Pediatric Heart Disease E-Book
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- Herausgeber: John Wiley & Sons
- Kategorie: Fachliteratur
- Sprache: Englisch
A companion book to Adult Congenital Heart Disease that will concentrate on the practical management of children with heart conditions. This is aimed at general paediatricians and physicians who are responsible for ongoing management, rather than specialists concerned with acute or rare presentations. The book will be illustrated with relevant radiology scans, demonstrating which investigations are appropriate, and will provide the relevant information for the generalist on patient management for different lesions. A section on emergency management is also included. Authorship is international, with contributions from both sides of the Atlantic and from Japan.
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Veröffentlichungsjahr: 2012
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Table of Contents
Cover
Title page
Copyright page
List of Contributors
Preface
Section I: General cardiology
1 Epidemiology and genetics
Understanding the causes of congenital cardiovascular malformations
Developmental mechanisms of congenital heart disease
Incidence of congenital heart disease
Genetic associations and congenital heart disease
Heart disease in twins
Maternal disorders associated with congenital heart disease
Polygenic inheritance
Summary
2 Basic cardiac physiology
Initiation of contraction
Properties of myocardium
The heart as a pump
Fetal circulation
Summary
3 Cardiac morphology and nomenclature
Morphologic approach to segmental analysis
Steps in sequential segmental analysis
Associated malformations
Section II: Clinical evaluation and investigation
4 History and clinical examination
History
Clinical examination
5 Basic non-invasive investigations
Chest radiography
Electrocardiography
6 Echocardiography and Doppler
Production of images
Imaging the heart and arterial and venous connections
Comparison of Doppler techniques
Quantitative Doppler measurements
7 Diagnostic cardiac catheterization and angiography
Indications
Techniques and equipment
Hemodynamics
Calculations used in diagnostic cardiac catheterization
Angiography
8 Advanced cardiac imaging
MRI compared to CT
Cardiovascular MRI
Computed tomography
Nuclear cardiology
Summary
Section III: Specific congenital heart lesions
Acyanotic lesions
9 Left-to-right shunts
Clinical features common to all left-to-right shunts
Specific lesions
10 Right-sided malformations
Pulmonary stenosis
Double chamber right ventricle
Idiopathic dilatation of the pulmonary artery
Ebstein malformation of the tricuspid valve
Tricuspid valve stenosis and regurgitation
11 Abnormalities of left ventricular inflow and outflow
Types of left heart anomaly
Incidence
Abnormalities of left ventricular outflow
Anomalies of left heart inflow
12 Aortic malformations, rings, and slings
Aortic coarctation
Interrupted aortic arch
Vascular ring
Pulmonary artery sling
Aorto-left ventricular tunnel
Aneurysm of the sinuses of Valsalva
13 Coronary artery lesions
Normal coronary arterial anatomy
Anomalous left coronary artery from the pulmonary artery
Investigations
Coronary artery fistula
Aberrant course with myocardial ischemia
Stenosis or atresia of the coronary arteries
Cyanotic lesions
14 Transposition and transposition complexes
Transposition of the great arteries
Congenitally corrected transposition of the great arteries
Isolated ventricular inversion
15 Abnormalities of right ventricular outflow
Tetralogy of Fallot
Absent pulmonary valve syndrome
Pulmonary atresia with ventricular septal defect
Double outlet right ventricle
Double outlet left ventricle
Pulmonary atresia with intact ventricular septum
16 Common mixing situations
Total anomalous pulmonary venous connection
Partial anomalous pulmonary venous connection
Hearts with univentricular atrioventricular connection
Hypoplastic left heart syndrome
Common arterial trunk (truncus arteriosus)
Other lesions
17 Heterotaxy, scimitar, and arteriovenous malformations
Atrial isomerism
Scimitar syndrome
Cerebral arteriovenous malformations
Congenital pulmonary arteriovenous malformations
Peripheral arteriovenous malformations
Section IV: Diseases of the peri-, endo- and myocardium
18 Pericardial disease and infectious endocarditis
Pericardial disease
Infective endocarditis
19 Cardiomyopathies and acute myocarditis
Definition and classification
Dilated cardiomyopathy
Hypertrophic cardiomyopathy
Restrictive cardiomyopathy
Non-compaction cardiomyopathy
Arrhythmogenic right ventricular dysplasia
Myocarditis
20 Cardiac tumors
Incidence and etiology
Clinical features
Investigations
Management
Late complications and long-term outcome
Types of cardiac tumors
Summary
Section V: Pulmonary hypertension
21 Primary pulmonary arterial hypertension in children
Incidence and etiology
Clinical features
Investigations
Management
Prognosis
22 Pulmonary arterial hypertension associated with congenital heart disease (including Eisenmenger syndrome)
Definition and clinical classification
Epidemiology
Pathophysiology
Clinical presentation
Clinical assessment
Management
Conclusions
Section VI: Rhythm disorders
23 Bradyarrhythmias
Presentation
Diagnosis
Investigations
Vasovagal syncope (see also Chapter 37)
Sick sinus syndrome
Heart block
24 Tachyarrhythmias
Presentation
Diagnosis
Atrial arrhythmias
Junctional arrhythmias
Ventricular arrhythmias
Sudden death
Section VII: Systemic disease with cardiovascular involvement
25 Rheumatic fever
Epidemiology
Pathogenesis
Clinical features
Major clinical manifestations
Diagnosis
Management
Secondary prophylaxis
Long-term outcome
26 Marfan syndrome and connective tissue disorders
Marfan syndrome
Ehlers–Danlos syndrome
27 Kawasaki disease and Takayasu arteritis
Kawasaki disease
Takayasu arteritis
28 Hyperlipidemia
Clinical features
Management
29 Systemic hypertension
Significance and prevalence
Natural history
Definition
Measuring blood pressure
Clinical presentation and etiology
Laboratory investigations
Treatment
Section VIII: Congenital heart disease at the extremes of life
30 Fetal cardiology
Why do we screen for congenital heart disease in the fetus?
When do we screen?
Whom do we screen?
How do we screen for congenital heart disease in the fetus?
Referral to the fetal cardiologist
Preparation for delivery
Fetal therapy
Conclusions
31 Adult congenital heart disease
General principles
Transition of care from pediatric cardiology to adult congenital heart disease
Pregnancy in congenital heart disease
Contraception and termination of pregnancy
Specific congenital heart lesions
Section IX: Management strategies
32 Principles of medical management
Acute heart failure
Chronic heart failure
Cyanosis in the newborn (see Chapter 41)
Left heart obstruction in the newborn (see Chapters 11, 12, and 16)
Fluid balance and nutrition
33 Catheter intervention
Planning for interventional catheterization
Valvuloplasty
Balloon angioplasty
Stents
Percutaneous valve replacement
Defect closure
Defect creation
The future
34 Principles of surgical management
Rationale for definitive repair
Biventricular repair
Univentricular repair (Fontan-type procedure)
Superior cavopulmonary anastomosis (partial right heart bypass or Glenn anastomosis)
Palliative procedures
35 Heart, lung, and heart–lung transplantation
Heart transplantation
Lung and heart–lung transplantation
Section X: Common clinical problems in the office
36 Murmurs in asymptomatic patients
History
Physical examination
Differential diagnosis
Investigation and referral
37 Syncope and presyncope
History
Physical examination
Differential diagnosis
Investigation and referral
38 Chest pain
History
Physical examination
Differential diagnosis
Investigation and referral
39 Palpitations
History
Physical examination
Differential diagnosis
Investigation and referral
40 Stridor
History
Physical examination
Differential diagnosis
Investigation and referral
41 Cyanosis and cyanotic spells
History
Physical examination
Classification and causes
Summary
42 Activity restriction
Clearance for airline travel
Appendices
Appendix A: Resuscitation algorithms
Bradycardia algorithm (with a pulse and poor perfusion)
Narrow complex tachycardia algorithm (with poor perfusion)
Wide complex tachycardia algorithm
Pulseless arrest algorithm
Hypercyanotic spell algorithm
Appendix B: Glossary of terms commonly used in pediatric cardiac disease
Appendix C: Pediatric cardiac drugs and dosages
Appendix D: Endocarditis prophylaxis
Appendix E: Anticoagulation guidelines
Prevention of thrombosis
Stopping antithrombotic medications prior to surgery
Treatment of femoral artery thrombosis
Treatment of venous thrombosis (ACCP Guidelines 2012)
Editor’s note on aspirin
Index
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Library of Congress Cataloging-in-Publication Data
Pediatric heart disease : a practical guide / Piers E. Daubeney ... [et al.].
p. ; cm.
Includes bibliographical references and index.
ISBN-13: 978-0-7279-1861-1 (hard cover : alk. paper)
ISBN-10: 0-7279-1861-3
I. Daubeney, Piers E. F.
[DNLM: 1. Heart Defects, Congenital. 2. Child. 3. Infant. WS 290]
LC-classification not assigned
618.92'12043–dc23
2011030257
A catalogue record for this book is available from the British Library.
Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books.
Cover designer: Nathan Harris
List of Contributors
Lee Beerman MDProfessor of PediatricsUniversity of Pittsburgh School of Medicine;Children’s Hospital of Pittsburgh of UPMCPittsburgh, PA, USA
Sian Bentley BPharm, MRPharmSSpecialist Pharmacist, PaediatricsRoyal Brompton HospitalLondon, UK
Margarita Burmester MBBS, MRCP, FRCPCHConsultant Paediatric IntensivistRoyal Brompton Hospital;Imperial CollegeLondon, UK
Jamie Cheong BPharm (Hons), Cert Pharmacy Practice, MScSpecialist Pharmacist, AntimicrobialRoyal Brompton HospitalLondon, UK
Michael Cheung BSc (Hons), MB ChB, MRCP (UK), MDDirector, Department of CardiologyHeart Research Group LeaderMurdoch Childrens Research Institute;Principal FellowUniversity of MelbourneThe Royal Children’s HospitalMelbourne, VIC, Australia
Piers E. F. Daubeney MA, DM, FRCP, FRCPCHConsultant Paediatric and Fetal CardiologistRoyal Brompton Hospital;Reader in Paediatric CardiologyNational Heart and Lung InstituteImperial CollegeLondon, UK
Brian Feingold, MDAssistant Professor of Pediatrics,University of Pittsburgh School of Medicine; Children’s Hospital of Pittsburgh of UPMCPittsburgh, PA, USA
Helena M. Gardiner PhD, MD, FRCP, FRCPCH, DCHReader in Perinatal CardiologyImperial College;Honorary ConsultantQueen Charlotte’s & Chelsea HospitalLondon, UK
Michael A. Gatzoulis MD, PhD, FACC, FESCProfessor of Cardiology, Congenital Heart DiseaseRoyal Brompton Hospital;National Heart and Lung InstituteImperial CollegeLondon, UK
Georgios Giannakoulas MD, PhDConsultant CardiologistAhepa HospitalAristotle UniversityThessaloniki, Greece;Royal Brompton HospitalLondon, UK
Alex Gooi FRACP, FCSANZ, MBBS, BSc (Med)Paediatric and Fetal CardiologistMater Children’s HospitalBrisbane, QLD, Australia
Nick Hayes BSc, MBChB, MRCPCHPaediatric Cardiology Specialist RegistrarRoyal Brompton HospitalLondon, UK
Michael Y. Henein MD, MSc, PHD, FESC, FACC, FECPProfessor of CardiologyHeart Centre and Department of Public Health and Clinical MedicineUmea UniversityUmea, Sweden
S. Yen Ho PhD, FRCPath, FESCProfessor of Cardiac MorphologyRoyal Brompton HospitalLondon, UK
Victoria Jowett MDPaediatric and Fetal CardiologistRoyal Brompton HospitalLondon, UK
Bradley B. Keller MDProfessor of Pediatrics, Pharmacology and Toxicology, and BioengineeringKosair Charities Chair and Chief, Division of Pediatric Heart ResearchCardiovascular Innovation InstituteVice Chair for Research, Department of PediatricsUniversity of LouisvilleLouisville, KY, USA
Alan G. Magee BSc, MRCP, MB, BCh (Hons), FRCPConsultant Paediatric CardiologistRoyal Brompton HospitalLondon, UK
William H. Neches MDEmeritus Professor of PediatricsCardiology DivisionChildren’s Hospital of Pittsburgh of UPMCPittsburgh, PA, USA
Koichiro Niwa MD, PhD, FACC, FAHADirectorDepartment of CardiologyCardiovascular CenterSt Luke’s International HospitalTokyo, Japan
Alan W. Nugent MBBS, FRACPAssociate Professor Pediatrics University of Texas Southwestern Medical Center;Director Cardiac Catheterization Children’s Medical CenterDallas, TX, USA
Eric Quivers MDMedical DirectorDean Health SystemMiddleton, WI, USA
Michael L. Rigby MD, FRCP, FRCPCHConsultant Paediatric CardiologistRoyal Brompton HospitalLondon, UK
Phil Roberts MBChB, DCH, MRCPCH, FRACPInterventional Cardiologist Heart Centre for ChildrenChildren’s Hospital at Westmead Sydney, NSW, Australia
Maria Virginia Tavares Santana PhDDirectorDepartment of Pediatric CardiologyInstituto Dante PazzaneseSaõ Paulo, Brazil
Cleusa Cavalcanti Lapa Santos MDPaediatric CardiologistDepartment of Pediatric CardiologyInstituto Dante PazzaneseSaõ Paulo, Brazil
Anna Seale MBBChir, MRCPConsultant Paediatric and Fetal CardiologistRoyal Brompton HospitalLondon, UK
Zdenek Slavik MD, FRCPCHConsultant Paediatric Cardiologist/IntensivistRoyal Brompton HospitalLondon, UK;Associate Professor of PaediatricsCharles UniversityPrague, Czech Republic
Mark S. Spence MD, MB, BCh, BAO (Hons), FRCPConsultant CardiologistRoyal Victoria HospitalBelfast Trust;Honorary Senior LecturerQueen’s UniversityBelfast, UK
Shigeru Tateno MDDirectorPediatric and Adult Congenital Heart Disease UnitChiba Cardiovascular CenterChiba, Japan
Gregory H. Tatum MDAssistant ProfessorPediatric CardiologyDuke University Medical CenterDurham, NC, USA
Jan Till MDConsultant Paediatric CardiologistDepartment of CardiologyRoyal Brompton HospitalLondon, UK
Anselm Uebing MDConsultant Congenital CardiologistAdult Congenital Heart Centre and Centre for Pulmonary HypertensionRoyal Brompton HospitalLondon, UK;Department of Congenital Heart Disease and Pediatric CardiologyUniversity Hospital of Schleswig-HolsteinKiel, Germany
Hideki Uemura MD, FRCSConsultant Cardiac SurgeonDepartment of Cardiothoracic SurgeryRoyal Brompton HospitalLondon, UK
Steven A. Webber MBChB, MRCPProfessor of Pediatrics and Clinical and Translational ScienceUniversity of Pittsburgh School of Medicine;Chief, Division of CardiologyChildren’s Hospital of Pittsburgh of UPMCPittsburgh, PA, USA
Preface
Pediatric cardiology is a niche specialty when compared to most others and international collaboration has been an essential part of the amazing progress in diagnosis and treatment achieved during the past 25 years. The frequency and range of congenital heart malformations, with few exceptions, is the same worldwide, whereas the incidence of acquired heart disease is subject to extreme variability. We have assembled experts from all over the world, who have combined their talents and knowledge in the production of this new textbook. This is a true manifestation of international friendship and collaboration and a reflection of the global family of pediatric cardiologists and cardiac surgeons caring for what is a common and global disease.
Nevertheless, many major congenital heart malformations are relatively rare; consequently, limited numbers of cases are seen in an individual institution or even in a single country. National and international research and audit must continue to develop, if further advances in management are to take place. Despite the emphasis on fetal, neonatal, and infant cardiology in modern practice, pediatric cardiology should merge seamlessly with adolescent and adult congenital heart disease; the involvement of Michael Gatzoulis in the editorial team has certainly assisted in this goal. An additional challenge to us all is the lack of availability of comprehensive cardiology services for children and young adults born with congenital heart disease in many countries around the world, including some with thriving economies. There must be a continuing stimulus to international collaboration in teaching and sharing expertise, research, and treatment.
It is therefore timely and appropriate that the editors have brought together experts from all continents, including Australasia, Asia, Europe, Africa, and North and South America, to produce this focused and much needed textbook, which will be an invaluable resource to physicians – senior and junior – and other disciplines involved with the care of the young patient with congenital heart disease. The list of contributors is impressive, which is not surprising, considering the international training and expertise of all four editors. We also count many of the contributors as personal friends and know they all accepted their invitations without hesitation and delivered excellent chapters. It is relatively unusual for a small textbook to have such an array of authors, but this reflects a major strength of the specialty of pediatric cardiology and long may it continue.
Piers E. F. DaubeneyMichael L. Rigby Koichiro NiwaMichael A. Gatzoulis
1
Epidemiology and Genetics
Bradley B. Keller
University of Louisville, Louisville, KY, USA
Understanding the Causes of Congenital Cardiovascular Malformations
This is usually the third question asked by new parents of a child with congenital heart disease. The first four questions are:
Over the past 50 years dramatic progress in the diagnosis and management of congenital cardiovascular malformations now allows almost all newborns with congenital heart disease to survive with either palliative or complete “repairs.” There has been comparable progress over the past 25 years in identifying the developmental mechanisms that regulate cardiovascular morphogenesis and that alter this complex process to generate malformations. This now provides the molecular and genetic insights that allow physicians to begin to answer parents when they ask, “Why did this happen?” With a more complete understanding of the mechanisms for congenital heart disease, physicians can also begin to answer more accurately the fifth question asked by some parents and patients:
Developmental Mechanisms of Congenital Heart Disease
While truly fascinating, a discussion of the developmental mechanism that produce “altered trajectories” in developing cardiovascular systems, trigger adaptive mechanisms, and result in the congenital heart disease detected at birth are beyond the scope of this handbook. However, for the purposes of understanding the specific malformations discussed in later chapters, it is important to recognize that normal cardiovascular development requires:
A complex and dynamic sequence of temporally- and spatially-restricted gene expression (and suppression);
The proliferation, migration, differentiation, and death of multiple cell subpopulations;
A dynamic process of tissue remodeling throughout the developing heart and vasculature;
A geometric increase in the biomechanical performance of the heart and vasculature;
Multiple adaptive mechanisms for altered developmental events;
A supportive “environment.”
For humans, this occurs within the uterine environment and thus also includes both maternal hemodynamic and metabolic influences, as well as the environmental influences of both biologic and inert teratogens. Numerous recent reviews of normal and altered cardiovascular development are available for further reading.
Incidence of Congenital Heart Disease
Congenital heart disease is commonly described to occur in 1% of liveborn infants based on several cross-sectional epidemiologic surveys. However, several important concepts require discussion to understand the accuracy (and limitations) of epidemiologic data on the incidence of congenital heart disease.
First, the definition used for heart disease greatly impacts the estimated incidence. For example, cross-sectional population studies suggest that approximately 1% of liveborn infants have heart disease, yet this estimate does not include affected fetuses who die in utero. Almost 30% of human pregnancies end during the first trimester and a major cause is failure of the developing heart and vasculature. The 1% incidence of congenital heart disease also does not include relatively “silent” abnormalities, such as a bicuspid aortic valve, small atrial septal defects, or subtly abnormal mitral valves, which may present as heart disease in adults or may be noted as incidental findings on postmortem examination. Finally, few studies on the incidence of congenital heart disease include the truly silent variations in cardiac anatomy, such as mitral valve-to-aortic valve discontinuity or aortic arch malformations, which may reflect genetic risk for congenital heart disease.
Second, the methods used to detect heart disease influence the estimation of incidence. Early population studies depended on family history and physical examination, but not all family members underwent echocardiography. Echocardiography has become one “gold-standard” in identifying congenital heart disease and with the increasing resolution and accuracy of current systems, the detection rate of silent or clinically “non-significant” findings continues to increase. These subtle abnormalities may still represent genetic risk for congenital heart disease with phenotypic expression determined by other modifying genes.
Third, the population studied greatly influences the rate of heart disease detected. While an estimated incidence of 1% is reasonable for newborns with obvious congenital heart disease, it is often the recurrence risk that parents want to know after they have had a first child with congenital heart disease. Accurately answering this important question is much more difficult as the recurrence risk for an individual couple is directly related to the underlying genetic or non-genetic (environmental) mechanism for the specific malformation. The basic answer for a family with a first child with non-syndromic and isolated congenital heart disease is that the recurrence risk for a second affected sibling may be as low as 2–5%, but may be higher based on the mechanism for a specific defect. It is important to note that there are differences in recurrence risk based on the sex of the affected child as well as the sex of the subsequent child.
The remainder of this chapter presents the general categories of congenital cardiovascular malformations grouped by underlying genetic or environmental mechanisms, including the relative incidence and recurrence risks for each group.
Genetic Associations and Congenital Heart Disease (Table 1.1)
Chromosomal Disorders
Most parents are aware that chromosomal disorders cause developmental defects. Autosomal disorders are due to a decreased or increased number of genes or to altered genes on chromosomes other than X or Y.
Table 1.1 Common congenital heart defects and genetic associations
Anatomic defect/syndrome
Genetic associations
Atrial septal defect (ASD)
GATA4
(8p23–22),
NKX2.5
(5q34)
Holt Oram syndrome
TBX5
(12q24.1)
ASD and cardiomyopathy
CSX
5Q34
Ellis–van Creveld syndrome
EVC
(4p16.1)
Ventricular septal defect
22q11 deletion syndrome
22q11
Atrioventricular septal defect
CRELD1
(3p25)
Down syndrome
Trisomy 21
Pulmonary valve stenosis
Noonan syndrome
PTPN11
(12q22)
Patent ductus arteriosus
Char syndrome
TFAP2B
(6p12-p21)
Tetralogy of Fallot
TBX1
(22q11),
GATA4
DiGeorge syndrome
22q11 deletion
Alagille syndrome
jagged 1
(20p12)
Aortic valve stenosis
Turner syndrome
45 (X,0)
Williams syndrome
7q11 deletion including
elastin
gene
Transposition of the great arteries
ZIC3, CFC1
Heterotaxy syndromes
ACVR2B, CRYPTIC, LEFTYA, PITX2, ZIC3
Connective tissue sisorders
Marfan syndrome
FBN1
(fibrillin, 15q21)
Ehlers–Danlos syndrome
col3A1
(2q31)
Cardiomyopathy
Barth syndrome
Tazaffin
(Xq28)
Duchenne muscular dystrophy
Dystrophin
(Xp21)
Fabry disease
α-gallactosidase
(Xq22)
Hunter syndrome
Iduronate sulphatase
(Xq27-28)
Hurler syndrome
IDUA
(4p16)
Pompe disease
α-glucosidase
(17q23)
Long QT syndrome
KCNE2
Jervell–Lange–Nielson syndrome
KCNQ1
(11p15),
KCNE1
(21q11)
Romano–Ward syndrome
KCNH2
“
HERG”
(7q3)
SCN5A
(3p2)
Down syndrome (trisomy 21; discovered in 1959) is the most commonly recognized disorder associated with congenital heart disease. Of children born with a heart defect, 1 in 20 has trisomy 21. Specific to cardiac malformations, at least 40% of patients with trisomy 21 have abnormal atrioventricular septal morphogenesis and 30% have multiple cardiac anomalies. In autopsy series, at least 50% of the hearts of patients with trisomy 21 are abnormal and if silent malformations are included the incidence is even higher. The association between trisomy 21 and atrioventricular septal defect has been shown to be due to abnormal remodeling of the endocardial cushions triggered by the overexpression of the cell adhesion molecule DSCAM.
Trisomy 18 (Edward syndrome) occurs in 1 in 3500 newborns and is often associated with dysplastic and thickened cardiac valves and a triangular-shaped large ventricular septal defect.
Trisomy 13 (Patau syndrome) occurs in 1 in 7000 newborns and has a high incidence of heart disease, including laterality defects and both atrial and ventricular septal defects.
There are numerous partial duplication or deletion disorders associated with multiple congenital anomalies, including congenital heart disease. The involvement of a clinical genetics team in identifying the pattern and underlying cytogenetic disorder in a patient with multiple congenital anomalies is required to provide the family with accurate information both on the mechanism and the recurrence risk.
Turner syndrome is a genetic disorder of aneuploidy of the X chromosome, resulting in 45 rather than 46 chromosomes. Often associated with congenital heart disease, Turner syndrome has an extremely high rate of intrauterine loss such that the liveborn incidence of 32 in 10 000 births may reflect only 8% of conceptions with 45 (X,O). Patients with Turner syndrome have a disorder of lymphatic drainage which may explain some of the phenotypic features of neck webbing, wide-spaced nipples, and puffy feet noted at delivery. The prevalence of heart disease in patients with Turner syndrome is approximately 10%, with the highest association to left heart structures, including the mitral and aortic valves, and aortic arch.
Microdeletions
The recognition that a microdeletion on the long arm of chromosome 22 (22q11) was the genetic cause of DiGeorge syndrome in the early 1980s has resulted in a dramatic increase in the interest of clinicians in identifying genetic causes of congenital heart disease. First, it is important to note that while the deletion of a contiguous region of a single chromosome during DNA replication can be associated with congenital heart disease, the absence of a “deletion” based on the use of fluorescent in situ hybridization (FISH) techniques in no way defines the region of interest to be normal.
The association between a deletion in the 22q11 region and DiGeorge syndrome became apparent with the identification of a family with a translocation between chromosomes 20 and 22 and features of DiGeorge syndrome. Additional cases led to the identification of the 22q11 deletion and to the search for the DiGeorge “critical region” required for the clinical features, and specifically required to produce congenital heart disease. Deletions in the 22q11 region are now known to cause defects in craniofacial development (producing both information processing disorders, unique facial features, and cleft lip and palate), pharyngeal arch development (producing hypoparathyroidism and thymic aplasia with immune deficiency), aortic arch malformations (aortic arch interruption type B and anomalous origin of the subclavian artery), and cardiac defects (truncus arteriosus, tetralogy of Fallot, ventricular septal defect, and others). It is important to note that there can be significant phenotypic variation within an individual family harboring a specific 22q11 deletion due to both genetic and epigenetic modifiers. For example, a parent may have only mildly dysmorphic facial features while three of four children may have structural heart disease; and the heart disease between siblings can vary in location and severity.
Developmental studies in mouse models continue to identify underlying mechanisms for cardiac malformations, including the abnormal migration and patterning by “neural crest cells” that are required for normal aortic arch and aortopulmonary septal formation. The role of neural crest cells in this developmental process was initially identified by Kirby and colleagues in a series of neural crest ablation experiments using chick embryos, and has been subsequently confirmed by mouse models targeting the genes and proteins that affect neural crest migration and fate. Elegant temporal and spatial mapping studies in animal models have identified genes within the 22q11 region as well as genes outside this region.
The incidence of a deletion in the 22q11 region is still under investigation in population studies, but it is estimated to be as common as 13 in 10 000 newborn infants. Since this deletion acts as an autosomal dominant disorder, the recurrence risk for subsequent first-degree relatives may be as high as 40% (10 times higher than the recurrence risk for the first-degree relatives of a patient with isolated and non-syndromic congenital heart disease).
Williams syndrome (microdeletion on chromosome 7q11 including the elastin gene) includes a developmental disorder of vasculogenesis that is associated with supravalvar aortic and pulmonary artery stenosis as well as stenosis at the origins of vessels, including the coronary ostia and aortic coarctation.
Alagille syndrome (microdeletion on chromosome 20p12) has been identified to be caused by a loss of function of the gene jagged 1 which produces a ligand for the transcription factor Notch 1 required for early laterality pattern formation. This results in cardiac anomalies including segmental pulmonary arterial hypoplasia.
Singe Gene Disorders
At least 80% of newborn infants with congenital heart disease have “normal” karyotypes as defined by standard genetic analysis including FISH probes. However, due to the many genes and proteins involved in cardiovascular morphogenesis, errors in a single gene down to the level of a single base pair error can still result in clinically significant and even lethal congenital anomalies. For some genes, loss of a single copy of the gene (heterozygous condition) is sufficient to alter cardiovascular morphogenesis and generate structural malformations.
Examples of single gene, heterozygous conditions include:
Holt–Oram syndrome
(atrial septal defect, conduction disorders, and cardiomyopathy) is caused by a heterozygous error in the
TBX5
gene;
Marfan syndrome
(connective tissue disorder with mitral valve prolapse and aortic aneurysm and rupture) is caused by a heterozygous error in the
fibrillin
gene;
Noonan syndrome
(pulmonary valve stenosis, hypertrophic cardiomyopathy) can be caused by heterozygous errors in a protein phosphatase PTPN11, as well as errors in the
SOS1
,
RAF1
,
KRAS
,
NRAS
, and
BRAF
genes.
Many of these genetic diseases are lethal in the homozygous mutant state in mice, and likely also in humans. The severity of disease in individuals with the same single gene heterozygous error is influenced by both genetic and epigenetic modifying factors during development, and these can either increase or decrease in severity in subsequent generations. For the parents of a child with a heterozygous, single gene disorder the recurrence risk for subsequent children can be as high as 50%, though often this is not the case owing to variations in the phenotypic severity due to modifier genes that can impact fetal survival. For example, left heart defects that may be due to an autosomal dominant gene in a single family may represent a clinical spectrum from very mild (silent) variations in aortic valve structure to very severe (in utero lethal) left heart hyperplasia. These syndromes can also occur as new mutations and this is more likely when both parents are phenotypically normal or if the syndrome is associated with significantly reduced fertility (such as in Turner syndrome).
Abnormalities of Metabolic and structural Pathways
For genes that are required for metabolic pathways, often two copies of the abnormal gene are required for a clinically detectable syndrome. For example, Pompe disease (glycogen storage disease type IIa or acid maltase deficiency) occurs in 1 in 40 000 newborns as an autosomal recessive disorder and is associated with progressive and lethal hypertrophic cardiomyopathy.
Duchenne muscular dystrophy (skeletal and cardiac myopathy) is a good example of of a disorder caused by genes restricted to the sex (X,Y) chromosomes; clinical presentation is usually restricted to affected males with females acting as carriers. The affected dystrophin gene is on the X chromosome. Rarely, affected carrier females inactivate the “normal” X chromosome and display the disease.
Heart Disease in Twins
Twins represent unique biologic siblings that can have concordant or discordant cardiac findings. The risk of congenital heart disease in all twins remains close to the population average of 1% with a slightly increased risk of almost 2% in monozygotic twins. The absence of heart disease in many siblings of monozygotic twins was an early rationale for a polygenic or environmental mechanism for congenital heart disease. In fact, monozygotic twins are not “identical” as the process of cleaving the early developing embryo results in two embryos with unequal laterality cues. These patterning cues for the developing embryo cause differences in gene expression (or suppression) that can dramatically alter final phenotype.
Maternal Disorders Associated with Congenital Heart Disease
For centuries, both mothers and physicians have suspected a maternal mechanism for congenital heart disease. Common maternal causes for congenital heart disease have included:
Maternal (and subsequently congenital) rubella infection
: 35% risk of patent ductus arteriosus, pulmonary arterial hypoplasia, septal defects;
Diabetes
: 3–5% risk of transposition of the great arteries, ventricular septal defect;
Alcohol abuse
: 25–30% risk of septal defects;
Phenylketonuria
: 25–50% risk of tetralogy of Fallot;
Systemic lupus erythematosus
: up to 40% risk of congenital heart block;
Lithium
: up to 20% risk of tricuspid valve anomalies;
Retinoic acid exposure
: associated with at least 50% risk of conotruncal defects.
The mechanisms by which these maternal diseases or exposures alter cardiovascular morphogenesis are varied, but reflect injury to vulnerable cells and tissues during unique developmental windows. The severity and lethality of these events can also be modified by both genetic and epigenetic factors.
Polygenic Inheritance
A basic set of rules for determining polygenic inheritance is:
Recurrence risk depends on the gene incidence in the population with the risk to first-degree relatives being the square root of the incidence;
Risk is greater in first-degree relatives than in distant relatives;
Risk is increased when there are multiple affected family members;
Risk may be higher when the disorder is more severe;
When the incidence varies by sex, the risk is greater in relatives of the more rarely affected sex.
Thus, one of the critical aspects of providing families with an accurate assessment of the possible causes and possible recurrence risk for congenital heart disease requires a detailed family history for congenital cardiac and non-cardiac malformations (with the greatest level of accuracy available).
Summary
Despite the complexity of cardiovascular morphogenesis, only 1% of children are born with obvious congenital heart disease. It is likely that many more affected fetuses with congenital heart disease die in utero, and there are many more individuals with subtle errors in cardiac structure and function who may present with heart disease later in life or who may carry a genetic risk for congenital heart disease with minimal phenotypic expression. The underlying genetic, molecular, and epigenetic mechanisms for congenital heart disease are becoming increasingly apparent, and together with the expanded availability of targeted and genome-wide genetic testing, this is aiding families in understanding both the underlying mechanism and the recurrence risk for these disorders. Most importantly, we need to be honest with families in stating that at the present time we simply do not know the underlying cause of congenital heart disease for most patients, but that for most families the risk of recurrence in subsequent children appears to be relatively low (<5%).
Further Reading
Boldt T, Andersson S, Eronen M. Etiology and outcome of fetuses with structural heart disease. Acta Obstet Gynecol Scand 2004;83:531–535.
Bruneau BG. The developing heart and congenital heart defects: a make or break situation. Clin Genet 2003;63:252–261.
Burggren W, Keller BB. Development of Cardiovascular Systems: Molecules to Organisms. New York: Cambridge University Press, 1997.
Burn J. The aetiology of congenital heart disease In: Anderson RH, Baker EJ, Macartney FJ, Rigby ML, Shinebourne EA, Tynan M, eds. Paediatric Cardiology, 2nd edn., London: Churchill Livingstone, pp. 141–213.
Epstein JA, Parmacek MS. Recent advances in cardiac development with therapeutic implications for adult cardiovascular disease. Circulation. 2005;112:592–597.
Ferencz C, Rubin JD, Loffredo CA, Magee CA. Epidemiology of Congenital Heart Disease: The Baltimore-Washington Infant Study 1981–1989. In: Anderson RH, ed. Perspectives in Pediatric Cardiology, Volume 4. Mount Kisco: Futura Publishing Co, 1993.
Harvey RP, Rosenthal N. Heart Development. San Diego: Academic Press, 1999.
Lin AE, Pierpont ME. Special issue: Heart developments and the genetics aspects of cardiovascular malformation. Am J Med Genet 2001;97.
Pierpont MEM, Moller JH. The Genetics of Cardiovascular Disease. Boston: Martinus Nijhoff Publishing, 1987.
Srivastava D. Genetic assembly of the heart: implications for congenital heart disease. Annu Rev Physiol 2001;63:451–469.
2
Basic Cardiac Physiology
Michael Cheung
Murdoch Childrens Research Institute and The Royal Children’s Hospital, Melbourne, VIC, Australia
The ability of the heart to alter contractile patterns and generate adequate cardiac output in response to demand is remarkable in terms of chronicity, rate of response, and also magnitude of change. Some of the governing factors in this process will be discussed in this chapter, and a brief account of the fetal circulation and postnatal changes will be presented.
Initiation of Contraction
Much of our knowledge regarding cardiac muscle contraction is derived from the study of skeletal muscle. Although there are some important differences between cardiac and skeletal muscle, the general scheme of excitation–contraction coupling is similar.
Cardiac muscle consists of thick (myosin) and thin (actin) filaments, contractile components linked to these, and a major protein titin, which is important in the passive spring-like properties of the myocardium. Associated with these filaments are the contractile components, which consist of troponin subunits (I, C, and T) and tropomyosin. The troponin subunits function to bind calcium (TnC) and tropomyosin (TnT), and also inhibit this interaction (TnI). Essentially then, the cardiac action potential influences ion channels, resulting in a transient calcium ion influx. This entry of calcium into the cell causes release of a larger amount of calcium from the sarcoplasmic reticulum, so-called calcium-induced calcium release. In the absence of calcium the interaction between myosin and actin is blocked by the binding of TnI to actin. With the binding of calcium by TnC however, a change in configuration of tropomyosin permits interaction between myosin and actin and subsequent force generation. This process requires energy and appears to be driven by the activity of myosin ATPase. Once attached to actin, the power stroke of myosin head rotation causes myofilament shortening. The reuptake and release of calcium from TnC permits relaxation to occur.
There are multiple levels where this process can be affected. For example, alterations in the myosin heavy chain isoforms and ATPase activity have been shown in disease states such as hypothyroidism and diabetes. Furthermore, genetic mutations resulting in abnormal troponin development account for particular types of cardiomyopathy.
Properties of Myocardium
Force–Velocity Relationship
Contractile performance of muscle, defined as its ability to do work, can be expressed in different ways. One of the fundamental properties of the myocardium is its force–velocity relationship. This relationship describes the ability of myofilaments to shorten more rapidly and to a greater degree when faced with a light load as compared to a heavy load. Conversely, in the face of a heavy load, a muscle shortens more slowly and also to a lesser degree. Using in vitro methods of measurement, such as the isovelocity release technique, plots of the load dependence of these shortening velocities yield hyperbolic force–velocity curves (Figure 2.1). It can be seen that maximal velocity of shortening (Vmax) occurs at zero load. Vmax is considered to reflect the intrinsic velocity of myosin cross-bridge turnover, which can be measured in vitro as myosin ATPase activity. The x-intercept of this curve, where generated force is maximal, is designated P0. It is important to note therefore, that for the same contractile state, the changes in performance in the face of changing load are a reflection of the way in which work is performed in the face of a changing hemodynamic environment.
Figure 2.1 Force–velocity relationship.
Length–Tension Relationship
This is another fundamental property of muscle which relates the maximum developed force to sarcomere length. It is thought that the generated force is dependent upon the degree of overlap of thick and thin myofilaments. As muscle length is gradually increased, developed force on contraction increases up to an optimal length. In skeletal muscle, it is possible to continue beyond this length to such a degree that the developed force decreases, to a point where there is no overlap of myofilaments and therefore force cannot be generated. Cardiac muscle differs significantly however, in that under physiologic conditions it does not appear possible to elicit this descending limb of the relationship. The heart therefore functions on the ascending limb of the length–tension curve. This relationship is thought to partly account for the Frank–Starling relationship (see below).
Force–Frequency Relationship
First described by Bowditch in 1871, the intrinsic property of the myocardium to alter contractile force with change in rate of stimulation is known as the force–frequency relationship (FFR) or “treppe” effect. The majority of data support rate-related fluctuations in calcium cycling as the underlying mechanism for this phenomenon.
In vitro studies have shown that the response of normal myocardium to an increasing stimulation rate is to increase the force of contractility (Figure 2.2), up to an optimal rate where generated force is maximal, after which there is a decline in force. The effect of increasing stimulation rate is thought to be an increase in activity of sarcoplasmic reticulum calcium ATPase. The rate-dependent intracellular flux of calcium can be demonstrated through the use of calcium dyes such as aequorin.
Figure 2.2 Plot of peak force versus rate of stimulation for normal non-failing myocardium (NF), and myocardium from patients with dilated cardiomyopathy (DCM) and chronic mitral regurgitation (MR).
(Reproduced from Alpert NR, Leavitt BJ, Ittleman FP, et al. A mechanistic analysis of the force-frequency relation in non-failing and progressively failing human myocardium. Basic Res Cardiol 1998;93:23–32, with kind permission of Springer Science + Business Media.)
Using the same approach, dramatically differing responses may be observed in samples of diseased myocardium. In patients with dilated cardiomyopathy, for example, the FFR may become negative. Consequently, at relatively low heart rates the generated force decreases with increasing rate of stimulation.
The Heart As a Pump
The main function of the heart is to act as a pump and supply the body with blood, and in order to understand this, it is worthwhile considering the different phases of the cardiac cycle as described in the Wiggers diagram (Figure 2.3). Wiggers divided the cardiac cycle for the left ventricle into separate phases. Systole begins with isovolumic contraction (A–C), followed by maximum ejection (C–D), and ending with a period of reduced ejection (D–F). In the first period of diastole, known as protodiastole (F–G), the first effect of relaxation is a drop in ventricular pressure leading to closure of the aortic valve. Ventricular pressure continues to fall as myocardial relaxation proceeds throughout this period of isovolumic relaxation (G–H). Once the ventricular pressure is lower than that of the atrium, the mitral valve opens and the period of early rapid filling begins (H–I). Ventricular pressure continues to fall during this phase, albeit at a slower rate. In the normal heart the majority of ventricular filling (approximately 70%) occurs during this period. A period of diastasis (I–J) may be observed when transmitral flow ceases, or occurs at a slow rate as pressure in the atrium and ventricle approximate prior to atrial contraction (J–K). It is important to consider blood flow in the heart as being driven by pressure gradients and that these changes in relative pressure in the connecting chambers and vessels explain the flow profiles demonstrated, for example, by echocardiography.
Figure 2.3 Wiggers diagram (see text for details).
Ventricular Function Curves
Understanding the properties of isolated myocardium presented above is useful; however, control of pump function in vivo is a more complicated issue since there are additional reflexes involved. The major factors that influence ventricular pump function in vivo are preload, afterload, contractility, and heart rate. The relationship of some of these factors can be described by examining the ventricular function curve (Figure 2.4). For the individual heart a whole family of curves is generated in response to the changing environment and demands of the patient. As can be seen in the control curve, the varying preload alters stoke volume or the amount of blood ejected per beat (Frank–Starling relationship). The most appropriate manner to assess preload (usually expressed as either end-diastolic pressure or end-diastolic volume) is debatable; however, essentially this is a reflection of the length–tension relationship mechanism (see above), which accounts partly for the Frank–Starling relationship. Note that the ventricular function curves do not have a downward or descending limb; indeed several studies have demonstrated no reduction in stroke volume despite elevation of preload to non-physiologic levels. In the control curve, the effect of increasing preload is to increase stoke volume. The effect of varying afterload is demonstrated by the other curves. Afterload reduction increases the amount of blood ejected and conversely an increase in afterload reduces stroke volume. Improved contractility causes a leftward shift to a different ventricular function curve.
Figure 2.4 Ventricular function curve (see text for details).
Optimizing Pump Function
In the heart that is failing due to impaired contractility, it can be seen from the ventricular function curves that improvements in stroke volume could be brought about through either afterload reduction or by giving a positive inotrope to improve contractility, both of which should induce a leftward shift to a different curve. Further increases in preload will produce less improvement in stroke volume since the curve is relatively flatter in these patients with failing myocardium. Indeed, in these patients, although preload reduction in the form of diuretics may provide symptomatic improvement, stroke volume may not increase.
Diastolic Function
It is of course obvious that if the heart does not fill properly, then output will be reduced. Referring to the Wiggers diagram (see Figure 2.3), there seem to be discrete phases of diastole which could potentially be assessed. The whole period of diastole is complex, however, with overlap of multiple processes affecting this part of the cardiac cycle. Following systolic contraction the ventricle has been deformed by shortening of myocardial fibers. The ventricle has passive elastic properties and as a consequence of this deformation there is stored potential energy which is released upon onset of relaxation. The process of relaxation is active and energy consuming. The fall in pressure during isovolumic relaxation therefore is influenced by a combination of active relaxation and also the release of the stored potential energy due to deformation of elastic material. Pressure cross-over with atrial pressure exceeding that of the ventricle opens the mitral valve and the generated pressure gradient across the valve induces flow into the ventricle during the so-called early rapid phase of ventricular filling. With equalization of ventricular and atrial pressures, a period of diastasis ensues during which time there may be no or only a small amount of low velocity flow. With atrial contraction an increase in the pressure gradient between the atrium and ventricle is developed, which drives blood into the ventricle. It can be seen therefore that during diastole there are two main phases of blood flow into the ventricle. These periods of blood flow during diastole can be routinely examined non-invasively using techniques such as echocardiography. Changes in diastolic filling may be due to abnormalities of relaxation, ventricular compliance, and timing, e.g. duration of diastole relative to the total duration of the cardiac cycle, atrioventricular delay, and rhythm. The common final mechanism, however, is the effect of these processes on the relative pressures within the atrium and ventricle and thus the impetus to blood flow.
Fetal Circulation
The circulation in the fetus is different from that in postnatal life in that the systemic circulation is fed by the left and right ventricles in parallel. Shunting of blood occurs at three important levels (ductus venosus, foramen ovale, and ductus arteriosus) in this circulation. The placenta serves to oxygenate blood in addition to many other functions. Of the blood returning from the placenta via the umbilical vein, some goes to the hepatic veins, and the rest goes through the ductus venosus to enter the right atrium. Some of this highly oxygenated blood is diverted through the foramen ovale to the left atrium where it mixes with the small amount of pulmonary venous return. Blood supply to the coronaries and cerebral circulation is largely via the left ventricle and with relatively highly oxygenated blood (approx 65% saturated). Since the fluid-filled lungs are not inflated in utero, vascular resistance in this compartment is relatively high. The blood entering the pulmonary artery via the right ventricle therefore goes predominantly to the descending aorta via the ductus arteriosus, with a small proportion (approx 10%) of blood from the right ventricle being directed to the lungs. The left ventricle largely supplies the upper body, cerebral circulation, and coronaries, whilst the lower body is supplied by the right ventricle. The two vascular beds are connected by the aortic isthmus, the portion of the aorta between the left subclavian artery and the insertion of the ductus arteriosus.
The parallel nature of the fetal circulation means that changes in output can occur in one ventricle to compensate for derangements in the contralateral ventricle. These changes lead to the disproportionate growth of ventricles seen in many forms of congenital heart disease.
Fetal Ventricular Function
The contractile performance of the fetal myocardium has been shown to be reduced in comparison with adult myocardium in vitro. At similar muscle lengths, less active tension is developed by the fetal myocardium. This is perhaps not surprising considering the immaturity of structure and function of the fetal myocardium. The responses of the fetal ventricle to changes in loading conditions are also different. It appears that, although the stroke volume of the fetal ventricle increases in response to an increase in preload, the magnitude of response is limited and furthermore the right ventricle responds less than the left ventricle. The Frank–Starling mechanism is intact but within the fetus the ventricle is operating at the top, relatively flat part of the function curve. The fetal ventricular response to an increase in afterload created by balloon occlusion of the descending aorta in animal studies is a dramatic fall in right ventricular output. It appears therefore that changes in fetal heart rate are the major determinant of cardiac output.
Postnatal Circulatory Changes
With the first postnatal breath and inflation of the lungs, pulmonary vascular resistance falls and the amount of blood flow to the lungs increases. With increasing pulmonary venous return, left atrial pressure rises above that of the right atrium, leading to closure of the foramen ovale. Pulmonary vascular resistance continues to fall but may take several weeks to reach the lowest levels. Increasing levels of blood oxygenation stimulate the ductus arteriosus to close and this usually occurs in the first few days of life. Closure of the shunts present in fetal life creates a circulation in series, in contrast to the previous situation of a circulation with the ventricles supporting a parallel circulation.
In addition to the changes in the circulation, changes occur in myocardial function in postnatal life, albeit more slowly. Continued maturation of the myocardium occurs with alterations in systolic function with increased active tension development and altered responses to changes in loading conditions. Ventricular filling patterns change with a gradual improvement in early relaxation during childhood prior to a gradual decline in diastolic function during adulthood, both in terms of active relaxation and also passive properties of the myocardium. These normal age-related changes in ventricular function must be considered during assessment of ventricular performance.
Summary
Consideration of the factors involved in the control of ventricular function is important in the assessment and interpretation of clinical findings. Furthermore, understanding these factors is useful in instituting appropriate therapy.
Further Reading
Alpert NR, Leavitt BJ, Ittleman FP, Hasenfuss G, Pieske B, Mulieri LA. A mechanistic analysis of the force–frequency relation in non-failing and progressively failing human myocardium. Basic Res Cardiol 1998;93:23–32.
Gwathmey JK, Slawsky MT, Hajjar RJ, Briggs GM, Morgan JP. Role of intracellular calcium handling in force–interval relationships of human ventricular myocardium. J Clin Invest 1990;85:1599–1613.
Pieske B, Kretschmann B, Meyer M, et al. Alterations in intracellular calcium handling associated with the inverse force–frequency relation in human dilated cardiomyopathy. Circulation 1995;92:1169–1178.
3
Cardiac Morphology and Nomenclature
S. Yen Ho
Royal Brompton Hospital, London, UK
To cope with the complexities of structural malformations of the heart and the myriad of variations that are observed, clinicians practicing in the field of congenital heart disease have developed ways of analyzing the heart in a systematic fashion. While the approaches used are similar, the terminologies employed differ widely. Some terminologies are in Latin, some relate to putative embryonic derivatives of cardiac structures or mechanisms of development, some are descriptive, and so on. Given the penchant of busy clinicians to use short-hand and acronyms, the nomenclature of congenital heart defects acquired an unwarranted reputation of being too complex and difficult for the novice in the field. This chapter summarizes an approach based entirely on morphology that is logical and simple.
The analysis of any congenitally malformed heart is simplified by first examining each segment of the heart:
Atria;
Ventricles;
Great arteries (
Figure 3.1
).
Figure 3.1 Summary of the morphologic features of cardiac chambers.
By taking note of how each chamber relates and connects to another in a sequential fashion, even seemingly complex malformations can be described readily. This approach, sequential segmental analysis, provides the basic framework, but is not complete until account is taken of all associated malformations. Thus, most hearts have usual connections and relations of the chambers, but the associated lesions, such as a large ventricular septal defect or severe stenosis of the pulmonary valve, will dictate the clinical course. It is imperative, nevertheless, to analyze the heart sequentially before embarking on listing the associated defects.
Morphologic Approach to Segmental Analysis
Based entirely upon recognition of the morphology of the cardiac chambers, this approach is not dependent on prior knowledge of embryology. Therefore, it has the advantage of not having to speculate on how the defect could have occurred during cardiac development. Instead, it is firmly based on descriptive anatomy. For segmental analysis, the morphologic distinction between right and left atria is as important as the distinction between right and left ventricles. The key is morphology rather than location. As is obvious in the human heart, right and left heart chambers are not strictly in the right and left positions. When the normal heart is viewed from the front, there is overlap of the right chambers over significant portions of the left chambers. Furthermore, the chambers in the malformed heart may also be abnormally located in relation to one another.
An in-depth description of the morphology of the cardiac chambers and great arteries is beyond the scope of this handbook and is well-described elsewhere. The salient morphologic features are summarized below. There are, undoubtedly, subtle differences from one patient to another, but one or more of the diagnostic features should be recognizable.
Briefly, the morphologic right atrium has a characteristic broad and triangular-shaped appendage that contains extensive pectinate muscles arising from the terminal crest, whereas the morphologic left atrium is smooth walled since the pectinate muscles are mainly confined to within its narrow, finger-like appendage that lacks a terminal crest. On the septal aspect of the morphologic right atrium, the valve of the oval fossa (septum primum) appears like a depression surrounded by a muscular rim (septum secundum). The fossa valve is the true interatrial septum and deficiencies in the valve are described as oval fossa defects (so-called secundum atrial septal defects). The septal aspect of the morphologic left atrium is the fossa valve itself but without a muscular rim.
Ventricles are described as having three components: inlet, apical trabecular, and outlet. The trabecular patterns, coarse in morphologic right and fine in morphologic left, are distinctive of the ventricles. The right ventricle has a muscle bundle known as the septomarginal trabeculation that is adherent to the septum. From it arises the moderator band that crosses the ventricular cavity to insert into the parietal wall of the right ventricle. In addition, the atrioventricular valves have characteristic features that can help diagnosis. The septal leaflet of the tricuspid valve has direct chordal attachments to the ventricular septum, whereas the mitral valve lacks a septal leaflet. The mitral valve adjoins the aortic valve through an area of valvar fibrous continuity, whereas the tricuspid and pulmonary valves are separated by muscle. The paired arrangement of the papillary muscles is a good guide for the mitral valve. The hinge lines (annulus) of the tricuspid and mitral valves are located at different levels. At the septum, there is valvar offset due to the tricuspid valve being hinged at a lower level, closer to the cardiac apex, than the mitral valve. The offset results in a part of the cardiac septum being located in between the right atrium and the left ventricle. Previously described as the “atrioventricular septum,” closer anatomic studies have revealed that much of this “septum” is not truly septal but is composed of atrial wall and ventricular wall separated by a fibro-fatty tissue plane that has invaginated from the epicardium. Atrioventricular septal defects, including the so-called primum atrial septal defect, occur in this part of the cardiac septum. There is then a common atrioventricular junction with abnormal formation of the atrioventricular valves (see Chapter 9).
Morphologic distinction of the great arteries is based on origin (or lack) of coronary arteries and the branching patterns upstream from the semilunar valve. Typically, the pulmonary trunk bifurcates into the left and right pulmonary arteries. In contrast, the aorta usually has three branches arising from its arch.
Having determined the morphology of each chamber, segmental analysis considers the connections across the atrioventricular junctions and those across the ventricular–arterial junctions (Figure 3.2). Connection refers to the anatomic linkage between atrial and ventricular chambers and between ventricular chambers and great arteries. “Connection” of adjoining chambers is usually, but not always, synonymous with “drainage.” In certain rare physiologies, drainage is abnormal even though the connection is normal.
Figure 3.2 The three segments of the heart are analyzed sequentially.
For the convenience of readers new to the morphologic approach, Table 3.1 lists some examples of the common short-hand terms and eponyms to show how the defects are described using sequential segmental analysis.
Table 3.1 Examples of how commonly occurring lesions can be described using the sequential segmental method of nomenclature
Commonly used term
Sequential segmental analysis
Atrial septal defect (ASD)
Usual atrial arrangement, concordant AV and VA connections
+ atrial septal defect (oval fossa defect)
Ventricular septal defect (VSD)
Usual atrial arrangement, concordant AV and VA connections
+ perimembranous inlet ventricular septal defect
Atrioventricular septal defect (AV canal)
Usual atrial arrangement, concordant AV and VA connections
+ atrioventricular septal defect with common valvar orifice
Coarctation
Usual atrial arrangement, concordant AV and VA connections
+ coarctation
Fallot’s tetralogy (with anomalous LAD and right aortic arch)
Usual atrial arrangement, concordant AV and VA connections
+ perimembranous outlet ventricular septal defect with subpulmonary stenosis (tetralogy of Fallot), overriding aorta, right ventricular hypertrophy, pulmonary valvar stenosis, anomalous origin of LAD from right coronary artery, right aortic arch
Transposition of the great arteries (d-TGA) with VSD, aortic stenosis and coarctation
Usual atrial arrangement, concordant AV and discordant VA connections
+ perimembranous ventricular septal defect, aortic stenosis, coarctation
Congenitally corrected transposition (l-TGA) with VSD, PS, and Ebstein malformation
Usual atrial arrangement, discordant AV and discordant VA connections
+ perimembranous ventricular septal defect, subpulmonary stenosis, Ebstein malformation
Tricuspid atresia with transposition and coarctation
Usual atrial arrangement, absent right AV connection and discordant VA connection
+ morphologic left atrium to morphologic left ventricle, ventricular septal defect, coarctation
Situs inversus, dextrocardia, double outlet right ventricle (DORV) with valvar PA
Mirror-image atrial arrangement, concordant AV connection and double outlet VA connection from the right ventricle
+ muscular inlet VSD, valvar pulmonary atresia, heart in right chest, apex to right
