudimentary second chamber can be identified in the ventricular mass, and the dominant chamber is then characterised as indeterminate. A Fontan operation is the usual surgical treatment of double inlet ventricle. A subset of patients can benefit from septation of the ventricle without the need for Fontan [3, 4].

Figure 5.4 (A) DILV. Close-up view of the ventricular septal defect. The defect is itself restrictive, but there is further narrowing of the aortic outflow by a hypertrophied muscular trabeculation immediately beneath the aortic valve. (B) Another case of DILV. The ventricular septal defect is visible in the centre of the field. It is narrow and is further narrowed by circumferential endocardial thickening around its edges.

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5.2 Double Outlet Ventricle This term describes a ventriculoarterial connection in which both great arteries (or to be more precise, more than half of each great artery) arise from the same ventricle [5]. Naturally, that ventricle may be either a right or a left ventricle – or even an indeterminate one. The term encompasses many conditions, some dominated by other features such as atrial isomerism.

5.2.1 Double Outlet Right Ventricle (DORV)

Figure 5.5 DILV. The roots of both great arteries have been transected and viewed from above. The aortic valve is anterior and to the left of the pulmonary valve. Both coronary arteries arise from the right-facing sinus (Sinus 1) of the aortic valve. The pulmonary valve is bicuspid and dysplastic.

Double outlet from the right ventricle is much commoner than double outlet from the left ventricle, albeit both conditions are rare. In the setting of usual atrial arrangement and concordant atrioventricular connections, DORV shows a VSD – usually of perimembranous type – located between the limbs of the septomarginal trabeculation, beneath the outflow tract of the aortic valve. When both valves arise exclusively from the right ventricle, the aorta has a complete muscular infundibulum and

Figure 5.6 (A) Double inlet right ventricle. Heart cut in a four-chamber view and viewed from behind. There is a common atrioventricular valve that is almost exclusively committed to the dominant right ventricle. The rudimentary left ventricle is present on the left of the field. (B) Double outlet right ventricle. Same heart as in part A, cut to show the ventriculoarterial junctions. The aorta (on the left of the picture) arises from the dominant right ventricle. It is separated by a muscular outlet septum from the pulmonary artery, also arising from the right ventricle (double outlet right ventricle).

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Figure 5.7 Double outlet right ventricle, bilateral muscular infundibulum. Heart from an infant with DORV. The heart is viewed from the right side following removal of its parietal wall. The aorta arises anteriorly (to the right of the picture) with a subaortic VSD. It has a complete muscular infundibulum and is separated from the narrowed pulmonary outflow by a muscular outlet septum. The pulmonary valve is severely stenotic.

Figure 5.8 Double outlet right ventricle of Fallot type. The anterior part of the pulmonary outflow tract has been removed to show the obstruction caused by the anomalous anterior insertion of the supraventricular crest into the anterior limb of the septomarginal trabeculation. The VSD is not well seen. The aorta is to the left of the pulmonary artery.

Double outlet right ventricle is a common feature of hearts with right atrial isomerism, pulmonary atresia or stenosis, occurring in approximately half of the cases. Coronary artery abnormalities are frequent with DORV such as origin of both arteries from the same sinus [6]. The aim of surgical correction is to connect the aorta to the left ventricle without causing obstruction to either arterial outflow [7]. This may involve only the use of a patch (Figure 5.9), but more complex operations involving tunnels and even arterial switch may be required where the anatomy is more complex. Arterial switch is the operation of choice in the Taussig–Bing heart [8].

5.3 Abnormalities of the Pulmonary Veins 5.3.1 A Preliminary Note on Terminology Figure 5.9 Double outlet right ventricle with patched VSD. A one-year-old child with DORV, subpulmonary stenosis and non-restrictive VSD treated by patch of the VSD and RV to PA conduit. The heart shows the aorta lying over the right ventricle, but the patch is inserted in such a way as to commit the aorta to the left ventricle. This new ventricular outflow tract incorporates what was originally part of the right ventricle. The left heart structures are relatively small and the VSD diameter is less than that of the aortic valve (restrictive VSD). Immediately beneath the aorta in the picture lies the RV–PA conduit.

the outlet septum is exclusively a right ventricular structure (Figure 5.7). It shows anterior deviation to cause subpulmonary obstruction. If the aortic valve overrides the VSD, the morphology then resembles that of tetralogy of Fallot (Figure 5.8). A less common variant is where the VSD is subpulmonary, but still between the limbs of the septomarginal trabeculation – the so-called Taussig–Bing heart. There is usually associated subaortic stenosis or coarctation of the aorta. A further variant of DORV shows a juxta-arterial doubly committed VSD with absence of the outlet septum.

Be careful with the terminology used to describe abnormal pulmonary veins. There is a difference between pulmonary venous connection and pulmonary venous drainage. Connection is an anatomical term denoting physical continuity between the pulmonary and systemic veins (either partial or total). Drainage is a physiological term denoting direction of the pulmonary venous blood to the systemic circulation. Thus, one can have normal connection with anomalous drainage as, for example, with a common atrium there is normal pulmonary venous connection but anomalous venous drainage. Anomalous connection with normal drainage does not occur.

5.3.2 Anomalous Pulmonary Venous Connection This may be partial or total [9]. Although the veins may connect separately to an anomalous site, it is more usual for them to join to form a single channel that then connects anomalously. The anomalous connection may be to the heart itself or to the veins draining to the superior caval vein (supracardiac) (Figure 5.10)or to those draining to the

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Figure 5.10 Total anomalous pulmonary venous connection (supracardiac). (A) The pericardium has been removed and the great vessels dissected to demonstrate an abnormal ascending vein that connects with the innominate vein on its left side. This ascending vein was formed by the confluence of the pulmonary veins that showed no attachment to the left atrium. (B) Same case with the heart lifted upwards to demonstrate the confluence of the pulmonary veins and the ascending vein that runs on the left side (right of the field) posterior to the left pulmonary artery. (C) Histological section of the ascending vein to demonstrate the normal pulmonary venous histology.

inferior caval vein (infracardiac) (Figure 5.11). Frequently there is an element of obstruction to flow in the anomalous pathway. Anomalous venous connection may occur as an isolated abnormality but may also occur as part of a more complex malformation. Morphologically, the left atrium is small in total anomalous pulmonary venous connection because of the lack of pulmonary venous inflow. Pulmonary hypertension develops early. (Figure 5.12). Clinically, the infant with non-obstructive total anomalous pulmonary venous connection does not present with symptoms for the first few months of life. Respiratory difficulty and failure to thrive are the commonest features. However, if obstruction is present, the infant presents in the first few days of life with cyanosis and respiratory difficulty. The sites of infracardiac connection include portal vein, hepatic vein and ductus venosus. Connection is rarely directly

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to the inferior caval vein. Obstruction is much more likely with infracardiac connection (Figure 5.11). Supracardiac connection is commoner and may be to superior caval vein (on either side), azygos vein or innominate vein. Cardiac connection is almost always to the coronary sinus. Total anomalous pulmonary venous connection is usual in right atrial isomerism. Partial anomalous pulmonary venous connection may involve one or more veins and may involve the drainage from a whole lung. Partial anomalous connection is an integral part of the sinus venosus ASD. It is also a component of the scimitar syndrome [10]. The aims of surgical correction are to achieve connection of the pulmonary veins to the left atrium without compromise to either systemic or pulmonary venous pathways. In the case

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Figure 5.11 Total anomalous pulmonary venous connection (infracardiac). A dissection of the posterior aspect of the liver following removal of part of the quadrate and left lobes. The inferior caval vein runs obliquely over the right upper field and the portal vein on the lower left. The hepatic artery and its branches are retracted adjacent to the gallbladder. The fibrous remnant of the venous duct connects the upper border of the portal vein confluence to the inferior caval vein. The upper forceps grasp the cut end of the descending pulmonary venous confluence that enters the left portal vein.

Figure 5.12 Obstructed total pulmonary venous connection – pulmonary venous hypertension. A histological section from the lung shows a large pulmonary vein with a greatly thickened wall caused by medial and intimal deposition of collagen and elastic tissue (EvG stain).

Figure 5.14 Pulmonary vein stenosis. The left atrium has been opened from behind to display the internal aspect of the pulmonary vein orifices. They are narrower than normal, albeit the external dimensions of the pulmonary veins are normal. The orifice of the left upper vein is completely occluded. Figure 5.13 Total anomalous pulmonary venous connection – reconnection of pulmonary veins to the left atrium. Three-day-old infant who died following repair of total anomalous pulmonary venous connection. The heart is viewed from behind. The cannula tips are inserted in the five pulmonary veins that have been anastomosed into the wall of the left atrium.

of connection to the coronary sinus this can usually be effected by simple excision of the roof of the sinus. For supracardiac and infracardiac defects the anomalous pulmonary veins are connected directly to the left atrium (Figure 5.13). Mortality rates may approach 10% [11].

5.3.3 Pulmonary Vein Stenosis Pulmonary vein stenosis usually affects all four pulmonary veins, but may be unilateral or affect a single vein [12]. The

vein is affected at its junction with the left atrium; the stenosis can be discrete or tubular. The narrowing may be visible externally or the affected vessels may appear macroscopically normal from the outside (Figure 5.14) [12, 13]. Obstruction to the pulmonary venous return causes pulmonary hypertension: the pulmonary veins show medial hypertrophy and fibrous intimal thickening. The parenchymal pulmonary arteries show medial hypertrophy with or without intimal fibrous proliferation (Figure 5.15). Plexiform lesions are not seen. The changes of pulmonary arterial hypertension may be present in both lungs, even in the presence of unilateral stenosis. Histologically, the stenotic segment of vein shows fibroelastic thickening of the intima (Figure 5.16) [13]. There may be

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Figure 5.15 Pulmonary vein stenosis – histology of the lungs. There is pulmonary arterial hypertension. The muscular pulmonary arteries are tortuous and show muscular thickening of their tunica media. The small arteries are muscularised and there is very prominent dilatation of lymphatic vessels in the connective tissue of the bronchovascular bundle.

Figure 5.16 Pulmonary vein stenosis. (A) Cross section of an affected segment of vein. The vessel is extremely thick-walled and the lumen slit-like. (B) Longitudinal section showing a plug of fibrovascular tissue occluding the lumen.

Figure 5.17 Ebstein’s anomaly. The right atrioventricular junction is viewed from the right side. The true atrioventricular junction in this picture runs in an arc from just beneath the coronary sinus to the pin head on the lower border used to fix the specimen in place. The septal leaflet of the AV valve is poorly formed and is not attached at this junction. Rather, it descends almost vertically from the medial commissure leaving a triangle of thinned ventricular myocardium above it as part of the right atrium.

associated disruption and irregularity of the media. There may be associated intracardiac abnormalities. The stenosis is congenital and is thought to develop in utero after the incorporation of the pulmonary veins into the left atrium. The lesions may progress by the development of thrombus. In its most severe form, congenital pulmonary vein stenosis is a progressive disease with rapid pulmonary hypertension and rare survival beyond the first year of life. Surgical intervention has not been successful in this group.

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5.4 Ebstein’s Malformation The essential defect in this malformation is an abnormally low attachment of the tricuspid valve. The attachment, instead of being at the atrioventricular junction, is in the inlet part of the right ventricle [14]. The valvar tissue, therefore, is attached to myocardium rather than the fibrous tissue at the atrioventricular junction. The septal and inferior leaflets show the abnormal attachment, and the septal leaflet is sometimes no more than a row of nodular excrescences descending towards the apex in an oblique line on the right aspect of the interventricular septum (Figure 5.17). The anterosuperior leaflet is also abnormal, being large and rectangular and attached to the papillary muscles in such a way as to obstruct the inflow (Figure 5.18). The valvar tissue is frequently dysplastic with excess of redundant valvar tissue. The area of ventricular myocardium incorporated into the right atrium by the abnormally low attachment of the valve becomes thin and

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Figure 5.19 Ebstein’s anomaly – atrialisation of the right ventricle. This fourchamber view of the heart shows that most of the right ventricle is incorporated into the right atrium. Only a shallow crescent of the cavity lies beneath the level of the AV valve.

Figure 5.18 Ebstein’s anomaly: anterosuperior leaflet. (A) The leaflet is abnormal in shape and shows numerous short chordal attachments to the papillary muscle forming a barrier to inflow of blood at this site. (B) Viewed from the right side, the obliteration of the normal pathway is evident. Blood is directed superiorly through the side of the leaflet rather than to the apex.

“atrialised” (Figure 5.19). The valve is incompetent, and there is massive dilatation of the right atrium (Figure 5.20). Pulmonary stenosis (or atresia) is a frequent association. The condition may present in utero with cardiac failure and hydrops. There is also frequently associated Wolff–Parkinson–White syndrome [15]. In congenitally corrected transposition, the left-sided tricuspid valve may show Ebstein’s malformation (Figure 5.21) [16]. Surgical repair depends on the severity of the displacement of the septal and inferior leaflets and involves mobilisation of the anterosuperior leaflet, reduction of the diameter of the annulus and longitudinal plication of the atrialised right ventricular wall [17].

5.5 Tricuspid Atresia The tricuspid valve may be very small in pulmonary atresia with intact septum, analogous to the mitral valve in

Figure 5.20 Ebstein’s anomaly – right atrial dilatation. The heart is viewed from the right side. Dysplastic valvar tissue is attached to the interventricular septum. The right atrium is dilated and is larger than the right ventricle.

hypoplastic left heart (Figure 5.22). It may at times be only a thin membrane occluding a small right atrioventricular junction. In both these instances there is a distinct right atrioventricular junction. In tricuspid atresia, by contrast the right atrium is separated from the right ventricle by a layer of muscle. Tricuspid atresia is an uncommon malformation where there is complete absence of the tricuspid valve, its site being marked by a dimple in the floor of the right atrium that is not the valve, but rather the atrioventricular membranous septum (Figure 5.23) [18]. Tricuspid atresia is associated with ASD with all the systemic venous return passing to the left ventricle; the right ventricle is small, even rudimentary, and, of necessity, connected to the left ventricle via a VSD, which is frequently restrictive (Figure 5.24) [1]. The ventriculoarterial connections are usually concordant, the restrictive VSD thus

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Figure 5.22 Tricuspid valvar stenosis. Four-month-old infant with pulmonary atresia with intact septum. A simulated four-chamber view of the heart shows hypertrophy of the walls of the right atrium and right ventricle. The right ventricular cavity is small and the right AV valve small in comparison with the left. Figure 5.21 Ebstein’s anomaly of left AV valve in congenitally corrected transposition. (A) The heart is cut in a simulated four-chamber view and viewed from the front. The left ventricle is on the left of the picture and the right ventricle on the right. Low attachment of the left atrioventricular valve leaflets gives a cup-like area of the left-sided ventricle that is atrialised. (B) An unfixed heart cut in a simulated long-axis view showing the attachment of the left atrioventricular valve half way between the atrioventricular junction and the ventricular apex causing the upper part of the ventricle to be incorporated into the left atrium.

causing subpulmonary stenosis. A persistent Chiari network may be found in the right atrium in association with tricuspid atresia (Figure 5.25) [19]. Surgical palliation is by Fontan operation and may require staging [20].

5.6 Other Abnormalities of the Tricuspid Valve 5.6.1 Unguarded Tricuspid Orifice This is a condition that clinically may mimic tricuspid atresia. It occurs in the setting of pulmonary atresia with intact

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septum. The right atrioventricular junction is widely patent but shows no atrioventricular valvar tissue. In contrast to most cases of pulmonary atresia with intact septum, where the right ventricle is small and very muscular, in unguarded tricuspid orifice the right ventricle is very dilated and very thin-walled. Papillary muscles are not discernible. The condition may occur on the left side in congenitally corrected transposition. When Ebstein’s malformation is present but with right ventricular dilatation, the condition may be difficult to distinguish from congenitally unguarded tricuspid orifice (Figure 5.26) [21].

5.6.2 Absent Commissure In cases of trisomy 21, there may be a defect in the tricuspid valve with absence of the commissure between the anterosuperior and septal leaflets, sometimes associated with enlargement of the membranous septum (Figure 5.27) [22].

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Figure 5.24 Tricuspid atresia. Heart cut in a simulated four-chamber view. There is no communication between the right atrium and right ventricle. They are separated by a double layer of myocardium. There is an ASD and a VSD. The left ventricle is dilated.

Figure 5.23 Tricuspid atresia. The heart is cut in a simulated four-chamber view and viewed from behind. The right atrium and right ventricle are both small, and there is no connection between them. The left ventricular cavity is dilated and shows endocardial fibrosis. There is a large VSD between the ventricles.

Figure 5.26 Unguarded tricuspid orifice. Fetal heart from a fetus who died of fetal hydrops. The heart is cut in a simulated four-chamber view. The left atrium and ventricle are of normal size, but the right ventricle and right atrium are greatly dilated and thin-walled. No tricuspid valvar tissue is identified.

5.7 Uhl’s Anomaly

Figure 5.25 Ebstein’s anomaly and Chiari network. The right atrium and right ventricle have been opened and displayed. A large sac-like Chiari network with fenestration of its basal part near its attachment to the atrial wall is visible in the upper part of the field.

This describes the very rare condition of congenital absence of the myocardium of the parietal wall of the right ventricle [23]. It may be detected in utero [24]. It can present into adulthood, but in the neonatal period presents as cyanosis and congestive heart failure [25]. The right atrium is hypertrophied and dilated with endocardial thickening. The right ventricle is very dilated and very thin-walled. There is near complete absence of the myocardium of the parietal wall of the right ventricle. The interventricular septum is unremarkable, and the septomarginal trabeculation and the papillary muscles of the tricuspid valve are normally muscularised. The tricuspid valve is

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Figure 5.27 Medial commissure tricuspid valve in trisomy 21. The membranous septum is enlarged and the valvar tissue of the septal and anterosuperior leaflets of the tricuspid valve does not quite meet over the septum. Viewed from the left side, such hearts show the plunging crest of the muscular interventricular septum that equates to the scooped-out crest seen in atrioventricular septal defect.

Figure 5.28 Uhl’s anomaly. Endomyocardial biopsy from a one-year-old boy. On echocardiography thin-walled right ventricle with dilated but normally sited tricuspid valve. The trabeculations are weedy and contain scant myocardium with thickening of the endocardium. On their own these features are not diagnostic of Uhl’s anomaly but in context are in keeping with the diagnosis.

normal. The extent of thinning of the free wall of the right ventricle varies, sometimes the entire free wall, including the apex, being free of muscle and in other cases, the apical trabeculations persisting, albeit in an atrophic state (Figure 5.28). Histologically, the parietal wall shows apposition of the endocardium and epicardium, separated by a thin layer of elastic and fibrous tissue with no fatty tissue interposed between these layers. These changes are present at birth and may be detected in utero. There has been confusion of Uhl’s anomaly with arrhythmogenic right ventricular cardiomyopathy (ARVC) in the literature in the past [26]. ARVC is characterised by patchy replacement of the parietal wall of the right ventricle by fibrofatty tissue. This adipose replacement occurs primarily within the ventricular outflow tract, but can also be seen in the inlet or apical regions, sometimes spreading to involve the left ventricle [26]. ARVC is not seen in children below the age of nine to ten years. Table 5.1 shows the differentiation of the various forms of thin-walled right ventricle. Surgical treatment of Uhl’s anomaly usually consists of plication of the ventricle and establishment of cavo-pulmonary anastomosis [27].

morphology of the atrial appendage. As noted in the section on normal anatomy, the right atrium has an appendage that is broad and triangular with a broad junction with its atrium and pectinate muscles that completely surrounds the AV valve orifice; the left atrial appendage is long and tubular with a distal hook, a narrow junction with its atrium and pectinate muscles confined to the appendage proper. Atrial isomerism, thus, can occur in right or left forms. Atrial isomerism may exist without other disturbance of laterality, but frequently occurs with isomerism of the bronchial arrangement (Figure 5.29) [28]. Normally, the right main bronchus is short and epiarterial, is that to say, it gives off its upper lobe branch at the same level as the pulmonary artery. The normal left main bronchus is long and hyparterial, that is to say, it divides below the level of the pulmonary artery on that side. In right bronchial isomerism both bronchi are short and epiarterial, while in left bronchial isomerism, both bronchi are long and hyparterial. There may be isomerism of other organs (see below). Within the chest the heart is often abnormally positioned and may be on the right, the left or in the middle, and, likewise, the apex may be directed to the left, the right or centrally [29].

5.8 Atrial Isomerism

5.8.1 Right Atrial Isomerism

Atrial isomerism represents complex anomalies of laterality. The normal arrangement of left and right atria is abolished and instead the heart has either two morphologically right atria or two morphologically left atria. It should be stressed that there is still a right-sided atrium and a left-sided atrium, but that both atria have the characteristics of either a morphologically right or of a morphologically left atrium. The recognition of morphologically right or left atrium depends on the

By definition, these hearts show bilateral morphologically right atrial appendages. Usually there are bilateral superior caval veins entering the roof of the atrial chamber (Figure 5.30). The inferior caval vein may be a central structure or may, less commonly, be bilateral. The interatrial septum is usually rudimentary. The coronary sinus is absent because, although draining to the right atrium, the coronary sinus is, in effect, a left-sided structure. The pulmonary venous connection is

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5: Congenital Heart Disease (II) Table 5.1 Differentiation of dilated, thin-walled right ventricle

Uhl’s anomaly

ARVC

Ebstein’s anomaly

Unguarded tricuspid orifice

RV dilatation

+++

++

+/

+++

RA dilatation

+

++

++

Fibrosis RV

++

Inlet

++

Fat RV

++ +++

Tricuspid valve

N

N

Displaced septal leaflet

Absent

Pulmonary valve

N

N

N/atretic

Atretic

Usual age at presentation

Neonate

Adolescent and older

Infant and child

Neonate

Associated cardiac malformations

+/

+

+

Arrhythmia

+++

+/

N, normal.

Figure 5.29 Bronchial isomerism. (A) Right atrial isomerism. The heart has been removed to demonstrate the trachea and bronchi. Both main bronchi are short and lie practically horizontally, in keeping with right bronchial morphology. There is anomalous pulmonary venous connection with the pulmonary veins coming to a confluence beneath the carina and ascending behind the trachea. (B) Left atrial isomerism. The main bronchi are again isomeric, but long and unbranched in keeping with left isomerism.

anomalous, to an extracardiac site in most cases. Typically there is double inlet ventricle with a common atrioventricular valve, discordant ventriculoarterial connection or double outlet ventricle with associated pulmonary stenosis or atresia

(Figure 5.31). There may be right bronchial isomerism with bilateral tri-lobed lungs, asplenia and a central liver with symmetrical right and left lobes. The stomach may be on the left or the right side, and there is intestinal malrotation.

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Figure 5.30 Right atrial isomerism. A fetus of 22 weeks’ gestation with isomerism of the right atrial appendages. There were also bilateral superior caval veins, complete atrioventricular septal defect, supracardiac total anomalous pulmonary venous connection, pulmonary atresia and aortopulmonary collateral arteries and absent arterial duct. The heart is viewed from the front after removing the aorta. There are bilateral right atrial appendages and both superior caval veins can be seen. The pulmonary trunk and pulmonary branch arteries are small. The ascending anomalous pulmonary vein can just be made out beneath the left main bronchus.

Figure 5.31 Right atrial isomerism. Double inlet right ventricle with AVSD, discordant VA connection and subpulmonary stenosis. The picture shows the aorta arising from a dominant right ventricle and the pulmonary trunk from a rudimentary left ventricle with VSD. A muscular outlet septum lies between the two outflows above the VSD. The pulmonary outflow is narrow.

Figure 5.32 Left atrial isomerism. A fetus of 13 weeks’ gestation. The heart shows bilateral morphologically left atrial appendages. There was also bilateral superior caval veins, double inlet left ventricle with common atrioventricular valve, rudimentary right ventricle with VSD and lacking an inlet, discordant ventriculoarterial connections with anterior aorta, right-sided stomach with multiple small spleens and intestinal malrotation.

Figure 5.33 Left atrial isomerism; azygos continuation of the IVC. The heart and lungs are viewed from behind; both lungs are bilobed. The aortic arch is left-sided. There are probes in both superior caval veins. An obturator is placed in the connection of the hepatic veins to the heart, and a pair of forceps is inserted into the azygos continuation of the interior caval vein that is greatly dilated and loops forward over the right main bronchus to join with the rightsided superior caval vein.

5.8.2 Left Atrial Isomerism Again, by definition, there are bilateral morphologically left atrial appendages (Figure 5.32). As with right atrial isomerism, there are usually bilateral superior caval veins. Pulmonary venous connection is usually to the atrial mass. Typically, there is interruption of the inferior caval vein with continuation as the azygos vein to the superior caval vein (Figure 5.33). The hepatic veins drain separately to the atria, sometimes bilaterally. The atrial septum tends to be better formed than in

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right isomerism. There is usually an atrioventricular septal defect (Figure 5.34). The ventriculoarterial connection is usually concordant with normal relations of the great arteries. Coarctation or interrupted aortic arch may be present. The viscera may show left bronchial isomerism with bilateral two-lobed lungs, and there may be polysplenia (Figure 5.35). Table 5.2 lists the features of both forms of isomerism of the atrial appendages.

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5: Congenital Heart Disease (II) Table 5.2 Comparison of cardiac morphology in typical cases of right and left atrial isomerism

Feature

RAA

LAA

Atrial appendage

Bilateral right

Bilateral left

Coronary sinus

Absent

Usually present

SVC

Bilateral

Bilateral

Pulmonary veins

Anomalous connection ~50% to extracardiac site

Connect to atrial mass usually bilaterally

IVC

Normal connection

Interruption with azygos continuation

Hepatic veins

Drain to IVC

Drain directly to atria

AV connections

Usually common junction DIRV

Usually common junction

VA connections

Discordant or DORV

Concordant

Ventricular outflow tract

RV outflow obstruction

LV outlet obstruction, coarctation, interruption of aorta

DIRV, double inlet right ventricle; DORV, double outlet right ventricle; LAA, left atrial appendage; RAA, right atrial appendage.

Figure 5.34 left atrial isomerism: AVSD. Fetal heart at 20 weeks’ gestation cut in a simulated four-chamber view and viewed from posteriorly. There is situs inversus with a right-directed apex. There are bilateral left atrial appendages and there is a complete atrioventricular septal defect with bridging leaflet.

Figure 5.35 Left atrial isomerism. Polysplenia. Same case as Figure 5.34. There were multiple right-sided spleens. A histological section shows multiple nodules of splenic tissue.

5.8.3 Juxtaposition of the Atrial Appendages

5.10 Other Abnormalities 5.10.1 Persistent Left Superior Caval Vein

In the normal situation the atrial appendages lie on either side of the great arteries. Sometimes both atrial appendages lie side by side on one side of the great arteries [30]. This situation is termed “juxtaposition of the atrial appendages”, and it is more common for the right atrial appendage to be thus abnormally located (Figure 5.36). This condition is usually associated with other cardiac malformations, particularly complete transposition [31].

5.9 Structural Abnormalities of the Coronary Arteries These are dealt with in some detail in the separate chapter on the coronary arteries.

This is a relatively frequent occurrence (approximately 0.5% of the general population) [32] and may occur in an otherwise normal individual. Its incidence is increased in association with congenital heart disease, and it is an almost invariable finding with right atrial isomerism (Figure 5.37). The vein drains to the coronary sinus, and the blood enters the right atrium. There is absence of the innominate vein in about 40% of cases.

5.10.2 Aberrant Origin of Right Subclavian Artery In this anomaly the right subclavian artery does not take origin from the brachiocephalic artery but from the left side

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Figure 5.37 Persistent left superior caval vein. Intrauterine fetal death from retroplacental haemorrhage at 24 weeks’ gestation. Following removal of the pericardium there are bilateral superior caval veins joined by a thread-like brachiocephalic vein. The left caval vein is connected to the coronary sinus, which was correspondingly enlarged. Internally there was a small ASD but no other abnormality.

Figure 5.36 Juxtaposition of the atrial appendages. Heart of a fetus of 15 weeks’ gestation viewed from the front. There is juxtaposition of the atrial appendages, both lying to the left-hand side of the aorta. The right appendage lying more to the left side than the left appendage. Internally there was pulmonary atresia with VSD.

of the descending aortic arch after it gives off the left subclavian artery. There is a female preponderance. The majority of cases occur in isolation (Figure 5.38), but it may be associated with coarctation (where it more usually arises distal to the coarctation than proximal to it) or interruption of the aortic arch [33]. An aberrant left subclavian artery may arise in the setting of a right aortic arch (Figure 5.39). In these cases the arterial ligament (ligamentum arteriosum) arises from the left pulmonary artery, passes to the left of the trachea and oesophagus, and connects to the aortic arch at the site of the aortic diverticulum (Kommerell), giving rise to the aberrant artery [34].

5.10.3 Kommerell’s Diverticulum Kommerell’s diverticulum describes the presence of the aneurysm-like funnel-shaped widening at the origin and proximal-most segment of an aberrant subclavian artery – whether right or left [35]. When associated with a right aortic arch and left duct, there is a complete vascular ring, and there is potential for oesophageal or tracheal compression. The

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Figure 5.38 Retro-oesophageal right subclavian artery. An eighteen-monthold child with tetralogy of Fallot (operated). The thoracic organs are viewed from behind. The aortic arch is left sided. Taking origin from the aorta as it begins to descend, there is a right subclavian artery that travels behind the oesophagus and trachea to reach the right axilla. There is no dilatation of the aorta at this point.

diverticulum is frequently of the same size as the aorta but does narrow at the origin of the subclavian artery. In adults aortic dissection beginning in the diverticulum is described and the diverticulum may also rupture. In adults there is a high incidence of cystic medial degeneration in the wall of the resected diverticulum [36]. Current treatment is to resect the diverticulum, divide the ligamentum arteriosum and reimplant the subclavian artery into the common carotid artery [37].

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Figure 5.39 Aberrant origin of left subclavian artery. Fetus of 34 weeks’ gestational age with tetralogy of Fallot. The thoracic and abdominal organs are viewed from behind. There is a right-sided aortic arch, as there is in approximately 25% of cases of Fallot. The left subclavian artery takes origin from a diverticulum (of Kommerell) at the left side of the descending aorta. A leftsided arterial duct is connected to the left side of the diverticulum forming a complete vascular ring enclosing trachea and oesophagus. There is a constriction of the diverticulum at its attachment to the aorta. This vascular ring has the potential to constrict the oesophagus.

Histologically the diverticulum may show intimal proliferation and may be obstructed (Figure 5.40).

5.10.4 Ectopia Cordis In this rare malformation the heart lies outside the thoracic cavity. In the most common variety there is a defect of the sternum, pericardium and overlying skin, and the anteriorly displaced heart lies exposed to the external environment (Figure 5.41). There are usually associated cardiac and extracardiac defects. A less common variation is when the heart lies in the upper abdomen, usually associated with a defect of the lower sternum, the diaphragm, pericardium and upper abdominal wall with protrusion of both heart and abdominal contents onto the body surface. There are usually associated cardiac defects, most commonly VSD [38]. This combination of abnormalities is sometimes termed pentad (or pentalogy) of Cantrell.

Figure 5.40 Kommerell’s diverticulum. (A) Resected diverticulum from a case of right aortic arch and left retro-oesophageal subclavian artery and left arterial duct. Viewed from the side, the closed arterial duct is on the top right of the specimen. The subclavian artery arises from the left side of the specimen, and the aorta is attached at the bottom right. (B) Histological section stained with Elastic vanGieson. The arterial duct is evident in the top right of the field, recognisable by its loose elastic structure. The ductal lumen shows fibrous obliteration. The subclavian arterial lumen is to the left and the aortic lumen to the lower right. There is a shelf-like protrusion into the lumen causing narrowing opposite the ductal insertion site.

5.10.5 Left Atrial Aneurysm Aneurysm of left atrial appendage is rare and often an incidental finding in a patient undergoing echocardiography. It may predispose to atrial tachyarrhythmia and thromboembolism. About 40% of cases are congenital and the remainder acquired as a result of surgery, trauma, and mitral stenosis or regurgitation [39]. Presentation is usually in the third decade but may be as young as 2 years of age [40]. The example illustrated (Figure 5.42) is from a 2-year-old girl. There is focal or diffuse enlargement of the atrial appendage, sometimes to giant proportions. Surgical resection is the standard of treatment.

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Figure 5.42 Left atrial aneurysm. One-year-old with congenital left atrial aneurysm. The specimen consists of dilated and thin-walled atrium without other distinguishing features. Internally there was thrombus.

5.11.2 Persistent Patency of the Venous Duct

Figure 5.41 Ectopia cordis. Termination of pregnancy at 14 weeks’ gestation for ectopia cordis. There is irregularity and pallor of the tissues above the umbilical cord that represents the ectopic location of the heart. The sternum is short and the diaphragm deficient anteriorly. The heart was elongated and distorted but showed normal vascular connections. Internally there was pulmonary stenosis and VSD.

5.11 Anomalies of the Venous Duct (Ductus Venosus) 5.11.1 Absence of the Venous Duct Absence of the venous duct is rare. It may be an isolated abnormality in about one-third of cases, but in the majority of cases it is associated with other abnormalities [41]. With absence of the duct there is shunting of umbilical venous blood, which may be intrahepatic or extrahepatic. The extrahepatic shunts include connection of the umbilical vein to the right atrium, to the coronary sinus, to the left atrium, to the inferior caval vein, to the renal vein or to the iliac vein (Figure 5.43A,B). Connection to the right atrium is the commonest. The post-natal outcome in cases with absence of the venous duct mainly depends on the presence of associated anomalies. These include trisomy 21, 18, 13, Turner’s syndrome, Noonan’s syndrome and congenital heart disease [42]. Most cases are identified by scan in the second trimester (41) with fetal hydrops, cardiomegaly and oligohydramnios as the most frequent associated fetal findings. In isolated cases the prognosis is generally good. Portosystemic shunt may persist after birth and a neonate’s shunt should be followed until its occlusion [43].

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In the normal infant the venous duct normally closes within hours of birth [44]. In the premature infant it is normally closed by 2 days [45]. It undergoes fibrous obliteration by three weeks of age [44]. Failure of closure of the duct results in a portosystemic shunt. The two commonest causes of failure of closure of the venous duct are anomalous pulmonary venous connection and hepatic arteriovenous malformation (Figure 5.44). The major complications of the portosystemic shunt are neonatal cholestasis, hepato-pulmonary syndrome, pulmonary hypertension and portosystemic encephalopathy [46]. There is also an increased risk of development of liver tumours [46]. Symptomatic cases may be closed either surgically or radiologically [47].

5.11.3 Aneurysm of the Sinus of Valsalva Aneurysms of the sinuses of Valsalva are rare. They affect the sinuses of the aortic valve, most commonly the right or noncoronary sinus [48]. Occasionally two or even all three sinuses may be affected [49] (Figure 5.45). The aneurysm may be congenital or acquired, and it is thought to result from a localised dystrophy of connective tissue in the sinuses that leads to discontinuity between aortic media and the fibrous annulus of the aortic valve. Aneurysms are generally asymptomatic because of slow growth, and rarely manifest before the age of 20 years with the median age at presentation in the fifth decade [50]. However, cases are described in utero [51] and with rupture in the newborn period [52]. Acquired aneurysms may result from infections such as bacterial endocarditis, syphilis or tuberculosis [48] or may be associated with Ehlers–Danlos syndrome or Marfan’s syndrome [53]. Approximately 44% of the patients have associated aortic regurgitation [50]. An unruptured aneurysm can obstruct the right ventricular outflow tract, cause aortic regurgitation

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5: Congenital Heart Disease (II)

IVC

(A)

Umb.V Hepatic.A

Portal V.

Figure 5.43 Absence of venous duct with porto-caval shunt. A male infant with trisomy 21. (A) A diagram of the liver viewed from behind. There is absence of the venous duct. The umbilical vein opened into the portal vein. There is a large intrahepatic communication between the right portal vein and the inferior caval vein. (B) The liver has been sliced in the coronal plane. The slices are viewed from posteriorly with the more anterior at the bottom of the field. The umbilical vein is still patent and is seen to enter the liver at the lower left. The portal vein is seen to enter the liver in the second slice from the top, and the uppermost slice shows the inferior caval vein, with towards its lower anterior aspect a large communication with the right portal vein.

due to distortion of the aortic valve, and compress the left coronary artery or the conduction system. Rupture occurs in about one-third of patients [50]. The aneurysms rupture into the cardiac chambers that surround the aortic root, or rarely into the pericardial cavity. Diagnosis can be confirmed by echocardiography, radiological imaging, aorto-/arteriography or cardiac catheterisation. Hospital mortality is less than 5%, and the late results are excellent in the absence of aortic valve damage.

5.11.4 Aorto-Left Ventricular Tunnel

Figure 5.44 Portosystemic shunt. A growth-restricted and premature infant with persistent pulmonary hypertension who during investigation was found to have a large hepatic arteriovenous malformation. Multiple attempts were made to close it. The liver is viewed from behind and dissected in a coronal plane. The portal vein runs horizontally in the centre of the field. A large umbrella device is visible in the venous duct connecting the portal vein and inferior caval vein. One tip protrudes into the portal vein lumen. Multiple tortuous veins are visible connected to the IVC at its junction with the liver.

An extremely uncommon condition in which there is an extracardiac communication between the left ventricle (very rarely the right ventricle) and the aorta. It consists of a channel opening into the left ventricular cavity usually beneath the right-facing cusp of the aortic valve, extending into the plane between the aorta and pulmonary artery and entering the aorta above the sinotubular junction [54]. It is this opening above the sinotubular junction that distinguishes it from a ruptured aneurysm of the sinus of Valsalva. There is abundant elastic tissue in the wall of the tunnel at its aortic end, while the wall at the ventricular end consists of fibrous tissue and smooth

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Figure 5.45 Aneurysm sinus of Valsalva. (A) A case of sudden death. The roots of the great arteries are viewed from the front with the right atrial appendage retracted. A pyramidal mass lies in the right atrioventricular groove between the pulmonary infundibulum and the right coronary artery and the ascending aorta. (B) A simulated long-axis view of the heart viewed from behind. Bulging from the non-coronary sinus of Valsalva, beneath the origin of the right coronary artery is an aneurysmal dilatation of the aortic wall. There was partial destruction of the non-coronary leaflet, not visible in this view.

muscle [55]. About half of the cases are associated with abnormalities of the proximal coronary arteries or with aortic or pulmonary valve abnormalities. There is also a described association with left ventricular non-compaction [56]. It develops in utero and may cause intrauterine fetal death [57, 58]. It usually presents in infancy with cardiac failure and progressive dilatation of the left ventricle. Treatment is by surgical closure in infancy with occlusion of both ends.

5.11.5 Cor Triatriatum This term, while not strictly describing three atria, refers to division of one or other atrium by a fibrous or fibromuscular diaphragm [59]. On the right side (cor triatriatum dexter) the division is by remains of the right valve of the sinus venosus, and this condition is identical to a Chiari network [19]. On the left side (cor triatriatum sinister) a fibromuscular diaphragm connected to the interatrial septum divides the atrium in two, the upper moiety connected to the pulmonary veins and the oval fossa. The lower moiety is in continuity with the atrial appendage and contains the vestibule of the left AV valve (Figure 5.46). Usually the two moieties are in continuity

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Figure 5.46 Cor triatriatum sinister. The left atrium and left ventricle have been opened. A horizontal cut has been made through the centre of the left atrium. A thick imperforate muscular septum divides the left atrium and bulges downwards towards the mitral valve. The upper chamber received the pulmonary veins and the lower moiety was connected to the left atrial appendage and via a restrictive atrial septum to the right atrium. The lungs showed severe lymphangiectasia.

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through an orifice in the dividing membrane. The condition is distinct from supravalvar mitral membrane where the oval fossa and the atrial appendage both lie above the membrane. There may be associated abnormalities of pulmonary or systemic venous drainage or other forms of congenital heart disease [60]. Treatment is by surgical excision of the dividing membrane [61].

5.11.6 Aneurysm of Left Ventricle and Left Ventricular Diverticulum Congenital left ventricular aneurysms and left ventricular diverticula are rare [62]. Left ventricular aneurysms consist of dyskinetic outpouchings of ventricular myocardium with a wide connection to the ventricular cavity. Microscopically they are usually fibrotic

Figure 5.47 Ventricular aneurysm. Ruptured aneurysm left ventricle. Sudden collapse and death in a male infant born normally at term. At post-mortem there was haemopericardium (A). There was underlying acute myocardial infarction with haemorrhagic discolouration of the basal left ventricular epicardium (B). No cause was found. The coronary arteries were normal. There was no vasculitis. A cross section of the infarcted area (C) shows marked thinning of the wall with haemorrhage and bulging outwards of the ventricular cavity. The corresponding histological section (D) from close to the area of rupture shows thinning of the ventricular wall and aneurysmal bulging of the left ventricular cavity.

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Figure 5.48 Left ventricular diverticulum. Sudden collapse in a neonate. At post-mortem there was haemopericardium and a ruptured diverticulum of the left atrioventricular junction. Longitudinal section through the lateral left atrioventricular junction stained with EvG. A diverticulum extends beneath the level of the attachment of the mural leaflet of the mitral valve through the connective tissue of the left atrioventricular junction ventricle. In the left atrioventricular groove on the epicardial surface the wall is extremely attenuated and had ruptured with fatal haemorrhage.

[63] (Figure 5.47). Left ventricular diverticula are sac-like outpouchings with normal contractility arising from the ventricular wall. Most occur in the setting of other cardiac malformations such as aortic coarctation or pulmonary atresia [64, 65]. Their cause is not known (Figure 5.48).

5.12 Pulmonary Vascular Disease in Congenital Heart Disease 5.12.1 Normal Histology [1] The normal pulmonary vasculature comprises elastic and muscular arteries, arterioles, capillaries, venules and veins, in addition to bronchial and pleural vessels and lymphatics [66]. The pulmonary trunk and its main branches (branch pulmonary arteries) are elastic pulmonary arteries and extend from the hilum of the lung peripherally to arteries with a diameter of less than 1 mm. In the pulmonary trunk and its

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main branches the elastic fibres are fragmented, but the smaller elastic pulmonary arteries show continuous laminae (Figure 5.49A). Smooth muscle cells lie between the elastic laminae, and the endothelial layer rests on the internal elastic lamina. There is gradual loss of elastic laminae peripherally to a point roughly where the bronchi lose their cartilage, where the arterial media becomes completely muscular. The muscular pulmonary arteries have a muscular media sandwiched between well-developed internal and external elastic laminae (Figure 5.49B). This is in contrast to systemic arteries that have only a well-developed internal elastic lamina, with a poorly developed external elastic lamina. The intima of the pulmonary arteries consists only of endothelial cells lying on the internal elastic lamina. Muscular pulmonary arteries, in general, follow the branching of the bronchi, but there are numerous supernumerary arteries that arise obliquely from elastic and muscular arteries directly into the parenchyma. A muscular pulmonary artery is roughly of the same diameter as the bronchus/bronchiole that it accompanies. The media occupies between 3% and 7% of the external diameter of the vessel. Each pulmonary artery is surrounded by a thick adventitia of dense collagen that is continuous with, but more prominent than, that surrounding the accompanying bronchus or bronchiole. As they extend peripherally, the muscular arteries gradually lose their muscular coat such that below a diameter of approximately 100 μm the vessels completely lack a muscle coat and consist of a single elastic lamina separating the endothelium from the adventitial collagen (Figure 5.49C). These vessels are arterioles but are also referred to as intraacinar arteries. Histologically, these non-muscular vessels are indistinguishable from venules. The pulmonary veins contain collagen fibres and interrupted elastic laminae and some smooth muscle cells in their tunica media. They have a fibrous adventitia that is much less prominent than that surrounding the pulmonary arteries. At a calibre of between 60 and 100 μm, the veins enter the interlobular septa from the parenchyma; they are not associated with the bronchioles (Figure 5.49D). The elastic arteries are the only vessels whose structure is the same antenatally and post-natally; the pulmonary trunk changes its elastic laminae, which before birth are continuous – similar to those in the aorta. The transition from elastic to muscular pulmonary arteries at birth takes place at 200 μm rather than at the 500 μm seen in the older child. During fetal life the media of the muscular arteries is thick and the lumen narrow. The smaller arteries appear almost closed. These are the vessels that open up at birth to permit the rapid fall in pulmonary artery pressure. Over the following two or three weeks there is gradual remodelling with thinning of the media. The bronchial arteries accompany the bronchi and are intimately associated with them. They have the structure of systemic arteries with a relatively thick muscular media and incompletely developed external elastic lamina (Figure 5.49E). They sometimes contain smooth muscle in the intima that may, at times, proliferate to occlude the vessel. Systemic vessels

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Figure 5.49 Normal pulmonary vasculature. (A) Normal elastic pulmonary artery. EvG-stained section of a large elastic pulmonary artery towards the lung hilum. There are well-developed internal and external elastic laminae. The defining histological characteristic of elastic pulmonary arteries is the presence of multiple parallel elastic laminae in the tunica media. (B) Normal muscular pulmonary artery. EvG-stained section of lung showing a bronchovascular bundle. The muscular pulmonary artery accompanies the airway and is enclosed in the same collagenous sheath. The airway and artery should be of approximately equal size although there is some variation. The muscular pulmonary artery is identified by its location and the presence of distinct internal and external elastic laminae. The muscular coat of the tunica media is thin and should occupy less than 10% of the vessel diameter. The tunica intima is inconspicuous. (C) Normal intra-acinar pulmonary artery (arteriole). The intra-acinar artery also accompanies the airway – in this case an alveolar duct identified by the dense elastic tissue in its wall. The artery lacks a continuous medial muscle coat around its circumference and separate internal and external elastic laminae are not identifiable. Histologically the vessel is indistinguishable from a venule, and only its co-location with the airway permits its identification. (EvG stain). (D) Normal pulmonary vein. This EvG-stained section shows a large pulmonary vein in an interlobular septum. The wall contains elastic tissue collagen and muscle but is thin-walled and lacks the organisation of the media that would be present in an artery of similar size. Distinct external and internal elastic laminae are not identifiable. (E) Normal bronchial artery. This vessel is located within the connective tissue investment of a bronchus. The vessel is thick walled and muscular and shows a well-developed internal elastic lamina. The tunica media occupies approximately one-half of the diameter of the vessel. The defining histological characteristic of bronchial arteries (and of systemic arteries in general) is the lack of a well-formed external elastic lamina (EvG stain).

are also found in the pleura but are generally inconspicuous, except in pathological conditions. Pulmonary lymphatics are not present in the alveolar septa but are numerous in the interlobular septa and in the connective tissue around the bronchovascular bundles. A sustained rise in pulmonary arterial blood pressure from any cause will give rise to a series of characteristic histological changes. The fifth World Pulmonary Hypertension Symposium,

held in Nice in 2013, has updated a classification of pulmonary hypertension that has five main categories based on common clinical features [67]. A summary of it is shown in Table 5.3. Biopsy of lung is now rarely performed to diagnose pulmonary hypertension. The diagnosis is usually made on echocardiography or other imaging. However, lung biopsy for pulmonary hypertension is still performed if there is doubt on echocardiography, severity cannot be assessed by the usual

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5: Congenital Heart Disease (II) Table 5.3 Clinical classification of pulmonary hypertension

1. Pulmonary arterial hypertension • Idiopathic pulmonary arterial hypertension • Heritable pulmonary arterial hypertension BMPR2 ALK-1, ENG, SMAD9, CAV1, KCNK3 Unknown • Drugs and toxin induced • Associated with: Connective tissue disease HIV infection Portal hypertension Congenital heart disease Schistosomiasis 1’ Pulmonary veno-occlusive disease and/or capillary haemangiomatosis 1’’ Persistent pulmonary hypertension of the newborn

Figure 5.49 (cont.)

means or there is the possibility of unusual pathology. For adequate assessment, the biopsy should include at least one bronchus (cartilage plate) with accompanying muscular pulmonary artery. It is important to appreciate that the changes may be focal, so it is essential to examine multiple levels. Assessment cannot be done without an elastic stain.

5.12.2 Histopathological Features of Pulmonary Hypertension The elastic pulmonary arteries may show atheromatous intimal plaques. The muscular pulmonary arteries are tortuous, sometimes multiple profiles of the vessel being cut in a single section. They show muscular thickening of their tunica media (Figure 5.50A). Muscle extends peripherally into the small intra-acinar arteries (Figure 5.50B). They may also show intimal thickening by fibrous or cellular tissue (Figure 5.50C). (Note that the arteries may be atrophic in severe cases because of the protective effect of severe proximal obstruction. In this situation the muscular pulmonary arteries have thin walls and sometimes show fibrous obliteration of their lumina.) In severe cases there is myxoid thickening of the intima, and there may be fibrinoid deposition and plexiform lesions (Figure 5.50D). Plexiform lesions usually affect supernumerary branches of larger and medium-sized muscular pulmonary arteries. They may be in the vessel lumen or in the adventitial sheath and there are frequently surrounding dilated vessels with thin walls. Very occasionally one will see anastomoses between pulmonary and bronchial arteries. In cases with a significant venous component the veins show wall thickening with realignment of the elastic tissue such that they resemble arteries, so-called arterialisation, and concentric intimal fibrous thickening (Figure 5.51). In veno-occlusive disease veins show fibrous and myxoid occlusion of the vessels [68].

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2. Pulmonary hypertension with left heart disease • Left ventricular systolic dysfunction • Left ventricular diastolic dysfunction • Valvar disease • Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathy • Congenital/acquired pulmonary vein stenosis 3. Pulmonary hypertension due to lung diseases and/or hypoxia • Chronic obstructive pulmonary disease • Interstitial lung disease • Other pulmonary diseases with mixed restrictive and obstructive pattern • Sleep-disordered breathing • Alveolar hypoventilation disorders • Chronic exposure to high altitude • Developmental lung disease 4. Pulmonary hypertension resulting from chronic thrombotic and/or embolic disease • Thromboembolic obstruction of proximal pulmonary arteries • Thromboembolic obstruction of distal pulmonary arteries • Pulmonary embolism (tumour, parasites, foreign material) 5. Pulmonary hypertension with unclear multifactorial mechanisms • Haematological disorders: chronic haemolytic anaemia, myeloproliferative disorders, splenectomy • Systemic disorders: sarcoidosis, pulmonary histiocytosis, lymphangio-leiomyomatosis • Neurofibromatosis • Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders • Other: tumoural obstruction, fibrosing mediastinitis, chronic renal failure, segmental pulmonary hypertension Source: Fifth World Pulmonary Hypertension Symposium (2013) [66].

The Heath–Edwards grading system has been widely used in the past [69], but is not much employed of late. A summary is given in Table 5.4.

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Figure 5.50 The arterial changes in pulmonary arterial hypertension. (A) Medial smooth muscle hypertrophy. This large muscular pulmonary artery shows an increase in thickness of its tunica media. At the nine o’clock position there is a “hoop” of elastic tissue protruding into the arterial lumen that encloses bundles of intimal longitudinal smooth muscle (EvG). (B) Muscularisation of the intra-acinar arteries. The small intra-acinar arteries in this section have acquired a medial coat of smooth muscle. The vessel at 12 o’clock now has distinct internal and external elastic laminae (EvG). (C) Intimal proliferation. The two arteries show intimal proliferation with narrowing of their lumina. The larger vessel shows eccentric cellular intimal thickening that extends into a small branch. The vessel beneath it shows near total occlusion by concentric cellular intimal proliferation (EvG). (D) Plexiform lesion. The artery shows concentric cellular intimal proliferation that has a slightly myxoid appearance. In the adventitia of the vessel there is a nodular expansion with multiple irregular, cellular vascular channels – a plexiform lesion. In addition there is dilatation of thin-walled vessels surrounding the plexiform lesion. Plexiform lesions are a marker of severe pulmonary arterial hypertension (H&E).

In the setting of pulmonary arterial hypertension secondary to congenital heart disease, the presence of widespread intimal fibrous thickening is regarded as irreversible. The presence of reversible changes on biopsy in such cases does not necessarily mean that the case is operable.

5.12.3 Congenital Heart Disease and Pulmonary Vascular Disease There are three main patterns of pulmonary vascular disease associated with congenital heart disease: 1. Left-to-right shunts with increased pulmonary artery flow and pulmonary arterial hypertension. Any left-to-right shunt will eventually lead to elevated pulmonary arterial

pressure, but it may take many years or even decades to develop. It is unusual for pulmonary arterial hypertension to occur in the first year of life [70] except in the setting of complete atrioventricular septal defect, common arterial trunk or transposition of the great arteries. Such lesions are operated on early with the specific intention of preventing the development of pulmonary arterial hypertension. It is distinctly uncommon for such cases to be biopsied for assessment of the pulmonary vasculature. These cases can show the full range of histological abnormalities, up to and including the development of plexiform and dilatation lesions. 2. Obstructive left-sided lesions with pulmonary venous hypertension.

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5: Congenital Heart Disease (II) Table 5.4 Heath–Edwards grading scheme for pulmonary arterial hypertension associated with congenital heart disease

Grade 1. Medial hypertrophy of small muscular pulmonary arteries Grade 2. Cellular intimal proliferation in muscular arteries Grade 3. Concentric intimal fibrosis in muscular arteries Grade 4. Plexiform lesions Grade 5. Dilatation lesions and angiomatoid lesions Grade 6. Fibrinoid necrosis

Figure 5.51 Venous hypertension. A section of lung showing a large interlobular septal vein. The tunica media is thickened, and there is marked concentric intimal deposition of fibrous and elastic tissue. Such changes may be seen in pulmonary veins in any left-sided lesion that obstructs pulmonary venous return and indicate a sustained rise in pulmonary venous pressure.

Figure 5.53 Bidirectional Glenn shunt. A child who died following stage 2 Norwood procedure for hypoplastic left heart. A view of the vessels at the hila of both lungs following retraction of the heart forward. There are numerous fibrous adhesions following the previous surgical procedures. At the bottom of the field are the pulmonary veins. The confluent pulmonary arteries run across the centre of the field. On the left side an old modified B–T shunt has been retracted downwards. The superior caval vein descends in front of the trachea and has been joined to the right side of the pulmonary artery confluence – a bidirectional Glenn shunt.

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Figure 5.52 Modified Blalock–Taussig (B–T) shunt. (A) A case of DORV and pulmonary stenosis treated by modified B–T shunt. The Gore-Tex tube extends from the right subclavian artery to the upper border of the right pulmonary artery. (B) Histological section of a B–T shunt at its anastomosis with the innominate artery. There is a layer of concentric intimal fibrosis at the junction, extending into the shunt. Elsewhere there was shunt thrombosis.

3. Obstructive right-sided lesions with decreased pulmonary blood flow such as in tetralogy of Fallot and pulmonary atresia. It is very unusual to have biopsies from this group of patients. There is reduced pulmonary flow and reduced

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Figure 5.54 Damus–Kaye–Stansel procedure. (A) Drawing of a heart from a child who had undergone a DKS anastomosis and bidirectional Glenn shunt. The pulmonary trunk is anastomosed end-to-side to the ascending aorta. The superior caval vein has been detached from the right atrium (the defect oversewn) and anastomosed to the pulmonary artery, the anastomosis augmented by a large patch. (B) An infant who died some months following a Stage 1 Norwood operation. The frontal view of the heart shows the DKS anastomosis. The pulmonary trunk is joined to the ascending aorta a short distance from its origin. A right modified B–T shunt is also visible. (C) The same heart viewed from above. The superior caval vein is retracted to the left of the field and the arterial pedicle to the right. The aortic root is hypoplastic and the suture lines where it has been joined to the pulmonary trunk are visible. The B–T shunt is visible on the right of the field connecting the brachiocephalic artery below to the detached pulmonary artery confluence above. (D) Another heart from an infant with hypoplastic left heart and Stage 1 Norwood procedure. The heart has been opened to demonstrate the right ventricular outflow pulmonary valve and proximal pulmonary trunk. The proximal aorta lying above the cut ends of the supraventricular crest and proximal right coronary artery has been partly opened. It has been anastomosed to the pulmonary trunk. The discrepancy in diameter is readily apparent. The ascending aorta has been augmented by a patch, and the suture line is just visible as a row of pockmarks in the vessels running upwards and leftwards from the anastomosis.

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Figure 5.55 Atrial septectomy as part of DKS procedure. Same heart as in Figure 5.51. The left side of the heart has been opened. The diminutive left ventricle with hypoplastic mitral valve are readily seen. The orifice of the left atrial appendage lies to the centre-left of the picture. The posterior wall of the left atrium has been retracted to demonstrate the wide interatrial communication formed by atrial septectomy.

pulse pressure with thin-walled muscular pulmonary arteries, often of larger calibre than the accompanying bronchus, and there is a propensity to intravascular thrombosis, especially in tetralogy of Fallot. Pulmonary thromboembolism is a relatively rare event in children with a frequency at autopsy of up to 4%. It is a cause of death in only 0.05% of autopsies. The predisposing factors are similar to those in adults Pulmonary lymphangiectasia may be primary, presenting with respiratory distress after birth and uniformly fatal, or secondary and usually associated with congenital heart disease, most notably total anomalous pulmonary venous connection with obstruction.

5.12.4 Pulmonary Venous Hypertension This can occur secondary to any left-sided obstructive lesion including congestive cardiac failure. If severe, it can be due to pulmonary vein stenosis. The muscular pulmonary arteries show prominent medial hypertrophy and there may be muscularisation of arterioles. There may be eccentric fibrous

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Figure 5.56 Fontan circulation. Single-ventricle physiology (double inlet left ventricle) with Fontan repair. (A) The heart–lung specimen is viewed from the right side. The heart has been retracted to the left. The superior caval vein has been joined to the right side of the confluence of the pulmonary arteries and the inferior caval circulation connected to the same vessel by means of an extracardiac Gore-Tex conduit. (B) The pulmonary artery has been opened to demonstrate the anastomosis of the extracardiac conduit to the right pulmonary artery. The retractor is in situ in the anastomosis of the superior caval vein to the same vessel.

intimal thickening of pulmonary arteries that affects long stretches of the arteries. No plexiform lesions are present in pulmonary venous hypertension. There is arterialisation and medial thickening of pulmonary veins with intimal fibrosis. Associated pulmonary parenchymal changes are frequent and consist of interstital fibrosis, marked alveolar haemosiderinladen macrophages and even osseous metaplasia, the latter a useful histological marker.

5.12.4.1 Pulmonary Vein Stenosis Pulmonary hypertension usually presents in the neonatal period. The stenosis is not always detected on

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Figure 5.57 Ross–Konno procedure. A four-year-old with DORV, VSD, bicuspid aortic valve and subaortic stenosis. He underwent resection of his aortic root and valve, which were replaced with his pulmonary homograft, Konno enlargement of left ventricular outflow tract and right ventricular outflow tract to pulmonary artery (RV–PA) conduit. (A) The anterior view of the heart shows the RV–PA conduit. (B) The left ventricular outflow tract has been opened by dividing the anterior leaflet of the mitral valve. The pulmonary homograft is visible together with the suture lines around the coronary artery buttons. Beneath the homograft is the patch of the VSD, and below this there is a raw area of ventricular septum where there has been resection of endocardium and myocardium for relief of outlet obstruction. Note the residual endocardial thickening in the ventricle towards the apex.

echocardiography. If the biopsy shows a significant venous component, this should always alert to the possibility (Figure 5.52).

5.12.4.2 Obstructed Total Anomalous Pulmonary Venous Connection This is not usually biopsied. There are very dilated bronchial veins that may be confused with misalignment of pulmonary veins in alveolar capillary dysplasia.

5.13 Surgical Operations for Congenital Heart Disease This is not intended as a comprehensive state of the art review of paediatric cardiac surgery: it would be presumptuous of a pathologist to attempt such [71, 72]. Rather, it is an attempt to give some background context to the assessments of hearts at post-mortem or following explanation that have undergone surgical intervention. In the discussions on the individual lesions, many have a short discussion on surgical correction. I have listed the commoner operations below,

many of them eponymous, but it is important to bear in mind that many interventions are catheter based. Thus stents (Figure 4.31), umbrella closure devices (Figure 4.7), coils (Figure 4.33) and balloon dilatation are all done intravascularly [73–75]. Balloon atrial septostomy (Rashkind septostomy) (Figure 4.28) is also done this way. Other operations not separately considered include removal of muscle (myectomy). Fetal interventions may also be by means of catheter [76] (Figure 12.22)

5.13.1 Patches Tissue patches may be of Dacron, Gore-Tex or pericardium [77]. They may be simple, such as those used in closing small defects in the atrial (Figure 4.29) or ventricular septum (Figure 4.8), or may form part of more complex procedures as discussed below. They regularly form a part of the twopatch repair of AVSD (Figure 4.22). Patches may also be used to increase the size of arteries as in augmentation of the pulmonary outflow in tetralogy of Fallot (Figure 4.53B) and of the aorta in a Damus–Kaye–Stansel procedure.

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SVC

Aorta

PA Patch

RCA LCA

(A)

IVC

Figure 5.58 Arterial switch operation. (A) Drawing of a post-mortem heart following a neonatal switch operation. The aorta originally arose to the right side of the pulmonary trunk and took origin from the right ventricle. Both great arteries have been transected and switched from their original origins. The coronary arteries have also been transferred, each with a surrounding cuff of arterial wall. The defects left in the wall of the neo-pulmonary trunk have been closed with a pericardial patch. (B) Infant with transposition who died shortly after neonatal arterial switch operation. The left ventricular outflow and aorta have been opened. The circumferential suture line in the aorta above the sinotubular junction is visible together with the suture lines around the coronary artery buttons. The left button is partly obscured by folding over of the cut edge of the aortic wall.

5.13.2 Modified Blalock-Taussig Shunt This is a systemic-to-pulmonary artery shunt designed to increase pulmonary blood flow (Figure 5.52A). It is often a temporary measure until more definitive surgery is undertaken. If this is the case, it is usually clipped and left in situ. The shunt is usually a Gore-Tex tube inserted from the brachiocephalic or right subclavian artery to the superior surface of the right pulmonary artery. Depending on local anatomy, it may also be left sided. With time, it normally develops dense fibrosis along the outer aspect. It is prone to thrombosis or to narrowing by endothelial thickening over time (Figure 5.52B) and, rarely, may develop endocarditis [78].

5.13.3 Bidirectional Glenn Shunt This is an operation for increasing pulmonary artery blood flow that is a systemic venous to pulmonary arterial shunt. It is often a stage of a total cavo-pulmonary anastomosis.

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It involves separation of the superior caval vein from the right atrium and anastomosis end-to-side to the right pulmonary artery with closure of the cavo-atrial junction (Figure 5.53). It may become narrowed at its junction with the pulmonary artery.

5.13.4 Damus–Kaye–Stansel (DKS) Procedure This is an operation used in the repair of transposition with VSD and subpulmonary stenosis. It is also used for repair of physiological single ventricles. The pulmonary artery is transected above the pulmonary valve and anastomosed end-toside to the ascending aorta (Figure 5.54) [79].

5.13.5 Norwood Procedure This procedure is used for surgical correction of hypoplastic left heart and other physiologically single ventricles [80]. It is usually a staged procedure: Stage 1 A DKS anastomosis is formed and the aortic arch is enlarged with a patch. The distal pulmonary artery is closed

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Figure 5.60 Mustard operation. Heart transplant age 16 years following infantile Mustard operation for transposition. A simulated four-chamber view of the heart. There has been arterial valve harvest post explant that accounts for the deficiency of the upper part of the interventricular septum. The right atrium is dilated. The interatrial septum has been removed and its original site is marked by a slight constriction just below the entry point of the pulmonary veins at approximately the 11 o’clock position. The caval veins lie posterior to the pulmonary venous component and bulge into it, emerging above the vestibule of the mitral valve. Note the marked thickening of the right ventricular wall, which is now the systemic ventricle.

with a pericardial patch, and pulmonary blood flow is established by a modified Blalock–Taussig shunt or a right ventricle to pulmonary artery conduit. An atrial septectomy is performed to ensure unobstructed pulmonary venous flow (Figure 5.55). Stage 2 Creation of a bidirectional Glenn shunt. Stage 3 Creation of a full Fontan circulation – see below.

5.13.6 Fontan Procedure

Figure 5.59 Rastelli operation. Transposition of the great arteries, VSD and subpulmonary stenosis. Sudden death many years later. (A) The right atrium and right ventricle have been opened. The suture line of the RV–PA conduit is visible towards the top right of the picture. Between it and the septal leaflet of the tricuspid valve there is an area of endocardial thickening that is the site of the interventricular patch. (B) The left ventricle and aorta showing the aorta overlying the right ventricle but committed to the left by the insertion of an interventricular patch. The circular outline of the original VSD is visible beneath the aorta. There is considerable endocardial fibrosis around the original VSD.

This is a total cavo-pulmonary connection. The bidirectional Glenn shunt, where blood from the superior caval vein flows directly to the pulmonary artery (Figure 5.56A), is supplemented by one of several methods for directing the inferior caval blood to the pulmonary artery [81]. The commoner modifications are a lateral tunnel and an extracardiac conduit. The lateral tunnel involves a Gore-Tex baffle in the right atrium to direct the blood from the inferior caval vein to the pulmonary artery via an anastomosis of the right pulmonary artery to the right atrium. The baffle is fenestrated to prevent overload. The extracardiac conduit is of Gore-Tex, autologous pericardium or a valveless homograft and connects the inferior caval vein to the pulmonary artery (Figure 5.56B).

5.13.7 Ross–Konno Procedure This is used for aortic valve disease [82]. The diseased aortic valve is removed and replaced with the child’s own pulmonary valve. The child’s pulmonary valve is then

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Figure 5.61 Senning operation. Sudden death many years later following Senning operation for transposition. (A) The right ventricle shows marked myocardial hypertrophy in keeping with its being the systemic ventricle. The aorta arises from it (the origin of the left coronary artery is just visible). The right atrium identified by its trabeculations is connected to the right ventricle via a tricuspid valve. There are multiple fine suture lines visible beneath the right atrial endocardium. The pulmonary venous blood flows along the posterior aspect of the cavity, posterior to the systemic component that has been isolated from it and connected to the mitral valve. (B) The forceps have been inserted into the IVC emerging from the SVC to demonstrate that the pulmonary venous pathway runs posterior and lateral to the systemic venous pathway in the Senning operated heart. (C) The left side of the heart shows the connection of the systemic venous pathway to the mitral valve. The pulmonary artery arises from the left ventricle. The ventricle is thin-walled. Part of the pulmonary venous pathway lies between the pulmonary artery and the systemic venous pathway before dipping down behind it to access the tricuspid valve.

replaced by a homograft (human aortic or pulmonary autograft) (Ross procedure). The use of a native pulmonary valve avoids the need for anticoagulation and its attendant hazards and permits growth of the valve [83]. Generally there is also enlargement of the aortic outflow and annulus by an anterior aorto-ventriculoplasty (Konno technique) (Figure 5.57A,B) [84].

5.13.8 Arterial Switch Operation This operation is most frequently performed for transposition, usually in the first weeks of life. Both great arteries transected above their valves and then switched. The coronary orifices and a surrounding cuff of aortic wall are removed separately and sewn into the neo-aorta (Figure 5.58), the defects in the neo-pulmonary artery being repaired with pericardium. The coronary artery anatomy is vital to the success of the operation, and the coronary arteries may become stretched or kinked. A number of patients develop aortic regurgitation but rarely need reoperation [85].

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5.13.9 Rastelli Operation This is another operation for transposition with VSD and subpulmonary stenosis, and is also employed for DORV with subpulmonary stenosis (Figure 5.9). A patch is inserted into the right ventricle beneath the VSD to connect the left ventricle to the aorta. The pulmonary trunk is transected and its proximal end oversewn. A conduit – usually a homograft – is fashioned to connect the right ventricle to the distal pulmonary arteries (Figure 5.59A,B). Long-term results are good with negligible operative mortality and late survival exceeding 70% with a risk of late left ventricular tract obstruction of around 15–20% [86].

5.13.10 Mustard and Senning Operations Both of these are atrial switch operations for transposition. They are rarely performed nowadays. Both atrial switch procedures are prone to narrowing of the systemic or pulmonary

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Figure 5.62 Pulmonary artery band. (A) An infant with multiple VSDs and pulmonary artery band. The right ventricle is enlarged. The band can be seen to cause pleating of the wall of the pulmonary artery, reducing its internal diameter. The arterial duct has been ligated. (B) Hybrid procedure for hypoplastic left heart. The pulmonary artery is viewed from above and behind. The pulmonary veins and left atrium form the lower part of the picture. There are bands applied to both the left and the right pulmonary arteries. The arterial duct arising between them is large and has been stented. (C) Heart that had a pulmonary artery band viewed from above after transection of the great arteries just below the level of the band. The pleating effect with reduction in diameter of the pulmonary artery is readily seen.

venous pathway. Both are prone to atrial arrhythmias because of the extensive atrial suture lines [87]. The right ventricle, being the systemic ventricle, is prone to failure [88].

in the atrial mass and the caval blood posteriorly to reach their appropriate ventricles (Figure 5.61).

5.13.10.1 Mustard Operation

5.13.11 Pulmonary Artery Band

The interatrial septum is removed. A Y-shaped baffle is sewn into the atrium with the one limb of the Y connecting to each of the caval orifices, and the stem to the left atrioventricular valve, thus directing the systemic venous return to the left ventricle and hence to the pulmonary artery. The pulmonary venous return flows around the baffle to the right atrioventricular valve and right ventricle (Figure 5.60).

This procedure is employed to reduce pulmonary blood flow in the presence of a large VSD. Banding of both branch pulmonary arteries with stenting of the arterial duct comprises the hybrid procedure for palliation of hypoplastic left heart. Pulmonary artery banding is also now used as a preliminary to transplant in dilated cardiomyopathy [88]. A band up to 5 mm wide is placed externally around the pulmonary trunk above the level of the pulmonary valve and sewn into place. It is tightened to the point where the appropriate pulmonary artery pressure is obtained. The band may be too tight, or not tight enough. It may distort the pulmonary valve, or it may become infected (Figure 5.62).

5.13.10.2 Senning Operation This is a more three-dimensionally complicated atrial arrangement where the pulmonary venous blood is directed anteriorly

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Figure 5.64 Valved conduit from RV to PA. The specimen shows the opened conduit from the RV to the PA that contains a valve.

Figure 5.63 Prosthetic mechanical valves. (A) Two-month-old who died following insertion of a St Jude prosthesis for dysplastic mitral valve. The valve is a bileaflet tilting disc valve shown here in the open position and viewed from the ventricular aspect. The fabric sleeve is visible and is sutured in situ. Death occurred shortly after insertion, and there is as yet no host tissue reaction around the valve. (B) An eight-month-old infant with AVSD. A mechanical valve was used to replace the left component of the AV valve that could not be successfully repaired. A hinged bileaflet tilting disc valve is in situ facing into the LV. It is too large to be accommodated in the left AV junction and instead sits in the left atrium above the junction.

5.13.12 Prosthetic Heart Valves All function passively secondary to pressure changes within the heart [90, 91]. They may be mechanical or biological. The mechanical valves may be: • Caged ball device (Starr Edwards) • Caged disc device (Beall) • Tilting disc valve (Bjork Shiley) • Bileaflet tilting disc valve (St Jude Medical, CarboMedics) (Figures 5.63 and 5.64). All are thrombogenic and require anticoagulation. All are composed of three parts: an occluder – ball or disc or hemidisc

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(graphite coated with pyrolytic carbon), a superstructure to contain the occluder (titanium or chromium cobalt alloy or graphite) and a fabric sewing-ring at the base. The biological valves may be: Medtronic, Hancock porcine valves Carpentier–Edwards porcine or pericardial valves Stentless tissue valves of two types: 1. Xenografts porcine aortic valve or bovine pericardium (aldehyde preserved) 2. Homografts: human aortic or pulmonary valves from explanted hearts or cadavers (cryopreserved) or autografts. A host tissue reaction develops to the devices (pannus), and it occurs at the host–fabric, host–tissue interface. Other prostheses that may be encountered in the operated heart include annuloplasty rings, artificial chordae, pacemaker leads (Figure 5.65), defibrillator leads, ventricular assist devices and vascular stents.

5.14 Assessment of the Operated Heart Surgical or endovascular operation for congenital heart disease in children is, nowadays, commonplace, safe and effective. Except in fetal practice it is uncommon for unoperated congenital heart disease to come to autopsy. Perioperative

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Figure 5.65 Pacing wire epicardium. A child with pulmonary atresia with intact septum. The child suffered a cardiac arrest during cardiac catheterisation and had complete heart block. Intracardiac pacing was attempted successfully, despite which, the child died. The intracardiac pacing wire has extended through the myocardium of the left ventricle to the epicardial surface where there is surrounding epicardial haemorrhage. It has not perforated the epicardium, and there was no haemopericardium. The small right ventricle is non-apex forming.

Figure 5.66 Post-mortem examination after cardiac surgery. A four-monthold male infant who underwent median sternotomy for congenital heart disease. The recent sternotomy wound is visible. The two rounded lesions below its lower edge are drain sites. There are surrounding suture marks and the entry points of epicardial electrodes. This appearance is fairly standard after paediatric heart surgery.

mortality is now very low and the risk of death in isolated simple defects is no higher than that in the general population. There is a group of conditions that does carry disproportionate risk, and these include complex congenital heart disease, Fontan physiology and Eisenmenger’s syndrome. Following operation, the risk of death from cardiac causes decreases with time from operation [67]. Lee and Gallagher give a protocol for examining the post-operative heart [91]. Admittedly, it refers to adults and specifically targets coronary artery bypass grafts, but the principles nonetheless are applicable to post-operative paediatric hearts. The details of the preoperative condition and imaging are important. The surgical operative notes must be to hand, and details of post-operative course are vitally important [92]. The external examination of the child should record all incisions, drains, cannulae, pacing wires, etc. (Figure 5.66).

Photography is useful in this regard. Most often there will be a median sternotomy, but it is important to look for evidence of previous lateral scars from thoracotomies. Depending on the terms of consent to the autopsy all the organs should be examined looking for evidence of multiorgan failure. The abdominal aorta and great veins should be opened. I prefer to remove the thoracic organs en-bloc and fix them in formalin before dissection. Samples of lung or myocardium can be taken fresh for culture or for freezing if required before immersion in fixative. Once fixed, the heart and lungs are dissected paying particular attention to the pericardium and any evidence of haemorrhage. The external examination of the heart is similar for non-operated cases of congenital heart disease and the connections are established. If not obscured by adhesions, all suture lines should be checked. The heart is then opened in the manner best suited to documenting the surgical anatomy. Histology is important on both heart and lungs.

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Although nearly 30 years old now, and dealing with both adult and paediatric cases and suffering from an unfortunate scarcity of illustrations, Dr Sally Allwork’s monograph

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Chapter

6

Ischaemia and Infarction

6.1 Introduction Most injury leading to necrosis or infarction of the myocardium in children is hypoxic or ischaemic in origin. The fetal heart is more resistant to hypoxic cell death than the adult heart because of its ability to increase glycolysis [1]. It is even possible that low oxygen tension in the developing fetus is necessary for normal heart formation and maturation [2]. Myocardial necrosis and infarction can occur in the neonate and infant, and are associated with congenital heart disease [3], coronary artery abnormalities [4–6], perinatal asphyxia [7, 8], myocarditis [9, 10] and tumours [4]. In some cases no underlying cause can be identified [11–16]. Studies show myocardial necrosis with a frequency of up to 29% of autopsy cases in neonatal intensive care populations [16], accounting for 0.18% of infant autopsies over 15 years in one large series [17]. In that series myocardial necrosis was present to some degree in around 10% of infant autopsies and was much more common in deaths occurring in the neonate and early infant than those occurring later in infancy. Myocardial necrosis in infants is most common in areas of the heart that are most sensitive to hypoxia: the subendocardial region and papillary muscles of the atrioventricular valves. The frequency of myocardial necrosis in the hearts of infants with various forms of congenital heart disease coming to autopsy is shown in Table 6.1. The link is not a simple one, and multiple factors are involved. The clinical presentation of myocardial infarction in the infant and child is with chest pain. There is ST segment depression in subendocardial ischaemia and ST elevation in transmural ischaemia. Measurement of levels of the enzymes cardiac troponin T and I and creatine kinase MB isoenzyme shows good sensitivity and specificity for myocardial damage. Their blood levels rise within two hours of injury. The creatine kinase level peaks at 24 hours whereas troponins persist for longer.

6.2 Macroscopic Appearance 6.2.1 Subendocardial Necrosis Regional infarction, so commonly seen in the adult practice, is rare in children. The commonest form of myocardial necrosis

Table 6.1 Types of congenital and acquired structural heart disease by European Association for Cardio-Thoracic Surgery/Society of Thoracic Surgeons (EACTS-SCS) diagnosis category identified in 105 infants with histologically proven myocardial necrosis and structural cardiac abnormalities

Category

Number

%

Atrial septal defect

52

49.5

Patent arterial duct

33

31.4

Ventricular septal defect

28

26.7

Coronary artery anomalies

24

22.9

Aortic valve disease

17

16.2

Tricuspid valve disease and Ebstein’s anomaly

12

11.4

Pulmonary atresia

12

11.4

Transposition of the great arteries

11

10.5

Hypoplastic left heart syndrome

10

9.5

Mitral valve disease

10

9.5

Pulmonary valve disease

9

8.6

Coarctation of aorta and aortic arch hypoplasia

8

7.6

Atrioventricular septal defect

7

6.7

Hypoplastic right ventricle

6

5.7

Truncus arteriosus

5

4.8

Total anomalous pulmonary venous connection

4

3.8

Tetralogy of Fallot

4

3.8

Interrupted arch

2

1.9

Pulmonary venous stenosis

2

1.9

Double outlet right ventricle

2

1.9

Double inlet left ventricle

2

1.9

Double outlet left ventricle

1

1.0

Dextrocardia

1

1.0

For EACTS-SCS diagnosis category, see ref. [50]. Source: Bamber et al. (2013) [17].

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6: Ischaemia and Infarction

Figure 6.1 Subendocardial myocardial necrosis. (A) Sudden collapse in a 13-year-old. A short-axis cut through the ventricular myocardium shows subendocardial necrosis on the left ventricular aspect of the interventricular septum and in the anterior left ventricular wall (including the anterior papillary muscle of the mitral valve). The affected area is identifiable by focal haemorrhage. Histologically the necrotic myocardium showed a neutrophilic infiltrate in keeping with a date of several days duration. The appearances suggest re-perfusion following a period of non-perfusion, and the myocardial injury is almost certainly secondary to the collapse rather than its cause. (B) A 5-week-old who died 24 hours after resuscitation following collapse of unknown cause. The myocardium shows extensive necrosis particularly beneath the endocardium of the interventricular septum and the left ventricle. The short-axis cut (C) shows the circumferential distribution of the haemorrhagic necrosis and its confinement to the inner part of the ventricular wall. Histologically, the necrotic myocardium showed loss of nuclei with intense eosinophilia of the myocyte cytoplasm and contraction bands. A few leucocytes only were present in the interstitium.

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is subendocardial necrosis (Figure 6.1), and a subgroup of this is necrosis of the papillary muscles of the atrioventricular valves. The tissue may be haemorrhagic, or at least hyperaemic with telangiectasia. In cases with jaundice, the necrotic myocardium may take on a green-yellow tinge. The atria may be affected, and the interventricular septum high on the base near the conduction system is frequently involved, as well as the atrioventricular junctions.

death. The muscles of the mitral valve are usually involved (Figure 6.2), but the tricuspid valve papillary muscles may also be affected (Figure 6.3) [18]. Papillary muscle rupture has been described in older children following blunt chest trauma, usually in road traffic accidents [19]. In many instances no explanation of the rupture is identified, but rupture of the chordae tendineae has been attributed to maternal anti-SSA antibodies [20].

6.2.2 Papillary Muscle Rupture

6.2.3 Regional Infarction

Ischaemic necrosis of the papillary muscles may result in their rupture and this may cause intractable heart failure and even

Extensive myocardial infarction may be found in the absence of coronary artery lesions. Focal coronary artery abnormalities,

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6: Ischaemia and Infarction

Figure 6.2 Rupture of attachment of anterior leaflet of mitral valve. Eightweek-old boy with trisomy 21 with oesophageal atresia without fistula. Two weeks before death he developed increasing dyspnoea. Echocardiograhy showed a large arterial duct. He collapsed acutely and echocardiography showed flail anterior leaflet of mitral valve. At post-mortem there was rupture of the anterior papillary muscle of the mitral valve at the insertion of the chordae, and there was a flail segment with a loose attachment that had become distorted and prolapsed into the left atrium. (A) The mitral valve is viewed from the left atrium. The chordae have become detached from the anterior papillary muscle, and their distal ends are haemorrhagic and twisted and have prolapsed into the atrium. (B) A section of the anterior papillary muscle shows coagulative necrosis of the centre of the muscle extending to its apex from where the chordae have detached. The non-necrotic myocardium is vacuolated.

nonetheless, may cause regional infarction. Infarction may complicate origin of the left coronary artery from the pulmonary trunk, and in these cases the distribution of the necrosis is in the territory of the left coronary artery [21]. Similarly, in Kawasaki disease [22] or fibromuscular dysplasia [23] the area of necrosis may have a regional distribution. Extensive infarction can occur in hypertrophic cardiomyopathy (Figure 6.4) [24]. It is also worth keeping in mind that the severe chronic allograft vasculopathy in cardiac transplantation results in severe chronic ischaemic damage to the myocardium above that caused by the cellular component of rejection, albeit frank regional infarction is rare.

6.2.4 Coronary Artery Atherosclerosis Coronary atherosclerosis, although very rare, does occur in children, usually in the setting of familial hypercholesterolaemia. Familial hypercholesterolaemia is an autosomal dominant disease with a risk of premature coronary artery disease in early adulthood. About 80% of cases are accounted for by mutation in the LDLR gene on chromosome 19 that results in absent or deficient low-density lipoprotein (LDL) receptors on the liver cells. The receptor defect leads to reduced uptake and metabolism of LDL by the hepatocytes with consequent increase in circulating LDL cholesterol [25].

Other genes, mutation in which cause familial hypercholesterolaemia, are APOB (apolipoprotein B) accounting for about 5% of cases and PCSK9 (proprotein convertase subtilisin/kexin type 9) accounting for only 1% of cases. A rare autosomal recessive form (LDLRAP1) occurs, and the remainder of cases are due to mutation in unknown genes or are polygenic. Heterozygous familial hypercholesterolaemia results from inheritance of the mutation from one parent and is a common defect with a prevalence of about 1:300. Inheritance of a mutation from both parents causes homozygous familial hypercholesterolaemia with a prevalence in European populations of 1:160 000 to 1:300 000. Untreated individuals have very high circulating levels of LDL cholesterol, and are at high risk of coronary artery disease in childhood and adolescence (Figure 6.5) [26]. Coronary artery calcification is rare before adolescence in homozygous familial hypercholesterolaemia, although it does develop in the teenage years in many cases [27]. In homozygous familial hypercholesterolaemia there is massive accumulation of cholesterol in the aortic valve and supravalvar aorta resulting in aortic stenosis and regurgitation and coronary artery ostial stenosis [28]. Heterozygous familial hypercholesterolaemia tends to involve the more distal coronary artery tree.

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6: Ischaemia and Infarction

Figure 6.4 Myocardial infarction in hypertrophic cardiomyopathy. A fifteenyear-old with MHY7 mutation causing hypertrophic cardiomyopathy who underwent orthotopic heart transplant following collapse with heart failure. The explanted heart shows extensive haemorrhagic infarction of the hypertrophied myocardium of the free wall of the left ventricle. The coronary arteries were normal.

Figure 6.3 Ruptured papillary muscle of tricuspid valve. An infant born at term who suffered respiratory distress and cyanosis in the first hours of life. Enlarged liver with tricuspid regurgitation on echo. Arrested on transfer for surgery. Ruptured anterior papillary muscle of the tricuspid valve on echo. The picture shows an area of black discolouration of the anterior papillary muscle with a raw area at the site of rupture. The more distal part of the papillary muscle is attached to the chordae attached to the anterosuperior leaflet of the tricuspid valve. Similar, smaller areas of necrosis are scattered in the right and left ventricular myocardium. No anatomical abnormality to account for the necrosis was identified, but the histological appearances suggest the necrosis has occurred within the previous 24 hours. Rupture of the papillary muscles of the tricuspid valve is a rare occurrence, and most cases have been attributed to perinatal hypoxia.

6.3 Microscopic Appearance The first tissue change that is evident by light microscopy is that the myocytes become hypereosinophilic (Figure 6.6) [29]. This change takes 6–8 hours to develop from the onset of the insult. The cross striations may become blurred, and there may be clumping of the cytoplasm. Contraction bands are frequently present (Figure 6.7). There is nuclear change, with blurring and loss of staining. Intercellular oedema develops and then infiltration by neutrophil polymorphs, usually by 12–24 hours. There is capillary dilatation, and often this may be the alerting sign to the presence of necrosis. Infant myocardium in particular has a propensity to calcify and may do so within a day of the insult, sometimes massively (Figure 6.8).

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Figure 6.5 Familial hypercholesterolaemia. Thirteen-year-old with familial hypercholesterolaemia and mixed valvar and supravalvar aortic stenosis who underwent aortic stenosis repair. A section through the thickened excised aorta shows a fibrous cap with underlying numerous foam cells with focal calcification in keeping with atheromatous plaque.

6.3.1 Dating of Injury Dating of hypoxic/ischaemic injury in adults is based on classical studies from many years ago [29] that need to be interpreted in the light of recent therapeutic interventions [30]. In particular reperfusion can markedly affect the appearance and histology of infarcted myocardium [31]. In children these dating schemes need even greater caution in their use, and the insult may have been present for longer than it appears. Inflammatory cell infiltration is usually not so prominent as in older individuals.

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6: Ischaemia and Infarction

Figure 6.6 Early myocardial necrosis. Term infant who died 48 hours after emergency caesarean section for fetal distress. A representative section from the right ventricular myocardium shows hypereosinophilia of the myocytes with intense capillary engorgement and loss of myocyte nuclei. There is margination of neutrophils in capillaries, but, as yet, no infiltration of the interstitium.

Figure 6.7 Contraction band necrosis. Two-week-old infant with tetralogy of Fallot who died of viral encephalitis. The myocardium of the right ventricle was hypertrophied and showed scattered small foci of contraction band necrosis. The Masson’s trichrome stained section shows myocytes with clumping of the filaments causing thick transverse bands in the cytoplasm, the so-called contraction bands. There is associated nuclear loss.

Figure 6.8 Myocardial calcification. A 4-month-old with transposition and VSD repaired. The infant developed pulmonary hypertension, and an attempt to close a residual VSD resulted in going on to extracorporeal membrane oxygenation (ECMO). They died shortly afterwards. The cut surface of the myocardium shows linear pale areas in the subendocardium representing necrotic and calcified myocytes.

Figure 6.9 Myocardial fibrosis. An 11-year-old with critical aortic stenosis who collapsed and died suddenly. The left ventricular wall showed multiple foci of old fibrosis in circumferential subendocardial distribution. The picture shows one of the papillary muscles of the mitral valve with a wedge-shaped area of scarring beneath the endocardium. There is no recent necrosis.

After myocardial infarction, there is activation of tissue matrix metalloproteinases that degrade the existing extracellular matrix and vasculature. This degradation declines after the first week because of a rise in tissue metalloproteinases. Neutrophils contribute to the proteolytic digestion, and macrophages contribute to phagocytosis. The inflammatory response peaks at weeks 1–2 post infarction and usually disappears by 3–4 weeks by apoptosis. Fibrosis begins with activation of TGF-β1with subsequent synthesis of collagen types 1 and III [32]. Eventually there is

fibrous scarring in the distribution of the original necrosis (Figure 6.9).

6.3.2 Haemolytic Uraemic Syndrome Haemolytic uraemic syndrome is a rare condition consisting of the triad of microangiopathic haemolytic anaemia, thrombocytopenia and acute renal failure, usually following a prodromal acute diarrhoeal illness. Most cases are caused by infection with Shiga-toxin-producing Escherichia coli 0157. The incidence in children under the age of 16 years in the

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Figure 6.10 Haemolytic uraemic syndrome. A child who died in the acute phase of haemolytic uraemic syndrome. A section from the myocardium stained with Martius–Scarlet–Blue shows multiple fibrin (red) thrombi within the coronary capillaries. There is associated interstitial oedema.

United Kingdom and Ireland is 0.71/100 000 [33], and most cases occur under the age of five years. The heart may be affected in the disease secondary to hypovolaemia, hypertension or electrolyte disturbance, but direct involvement with thrombotic microangiopathy is distinctly uncommon. When thrombotic microangiopathy develops in the coronary microcirculation (Figure 6.10), ischaemia and infarction may result and heart failure, dilated cardiomyopathy or pericardial effusion may ensue [34]. The majority of patients develop cardiac symptoms within 1–3 weeks of original presentation. There may be signs of poor peripheral perfusion or pulmonary oedema. ECG usually shows non-specific ST changes. Echocardiography may show global cardiac dysfunction with reduced ejection fraction. Troponin levels may be elevated. Cardiac involvement is usually reversible but long-term sequelae may occur [35].

6.3.3 Antiphospholipid Syndrome The antiphospholipid syndrome (APS) is an autoimmune disorder characterised by thrombosis (and/or pregnancy morbidity) accompanied by persistently positive tests for antiphospholipid antibodies [36]. Antiphospholipid antibodies involved may be lupus anticoagulant, anti-cardiolipin or directed against the antigen β2GPI. The thrombosis may be arterial or venous. In about one-half of cases it occurs in isolation (primary) and in the remainder of cases is associated with lupus erythematosus and sometimes other disorders. A severe form of the disease – catastrophic antiphospholipid syndrome – is defined as microvascular thrombosis affecting three or more organs within a period of one week with histological confirmation of small vessel thrombosis [37]. Catastrophic antiphospholipid syndrome occurs in fewer than 1% of patients with antiphospholipid antibody, but carries a

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Figure 6.11 Catastrophic antiphospholipid syndrome. (A) A 12-year-old with a history of presumed rheumatic disease who presented with mitral regurgitation and acute heart failure. The endomyocardial biopsy showed multiple small vessels occluded by thrombus. The surrounding interstitium is oedematous. There is no vasculitis. (B) This appearance should not be confused with the artefactual telescoping of myocardium into vessels in an endomyocardial biopsy. This is a not infrequent finding. Note that the material in the vessel lumen has the same texture and colour as the surrounding myocytes.

mortality rate of 33–50%, mostly from cerebral, renal or cardiac involvement [38]. Antiphospholipid antibodies react to the phospholipid binding protein β2GPI when bound to endothelial cells or platelets and thus initiate clotting [39]. The usual involvement of the heart in antiphospholipid syndrome (in about one-third of patients) is with heart valve thickening or vegetations similar to that in systemic lupus erythematosus, but significant valvar dysfunction is unusual [40]. The mitral valve is the most frequently affected, followed by the aortic valve. The right-sided valves are rarely involved [41].

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Figure 6.12 Myocardial calcification following injury. (A) An infant with origin of the left coronary artery from the pulmonary artery. He suffered cardiac arrest, was resuscitated, operated and placed on ECMO and died four weeks later. An H&E stained section through the left ventricular myocardium shows multiple foci of calcification generally in a subendocardial distribution in the territory of the left coronary artery. (B) Fetus of 20 weeks’ gestation with maternal lupus. Scan had shown echogenicity around both atrioventricular and arterial valves. This was confirmed at post-mortem, which showed necrosis at these sites with calcification. The section shows subepicardial necrosis with calcification of individual myocytes typical of fetal cardiac involvement in maternal lupus. (C) Four-week-old infant who underwent heart transplant following Enterovirus myocarditis. The explanted heart shows multiple yellow foci of necrosis with calcification in the papillary muscle of the tricuspid valve, at the crest of the interventricular septum and in the free wall of the left ventricle.

The heart is involved in 50% of cases of catastrophic antiphospholipid syndrome [42]. Its presence may be detected on endomyocardial biopsy (Figure 6.11). Pulmonary hypertension may also develop. The disease can occur in children from the neonate through to adolescence [43].

6.3.4 Myocardial Calcification Foci of calcification of the myocardium may be detected in utero. They may be caused by infection or maternal lupus. Small foci may occur in the papillary muscles of the left or right ventricles or beneath the endocardium of the ventricle. Usually single, two or sometimes three foci may be present [44]. They can be detected on ultrasound scan as a hyperechogenic focus in the myocardium. There is evidence of ethnic variation in occurrence with the highest prevalence

in African Americans [45]. In pregnancies at high risk of chromosomal abnormality they are reported to be associated with the presence of chromosomal abnormality, particularly trisomy 21 [46]. A single focus in a low-risk pregnancy and in the absence of other abnormalities is not associated with impaired ventricular function [47] and is probably normal [48]. Injured myocardium in the child and in particular in the neonate is peculiarly susceptible to calcification [49]. It is not uncommon to see hearts from children who have died from a multitude of causes associated with myocardial injury who share a common feature of heavy myocardia calcification. Causes include direct hypoxic injury (Figure 6.12A), immunological injury as in maternal lupus (Figure 6.12B) or following cardiac surgery or viral myocarditis (Figure 6.12C). Foci of extramedullary haematopoiesis are frequent in areas of necrosis (Figure 6.13).

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Hypotension Neonatal intensive care Congenital heart disease Anomalous coronary artery from the pulmonary artery Kawasaki disease Aortic stenosis Coronary artery fistula Thromboembolic disease Coronary atherosclerosis Severe anaemia Hypertrophic cardiomyopathy Figure 6.13 Extramedullary haematopoiesis associated with myocyte necrosis. Same case as in Figure 6.12A. There is extramedullary haematopoiesis in the epicardium overlying one of the multiple necrotic foci in the myocardium.

echocardiographic and enzymatic correlations. Eur J Pediatr 1999; 158: 742–747.

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autopsy population: incidence and associated clinical manifestations. J Pediatr 1980; 96: 289–294. 17. Bamber AR, Pryce J, Cook A, Ashworth M, Sebire NJ. Myocardial necrosis and infarction in newborns and infants. Forensic Sci Med Pathol 2013; 9: 521–527. 18. Riede FT, Dähnert I, Razek V, Kostelka M. Rupture of the papillary muscle of the tricuspid valve – echocardiographic diagnosis of a rare anomaly leading to critical tricuspid valve regurgitation in the newborn. Eur J Pediatr 2010; 169: 165–166. 19. Bakiler AR, Aydoğdu SA, Erişen S, Yenigün A, Atay Y. A case of mitral papillary muscle rupture due to blunt chest trauma. Turk J Pediatr 2011; 53: 97–99. 20. Hamaoka A, Shiraishi I, Yamagishi M, Hamaoka K. A neonate with the rupture of mitral chordae tendinae associated with maternal-derived antiSSA antibody. Eur J Pediatr 2009; 168: 741–743. 21. Birk E, Stamler A, Katz J et al. Anomalous origin of the left coronary artery from the pulmonary artery: diagnosis and postoperative follow up. Isr Med Assoc J 2000; 2: 111–114.

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a 12-year old secondary to fibromuscular dysplasia. Am J Emerg Med 2014; 32: 812.e5–7. 24. Tome-Esteban MT, Ashworth M. Hypertrophic cardiomyopathy and acute myocardial necrosis with normal coronary arteries. Heart 2008; 94: 1357. 25. Usifo E, Leigh SE, Whittall RA et al. Low-density lipoprotein receptor gene familial hypercholesterolemia variant database: update and pathological assessment. Ann Hum Genet 2012; 76: 387–401. 26. Sjouke B, Kusters DM, Kindt I et al. Homozygous autosomal dominant hypercholesterolaemia in the Netherlands: prevalence, genotypephenotype relationship, and clinical outcome. Eur Heart J 2015; 36: 560–565. 27. Awan Z, Alrasadi K, Francis GA et al. Vascular calcifications in homozygote familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 2008; 28: 777–785. 28. Kolansky DM, Cuchel M, Clark BJ et al. Longitudinal evaluation and assessment of cardiovascular disease in patients with homozygous familial hypercholesterolemia. Am J Cardiol 2008; 102: 1438–1443. 29. Mallory GK, White PD, Salcedo-Salgar J. The speed of healing of myocardial infarction: a study of the pathologic anatomy in seventy-two cases. Am Heart J 1939; 18: 647–671. 30. Michaud K. Ischemic heart disease. In Suvarna SK (ed.) Cardiac Pathology. A Guide to Current Practice. London: Springer; 2013, pp. 117–131. 31. Basso C, Rizzo S, Thiene G. The metamorphosis of myocardial infarction following coronary recanalization. Cardiovasc Patholol 2010; 19: 22–28.

34. Rigamonti D, Simonetti GD. Direct cardiac involvement in childhood hemolytic-uremic syndrome: case report and review of the literature. Eur J Pediatr 2016; 175: 1927–1931. 35. Machol K, Vivante A, Rubinsthein M et al. Keeping the heart in mind when managing hemolytic: uremic syndrome. Isr Med Assoc J 2011; 13: 446–447. 36. Miyakis S, Lockshin MD, Atsumi T et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 4: 295–306. 37. Asherson RA, Cervera R, de Groot PG et al.; Catastrophic Antiphospholipid Syndrome Registry Project Group. Catastrophic antiphospholipid syndrome: international consensus statement on classification criteria and treatment guidelines. Lupus 2003; 12: 530–534. 38. Cervera R, Espinosa G. Update on the catastrophic antiphospholipid syndrome and the “CAPS Registry”. Semin Thromb Hemost 2012; 38: 333–338. 39. McNeil HP, Simpson RJ, Chesterman CN, Krilis SA. Anti-phospholipid antibodies are directed against a complex antigen that includes a lipidbinding inhibitor of coagulation: beta 2-glycoprotein I (apolipoprotein H). Proc Natl Acad Sci U S A 1990; 87: 4120–4124. 40. Hojnik M, George J, Ziporen L, Shoenfeld Y. Heart valve involvement (Libman–Sacks endocarditis) in the antiphospholipid syndrome. Circulation 1996; 93: 1579–1587.

32. Sun Y. Myocardial repair/remodelling following infarction: roles of local factors. Cardiovasc Res 2009; 81: 482–490.

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42. Rodríguez-Pintó I, Moitinho M, Santacreu I et al.; CAPS Registry Project Group (European Forum on Antiphospholipid Antibodies). Catastrophic antiphospholipid

syndrome (CAPS): Descriptive analysis of 500 patients from the International CAPS Registry. Autoimmun Rev 2016; 15: 120–1124. 43. Berman H, Rodríguez-Pintó I, Cervera R et al.; Catastrophic Registry Project Group (European Forum on Antiphospholipid Antibodies). Pediatric catastrophic antiphospholipid syndrome: descriptive analysis of 45 patients from the “CAPS Registry”. Autoimmun Rev 2014; 13: 157–162. 44. Tennstedt C, Chaoui R, Vogel M, Göldner B, Dietel M. Pathologic correlation of sonographic echogenic foci in the fetal heart. Prenat Diagn 2000; 20: 287–292. 45. Tran SH, Caughey AB, Norton ME. Ethnic variation in the prevalence of echogenic intracardiac foci and the association with Down syndrome. Ultrasound Obstet Gynecol 2005; 26: 158–161. 46. Manning JE, Ragavendra N, Sayre J et al. Significance of fetal intracardiac echogenic foci in relation to trisomy 21: a prospective sonographic study of high-risk pregnant women. Am J Roentgenol 1998; 170: 1083–1084. 47. Yozgat Y, Kilic A, Ozdemir R et al. Modified myocardial performance index is not affected in fetuses with an isolated echogenic focus in the left ventricle. J Matern Fetal Neonatal Med 2015; 28: 333–337. 48. Lamont RF, Havutcu E, Salgia S, Adinkra P, Nicholl R. The association between isolated fetal echogenic cardiac foci on second-trimester ultrasound scan and trisomy 21 in low-risk unselected women. Ultrasound Obstet Gynecol 2004; 23: 346–351. 49. Drut R, Drut RM, Alba Greco M. Massive myocardial calcification in the perinatal period. Pediatr Devel Pathol 1998; 1: 366–374. 50. Franklin RC, Jacobs JP, Krogmann ON et al. Nomenclature for congenital and paediatric cardiac disease: historical perspectives and The International Pediatric and Congenital Cardiac Code. Cardiol Young 2008;18 (Suppl 2): 70–80.

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Chapter

7

Cardiomyopathy

7.1 Introduction Cardiomyopathy has been defined as “a myocardial disorder in which the heart muscle is structurally and functionally abnormal, in the absence of coronary artery disease, hypertension, valvular disease and congenital heart disease sufficient to cause the observed myocardial abnormality” [1]. Cardiomyopathy in children is a cause of significant morbidity and mortality. It is a cause of sudden unexpected death in this age range and is the commonest indication for paediatric heart transplant. Heart muscle disease associated heart failure in children in the United Kingdom and Ireland has an incidence of 0.87/100 000 of the population less than 16 years of age, with a median age of presentation of 1 year [2]. Although showing a similar spectrum of abnormalities to that found in adults, cardiomyopathy in children presents its own peculiarities. Some forms of cardiomyopathy are found exclusively in children, while others, common in adults, are scarcely seen in this population. Clinically and pathologically, cardiomyopathies have traditionally been classified into three basic types according to their pathophysiology: 1. Dilated cardiomyopathy in which the left, or sometimes both, ventricles are dilated and show decreased systolic function as measured by decreased shortening fraction (normal greater than 30%) or decreased ejection fraction (normal greater than 55%) on echocardiography (Figure 7.1A). 2. Hypertrophic cardiomyopathy in which there is abnormal thickening of (principally) the left ventricular myocardium. There may be associated left ventricular outflow tract obstruction. There is disturbed systolic and diastolic myocardial function (Figure 7.1B). 3. Restrictive cardiomyopathy in which there is decreased diastolic ventricular filling often with atrial enlargement. There is abnormal relaxation of the ventricular myocardium with decreased ventricular compliance and consequent restriction of ventricular filling. This causes raised end diastolic pressure with secondary increase in atrial pressure and consequent atrial dilatation (Figure 7.1C). There are currently two major clinical systems of classifying cardiomyopathy that, while agreeing on broad categories,

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differ in their details, most notably the inclusion or exclusion of ion channelopathies. These are the 2006 American Heart Association Classification [3] (Table 7.1) and the 2007 European Society of Cardiology classification (Table 7.2) [1]. Both classifications recognise the traditional divisions and also take into account genetic (or familial) occurrence [4]. From the point of view of the pathologist, the morphology of the main types of cardiomyopathy tends to be distinctive, at least in their fully established forms, but there are areas of overlap; some forms of hypertrophic cardiomyopathy may, in their course, develop a dilated phenotype and most forms of dilated and restrictive cardiomyopathy show increased heart weight and histological evidence of myocyte hypertrophy. The aetiology of some cardiomyopathies is known, for example cardiomyopathy due to metabolic disorder or in association with muscular dystrophy or other skeletal muscle disease. Many forms of cardiomyopathy have a genetic or familial basis, but some forms of heart muscle disease are undoubtedly acquired as a result of exposure of susceptible individuals to infectious agents or toxins. There may be no factor to which the heart muscle disease is as yet attributable – so-called primary or idiopathic cardiomyopathy. The European Society of Cardiology classification abandoned the distinction between primary and secondary cardiomyopathy and based their classification on groupings of specific morphological and functional phenotypes rather than putative pathophysiological mechanisms, which may be more suited to research purposes than to everyday practice, and did not include rhythm disturbance in their classification [1]. They further subclassified their groups into familial and nonfamilial forms so as to raise awareness of genetic determinants of cardiomyopathies and to orient diagnostic tests. This classification is given in Table 7.2.

7.2 Hypertrophic Cardiomyopathy This refers to disease of the heart muscle where the primary pathology is hypertrophy of the ventricular myocardium in the absence of a predisposing factor such as systemic hypertension or valvar heart disease. Often displaying asymmetrical involvement of the interventricular septum, this form of cardiomyopathy is sometimes associated with obstruction of the left ventricular outflow [5].

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Figure 7.1 Traditional morphological classification of cardiomyopathy. The basic morphological and physiological classification into hypertrophic (A), dilated (B) and restrictive (C) phenotypes. Hypertrophic cardiomyopathy in its classical form shows marked increase in thickness in the left ventricular myocardium, sometimes with outlet obstruction. Dilated cardiomyopathy, while also showing increased muscle mass, is characterised by ventricular dilatation and frequently by ventricular endocardial fibroelastosis. The characteristic morphological feature of restrictive cardiomyopathy is the disproportionate dilatation of the atria.

Grossly, the heart is enlarged, and the heart weight increased. There is hypertrophy of the ventricular myocardium. This may be confined to the septum but usually involves all of the left ventricle (Figure 7.2). Whorling of the hypertrophied myocardium may be evident macroscopically, as may fibrosis (Figure 7.3). An impact lesion of the left ventricular outflow endocardium, representing an area of white fibrous thickening of the septal endocardium corresponding to the shape of the anterior mitral valve leaflet and caused by abnormal impact of this leaflet on the hypertrophied septum, is commonly seen in adults (Figure 7.4), but is distinctly unusual in children. The septal thickening may cause obstruction to the left ventricular outflow (Figure 7.5). The histological hallmark of hypertrophic cardiomyopathy is myocyte disarray. Disarray consists of disorganised hypertrophied myocytes that have a splayed appearance. They lack the normal fascicular arrangement and run in various directions, often overlap and may have a whorled appearance (Figure 7.6). Fibrosis is a usual

accompaniment (Figure 7.7). There are frequently dysplastic changes in the intramyocardial arteries (Figure 7.8). The disease was originally described in adolescents and was associated with a high frequency of sudden death. It can occur in neonates and even in utero. In paediatric practice it is an uncommon cause of death. A family history of hypertrophic cardiomyopathy is present in about 60% of cases of childhood cardiomyopathy, and just over 50% show sarcomeric protein gene mutations [6]. Most cases of idiopathic hypertrophic cardiomyopathy are now known to be caused by mutations in the genes encoding structural proteins of the contraction apparatus of the cardiac myocyte [7]. To date, mutations in 26 genes coding principally for cardiac sarcomeric proteins have been claimed to cause hypertrophic cardiomyopathy [8–26], albeit the association for some of them is putative rather than confirmed (Table 7.3) [27]. Of these, mutations in MYH7 and MYBPC3 account for 75% of cases with an identifiable pathogenic variant [28]: the

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7: Cardiomyopathy Table 7.1 American Heart Association 2006 classification of cardiomyopathy

PRIMARY CARDIOMYOPATHY Genetic Hypertrophic cardiomyopathy Glycogen storage • PRKAG2 • Danon Arrhythmogenic right ventricular cardiomyopathy Left ventricular non-compaction Conduction system disease Mitochondrial myopathies Ion channelopathies • Long QT syndrome • Brugada syndrome • Short QT syndrome • Catecholaminergic polymorphic ventricular tachycardia • Asian SUNDS

• •

Phaeochromocytoma Acromegaly

Cardiofacial • Noonan’s syndrome • Lentiginosis Neuromuscular/neurological • Friedreich’s ataxia • Duchenne–Becker muscular dystrophy • Emery–Dreifuss muscular dystrophy • Myotonic dystrophy • Neurofibromatosis • Tuberous sclerosis Nutritional deficiencies • Beri-beri, pellagra, scurvy, selenium, carnitine, kwashiorkor

Mixed

Autoimmune/collagen • Systemic lupus erythematosus • Dermatomyositis • Rheumatoid arthritis • Scleroderma • Polyarteritis nodosa

Dilated cardiomyopathy

Electrolyte imbalance

Restrictive cardiomyopathy

Inflammatory (myocarditis)

Consequence of cancer therapy • Anthracyclines • Cyclophosphamide • Radiation

Stress provoked (takotsubo)

Source: American Heart Association Classification (2006) [3].

Acquired

Peripartum Tachycardia induced Infants of insulin-dependent diabetic mothers SECONDARY CARDIOMYOPATHY Infiltrative • Amyloidosis • Gaucher disease • Hurler’s disease • Hunter’s disease Storage • Haemochromatosis • Fabry’s disease • Glycogen storage disease (type II, Pompe) • Niemann–Pick disease Toxicity • Drugs, heavy metals, chemical agents Endomyocardial • Endomyocardial fibrosis • Hypereosinophilic syndrome (Loeffler’s endocarditis) Inflammatory (granulomatous) • Sarcoidosis Endocrine • Diabetes mellitus • Hyperthyroidism • Hypothyroidism • Hyperparathyroidism

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Table 7.2 European Society of Cardiology 2008 classification of cardiomyopathy

Dilated cardiomyopathy Hypertrophic cardiomyopathy Restrictive cardiomyopathy Arrhythmogenic right ventricular cardiomyopathy Unclassified Non-compacted myocardium Fibroelastosis Mitochondrial The categories are subdivided into familial (genetic) and nonfamilial types Source: European Society of Cardiology (2008) [1].

phenotype of mutations in both genes is indistinguishable [29]. By no means have mutations in all these genes been demonstrated in cardiomyopathy in children. Among these genes are those encoding α- and β-myosin heavy chains, actin, tropomyosin and cardiac troponins T, C and I. It is also recognised that particular mutations may correlate with a particular phenotype and correspond with, for example, the degree of myocyte hypertrophy or the magnitude of the risk of sudden death [30]. More recently, mutations in genes coding for proteins other than sarcomeric proteins have been identified. These genes code for proteins of the Z-disc, the sarcolemma or the sarcoplasmic reticulum [16–26].

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7: Cardiomyopathy

Figure 7.2 Hypertrophic cardiomyopathy. Adolescent male who died suddenly. The heart weighed 570 g. A section at mid-ventricular level through the ventricles shows concentric thickening of the left ventricular wall, most prominent in the interventricular septum. Streaks of pale fibrosis are seen in the anterior septum.

Figure 7.3 Hypertrophic cardiomyopathy. A close-up view of the anterior interventricular septum showing whorling of the muscle bundles. There is a focal increase in pale interstitial fibrous tissue. The endocardium is not thickened.

Figure 7.5 Hypertrophic cardiomyopathy outflow obstruction. A 12-year-old who died suddenly without any previous medical history of note. There is hypertrophic cardiomyopathy. This simulated long-axis view of the heart shows that there is disproportionate enlargement of the interventricular septum that bulges into the left ventricular outflow.

Figure 7.4 Hypertrophic cardiomyopathy. An adult male with hypertrophic cardiomyopathy. The left ventricular outflow tract has been opened to display the septum. On the septum, immediately beneath the aortic valve, is a triangular area of endocardial fibrosis, the apex of the triangle pointing towards the cardiac apex. The shape of this so-called impact lesion corresponds to that of the anterior leaflet of the mitral valve, which has been retracted to the right in this picture. This appearance is rarely, if ever, seen in children.

Although myocyte disarray is the defining histological hallmark of hypertrophic cardiomyopathy, it can occur in other settings. Myofibre disarray occurs in the normal heart at the junction of the free wall of the ventricles with the interventricular septum (Figure 7.9). The area involved is small, and disarray should not be seen in the normal heart in the interventricular septum or lateral ventricular walls. Myocyte disarray is present in the hypertrophy accompanying many forms of congenital heart disease, most notably hypoplastic left heart, where it is described in up to 80% of cases (Figure 4.42). Myocyte disarray may also be seen in restrictive cardiomyopathy. The muscle fibre hypertrophy with disarray in hypertrophic cardiomyopathy affects not just the ventricles but can

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7: Cardiomyopathy Table 7.3 Sarcomeric protein genes mutated in familial hypertrophic cardiomyopathy

Gene

Symbol

Location

Ref.

β-Myosin heavy chain

MYH7

14q12

8

α-Myosin heavy chain

MYH6

14q12

9

Cardiac α actin

ACTC1

15q14

10

α-Tropomyosin

TPM1

15q22

11

Cardiac troponin C

TNNC1

3p21

12

Cardiac troponin I

TNNI3

19p13

13

Cardiac troponin T

TNNT2

1q32

11

Cardiac myosin binding protein C

MYBPC3

11p11

14

Regulatory myosin light chain

MYL2

12q23

15

Essential myosin light chain

MYL3

3p21

15

Cysteine and glycine-rich protein 3

CSRP3

11p15.1

16

Alpha actinin 2

ACTN2

1q43

17

Telethonin

TCAP

17q12

18

Cardiac phospholamban

PLN

6q22.31

19

Myozenin 2

MYOZ2

4q26

20

Nexilin

NEXN

1p31.1

21

Vinculin

VCL

10q22.2

22

Myopalladin

MYPN

10q21.3

23

Calreticulin 3

CALR3

19p13.11

24

Caveolin 3

CAV3

3p25.3

25

Junctophilin 2

JPH2

20q13.12

26

LIM binding domain 3 protein

LDB3

10q23.2

17

Figure 7.7 Hypertrophic cardiomyopathy – fibrosis. Sudden death of a male age 23 years with MYBPC3 mutation positive hypertrophic cardiomyopathy. The heart showed hypertrophy, disarray and multiple foci of interstitial fibrosis. One such focus is illustrated. There are small scars in addition to fibrosis surrounding individual myocytes.

Figure 7.8 Hypertrophic cardiomyopathy – dysplastic intramyocardial artery. A myectomy specimen from obstructive cardiomyopathy stained with Masson’s trichrome stain. This small intramyocardial artery is dysplastic: its wall shows nodular proliferation of smooth muscle cells with fibrosis and the lumen is irregular in outline.

also be found in the atrial myocardium (Figure 7.10). The identification of hypertrophic cardiomyopathy has important implications for other siblings and family members, and, where possible, genetic material should be obtained at autopsy to permit gene screening, as appropriate [31].

Figure 7.6 Hypertrophic cardiomyopathy – myocyte disarray. An area of myocyte disarray from the explanted heart of a 14-year-old girl who underwent heart transplant for hypertrophic cardiomyopathy. The myocytes are enlarged and splayed and run in multiple different directions imparting a swirling appearance. There is also an increase in interstitial tissue. Disarray is usually very prominent in hypertrophic cardiomyopathy and not difficult to discern.

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7.3 Other Cardiomyopathies with a Hypertrophic Phenotype The hypertrophied left ventricular myocardium of hypertrophic cardiomyopathy is a phenotype, and diseases other than those caused by mutations in sarcomeric protein genes can present

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7: Cardiomyopathy Table 7.4 Conditions in children with a hypertrophic cardiac phenotype

Hypertrophic cardiomyopathy Restrictive cardiomyopathy Mitochondrial cardiomyopathy Barth syndrome Glycogen storage disease: Pompe, Danon PRKAG2 Anderson–Fabry disease Friedreich’s ataxia Noonan’s syndrome Infant of diabetic mother Infant steroid administration

Figure 7.9 Normal heart myocyte disarray. A section from the normal heart of a term stillbirth. This area is at the junction of the septum with the ventricular free wall. It shows myocyte disarray with whorling of the muscle bundles in no uniform direction.

[33]. The condition tends to remain stable during childhood. The length of the trinucleotide repeats appears not to correlate with the severity of the cardiac disease [34].

7.3.2 Noonan’s Syndrome

Figure 7.10 Hypertrophic cardiomyopathy – myocyte disarray in atrial wall. Explanted heart from a 15-year-old with familial hypertrophic cardiomyopathy. A section from the left atrial wall shows myocyte disarray.

with a hypertrophic phenotype. A list of the commoner conditions is given in Table 7.4. Such diseases include Pompe disease (glycogen storage disease type II), mutations of the PRKAG2 gene, Danon disease and Anderson–Fabry disease. These conditions are treated at length in Chapter 10.

7.3.1 Friedreich’s Ataxia Friedreich’s ataxia is a rare autosomal recessive disorder characterised by spinocerebellar degeneration. It is caused by an unstable GAA trinucleotide repeat expansion (>120 repeats) in the first intron of both alleles of the frataxin gene on chromosome 9q13. Most cases that have cardiac involvement demonstrate concentric left ventricular hypertrophy, but dilated cardiomyopathy and electrical disturbance also occur [32]. Pathologically there is myocyte hypertrophy with disarray and interstitial fibrosis, and deposition of calcium and iron in myocytes is described and there is focal inflammation

Noonan’s syndrome is an autosomal dominant disease characterised by short stature, facial dysmorphism and cardiac defects. The most common cardiac defect is pulmonary stenosis occurring in about 50% of cases. Other cardiac defects include polyvalvar dysplasia [35]. About 10% of patients have a hypertrophic cardiomyopathy [36]. Germline mutations in the RAS mitogen-activated protein kinase (MAPK) pathway are involved in the pathogenesis of Noonan’s syndrome. About 45% of cases of Noonan’s syndrome are due to missense mutations in the PTPN11 gene on 12q24.1 [37]. That gene encodes SHP-2, a protein tyrosine kinase that has multiple functions in signal transduction including signalling via the RAS MAPK pathway. Noonan’s syndrome-associated PTPN11 mutations are gain-of-function mutations that disrupt the activation– inactivation mechanism of SHP-2. Mutations in the genes encoding for other proteins in the RAS/MAPK pathway have been identified in those cases of Noonan’s syndrome that do not have PTPN11 mutations, namely SOS1, RAF1, MEK1 and KRAS. Hypertrophic cardiomyopathy is more frequently observed in patients with RAF1 mutations [38]. Histologically there is myocyte disarray (Figure 7.11) [39]. Infants of diabetic mothers may develop myocardial hypertrophy identical to hypertrophic cardiomyopathy in the neonatal period [40]. This cardiomyopathy is usually transient and resolves spontaneously. Hypertrophic cardiomyopathy is also described in infants who have received steroids for pulmonary immaturity or chronic lung disease [41]; again, this cardiomyopathy tends to be transitory but shows identical

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Figure 7.12 Dilated cardiomyopathy. Post-mortem in a five-month-old infant who died suddenly and unexpectedly. The opened thorax shows the heart is enlarged and occupies most of it. A few petechiae are present along the epicardial course of the coronary arteries.

Figure 7.11 Noonan’s syndrome. (A) Infant aged 8 months with hypertrophic cardiomyopathy and polyvalvar dysplasia. The four-chamber view of the heart demonstrates the ventricular hypertrophy and the myxoid thickening of the atrioventricular valves. These appearances strongly suggest Noonan’s syndrome. (B) A separate case – a section from the heart of one of twins with genetically proven Noonan’s syndrome. The myocardium shows hypertrophy and disarray.

echocardiographic appearances and haemodynamics to idiopathic hypertrophic cardiomyopathy. Mitochondrial cardiomyopathies in infancy frequently display a hypertrophic phenotype (Section 7.7).

7.4 Dilated Cardiomyopathy This term denotes the phenotype of biventricular dilatation with atrial dilatation and reduced myocardial contractility. There may be associated conduction system disturbance, and in some cases there are extracardiac manifestations, most frequently skeletal myopathy, but also skin abnormalities, haematological disorders or hearing loss [42].

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Pathologically, the histological features are not specific. There is histological evidence of myocardial hypertrophy and fibrosis [42]. The heart is enlarged, sometimes markedly so (Figure 7.12), is dilated, has a globular shape (Figure 7.13) and the weight is increased. The muscular trabeculae, including the papillary muscles of the atrioventricular valves, appear stretched and thin. There is associated endocardial fibroelastosis of the left ventricle. The affected endocardium is opaque and white and may be up to several millimetres thick. The thickening affects the papillary muscles and extends into the inter-trabecular recesses (Figure 7.13). The right ventricle usually does not show significant endocardial fibrosis. There may be fibrosis of the myocardium – particularly the papillary muscles of the mitral valve. If there are multiple small foci of fibrosis scattered throughout the ventricles, especially in the younger child, the possibility of resolving myocarditis should be considered (Figure 7.14). The atria may show endocardial thickening. Mural thrombus may form in the atria or in the ventricles (Figure 7.15). If there has been treatment with a ventricular assist device there may be remodelling of the ventricle that may no longer be dilated and may even have normal dimensions: the

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endocardial fibrosis, however, persists (Figure 7.16). Histologically, the myocytes show nuclear enlargement and hyperchromasia and they are stretched, thin and wavy (Figure 7.17). Inflammatory cell infiltration is not usually a prominent feature, but scattered lymphocytes may be present. The presence of more than a few inflammatory cells suggests myocarditis, and appropriate samples need to be assessed for the presence of viruses (Figure 7.18). Mast cell numbers are increased in the interstitium [43] (Figure 7.19). The epicardium may show a chronic inflammatory cell infiltrate or fibrosis. Secondary degenerative changes are often present in the valves in the form

Figure 7.13 Dilated cardiomyopathy. The same heart as in Figure 7.12, removed and opened showing the dilated left ventricular cavity with globular shape and the opaque, white thickening of the left ventricular endocardium.

of thickening of the leaflets. There is usually a considerable degree of interstitial myocardial fibrosis (Figure 7.17B). The intramyocardial vessels are usually normal, but in areas of dense scarring they may show intimal fibroelastic thickening. The endocardial fibroelastosis consists of dense laminar fibroelastic tissue that usually does not show increased vascularity or inflammatory cell infiltration (Figure 7.20). There may be smooth muscle hyperplasia in the endocardium. The dilated form of cardiomyopathy represents a phenotype and it has many causes [44]. About one-third of patients with dilated cardiomyopathy have an affected first-degree relative [45]. The most common mode of transmission of the familial forms is autosomal dominant, but recessive, X-linked and mitochondrial inheritance is also reported. There are more than 40 genes known to be mutated and they encode for proteins that have a wide range of unrelated functions including transcripts encoding sarcomeric contractile proteins, cytoskeletal proteins, nuclear membrane proteins and the dystrophin-associated glycoprotein complex [46]. Table 7.5 lists genes, mutations in which have been associated with dilated cardiomyopathy [47–81]. It is intended to be indicative rather than definitively comprehensive. Mutations may occur in genes encoding sarcomeric proteins such as troponins T, C and I, actin, or β-myosin heavy chain [50]. The mutations occur in regions affecting functionally different domains of the molecules from those occurring in hypertrophic cardiomyopathy. Mutations may also occur in the myocyte cytoskeleton that connects the sarcomere to the sarcolemma. Such genes include those coding for δ-sarcoglycan [61], desmin [60], dystrophin [63], lamin [67], vinculin [81], Cypher/ZASP [59], cardiac LIM protein [47] and desmoplakin [62]. Such mutations

Figure 7.14 Dilated cardiomyopathy post myocarditis. (A) Three-month-old who underwent heart transplant for severe dilated cardiomyopathy post Enterovirus myocarditis and cardiac arrest. The four-chamber view shows a dilated left ventricle with extensive dystrophic calcification of the free wall of the left ventricle and upper interventricular septum. An incidental large blood cyst is present on the mitral valve leaflet. (B) An 11-year-old with dilated cardiomyopathy. The explanted heart shows ventricular dilatation with thinning of the walls. The cut surface of the myocardium is blotchy caused by multiple scattered foci of fibrosis suggestive of healed myocarditis. No virus was recovered in this case.

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Figure 7.15 Dilated cardiomyopathy – thrombus formation. Four-month old child who died of sepsis and cardiac failure after a prolonged hospital course. There is cardiomyopathy with bilateral ventricular dilatation and there is apical thrombus in both ventricles.

Figure 7.16 Dilated cardiomyopathy. Two-year-old child. Explanted heart with a cannula from a ventricular assist device in the left ventricular apex. The left ventricular cavity dimensions are near normal, but there is dense endocardial fibroelastic thickening. The heart weight was 165 g.

Figure 7.17 Dilated cardiomyopathy. (A) Five-year-old with severe dilated cardiomyopathy. Biopsy shows muscle fibres that are elongated, wavy, stretched and thinned. There is considerable fine interstitial fibrosis. There is no significant inflammatory cell infiltrate. (B) Masson-trichrome-stained section from the same case shows fibrotic thickening of the endocardium and fibrous tissue extending around individual atrophic myocytes.

compromise the transmission of contractile force from the sarcomere to the extracellular matrix or impair the normal response of the sarcomere to stretching. Viral myocarditis may progress to dilated cardiomyopathy, and some forms of dilated cardiomyopathy yield virus on culture or polymerise chain reaction (PCR). It has been shown that enterovirus proteases cleave dystrophin in vitro [82]. Mutations are described also in genes regulating transcription such as EYA4 [65]. Mutations in the phospholamban gene are thought to cause dilated cardiomyopathy by inhibition of calcium uptake in the sarcoplasmic reticulum [74]. Rbm20-deficient rats and humans with RBM20 missense mutations share cardiomyopathy with fibrosis and arrhythmia

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with sudden death [76]. Mutations in RBM20 cause a clinically aggressive form of dilated cardiomyopathy (DCM), with an increased risk of malignant ventricular arrhythmias (Figure 7.21) [83]. A specific form of infantile dilated cardiomyopathy has been described fairly recently, the defining feature of which is the presence of numerous myocyte mitotic figures. The condition has been termed mitogenic cardiomyopathy [84]. The condition is as yet not fully characterised. The initial report lists five infants, all females, including two pairs of siblings, all of whom died in early infancy. They had no specific birth or neonatal problems and presented with general lethargy, decreased feeding, respiratory distress and cyanosis with

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Figure 7.18 Dilated cardiomyopathy post-myocarditis. Three-month-old who underwent heart transplant for dilated cardiomyopathy following Enterovirus myocarditis. A section from the left ventricular myocardium of the explanted heart shows foci of heavy lymphocytic infiltration. This degree of lymphocytic infiltration is not seen in idiopathic dilated cardiomyopathy and indicates an inflammatory aetiology for the cardiomyopathy.

Figure 7.20 Dilated cardiomyopathy. Explanted heart from a fifteen-year-old with idiopathic dilated cardiomyopathy. A high-power view of the thickened endocardium of the left ventricle. There is fibrous expansion of the tissue with numerous elastic fibres. In the centre there is a small nodule of smooth muscle cells. There is no inflammatory cell infiltration.

signs of congestive cardiac failure. At post-mortem, the hearts were enlarged and heavy with dilated chambers, ventricles more so than atria, and mild to moderate endocardial fibroelastosis in all. Histologically there was prominent hypertrophic myofibre changes with elongated, enlarged and hyperchromatic nuclei, and increased mitotic activity with up to four mitotic figures per single high-power field (Figure 7.22A and B). Scattered atypical mitotic figures were present. There was a proliferation index of up to 20% (normal age matched less than 1%). Mutation in the Alstrom gene is described in at least some cases [85].

Figure 7.19 Dilated cardiomyopathy: mast cells. Two-year-old boy with idiopathic dilated cardiomyopathy who underwent heart transplant. A section from the explanted heart showing interstitial fibrous tissue with at least three mast cells visible. Interstitial mast cell numbers are increased in dilated cardiomyopathy, in myocarditis and, indeed, in any condition leading to an increase in interstitial fibrous tissue.

The significance of these changes is not yet fully apparent, although mitotic figures should not be seen in the myocardium post-natally. The implication is that there is failure of the normal switching off of myocardial cell mitosis that should occur around the time of birth. I have seen approximately 10 cases of mitotic figures in the post-natal myocardium, many associated with cardiomyopathy, but at least one occurring in the setting of viral myocarditis. Infants of exclusively breast-fed mothers may suffer vitamin D deficiency with development of rickets and may present with dilated cardiomyopathy, which, rarely, may be fatal (Figure 7.23). The condition resolves on administration of vitamin D [86–89]. In infants, hypocalcaemia is usually due to maternal vitamin D deficiency and is accompanied by compensatory hyperparathyroidism. In contrast, in adult patients, hypocalcaemic cardiomyopathy is usually a result of hypoparathyroidism, with or without concomitant vitamin D deficiency [90].

7.5 Restrictive Cardiomyopathy This form of cardiomyopathy has a physiology different from the other two main forms of cardiomyopathy [91]. It accounts for 2–5% of cardiomyopathies in childhood [92]. The defining characteristics are a stiff ventricular myocardium with diastolic dysfunction. This leads to high diastolic pressures and dilatation of the atria. Clinically, restrictive cardiomyopathy mimics constrictive pericarditis [93]. The high left-sided diastolic pressure leads to congestive vasculopathy in the lungs and the development of pulmonary hypertension. Up to one-third of cases show mutations in cardiac sarcomeric protein genes, most notably troponin I, troponin T and alpha-cardiac-actin [94]. Macroscopically, the atria, particularly the right atrium, are dilated (Figure 7.1C). The heart shows thickened ventricular

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7: Cardiomyopathy Table 7.5 Proteins whose genes may be mutated in dilated cardiomyopathy

Protein

Gene symbol

Location

Ref.

Category

α-Actinin-2

ACTN2

1q42

47

Sarcomere

α-B crystallin

CRYAB

11q23.1

48

Cytosol

α-Tropomyosin

TPM1

15q22

49

Sarcomere

β-Myosin heavy chain

MYH7

14q12

50

Sarcomere

Cardiac α-actin

ACTC1

15q14

51

Sarcomere

Cardiac ankyrin repeat protein (CARP)

ANKRD1

10q23

52

Intercalated disc

Cardiac LIM protein

CSRP3

11p15

47

Z-disc

Cardiac myosin binding protein C

MYBPC3

11p11

53

Sarcomere

Cardiac Na channel

SCN5A

3p22.2

54

Cell membrane

Cardiac troponin C

TNNC1

3p21

55

Sarcomere

Cardiac troponin I

TNNI3

19p13

56

Sarcomere

Cardiac troponin T

TNNT2

1q32

57

Sarcomere

Cardiotrophin 1

CTF1

16p11

56

Cytokine

Cypher/ZASP

LDB3

10q22

59

Cytoskeleton

Desmin

DES

2q35

60

Delta sarcoglycan

SGCD

5q33

61

Desmoplakin

DSP

6q23

62

Intercalated disc

Dystrophin

DMD

Xp21

63

Cytoskeleton

Emerin

EMD

Xq28

64

Nuclear

Eyes absent homolog 4

EYA4

6q223

65

Nuclear

K-ATP channel

ABCC9

12p12.1

66

Lamin A/C

LMNA

1q1

67

Laminin alpha 4

LAMA4

6q21

68

Muscle-restricted coiled coil

MURC

9q31.1

69

Myopalladin

MYPN

10q21.3

70

Nebulette

NEBL

10q12.31

71

Nexilin

NEXN

1p31.1

72

Plakophilin-2

PKP2

Phospholamban

PLN

6q22

74

RNA-binding motif protein 20

RBM20

10q25.2

75, 76

Tafazzin

TAZ

Xq28

77

Thymopoietin

TMPO

12q23.1

78

Titin

TTN

2q31

79

Z-disc

Titin-cap (telethonin)

TCAP

17q12

80

Z-disc

Vinculin (metavinculin)

VCL

10q22

81

Z-disc

myocardium. Histologically, the myocytes are hypertrophied; there may be myocyte disarray, identical to that in hypertrophic cardiomyopathy, even to the extent of associated small vessel dysplasia (Figure 7.24). There may be myocyte

174

Nuclear

Z disc

73

Nuclear

vacuolation or myocyte inclusions (Figure 7.25). There is prominent interstitial fibrosis, sometimes with a pericellular distribution. Cardiac involvement by amyloid may give a restrictive cardiomyopathy, but this is very rare in children.

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Figure 7.21 Dilated cardiomyopathy. Two-year-old with dilated cardiomyopathy and RBM20 mutation. Biopsy of right atrial wall. There is endocardial thickening and patchy interstitial fibrosis and scarring. The appearances are non-specific.

Figure 7.23 Vitamin D deficiency in fatal dilated cardiomyopathy. Exclusively breast fed nine-month-old child of Asian origin who was found dead in bed. At post-mortem there was rickets, both radiologically and in the macroscopic appearance of the ribs and softening of the skull. Blood tests showed severe vitamin D deficiency. There was cardiomyopathy and enlarged dilated left heart with endocardial fibrosis and pericardial effusion. Death is attributed to cardiomyopathy. Dilated cardiomyopathy is well recognised in vitamin D deficiency and may, on occasion, be fatal.

Similarly, myofibrillary myopathy – a form of myopathy that shows characteristic myocyte inclusions in association with skeletal myopathy and restrictive cardiomyopathy – is rare in children (Figure 7.25) [95]. Glycogen storage disorders and the mucopolysaccharidoses may present as restrictive cardiomyopathy as may primary endocardial fibroelastosis. Secondary endocardial fibroelastosis generally does not.

7.6 Eosinophilic Endomyocardial Disease Endomyocardial disease with restrictive physiology may develop in patients with hypereosinophilia, whether idiopathic

Figure 7.22 Mitogenic cardiomyopathy. (A) One of a pair of siblings who died of dilated cardiomyopathy. The heart showed features of dilated cardiomyopathy including prominent endocardial fibroelastosis. There are at least three mitotic figures within this single high-power field of the myocardium. (B) Her sister died some years later of dilated cardiomyopathy. A section of her myocardium shows at least four mitotic figures in this field.

or secondary to leukaemia/lymphoma, vasculitis syndromes or infections [96]. Also known as Löffler’s endocarditis [97], three stages are described [98]. The first is a necrotic phase characterised by acute eosinophilic myocarditis with diffuse infiltration of eosinophils in endocardium and myocardium with variable necrosis. There is intramural arteritis in some cases. The second phase is a thrombotic phase associated with mural thrombosis along the ventricular inflow tracts. The process begins at the ventricular apex but extends upwards to involve the papillary muscles. Eosinophils are prominent in the thrombus (Figure 7.26). Organisation leads to endocardial thickening. The final phase is the fibrotic phase, which is identical to tropical endomyocardial fibrosis and characterised by thick

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Figure 7.24 Restrictive cardiomyopathy histology. Sixteen-year-old with restrictive cardiomyopathy who underwent orthotopic heart transplant. Sections from the explanted heart. (A) There is myocyte disarray indistinguishable from hypertrophic cardiomyopathy. (B) There is widespread interstitial fibrosis (Masson’s trichrome stain). (C) Many small intramyocardial vessels are dysplastic, again indistinguishable from hypertrophic cardiomyopathy.

endocardial fibrous plaques with distinct rolled borders (Figure 7.27) [99]. It is frequently accompanied by atrioventricular valvar regurgitation. There is eventually obliteration of the ventricular cavity. Atrial dilatation is typical, caused by restrictive physiology and atrioventricular valve regurgitation.

7.7 Mitochondrial Cardiomyopathy These are disorders of the heart presenting as cardiomyopathy in which the defect is mutation of genes affecting mitochondrial oxidative phosphorylation. These cardiomyopathies are often associated with neurological disorders. Such disorders include MELAS (myopathy, encephalopathy, lactic acidosis, stroke) [100] or Kearns–Sayre syndrome (ataxia, ophthalmoplegia, pigmentary retinopathy, heart block). The cardiac mitochondria are more numerous than usual and show abnormalities of size or structure with abnormal internal structure [101,102]. Clinically, infants with mitochondrial cardiomyopathy typically show failure to thrive, lactic acidosis and cardiomegaly.

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Hypertrophic cardiomyopathy is commoner in infancy than dilated cardiomyopathy (Figure 7.28). Left ventricular noncompaction is also described [103]. There are frequently associated conduction abnormalities [104]. Histologically, the myocytes are hypertrophied. The myocyte cytoplasm may appear prominently vacuolated. Frequently there is perinuclear clearing and replacement of cross striations by fine eosinophilic granules representing increased numbers of mitochondria (Figure 7.29) [105,106]. Staining of frozen sections of myocardium may show reduction in oxidative enzymes or increase in cytoplasmic lipid. Electron microscopy may show abnormal mitochondria (Figure 7.30) [107]. Mitochondrial cardiomyopathies are caused by defects in genes coding for specific enzymes of the mitochondrial oxidative phosphorylation system that may affect any of complexes I, II, III, IV and V or affect multiple complexes. Disease may also result from mutations in genes linked to mitochondrial DNA maintenance, mitochondrial protein translation, lipid

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Figure 7.25 Restrictive cardiomyopathy: myocyte inclusions. Explanted heart from a 12-year-old with familial restrictive cardiomyopathy. (A) The myocardium shows scattered filamentous eosinophilic myocyte inclusions. (B) The semi-thin sections (toluidine blue) show hyaline structures that on electron microscopy consisted of aggregated filaments. The appearances are indistinguishable from myofibrillary myopathy.

Figure 7.26 Eosinophilic endomyocardial disease: thrombus. Thrombus overlying an area of inflammation and containing numerous eosinophils.

bilayer structure or other aspects of mitochondrial function. Mitochondrial DNA, unlike nuclear DNA, is only maternally inherited, does not show recombination and has a high rate of spontaneous mutation. Mitochondrial DNA encodes for some – but not all – of the proteins of the oxidative phosphorylation complexes. The reminder is encoded in the nuclear DNA. These latter genes are inherited in the usual Mendelian fashion. The majority of the mutations causing mitochondrial cardiomyopathy in adults are mutations in the mitochondrial DNA and are thus maternally inherited [108]. However, mutations occur in nuclear genes involved in mitochondrial DNA replication [109] and, indeed, in children they account for more than 80% of cases of mitochondrial cardiomyopathy [110]. Isolated Complex I deficiency accounts for 30% of mitochondrial disease in children [111].

Figure 7.27 Eosinophilic endomyocardial disease: thrombus. Same patient as in Figure 7.26 but biopsied later in the course of the illness. The lower right of the field shows fibrotic myocardium. There is a thick elastic layer in the endocardium above which is abundant fibrovascular tissue, the result of organisation of luminal thrombus (EvG stain).

Coenzyme Q10 deficiency causes hypertrophic cardiomyopathy and can be treated by COQ10 supplementation [112]. Barth syndrome caused by tafazzin gene mutations may be regarded as a form of mitochondrial cardiomyopathy [113]. Disease may also be caused by mitochondrial DNA depletion in cardiac muscle [114]. The depletion may involve the heart with a hypertrophic phenotype but is unusual.

7.8 Arrhythmogenic Cardiomyopathy A rare inherited disease characterised by right ventricular dysfunction and ventricular arrhythmias that may cause

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Figure 7.28 Mitochondrial cardiomyopathy. The phenotype of mitochondrial cardiomyopathy is variable. It is commonly hypertrophic in neonatal cases, and at a later age there may be dilated, restrictive or non-compaction phenotypes. (A) A male infant born with Complex I deficiency. The heart weighed 104 g and shows marked hypertrophy of the left ventricular myocardium. (B) Fourteen-year-old male with MELAS and dilated cardiomyopathy who underwent heart transplant. The explanted heart shows the typical phenotype of dilated cardiomyopathy.

Figure 7.29 Mitochondrial cardiomyopathy – giant mitochondria. Female infant with skeletal and cardiac myopathy. A section for a left apical biopsy at the time of insertion of a ventricular assist device shows vacuolated myocytes with numerous giant mitochondria typical of mitochondrial cardiomyopathy. The mitochondria, as here, are much more readily visualised on Masson’s trichrome staining.

sudden death precipitated by physical exercise. Pathologically it is characterised by fatty and fibrous replacement of the right (and sometimes the left) ventricular myocardium [115]. It usually presents in the teenage years or early twenties. It does not occur in the neonatal period, although it does have some phenotypic overlap with Uhl’s anomaly. It is doubtful if it occurs at all in the first decade of life. Mutations have been detected in approximately 40% of cases. These occur in the genes encoding the desmosomal junction proteins desmoplakin [116], plakoglobin [117],

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Figure 7.30 Mitochondrial cardiomyopathy - electron microscopy. Sixteen-year-old with dilated cardiomyopathy. Light microscopy showed vacuolated myocytes and giant mitochondria. Ultrastructural examination of the myocytes shows that they contain increased numbers of mitochondria, which are variable in size. There is irregularity of the cristae, but no inclusions are seen.

plakophilin 2 [118], desmocollin 2 [119] and desmoglein 2 [120]. Desmoplakin mutations cause Naxos disease, which is characterised by cardiomyopathy, keratoderma and woolly hair [62]. Macroscopically, there is fatty replacement of the right ventricular myocardium extending from epicardium to endocardium (Figure 7.31). This fatty infiltration usually affects the so-called triangle of dysplasia that encompasses the anterior wall of the right ventricular outflow tract and apex and the postero-basal wall of the right ventricle. There is sparing of the muscular trabeculations (Figure 7.32). It may affect the left

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Figure 7.31 ARVC. Eleven-year-old boy with dilated cardiomyopathy who underwent cardiac transplant. The explanted heart shows extensive thinning of the wall of the right ventricle and replacement by adipose tissue. There is patchy fibrosis in the interventricular septum and free wall of the left ventricle.

Figure 7.32 ARVC sparing trabeculations. Sudden death during exercise in a fourteen-year-old boy. A close-up view of the right ventricular wall shows extensive fatty replacement but with sparing of the muscular trabeculations.

Figure 7.33 ARVC histology. The histology of the right ventricular wall from Figure 7.31 shows some surviving myocardium but extensive fatty infiltration and extensive collagenous fibrosis Again, note that there is little adipose tissue in the muscular trabeculations (EvG).

ventricle or interventricular septum. Fibrosis may be obvious macroscopically. There is thinning of the wall, which may bulge to form aneurysms. Microscopically, it is characterised by fatty and fibrous replacement of the right (and sometimes the left) ventricular myocardium (Figure 7.33). Myofibre disarray may be seen, and there may be a minor lymphocytic infiltrate. Fatty replacement may be seen in the normal right ventricular myocardium particularly in obese subjects. Small collections of adipocytes are a normal finding along the intramural course of the coronary arteries in the right and left ventricle in normal subjects,

and adipose tissue may even be seen beneath the endocardium in normal hearts. One can see fatty replacement in a variety of pathological conditions including dilated cardiomyopathy. Recently, immunohistochemical detection of reduced levels of plakoglobin in endomyocardial biopsies has been postulated as a diagnostic test for the condition [121].

7.9 Non-Compaction of the Ventricular Myocardium This is a form of cardiomyopathy of unknown cause. The clinical presentation is with heart failure and ventricular arrhythmias. There is an increased risk of thromboembolic disease, and the phenotype is particularly severe in infants and young children. It affects predominantly the left ventricular myocardium imparting a spongy appearance (Figure 7.34) [122]. The appearance is described as reminiscent of the developing embryonic heart. The ventricular cavity extends almost to the epicardial surface among multiple thin muscular trabeculations (Figure 7.35); the normal compact layer separating the muscular trabeculations of the ventricular lining

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Figure 7.35 Ventricular non-compaction. Premature (33 weeks) infant with multiple congenital abnormalities who also had atrioventricular septal defect. Died on day 3 of life. The heart is enlarged with dilated cavities. The wall of both ventricles is a meshwork of trabeculations with thinning of its outer compact layer and with obscuring of the papillary muscles.

Figure 7.34 Ventricular non-compaction. One-year-old boy who underwent heart transplant for ventricular con-compaction cardiomyopathy. The explanted heart had been partly opened and distorted before receipt. It is cut in a simulated four-chamber view and viewed from behind. The left ventricular myocardium is greatly thickened and shows multiple curved slit-like spaces extending from the cavity into the wall towards the epicardium, imparting a “spongy” appearance to the wall.

from the epicardium is reduced in thickness. The papillary muscles of the mitral valve are poorly developed. There is quite often prominent endocardial fibroelastosis. Histologically, there are anastomosing endocardial fibrous tissue lined recesses that extend deeply into the myocardium (Figure 7.36). There may be foci of subendocardial ischaemic necrosis. In children, half the cases show associated cardiac abnormalities such as VSD, polyvalvar dysplasia and pulmonary stenosis (Figure 7.37). The case may present in the neonatal period with cardiac failure or with sudden death, although other cases may not present until later in life. The later-presenting cases tend not to have associated cardiac abnormalities. About 25% of cases are familial [123], usually showing autosomal dominant transmission with incomplete penetrance [124]. X-linked left ventricular non-compaction has been described in Barth syndrome [125], which is associated with mutations in the

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Figure 7.36 Ventricular non-compaction. A histological section from the left ventricular wall of the case in Figure 7.33 stained with Elastic vanGieson. There is a complex labyrinth of recesses extending among the muscular trabeculations of the ventricular wall. There is also focal fibrosis.

tafazzin (TAZ) gene at Xq28 [77] that result in cardiolipin deficiency and abnormal mitochondria. Some cases of ventricular non-compaction have been linked to mutations in genes for α-dystrobrevin [126], the Z-line protein Cypher/ ZASP [127] and the β-myosin heavy chain [128]. Syndromes associated with ventricular non-compaction are DiGeorge syndrome [129] and Melnick–Needles syndrome [130], an X-linked connective tissue disorder characterised by craniofacial and skeletal abnormalities. However, the phenotype may be seen in normal adults without evidence of heart failure or arrhythmia [131].

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Figure 7.38 Histiocytoid CMP. The defining pathological feature of this condition is groups of rounded granular eosinophilic myocytes that look like histiocytes. In this photo the nodule of such cells lies immediately beneath the endocardium and interdigitates with the surrounding normal myocardium from which it is readily distinguished. The ventricular lining is fibrotic.

Figure 7.37 LVNC with congenital heart disease. A five year-old with 1p deletion syndrome and multiple abnormalities, including multiple muscular VSDs and non-compaction cardiomyopathy. The heart is viewed from behind and shows a defective lower interventricular septum. There is hypertrophy of the myocardium of both ventricles, and there is an irregular meshwork of spaces between the apical trabeculations.

7.10 Histiocytoid Cardiomyopathy This rare, X-linked condition occurs usually in female infants and is characterised by severe, sometimes fatal, arrhythmia. Its histological hallmark is collections of myocytes with vacuolated cytoplasm (Figure 7.38) that resemble histiocytes [132]. Ultrastructurally these cells contain large numbers of mitochondria (Figure 7.39). Macroscopically, the heart may appear enlarged but otherwise unremarkable (Figure 7.40), or there may be multiple nodules in the myocardium. These nodules, which range in size from a few millimetres to more than 1 cm, may be subendocardial or scattered throughout the myocardium and may even occur in the valves. The condition may present in utero with tachyarrhythmia and heart failure, or presentation may be delayed until after birth to the age of 4 years when the presenting features may be arrhythmia, seizures, heart failure, cyanosis or sudden death. Structural heart disease such as VSD or hypoplastic left heart may be present (Figure 7.41) [133]. The condition is regarded as

Figure 7.39 Histiocytoid cardiomyopathy. A high-power view of a group of histiocytoid myocytes showing the lack of contractile elements and the fine granularity due to numerous mitochondria. There are also multiple tiny fat droplets.

hamartomatous and of Purkinje cell origin; it is associated with mitochondrial DNA mutations [134, 135]. Histiocytoid cardiomyopathy has been reported in numerous cases of MLS (microphthalmia, linear skin defects) syndrome (also known as MIDAS syndrome) – a disorder in which there is deletion of the p22 region of the X chromosome [136], suggesting that the gene associated with histiocytoid cardiomyopathy lies in that region of the X chromosome. More recently, mutation in NDUFB11 has been described in histiocytoid cardiomyopathy and microphthalmia with linear skin defects syndrome [137].

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Figure 7.40 Histiocytoid cardiomyopathy. Sixteen-month-old child who died suddenly with histiocytoid cardiomyopathy. Although some cases of the condition may have macroscopically obvious yellow nodules scattered throughout the myocardium, this case was macroscopically normal, and the diagnosis was made on histological examination. The yellow staining of the ventricular aspect of the anterior leaflet of the mitral valve is a normal feature of paediatric hearts and does not indicate the presence of disease.

7.11 Other Forms of Cardiomyopathy As Tables 7.1–7.5 make clear, there are many other causes of cardiomyopathy. Some forms of cardiomyopathy with a specific origin such as the cardiomyopathy associated with congenital disorders of glycosylation do not show specific histological features (Figure 7.41), and the presentation may be as dilated or hypertrophic cardiomyopathy [138]. Endomyocardial biopsy does not permit the specific diagnosis to be made.

Epidemiology and Prevention. Contemporary definitions and classification of the cardiomyopathies. Circulation 2006; 113: 1807–1816.

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119. Heuser A, Plovie ER, Ellinor PT et al. Mutant desmocollin-2 causes arrhythmogenic right ventricular cardiomyopathy. Am J Hum Genet 2006; 79: 1081–1088.

128. Budde BS, Binner P, Waldmüller S et al. Noncompaction of the ventricular myocardium is associated with a de novo mutation in the beta-myosin heavy chain gene. PLoS One 2007; 2: e1362.

120. Syrris P, Ward D, Asimaki A et al. Desmoglein-2 mutations in arrhythmogenic right ventricular cardiomyopathy: a genotype-phenotype characterization of familial disease. Eur Heart J 2007; 28: 581–588.

129. Pignatelli RH, McMahon CJ, Dreyer WJ et al. Clinical characterisation of left ventricular noncompaction in children: a relatively common form of cardiomyopathy. Circulation 2003; 108: 2672–2678.

132. Malhotra V, Ferrans VJ, Virmani R. Infantile histiocytoid cardiomyopathy: three cases and literature review. Am Heart J 1994; 128: 1009–1021. 133. Shehata BM, Patterson K, Thomas JE et al. Histiocytoid cardiomyopathy: three new cases and review of the literature. Paediatr Dev Pathol 1998; 1: 56–69. 134. Vallance HD, Jeven G, Wallace DC, Brown MD. A case of sporadic infantile histiocytoid cardiomyopathy caused by the A8344 G (MERRF) mitochondrial DNA mutation. Pediatr Cardiol 2004; 25: 538–540. 135. Finsterer J. Histiocytoid cardiomyopathy: a mitochondrial disorder. Clin Cardiol 2008; 31: 225–227. 136. Bird LM, Krous HF, Eichenfield LF, Swalwell CI, Jones MC. Female infant with oncocytic cardiomyopathy and microphthalmia with linear skin defects (MLS): a clue to the pathogenesis of oncocytic cardiomyopathy? Am J Med Genet 1994; 53: 141–158. 137. Rea G, Homfray T, Till J et al. Histiocytoid cardiomyopathy and microphthalmia with linear skin defects syndrome: phenotypes linked by truncating variants in NDUFB11. Cold Spring Harb Mol Case Stud 2017; 3: a001271. 138. Gehrmann J, Sohlbach K, Linnebank M et al. Cardiomyopathy in congenital disorders of glycosylation. Cardiol Young 2003; 13: 345–351.

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Chapter

8

Inflammation of the Myocardium, Endocardium and Aorta

8.1 Introduction Inflammatory diseases of the myocardium are important causes of morbidity and mortality and a frequent cause of myocardial biopsy [1]. In the setting of heart transplantation infectious complications are a serious threat to the survival of the graft. Allograft rejection is itself an inflammatory reaction but will be discussed separately in Chapter 14. Inflammatory disease of the heart is rarely confined exclusively to one compartment; thus, myocarditis is frequently associated with pericarditis or involvement of the endocardium, albeit of lesser severity than in the myocardium. Pericarditis is discussed separately in Chapter 11.

8.2 Myocarditis The term myocarditis is defined differently depending on whether it is being used clinically, radiologically or pathologically. Clinically, there is no universally accepted definition of acute myocarditis [2]. There is wide variation both in symptoms and in their severity. Symptoms may be shortness of breath, chest pain, arrhythmia, gastrointestinal symptoms, fever and myalgia. At the most severe end the disease may present with cardiogenic shock or sudden death. There may be ST and T wave changes on ECG, impaired function on echocardiography and elevated blood troponin levels. Pathologically, myocarditis is defined as an inflammatory cell infiltrate of the myocardium with necrosis and/or degeneration of adjacent myocytes not typical of the ischaemic injury associated with coronary artery disease [3]. The diagnosis can be made on endomyocardial biopsy [1] or on the whole heart at autopsy [4]. It is generally assumed to be a diffuse process, but the inflammatory infiltrates can be patchy and there is an element of chance as to whether an area of inflammation is actually biopsied [5]. There are no reliable figures for the incidence in children. There is a slight male preponderance [6]. Children are said to have a more fulminant presentation [7]. Myocarditis may be caused by drugs, toxins, infectious agents or an immunological reaction (Table 8.1). Many cases are idiopathic (approximately 50%), the cause simply being unknown. Sometimes a combination of factors is involved, as when a viral infection initiates an autoimmune reaction [2].

The inflammatory process may be confined to the heart or may be part of a more generalised inflammatory reaction, e.g. rheumatic fever or systemic lupus erythematosus. Most cases of myocarditis in which the aetiology is identified are infectious in origin with viral myocarditis being by far the commonest category [8]. During many viral illnesses there are subtle changes in ECG and there may be associated subclinical cardiac functional disturbance, sometimes with elevated troponin levels. From this it is inferred that there is a mild inflammatory reaction within the heart muscle that resolves completely. The commonest virus causing myocarditis is coxsackie B virus [9]. Infection with these viruses is particularly common in infants. Approximately 20% of cases of dilated cardiomyopathy show evidence of coxsackievirus RNA by PCR [10]. Most viruses causing disease in man have at some time or other been reported as being responsible for myocarditis. Other viruses causing myocarditis include Influenzavirus [11], human immunodeficiency virus [12], cytomegalovirus [13,14], adenovirus [15], herpes simplex virus [16] and human herpes virus 6 [17]. Cardiovascular problems Table 8.1 Myocarditis classification

Aetiology

Cell type

Clinical type

Virus

Lymphocytic

Acute

Bacteria

Giant cell

Fulminant

Fungi

Eosinophilic

Chronic

Rickettsia

Granulomatous

Spirochaetes Protozoa Drugs, chemicals Allergy, autoimmune Collagen disease Kawasaki disease Sarcoidosis Unknown Based on JCS Joint Working Group. Guidelines for diagnosis and treatment of myocarditis (JCS 2009): digest version. Circ J 2011;75: 734–743.

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Figure 8.1 Macro myocarditis. (A) A ten-year-old who died on extracorporeal life support following a diagnosis of myocarditis caused by parvovirus B19. The heart is opened to display the left ventricular outflow tract. The left ventricle is dilated, and the papillary muscles and the interventricular septum have a blotchy and haemorrhagic appearance. (B) A three-year-old boy who died suddenly following a short upper respiratory illness. There was florid myocarditis. No virus was identified. A transverse section at the mid-ventricular level of the left ventricular wall shows patchy pallor and hyperaemia.

associated with HIV infection, including left ventricular dysfunction and increased left ventricular mass, are common and clinically important indicators of survival for children with HIV [11]. In utero infection with parvovirus B19, while usually causing anaemia leading to hydrops, may cause myocarditis by direct infection of the myocardium with resulting hydrops and intrauterine death [18]. Parvovirus B19 infection is also increasingly being recognised as a cause of myocarditis and cardiac dysfunction in children [19,20]. Clinical myocarditis depends on a complex interplay between the infecting virus and the T-cell response of the host. It is noteworthy that many cases are associated with immunosuppression [13,17]. Myocarditis may present with nonspecific clinical features of progressive cardiac dysfunction or with dilated cardiomyopathy [2]. It is also a recognised cause of sudden unexpected death in both children and adults [4]. About half of all cases of sudden death due to myocarditis in children occur in infants less than 1 year of age [4].

8.2.1 Macroscopic Pathology In fatal cases, or following transplant, the macroscopic appearance of the heart is usually described as resembling dilated cardiomyopathy; there is frequently a small pericardial effusion, the ventricles are dilated and the cut surface of the myocardium has a blotchy appearance (Figure 8.1A,B). There may be areas of frank necrosis or of epicardial or endocardial haemorrhage. In almost 40% of cases of children dying suddenly due to myocarditis, there is no macroscopic cardiac abnormality (Figure 8.2), and the heart weight is normal in the majority of cases [4]. Explanted hearts post-myocarditis may show areas of myocardial necrosis and dystrophic calcification with or without residual patchy inflammatory infiltrate (Figure 8.3). Otherwise, they resemble dilated cardiomyopathy

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Figure 8.2 Macroscopically normal heart in myocarditis. Female infant who was found dead. The heart is opened to display the left atrium and left ventricle. It is macroscopically normal. Histologically there was myocarditis. No virus was identified.

(Figure 8.4). Where the heart appears otherwise normal, the presence of a small to moderate pericardial effusion may cause suspicion of underlying myocarditis.

8.2.2 Microscopic Pathology Histopathological features of myocarditis are an inflammatory cell infiltrate in the myocardium that may be scanty and patchy, or diffuse and heavy (Figure 8.5) [2]. Neutrophils may be prominent, particularly in early stages. Lymphocytes are the main inflammatory cell. The lymphocytes are predominantly CD3-positive T-cells with some B-cells and CD68positive macrophages (Figure 8.6). Eosinophils, plasma cells

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Figure 8.3 Explanted heart with myocarditis. An infant with Enterovirus myocarditis who underwent cardiac transplant. The explanted heart is cut in a simulated four-chamber view. There is myocardial necrosis with calcification that appears yellow in the papillary muscles of the right ventricle, the interventricular septum and the free wall of the left ventricle. The left ventricle is dilated.

Figure 8.5 Myocarditis – inflammatory cell infiltrate. Biopsy of myocardium shows oedema of the interstitium with a patchy and heavy infiltrate of lymphocytes, in places obliterating the morphology of the underlying myocytes.

and mast cells may also be present [21,22]. Myocyte necrosis or damage must be present to sustain the diagnosis (Figure 8.7). Occasionally, the extent of necrosis is such as to cause difficulty in differentiation from infarction [23]. The myocytes usually contain abundant intracytoplasmic lipid, if looked for, and this should not be confused with a disorder of fatty acid oxidation (Figure 8.8) [24]. The histological features in myocarditis do not permit distinction between the various viral causes.

8.2.3 The Dallas Criteria The Dallas criteria for diagnosis of myocarditis are based on histological features on endomyocardial biopsy [2]. They

Figure 8.4 Dilated cardiomyopathy post-viral myocarditis. Teenage girl with dilated cardiomyopathy after an episode of myocarditis. No specific virus was identified. She underwent heart transplantation some years later. The explanted heart, cut in a simulated four-chamber view, shows a dilated left ventricle with endocardial thickening. The blotchy pallor of the myocardium is due to fibrosis, and this pattern of abnormality is typical of myocarditis.

require inflammatory cell infiltration and myocyte damage for a definitive diagnosis of myocarditis. According to this scheme, a biopsy may show one of three patterns: myocarditis, no myocarditis or borderline. Repeat biopsy may show the myocarditis to be persisting, healing or healed. Objections to the Dallas criteria abound [25] and include: They were developed before the widespread use of • immunohistochemistry to characterise inflammatory cell infiltrates • Infiltrates other than lymphocytes are ignored • Myocyte damage is not fully characterised • The term “borderline” is unhelpful • No account is taken of aetiological factors • Sampling affects the diagnostic yield, and increasing the number of specimens and how they are examined increases yield. The Padova group from the Veneto region of Italy have proposed a system of grading and staging of endomyocardial biopsy in addition to the inflammatory infiltrate. They propose a value of >14 leukocytes per mm2 with >7 T-cells per mm2 [21,26]. See Table 8.2 below for a method of calculating the highpower field (HPF) area. The World Health Organisation/International Society and Federation of Cardiology Task Force on the Definition and Classification of Cardiomyopathies has defined inflammation in an endomyocardial biopsy by immunohistochemical detection of focal and diffuse mononuclear infiltrates (T-cells and macrophages) with >14 cells/mm2, in addition to enhanced expression of HLA class II molecules [27]. At post-mortem, small foci of lymphocytes, with or without associated small foci of fibrosis, may be seen without

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Figure 8.6 Myocarditis – inflammatory cell immunohistochemistry. (A) Sudden infant death due to viral myocarditis. A section of the left ventricular wall stained with antibody to CD3. It shows focal aggregates of CD3+ lymphocytes in the myocardium and also the endocardium. (B) Endomyocardial biopsy in a case of coxsackievirus myocarditis stained with antibody to CD68. It shows a heavy concentration of macrophages around damaged myocytes.

Figure 8.7 Myocarditis – myocyte necrosis. A high-power view of left ventricular myocardium in a case of viral myocarditis. The myocytes are cut longitudinally and there is a myocyte closely surrounded by lymphocytes. It is shrunken with a hyalinised appearance and has lost its normal internal structure. The cytoplasm consists of a series of dense eosinophilic micronodules.

Figure 8.8 Myocarditis – cytoplasmic lipid in myocytes. A frozen section from a case of viral myocarditis stained with oil-red-O to demonstrate cytoplasmic lipid. There is heavy accumulation of microvesicular lipid droplets in the myocyte cytoplasm. This is a frequent finding in myocarditis and should not be taken as evidence of an underlying metabolic abnormality.

myocyte necrosis [28], which do not necessarily represent myocarditis (Figure 8.9). Increasingly, the diagnosis of myocarditis is being made on the basis of imaging, particularly cardiac MRI. The Lake Louise Criteria have been developed in an attempt to standardise radiological diagnostic criteria (Table 8.3) [29].

cases have associated autoimmune disorders. The disease is rapidly fatal. It may occur in neonates [31]. Histologically, there is widespread myocardial necrosis associated with an inflammatory infiltrate with multinucleated giant cells (Figure 8.11). Importantly, there are no granulomata. The inflammatory cell infiltrate includes lymphocytes (largely CD8+ T-cells), histiocytes and eosinophils and sometimes neutrophils (Figure 8.12) [32]. The infiltrate also involves epicardium and endocardium, but giant cells are found only in myocardium. Transplantation is the treatment of choice, but the disease may recur in transplanted heart [33].

8.2.4 Giant Cell Myocarditis Giant cell myocarditis [30] is a rare and fulminant myocarditis that presents with congestive heart failure, ventricular arrhythmia or heart block (Figure 8.10). About one-fifth of

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8: Inflammation of the Myocardium, Endocardium and Aorta Table 8.2 Area of high-power field

Area of 40 HPF = πr² Π = 3.14 r = field radius (field diam. (mm)  2) Eyepiece with standard 22-mm diameter and 40 objective r = eyepiece diameter (mm) (22/40 )  2 r = 0.275 Area of 40 HPF = 3.14  (0.275)² = 0.237 mm² (4.2194 to convert to 1 mm²)

Table 8.3 Lake Louise Diagnostic Criteria for suspected myocarditis on cardiac MRI

Cardiac MRI findings are consistent with myocardial inflammation if at least two of the following criteria are present: 1. Regional or global myocardial signal intensity increase in T2weighted images

Figure 8.9 Focal lymphocytic infiltration of myocardium. A four-year-old child who died suddenly and for whom no cause of death was found at autopsy. The heart showed a few scattered foci of lymphocytic infiltration without associated myocyte necrosis. No viral genome was identified in the myocardium. The appearances cannot confidently be ascribed to myocarditis.

2. Increased global myocardial early enhancement ratio between myocardium and skeletal muscle in gadolinium-enhanced T1weighted images 3. There is at least one focal lesion with non-ischaemic regional distribution in inversion-recovery prepared gadoliniumenhanced T1-weighted images (delayed enhancement) Cardiac MRI study is consistent with myocyte injury or scar caused by myocardial inflammation if the third criterion is present. A repeat cardiac MRI study between 1 and 2 weeks after the initial cardiac MRI study is recommended if: 1. None of the criteria are present but onset of symptoms is very recent and there is strong clinical evidence for myocardial inflammation 2. One of the criteria is present 3. The presence of left ventricular dysfunction or pericardial effusion provides additional supportive evidence for myocarditis

8.2.5 Eosinophilic Myocarditis

Figure 8.10 Giant cell myocarditis. Heart transplant for biopsy-proven giant cell myocarditis. The child had been on support with a left ventricular assist device for some weeks before transplant. The heart is cut in a simulated fourchamber view. The left ventricular cannula of the assist device is visible. The myocardium is remarkably normal looking.

Eosinophilic endomyocarditis is rare and is characterised by infiltration of the endocardium and myocardium by eosinophils (Figure 8.13) [34]. The endocardium is thickened and mural thrombus is common. The disease may occur in isolation or be associated with peripheral eosinophilia. There may be associated drug hypersensitivity, parasitic infestation or eosinophilic leukaemia. The drugs implicated include ampicillin, furosemide, digoxin, tetracycline, methyldopa, hydrochlorothiazide, phenytoin, benzodiazepines and tricyclic antidepressants [35]. The characteristic microscopic appearance is of a mixed inflammatory cell infiltrate within the myocardium containing

variable numbers of eosinophils [36]. The eosinophil density ranges from mild, with small foci of inflammatory cells containing few eosinophils, to widespread infiltrates readily appreciated at scanning magnification. The inflammatory cell infiltrate may be perivascular or interstitial (Figure 8.14). Both epicardium and endocardium may be involved. Myocyte necrosis is variable. It is common with hypereosinophilic syndrome when it is associated with extensive endocardial eosinophilic infiltration that results in endocardial fibrosis and eventual restrictive cardiomyopathy (Figure 8.15).

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Figure 8.11 Giant cell myocarditis. This is the same case as Figure 8.10. (A) Low-power view of the myocardium shows extensive loss of myocytes and a patchy inflammatory cell infiltrate. (B) Focally there are multinucleate giant cells. In this instance they appear to be of myocyte origin, but others may derive from macrophages. Significantly there are no granulomata, a point of distinction from sarcoidosis.

Figure 8.12 Giant cell myocarditis. There is a dense inflammatory cell infiltrate within the myocardium with isolated multinucleated giant cells. In the lower part of the field there are scattered eosinophils. Eosinophils are found much more readily in giant cell myocarditis than in sarcoidosis.

Myocyte necrosis is much less common in drug-associated or hypersensitivity eosinophilic myocarditis. A more severe form of hypersensitivity eosinophilic myocarditis does occur and is termed acute eosinophilic necrotising myocarditis, characterised by a heavy eosinophilic infiltrate, florid oedema and myocyte necrosis with a fulminant course [37]. Eosinophilic granulomatosis with polyangiitis (formerly Churg–Strauss syndrome) is discussed in Chapter 9.

8.2.6 Bacterial and Protozoal Myocarditis 8.2.6.1 Bacterial Myocarditis Bacterial myocarditis in the absence of endocarditis, while rare, can occur, usually in the setting of overwhelming

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Figure 8.13 Eosinophilic myocarditis. Section of the explanted heart of a 15-year-old with dilated cardiomyopathy. There is a focally dense myocardial infiltrate composed predominantly of eosinophils. Although there is separation and attenuation of myocytes, no myocyte necrosis is seen.

bacteraemia [38]. The leading bacterial pathogen is Staphylococcus aureus. There are multiple small abscesses in the myocardium, usually of the left ventricle. Disturbance of cardiac contraction or of rhythm may occur, or there may be rupture into the pericardium with development of suppurative pericarditis. Occasionally, histological sections taken from the heart at autopsy may show blood vessels filled with bacteria, but without an inflammatory cell reaction within the myocardium (Figure 8.16). This usually occurs in the setting of a terminal bacteraemia with a delay in the performance of post-mortem such that organisms, present in the blood at the time of death, have time to multiply in the anaerobic conditions of the heart

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Figure 8.14 Eosinophilic myocarditis. A high-power view of the case in Figure 8.13 confirms the interstitial and perivascular nature of the infiltrate of eosinophils. Intravascular eosinophils can also be appreciated. There is no myocyte necrosis.

Figure 8.15 Eosinophilic endomyocardial disease. There was peripheral blood eosinophilia associated with cardiomyopathy. There was biventricular hypertrophy with endocardial thickening particularly on the right side and, there was right atrial and right ventricular thrombus. The ventricular myocardium was scarred and there was fibrosis of the endocardium. The section shows the thrombus overlying the thickened endocardium that contains eosinophils.

Figure 8.16 A child who died of Group B streptococcal septicaemia. There was an interval of three days between death and post-mortem. A section through the myocardium shows a vessel that is distended with cocci. They are confined to the vessel, and there is no associated inflammatory cell infiltrate. The appearance is interpreted as post-mortem overgrowth of bacteria present in the vessel at the time of death.

Figure 8.17 Toxoplasma infection. A high-power view of the myocardium showing a myocyte that contains multiple small cysts of Toxoplasma. They are visible as multiple small rounded basophilic bodies with surrounding clearing.

vessels after death. Naturally, the organisms are usually anaerobic; necrotising enterocolitis or other bowel pathology is a frequent source of such. If gas-forming organisms are involved, the vessels may contain gas bubbles.

heart transplant Toxoplasma and Cytomegalovirus are the most frequent causes of infections of the myocardium [40]. The presence of neutrophils in the absence of severe acute cellular rejection should raise suspicion of infection.

8.2.6.2 Toxoplasma

8.2.6.3 Chagas Disease

Toxoplasma may cause myocarditis following maternal infection and transplacental passage. Myocardial necrosis, scarring and calcification have been described [39]. There are usually associated brain abnormalities. Pseudocysts may be seen in the placenta or even in the myocardium (Figure 8.17). Following

This disease is caused by infection with the protozoan parasite Trypanosoma cruzi and is prevalent in Southern and Latin America. It is usually transmitted by insect bite, but it can also be transmitted through infected blood transfusion and vertically from mother to infant [41]. The initial infection is usually

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Figure 8.18 Acute Chagas myocarditis. A section of the myocardium of the heart of a two-year-old boy infected with Trypanosoma cruzi. Multiple myocytes are swollen by small rounded basophilic bodies that are the amastigotes of T. cruzi. There is an associated lymphocytic infiltrate in the interstitium.

asymptomatic, but an acute illness may arise. Most people spontaneously clear the infection, but a minority develop a chronic form with dilated cardiomyopathy, achalasia or intestinal pseudo-obstruction. Children may present with the acute form, which is manifest as fever lymphadenopathy, hepatosplenomegaly and tachycardia. Death in the acute phase is usually the result of myocarditis or meningoencephalitis. At post-mortem in these cases the heart is oedematous and shows myocarditis. The form of the organism known as amastigotes can be seen in myocytes (Figure 8.18). Although the chronic form is most often seen in adults, it may affect children [42]. Pathologically there is dilated cardiomyopathy with characteristic thinning of the ventricular apex [43]. Histological examination shows widespread destruction of myocardial cells, diffuse fibrosis, oedema, mononuclear cell infiltration of the myocardium and scarring of the conduction system [44]. Parasites are very difficult or impossible to identify [45].

8.3 Systemic Inflammatory Diseases with Heart Involvement There is a group of systemic inflammatory disorders with a strong autoimmune component that may involve the heart to a greater or lesser degree. This group includes rheumatic disease, lupus erythematosus, systemic sclerosis, idiopathic juvenile arthritis and sarcoidosis [46]. The heart involvement may be predominantly confined to one compartment out of the pericardium, myocardium or endocardium, or may affect any combination of the three. Endocarditis is a feature of lupus erythematosus and rheumatoid disease and rheumatic fever.

8.3.1 Rheumatic Disease Rheumatic fever occurs in children, but is uncommon under five years of age and is exceptionally rare under the age of one

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year [47]. In acute rheumatic fever the valves are affected by the inflammatory process with diffuse involvement of the valve leaflet or cusp and foci of fibrinoid necrosis. Aschoff nodules are the characteristic and diagnostic granulomatous lesions of rheumatic heart disease [48]. They may occur in endocardium, myocardium or pericardium. Typically, they are present in relation to blood vessels. They consist of a central core of fibrinoid with surrounding histiocytes and scanty lymphoid cells (Figure 8.19) [49]. The characteristic histiocytes, known as Anitschkow’s cells, show a central longitudinal bar of nuclear chromatin. Giant cells (Aschoff cells) may also be present. There is formation of small verrucae along the lines of apposition of the valve leaflets, with the mitral valve being the most frequently involved. There is involvement with decreasing frequency of the valves – aortic, tricuspid and pulmonary valve. The leaflet tissue shows ingrowth of capillaries. The lesions heal by fibrous scarring with shortening and thickening of chordae. This leads to fusion of commissures and nodular thickening of the valve. These valves rarely come to the surgical pathologist in the acute phase.

8.3.2 Lupus Erythematosus Systemic lupus erythematosus is rare before the age of five years, but up to 10% of cases have their onset before the age of 15 years. Girls account for more than 80% of cases [50]. Cardiac involvement in many cases is confined to pericarditis with or without effusion. The characteristic lesion is atypical verrucous endocarditis, known as Libman–Sacks endocarditis. The lesions affect the valves and are typically flat and granular and larger than those seen in rheumatic endocarditis. They may extend onto the myocardium or chordae. Histologically these vegetations consist of fibrinoid material. A mild inflammatory infiltrate with vascularisation is usually present (Figure 8.20). Vasculitis may also be present. There is overlap with antiphospholipid syndrome, the valvar involvement of which may be indistinguishable from SLE. Myocarditis may develop in about 10% of patients, and in about 1% dilated cardiomyopathy develops [51]. This is associated with the presence of IgG anticardiolipin antibodies and responds to steroid administration. Heart involvement in the fetus of mothers with lupus is discussed in Chapter 12.

8.3.3 Systemic Sclerosis Although usually clinically asymptomatic, cardiac involvement is common in systemic sclerosis and scleroderma and may lead to arrhythmias, congestive heart failure, angina pectoris with normal coronary arteries and sudden death [52]. Vasospasm of the small intramyocardial arteries is thought to impair both perfusion and function, leading to intimal arterial proliferation and myocardial loss with fibrosis [53,54]. Echocardiography and cardiac MRI demonstrate increased left ventricular mass and decreased left ventricular ejection fraction. Although heart block is common, specific lesions of the atrioventricular conduction tissue have not been demonstrated [55].

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Figure 8.19 Rheumatic fever. (A) An Aschoff nodule composed of a rounded collection of histiocytes with irregular areas of fibrinoid. A sprinkling of other inflammatory cells is present at the periphery of the nodule. There are no giant cells. (B) A smaller Achoff nodule within the myocardium. The constituent cells show the nuclear features of Anitschkow cells with a central longitudinal bar of chromatin that appears as a “bullseye” when cut in cross section. (C) Excised anterior leaflet of mitral valve from a case of chronic rheumatic carditis showing thickening of the body of the leaflet and of the tendinous cords.

The fibrosis is of equal severity in the right and left ventricles with no correlation with coronary artery distribution. The fibrosis frequently extends to the endocardium without a surviving subendocardial layer of myocytes, as is generally seen in the replacement fibrosis of healed myocardial infarction (Figure 8.21). In some patients this pattern of destruction of myocardium causes grossly visible “pockmarks” where the focal myocardial scars can easily be seen through the unaltered endocardium [52]. Skeletal myositis is documented histologically in cases of scleroderma. Reports of myocarditis are based on clinical evidence of resting tachycardia without fever, non-specific ST-T wave changes on electrocardiogram and the presence of congestive heart failure, cardiomegaly without pericardial effusion, ventricular arrhythmias, or the new development of various degrees of heart block and the presence of the MB isoenzyme of creatine phosphokinase (CPK) [56]. More recently there are reports of myocarditis on endomyocardial biopsy, almost always associated with fibrosis [57,58].

Figure 8.20 SLE. Biopsy from a case of systemic lupus erythematosus with cardiac involvement. The biopsy shows loss of myocytes with irregular areas of fibrosis and a sprinkling of inflammatory cells. There is no active myocarditis.

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Figure 8.21 Systemic sclerosis. Endomyocardial biopsy from a patient with systemic sclerosis. The fragment to the right of the field shows replacement fibrosis of myocardium with a slight increase in inflammatory cells.

Figure 8.23 Takayasu disease aorta. A four-year-old child who died suddenly because of occlusion of the left coronary artery. There is aortitis affecting the proximal aorta and extending into the aortic valve. Histology excluded the presence of bacterial endocarditis.

8.3.4 Juvenile Idiopathic Arthritis Juvenile idiopathic arthritis is the most common rheumatic disease in children. It is a group of conditions all sharing the features of chronic arthritis in children without apparent cause. The incidence is reckoned to be 2–20 cases per 100 000 children. Cardiac involvement is present in 10–20% of patients but function is not severely compromised [59]. Cardiac involvement takes the form of pericarditis, myocarditis and valvar disease. Pericarditis may be non-specific or rheumatoid nodules may be present. Myocarditis is usually silent, but heart failure may occur. The aortic and mitral valves are the most frequently affected of the valves. There may be non-specific inflammation, or there may be granulomatous inflammation

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Figure 8.22 Sarcoidosis. This post-mortem heart shows dense interstitial fibrosis forming a scar, at the edge of which there is a non-caseating granuloma that contains multinucleate giant cells. The presence of a well-formed granuloma excludes giant cell myocarditis.

Figure 8.24 Takayasu disease affecting mitral valve. One-year-old girl with mitral and aortic regurgitation. Cardiac MRI and MRA showed a very hot and thickened aorta extending down to the mesenteric arteries, with early occlusion of the subclavian arteries, and left common carotid artery, diagnostic of Takayasu arteritis. Aortic and mitral valve repair with biopsy of aorta, mitral and aortic valves. A section of the mitral valve shows thickening and an inflammatory cell infiltrate.

at the bases of the valves. The coronary arteries may be involved, as may the aorta.

8.3.5 Sarcoidosis Sarcoidosis, a multisystem granulomatous disease of unknown cause, is rare in children [60]. In a Danish study, the incidence was 0.06 per 100 000 children aged 4 years or younger, increasing gradually with age to 1.02 per 100 000 children who were aged 14–15 years [61]. Two distinct childhood forms exist [62]. That presenting after the age of eight years is akin to the form

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Figure 8.25 Bacterial endocarditis valve. A surgically excised semilunar valve cusp that shows a fungating vegetation on its free border extending into both arteria and ventricular aspects of the cusp. Histologically there was bacterial endocarditis.

occurring in young adults and presents with lung infiltrates and hilar lymphadenopathy. That presenting before the age of four years is an aggressive disorder characterised by rash, uveitis and arthropathy [63]. Cardiac involvement is even rarer. Cardiac granulomas are found in about 25% of patients with sarcoidosis who are examined at autopsy, but cardiac sarcoidosis is clinically apparent in only about 5% of all patients [64]. The most common location for granulomas and scars is the left ventricular free wall, followed by the interventricular septum, often with involvement of the conducting system. On cardiac MRI sarcoidosis has a mid-myocardial or subepicardial pattern of late gadolinium enhancement. Cardiac sarcoidosis is manifested clinically as cardiomyopathy with loss of muscle function, or tachyarrhythmias and bradyarrhythmias (palpitations, syncope and death). In adults about 50% of deaths due to the disease are due to cardiac involvement [65]. Endomyocardial biopsy has a low diagnostic

Figure 8.26 Endocarditis VSD edge. A longitudinal section through the crest of the interventricular septum. The aortic valve is visible on the left of the field. There is a VSD between the right ventricular cavity and the left ventricular outflow tract. On the left ventricular aspect its endocardial surface is fibrotic. On the right ventricular aspect, there are fungating masses of fibrin and inflammatory cells form vegetations of bacterial endocarditis (From Suvarna SK (ed.) Cardiac Pathology: A Guide to Current Practice. London: Springer; 2013, with permission).

yield (less than 20%) because cardiac involvement tends to be patchy, and granulomas are more likely to be located in the left ventricle and basal ventricular septum than in the right ventricle, where endomyocardial biopsies are usually performed (Figure 8.22) [60].

8.4 Aortitis Aortitis, inflammation of the aorta, may be infectious or non-infectious and leads to aortic dilatation and aneurysm or to aortic valve insufficiency. The classification system for childhood vasculitides published under the auspices of the European League against Rheumatism (EULAR) and the Paediatric Rheumatology European Society (PRES) includes Takayasu arteritis as the only form of large vessel vasculitis in childhood [66].

8.4.1 Takayasu Arteritis This is an inflammatory and stenosing disease of medium- and large-sized arteries with a predilection for the aortic arch and

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Figure 8.27 Endocarditis in a Blalock–Taussig shunt. Sudden death in an infant with pulmonary atresia palliated with a Blalock–Taussig shunt. At postmortem the shunt was blocked, and histologically there is filling of the shunt lumen with fibrin and bacterial colonies. The walls of the shunt are visible as the slightly refractile thick bands running diagonally across the field from top left.

its branches (sometimes referred to as the aortic arch syndrome) [67]. The pathogenesis is unknown, but intimal fibrous proliferation of the aorta, great vessels, pulmonary arteries and renal arteries results in segmental stenosis, occlusion, dilatation and development of aneurysms in these vessels [68]. An alternative term, idiopathic or non-specific aortitis has been used to describe the spectrum of vascular abnormalities associated with the condition. Takayasu arteritis bears some similarities to temporal (giant cell) arteritis. These arteritides differ in their age of onset, with temporal arteritis rarely occurring before the age of 50 years and Takayasu arteritis rarely after 50 years [67]. Takayasu arteritis is worldwide in distribution, with an incidence of 1.2–2.6/million per year in the Western population. It most often affects young women in their second and third decades, and the age of onset is usually between 15 and 30 years, but the age of onset may vary from infancy to middle age. In one series of 60 patients, 30% were younger than 20 years at diagnosis [68]. Systemic symptoms are seen in a high proportion (60–70%) of children with Takayasu arteritis [67]. The usual presenting symptoms are due to hypertension, heart failure or a neurological event. Claudication, bruit or a missing pulse in an asymptomatic child are uncommon presentations. One common finding in the disorder is the persistence of vascular inflammation in patients whose condition

Figure 8.28 Fungal endocarditis. (A) A semilunar valve cusp from an infected pulmonary homograft. The ventricular aspect shows a fungating mass of yellowish material that represents the vegetation. (B) Histologically, the vegetation consists of fibrin, inflammatory cells and numerous fungal spores and pseudohyphae of Candida spp (periodic acid–Schiff stain).

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Figure 8.29 Bacterial endocarditis histology. (A) A vegetation from bacterial endocarditis shows it to consist of amorphous masses of fibrin with a heavy infiltrate of inflammatory cells and numerous bacterial colonies. (B) Gram stain shows numerous colonies of Gram-positive bacteria.

appears to be clinically silent. Surgical specimens from patients in whom the disease is in clinical remission have revealed histological evidence of vasculitis in approximately 40% of cases. Thus, most patients have a disease that is chronic or relapsing in nature [68]. Histologically, the arterial wall is thickened with disruption of the elastic laminae and a variably heavy infiltrate of plasma cells, lymphocytes and histiocytes, sometimes with giant cells (Figure 8.23). Fibrosis develops in longstanding cases. There is fibrous and cellular intimal proliferation, but intimal inflammatory cell infiltration is unusual. There is perivascular inflammation in the adventitia and, in longstanding cases, fibrosis [69]. In about 10% of cases there is involvement of the aortic root and the aortic valve. There are few histological descriptions of the valvar pathology but inflammation and fibrosis are recorded (Figure 8.24) [70].

8.4.2 Infectious Aortitis

Figure 8.30 Non-bacterial thrombotic endocarditis – neonate. Warty growths are present at the edges of the leaflets of the tricuspid valve and extending onto the chordae. The vegetations are smaller than those generally seen with bacterial endocarditis. Histologically there was no significant inflammatory cell infiltrate, and gram stain and fungal stains were negative. The infant also had persistent pulmonary hypertension of the newborn. (From Khong TY & Malcolmson RDG (eds) Keeling’s Fetal and Neonatal Pathology London: Springer; 2015, with permission).

This is a very rare condition that is commoner in adults where causes include septic emboli from endocarditis [71], contiguous spread from an infected site, bacterial contamination from penetrating trauma, and as a complication of angiography [72]. It may lead to rupture of the aorta, with or without the formation of an aneurysm. Syphilitic aortitis, common at the beginning of the twentieth century is nowadays practically unknown in Western countries [73]. Aneurysm of the sinus of Valsalva, although some cases may be acquired, is discussed under congenital heart disease.

8.5 Endocarditis 8.5.1 Infectious Endocarditis Infectious endocarditis is infection confined to the endocardium and the immediately subjacent structures. It usually

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affects the valves of the heart or the immediately surrounding endocardium (Figure 8.25). It may affect the edges of VSDs (Figure 8.26), patent arterial duct, coarctation, indwelling catheters or prosthetic material within the heart (Figure 8.27). There is usually underlying valvar pathology, but with aggressive pathogens, endocarditis can occur in a healthy valve. In the setting of congenital heart disease, VSD, obstruction of the left ventricular outflow tract, tetralogy of Fallot and tricuspid atresia are the most common underlying lesions [74]. The most common microorganisms are viridans streptococci and Staphylococcus aureus [75]. Less frequent organisms are coagulase-negative staphylococci and Candida spp. Pneumococcal endocarditis is an aggressive disease with a high mortality [76]. Fungi may be present in immunosuppressed patients (Figure 8.28). The vegetations tend to occur on the right side of the heart, predominantly the tricuspid valve and in the setting of a VSD, on the right side of the defect. Associated with coarctation, they may be on the aortic valve or in the aorta just distal to the coarctation. With a patent arterial duct the

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Chapter

9

The Coronary Arteries

9.1 Introduction The anatomy of the normal epicardial coronary arteries has already been described in Chapter 1 and their embryological development is reviewed in Chapter 3. The coronary arteries have a fairly consistent basic normal anatomy, but variations do occur that at their most extreme result in disease. The large burden of congenital heart disease carries with it variations in coronary artery anatomy, particularly in those cases with abnormal ventricular outflow tracts, and these variations have implications for the natural history of the diseases as well as having an impact on the approach to their surgical correction. Atherosclerosis, which accounts for so much morbidity and mortality in adult pathology practice, is very rare in children, but other diseases scarcely seen in adults, such as Kawasaki disease, have a disproportionate effect on the coronary circulation.

9.2 Normal Structure The normal neonatal coronary artery has an endothelial cell layer resting directly on the internal elastic lamina. The tunica media is muscular and contains a few fine elastic fibrils. The tunica adventitia is fibrous, and an external elastic lamina is not well developed. At the origins of the coronary arteries from the aortic sinuses the elastic tissue of the aortic tunica media extends for a variable distance into the tunica media of the proximal coronary arteries, usually for no more than a millimetre or two (Figure 1.76) [1]. During the first few months of life the coronary arteries develop irregular intimal thickenings, most pronounced in the left anterior descending artery and usually in association with arterial branching points. These areas are fibrous and contain elastic fibres and cells (Figure 1.77). There may be associated breaks in the underlying internal elastic lamina. The exact nature of these histological lesions is still debated. Some claim them to be progenitors of atherosclerosis in later life [2], and others suggest that they arise at points of weakness in the vessel wall associated with branching [3]. Similar changes may sometimes be seen in late stillbirths. They become less conspicuous with the growth in size of the vessels.

9.3 Common Normal Variants of the Coronary Arteries In the normal situation, the coronary arteries arise from the right- and left-facing sinuses of the aortic valve close to the sinotubular junction. The right coronary artery travels downwards and to the right to enter the right atrioventricular groove and, in that location, courses around to the posterior aspect of the heart. It supplies branches to the pulmonary infundibulum and to the sinoatrial node, the right ventricular myocardium and in about 90% of cases supplies the posterior interventricular artery (right dominant circulation) (Figure 9.1A). The left coronary artery branches after a course of a few millimetres from its origin from the aorta to give an anterior descending artery and a circumflex branch, the latter travelling in the left atrioventricular groove to supply a variable amount of the left ventricular myocardium (Figure 9.1B). The coronary arteries exit the aorta at right angles to that vessel, and although both main vessels skirt the pulmonary trunk, they are not compressed between it and any other structure. A variant of normal is the presence of a single coronary artery, usually arising from the left-facing sinus of the aorta, that then gives rise to all the epicardial arteries (Figure 9.1C). The incidence of an isolated, single coronary artery is noted to be 0.03% of adults referred for coronary arteriography [4]. The incidence of single coronary artery is much higher in patients with congenital heart disease and in particular those with conotruncal malformations: approximately one-third of the cases of isolated coronary arteries have been reported in the setting of transposition of the great vessels and tetralogy of Fallot (Figure 9.2). The single artery may arise from either the right or left sinus of the aortic valve, and the epicardial course is very variable [5]. For most of their proximal course the coronary arteries rest on the epicardial surface of the heart. They may dip down into the myocardium for a variable length and to a variable depth before re-emerging onto the epicardial surface (Figure 9.3). The significance, if any, of this myocardial bridging is debated. It is generally not thought to have any pathological

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Figure 9.1 Variant coronary artery patterns in the structurally normal heart. Plasticine models of the base of the heart. The pulmonary trunk is to the top of the model and the aorta in the centre of the base of the heart. The atrial walls are not shown. The mitral valve is represented on the left of the model and the tricuspid valve to the right. The proximal course of the epicardial coronary arteries is in red. (A) Right dominant normal circulation: the right coronary artery supplies the posterior interventricular artery. (B) Left dominant normal circulation: the left circumflex artery provides the posterior interventricular artery. (C) Single coronary artery: in this instance the single artery arises from the left sinus and the right coronary artery runs posterior to the aorta. (D) Origin of the left coronary artery from the right sinus: the left artery runs anterior to the pulmonary trunk before giving of an anterior interventricular artery and continuing around the left side of the heart as the circumflex artery. (E) Origin of the right coronary artery from the left sinus: the right artery runs posterior to the aorta to reach the right heart. This configuration has similarities to 9.1C, but there are separate orifices for right and left coronary arteries. (F) Origin of the left anterior descending artery from the right sinus: the vessel runs anterior to the pulmonary trunk. (G) Origin of the left circumflex artery from the right sinus: the circumflex vessel runs posterior to the aorta. In none of the examples above does any of the coronary arteries run between the aorta and the pulmonary trunk. Contrast with Figure 9.7.

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Figure 9.1 (cont.)

Figure 9.2 Single coronary artery in congenital heart disease. A case of pulmonary atresia with VSD. A single coronary artery arises from the right sinus of Valsalva and immediately divides into right and left branches. The atretic pulmonary trunk is visible as a fibrous cord to the left of the artery origin (From Khong TY & Malcolmson RDG (eds) Keeling’s Fetal and Neonatal Pathology. London: Springer; 2015, with permission).

Figure 9.3 Intramyocardial course of epicardial coronary artery. A case of pulmonary atresia with intact septum. There is no epicardial pulmonary trunk. The left anterior interventricular artery dips into the myocardium from the epicardial surface and emerges more distally where it is crossed by the vein.

significance, except perhaps in the context of hypertrophic cardiomyopathy [6]. Some variations to the above pattern occur so frequently as to be part of the normal spectrum. In about 50% of cases, two, sometimes even three, right coronary arteries arise from the right-facing sinus (Figure 1.42) [7]. The extra vessel is usually small, supplying only a small part of the pulmonary infundibulum and may anastomose with the left coronary system [8]. One or both of the major coronary arteries may take origin from an inappropriate aortic sinus of Valsalva. The possibilities involve usually only the right- or left-facing sinuses and include origin of both coronaries from the right sinus, origin of both arteries from the left sinus, origin of either the left anterior descending artery or the left circumflex artery from

the right sinus, or independent origin of both left anterior descending artery and left circumflex from the left sinus (Figure 9.1D–G). Abnormal origin involving the non-coronary (posterior) sinus is very rare, but possibilities include origin of both right and left coronary arteries from the posterior sinus or origin of either the left or the right artery from the posterior sinus. Of these possibilities, the least uncommon is origin of the right artery from the posterior sinus, a pattern seen with some frequency in transposition of the great arteries [9]. A case is described of right coronary artery arising from the posterior sinus in a normal heart by MRI [10]. The left coronary artery has been described on at least one occasion as arising from the posterior sinus in a normal heart [11].

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9.4 Abnormal Variations in the Epicardial Distribution of the Coronary Arteries in the Normally Formed Heart

myocardial damage persists and cardiovascular events (arrhythmia, sudden death, heart failure) may occur especially in the post-infantile presentation group [16].

Abnormalities of origin of the arteries occur with a frequency of about 0.5% in paediatric autopsies [12] and of 1.55% in a large population investigated by angiography [13]. Many forms are described not all of which are pathological.

9.4.2 Pathological Anomalous Origin of the Coronary Arteries from the Aorta

9.4.1 Anomalous Origin of the Coronary Arteries from the Pulmonary Artery Among the most serious of the anomalous coronary artery origins is origin of one of the coronary arteries from the pulmonary trunk (Figure 9.4) [14]. The commonest manifestation of this condition is origin of the left coronary artery from one of the sinuses of the pulmonary trunk, usually the left sinus, occasionally the anterior sinus. The right coronary artery in these cases arises normally from the right-facing sinus of the aorta (Figure 9.4). The condition is sometimes referred to by the acronym ALCAPA or Bland– White–Garland syndrome. Much less frequently, both right and left coronary arteries arise from the pulmonary trunk and, even more rarely, may arise from the branch pulmonary arteries. Origin of the left coronary artery from the pulmonary trunk usually presents in the neonatal period when the perfusion pressure in the pulmonary artery relative to the aorta plummets. This results in myocardial infarction in the area supplied by the left artery. The infant is restless, crying, tachypnoeic, tachycardic and sweaty, and death may ensue from heart failure. If the infant survives, by developing a collateral circulation, the infarcted area scars and the child develops dilated cardiomyopathy and is at risk of sudden death on exertion. Pathologically, the affected left coronary artery is dilated and thin-walled, resembling a vein (Figure 9.4). The left ventricle is enlarged and dilated and, if there has been prolonged survival, there is scarring of the anterolateral wall with fibrosis of the papillary muscles and sometimes calcification. There is endocardial fibroelastosis throughout the left ventricle (Figure 9.5), sometimes also affecting the right ventricle. There may be mitral regurgitation because of ischaemic papillary muscle damage. The intramyocardial branches of the left coronary artery may show intimal thickening (Figure 9.6) [14]. Anomalous origin of the right coronary artery from the pulmonary trunk is much less common than ALCAPA and compatible with normal life. Treatment is surgical and involves either re-implantation of the coronary artery into the aorta or the so-called Takeuchi procedure whereby an aortopulmonary window is created and a patch inserted to create an intrapulmonary tunnel directing aortic blood to the anomalous coronary artery [15]. Those patients who survive the perioperative period have a good prognosis, and cardiac function improves greatly. However,

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The clinical significance of anomalous origin of the coronary arteries depends principally on two factors, the obliquity of the course of the vessel through the aortic wall and on whether or not the coronary artery courses between the aorta and the pulmonary artery (Figure 9.7), both of which factors may result in compression of the vessel [17]. Such abnormalities have been linked to sudden death [18]. In this group the most common anomaly is origin of the left coronary artery from the right sinus of Valsalva (Figure 9.8). Origin of the right artery from the left sinus is less frequent (Figure 9.9). It is proposed as a cause of sudden death usually on exertion. In a proportion of cases the artery has an intramural course in the aortic wall before exiting onto the adventitial surface. Frequently there is fibrosis in the myocardium of the affected supplied part of myocardium. An abnormally high take-off of the coronary arteries from the aorta, arbitrarily defined as greater than 1 cm above the sinotubular junction, may be associated with increased cardiac morbidity, possibly because of an oblique course through the aortic wall [19,20]. The situation of disconnection of the coronary arteries from their aortic attachment has already been mentioned in the context of pulmonary atresia with intact ventricular septum [21].

9.5 Coronary Artery Fistula Congenital coronary fistula is rare [22]. The fistulous communication is between one or both coronary arteries and the coronary sinus, the pulmonary trunk or one of the cardiac chambers. Coronary fistula may occur in isolation, or may be associated with other cardiac abnormalities such as pulmonary atresia with VSD (Figure 4.41A) or hypoplastic left heart [23]. The defect results in left-to-right shunt and, depending on the magnitude of the shunt, symptoms develop. This usually does not occur until adulthood when the patient may develop congestive cardiac failure or bacterial endocarditis [24]. Only 10–20% of childhood cases are symptomatic [25]. Rupture is a very rare occurrence [26]. Intervention in childhood is rarely needed [27]. The affected vessel is more frequently the right coronary artery. The vessels are enlarged and thin-walled and tortuous (Figure 9.10); further aneurysmal dilatations may be present with fibrosis and calcification of their walls. The changes become more noticeable with age. When there is fistula between the coronary artery and coronary sinus, the coronary sinus is also dilated and tortuous. Histologically the walls of

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Figure 9.4 Anomalous origin of the left coronary artery from the pulmonary artery. (A) Model of the abnormality. (B) On the epicardial surface of the heart the anomalous coronary artery is visible in the left atrioventricular groove and coursing over the anterior wall of the left ventricle. It is dilated and thin-walled. (C) The right ventricular outflow tract is opened to expose the pulmonary valve. To the right of the picture a coronary artery is seen to arise from the sinus of the valve. On the external surfaces a thin-walled, partially collapsed large artery is visible. (D) The corresponding view of the left ventricular outflow tract shows the origin of the coronary artery from the right sinus of Valsalva just beneath the sinotubular junction and towards the commissure with the non-coronary cusp, to the right of the field. The left sinus is plainly visible, to the left of the picture, and does not contain a coronary artery orifice. (E) A four-month-old who died suddenly and at post-mortem an ALCAPA was identified. There was associated dilated cardiomyopathy. The probe is in the left coronary artery orifice as it arises from the pulmonary trunk. The left coronary artery abuts the aorta where it would normally be expected to arise, but there was no communication with the aortic lumen. The right coronary artery can be seen arising normally from the aorta (From Suvarna SK (ed.) Cardiac Pathology: A Guide to Current Practice. London: Springer; 2013, with permission).

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Figure 9.5 Dilated cardiomyopathy due to ALCAPA. Death in the early teenage years in a case of undiagnosed ALCAPA. The case was thought to be one of dilated cardiomyopathy, and the phenotype is that of DCM with a dilated LV showing EFE (From Suvarna SK (ed.) Cardiac Pathology: A Guide to Current Practice. London: Springer; 2013, with permission).

Figure 9.6 Intramyocardial coronary arteries in ALCAPA. There is an increase in adventitial collagen, the tunica media is hypertrophied and there is concentric intimal fibroelastic proliferation.

Figure 9.7 Anomalous origin of one coronary artery from an inappropriate sinus and with an inter-arterial proximal epicardial course. A plasticine model of the three commonest occurrences of such a situation. (A) Origin of the left anterior descending (LAD) artery from the right sinus. The proximal LAD runs between the aorta and pulmonary artery where there is a theoretical risk of compression. Probably of more significance is the acute angle of origin from the aorta. (B) Origin of the right artery from the left sinus. (C) The left main stem rather than just the LAD takes origin from the right sinus.

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Figure 9.8 Origin of the left main stem from the right sinus of Valsalva. (A) The left ventricular outflow tract of the heart opened to demonstrate anomalous origin and intramural course of the left coronary artery from the right sinus of Valsalva. The right coronary artery can be seen at the centre of the field arising from the right-facing sinus of the aortic valve. Immediately to its left is an elliptical depression where the left coronary artery takes origin, running through the aortic wall to exit on the epicardial surface adjacent to the usual position of the left coronary artery. No coronary artery orifice is seen in the left sinus. (B) The aorta viewed from behind. The origins of the coronaries can be discerned in the opened aorta. To the left the emergence of the left artery from the aortic wall is visible. (C) A histological section demonstrates the intimate relation of the proximal course of the left coronary artery and the aortic wall. The pulmonary trunk is to the left and the coronary artery runs between the two great vessels.

the affected but non-aneurysmal artery show medial hypertrophy with disruption of its elastic laminae, and intimal fibrosis (Figure 4.41B). The aneurysmal parts show fibrous replacement of the wall with focal calcification [27]. The treatment of choice is transcatheter closure [28]. Anomalous connections of the coronary arteries to the pulmonary trunk are dependent on an accessory coronary artery arising from the pulmonary trunk. Coronary artery fistula may be acquired, particularly in association with Kawasaki disease [29].

9.6 Coronary Artery Hypoplasia and Atresia Both coronary artery hypoplasia and atresia are rare and are usually associated with other cardiac defects. Pulmonary atresia with intact septum and ventriculocoronary sinusoids may

be associated with coronary atresia. Isolated hypoplasia has been reported as a cause of sudden death [30].

9.7 Variations in the Epicardial Coronary Arteries in Congenital Heart Disease The frequency of abnormal epicardial coronary artery distribution in congenital heart disease with normal outflow tracts appears to be no higher than in normal hearts [31]. Those with conotruncal abnormalities have the highest rate of abnormal coronary distribution.

9.7.1 Tetralogy of Fallot The commonest abnormality described in tetralogy of Fallot is the origin of the LAD artery from the right sinus of Valsalva or as a branch of the right coronary artery (Figure 9.11). This

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Figure 9.9 Origin of the right coronary artery from the left sinus of Valsalva. (A) The left ventricular outflow tract is opened to show the aortic valve. The left coronary artery orifice is the larger and arises from the centre of the left sinus of Valsalva. The right artery orifice is smaller and arises from the left sinus close to the commissure. (B) The epicardial aspect of the same case showing the oblique origin of the right coronary artery and its proximal course between the aorta and the pulmonary trunk (From Suvarna SK (ed.) Cardiac Pathology: A Guide to Current Practice. London: Springer; 2013, with permission).

Figure 9.10 Coronary artery fistula. Fistula between the right coronary artery and the coronary sinus. The course of the right coronary artery in the right atrioventricular groove is opened from its aortic origin. The vessel is greatly dilated and tortuous and has a roughened intimal surface.

abnormality accounts for about 80% of abnormal coronary artery patterns [32]. A dominant left coronary artery is found more frequently in tetralogy of Fallot patients compared to normal subjects (28% vs 10%) [33]. In all cases of tetralogy of Fallot the conal branch arising from the right coronary artery is enlarged to supply the hypertrophied right ventricle (Figure 9.12). In some cases it may arise via a separate ostium in the right sinus [32]. The incidence of major coronary artery crossing the right ventricular outflow tract is between 5% [34] and 19% [33], the discrepancy being accounted for, to some extent, by the investigation method (echocardiography vs angiography). There may be fistulae between the left circumflex artery and the bronchial arteries [35].

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Figure 9.11 LAD from RCA in tetralogy of Fallot. A one-day-old infant with tetralogy of Fallot. There is a single coronary artery arising from the right sinus of Valsalva.

9.7.2 Transposition of the Great Arteries Variations in coronary artery anatomy in transposition of the great arteries are more prevalent when the great arteries have a side-by-side arrangement than when the aorta is anterior [36]. The commonest pattern found is the origin of the left artery from the left sinus of Valsalva but with a course anterior to the pulmonary trunk (Figure 9.13). The right coronary artery arises from the posterior sinus [32]. The circumflex artery may also arise from the posterior sinus. There is a six-fold increase in early mortality after arterial switch operation associated with the presence of an intramural coronary artery and a

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three-fold increase in mortality associated with a single coronary artery [37].

9.7.3 Common Arterial Trunk In common arterial trunk the coronary artery pattern is very variable and depends on whether the arterial valve consists of three, fewer or more leaflets. It is most likely to be normal if the truncal valve is tricuspid (Figure 9.14) [38].

9.7.4 Double Outlet Right Ventricle (DORV) The distribution of the coronary arteries in DORV follows the position of the great arteries. The normal pattern is the most

frequently observed occurring in about one-third of cases. This is usually the case when the aorta is relatively posterior and rightward and the physiology is similar to tetralogy of Fallot. When the aorta is more anterior, then the coronary artery pattern is similar to the usual pattern seen in TGA (25%). As in transposition, variant coronary artery patterns are often seen in side-by-side great arteries (27%) (Figure 9.15). When the aorta is anterior and leftward, the right coronary artery crosses in front of the right ventricular outflow (Figure 9.16) [39].

9.7.5 Hypoplastic Left Heart Left dominance is more frequent in hypoplastic left heart syndrome than in normal hearts, and even more prevalent in the subgroup with mitral stenosis (Figure 9.17) [40]. Ventriculocoronary communications may be present. Most are small and probably have no effect on coronary perfusion (Figure 9.18) [41].

9.7.6 Congenitally Corrected Transposition The coronary artery distribution usually follows that of the ventricles [42]. The coronary arteries arise from an anteriorly situated aorta and have an inverted origin with the coronary artery arising from the left-facing sinus supplying the peripheral distribution of the usual right coronary artery. The right sinus gives rise to an artery supplying the anterior interventricular artery and a circumflex artery [43]. The artery to the sinoatrial node and also that to the AV node arise from the right-sided circumflex artery [44]. Figure 9.12 Large conal branch tetralogy of Fallot. The epicardial surface of the heart exposing the right coronary artery. The artery gives rise to several infundibular branches immediately after exiting from the aorta and then turns sharply to the left in the right atrioventricular groove. The LAD artery is visible emerging to the left of the pulmonary trunk.

9.8 Vasculitis Including Kawasaki Disease Inflammation of the coronary arteries is a feature of cardiac involvement in polyarteritis nodosa and Kawasaki disease and

Figure 9.13 Transposition of the great arteries. (A) The aorta lies beside the pulmonary artery. The right coronary artery is exposed. In addition to the usual right coronary artery anatomy, the LAD artery arises from the vessel. (B) The circumflex artery arises normally from the left sinus.

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Figure 9.14 Common arterial trunk. The trunk is opened and the VSD is visible as is the orifice of the pulmonary arteries. The origins of the coronary arteries can just be discerned beneath the sinotubular junction.

Figure 9.16 Double outlet right ventricle with anterior and left aorta. The coronary arteries arise from a single sinus of the aortic valve. This sinus is the most anteriorly situated. Two arteries arise each approximately 0.15 cm in diameter. The left artery has a rather oblique angle of origin and supplies the anterior interventricular artery. The posterior interventricular artery is supplied by the right coronary artery. A Blalock–Taussig shunt is visible.

may also complicate systemic sclerosis and systemic lupus erythematosus. Arterial involvement may also be a feature of eosinophilic granulomatosis with polyangiitis.

9.8.1 Kawasaki Disease Kawasaki disease, first described in 1961, is marked clinically by fever, conjunctivitis, erythema of the mucosa of the lips and mouth, strawberry tongue, palmar erythema and desquamation, polymorphous, non-vesicular body rash and cervical lymph node enlargement (mucocutaneous lymph node syndrome). Most cases occur in children between six months and five years of age, but the disease can occur in infants younger

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Figure 9.15 Double outlet right ventricle. Eleven-year-old with surgically treated DORV. The aortic root is viewed from above. Both coronary arteries arise from the right sinus of Valsalva. They arise very close together, such that from the outside they appear to be a single vessel. But two separate orifices are discernible on the inside. The left artery supplies a branch to the pulmonary infundibulum and the anterior interventricular artery. The right artery supplies the marginal branches on the right side and the posterior interventricular artery and runs behind the left atrium to supply the greater part of the posterior and inferolateral left ventricle.

than six months of age [45]. An infectious agent is suspected but the aetiology remains unknown. Silent cardiac involvement is common with myocarditis and arteritis of the coronary arteries. Coronary arteritis occurs in about one-third of cases, and in about 1% of cases there is sudden unexpected death due to coronary artery thrombosis. Aneurysms are common and they may rupture causing haemopericardium [46]. The early phase of the disease is marked by myocarditis [47] with involvement of the coronary arteries occurring by about day 10 of the illness [48]. Aneurysms develop in up to a quarter of untreated patients in the healing phase and may progress to occlusive thrombosis causing myocardial ischaemia or sudden death (Figure 9.19). In the United States Kawasaki disease has overtaken rheumatic fever as the leading cause of acquired heart disease in children [49]. The atrioventricular conduction system may also be involved [48, 50]. There may be rupture of the tendinous cords of the atrioventricular valves [51]. The inflammation of the coronary arteries shows an infiltrate of macrophages, lymphocytes and a few neutrophils in the tunica media without fibrinoid necrosis (a point of distinction from polyarteritis nodosa) (Figure 9.20). The arteritis is histologically most severe at about 6 weeks and thereafter abates leaving a scarred vessel wall. There is frequently thrombosis of the lumen that is sometimes occlusive (Figure 9.21). A recent multicentre US study describes three linked pathological processes in Kawasaki disease [52]: • An acute necrotising arteritis in the first weeks of the illness that destroys the vessel wall leading to the formation of saccular aneurysms that may thrombose and cause death.

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Figure 9.18 Hypoplastic left heart. Histological section of the left ventricle in an explanted heart with hypoplastic left heart. The left atrium is to the top right of the field, and the arcade of the mitral valve separates it from the left ventricle. The ventricle shows marked fibroelastic thickening of its endocardium, and there is some obliteration of the cavity towards the ventricular apex. The atretic aortic valve site is at the top left. On the right of the picture are multiple irregular channels with fibroelastic walls that communicate with the ventricular cavity and represent coronary artery sinusoids.

Figure 9.17 Hypoplastic left heart. Explanted heart from a child with mitral and aortic hypoplasia and hypoplastic left ventricle who underwent Norwood operation and subsequently proceeded to heart transplant. The heart is viewed from the base. The Damus–Kaye anastomosis is clearly visible linking the anterior pulmonary trunk and the small aorta. There are two coronary arteries. The right coronary artery is dominant supplying the posterior aspect of the heart. No circumflex artery arises from the left coronary artery.

• •

A subacute or chronic vasculitis that occurs at any stage of the illness and causes aneurysms. A proliferative, myofibroblastic form that causes near occlusion of the vessels and does not form aneurysms (Figure 9.22)

The disease is a systemic disease, and vasculitis may also develop in muscular arteries outside the heart, but not in the cerebral circulation. There may also be extra coronary aneurysms particularly in the iliac and axillary arteries [53]. Coronary artery fistulae may also develop [29].

9.8.2 Polyarteritis Nodosa Polyarteritis nodosa is a systemic inflammatory necrotising vasculitis of medium-sized arteries [54]. Anti-neutrophilic cytoplasmic antibodies are negative – a feature that together

with the absence of associated glomerulonephritis is very helpful in differentiating the disease from microscopic polyangiitis [55]. There are no specific laboratory features. Although sometimes triggered by viral infection, the cause in most causes is unknown. The peak age of occurrence is the 5th and 6th decades, but children can be affected [56]. Children with familial Mediterranean fever may also develop polyarteritis nodosa [57]. Polyarteritis nodosa is rare, with an prevalence of approximately 31 cases per million [58]. The skin and peripheral nerves are the most frequently affected sites, but kidney muscle central nervous system, gut and heart may all be involved. Cardiac involvement occurs in less than one-third of cases [54] and is rarely the presenting feature [56]. Cardiac involvement may be limited to pericarditis or the coronary arteries may be affected (Figure 9.23). The pericardial or intramural arteries may be involved. Myocardial infarction can result from vascular thrombosis. Sudden death has been reported. The affected vessels show transmural inflammation and aneurysms. The aneurysms may be detected angiographically. The vessel inflammation is characteristically segmental and most frequent at vessel branching points. The inflammatory cell infiltrate is usually mixed and includes lymphocytes, macrophages and variable numbers of neutrophils and eosinophils. Granulomata and multinucleate giant cells are not usually seen. The active lesions frequently show fibrinoid necrosis with associated neutrophilic infiltrates. Older lesions show intimal cellular proliferation and diffuse mural fibrosis. Typically lesions of different ages are present together. There may be thrombosis. The vascular injury results in the development of microaneurysms. The histological features alone do not permit distinction from other necrotising vasculitides such as

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microscopic polyangiitis or granulomatosis with polyangiitis (previously called Wegner’s granulomatosis).

9.9 Eosinophilic Granulomatosis with Polyangiitis (Formerly Churg–Strauss Syndrome) Eosinophilic granulomatosis with eosinophilia, which used to be called Churg–Strauss syndrome, is a necrotising granulomatous inflammatory process often involving the respiratory tract, with necrotising vasculitis predominantly affecting small

Figure 9.19 Kawasaki disease. Explanted heart showing the site of a ventricular assist device at the left ventricular apex. Between the left ventricular outflow tract and the left atrium is a large thrombus-filled pear-shaped structure. This is an aneurysm of the left coronary artery that is thrombosed. Much of the adjacent left ventricular wall shows ischaemic damage.

Figure 9.20 Kawasaki disease. Seven-month-old male infant who died six weeks after the start of his illness. The section of an epicardial coronary artery shows a dense inflammatory cell infiltrate without fibrinoid necrosis or giant cells. The structure of the wall is, nonetheless, destroyed.

Figure 9.21 (A) Histological section through the coronary artery aneurysm shown in Figure 9.19. A scattered inflammatory cellular infiltrate is visible at multiple points around the wall. The surrounding myocardium is almost totally replaced by scar tissue, a thin subendocardial layer surviving. (B) An EvG-stained section of the interventricular septum in the same case shows the extent of the myocardial devastation.

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Figure 9.22 Kawasaki disease. A fatal case of Kawasaki disease four months after the onset of symptoms. There were no aneurysms but all the epicardial arteries showed florid concentric fibrous intimal proliferation with patchy inflammation. This is the left circumflex artery.

Figure 9.23 Polyarteritis nodosa. Fatal case of the disease showing multiple haemorrhagic lesions on the epicardial surface of the heart representing areas of vasculitis.

Figure 9.25 Eosinophilic periarteritis. Stillbirth with finding of eosinophilic periarteritis with scattered giant cells. Figure 9.24 Eosinophilic granulomatosis with polyangiitis (Churg–Strauss syndrome). Adolescent girl who underwent orthotopic heart transplant for cardiac failure. The explanted heart shows foci of eosinophilic vasculitis.

to medium-sized vessels, associated with asthma and eosinophilia [55]. In the typical case there is a prodromal phase with symptoms of asthma and allergic rhinitis, followed by a period of peripheral blood hypereosinophilia and extravascular accumulation of eosinophils, succeeded by a phase of systemic vasculitis. Extra-pulmonary involvement is common, with cutaneous, gastrointestinal and cardiac involvement. The disease is commonest in the third to fifth decades but is well recognised in children [59]. Cardiac involvement in childhood cases is more frequent than in adults, and cardiac symptoms at presentation are present in over half of the childhood cases [60]. Pericarditis, myocarditis and cardiomyopathy all occur, and coronary artery involvement is frequent. The vasculitis affects small- and medium-sized vessels and the necrotising

vasculitis may be histologically indistinguishable from granulomatosis with polyangiitis (Wegner’s) and polyarteritis nodosa. However, a heavy eosinophilic infiltrate is usual as are necrotising granulomata in the periadventitial tissue (Figure 9.24). In consultation I have seen one case from a stillbirth (Figure 9.25). The disease appears different to eosinophilic coronary periarteritis, a disease of adults that presents with angina and coronary artery dissection, and sometimes sudden death [61]. It has not been reported in children. Histologically it has a periarterial heavy eosinophilic infiltrate but lacks giant cells or granulomata.

9.10 Thrombosis and Embolism Emboli derived from thrombus, tumour, infective organisms, adipose tissue or bone marrow, air or foreign material may all

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be found within the coronary circulation (Figure 9.26) [62]. The emboli may be single, or even sometimes multiple. Embolism of cerebellar tissue to the coronary arteries is described following traumatic delivery [63]. The emboli may be an incidental finding (Figure 9.27) or they may cause myocardial infarction secondary to vessel occlusion [64]. Antiphospholipid syndrome may result in multiple intravascular thromboses in the coronary circulation [65]. Tumours with a propensity to embolise to the coronary circulation include papillary fibroelastoma [66] and inflammatory myofibroblastic tumour [67].

9.11 Fibromuscular Dysplasia Fibromuscular dysplasia refers to a segmental, noninflammatory, non-atherosclerotic condition of medium-sized

Figure 9.26 Coronary artery thromboembolus. Muscular intramyocardial artery showing luminal thrombus.

and small systemic arteries characterised by variable intimal and medial fibromuscular proliferation [68]. Almost any artery can be affected, but the most frequently involved are the renal and cerebral arteries. Coronary artery involvement is well described and can affect the heart as part of a more generalised process or affect the coronary arteries alone [69]. The epicardial arteries and intramyocardial vessels can be involved, either in combination or alone. The sinus nodal artery may also be involved. It should be cautioned, however, that the finding of fibromuscular dysplasia type changes in the arteries to the sinoatrial and AV nodes in cases of sudden death should not be taken as pathological in the absence of changes in the other coronary arteries [70]. Pathologically, the disease is recognised by variable medial and intimal proliferation and disorganisation and irregularity. Harrison and McCormack [71] provided the standard pathological classification of fibromuscular dysplasia (Table 9.1). It is based on the pathology of the renal artery and recognises three distinct types based on the arterial layer most affected: medial, intimal and adventitial/periarterial (Figure 9.28). There are no detailed studies of the applicability of this classification to the pathology in the coronary arteries. [72] The clinical effects of arterial fibromuscular dysplasia are mediated by vessel narrowing with consequent ischaemia and infarction, aneurysm formation with rupture or arterial dissection. The disease may present at a young age. The youngest patient in the United States Registry for Fibromuscular Dysplasia is aged 5 years [73]. Coronary artery fibromuscular dysplasia is described as one cause of sudden unexpected death in infancy [74]. Usually there is associated myocardial scarring, sometimes with recent infarction, but it is not invariably present [75]. Fibromuscular dysplasia may also cause sudden death as a result of aortic dissection. In current practice the diagnosis of fibromuscular dysplasia is based not on pathology, but on radiological investigation [71,73,76].

Figure 9.27 Coronary artery resolved thromboembolus. One-year-old who underwent heart transplant for cardiomyopathy. The explanted heart showed a few foci of cellular eccentric intimal proliferation typical of post embolic disease. No foreign material was identified. The elastic stain shows no evidence of vasculitic destruction of the wall. (A) H&E. (B) EvG.

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9: The Coronary Arteries Table 9.1 Classification of fibromuscular dysplasia

Histological

Angiographic

Harrison and McCormack (1971)

French/Belgian Consensus (2012)

American Heart Association (2014)

Medial

Multifocal

Multifocal

Unifocal (