Pediatric Cardiac Surgery [5 ed.] 1119282314, 9781119282310

Table of contents :
Cover
Title Page
Copyright
Table of Contents
Contributors
Preface to the Fifth Edition
A Note on Nomenclature
Chapter 1 Development of the Heart and Great Vessels
Origin of Cardiac Precursor Cells
Formation of the Heart Tube and Early Segmentation
Looping
Development of the Inflow (Venous) Pole of the Heart
Systemic Venous Inflow
Pulmonary Venous Inflow
Atrial Septation
Atrioventricular Valvar Formation
Ventricular Chamber Formation and Septation
Outflow Tract
Outflow Tract Septation
Development of the Arterial Valves
Aortopulmonary Septation
Development of the Aortic Arch
Coronary Arterial Development
Conduction
Conclusion
References
Chapter 2 Genetics of Congenital Heart Disease
Common Variants
Common Variants as Gene Modifiers
Rare de novo Variants and Whole‐Exome Sequencing
Copy Number Variants
Conclusion
References
Chapter 3 Fetal Cardiac Physiology and Fetal Cardiac Intervention
Physiology of the Fetal Circulation
History of Fetal Circulation Research
Fetal Circulation
Fetal Intra‐ and Extracardiac Shunts
Venous Return
Cardiac Output, Oxygenation, and Distribution
Intracardiac and Vascular Pressures
Circulatory Changes at Birth
The Transition
Closure of the Arterial Duct
Pulmonary Circulation
Myocardial Performance
Fetal Cardiac Intervention
Rationale for Fetal Cardiac Intervention
Limitations for Success of Fetal Cardiac Surgery
Clinical Outcomes of Fetal Cardiac Intervention
Fetal Aortic Valvuloplasty
Fetal Atrial Septoplasty/Stenting
Fetal Pulmonary Valvuloplasty
Future Directions
References
Chapter 4 Preoperative Diagnostic Evaluation
Extracardiac and Genetic Evaluation
Electrocardiogram and Rhythm Evaluation
Noninvasive Imaging of Congenital Heart Disease
Echocardiography
Cardiac Magnetic Resonance Imaging
Cardiac Computed Tomography
Predischarge Imaging or Catheterization
Cardiac Catheterization
Catheter‐Based Interventions
Neonatal Cardiac Surgery
d‐Transposition of the Great Arteries
Coarctation of the Aorta
Tetralogy of Fallot
Pulmonary Atresia with Intact Ventricular Septum
Hypoplastic Left Heart Syndrome and Functionally Univentricular Heart Disease
Total Anomalous Pulmonary Venous Connection
Common Arterial Trunk
Cardiac Surgery in Older Infants and Children
Atrial Septal Defects
Ventricular Septal Defects
Atrioventricular Septal Defect
Ebstein Anomaly
Anomalous Origin of the Coronary Arteries
Cardiac Reoperations in Adolescents and Adults with Congenital Heart Disease
Conduit Replacements or Insertions
References
Chapter 5 Hybrid Procedures for Congenital Heart Disease
Hybrid Approach for Hypoplastic Left Heart Syndrome with the Objective of Generating a Fontan Circulation
Technical Considerations
Results
Hybrid Approach for Hypoplastic Left Heart Complex with the Objective of Biventricular Repair
Hybrid Procedures in Congenital Heart Defects beyond Hypoplastic Left Heart Syndrome and Hypoplastic Left Heart Complex
Hybrid Procedure Lessons Learned: Extended Therapeutic Options for “End‐Stage” Heart Failure
Case 1
Case 2
Case 3
Summary
References
Chapter 6 Anesthesia for the Patient with Congenital Heart Disease
Demographics
Anesthetic Assessment
Anesthetic Management
Fast Tracking and Early Extubation
Regional Anesthesia
Cardiac Imaging and Intervention
Pulmonary Hypertension
Cardiac Pharmacology
Postanesthesia Process
Advanced Anesthesia Fellowships
Conclusion
References
Chapter 7 Perioperative Care
Preoperative Care
Specific Considerations for the Neonate
Operative Care
Electrocardiogram Leads
Temperature Monitoring
Oxygen Saturation Probe
Arterial Catheter
Percutaneous Venous Catheters
Atrial Catheters
Pulmonary Artery Catheter
Near‐Infrared Spectroscopy
Pacemaker Wires
Chest Tubes
Nasogastric Tube
Urinary Catheter
Empiric Corticosteroids
Postoperative Care
Transport to the Intensive Care Unit and Handoff
Airway and Breathing
Cardiovascular System
Fluid and Electrolyte Management
Hyperglycemia
Renal Function
Nutrition
Infection Prophylaxis
Complications
Low Cardiac Output
Cardiac Arrhythmias
Bleeding
Cardiac Tamponade
Post‐Pericardiotomy Syndrome
Pulmonary Hypertensive Crisis
Cardiac Arrest
Pulmonary Dysfunction
Renal Failure
Infectious Complications
Central Nervous System Injury
Conclusion
References
Chapter 8 Palliative Operations
Pulmonary Artery Band
Aortopulmonary Shunts
Classic Blalock–Taussig–Thomas Shunt
Modified Blalock–Taussig–Thomas Shunt
Central Aortopulmonary Shunt
Waterston/Cooley Shunt
Potts Shunt
Miscellaneous Palliative Procedures
Conclusion
Data from the Society of Thoracic Surgeons Congenital Heart Surgery Database about Palliative Operations
References
Chapter 9 Management of Pediatric Cardiopulmonary Bypass
History
Principles of Pediatric Cardiopulmonary Bypass
Special Considerations for Pediatric Patients
Systemic Inflammatory Response to Cardiopulmonary Bypass
Monitoring
Anticoagulation and Reversal
Hemodilution and Hematocrit
Blood Gas Management
Temperature
Regional Perfusion Strategies
Ultrafiltration
Management of Post‐Bypass Coagulopathy
Initiation and Termination of Cardiopulmonary Bypass
Circuit Considerations for Pediatric Patients
Circuit Miniaturization
Surface Modifications
Oxygenators
Augmented Venous Return
Heater–Cooler Units and Infection Concerns
End‐Organ Injury and Protection
Myocardium
Neurologic
Pulmonary
Renal
Endocrine
Conclusion
References
Chapter 10 Pediatric Myocardial Protection
Historical Aspects
Uniqueness of the Infant Myocardium
Structural Differences
Metabolic Differences
Calcium Metabolism
Enzymatic Activity
Catecholamine Sensitivity
Functional and Physiological Differences
Ischemic Preconditioning
Principles of Myocardial Protection
Hypothermia
Cardioplegia
Membrane Stabilizers
Substrates
Osmolar Agents
Ions
Buffers
Special Additives
Venous Drainage and Venting
Precise Surgical Correction
Types of Cardioplegia
Crystalloid Cardioplegia
Blood Cardioplegia
Cardioplegia Protocols
Tepid Blood Cardioplegia
Routes of Cardioplegia Administration
Single‐Dose versus Multiple‐Dose Cardioplegia
Intermittent/Continuous Infusion
Surgical Strategies for Effective Cardioplegia
Induction of Cardioplegia
Maintenance Phase
Reperfusion
Cardioplegia Administration Pressure
Integrated Myocardial Protection
Special Circumstances
Cardioplegia: The Future?
Insulin Cardioplegia
Cardioplegia Enrichment with L‐Arginine
Polarizing Cardioplegia
Conclusion
References
Chapter 11 Patent Arterial Duct
Anatomy and Pathophysiology
Natural History
Clinical Features and Diagnosis
Treatment – Premature Infants
Medical
Transcatheter
Surgical
Treatment – Older Infants and Children
Surgical
Video‐Assisted Thoracoscopy
Transcatheter
Data from the Society of Thoracic Surgeons Congenital Heart Surgery Database (STS CHSD) about Patent Arterial Duct
References
Chapter 12 Vascular Rings and Pulmonary Artery Sling
Embryology and Pathology
Double Aortic Arch
Right Aortic Arch
Pulmonary Artery Sling
Innominate Artery Compression
Aberrant Right Subclavian Artery
Rare Vascular Rings
Clinical Presentation and Diagnosis
Chest Radiograph
Barium Esophagogram
Computed Tomography
Magnetic Resonance Imaging
Bronchoscopy
Tracheograms
Cardiac Catheterization
Echocardiography
Surgical Management
Double Aortic Arch
Right Aortic Arch with Left Ligament
Innominate Artery Compression Syndrome
Pulmonary Artery Sling
Tracheal Stenosis
Video‐Assisted Thoracoscopic Surgery
Adults with Vascular Rings
Postoperative Care
Conclusion
Data from the Society of Thoracic Surgeons Congenital Heart Surgery Database (STS CHSD) about Rings and Slings
References
Chapter 13 Coarctation of the Aorta
Embryology and Anatomy
Embryology
Anatomy
Natural History and Pathophysiology
Diagnosis
Surgical Techniques
General Considerations
Resection and End‐to‐End Anastomosis
Prosthetic Patch Aortoplasty
Prosthetic Interposition Graft
Subclavian Flap Aortoplasty
Resection with Extended End‐to‐End Anastomosis
Balloon Dilation Angioplasty
Complications
Conclusion
Data from the Society of Thoracic Surgeons Congenital Heart Surgery Database (STS CHSD) about Coarctation and Aortic Arch Hypoplasia
References
Chapter 14 Interrupted Aortic Arch
Developmental Biology
Genetics
Chromosome 22q11.2 Deletion
Other Chromosomal Deletions
Anatomy and Pathology
Associated Anomalies
Pathophysiology and Clinical Features
Prenatal Diagnosis
Management
Historical Perspective
Diagnosis of Interrupted Aortic Arch
Management of Interrupted Aortic Arch
Preoperative Management
Surgical Approach
Standard Surgical Technique: IAA/VSD
Circulatory Arrest versus Selective Cerebral Perfusion
Interrupted Aortic Arch with Ventricular Septal Defect and Left Ventricular Outflow Tract Obstruction
Interrupted Aortic Arch in Adults
Interrupted Aortic Arch with Other Anomalies
Postoperative Management
Results of Surgery
Complications of Surgery
Early
Late
Special Considerations
Bicuspid Aortic Valve
Unstable Child: Staged Repair of IAA/VSD
Yasui or Left Ventricular Outflow Tract Bypass Procedure for IAA/VSD
Chromosome 22q11.2 Deletion (DiGeorge Syndrome)
Quality of Life
Conclusions
References
Chapter 15 Atrial Septal Defect, Partial Anomalous Pulmonary Venous Connection, and Scimitar Syndrome
Anatomy and Pathology
Ostium Secundum Atrial Septal Defect
Vestibular Atrial Septal Defect
Sinus Venosus Interatrial Communication
Coronary Sinus Defect
Atrioventricular Septal Defect with Exclusive Atrial Shunting (Ostium Primum Defect)
Common Atrium
Pathophysiology and Natural History
Diagnosis
Transcatheter Closure
Surgical Technique
Postoperative Care
Technical Pitfalls
Results of Operation
Results of Transcatheter Closure
Results in Older Patients
Scimitar Syndrome
Conclusion
References
Chapter 16 Ventricular Septal Defect
Definition and Prevalence
Historical Perspectives
Embryology and Pathologic Anatomy
Pathophysiology
Natural History
Diagnosis
Medical Management
Patient Selection
Patients with Large Ventricular Septal Defects
Patients with Small Defects
Patients with Defects Opening Directly beneath the Pulmonary Valve (Doubly Committed and Juxtaarterial Ventricular Septal Defects)
Surgical Considerations
Right Atrial Approach
Transatrial Closure of Perimembranous or Central Ventricular Septal Defect: Exposure by Tricuspid Valve Retraction
Transatrial Closure of Perimembranous or Central Ventricular Septal Defect: Exposure by Tricuspid Valve Incision
Transpulmonary Arterial Approach
Transaortic Approach
Right Ventricular Approach
Left Ventricular Approach
Relationship of the Conduction Pathways to Different Types of Ventricular Septal Defects
Avoiding Conduction Injury during Closure of Different Types of Ventricular Septal Defects Having a Muscular Posteroinferior Rim
Central or Perimembranous Ventricular Septal Defects
Perimembranous Inlet Ventricular Septal Defects
Muscular Ventricular Septal Defects
Gerbode Ventricular Septal Defects
The Conduction System and the Transaortic Approach
Surgical Management of Ventricular Septal Defects with Associated Lesions – Patent Arterial Duct
Ventricular Septal Defect with Aortic Insufficiency
Ventricular Septal Defects with Coarctation of the Aorta
Ventricular Septal Defect with Elevated Pulmonary Artery Pressure
Residual Ventricular Septal Defects in Anatomically Challenging Locations
Results
Pulmonary Artery Bands
Complications
Transcatheter/Transventricular Device Closure
Conclusion
Data from the Society of Thoracic Surgeons Congenital Heart Surgery Database about Ventral Septal Defect
References
Chapter 17 Atrioventricular Septal Defects
Pathology and Anatomy
Hemodynamics/Natural History
Diagnosis
Indications and Timing of Operation
Operative Management and Results
Partial Atrioventricular Septal Defect
Intermediate Atrioventricular Septal Defect
Complete Atrioventricular Septal Defect
Atrioventricular Septal Defect with Tetralogy of Fallot
Results
Risk Factors
Age at Operation
Preoperative Atrioventricular Valve Incompetence
Double‐Orifice Left Atrioventricular Valve
Zone of Apposition
Coarctation of the Aorta
Trisomy 21
Postoperative Management
Conclusion
Data from the Society of Thoracic Surgeons Congenital Heart Surgery Database about Atrioventricular Septal Defect
References
Chapter 18 Common Arterial Trunk
Embryologic and Anatomic Features
Historical Perspectives
Physiology and Clinical Findings
Natural History
Operative Technique
Surgical Repair of Common Arterial Trunk
Surgical Repair of Anatomic Variants
Interrupted Aortic Arch
Truncal Valve Repair for Truncal Regurgitation
Truncal Valve Repair in the Presence of Coronary Artery Anatomy Concerns
Recent Results of Total Correction
Results for Repair of Common Arterial Trunk and Interrupted Aortic Arch
Results for Repair of Common Arterial Trunk and Truncal Regurgitation
Right Ventricular to Pulmonary Artery Continuity
Conclusion
Data from the Society of Thoracic Surgeons Congenital Heart Surgery Database (STS CHSD) about Common Arterial Trunk (Truncus Arteriosus)
References
Chapter 19 Aortopulmonary Window and Aortic Origin of a Pulmonary Artery
Historical Aspects
Embryology and Anatomy
Clinical Features and Natural History
Diagnosis
Surgical Treatment
Postoperative Course
Outcome after Surgery
References
Chapter 20 Isolated Right Ventricular Outflow Tract Obstruction
Pulmonary Atresia with Intact Ventricular Septum
Definition, Etiology
Morphology
Clinical Presentation and Initial Management
Interventional/Surgical Management
Initial Palliation
Definitive Repair, Outcomes, Late Survival
Pulmonary Stenosis with Intact Ventricular Septum
Definition, Epidemiology
Morphology
Pathophysiology and Natural History
Clinical Presentation and Initial Management
Interventional/Surgical Management
Outcomes, Late Survival
References
Chapter 21 Tetralogy of Fallot
Definition, Morphology, and Nomenclature
History of Surgical Management
Presentation and Diagnosis
Medical Management
Surgical Repair
Palliative Procedures
Complete Repair
Results
Mortality
Morbidity
Early Reoperation and Reinterventions
Arrhythmias and Sudden Death
Long‐Term Complications Following Repair of Tetralogy of Fallot
Pulmonary Valve Restoration
Pulmonary Valve Replacement
Bioprosthetic Pulmonary Valve Insertion for Severe Pulmonary Regurgitation without Pulmonary Stenosis
Bioprosthetic Pulmonary Valve Insertion for Combined Pulmonary Regurgitation and Pulmonary Stenosis
Neurologic Outcomes
Aortic Valve and Root Problems
Special Circumstances
Tetralogy of Fallot with Absent Pulmonary Valve
Tetralogy of Fallot and Atrioventricular Septal Defect
Conclusion
Data from the Society of Thoracic Surgeons Congenital Heart Surgery Database about Tetralogy of Fallot
References
Chapter 22 Tetralogy of Fallot with Pulmonary Atresia and Major Aortopulmonary Collaterals
Clinical Features
Diagnostic Evaluation
In the Neonatal Period
Prior to Final Repair
Suitability for Repair
Surgical Management
Tetralogy of Fallot with Pulmonary Atresia and Ductus‐Dependent Lung Circulation
Tetralogy of Fallot with Pulmonary Atresia with Major Aortopulmonary Collateral Arteries
Indication for Surgery and Surgical Strategy
Surgical Techniques
Primary Rehabilitation Strategy
Primary Unifocalization Strategy
Postoperative Management
Primary Rehabilitation
Primary Unifocalization
Outcomes
Tetralogy of Fallot with Pulmonary Atresia and Major Aortopulmonary Collateral Arteries
Conclusion
Data from the Society of Thoracic Surgeons Congenital Heart Surgery Database (STS CHSD) about Tetralogy of Fallot with MAPCAs
REFERENCES
Chapter 23 Ventricular to Pulmonary Artery Conduits
Polytetrafluoroethylene Ventricular Outflow Tract Reconstruction
Allograft Conduits
Pulmonary Allografts in Ross Aortic Valve Replacement Patients
Bovine Jugular Venous Valved Conduit
Percutaneous Pulmonary Valves
Nonvalved Right Ventricular to Pulmonary Artery Conduits
Stentless and Stented Xenograft Valves in the Right Ventricular to Pulmonary Artery Position
Mechanical Valves in the Pulmonary Position
Bioengineered Valved Conduits for Right Ventricular Outflow Tract Reconstruction
When to Operate for Right Ventricular Outflow Tract Dysfunction
Conclusion
Data from the Society of Thoracic Surgeons Congenital Heart Surgery Database about Conduit Operations
References
Chapter 24 Double‐Outlet Right Ventricle
Controversies
History
Embryology
Morphology
Atrioventricular and Ventriculoarterial Connections
Subaortic Defects
Double‐Outlet Right Ventricle with Left‐Sided Aorta
Doubly Committed Defect
Subpulmonary Defect (Taussig–Bing)
Noncommitted (Remote) Defects
Right Ventricular Outflow Tract Obstruction
Subaortic Stenosis
Conduction System
Coronary Arterial Anatomy
Associated Cardiac Abnormalities
Classification
Pathophysiology
Congestive Heart Failure
Cyanosis
Diagnosis
Physical Examination, Electrocardiogram, and Chest Radiograph
Echocardiogram
Cardiac Catheterization and Cineangiography
Magnetic Resonance Imaging/Computed Tomographic Imaging
Three‐Dimensional Imaging
Natural History
Treatment
Impediments to Complete Anatomic Repair
General Aspects of Surgical Repair
Double‐Outlet Right Ventricle, Interventricular Defect Type (Subaortic or Doubly Committed Defects without Pulmonary Stenosis)
Double‐Outlet Right Ventricle, Tetralogy of Fallot Type (Subaortic or Doubly Committed Defect with Pulmonary Stenosis)
Double‐Outlet Right Ventricle, Transposition of the Great Arteries Type (Subpulmonary Defect)
Double‐Outlet Right Ventricle with Subpulmonary Defect and Pulmonary Stenosis
Double‐Outlet Right Ventricle, Remote Defect Type
Double‐Outlet Right Ventricle with Atrioventricular Septal Defect
Double‐Outlet Left Ventricle
History
Embryology
Morphology
Pathophysiology
Diagnosis
Natural History
Treatment
Double‐Outlet Left Ventricle with Pulmonary Stenosis
Complete Intraventricular Repair
Pulmonary Artery Translocation
REV Procedure
Rastelli Procedure
Double‐Outlet Left Ventricle without Pulmonary Stenosis
Double‐Outlet Left Ventricle with Tricuspid and Right Ventricular Hypoplasia
References
Chapter 25 Transposition of the Great Arteries
Embryologic and Anatomic Considerations
Physiology
Clinical Presentation
Medical Management of the Neonate
Surgical Management
Arterial Switch Operation for Transposition of the Great Arteries with Intact Ventricular Septum
Technique
Pericardial Harvest, Evaluation, and Dissection
Cannulation and Cardiopulmonary Bypass
Conduct of Cardiopulmonary Bypass
Myocardial Protection
Neoaortic Reconstruction and Coronary Artery Transfer
Special Coronary Problems
Neopulmonary Artery Reconstruction
Separation from Cardiopulmonary Bypass and Postoperative Care
Results and Analysis
Arterial Switch and Ventricular Septal Defect Closure for Transposition of the Great Arteries and Ventricular Septal Defect
Current Approach
Staged Repair of Transposition of the Great Arteries with Intact Ventricular Septum
Arterial Switch Operation for Double‐Outlet Right Ventricle and Subpulmonary Ventricular Septal Defect (Taussig–Bing Anomaly)
Staged Arterial Switch Operation for Right Ventricular Failure after the Atrial Baffle Procedures
Late Complications and Reoperations Following the Arterial Switch Operation
Acquired Supravalvar Pulmonary Stenosis
Postoperative Arrhythmias
Neoaortic Insufficiency and Neoaortic Anastomotic Stenosis
Coronary Artery Problems
Damus–Stansel–Kaye Procedure
Transposition of the Great Arteries, Ventricular Septal Defect, and Pulmonary Stenosis
Transposition of the Great Arteries–Ventricular Septal Defect–Coarctation/Interrupted Aortic Arch
Functional Status and Quality of Life
Future Considerations
References
Chapter 26 Congenitally Corrected Transposition of the Great Arteries
Important Historical Aspects
Diagnosis
Natural History and Clinical Presentation
Surgical Indications and Options
Interim (Palliative or Nondefinitive) Operations for ccTGA
Definitive Operations for ccTGA
Management of Systemic Right Ventricular Failure in ccTGA
Specific Surgical Techniques for ccTGA
Physiologic Repair for ccTGA with Ventricular Septal Defect with or without Left Ventricular Outflow Tract Obstruction
Anatomic Correction of ccTGA via Double Switch
Anatomic Correction of ccTGA via Senning or Mustard plus Rastelli Operation
Anatomic Correction using Intra‐atrial Baffle plus Translocation of the Great Vessels
Cavopulmonary Connection Technique in ccTGA
Pacemakers in ccTGA
Cardiac Transplantation in ccTGA
Analysis of Outcome for ccTGA: Physiologic Repair
Anatomic Repair
Univentricular Repair
Conclusion
References
Chapter 27 The Functionally Univentricular Heart
Background
Definition
Classification
Cardiac Lesions
Double‐Inlet Ventricles
Mitral Atresia
Tricuspid Atresia
Unbalanced Atrioventricular Septal Defect
“Single Ventricle with Heterotaxy Syndrome”
“Single Ventricle with Total Anomalous Pulmonary Venous Connection” and Other Lesions
Clinical Presentation
Diagnosis
Indications for Surgical Intervention
Historical Surgical Management
Current Surgical Management
First‐Stage Palliation
Second‐Stage Palliation
Third‐Stage Fontan Circulation
Other Considerations
Fenestration
Atrioventricular Valvar Repair or Replacement
Severe Cyanosis Following Second‐Stage Palliation
Fontan Takedown
Mechanical Circulatory Support
Transplantation
Results
Late Considerations
Protein‐Losing Enteropathy
Plastic Bronchitis
Hepatic Dysfunction
Arrhythmias and Fontan Conversion
Exercise Capacity
Thromboembolism and Stroke
Collaterals
Pulmonary Arteriovenous Malformations
Conclusion
Data from the Society of Thoracic Surgeons Congenital Heart Surgery Database about Glenn and Fontan
References
Chapter 28 Fontan Conversion
Evolution of Chronic Fontan Physiology
Early Catheter Ablation Techniques
Introduction of Fontan Revision
Introduction of Fontan Conversion
Fontan Conversion with Associated Procedures
Conduct of Fontan Conversion
Pacemaker Implantation
Anatomic and Electrophysiologic Variations of Fontan Conversion
Takedown of Right Atrial–Right Ventricular Bjork Modification
Takedown of Atrioventricular Valve Isolation Patch for Right‐Sided Maze Procedure
Right Atrial Cannulation in the Presence of a Right Atrial Clot
Distended Left Superior Caval Vein Causing Left Pulmonary Vein Stenosis
Discontinuous Pulmonary Arteries
Right Ventricular Hypertension and Tricuspid Regurgitation after Atriopulmonary Fontan for Pulmonary Atresia and Intact Ventricular Septum
Right Atrial Reduction in the Setting of a Systemic Right Ventricle Leading to Pulmonary Vein Stenosis
Unwanted Inferior Caval Vein Retraction during the Extracardiac Connection
Surgical Translocation of Atrial Septal Alignment
The Modified Right‐Sided Maze Procedure for Various Single‐Ventricle Pathology
Fontan Conversion as a Reproducible Procedure
Conclusion
Data from the Society of Thoracic Surgeons Congenital Heart Surgery Database Fontan conversion
References
Chapter 29 Ebstein Malformation
Overview
Anatomy
Physiology
The neonate
Presentation and Diagnosis
Indications for Surgery
Surgical Strategies
Children and Adults
Presentation and Diagnosis
Indications for Surgery
Surgical Strategies
Tricuspid Valve Repair
Tricuspid Valve Replacement
One‐and‐a‐half ventricle repair
Plication of the Atrialized Right Ventricle
Right Reduction Atrioplasty and Surgical Arrhythmia Management
Heart Transplantation
Postoperative Management
Neonates
Children and Adults
Risk Factors and Outcome
References
Chapter 30 Left Ventricular Outflow Tract Obstruction
Valvar Aortic Stenosis
Critical Aortic Stenosis
Anatomy
Diagnosis
Pathophysiology
Management
Surgical Valvotomy
Balloon Valvotomy
Results of Valvotomy
Which Initial Palliation Is Better?
Critical Aortic Stenosis Associated with Severe Annular Hypoplasia
Results of Infant Ross/Ross–Konno
Fetal Aortic Valvuloplasty
Aortic Valve Stenosis beyond the Newborn Period
Embryology
Anatomy
Pathophysiology
Clinical Features
Diagnosis
Future Directions in Diagnosis and Evaluation
Indications for Intervention
Treatment
Surgical History
Surgical Techniques
Results
Subvalvar Aortic Stenosis
Embryology and Anatomy
Pathophysiology
Clinical Features
Diagnosis and Indication for Intervention
Surgical Treatment
Results
Supravalvular Aortic Stenosis
Embryology: Systemic Elastin Arteriopathy and Williams–Beuren Syndrome
Anatomy
Pathophysiology
Clinical Features
Diagnosis
Medical and Interventional Management
Indication for Surgical Intervention
Surgical Management
Diffuse Supravalvular Aortic Stenosis
Results
Data from the Society of Thoracic Surgeons Congenital Heart Surgery Database about Left Ventricular Outflow Tract Obstruction and Left Heart Lesions
References
Chapter 31 Hypertrophic Cardiomyopathy
Definition, Classification, Etiology, and Diagnosis
Natural History
Treatment
Outcome
Hypertrophic Cardiomyopathy with Left Ventricular Outflow Tract Obstruction
Operative Management of Hypertrophic Cardiomyopathy with Left Ventricular Outflow Tract Obstruction
Preoperative Echocardiography
Surgical Procedure
Implantable Cardioverter‐Defibrillator Placement
Complications
Outcomes of Surgery for Hypertrophic Cardiomyopathy with Left Ventricular Outflow Tract Obstruction in Children
Conclusions
Data from the Society of Thoracic Surgeons Congenital Heart Surgery Database (STS CHSD) about Cardiomyopathy
References
Chapter 32 Hypoplastic Left Heart Syndrome
Epidemiology
Fetal Development
Anatomy
Common Anatomic Features
Additional Anatomic Features
Clinical Features and Diagnosis
Management of the Neonate with HLHS
Initial Stabilization
Staged Reconstruction
Stage 1 Palliation: Norwood Procedure
Postoperative Management
Mechanical Circulatory Support
Interstage Management
Medical Therapy
Home Monitoring
Stage 2 Palliation: Cavopulmonary Connection
Stage 3 Palliation: The Fontan Procedure
Outcomes of Staged Reconstruction
Heart Transplantation
Neurodevelopmental Outcome
Conclusion
Data from the Society of Thoracic Surgeons Congenital Heart Surgery Database about Hypoplastic Left Heart Syndrome
References
Chapter 33 Aorto‐Left Ventricular Tunnel
Pathophysiology and Anatomy
Pathogenesis
Presentation and Diagnosis
Treatment
Conclusion
References
Chapter 34 Congenital Anomalies of the Mitral Valve
Historical Note
Normal Mitral Valve Anatomy
Mitral Valve Pathology, Classification, and Analysis
Supravalvar Region
Annulus
Valve Leaflets
Subvalvar Apparatus
Congenital Mitral Stenosis
Congenital Mitral Regurgitation
Ischemic Mitral Regurgitation
Pathophysiology and Clinical Presentation
Imaging and Studies
Treatment
Medical Management
Indications for Surgical Management
Transcatheter Therapy
Surgical Repair Techniques
Supravalvar Repair
Annular Remodeling
Leaflet Repair
Subvalvar Reconstruction
Mitral Valve Replacement
Postoperative Management
Outcomes
Conclusion
Data from the Society of Thoracic Surgeons Congenital Heart Surgery Database (STS CHSD) about Mitral Valve Anomalies
References
Chapter 35 Total Anomalous Pulmonary Venous Connection
Embryology
TAPVC and Genetics
Classification
Cardiac Anatomy, Associated Lesions
Natural History
Diagnosis
Operative Management and Anesthetic Considerations
Surgical Repair of Supracardiac Type
Repair of the Cardiac Type
Repair of the Infracardiac Type
Repair of the Mixed Type
Ligation of the Vertical Vein
Results
Postoperative Pulmonary Vein Stenosis
Surgical Management for Postoperative Pulmonary Vein Stenosis
Sutureless Technique for Primary Repair of TAPVC
Data from the Society of Thoracic Surgeons Congenital Heart Surgery Database (STS CHSD) about Pulmonary Venous Anomalies
References
Chapter 36 Cor Triatriatum, Pulmonary Vein Stenosis, and Atresia of the Common Pulmonary Vein
Embryology of the Pulmonary Venous System
Pathologic Anatomy
Cor Triatriatum (Divided Left Atrium)
Anatomy
Pathophysiology
Clinical Presentation
Treatment
Atresia of the Common Pulmonary Vein
Pulmonary Vein Stenosis
Cor Triatriatum Dexter (Divided Right Atrium)
Data from the Society of Thoracic Surgeons Congenital Heart Surgery Database (STS CHSD) about Cor Triatriatum
References
Chapter 37 Anomalous Systemic Venous Connections
History
Incidence
Anatomy
Left Superior Caval Vein to Coronary Sinus without Coronary Sinus Ostial Atresia
Left Superior Caval Vein with Coronary Sinus Ostial Atresia
Unroofed Coronary Sinus Syndrome
Complete Unroofing with Left Superior Caval Vein
Complete Unroofing without Left Superior Caval Vein
Partially Unroofed Coronary Sinus with or without Left Superior Caval Vein
Right Superior Caval Vein to the Left Atrium
Direct Inferior Caval Vein Connections
Indirect Inferior Caval Vein Connections
Atrial (Appendage) Isomerism
Diagnosis
Pathophysiology and Natural History
Surgical Management of Systemic Venous Route Abnormalities
Left Superior Caval Vein with Coronary Sinus Ostial Atresia
Left Superior Caval Vein to the Coronary Sinus without Coronary Sinus Ostial Atresia
Azygos or Hemiazygos Continuation of the Inferior Caval Vein
Separate Connection of Hepatic Veins into the Right Atrium
Surgical Management of Systemic Venous Destination Abnormalities
Left Superior Caval Vein to the Left Atrium without a Coronary Sinus
Repositioning the Atrial Septum
Superior Atrial Approach
Left Superior Caval Vein Translocation with Interatrial Septal Repositioning
Bidirectional Cavopulmonary Connection
Roofing the Coronary Sinus
Translocation of the Left Superior Caval Vein to the Right Atrium
Partially Unroofed Midportion of the Coronary Sinus
Inferior Caval Vein to the Left Atrium
Total Anomalous Systemic Venous Drainage
Right Superior Caval Vein to the Left Atrium
Results
Special Situations
Heart Transplantation in Patients with Anomalies of Systemic Venous Connection
Cavopulmonary Connections in Patients with Complex Functionally Single Ventricle
References
Chapter 38 Connective Tissue Disorders
Diagnostic Syndromes and Associated Heart Disease
Marfan Syndrome
Loeys–Dietz Syndrome
Ehlers–Danlos Syndrome
Osteogenesis Imperfecta
Aortic Surgery in Connective Tissue Diseases
Aortic Root Aneurysms
Aortic Root Replacement: Surgical Techniques
Bicuspid Aortic Valves and Valve Repair
Aortic Arch Repair
Simultaneous Repair of Pectus Excavatum
Outcomes Following Valve‐Sparing Aortic Root Replacement
Mitral Valve Surgery in Connective Tissue Diseases
Techniques for Mitral Valve Surgery
Conclusion
Data from the Society of Thoracic Surgeons Congenital Heart Surgery Database (STS CHSD) about Aortic Aneurysms
References
Chapter 39 Coronary Artery Anomalies
Anomalous Left Coronary Artery from Pulmonary Artery
Pathophysiology
Clinical Features
Surgical Management
Results
Discussion
Anomalous Pulmonary Origin of Right Coronary Artery
Anomalous Aortic Origins of Coronary Arteries
Left Main Coronary Artery from Right Aortic Sinus of Valsalva
Right Coronary Artery from Left Aortic Sinus of Valsalva
Anomalous Circumflex Coronary Artery from Right Aortic Sinus of Valsalva or Right Coronary Artery
Surgical Management
Single Coronary Artery
Left Main Coronary Artery Atresia
Surgical Management
Coronary Arteriovenous Fistulas
Intramyocardial Course of Coronary Arteries (Bridging)
Therapeutic considerations
Coronary Aneurysms
Coronary Aneurysms in Kawasaki Disease
Surgical Management
References
Chapter 40 Cardiac Tumors
Historical Background
Nomenclature and Classification
Incidence
Primary Cardiac Tumors
Secondary Cardiac Tumors
Tumor Histotypes
Primary Cardiac Tumors
Genetic Predisposition
Clinical Appearance
Symptoms Related to Intracavitary Obstruction and Infiltration
Arrhythmias
Diagnostic Modalities
Chest Roentgenography
Electrocardiography
Echocardiography
Magnetic Resonance Imaging
Computed Tomography
Angiography
Biopsy
General Principles of Surgical Resection
General Considerations of Treatment Strategies
Primary Cardiac Tumors
Rhabdomyomas
Fibromas
Myxomas
Intrapericardial Teratomas
Angiomas
Hamartomas
Other Primary Benign Cardiac Tumors
Primary Malignant Cardiac Tumors
Secondary Cardiac Tumors
Data from the Society of Thoracic Surgeons Congenital Heart Surgery Database (STS CHSD) about Heart Tumors
References
Chapter 41 Diseases of the Pericardium
Historical Perspectives
Embryology and Anatomy
Diseases of the Pericardium
Effusive Pericarditis
Constrictive Pericarditis
Cardiac Tamponade
Postoperative Pericardial Effusion
Postoperative Cardiac Tamponade
Postpericardiotomy Syndrome
Congenital Defects of the Pericardium
Pericardial Neoplasia
Benign Pericardial Mass
Pericardial Cyst
Pneumopericardium
Chylopericardium
References
Chapter 42 Surgical and Transcatheter Management of Arrhythmias
History of Arrhythmia Surgery
Recommendations for Arrhythmia Surgery
Arrhythmia Surgery Techniques
Focal Atrial Tachycardia, Atrioventricular Nodal Reentry Tachycardia, and Supraventricular Tachycardia due to Accessory Connections
Focal or Automatic Atrial Tachycardia
Atrioventricular Nodal Reentry Tachycardia
Accessory Connection‐Mediated Tachycardia
Macroreentrant Atrial Tachycardia
Atrial Fibrillation
Prophylactic Atrial Arrhythmia Surgery
Device Therapy of Congenital Heart Disease
Conclusion
Data from the Society of Thoracic Surgeons Congenital Heart Surgery Database about Arrhythmia Surgery
References
Chapter 43 Pediatric Heart Transplantation
Indications
Cardiomyopathy
Congenital Heart Disease
Retransplantation
Contraindications
Ventricular Assist Device
Pretransplant Evaluation
Donor Evaluation
Immunosuppression and Rejection
Transplant Techniques
Donor Operation
Recipient Operation
Outcomes
Conclusion
Data from the Society of Thoracic Surgeons Congenital Heart Surgery Database about Heart Transplantation
References
Chapter 44 Lung and Heart–Lung Transplantation
Lung Transplantation
Indications
Cystic Fibrosis
Pulmonary Hypertension
Pulmonary Fibrosis
Surfactant Genetic Anomalies
Retransplantation
Heart–Lung Transplantation
Indications
Contraindications
Listing and Donor Evaluation
Surgical Technique
Organ Harvest
Transplant Procedure
Living Donor Lung Transplantation
Heart–Lung Transplantation
Posttransplant Immunosuppression
Posttransplant Management and Complications
Late Complications
Survival
Special Considerations
Infant Lung Transplantation
Mechanical Support
Growth
Conclusions and Future Directions
Data from the Society of Thoracic Surgeons Congenital Heart Surgery Database (STS CHSD) about Heart Transplantation
References
Chapter 45 Endocarditis in Patients with Congenital Heart Disease
Definition
Epidemiology
Pathophysiology
Microbiology
Diagnosis
Clinical Manifestations
Laboratory Investigations
Imaging Studies
Antimicrobial Therapy
Indications for Surgery
Congestive Heart Failure
Valvar Dysfunction
Mechanical Intracardiac Complications
Remote Embolic Complications
Failure of Adequate Medical Therapy
Culture‐Negative Endocarditis
Prosthetic Valve/Device Endocarditis
Timing of Surgery
Surgical Procedures
Technique of Cardiopulmonary Bypass
Endocarditis Associated with Specific Lesions in Patients with Congenital Heart Disease
Endocarditis Associated with Small Residual or Persistent Ventricular Septal Defects
Tricuspid Valve Repair/Replacement and Ventricular Septal Defect Closure for Bacterial Endocarditis
Aortic Valve Repair/Replacement and Ventricular Septal Defect Closure for Bacterial Endocarditis
Mitral Valve Repair/Replacement for Bacterial Endocarditis
Hemodynamic Jet Lesions Causing Endocarditis in Patients with Patent Arterial Duct or Coarctation of the Aorta
Endocarditis Associated with Patent Arterial Duct
Endocarditis Associated with Coarctation of the Aorta
Endocarditis Associated with Surgical or Transcatheter Pulmonary Valve Insertion
Results
Infective Endocarditis in Children
Early Surgery
Risk Factors for Death
Conclusions
Data from the Society of Thoracic Surgeons Congenital Heart Surgery Database about Endocarditis
References
Chapter 46 Pediatric Mechanical Circulatory Support
Patient Selection for Ventricular Assist Device Support
Preimplant Patient Status
Intent of Device Therapy
Underlying Diagnosis
Patient Size
Patient Comorbidities
Device Selection
Extracorporeal Membrane Oxygenation
Short‐Term Ventricular Assist Devices
Durable Ventricular Assist Devices
Pulsatile Devices
Continuous‐Flow Devices
Biventricular Support
Operative Care
Postoperative Care
Transition to Outpatient Management
Unique Pediatric Issues
Mechanical Support for Congenital Heart Disease
Mechanical Support of the “Failing Fontan”
Device Fitting
Conclusion
References
Chapter 47 Adult Congenital Heart Disease
General Considerations
Heart Failure
Pulmonary Arterial Hypertension
Arrhythmias
Cyanosis
Hemostatic Dysfunction
Stroke
Renal Dysfunction
Metabolic Complications
Hemoptysis
Pregnancy and Heart Disease
Surgical Considerations
Resternotomy
Collateral Vessels
Blalock–Taussig–Thomas Shunt
Glenn Shunt
Pulmonary Artery Band
Anesthesia Considerations
Monitoring
Anesthesia in Specific Defects
Postoperative Care
Respiratory Management
Cardiovascular Monitoring
Low Cardiac Output
Mechanical Assist Devices
Short‐Term Devices
Long‐Term Devices
Specific Congenital Heart Defects
Atrial Septal Defects
Fossa Ovalis Membrane Aneurysm
Ventricular Septal Defects
Tetralogy of Fallot
Coarctation of the Aorta
Fontan‐Type Repair
Transposition of the Great Arteries
Left Ventricular Outflow Tract Obstruction
Discrete Subaortic Stenosis
Diffuse/Tunnel Subaortic Stenosis
Konno Procedure
References
Chapter 48 Bioethics in Congenital Heart Surgery
Informed Consent
Transparency, Informed Consent, and Nudging In Pediatric Aortic Stenosis and Symptomatic Left Ventricular Endocardial Fibroelastosis
Case Presentation
Commentary
Rhetoric, Persuasion, and Psychology
Surgeon Responsibility and Psychological Techniques of Persuasion
Selective Emphasis
Beneficent Persuasion
Nudging and Informed Consent
Shared Decision‐Making
Competency, Transparency, and Informed Consent
Autonomy and Transparency
Clinical Outcome
Rare and Expensive Medical Conditions
Government‐Level Funding
Utility, Economics, and Resource Allocation
Healthcare Economics
Respect for Patient Autonomy as a Medical Virtue
Centrality of the Principle of Respect for Patient Autonomy
From Principles to Virtues
Respect for Patient Autonomy as a Medical/Professional Virtue: Classical Understanding of “Virtue” (Arête)
Fetal Cardiac Intervention: The Burden of Knowledge
The Problem of Language: Throwing the Proverbial Baby out with the Bathwater?
Aporia and Postmodernism: Philosophic Considerations
Postmodernity and Medicine?
The Future of Fetal Cardiac Surgery: Gazing into the Abyss
Ethical Considerations for Postcardiotomy Extracorporeal Membrane Oxygenation
Evolution of Selection Criteria for Postcardiotomy Extracorporeal Membrane Oxygenation
Ethical Issues
Medical Futility: “When Further Therapy Is Hopeless”
Power
Trust
Money
Hope
Attempts to Define Futility
References
Chapter 49 Education in Congenital Cardiac Surgery
“Boot Camp”
Surgical Training of Congenital Heart Surgery Using Three‐Dimensional Print Models
Biologic Simulation Methods That Recreate Congenital Heart Operations
Conclusion
Reflections by the Editors
References
Index
EULA

Citation preview

Pediatric Cardiac Surgery FIFTH EDITION

Editors

Constantine Mavroudis, MD Chief of Pediatric Cardiothoracic Surgery Peyton Manning Children’s Hospital Indianapolis, Indiana Professor Emeritus of Surgery Johns Hopkins University School of Medicine Baltimore, Maryland

Carl L. Backer, MD Chief, Section of Pediatric Cardiothoracic Surgery UK Healthcare Kentucky Children’s Hospital Lexington, Kentucky Professor, Cardiothoracic Surgery Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio

This fifth edition first published 2023 © 2023 by John Wiley & Sons Ltd. Edition History John Wiley & Sons (4e, 2013) Mosby (3e, @2003; 2e, 1994) All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by law. Advice on how to obtain permission to reuse material from this title is available at http://www.wiley.com/go/permissions. The right of Constantine Mavroudis and Carl L. Backer to be identified as the authors of the editorial material in this work has been asserted in accordance with law. Registered Office John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK For details of our global editorial offices, customer services, and more information about Wiley products visit us at www.wiley.com. Wiley also publishes its books in a variety of electronic formats and by print-on-demand. Some content that appears in standard print versions of this book may not be available in other formats. Trademarks: Wiley and the Wiley logo are trademarks or registered trademarks of John Wiley & Sons, Inc. and/or its affiliates in the United States and other countries and may not be used without written permission. All other trademarks are the property of their respective owners. John Wiley & Sons, Inc. is not associated with any product or vendor mentioned in this book. Limit of Liability/Disclaimer of Warranty The contents of this work are intended to further general scientific research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting scientific method, diagnosis, or treatment by physicians for any particular patient. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. While the publisher and authors have used their best efforts in preparing this work, they make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives, written sales materials or promotional statements for this work. The fact that an organization, website, or product is referred to in this work as a citation and/or potential source of further information does not mean that the publisher and authors endorse the information or services the organization, website, or product may provide or recommendations it may make. This work is sold with the understanding that the publisher is not engaged in rendering professional services. The advice and strategies contained herein may not be suitable for your situation. You should consult with a specialist where appropriate. Further, readers should be aware that websites listed in this work may have changed or disappeared between when this work was written and when it is read. Neither the publisher nor authors shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages. Library of Congress Cataloging-in-Publication Data is Applied for Hardback ISBN: 9781119282310 Cover image: © Pobytov/Getty Images; Courtesy of Constantine Mavroudis Cover design by Wiley Set in 9.25/12pt Palatino by Straive, Chennai, India

Table of Contents

Contributors, v Preface to the Fifth Edition, x A Note on Nomenclature, xii

Chapter 1

Development of the Heart and Great Vessels, 1 Ram Kumar Subramanyan, Robert H. Anderson, and Peter J. Gruber

Chapter 2

Genetics of Congenital Heart Disease, 25 Peter J. Gruber

Chapter 3

Fetal Cardiac Physiology and Fetal Cardiac Intervention, 35 Timothy S. Lancaster, Jacob R. Miller, and Pirooz Eghtesady

Chapter 4

Preoperative Diagnostic Evaluation, 47 Barbara J. Deal, Amanda L. Hauck, Sabrina Tsao, Angira Patel, Simon Lee, and Doff B. McElhinney

Chapter 5

Hybrid Procedures for Congenital Heart Disease, 87 Hakan Akintuerk, Dietmar Schranz, and Norbert Voelkel

Chapter 6

Anesthesia for the Patient with Congenital Heart Disease, 99 H. Jay Przybylo

Chapter 10 Pediatric Myocardial Protection, 191 Sachin Talwar and Shiv Kumar Choudhary Chapter 11 Patent Arterial Duct, 213 Elizabeth H. Stephens, Paul Tannous, Carl L. Backer, and Constantine Mavroudis Chapter 12 Vascular Rings and Pulmonary Artery Sling, 225 Carl L. Backer, Cynthia K. Rigsby, and Constantine Mavroudis Chapter 13 Coarctation of the Aorta, 249 Carl L. Backer, Joseph A. Dearani, and Constantine Mavroudis Chapter 14 Interrupted Aortic Arch, 279 Dilip S. Nath and Richard A. Jonas Chapter 15 Atrial Septal Defect, Partial Anomalous Pulmonary Venous Connection, and Scimitar Syndrome, 299 Carl L. Backer, Paul Tannous, and Constantine Mavroudis Chapter 16 Ventricular Septal Defect, 317 Constantine Mavroudis, Carl L. Backer, and Robert H. Anderson Chapter 17 Atrioventricular Septal Defects, 361 Carl L. Backer and Constantine Mavroudis Chapter 18 Common Arterial Trunk, 383 Constantine Mavroudis and Carl L. Backer

Chapter 7

Perioperative Care, 113 Mjaye L. Mazwi, Carl L. Backer, John M. Costello, and Constantine Mavroudis

Chapter 19 Aortopulmonary Window and Aortic Origin of a Pulmonary Artery, 409 Stephanie Fuller and Robert H. Anderson

Chapter 8

Palliative Operations, 143 Carl L. Backer and Constantine Mavroudis

Chapter 9

Management of Pediatric Cardiopulmonary Bypass, 161 Nicholas D. Andersen, James M. Meza, and Joseph W. Turek

Chapter 20 Isolated Right Ventricular Outflow Tract Obstruction, 419 Ali Dodge-Khatami and Christopher E. Greenleaf Chapter 21 Tetralogy of Fallot, 431 Ali Dodge-Khatami, Peter Chen, and Constantine Mavroudis iii

iv

Table of Contents

Chapter 22 Tetralogy of Fallot with Pulmonary Atresia and Major Aortopulmonary Collaterals, 463 Matthew Liava’a and Yves d’Udekem

Chapter 37 Anomalous Systemic Venous Connections, 801 Henry L. Walters III and Ralph E. Delius

Chapter 23 Ventricular to Pulmonary Artery Conduits, 481 John W. Brown and Jeremy L. Herrmann

Chapter 38 Connective Tissue Disorders, 821 Charles D. Fraser III, Trevor A. Ellison, Duke E. Cameron, and Luca A. Vricella

Chapter 24 Double-Outlet Right Ventricle, 499 Constantine Mavroudis, Carl L. Backer, and Robert H. Anderson

Chapter 39 Coronary Artery Anomalies, 835 Constantine Mavroudis, Ali Dodge-Khatami, and Carl L. Backer

Chapter 25 Transposition of the Great Arteries, 539 Constantine Mavroudis, Carl L. Backer, and Jeremy L. Herrmann

Chapter 40 Cardiac Tumors, 867 Rüdiger Lange and Thomas Günther

Chapter 26 Congenitally Corrected Transposition of the Great Arteries, 581 Tom R. Karl and Jeffrey P. Jacobs Chapter 27 The Functionally Univentricular Heart, 601 Peter Sassalos, Ming-Sing Si, Jennifer C. Romano, Edward L. Bove, and Richard G. Ohye Chapter 28 Fontan Conversion, 629 Constantine Mavroudis, Barbara J. Deal, and Carl L. Backer

Chapter 41 Diseases of the Pericardium, 883 Elizabeth H. Stephens and Victor O. Morell Chapter 42 Surgical and Transcatheter Management of Arrhythmias, 895 Barbara J. Deal and Constantine Mavroudis Chapter 43 Pediatric Heart Transplantation, 921 Charles B. Huddleston and Andrew C. Fiore Chapter 44 Lung and Heart–Lung Transplantation, 941 Charles B. Huddleston and Andrew C. Fiore

Chapter 29 Ebstein Malformation, 649 Kimberly A. Holst and Joseph A. Dearani

Chapter 45 Endocarditis in Patients with Congenital Heart Disease, 957 Peter D. Wearden and Constantine Mavroudis

Chapter 30 Left Ventricular Outflow Tract Obstruction, 669 William M. DeCampli and Kamal K. Pourmoghadam

Chapter 46 Pediatric Mechanical Circulatory Support, 983 Michelle Ploutz, Angela Lorts, and David L.S. Morales

Chapter 31 Hypertrophic Cardiomyopathy, 705 William M. DeCampli and Kamal K. Pourmoghadam

Chapter 47 Adult Congenital Heart Disease, 999 Maria Drakopoulou, Konstantinos Dimopoulos, Stamatia Prapa, Darryl F. Shore, Stella Brili, and Michael Gatzoulis

Chapter 32 Hypoplastic Left Heart Syndrome, 719 Chun Soo Park and James S. Tweddell Chapter 33 Aorto-Left Ventricular Tunnel, 743 Jeremy L. Herrmann and Stephanie Fuller Chapter 34 Congenital Anomalies of the Mitral Valve, 749 Perry S. Choi and Sitaram M. Emani Chapter 35 Total Anomalous Pulmonary Venous Connection, 771 Rachel D. Vanderlaan and Christopher A. Caldarone Chapter 36 Cor Triatriatum, Pulmonary Vein Stenosis, and Atresia of the Common Pulmonary Vein, 787 Constantine D. Mavroudis, Robert H. Anderson, and Constantine Mavroudis

Chapter 48 Bioethics in Congenital Heart Surgery, 1055 Constantine Mavroudis, Constantine D. Mavroudis, Thomas Cook, Catherine L. Mavroudis, Allison Siegel, and Alex Golden Chapter 49 Education in Congenital Cardiac Surgery, 1087 Constantine D. Mavroudis, Constantine Mavroudis, Carl L. Backer, and Richard H. Feins

Index, 1095

Contributors

Editors Constantine Mavroudis, MD Chief of Pediatric Cardiothoracic Surgery Peyton Manning Children’s Hospital Indianapolis, IN, USA Professor Emeritus of Surgery Johns Hopkins University School of Medicine Baltimore, MD, USA

Carl L. Backer, MD Chief, Section of Pediatric Cardiothoracic Surgery UK Healthcare Kentucky Children’s Hospital Lexington, KY, USA Professor, Cardiothoracic Surgery Heart Institute, Cincinnati Children’s Hospital Medical Center Cincinnati, OH, USA

Associate Editors Robert H. Anderson, MD, PhD Professor Emeritus Institute of Genetic Medicine Newcastle University Newcastle upon Tyne, UK

Jeffrey P. Jacobs, MD, FACS, FACC, FCCP Professor of Surgery and Pediatrics Congenital Heart Center Division of Cardiovascular Surgery Department of Surgery University of Florida Gainesville, FL, USA

Cynthia K. Rigsby, MD Department Head Department of Medical Imaging Ann & Robert H. Lurie Children’s Hospital of Chicago Professor of Radiology and Pediatrics Northwestern University Feinberg School of Medicine Chicago, IL, USA

Diane Spicer, PA Congenital Heart Center University of Florida Gainesville, FL, USA

Contributors Hakan Akintuerk, MD Pediatric Heart Center Justus-Liebig University Giessen, Germany

Nicholas D. Andersen, MD Assistant Professor of Surgery Department of Thoracic and Cardiovascular Surgery Duke University School of Medicine Durham, NC, USA

Edward L. Bove, MD Emeritus Professor of Surgery Chair, Department of Cardiac Surgery Section of Pediatric Cardiovascular Surgery University of Michigan Medical School Ann Arbor, MI, USA

Stella Brili, MD First Department of Cardiology Athens Medical School National and Kapodistrian University of Athens Hippokration Hospital Athens, Greece

John W. Brown, MD Harris B. Shumacker Professor Emeritus of Surgery Indiana University School of Medicine Indianapolis, IN, USA

Christopher A. Caldarone, MD Chief, Congenital Heart Surgery Texas Children’s Hospital Houston, TX, USA

v

vi

Contributors

Duke E. Cameron, MD

Konstantinos Dimopoulos, MD

Cardiothoracic Surgeon Division of Cardiac Surgery The Massachusetts General Hospital Boston, MA, USA

Professor of Adult Congenital Heart Disease Adult Congenital Heart Centre Royal Brompton Hospital National Heart and Lung Institute Imperial College London London, UK

Peter Chen, MD Pediatric Cardiothoracic Surgery Memorial Hermann Hospital Assistant Professor Division of Pediatric Cardiovascular Surgery McGovern Medical School University of Texas Health Science Center Houston, TX, USA

Ali Dodge-Khatami, MD, PhD Professor of Cardiac Surgery Clinic for Pediatric and Congenital Heart Surgery University of Aachen RWTH Aachen, Germany

Maria Drakopoulou, MD Perry S. Choi, MD Surgical Resident Department of Cardiothoracic Surgery Stanford University School of Medicine Stanford, CA, USA

Shiv Kumar Choudhary, MD Department of Cardiothoracic and Vascular Surgery All India Institute of Medical Sciences New Delhi, India

Thomas Cook, PhD Professor of Philosophy Rollins College Department of Philosophy Winter Park, FL, USA

John M. Costello, MD, MPH

Adult Congenital Heart Centre Royal Brompton Hospital National Heart and Lung Institute Imperial College London London, UK First Department of Cardiology Athens Medical School National and Kapodistrian University of Athens Hippokration Hospital, Athens, Greece

Yves d’Udekem, MD, PhD Chief, Section of Pediatric Cardiac Surgery Children’s National Hospital Washington, DC, USA

Pirooz Eghtesady, MD

Vice Chair of Clinical Research, Department of Pediatrics Director of Research, Children’s Heart Center Medical University of South Carolina Children’s Hospital Charleston, SC, USA

Chief, Section of Pediatric Cardiothoracic Surgery St Louis Children’s Hospital Professor of Pediatrics and Surgery Washington University School of Medicine St. Louis, MO, USA

Barbara J. Deal, MD

Trevor A. Ellison, MD, PhD

Professor Emeritus Pediatric Cardiology Northwestern University Feinberg School of Medicine Chicago, IL, USA

Joseph A. Dearani, MD Chair, Department of Cardiovascular Surgery Mayo Clinic Professor of Surgery Mayo Clinic College of Medicine Rochester, MN, USA

William M. DeCampli, MD, PhD Pediatric Cardiovascular Surgeon The Heart Center Orlando Health Arnold Palmer Hospital for Children Orlando, FL, USA

Ralph E. Delius, MD Former Vice Chief, Department of Cardiovascular Surgery Children’s Hospital of Michigan Wayne State University School of Medicine Detroit, MI, USA

Attending Cardiac Surgeon Mount Carmel Health System Columbus, OH, USA

Sitaram M. Emani, MD Associate, Department of Cardiac Surgery Surgical Director, Adult Congenital Heart Program Boston Children’s Hospital Associate Professor of Surgery Harvard Medical School Boston, MA, USA

Richard H. Feins, MD Professor of Surgery Division of Cardiothoracic Surgery University of North Carolina at Chapel Hill Chapel Hill, NC, USA

Andrew C. Fiore, MD Cardinal Glennon Hospital St. Louis, MO, USA

Contributors Charles D. Fraser III, MD

Jeremy L. Herrmann, MD

Executive Director Texas Center for Pediatric and Congenital Heart Disease Professor, Departments of Surgery and Perioperative Care Dell Medical School Austin, TX, USA

Attending Surgeon Riley Hospital for Children Assistant Professor of Surgery Division of Cardiothoracic Surgery Indiana University School of Medicine Indianapolis, IN, USA

Stephanie Fuller, MD Attending Surgeon Division of Cardiovascular-Thoracic Surgery Children’s Hospital of Philadelphia Professor of Clinical Surgery Department of Surgery University of Pennsylvania School of Medicine Philadelphia, PA, USA

Michael Gatzoulis, MD Academic Head Adult Congenital Heart Centre Royal Brompton Hospital National Heart and Lung Institute Imperial College London London, UK

Alex Golden, MD Clinical Director, Inpatient Cardiology Connecticut Children’s Medical Center Assistant Professor of Pediatrics University of Connecticut School of Medicine Hartford, CT, USA

Christopher E. Greenleaf, MD Pediatric Cardiothoracic Surgery Memorial Hermann Hospital Assistant Professor of Pediatric and Congenital Heart Surgery Department of Pediatric Surgery McGovern Medical School University of Texas Health Science Center Houston, TX, USA

Peter J. Gruber, MD, PhD Chief, Pediatric Cardiac Surgery Yale New Haven Children’s Hospital Professor of Surgery Yale School of Medicine New Haven, CT, USA

Thomas Günther, MD Department of Cardiovascular Surgery German Heart Center Munich, Germany

Amanda L. Hauck, MD Attending Physician Division of Cardiology Ann & Robert H. Lurie Children’s Hospital of Chicago Assistant Professor of Pediatrics Northwestern University Feinberg School of Medicine Chicago, IL, USA

Kimberly A. Holst, MD Department of Cardiovascular Surgery Mayo Clinic Rochester, MN, USA

Charles B. Huddleston, MD Professor of Surgery Cardinal Glennon Children’s Hospital Department of Cardiothoracic Surgery St. Louis University School of Medicine St. Louis, MO, USA

Richard A. Jonas, MD Emeritus Chief, Cardiac Surgery Children’s National Hospital Washington, DC, USA

Tom R. Karl, MS, MD, FRACS Queensland Pediatric Cardiac Service University of Queensland Brisbane, Australia

Timothy S. Lancaster, MD, MS Thoracic Surgery Fellow Section of Pediatric Cardiothoracic Surgery St. Louis Children’s Hospital Washington University School of Medicine St. Louis, MO, USA

Rüdiger Lange, MD, PhD Department of Cardiovascular Surgery German Heart Center Munich, Germany

Simon Lee, MD Pediatric Cardiologist The Heart Center Nationwide Children’s Columbus, OH, USA

Matthew Liava’a, MBChB, MS, FRACS Cardiac Surgery Department Royal Children’s Hospital Melbourne, Australia

Angela Lorts, MD Pediatric Cardiology Cincinnati Children’s Medical Center University of Cincinnati College of Medicine Cincinnati, OH, USA

vii

viii

Contributors

Catherine L. Mavroudis, MD

Dilip S. Nath, MD

Surgical Resident Department of Surgery University of Pennsylvania Philadelphia, PA, USA

Pediatric Cardiac Surgeon St. Louis Children’s Hospital St. Louis, MO, USA

Richard G. Ohye, MD Constantine D. Mavroudis, MD, MSc, MTR Pediatric Cardiothoracic Surgery Children’s Hospital of Philadelphia Assistant Professor of Surgery Perelman School of Medicine, University of Pennsylvania Philadelphia, PA, USA

Mjaye L. Mazwi, MD Staff Physician, Critical Care Medicine The Hospital for Sick Children Assistant Professor of Pediatrics University of Toronto School of Medicine Toronto, Ontario, Canada

Doff B. McElhinney, MD Pediatric Cardiologist Department of Cardiothoracic Surgery Lucille Packard Children’s Hospital Professor of Cardiothoracic Surgery and Pediatrics Stanford University Medical Center Palo Alto, CA, USA

James M. Meza, MD Division of Thoracic and Cardiovascular Surgery Department of Surgery Duke University Medical Center Durham, NC, USA

Professor and Associate Chair, Department of Cardiac Surgery Head, Section of Pediatric Cardiovascular Surgery University of Michigan Medical School Ann Arbor, MI, USA

Chun Soo Park, MD, PhD Pediatric Cardiac Surgery Thoracic and Cardiovascular Surgery Congenital Heart Disease Center Asan Medical Center University of Ulsan College of Medicine Seoul, South Korea

Angira Patel, MD, MPH Attending Physician Division of Cardiology Ann & Robert H. Lurie Children’s Hospital of Chicago Assistant Professor of Pediatrics, Medical Humanities and Bioethics Northwestern University Feinberg School of Medicine Chicago, IL, USA

Michelle Ploutz, MD, MPH Assistant Professor of Pediatrics Division of Pediatric Cardiology University of Utah Salt Lake City, UT, USA

Jacob R. Miller, MD Congenital Cardiac Surgery Fellow Section of Pediatric Cardiothoracic Surgery St. Louis Children’s Hospital Washington University School of Medicine St. Louis, MO, USA

Kamal K. Pourmoghadam, MD

David L.S. Morales, MD

Adult Congenital Heart Centre Royal Brompton Hospital National Heart and Lung Institute Imperial College London London, UK

Pediatric Cardiothoracic Surgery Cincinnati Children’s Medical Center Professor of Surgery University of Cincinnati College of Medicine Cincinnati, OH, USA

The Heart Center Orlando Health Arnold Palmer Hospital for Children Orlando, FL, USA

Stamatia Prapa, MD

H. Jay Przybylo, MD Victor O. Morell, MD Chief, Pediatric Cardiothoracic Surgery Children’s Hospital of Pittsburgh Eugene S. Wiener Professor of Pediatric Cardiothoracic Surgery University of Pittsburgh Medical Center Heart and Vascular Institute Pittsburgh, PA, USA

Muhammad Ali Mumtaz, MD Section Chief, Cardiothoracic Surgery The Children’s Hospital of San Antonio San Antonio, TX, USA

Former Associate Professor of Anesthesiology Northwestern University Feinberg School of Medicine Chicago, IL, USA

Athar Qureshi, MD Pediatric Cardiologist Cleveland Clinic Children’s Hospital Cleveland, OH, USA

Contributors Jennifer C. Romano, MD, MS

Paul Tannous, MD, PhD

Associate Professor, Department of Cardiac Surgery and Pediatrics Section of Pediatric Cardiovascular Surgery University of Michigan Medical School Ann Arbor, MI, USA

Assistant Professor of Pediatrics (Cardiology) Northwestern University Feinberg School of Medicine Attending Cardiologist Ann & Robert H. Lurie Children’s Hospital of Chicago Chicago, IL, USA

Peter Sassalos, MD

Sabrina Tsao, MD

Clinical Lecturer, Department of Cardiac Surgery Section of Pediatric Cardiovascular Surgery University of Michigan Medical School Ann Arbor, MI, USA

Pediatric Electrophysiologist Queen Mary Hospital University of Hong Kong Hong Kong

Dietmar Schranz

Joseph W. Turek, MD, PhD

Pediatric Heart Center Justus-Liebig University Giessen Pediatric Cardiology Frankfurt University Hospital Frankfurt am Main, Germany

Chief, Professor of Surgery Department of Surgery Duke University Medical School Durham, NC, USA

James S. Tweddell, MD Darryl F. Shore, MD Consultant Cardiac Surgeon Professor of Practice – Congenital Cardiac Surgery Adult Congenital Heart Centre Royal Brompton Hospital National Heart and Lung Institute Imperial College London London, UK

Ming-Sing Si, MD Assistant Professor, Department of Cardiac Surgery Section of Pediatric Cardiovascular Surgery University of Michigan Medical School Ann Arbor, MI, USA

Allison Siegel, MSSA Education Institute Cleveland Clinic Cleveland, OH, USA

Elizabeth H. Stephens, MD, PhD Senior Associate Consultant Department of Cardiovascular Surgery Mayo Clinic Rochester, MN, USA

Ram Kumar Subramanyan, MD, PhD Attending Cardiothoracic Surgeon Children’s Hospital of Los Angeles Assistant Professor of Surgery Keck School of Medicine University of Southern California Los Angeles, CA, USA

Sachin Talwar, MD Professor Department of Cardiothoracic and Vascular Surgery All India Institute of Medical Sciences New Delhi, India

Director, Cardiothoracic Surgery Heart Institute Cincinnati Children’s Hospital Medical Center Professor of Surgery University of Cincinnati Cincinnati, OH, USA

Rachel D. Vanderlaan, MD, PhD Assistant Professor, Division of Cardiac Surgery University of Toronto Toronto, Ontario, Canada

Norbert Voelkel, MD Affiliate Professor Virginia Commonwealth School of Pharmacy Richmond, VA, USA

Luca A. Vricella, MD Chief of Pediatric Cardiac Surgery University of Chicago Advocate Children’s Hospital Oak Lawn, IL, USA

Henry L. Walters III, MD Former Chief, Department of Cardiovascular Surgery Children’s Hospital of Michigan Professor of Surgery Wayne State University School of Medicine Detroit, MI, USA

Peter D. Wearden, MD Pediatric Cardiac Surgeon Nemours Children’s Hospital Orlando, FL, USA

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Preface to the Fifth Edition

This is the fifth edition of Pediatric Cardiac Surgery. The first edition was published by Arciniegas in 1985 and was followed by the second edition in 1994, the third edition in 2003, and the fourth edition in 2013 by the present editors. Timely updates are important for any textbook since scientific intellectual curiosity, sentinel discoveries, and technologic improvements have progressed at lightning speed. Even cardiac embryology, a field that was thought to be constant and thoroughly studied, has emerged with the new findings of a second heart field, detailed results of syndromic genomes, and the promise of new paradigms and ontologies. Our readership from around the world has included numerous colleagues, ranging from surgeons to cardiologists, intensivists, anesthesiologists, residents, students, perfusionists, and nurses. They have found the book to be well organized, easy to read, and to the point. We have preserved this format for the fifth edition and added several chapters that have mirrored the directions and practice of pediatric and congenital heart surgery in the twenty-first century. Several fresh chapters by new authors have highlighted the advances in congenital heart surgery. While this textbook emphasizes the pediatric nature of the specialty, it is clear that there are more adults with congenital heart disease living today than there are children with congenital heart disease. This is testimony to the years of scientific and clinical research that has combined to improve the lot of these patients who now present with medical and surgical problems of their own. The new chapter on adult congenital heart disease reviews these very important issues and serves as an important contribution to the textbook. Several new and updated chapters, written by experts in their field, review advances that have been made in congenital heart surgery such as right ventricular to pulmonary artery conduits, arrhythmia surgery, double-outlet ventricles, and cardiac transplantation. Chapters on surgical education and bioethical issues are new and to our knowledge have not appeared in any other textbook of congenital heart disease. In some cases, the same authors have updated their previous chapters. x

In others, new authors have been selected because of their demonstrated expertise. Associate Editors have registered their expertise in nomenclature, imaging, and database outcomes. Dr. Robert H. Anderson and Diane Spicer, BS, PA (ASCP), have enhanced appropriate chapters with new concepts in nomenclature, pathology, and embryology. Dr. Cynthia Rigsby has contributed the latest in imaging techniques. Dr. Jeffrey P. Jacobs provided a Society of Thoracic Surgeons Congenital Heart Surgery Database synopsis of appropriate congenital anomalies regarding perioperative mortality and complication rates. The fifth edition maintains its comprehensive coverage of the breadth of congenital heart surgery and related fields. Each chapter reviews the embryology, physical findings, diagnostic criteria, and therapeutic choices associated with each disease entity. State-of-the-art technology and the latest in surgical techniques are discussed. As in previous editions of Pediatric Cardiac Surgery, the figures have predominantly been illustrated by Rachid Idriss. His drawing techniques are legendary not only because of his artistic talents, but more so for his ability to see an operation in his mind’s eye and demonstrate with a few lines the important parts of the relative anatomy and reparative operation. Sutures are clear, pledgets are well placed, and structures are anatomically correct. Hidden intracardiac anatomy is displayed by ghost techniques that transform the image into a three-dimensional living characterization of reality. His contribution to this fifth edition cannot be overstated. This textbook is reflective of the cooperation, expertise, and altruism that the contributing authors have so generously demonstrated to the readership. Simply stated, these chapters are a delight to read. We are sure that the reader will have the same experience. All royalties from the sale of this book will be contributed to the Congenital Heart Surgeons’ Society in support of the John W. Kirklin–David A. Ashburn Fellowship. We are greatly indebted to Kate Newell and the editorial staff at Wiley-Blackwell for their support. Important editorial

Preface to the Fifth Edition

contributions were made by Allison Siegel and Melanie Gevitz, who were instrumental in organizing the successful efforts associated with the second, third, and fourth editions. We found a jewel, Patricia Heraty, who took on this project with impressive zeal, expertise, and commitment that are rarely found anywhere. We finish this Preface with the final paragraph from the Preface of the third edition, since it stands as a timeless dedication to our loved ones and family members who have shown their devotion, calmed the children, and explained our absences on countless occasions without rancor, excuses, or disappointment.

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Finally, as with all surgeons and physicians, our accomplishments are facilitated by the sacrifices made by our families. Every author who wrote a chapter for this textbook, no doubt, has loved ones who have contributed in one way or another to their creativity, stability, and industry. We thank each and every one of these wives, husbands, children, parents, and friends, including our own, who have had the patience, perseverance, and equanimity to stand by. Constantine Mavroudis, MD Carl L. Backer, MD

A Note on Nomenclature

The history and evolution of the English language have been highlighted by historical events including transformation of the Indo-European language to the Germanic languages and migration to the British Isles. This was followed by the Norman Conquest in 1066 (influx of Northern French) and the metamorphosis of Old English through Middle English to Modern English. At one point in the twelfth and thirteenth centuries, England was trilingual; namely, Old English (language of the agrarian and worker class), Latin (language of government, religion, medicine, and academia), and French ((language of the aristocracy and gentry). Therefore, it should surprise no one that medical nomenclature would retain original remnants of Latin and Greek, both in the original Latin and in anglicized versions from Greek. Some examples of this include truncus arteriosus, patent ductus arteriosus, superior vena cava, and ductus venosus, to name only a few. In an attempt to provide the plural case for these words, ductus becomes ducti, vena cava becomes venae cavae, and so on. Latin has five declensions. In some cases, the noun declensions that have come into usage are simply wrong. For instance, ductus is a masculine noun and is governed by the fourth declension. In this case, the nominative plural of ductus is ductus, not ducti. On the other hand, truncus

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is a masculine noun governed by the second declension, the nominative plural of which is trunci. To obviate this system and bring congenital heart nomenclature and grammar into the twenty-first century, we have determined that American English words should replace Latin words. In this light, patent ductus arteriosus becomes patent arterial duct, the plural of which changes from patent ducti to patent arterial ducts. Similarly, truncus arteriosus becomes common arterial trunk, the plural of which becomes common arterial trunks. We do, nevertheless, need to be pragmatic as we produce the fifth edition. As we are moving slowly toward the introduction of American English, we recognize for the sake of economy that we have retained the old terminology in some illustrations from the earlier editions. It is also the case that we do not need necessarily to alter illustrations simply for the sake of change. Consequently, the reader will note that American English has not in every case replaced the Latin nomenclature that appears in the drawings. Change is not foreign to the English language. Webster’s Dictionary not only defined words, but also prescribed spelling, word usage, syntax, and grammar. Our language is a biologic entity, changing and redefining itself with time and necessity.

CH A P T E R

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Development of the Heart and Great Vessels Ram Kumar Subramanyan1 , Robert H. Anderson2 , and Peter J. Gruber3 1 Children’s Hospital of Los Angeles, Los Angeles, CA, USA 2 Institute of Genetic Medicine, Newcastle upon Tyne, UK 3 Yale New Haven Children’s Hospital, New Haven, CT, USA

Major advances in molecular genetics, establishment of appropriate animal models, and improvements in analytical techniques have contributed to a greater understanding of cardiac development. Modern cardiac embryology now combines molecular and cellular biologic techniques with traditional embryologic morphologic approaches across multiple model systems. A significant proportion of our understanding continues to be derived from nonhuman experimental models, supplemented by observations imputed from the congenitally malformed human heart [1]. In early studies, avian embryos were the favored experimental model because of the ease with which they could be observed and manipulated. Due to the strength of genetic and molecular investigative tools, the mouse has now become the preferred model for studying cardiac development. Table 1.1 provides a simplified comparison of developmental staging in human, mouse, and chicken embryos [2–8]. Understanding cardiac development not only has implications for classifying and managing congenital heart disease, but also provides a platform for the development of novel management approaches, in both children and adults. With a goal of simplifying the description of complex developmental structures, in this chapter we have made efforts to harmonize nomenclature using descriptive terms that relate as much as possible to human development. Thus, “anterior-posterior axis” is replaced by “dorsal–ventral axis” or “cranial–caudal.” “Anterior” is often replaced by “ventral” or “cranial.” “Posterior” is frequently replaced by “dorsal” or “caudal.” “Conus” is replaced by “proximal outflow tract,” and “truncus” is replaced by distal outflow tract. The “dorsal mesocardial protrusion” is referred to as the “vestibular spine.”

Origin of Cardiac Precursor Cells All cells destined to become part of the heart derive from populations of undifferentiated precursors. These precursor cells are influenced by external signals and guided to their final developmental state. In humans, during the second week following fertilization, the blastocyst has partially embedded into the uterine endometrium. At this stage, the inner cell mass, or embryoblast, differentiates into two distinct layers of cells: a larger columnar epiblast layer and the smaller cuboidal hypoblast layer. The third week of development is characterized by the next critical embryonic process, termed gastrulation. A primitive streak is formed in the epiblast layer, following which some epiblast cells invaginate under and displace the hypoblast. Subsequent widespread cell migration into, and reorganization within, the blastocele cavity results in the formation of three germ layers: the ectoderm, mesoderm, and endoderm. This sets the stage for the determination of the future body plan of the embryo (Figure 1.1) [3,9]. Migrating epiblast cells, which have now formed the mesoderm of the embryo, gradually travel cephalad. During this migration, they join the lateral plate mesoderm at the level of the primitive node. The lateral plate mesoderm then divides into two layers: a splanchnic layer directly above the endoderm, and a somatic layer directly below the ectoderm. The anterior endoderm provides signals to splanchnic mesodermal cells to enter the precardiac lineage. Fibroblast growth factors (FGFs)-1, -2, and -4, and bone morphogenetic protein 2 (BMP-2), are proteins that appear to be critical to this process [10]. To date, however, no single gene has been identified whose ablation leads to a specific failure of all myocardial

Pediatric Cardiac Surgery, Fifth Edition. Edited by Constantine Mavroudis and Carl L. Backer. © 2023 John Wiley & Sons Ltd. Published 2023 by John Wiley & Sons Ltd.

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Table 1.1 Simplified comparison of developmental stages between human, mouse, and chicken embryos. Human

Mouse

Chicken

Carnegie Stage

Streeter horizon

Days’ gestation

Embryonic days (Theiler’s stage)

Hamburger/Hamilton stage (days of incubation)

Human cardiac developmental milestone

9 10 11 12 13 14 15 16

IX X XI XII XIII XIV–XV XVI XVIII

20 22 24 26 28 32 33 37

8–8.5 (12) 8.5–9 (13) 9–9.5 (14) 9.5–10.25 (15) 10.25–10.5 (16) 10.5–10.75 (17) 11 (18) 11.5 (19)

7–8 (1.1) 10 (1.5) 11 (1.8) 14 (2.2) 17 (2.6) 19 (2.9) 20–21 (3.3) 24 (4)

Circulation begins

17 18 19 20 21 22 23

XX XXI–XXII XXIII

41 44 47 50 52 54 56

12 (20) 12.5 (21) 13 (21) 14 (22) 14 (22) 14 (22) 14 (22)

26 (4.8) 28 (5.6) 29–30 (6.4) 31–32 (7.2) 34 (8) 35 (8.7) 36 (9.6)

Looping Atrial septation begins OFT septation begins Ventricular and AV septation begins Valvar maturation

AV, atrioventricular; OFT, outflow tract.

differentiation from precardiac mesoderm. It is reasonable to speculate that such lack of reliance on one gene was likely gained as an evolutionary advantage. This could be the result of either (i) considerable genetic redundancy in precardiac myocyte differentiation, or (ii) an unsuspected diversity of precardiac myocyte lineages following independent genetic pathways. By this time in development, precardiac cells begin to express a variety of specific molecular markers, such as the transcription factors NKX2-5, MEF2, HAND1, HAND2, GATA4, TBX5, and ISL1 [11–17]. The region of splanchnic mesoderm expressing precardiac markers is also known as the “heart-forming field.” It is larger than the region that will eventually contribute cells to the heart tube [18]. In rodent embryos, precardiac mesodermal cells exhibit spontaneous contractile activity, indicating a relatively advanced state of differentiation toward the cardiac myocyte lineage [19,20]. The precardiac mesodermal cell mass continues to migrate cephalad as a coalesced single unit, rather than as a collection of independent cells. Ultimately, they pass on either side of the prochordal plate to finally converge in the midline cranial to the intestinal portal. Following their convergence, the total premyocardial cell population forms a horseshoe-shaped crescent called the first, or primary, heart field. The cues that enable and promote movement of these cells are provided by a noncardiac tissue, the endoderm, as demonstrated by experimental removal of the endoderm and/or ectoderm

[10]. The extracellular matrix molecule fibronectin may be one of the important components of the endodermal surface to which the precardiac cells are responding [21]. Precursors of the endocardium follow similar migratory pathways as the precardiac cells, but with important differences. Pre-endocardial cells and pre-endothelial cells are known as angioblasts. The endocardial angioblasts are first detectable in the splanchnic mesoderm. Mesodermal cells are induced to enter the angioblast lineage by signals such as transforming growth factor beta (TGF𝛽) 2–4 and vascular endothelial growth factor (VEGF) signaling from the endoderm [10]. Endocardial angioblasts migrate anteriorly and to the midline with the premyocardial cell mass, but they do so as individual cells. At this point in cardiac organogenesis, the developing heart has not yet obtained its full complement of cell populations necessary for development. Based on early fate-mapping studies [22–24], the primary bilateral fields of precardiac mesoderm that form the early heart structure are collectively called the first heart field. This precardiac mesoderm was long considered the precursor tissue of the heart. Further studies then showed that growth of the heart tube, specifically at the arterial pole, depended on the addition of cardiac tissue from a secondary pool of progenitor cells [25]. It was not until the early twenty-first century that the nature of this additional cell population, called the second heart field, was finally elucidated. The combined studies of various laboratories [26–30] have provided significant

Development of the Heart and Great Vessels

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(A)

(B)

(C)

(D)

Figure 1.1 Simplified schema of gastrulation, precardiac cell migration, and formation of the heart-forming fields. (A) Cells destined to become cardiac cells migrate from the epiblast into the primitive streak through a broad region caudal to the most anterior portion of the primitive streak. The direction of migration of the gastrulated cells, as indicated by the arrows, is away from the midline and anteriorly on each side. (B) The embryo in cross-section at the level indicated by the dotted line in (A). The precardiac mesoderm forms an epithelial sheet closely associated with the endoderm. The pre-endocardial cells are scattered throughout the same region and can be distinguished immunohistochemically from the general precardiac mesoderm. (C, D) Two lateral precardiac mesoderm populations (also known as heart-forming fields) migrate cranially before turning toward the midline (C). They meet in the midline, as shown in (D), at a location immediately cranial to the anterior intestinal portal. Source: McQuinn T, Wessels A 2003 / With permission of Elsevier.

Figure 1.2 Formation of the heart tube is initiated by fusion of the bilateral precardiac mesoderm populations in the midline, resulting in formation of a myocardial tube surrounding an endothelial (endocardial) channel. The myocardial population of the cardiac tube at this stage consists of only the precursors of the future trabeculated portions of the left ventricle. Additional segments are added by ongoing migration of precardiac mesoderm into the heart tube. Source: Reproduced by permission from McQuinn T, Wessels A, in Pediatric Cardiac Surgery, 3rd ed. Philadelphia, PA: Mosby; 2003, pp. 1–24.

new insights into the importance of this additional population of cells regarding the elongation and growth of the heart tube, the outflow tract development, and the formation of a mature four-chambered heart (Figures 1.2 and 1.3) [3]. This second cardiogenic field of cells is located dorsal and caudal to the wall of the developing pericardial cavity, and lies contiguous with and medial to the primary cardiac crescent. Immunohistochemical, in situ hybridization, and cell fate-tracing techniques have demonstrated that the outflow tract primordia, the right ventricle, much of the muscular ventricular septum, and parts of the cardiac venous pole develop from the second heart field [29,31]. A developmentally distinct, third set of cells, the neural crest, contributes to the ultimate structure of the heart. These arise from the ectodermal neural tube. In vertebrate development, the neural crest is a transient structure originating in the most dorsal region of the neural tube [32,33]. The cells of the neural crest reside on the lateral

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(A)

(B)

Figure 1.3 Normal heart development requires integration of cell populations from multiple sources. (A) Precardiac mesoderm gives rise to the endocardium and most cardiac cushion cells. Premyocardial cells give rise to the entire spectrum of cardiac myocyte phenotypes. The primary heart-forming field will give rise to most of the myocardium of the atria and left ventricle. The anterior heart-forming field will give rise to the myocardium of the outflow tract, right ventricle, and interventricular septum. (B) Multiple extracardiac embryonic tissues provide critical cell populations to normal cardiac development. These cell populations include cardiac neural crest cells as well as cells from the proepicardium and the dorsal mesocardium. Source: McQuinn T, Wessels A 2003 / With permission of Elsevier.

margins of the neural plate. These right- and left-sided populations are brought into apposition by the folding of the neural plate into the neural tube. The cells then disperse and migrate to multiple destinations. As with closure of the neural tube, this process is initiated cranially and extends caudally [9]. Specific regions of the neural crest seed cells to specific structures [34]. The region of the neural crest contributing to cardiac and fourth aortic arch morphogenesis is often referred to as the “cardiac” neural crest [9,32]. Cells from the cardiac neural crest migrate along the third, fourth, and sixth aortic arch vessels to reach the developing heart. These cells are necessary for aortopulmonary septation, outflow tract septation, and formation of the tunica media of the third, fourth, and sixth aortic arch vessels [32,35]. An additional population of neural crest cells differentiates into the entirety of the autonomic nervous system of the heart [36]. Other neural crest–derived structures in proximity to the developing

heart and great vessels include the thymus, thyroid, and parathyroid glands [37,38]. Last, an epicardial layer of the heart develops from a histologically and functionally complex precursor tissue called the proepicardium, or proepicardial organ [39]. This is a transient cluster of cells that arise as a mesothelial outgrowth ventral and caudal to the developing heart. Soon after formation, the proepicardium migrates away from the body wall, with its cells extending over the surface of the heart to give rise to the epicardium. These cells eventually flatten over the surface of the myocardium, and develop morphologic characteristics compatible with primitive epithelial cells. The flattening process also causes cells to occupy a greater surface area, bringing adjacent clusters of cells into contact with each other until a continuous sheet results. A subset of the proepicardial cells invades the underlying heart tube and contributes to nonmyocardial mesenchymal cells such as fibroblasts and smooth muscle cells of the coronary arteries. In the mouse, where the process is well studied, these events occur in mid-gestation, although in the human they likely occur earlier [39,40]. Building on prior work, more recent studies suggest an important role for the epicardium in the diversification of cardiac lineages and potentially as a source of progenitor cell populations [41,42].

Formation of the Heart Tube and Early Segmentation The initial cardiac crescent is located cranial to the prochordal plate. With closure of the neural tube, there is rapid cephalad growth of the central nervous system such that it extends over and around the developing heart. This leads to a cephalocaudal flexion of the embryo, bringing the cardiogenic plate ventral and caudal to the prochordal plate. At approximately the same time, the embryo folds in a transverse plane, bringing onto close apposition the lateral tubes of endothelial cells that were formed from early angioblasts. These tubes then fuse in a cephalocaudal direction to form the primitive single endocardial heart tube. Soon after the formation of the cardiac tube, the heartbeat is initiated and blood circulation can be observed. These events take place at embryonic day 8.5 in the mouse, and day 20 in the human. With the initiation of circulation, the heart becomes the first organ to adopt its essential mature function in the embryo. The heart tube at the time of its formation is connected to the foregut along its dorsal surface throughout its length by a structure called the dorsal mesocardium [43]. As cardiac looping proceeds, the dorsal mesocardium degenerates until it remains connected only at the atrial and arterial poles of the heart. The disintegration of the central portion of the dorsal mesocardium is a key event for looping to proceed

Development of the Heart and Great Vessels

normally, while the arterial and venous attachments provide “anchors” for the looping heart tube. A dorsal mesenchymal protrusion, described centuries earlier as the “spina vestibule” or vestibular spine [44], extends into the atrial walls through the rightward margin of the persisting dorsal mesocardium, and is likely a derivative of the second heart field [28,45]. An important pathway for cellular migration, it contributes to atrioventricular (AV) septation, and serves as a scaffold for entry to the atria of the developing pulmonary veins [46,47]. At the time the heartbeat is initiated, the heart tube primarily consists of cells from the first heart field that form the future left ventricular tissues [48,49]. Cells that form the outflow tract, the right ventricle [25], the AV junction [48], the atria, and the systemic venous sinus, also known as the sinus venosus, are added to the heart as looping proceeds [50]. In prelooping and early looping stages the primitive heart tube consists of circumferential sheets of myocardial cells 2–3 layers thick surrounding the inner endothelial tube. These layers are separated by an acellular matrix–rich space known as the cardiac jelly. As looping continues, the future segments can be distinguished morphologically by their position in the heart tube, and by structural features, such as the concentration of cardiac jelly in the AV canal and outflow segments. Segments can be distinguished physiologically by measurement of the differences in their velocity of muscular contraction and relaxation, their rates of spontaneous pacemaker activity, and the speed of electrical impulse conduction [51,52]. Segmental differentiation creates the physiologic competence of the embryonic heart [53]. Unidirectional antegrade blood flow is maintained by organization of the heart tube into alternating regions of rapid and slow contractile properties [54]. The atrium has the fastest rate of spontaneous contractility, and is the site of pacemaker activity. A wave of depolarization spreads from myocyte to myocyte from the atrium to the outflow tract, but the velocity of conduction is not uniform throughout the length of the heart tube. Atrial conduction is rapid, AV conduction is slow, ventricular conduction is rapid, and outlet conduction is slow. The zones of rapid conduction show rapid contraction–relaxation mechanical properties, while the slow zones of conduction demonstrate slow, sustained contractions. The result is a forceful contraction of the atria, followed by a sphincter-like contraction of the AV junction. Prior to maturation of AV valves, these contractions prevent the retrograde flow of blood during the forceful ventricular ejection phase. The cardiac cycle of the heart tube is completed by a sphincter-like contraction of the outflow tract. Prior to maturation of the arterial valves, this area similarly prevents retrograde blood flow from the aortic arches.

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In addition to these functional differences, the cardiac segments can be distinguished by unique patterns of gene expression. While data suggest that the final determination of lineage fate likely occurs in the precardiac mesoderm [24,55], the timing and nature of the mechanisms are incompletely understood. Perhaps the best-studied molecular determinants of the dorsal–ventral axis in the gastrulating embryo are retinoids [56,57]. Retinoids are products of vitamin A metabolism. Manipulation of retinoid signaling pathways results in significant abnormalities in axial patterning in general and cardiac development [58–60]. Abnormal development of the atrial segments and systemic venous tributaries is observed in conditions of retinoid deficiency [61–63]. Excess retinoids create malformations often involving the outflow tract [64,65], and result in ventricular expression of several genes that are normally largely restricted to the atria at these stages of development [66–68]. The spatial and temporal patterns of retinoid signaling in early cardiac development are highly correlated with the presence of retinaldehyde dehydrogenase 2 (RALDH2), a key enzyme in the retinol (vitamin A) to retinoic acid conversion pathway [69–71]. Retinoid signaling pathways are clearly key mechanisms of segmental differentiation within the heart, but it is clear that other components intersect and augment this pathway.

Looping With the addition of cardiac tissue to the arterial and venous poles, the heart tube elongates and begins to bend. Looping becomes more complex as morphogenesis proceeds. The cranial portion of the tube bends caudally and to the right, while the caudal portion bends cranially to the left. The net outcome of this looping results in the left ventricle being positioned inferior and anterior to the atrium, while the right ventricle is slightly anterior and to the right of the left ventricle. The mechanisms regulating bending of the heart tube are incompletely understood. Interestingly, many looping movements are intrinsic to the heart, and can be observed even if the heart is isolated from the embryo, with or without beating [72,73]. Evidence suggests that deformation of the linear heart tube into a looped structure may be a result of mechanical force [74]. Additionally, bending may simply be the result of asymmetric changes in cell shape. Alternatively, myocytes may replicate faster in the larger curvature of the loop, and more slowly in the lesser curvature [75,76]. Additional studies suggest that asymmetric mechanical tension in the developing heart can induce bending. Experimentally, inhibitors of actin polymerization and cytoskeletal rearrangements can either abolish looping or reverse its direction, according to whether they have been universally or selectively applied [77].

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Regardless of the regulatory mechanisms governing the process, bending of the heart tube confirms that the left and right sides of the embryo will not be morphologic mirror images. Although initial evidence of laterality is found in the atrioventricular canal prior to looping, cardiac development is inextricably linked to correct establishment of the three body axes [78,79]. All vertebrate, and most invertebrate, body plans demonstrate fundamental asymmetry about the three body axes: cranial–caudal (C–C), dorsal–ventral (D–V), and left–right (L–R). At the molecular level, the axes are determined by asymmetric propagation of signaling events early in development. The process of L–R axis determination as it governs heart development is broadly conceptualized as requiring three steps, which involve the initiation, elaboration, and interpretation of the sidedness signals [80,81]. The first step requires initiation of polarity along the C–C, D–V, and L–R axes. The second step is an elaboration and amplification of the initial L–R asymmetry. As is true in general for developmental processes, most of the molecules controlling the L–R signaling process in mice have recognized homologues in multiple species. Emphasizing the necessity to carefully examine multiple models, some of the molecules required for left-sidedness in mice are determinants of right-sidedness in birds [82]. The third step of axis determination is the interpretation of the asymmetric signals elaborated in the second step by the cells and tissues of developing organs. Paired structures develop as two fates, either as mirror symmetries, such as the limbs and parietal body parts, or as paired but unequal structures, such as the lungs, abdominal organs, and atrial appendages. These decisions are governed by both the signal delivered to the organ primordia as well as the reaction of the organ primordia to the signal. Such L–R axis determination in cardiac development is complex and several genetic models of abnormal cardiac looping have been described in mice [83]. Some models reflect an abnormal direction of looping, while others also show misalignment of cardiac segments. Mouse models of globally randomized arrangement of the organs [84,85], global mirror imagery [86], defects affecting different embryonic organs [87], and defects with preferential bilateral right- or left-sidedness resulting in isomerism have all been described [88]. Some genes implicated in the mouse models are likely also important in human isomerism [89]. There is often an increased incidence of abnormal ventriculo-arterial connections in mouse models of abnormal L–R axis determination [73], suggesting an element of L–R signaling in normal development of the outflow tract. Looping determines not only the sidedness of the heart, but, importantly, the correct relationship of the segments of the heart to each other. After looping, it is possible to recognize inner and outer curvatures relative to the

ventricular components of the heart tube (Figure 1.4). By nature of the tight angulation of the inner curvature, the primitive atrial, AV, ventricular, and outflow segments are near each other for the remainder of cardiac development. The inner curvature of the heart is arguably the most critical, complex, and dynamic site in normal cardiac development: it is the region where the right ventricle acquires its inflow, and the left ventricle acquires its outflow. On the luminal surface of the heart, the fold in the heart at the inner curvature results in a small muscular ridge inside the heart between the AV junction and the outflow tract called the ventriculo-infundibular flange, or ridge. Other key landmarks are the two major endocardial cushions of the AV junction, and the two comparable endocardial cushions extending through the outflow tract. The inferior endocardial cushion is attached to the dorsal AV myocardium, while the superior cushion is attached to the ventral AV myocardium. Then, small right and left lateral AV endocardial cushions arise. The two outflow cushions in the outflow tract form extended spiral ridges, initially extending from the pericardial margins cranially to the body of the right ventricle caudally. The endocardial ridge ending in the anterior right ventricle is called the septal endocardial ridge. The endocardial ridge terminating posteriorly in the right ventricle is called the parietal endocardial ridge. The parietal endocardial ridge contacts the right lateral endocardial cushion, which itself will become continuous with the superior endocardial cushion. The septal endocardial ridge contacts the inferior endocardial cushion. As the atrioventricular endocardial cushions fuse during normal septation, together with the mesenchymal cap of the primary atrial septum and the dorsal mesenchymal protrusion, they create the central AV mesenchymal complex. This process continues, via the outflow cushions, to the distal extent of the myocardial outflow tract. The distal margin of the myocardial outflow tract, however, itself regresses proximally during development. The distal outflow tract is then separated by growth of an additional protrusion from the dorsal wall of the aortic sac. It is this protrusion that forms the embryonic aortopulmonary septum. At the most basic level, the process of fusion of mesenchymal tissues can be thought of as a tissue zipper that septates the heart [45]. With respect to human congenital heart disease, this is a critical series of events. Disease phenotypes such as transposition of the great arteries, common arterial trunk, and several tetralogy variants all derive from aberrations of these normal developmental steps. This developmental insight has informed the genetics of congenital heart disease. Similar, yet discrete, anatomic phenotypes may have mechanistically less to do with each other than more disparate anatomic phenotypes derived from common developmental mechanisms.

Development of the Heart and Great Vessels Systemic venous sinus

Primary atrial septum

Distal outflow tract

Intermediate outflow tract

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Proximal outflow tract

Inferior AV cushion Developing right atrium Embryonic iv communication Developing right ventricle Developing left ventricle

Developing right ventricle

Figure 1.4 The images are from an episcopic dataset prepared from a human embryo at Carnegie Stage 14, equivalent to day 11 of development in the mouse (E10.5). The left-hand panel shows a section through the atrial and ventricular components of the developing heart after looping. The systemic venous sinus has been transferred to open to the right side of the atrial component of the primary heart tube, and the atrial appendages are beginning to balloon to right and left (white arrows with red borders). The primary atrial septum has begun to grow from the atrial roof toward the atrioventricular canal. The ventricular component of the heart tube has looped to the left, and the apical ventricular components are beginning to provide the primordiums of the developing right and left ventricles.

The double-headed white arrow shows the embryonic interventricular communication, which is roofed by the inner heart curvature, since at this stage the atrioventricular canal is supported exclusively by the developing left ventricle. The right-hand panel shows how the developing right ventricle supports the outflow tract, which has proximal, intermediate, and distal components. Cushions extend through the intermediate and proximal components, but the distal part has a wide-open lumen. Note that, at this early stage, the developing right atrium has no direct connection with the developing right ventricle, with the dashed white line showing the extensive right atrioventricular groove. AV, atrioventricular, iv, interventricular.

The right AV junction is formed by rightward expansion of the AV junction, while at the same time the midline superior and inferior endocardial cushions are approaching each other in the center of the lumen of the AV junction. The outflow tract endocardial cushions, although unfused, define distinct proximal aortic and pulmonary channels. The aortic channel moves leftward and ventral of its original position. Because of the combined rightward expansion of the AV orifice, and the leftward movement of the aortic outflow tract, the acute angle of the inner curvature now defines the region where the AV junction and the outflow tract are in continuity. These same morphogenetic movements result in rotation of the proximal outflow cushions to a plane that is more closely parallel to that of the growing muscular ventricular septum. Following initial heart assembly, the various segments of the heart continue to develop simultaneously, yet often at different rates. For the rest of the chapter, these events will be presented from the standpoint of the final cardiac

segments formed, rather than in the temporal order in which they develop.

Development of the Inflow (Venous) Pole of the Heart Systemic Venous Inflow The embryonic systemic venous tributaries are formed by a process of vasculogenesis (Figures 1.5 and 1.6). Initially there are three bilaterally symmetric venous drainages: (i) the vitelline or omphalomesenteric, (ii) umbilical, and (iii) cardinal venous systems [90,91]. The vitelline veins drain the embryonic gastrointestinal tract and gut derivatives. The umbilical veins bring oxygenated blood from the placenta to the heart. The cardinal venous system returns blood from the embryonic head, neck, and body wall. All three of these drainage systems enter the systemic venous component of the primitive heart tube, known as the sinus venosus. The final, adult pattern of

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Pediatric Cardiac Surgery Venous valves

Pulmonary vein

Systemic venous sinus

Pulmonary vein

LSCV Dorsal mesocardium

Vestibular spine SCV

ICV Atrioventricular cushions

Left superior caval vein Developing right ventricle

Developing left ventricle

Figure 1.5 The images show how the systemic and pulmonary veins gain their connections to the right and left sides of the initial common atrial component of the primary heart tube. The left-hand panel is a dorsal coronal section through the venous pole of the human embryo shown in Figure 1.1, at Carnegie Stage 14. The left superior caval vein is cut in its long axis as it extends through the dorsal left atrioventricular groove. It opens to the right side of the atrial components, along with the right-sided superior caval vein and the inferior caval vein (SCV, ICV), with the boundaries of the systemic venous sinus marked by the venous valves. The section is cut through the connection of the atrial

component of the heart tube to the pharyngeal mesenchyme, which is the dorsal mesocardium. The orifice of the pulmonary vein is visible in the center of the connection. The right-hand panel is from an episcopic dataset prepared from a mouse embryo sacrificed at E11.5. It shows how the rightward margin of the dorsal mesocardium has proliferated to become the vestibular spine, with its growth serving to commit the pulmonary vein to the cavity of the developing left atrium. Note that the left superior caval vein (LSCV) has its own discrete walls as it runs behind the cavity of the left atrium to enter the atrioventricular groove.

venous drainage is established through complex patterns of regression, remodeling, and replacement of these embryonic venous systems and their connections to the definitive right atrium [92]. Initially, the systemic venous component is bilaterally symmetric, with no anatomic boundaries initially present between it and the atrial component of the heart tube. As development progresses, the junction of tributaries and atrium shifts toward the right, perhaps influenced from blood shunting left to right. Normally, the connections of the left-sided cardinal, vitelline, and umbilical venous systems with the left horn of the systemic venous component regress. This results in the coronary sinus remaining as the primary structural derivative of the left horn of the systemic venous sinus in the normal fetal and postnatal heart. Failure of regression of the connections with the left venous horn results in persistence of the left superior caval vein. The right horn of the systemic venous sinus normally accommodates the entirety of the systemic venous drainage, except the portion from the heart, which is returned via the coronary sinus. A portion of this right horn is incorporated into the right atrium to form its smooth systemic venous portion between the orifices

of the caval veins. At the same time, it is possible to recognize valves at the boundaries between the atrial and venous components. The inferior portion of the rightward venous valves becomes the Eustachian and Thebesian valves. They are related to the orifices of the inferior caval vein and the coronary sinus, respectively. During these processes, the umbilical and vitelline plexuses remodel and regress. Remodeling of the umbilical system produces the venous duct, or ductus venosus, which retains its connection with the cardinal system so as to connect to the developing inferior caval vein, thus bypassing liver sinusoids derived from the vitelline system. After birth, the venous duct becomes ligamentous. Hence, no derivatives of the embryonic umbilical venous drainage connect to the heart or persist in postnatal life. The cardinal venous system initially consists of bilateral anterior cardinal veins, which drain the cephalic portion of the embryo, and bilateral posterior cardinal veins, which drain the caudal portion of the embryo. Fusion of the cardinal veins at the level of the systemic venous sinus forms the sinus horns, or common cardinal veins. The left anterior cardinal vein eventually loses its connection with the left sinus horn, but a small remnant on the

Development of the Heart and Great Vessels

Left atrium

Right atrium

Outflow tract Pulmonary vein

Left superior caval vein

Superior caval vein

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The portion of the right anterior cardinal vein between the right atrium and the drainage of the left anterior cardinal vein proximally, via the intercardinal anastomosis, becomes the normal right superior caval vein. The posterior cardinal veins originally drain the body wall, gonadal, and renal structures. Their function in venous drainage of the body wall is supplanted by the supracardinal venous plexus. The gonadal and renal venous drainage is captured by the subcardinal venous plexus and the lower extremities are drained by the sacrocardinal veins. The various venous beds contribute the segments that form the definitive inferior caval vein to the level of the persisting segment derived from the right vitelline vein, which then connects to the right atrium. The supracardinal venous system persists as the azygous and hemiazygous veins. In both the supracardinal and subcardinal venous systems, the initial vascular structures are bilaterally symmetric. The left-sided channels subsequently regress, underscoring the typical right-sided location of the inferior caval vein. The frequency of venous drainage abnormalities in human and animal models of altered L–R axis differentiation [88] strongly suggest that the mechanisms of venous morphogenesis depend upon appropriate left–right signaling.

Pulmonary Venous Inflow Figure 1.6 The images are from a serially sectioned human embryo at Carnegie Stage 14. The upper section has been incubated with an antibody to NKX 2.5, which marks the myocardium of the atrial walls and the proximal part of the outflow tract. The opening of the pulmonary vein can be seen between the margins of the dorsal mesocardium. The antibody does not, however, mark the walls of the systemic venous tributaries. As is shown in the lower panel, which is an adjacent serial section but incubated with an antibody to TBX18, the venous myocardium is positive to the second antibody, which does not mark the myocardium of either the atrial walls or the outflow tract. The findings support the notion that the pulmonary venous myocardium is not derived from the systemic venous component of the developing heart. Reproduced with the permission of Aleksandr Sizarov.

surface of the heart normally persists as a passage of coronary venous blood to the coronary sinus, and is known as the oblique vein of the left atrium. Another portion of the left anterior cardinal vein persists as the left internal jugular vein. As the left anterior cardinal vein loses connection with the heart, it becomes connected to the right anterior cardinal vein via the intercardinal anastomosis that forms between the thyroid vein and the thymic vein. This connection persists as the left brachiocephalic vein.

The earliest evidence of the formation of the common pulmonary vein in the embryo is the presence of a strand of endothelial cells in the pharyngeal mesenchyme, pointing to the dorsal mesocardium. This endothelial strand forms a lumen, and initially is a midline structure. As the vestibular spine is developing and projecting into the atrial cavity on the right side of the primitive pulmonary vein, the relative position of the common pulmonary vein changes as it occupies a position to the left of center [93]. The continued development of the vestibular spine [44], the myocardialization of this mesenchyme, and the concomitant growth of the primary atrial septum eventually result in the normal connection of the pulmonary vein to the left atrium [94]. The development of the pulmonary vein does not result from an outgrowth of the atrial wall. During this process, the lungs themselves develop from the foregut, with venous elements from the lungs bilaterally fusing with the common pulmonary vein. Abnormal formation of the common pulmonary vein results in persistence of initial connections of the pulmonary plexuses to the cardinal veins, resulting in various forms of anomalous pulmonary venous return. Initially, the walls of the pulmonary veins are not muscular. As development proceeds, myocardial sleeves are formed around these veins [95]. Semaphorin signaling

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Pediatric Cardiac Surgery

has been linked to defects in this process [96]. As pulmonary myocardium is a frequent site initiating atrial fibrillation, a clear understanding of the molecular and genetic mechanisms that direct these events is important.

Atrial Septation The major steps in cardiac septation occur between the fourth and fifth weeks of human gestation. Proper atrial septation requires two important processes. The first is differential proliferation of tissues: for example, the folds often described as the “septum secundum.” The second process is active proliferation of cells that approach each other and fuse, resulting in septation of the chamber: for example, growth of the primary septum and the endocardial cushions. Atrial septation and connection of the common pulmonary vein to the left atrium are closely related events in the normal heart [94]. Experiments in mouse, chick, and human embryos highlight the importance of the dorsal mesocardium to these events [44]. Unlike other mesenchymal tissues in the AV junction, the vestibular spine, which grows through the rightward margin of the dorsal mesocardium, is not derived from an

epithelial-to-mesenchymal transformation, but rather is a derivative of the second heart field [28,45]. The vestibular spine extends into the atrial cavity, becoming contiguous with the mesenchymal cap on the leading edge of the primary atrial septum. Together with the superior and inferior atrioventricular cushions, the vestibular spine and the cap eventually fuse to form the atrioventricular mesenchymal complex. This process is essential for normal atrioventricular septation (Figure 1.6). Recent work suggests that perturbation of the development of the protrusion might be one of the contributing mechanisms in the pathogenesis of atrioventricular septal defects [97]. Based on the expression of several molecular markers that distinguish left and right atrial myocardium, the primary atrial septum is derived from left atrial myocardium. Growth of the septum occurs by lengthening of its myocardial portion. As described above, the cap on the leading edge of the septum primum is mesenchymal, the cells being derived by endothelial-to-mesenchymal transformation like that seen in the endocardial cushions [93]. As growth of the septum proceeds, it brings the mesenchymal cap, as well as the vestibular spine, into contact with the AV endocardial cushions (Figure 1.7).

Primary atrial septum

Venous valves

Secondary foramen Mesenchymal cap Primary atrial septum Left atrium

Right atrium

Right atrium

Mesenchymal cap Primary foramen

Inferior AV cushion

Developing right ventricle Interventricular communication

Developing left ventricle

Figure 1.7 The images are “four-chamber” sections through episcopic datasets prepared from human embryos at Carnegie Stage (CS) 14 (left-hand panel) and CS 16 (right-hand panel). They show how expansion of the right atrioventricular (AV) junction brings the cavity of the right atrium into direct continuity with that of the developing right ventricle. Initially, as shown in the left-hand panel, the AV canal opens exclusively to the developing left ventricle (white arrow with red borders). The blood then enters the developing right ventricle through the embryonic interventricular communication. Note the growth of

Developing right ventricle

Developing left ventricle

the primary atrial septum toward the AV canal, with a mesenchymal cap on its leading edge. By CS 16 (right-hand panel), the primary septum has broken away from the atrial roof, producing the secondary interatrial foramen. The primary atrial foramen is now bounded by the mesenchymal cap carried on the primary atrial septum and the cranial margin of the inferior AV cushion. Note that, by virtue of the expansion of the right AV junction, the cavity of the right atrium is now in direct communication with that of the developing right ventricle (white arrow with red borders).

Development of the Heart and Great Vessels

The primary interatrial foramen is closed by fusion of these mesenchymal tissues as they form the AV mesenchymal complex [45]. Knowledge of this process is critical to understanding the pathogenesis of deficient atrioventricular septation, as well as understanding the tissue relationships relevant to its repair. Before closure of the primary interatrial foramen, the foramen secundum appears at the cranial margin of the septum primum. In humans, this process is initiated by the appearance of small fenestrations that increase in number and size until they coalesce into a definitive foramen [94]. The “septum secundum” then forms as an infolding of the atrial roof in the intervalvar space between the left venous valve of the systemic venous sinus and the primary atrial septum. The infolding also marks the site of the boundary between left and right atrial tissues.

Atrioventricular Valvar Formation An important step in the formation of both AV and arterial valves is the formation of endocardial cushions. When the heart tube initially forms, the myocardial and endocardial cell layers are separated by an acellular substance traditionally called “cardiac jelly” [98]. As it lies between the juxtaposed myocardial and endocardial epithelia, cardiac jelly is a type of basement membrane that contains traditional basement membrane proteins. Cardiac jelly condenses into opposing swellings at the outflow and AV regions of the early, looped heart. The resulting endocardial cushions function in combination with the specialized contractile properties of the AV junction and outflow tract myocardium to limit reversal of blood flow [99]. The AV endocardial cushions also function as the substrate for the formation of the mesenchymal tissues of the crux of the heart, including the AV valves and central fibrous body [100]. Endocardial cushions of the embryonic outflow tract participate in the formation of the arterial valves and free-standing subpulmonary infundibular sleeve [101]. During morphogenesis of the endocardial cushions, the mesenchymal cell population that populates the original acellular cardiac jelly is derived from two sources: (i) the endothelial cells of the heart, and (ii) a population of epicardially derived cells that migrate into the AV cushions [93,102]. Interestingly, this cell population does not populate the outflow tract cushions, which are populated by cells derived from the neural crest [103]. Endothelial invasion of the cardiac jelly results in a true transdifferentiation of cell phenotype, from a cell within a typical epithelium to an independently migratory, fibroblast-like mesenchymal cell [104,105]. This process has been compared to cellular changes during malignant transformation. It is at least partially under the control

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of TGF𝛽-mediated signaling processes [106,107]. Only endocardium from the outflow tract and AV cushions is competent to undergo this transition, and only outflow tract and AV junction myocardium can induce transformation [106,108]. Not all the endocardial cells of the AV and outflow regions participate in these changes. As migration proceeds, residual endocardial cell populations undergo divisions to replenish their numbers. The mesenchymal cells also replicate actively to populate the cushions [104]. There are four endocardial cushions at the AV junction. The superior and inferior cushions are the first to appear, and are the most prominent endocardial cushion masses. There are also important contributions from the lateral endocardial cushions that are visible only after Carnegie Stage 17, representing approximately 42 days of development [100,109]. The left lateral cushion contributes to the mural leaflet of the mitral valve. The right lateral cushion, which becomes continuous anteriorly with the septal endocardial cushion of the outflow tract, contributes to the formation of the anterosuperior and inferior leaflets of the tricuspid valve. Atrioventricular valvar leaflets are formed by separation of endocardial cushion tissue and myocardium from the ventricular walls via a poorly understood process of maturation that includes delamination [109–111]. Other simultaneous events influence normal valvar morphogenesis, and may contribute to the delamination process. These include incorporation of ventricular trabeculations to form the papillary muscles, and apical expansion of the ventricular cavity. At the time of delamination, the atrial surfaces of the valvar leaflets are composed of endocardial cushion tissue, while the ventricular surfaces are primarily myocardial. The myocardial layer provides continuity with the evolving subvalvar tension apparatus. As leaflet morphogenesis proceeds, the myocardial component is eliminated by poorly understood processes. Initially, the ends of the AV leaflets are connected to the compact ventricular myocardium either directly or via the compacting trabeculations. As development proceeds, papillary muscles mature by two mechanisms. First, initially independent, pre-existing trabeculations coalesce to form papillary muscles. Second, myocardium delaminates into myocardial structures and joins with trabeculations to form papillary muscles [111]. The surgically challenging group of patients with parachute mitral valve derivatives are likely due to deficiencies in these processes. Tricuspid valve papillary muscles develop independently from each other and via distinct mechanisms. The anterior papillary muscle of the tricuspid valve in humans derives from an early coalescence of trabeculations detectable at 6 weeks’ gestation. The papillary muscles supporting the septal leaflet are the product of delamination during the 10–12 weeks’ gestation, while

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Pediatric Cardiac Surgery

the inferior papillary muscle complex is still a relatively indistinct structure at 12 weeks’ gestation [110]. The tendinous cords are formed by progressive fenestration and fibrous differentiation of trabeculations and the initially solid individual valvar leaflets [109,112]. Atrioventricular valvar morphogenesis is one of the most prolonged aspects of human cardiac development. Recognizable elements of the tricuspid valve begin formation at 5–6 weeks’ gestation. Now the AV endocardial cushions are actively reconfiguring, with fusion of the superior and right lateral AV endocardial cushions to each other. Simultaneously, the proximal outflow cushions are also completing their fusion. The fused outflow cushions then fuse with the crest of the muscular ventricular septum as the aortic root is transferred to the left ventricle. The surface of the cushions then muscularizes to form the supraventricular crest, with the core of the fused cushion mass attenuating to give rise to the fibroadipose tissues that interpose between the free-standing subpulmonary infundibulum and the aortic root. At this point, the tricuspid valvar leaflets are still very primitive in appearance and not yet freely mobile (Figure 1.8). The inferior leaflet is fully delaminated by the end of Pulmonary valve

Aortic valve

Parietal cushion Septal cushion

Right ventricle

Tricuspid valve

Embryonic interventricular communication

Figure 1.8 The image shows the developing right ventricle as seen having removed its parietal wall in a mouse embryo sacrificed early during E12.5. At this stage, the intermediate part of the outflow tract has separated into the aortic and pulmonary roots, but both roots remain supported by the developing right ventricle. The proximal outflow cushions have yet to fuse completely. The blood from the left ventricle, therefore, continues to enter the aortic root through the embryonic interventricular communication. It is necessary to transfer the aortic root to the left ventricle before ventricular septation can be completed.

8 weeks’ gestation, the anterosuperior leaflet by 11 weeks, and the septal leaflet in week 12. The zone of apposition separating the anterosuperior and septal leaflets is not complete until the septal leaflet is fully delaminated [100]. In development of the mitral valve, the superior and inferior AV cushions begin to fuse at 5 weeks’ gestation. Even prior to the completion of their fusion, the trabeculations will evolve into the two papillary muscles supporting the ends of the solitary zone of apposition between the developing aortic and mural leaflets. It is the fused superior and inferior cushions that give rise to the aortic leaflet of the mitral valve. The left lateral cushion, the precursor to the mural leaflet, is visible by week 7 of gestation. Now initial delamination of the mitral valvar structures becomes detectable and continues until the week 10 of development. Between weeks 10 and 14 of development, myocardial elements of the leaflets are eliminated, papillary muscles achieve their adult appearance, and there is differentiation of the tendinous cords [109,111]. The electrophysiologic and physiologic properties of the junctional myocardium between the primitive atria and ventricles are critical to the preseptated heart. Myocardial continuity between the AV junctional myocardium, the atrial myocardium, and the ventricular myocardium must be interrupted for the development of the fibrous crux of the heart and correct function of the conduction system. This is accomplished by formation of a layer of fibrous insulation, the fibrous annulus or annulus fibrosis. Except for the penetrating bundle of His, the insulating tissues will completely interrupt and insulate myocardial continuity between the AV and the ventricular myocardium. The fibrous annulus forms by fusion of mesenchymal cell populations of the AV endocardial cushions with a mesenchymal cell population found in the AV grooves on the external surface of the looped heart. Atrioventricular groove mesenchyme cells are brought to the heart during the epicardial cell migration (Figure 1.9) [3]. Studies suggest that the mesenchyme of the AV groove actively invaginates into the endocardial cushions, although the mechanisms driving mesenchymal invagination are unknown [113]. Interruption of myocardial continuity begins at 52–60 days’ gestation in the human heart, and is complete by the fourth month [100]. Failure to properly form the insulating tissues of the AV junction may underlie clinical pre-excitation syndromes. Interestingly, isolated myocytes have been identified bridging the fibrous insulation of normal neonatal hearts. These myocytes may represent remnants of the embryonic junctional myocardium, originally present between the mesenchyme of the AV groove and the endocardial cushion mesenchyme. The relationship between pre-excitation pathways in general and normal morphologic events requires further investigation [114,115].

Development of the Heart and Great Vessels (A)

(C) Atrium

LV RV

(B)

RA

PA

Ao

LBB

IVC LA AV Node

RV

RBB

LV Right atriventricular ring bundle

Figure 1.9 The development of the conduction system from a ring of myocardium detected in human embryonic heart by the expression of a carbohydrate epitope recognized by the antibodies Gln2, HNK1, and Leu7. (A) Human heart at roughly 5 weeks’ gestation. A ring of myocardium surrounding the primary interventricular foramen is detected. Note that the superior aspect of the ring is at the junction of atrioventricular (AV) myocardium and ventricular myocardium. (B) In the human heart of roughly 7 weeks’ development, convergence has resulted in expansion of the small segment of AV junctional myocardium to the right, accompanying the rightward expansion of the AV inlet. The leftward movement of the outlet results in the looping of the ring around the aortic root. As the muscular ventricular septum begins to grow, strands of ring tissue can be found extending from the major aspect of the ring on the crest of the septum down the septal walls toward the expanding apices of the right and left ventricles. (C) The mature cardiac conduction system of AV node, bundle of His, and right bundle branch (RBB) and left bundle branch (LBB) is derived from the primitive ring tissue. In addition, remnants of the primitive ring in the adult heart can be found on the atrial side of the tricuspid valve fibrous annulus as well as in retroaortic myocardium. Ao, aorta; IVC, inferior caval vein; LA, left atrium; LV, left ventricle; PA, pulmonary artery; RA, right atrium; RV, right ventricle. Source: Adapted from Moorman AF et al. Circ Res. 1998;82:629–644; Wessels A et al. Anat Rec. 1992;232:97–111.

Atrioventricular valvar development may be tied to the process of ingrowth of the insulating tissues, as the hinge points of the definitive leaflets are normally found at the point of juncture between the endocardial cushion tissues and the invaginating tissue.

Ventricular Chamber Formation and Septation Shortly after looping, the myocardial layers of the heart tube are only a few cells thick. After looping, the ventricular chambers enlarge caudally in a pouch-like fashion.

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The pouches are located on the greater curvature of the looped heart, and quickly develop a series of circumferential ridges on their internal surfaces (Figure 1.4) [3,112]. The myocytes of these primitive trabeculations differ from the subjacent compact myocardium in that the myocytes of the compact myocardium are actively proliferating, while the trabecular myocytes have withdrawn from the cell cycle and are not dividing. The “germinal layer” of compact myocardium provides increases in the numbers of ventricular wall myocytes, but the initial major increases in myocardial mass occur through increase in the trabecular component of the myocardium. The compact myocardium “feeds” cells into the ventricular junctions of the developing trabeculations, a relationship that persists throughout embryonic myocardial growth [3,112]. The primitive trabecular ridges become fenestrated and sponge-like as they expand. Trabeculations are hypothesized to assume several physiologic functions in the primitive heart. They may enhance contractile function of the ventricles [116]. The surface area of the endocardium is greatly increased by their presence. This increase may improve nutrient and gas exchange with the developing myocardium before the development of a true coronary vasculature [117]. The trabeculations have been shown to persist as the distal bundle branches and Purkinje fibers in the postnatal heart [54]. Trabeculations also help to direct the flow of blood in the preseptated heart [118]. Thus, the infrequent yet important echocardiographic finding of the presence of excessive trabeculations bears important implications [119]. The molecular signatures of the compact and trabecular myocardium are distinct. The compact myocardium can respond to signals that direct cell proliferation, and maintain the growth of the embryonic heart by adding new cardiomyocytes. These proliferative signals include proteins such as neuregulin that are secreted by the endocardial cells. This stimulates their cognate receptor proteins in the myocardium, thereby inducing proliferations [120,121]. Similarly, the epicardium may also secrete proteins such as insulin-like growth factor that can trigger cardiomyocyte proliferation [122,123]. The myocardial cells themselves are capable of initiating cell division directly, or indirectly via downstream signaling into the endocardial cells [124]. Recent evidence indicates that there may be extracardiac control of cardiomyocyte proliferation by molecules such as erythropoietin, which may be secreted in the developing liver [125]. Regardless of the source of these signals, the embryonic heart can add new cardiomyocytes to increase the extent of the trabeculations as well as the thickness of the compact layer of the myocardium. This capability is lost in postnatal life in mammals, such that any increase in heart size in the adult is a result of cardiomyocyte hypertrophy rather than the addition of new cells. What molecular changes are

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Pediatric Cardiac Surgery

responsible for this shift, and how they may be reversed, is a subject of active research in the field of cardiac regeneration. Data now suggest that the neonatal mouse is also capable of regenerating new cardiomyocytes, implying that the loss in regenerative capability is likely a postnatal event [126]. The increase in thickness of the compact layer of the embryonic myocardium may decrease diffusion of nutrients from the lumen. This correlates with and, via hypoxic signals, may accelerate the formation of a mature coronary vascular plexus. With the demand for increased surface area now diminished, a large portion of the trabeculations protrude into the myocardial wall, resulting in an even thicker ventricular wall. This process is more robust in the left ventricle, due to unknown mechanisms that correlate with the more densely trabeculated morphology of the right ventricle. Ventricular septation is the process of closing the embryonic interventricular foramen while bringing the muscular ventricular septum into continuity with the muscularizing proximal outflow cushions (Figure 1.10). The embryonic interventricular foramen initially provides all the inflow to the right ventricle and the entire outflow for the left ventricle. It cannot be closed, therefore, until after the right ventricle has achieved its inlet and the left ventricle its outlet. These processes are achieved by

Pulmonary valve

Pulmonary valve

Septal cushion

remodeling the cavity of the initial primary heart tube. Only after this remodeling can the persisting interventricular foramen be closed by coordinated growth of the muscular interventricular septum and fusion of the endocardial cushions in the AV junction and the outflow tract. Growth of the muscular interventricular septum is closely associated with dynamic changes in patterning of the ventricular myocardium [112]. In the mammalian heart, the primitive muscular septum appears to be the product of infolding of the compact myocardium produced by growth of the ventricular apices. The primitive muscular interventricular septum is initially a crescent-shaped structure that extends at its dorsal limit to the inferior endocardial cushion, and at its anterior limit to the superior endocardial cushion. Part of the process of closure of the primary interventricular foramen consists of expansion of the superior and inferior endocardial cushions toward each other, where they will make contact and fuse at approximately 6 weeks’ gestation in the human. Further growth of the interventricular muscular septum results in fusion of the crest of the septum with the fused cushions. In humans, the AV membranous septum is the only nonmyocardial septal structure derived from endocardial cushion tissue. It is derived from

Muscularising surface of cushions

Pulmonary trunk

Excavating distal cushions

Muscularising proximal cushions

Aortic valve

Supraventricular crest

Aortic root

Aortic valve Right ventricle Atrioventricular cushions Interventricular foramen

Atrioventricular cushions

Figure 1.10 The images show the steps involved in the completion of ventricular septation. The left-hand panel is prepared from a mouse embryo sacrificed late during E12.5, while the right-hand panel is from an embryo sacrificed at E13.5. As can be seen in the left-hand panel, the proximal septal outflow cushion has fused with the crest of the muscular ventricular septum, committing the aortic root to the left ventricle. Tubercles growing from the ventricular surfaces of the atrioventricular cushions are now sealing off the interventricular communication. The middle panel shows how the tubercles come together with the margin of the outflow cushion to close the interventricular foramen. The tubercles, with ongoing development, will become the membranous part of the ventricular septum. The white star shows the core of the proximal outflow cushions, which will

Closing interventricular foramen

attenuate to produce the plane between the newly formed subpulmonary infundibulum, derived from the muscularized surface of the proximal cushions, and the aortic root. The black arrow shows the plane that has separated the aortic root from the pulmonary root. The trabeculations of the right ventricle coalesce to form the septomarginal trabeculation, or septal band. The right-hand panel shows a subcostal oblique section through the developing heart from a human embryo at Carnegie Stage 17. The distal parts of the outflow cushions, occupying the intermediate part of the outflow tract, are remodeling to produce the leaflets of the aortic and pulmonary valves. The distal part of the outflow tract itself has already separated to produce the intrapericardial components of the aorta and pulmonary trunk. Only the pulmonary trunk is seen in the section.

Development of the Heart and Great Vessels

tubercles formed at the approximate site of final union between the muscular septum and the AV endocardial cushions [127].

Outflow Tract In the early phases of looping, the outflow tract is short. Later it becomes elongated, with a distinct bend. The site of the bend is the primary external landmark dividing the distal component, sometimes referred to as truncus, from the proximal part, sometimes referred to as conus. The bend itself then achieves prominence, since the primordia of the arterial valves are formed at this site. The tract extends initially from the outlet of the developing right ventricle to the aortic sac. The distal boundary is marked by the reflections of the pericardium. Initially the entire tract is lined by cardiac jelly and has myocardial walls. As the jelly becomes converted into the outflow cushions, however, additional nonmyocardial tissues grow into the distal outflow tract from the second heart field. This produces shortening of the myocardial component, with regression of the distal myocardial border from the pericardial margins. The nonmyocardial component is then separated into aortic and pulmonary components by growth of an oblique protrusion from the dorsal wall of the aortic sac. Growing between the origins of the arteries of the fourth and sixth pharyngeal arches, this protrusion is the embryonic aortopulmonary septum. The persisting outflow tract with myocardial walls is separated by the outflow cushions into the ventricular outflow tracts and the arterial roots. At the base of the heart, the outflow cushions are continuous with the AV endocardial cushions. During remodeling of the proximal outflow tract, the mesenchymal continuity of the cushions will be retained between the mitral and aortic valves, but will be lost between the tricuspid and pulmonary valves [128,129]. The mechanisms that control outflow tract remodeling are increasingly understood. During early development, the outflow tract is positioned such that it receives blood only from the right ventricle. The addition of cells from the second heart field allows the elongation of this tract such that it is positioned medially over the ventricular septum [130–132]. For simplicity, three interrelated yet distinct processes are believed to govern the maturation of the outflow tract. The first of these is alignment, which ensures that the systemic and pulmonary outflow tracts align with the appropriate ventricle. The second is separation, resulting in the initially solitary cavity of the outflow tract becoming the separate aortic and pulmonary pathways. The third is rotation, such that the outflow from the pulmonary and systemic ventricles is joined to the appropriate arterial trunk. It is precisely these mechanisms that are of particular importance in understanding the

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pathogenesis of a large number of clinically challenging congenital heart disease phenotypes. A deficiency of cells from the second heart field results in a shortened outflow tract, which cannot then be properly aligned with the ventricular septum. An extended discussion of these mechanisms can be found in Chapter 2. During their initial septation, the newly formed aortic and pulmonary roots remain connected to the right ventricle, resulting in double outlet right ventricle (DORV). A defect in outflow tract septation, but with normal outflow tract elongation and alignment, results in a medially positioned but undivided common arterial trunk. Finally, lack of proper rotation of the great vessels, or more likely a defect in the spiral septation of the aortic and pulmonary trunks, results in discordant ventriculoarterial connections, known as transposition of the great arteries. While the cellular components that participate in outflow tract morphogenesis are recognized, the molecular signals and cellular interactions that underlie normal morphogenesis have yet to be fully elucidated [133,134]. Several molecular pathways have been implicated in these processes, including retinoic acid signaling [135], TGF𝛽 [106], and Notch pathway components [136].

Outflow Tract Septation Separation of the intermediate and proximal parts of the outflow tract is a multistep process. Initially the developing endocardial cushions are “simple” structures consisting of cardiac jelly bounded by endocardium and myocardium. As in the AV cushions, a subset of endocardial cells transdifferentiates into mesenchymal cells that then invade the cardiac jelly. The cushions thus formed subsequently enlarge and are brought into apposition [99]. Fusion proceeds temporally from the union with the nonmyocardial distal outflow tract to the base of the heart, and results initially in the formation of a mesenchymal outflow septum. When the proximal cushions fuse, they complete the separation of the subaortic and subpulmonary outflow tracts. The right ventricular surface of the fused endocardial cushions is then replaced by myocardium, which is then transformed into the free-standing subpulmonary infundibular sleeve as the central core of the cushion mass attenuates. The newly formed myocardial component becomes the supraventricular crest, with no muscular outlet septum to be found postnatally. The process of initial septation is dependent on the cells derived from the neural crest. These can be recognized as the so-called prongs that extend from the site of fusion of the aortopulmonary septum derived from the protrusion from the dorsal wall of the aortic sac and the distal margins of the outflow cushions themselves. The neural crest cells in the proximal cushions subsequently disappear, as they do in the intermediate part of the outflow tract.

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Pediatric Cardiac Surgery

It is the disappearance of these cells that creates the area of fibroadipose tissue that interposes between the arterial roots in the postnatal heart, and between the aortic root and the free-standing subpulmonary infundibular sleeve [137].

Development of the Arterial Valves The arterial valves develop in the intermediate part of the outflow tract, at the junction between the aortopulmonary septum and the fused distal outflow cushions [129,138]. They are derived from the distal ends of the parietal and septal cushions, along with the intercalated cushions that form between the edges of the major cushions. Fusion of the cushions themselves occurs by contact, followed by disappearance of the endothelial cells at the site of contact. The site of fusion of the cushions with the protrusion from the dorsal wall of the aortic sac is marked by a whorl or knot-like structure. Prongs extend from the knot into the proximal cushions. In the past, these have been said to contribute to aortopulmonary septation. The so-called prongs, however, do not become visible until after the intrapericardial arterial trunks are separated one from the other. The prongs are involved with initial separation of the proximal outflow tract, which then becomes the outlets for the right and left ventricles. Development of the arterial valvar leaflets begins shortly after septation of the intermediate part of the outflow tract. In mice, the initial process is excavation of tissue corresponding to the future leaflets from the arterial surface of the distal and intercalated cushions [139]. Valvar sinuses are then formed by ongoing proliferation of cells into the distal outflow tract from the second heart field. The leaflets are initially thickened structures filled with an abundant extracellular ground substance, densely populated with endocardial-derived mesenchymal cells, bordered by a cuboidal endothelium on the arterial surface, and by a flattened, streamlined endothelium on the ventricular surface [129,140]. After the sinuses are fully excavated, the thickened structures remodel into the thin fibrous tissue characterizing mature semilunar leaflets. Valve remodeling is a slow process that even at birth may be incomplete. The mechanisms that guide this remodeling are incompletely understood. The only neural crest–derived cells present in the developing semilunar leaflets are at the junctures of the zones of apposition between them and the arterial wall of the valvar sinuses, and then only in all components of the aortic root [141,142]. These locations may hint at links between neural crest abnormalities and abnormalities of valvar formation or location. An animal model of both aortic and pulmonary valve aplasia is found in mice deficient in the NFATC gene [143,144]. NFAT proteins are transcription factors

known to be important mediators of intracellular calcium signaling in the immune system, nervous system, myocardium, and skeletal muscle [145,146]. NFAT signaling is initiated by calcineurin, the primary intracellular target of cyclosporine and FK506. During heart development in mice, expression of the NFATC gene is limited to a subset of cells in the endocardium, but beyond this observation the mechanism of contribution of NFATc to arterial valvar development is unknown. Although rare, aplasia of both arterial valves has been described in humans [147,148]. Additionally, dysplasia of one or another arterial valve is one of the most common forms of congenital heart disease, either seen in isolation, as in the aortic valve with only two leaflets, or in conjunction with other defects such as tetralogy of Fallot, tetralogy of Fallot with absent pulmonary valve syndrome, or pulmonary atresia. Valvar problems are also encountered in a wide variety of left ventricular outflow tract defects that include aortic valvar hypoplasia and hypoplastic left heart syndrome as their most severe manifestation. Mutations in the Notch/Jagged pathway genes, as well as EGFR, have been implicated in bicuspid aortic valves, and as contributing factors to accelerated aortic valvar calcification [136,149]. Recent work targeting these pathogenic signaling pathways may serve as novel adjunctive therapies in the future [150]. The anatomy of the calcified aortic valve is unique such that the degree of calcification varies between the ventricular and arterial surfaces of the leaflets. Whether this reflects a difference in embryology, is affected by blood flow dynamics, or is a consequence of genetic background remains to be clearly elucidated. Indeed, evidence is mounting that it is multifactorial.

Aortopulmonary Septation The aortopulmonary septum is initially formed as a protrusion from the dorsal wall of the aortic sac between the fourth and sixth aortic arches (Figure 1.11) [128,138]. The extracardiac origin of this mesenchyme has been well recognized since the late 1970s [151]. Kirby identified a population of neural crest cells that contribute to aortopulmonary septation [35]. This protrusion grows toward the opposing cushions that are forming within the persisting myocardial component of the outflow tract. As the cushions themselves initially fuse distally, so an embryonic aortopulmonary foramen can be recognized between the protrusion and the fused cushions. It is obliteration of the foramen that completes the formation of the nonmyocardial intrapericardial arterial trunks. Only after this process is complete is it possible to recognize the two prongs of mesenchymal condensations that penetrate caudally to occupy the proximal cushions, which are themselves unfused at this stage. Septation then moves proximally toward the heart and is accomplished by

Development of the Heart and Great Vessels

fusion of the cushions containing the prongs of neural crest–derived mesenchyme. With ongoing maturation, the arterial trunks and roots achieve their components of neural crest–derived smooth muscle cells, so the components of the outflow tract separate one from the other. It is failure to close the embryonic aortopulmonary foramen that produces the various forms of aortopulmonary window. These are found only in the presence of normal separation of the arterial roots and ventricular outflow tracts. Failure of fusion of the outflow cushions themselves is the cause of common arterial trunk.

Development of the Aortic Arch The great vessels are the conduits for blood to flow from the heart to the body and therefore must be formed and functional at the time of initiation of embryonic circulation, which takes place at approximately day 20–22 of gestation in humans. The vessels of the embryo are formed by a process called vasculogenesis. Vasculogenesis occurs by aggregation of pre-endothelial cells, or angioblasts, into networks of small endothelial channels. This contrasts with the process of building vessels by sprouting growth or branching, called angiogenesis. These endothelial channels assume arterial or venous identity based on distinct molecular signatures, even before the initiation of circulation. The dorsal aorta and aortic arches develop by fusion of independently formed regional arterial vasculogenic networks. Loss of arterial-specific markers adversely impacts the maturation of this nascent arterial network, and can result in embryonic lethality [152]. After communications between the arterial and venous networks are established, the definitive lumen is formed through merging of the small endothelial passages into larger channels [153]. The channels are functional vessels composed of only endothelial cells. Mesenchymal cells in the descending aorta and neural crest cells in the aortic arch region are then recruited to form the smooth muscle cells of the media of the developing arteries [154–156]. These enveloping events require signaling through extracellular proteins known as angiopoietins via the Tie1 (TIE) and Tie2 (TEK) receptors in endothelial cells [157]. The transcription factor KLF2 (LKLF) has also been shown to be necessary for formation of the tunica media in embryonic vessels [158]. Initially, the embryonic arterial circulation is bilaterally symmetric, and consists of multiple pairs of aortic arch vessels connecting the heart outflow to the paired dorsal aortas (Figure 1.11). The dorsal aortas are initially paired for the full length of the embryo. Fusion of the paired aortas into a single structure begins distally and progresses in retrograde fashion. As development proceeds, the paired first, second, third, fourth, and sixth aortic

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vessels, and the dorsal aortas, undergo an intricate series of transformations. The first and second aortic arch vessels regress, remaining patent only as capillary structures. The dorsal aorta between the third and fourth aortic arch vessels, known initially as the carotid duct, regresses completely, leaving no remnant, resulting in the paired third aortic arch vessels becoming the only source of blood flow from the intrapericardial aorta to the head of the embryo. The third aortic arch vessels become the precursors of the definitive common carotid arteries. The right dorsal aorta completely regresses at the site of dorsal aortic bifurcation. This leaves the right fourth aortic arch vessel to become a short stub connecting the right seventh intersegmental, the future subclavian artery, to the aortic sac. The left sixth aortic arch vessel becomes the arterial duct, with the right and left pulmonary arteries canalizing in the ventral pharyngeal mesenchyme, taking their origin from the floor of the aortic sac. The left dorsal aorta remains widely patent throughout its length, but remodels so that the definitive left fourth and sixth aortic arch vessels, along with the left seventh intersegmental artery, the future left subclavian artery, all connect to the left dorsal aorta [159]. Understanding these developmental concepts and relationships is helpful in planning repair of abnormalities of the great arteries as well as vascular rings. Despite the generally superb imaging now provided by echocardiography, computed tomography angiography, and magnetic resonance imaging that accompanies patients with aortic patterning defects, one is occasionally surprised by intraoperative findings. A basic knowledge of great vessel developmental derivatives can help troubleshoot an intraoperative surprise, and potentially limit the dissection required to reveal relevant operative anatomy. The vertebral arteries are derived from anastomoses between the seven cervical intersegmental arteries. After continuity is established between the intersegmental arteries, their connections to the dorsal aorta regress, apart from the connection of the seventh intersegmental vessel, which becomes the subclavian artery. It is this process that accounts for the subclavian origin of the definitive vertebral arteries. Neural crest cells are critical to the normal pattern of regression or maintenance of aortic arch vessel patency [3,32]. When neural crest cells are physically ablated in chick embryos, vascular patterning is abnormal in 100% of experiments, although the specific pattern of ablation-induced abnormalities is not predictable. Neural crest cells invade and replace the original tunica media of the aortic arch vessels, but it is not known by what specific mechanisms neural crest cells determine the future vascular pattern. Several genetic models of abnormal aortic vessel patterning that are not yet linked to neural crest abnormalities have been identified in mouse and zebra fish. Genetic engineering experiments

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Pediatric Cardiac Surgery Pharyngeal arch arteries

Right fourth arch

Pulmonary trunk Left fourth arch

Aortic sac Aorta Left sixth arch

Parietal outflow cushion

Distal lumen Descending aorta Septal outflow cushion Right dorsal aorta

Pulmonary arteries

Figure 1.11 The images show how remodeling of the branches from the aortic sac produces the extrapericardial arterial

channels. The left-hand panel is a reconstruction of a mouse embryo.

in mice involving the closely related transcription factors mesoderm Forkhead Box C1 (Foxc1) and mesenchyme Forkhead Box C2 (Foxc2) demonstrate cardiovascular phenotypes that include coarctation of the aorta, interrupted aortic arch, ventricular septal defects, and, in the case of Foxc1, thickening and partial fusion of arterial valvar leaflets [160]. It is also interesting to note that abnormalities with left fourth pharyngeal arch artery maturation are disproportionately represented in clinically observed arch artery anomalies, such as interrupted aortic arch, right-sided aortic arch, and cervical arch.

In addition to being a key site for coronary vasculogenesis, the mesenchymal cells that come to populate the AV groove matrix will form most of the fibrous insulating tissues between the atria and the ventricles [100]. All the cell populations just described as invading the myocardium and/or subepicardial extracellular matrix have come to be known as epicardial-derived cells (EPDCs) [103]. As identified by lineage markers, EPDCs migrate into the matrix of the AV grooves, and subsequently into the AV endocardial cushions. In addition to entering the AV cushions, EPDCs also migrate into the myocardium and subendocardium. Specific possible morphogenetic roles of the myocardial and subendocardial EPDCs have not been determined, but abnormalities of the compact myocardium, AV cushions, and coronary vasculature have all been documented in their absence [164]. The subepicardial space is the site of origin of the vascular plexus of the coronary vessel precursors. The exact origin of the coronary endothelium is controversial. Reports have suggested that these cells may originate from the AV groove or the endothelium of the systemic venous sinus [165], from endocardium of the heart [166], or from circulating angioblasts. There are three sequential and overlapping phases of nutrient delivery to the myocardium during embryogenesis of the heart [117,159]. The first phase is associated with the development of an extensive network of intratrabecular spaces lined by endocardial cells, through which nutrient flow to the myocardium is hypothesized to occur. The second phase is the development of a subepicardial

Coronary Arterial Development As the epicardial layer of cells extends over the heart, an extensive acellular extracellular matrix layer appears between the epicardium and the myocardium. If migration from the proepicardial organ is physically disrupted in chick embryos, then no epicardium develops, and there is failure of formation of the subepicardial extracellular matrix [161]. More recent experiments using genetic lineage-tracing techniques in mice confirm that proepicardial-derived endothelial cells contribute significantly to the coronary vasculature [162,163]. The subepicardial space becomes populated by mesenchymal subepicardial cells, generally accepted to provide the precursors of cardiac fibroblasts, and coronary vascular smooth muscle cells. The subepicardial extracellular matrix accumulates to its greatest degree in the AV groove.

Development of the Heart and Great Vessels

plexus of endothelial-lined channels that penetrate the myocardium. A subset of these channels communicates with the intratrabecular spaces. The third stage is regression and coalescence of the vascular subepicardial network into muscular arterial channels. As soon as the vessels are readily identifiable, they are noted to penetrate the ventricular and atrial walls, where they establish a mid-myocardial network. The vessels spread to the ventral surface of the heart and follow the grooves, especially the AV grooves, to the outflow tract, where they form a plexus in the myocardial sheath surrounding the developing arterial roots. Coalescence of vessels, and capillary outgrowth from the developing aortic root, results in formation of the proximal coronary arteries [39,167,168]. Abnormalities of this process likely contribute to the pathogenesis of several surgically important disease phenotypes, including intramural coronary orifices, abnormalities of coronary positioning in both normally related and transposed great vessels, and anomalous origin of the coronary arteries from the pulmonary trunk.

Conduction The sinus node is formed at the junction of the superior caval vein with the expanding right atrial appendage. The cells that will condense to become the node occupy the epicardial tissue of the terminal groove [169]. The AV node has a more complex developmental evolution, since it cannot achieve the structure seen postnatally until after the completion of atrial septation. Indeed, new imaging techniques suggest additional complexity [170]. The muscularization of the vestibular spine and mesenchymal cap forms the anteroinferior buttress that anchors the septum against the insulating tissues of the central fibrous body. The continuity between the compact component of the node and the ventricular parts of the atrioventricular conduction axis are present earlier. They are part of the ring of cardiomyocytes that surrounds the embryonic interventricular communication. Part of this ring becomes sequestrated within the vestibule of the right atrioventricular junction, providing the potential for alternative nodes to be formed around the orifice of the right AV valve [171]. In the normal heart, it is the AV conduction axis that remains as the solitary muscular connection between the atrial and ventricular masses [115,172]. Invagination of the mesenchyme of the atrioventricular groove serves to encase the future bundle of His in the insulating tissue of the central fibrous body. Differentiation of ventricular components of the conducting tissues occurs by recruitment of “working” myocardium into the conduction lineage [173,174]. It is the trabeculations of the inner layer of the initial ventricular walls that are used to connect the proximal bundle branches, derived from

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the primary ring, with the ventricular free walls [175]. Subsets of these trabeculations remain as elements of the conduction tissue in the mature heart [176].

Conclusion Intricate spatial and temporal regulatory mechanisms govern morphogenesis of the heart. The efficiency of these regulatory mechanisms is evident when one considers that, despite the complexities involved, abnormal development of the heart is seen in only a small proportion of normal pregnancies. A greater appreciation of the developmental mechanisms can enhance our understanding of congenital heart diseases. As physicians, such knowledge can help us to care for these complex patients.

Acknowledgments The authors thank Andy Wessels and Steven Kubalak for their important contributions on earlier editions of the text.

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CH A P T E R

2

Genetics of Congenital Heart Disease Peter J. Gruber Yale New Haven Children’s Hospital, New Haven, CT, USA

The completion of the Human Genome Project in 2004 resulted in the initial sequencing of a reference human genome. This achievement ushered in a period of unprecedented growth in our understanding of the genetic underpinnings of human disease [1–3]. Recent advances have dramatically improved our knowledge of the genetic architecture of congenital heart disease (CHD), identifying important gene regulatory mechanisms [4–6]. The wealth of new putatively causative genes has had important implications for cardiac development [7,8]. However, with these new discoveries came the growing realization of the enormous complexity of the human genome, especially as it relates to human CHD [9–11]. This emphasizes the importance of incorporating nuanced genetic features beyond coding sequence alterations in analyses [12–14]. Much of what now appears in the literature focuses on alterations in DNA sequence data that can be categorized and understood in terms of the size, character, location, or frequency of sequence variants, with important implications for gene expression and inheritance. Given what we know of the extreme phenotypic (both anatomic and physiologic) variability of CHD, even within narrow CHD anatomic subtypes, it is not surprising that the genetic underpinnings of CHD are complex and incompletely understood. The objective of this chapter is to provide some insight into known CHD inheritance patterns and recurrence risk and review the newest findings regarding the genetic basis of CHD. Rather than discuss a “laundry list” of identified genes and review basic Mendelian inheritance, we instead provide a conceptual framework for the relationship between genomic variation and CHD. We focus on clarifying recent studies that utilize the most recent genomic discovery techniques that may be difficult to interpret and are dependent upon a baseline knowledge of complex techniques. This overview aims to educate clinicians to analyze the pertinent genetic literature and

understand the impact of new discovery. An updated list of commonly associated chromosomal aneuploidies, copy number variants, and putative causative genes are presented separately in Tables 2.1,2.2, and 2.3 [10], but will not be discussed individually in any significant depth.

Common Variants Although a single reference genome exists in theory, the 6 billion base diploid genome is characterized by diversity and ongoing polymorphic variations through subsequent generations. Any two unrelated genomes typically vary at millions of loci (a genetic position) totaling upward of 25 million base pairs of DNA [15,16]. These genetic differences can be categorized as small-scale, intermediate-scale, or large-scale structural variants (Tables 2.1,2.2, and 2.3). Small-scale structural variants are composed of single-nucleotide changes and short insertions and deletions, called “indels.” Intermediate-scale sequence variants can also be deletions, but more commonly refer to copy number variants (with gain or loss) that impact hundreds of thousands to millions of base pairs. Large-scale structural variants refer to chromosomal abnormalities that can be evaluated microscopically. Each type of genetic variation will be described here. It is in this genetic variation that the key to both individuality as well as disease pathogenesis lies. Essentially all of the methodology for genetic discovery used in the past decade is based upon the simple concept of identifying the genetic differences between patients and controls. One looks for either sequence variation or structural variation by selecting candidate genes to examine or compare the entire genome. The classical “forward genetic” approach begins with the identification of a phenotype, followed by various techniques to map the

Pediatric Cardiac Surgery, Fifth Edition. Edited by Constantine Mavroudis and Carl L. Backer. © 2023 John Wiley & Sons Ltd. Published 2023 by John Wiley & Sons Ltd.

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Table 2.1 Syndromes associated with congenital heart disease (CHD). Syndrome

Locus

Causal gene(s)

Most common CHD

% with CHD

Chromosomal abnormalities Down Trisomy Turner Monosomy

Chr21 ChrX

Unknown Unknown

40–50% 20–50%

Patau

Trisomy

Chr13

Unknown

Edwards

Trisomy

Chr18

Unknown

AVSD COA; BAV; dilation of ascending aorta; HLH; PAPVC without ASD ASD, VSD, PDA, polyvalvular disease ASD, VSD, PDA, polyvalvular disease

Chromosomal structural syndromes 22q11 Deletion Deletion

22q11.2

TBX1

80–100%

Williams-Beuren

Deletion

7q11.23

ELN

Cri-Du-Chat Cat Eye

Deletion Inversion Duplication Deletion Deletion

5p15.2 22q11

CTNND2 Unknown

TOF; IAA type B; TA; VSD; aortic arch abnormalities SVAS; PAS: multiple arterial stenoses; AV and MV defects VSD, PDA, ASD, TOF TAPVC, TOF

11q23 1p36

Unknown, JAM-3 DVL1

HLH, LVOT defects PDA, noncompaction cardiomyopathy

>50% 43–70%

20p12; 1p12

JAG1; NOTCH2

>90%

12q24; 12p1.21; 2p21; 3p25.2; 7q34; 15q22.31; 11p15.5; 1p13.2; 10q25.2; 11q23.3; 17q11.2 12q24 6p12 4p16 11p15.5

PTPN11; KRAS; SOS1; RAF1; BRAF; MEK1; HRAS; NRAS; SHOC2; CBL; NF1 TBX5 TFAP2B EVC; EVC2 HRAS

Peripheral pulmonary hypoplasia; PS; TOF PS; ASD; VSD; PDA

ASD; VSD; PDA PDA ASD/single atrium PS; other structural heart disease; hypertrophy; rhythm disturbances PS; ASD; HCM

85% 100% 60% 63%

TOF; ASD; VSD VSD, PFO, TOF

85% ....

VSD, ASD, TOF, SV, COA, PDA, TGA, RBBB

31–55%

Jacobsen 1p36 Deletion

Defect

Single-gene mutation syndromes Alagille Single gene Noonan

Single gene

Holt-Oram Char Ellis-van Creveld Costello

Single gene Single gene Single gene Single gene

Cardiofaciocutaneous

Single gene

12p12.1; 7q34; 15q22.31; 19p13.3

CHARGE Duane-radial Ray Syndrome DDRS (Okihiro Syndrome) Kabuki Syndrome

Single gene Single gene

8p12; 7q21.11 20q13.2

KRAS; BRAF; MAP2K1; MAP2K2 CHD7; SEMA3E SALL4

Single gene

12q13.12

MLL2

80–100% 80–100%

80–100% 10–55% >50%

80%

71%

ASD, atrial septal defect; AV, aortic valve; AVSD, atrioventricular septal defect; BAV, bicuspid aortic valve; COA, coarctation of the aorta; HCM, hypertrophic cardiomyopathy; HLH, hypoplastic left heart; IAA, interrupted aortic arch; LVOT, left ventricular outflow tract; MV, mitral valve; PAPVC, partial anomalous pulmonary venous connection; PAS, pulmonary artery stenosis; PDA, patent arterial duct; PFO, patent foramen ovale; PS, pulmonary stenosis; RBBB, right bundle branch block; TAPVC, total anomalous pulmonary venous connection; SVAS, supravalvular aortic stenosis; TA, temporal arteritis; TGA, transposition of the great arteries; TOF, tetralogy of Fallot; SV, single ventricle; VSD, ventricular septal defect. Source: Adapted from [10].

Genetics of Congenital Heart Disease

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Table 2.2 Copy number variants associated with nonsyndromic congenital heart disease. Locus

Size (Kbp)

CNV

No of genes

Genes*

Phenotype

1q21.1

418–3,981

Gain, loss

3–45

TOF, AS, COA, PA, VSD

3p25.1 3q22.1–3q26.1

175–12,380 680–32134

Gain Gain, loss

2 0–300

4q22.1 5q14.1–q14.3 5q35.3

45 4,937–5454 264–1777

Gain Gain Gain

1 41103 19–38

7q11.23 8p23.1 .9q34.3 11p15.5 13q14.11 15q11.2

330–348 67–12,000 190–263 256–271 555–1430 238–2,285

Gain Gain, loss Loss Gain Gain Loss

5–8 4 2–9 13 7 4

PRKAB2, FM05, CHD1L, BCL9, ACP6, GJA5, CD160, PDZK1, NBPF11, FMO5, GJA8 RAF J, TMEM40 FOXL2, NPHP3,FAM62C, CEP70, FAIM, PIK3CB, FOXL2, BPESC1 PPM1K EDIL3, VCAN, SSBP2, TMEM167A CNOT6, GFPT2, FLT4, ZNF879, ZNF345C, ADAMTS2, NSD1 FKBP6 GATA4, NEIL2, FDFT1, CSTB, SOX7 NOTCH1, EHMT1 HRAS TNFSF11 TUBGCP5, CYFIP1, NIPA2, NIPA1

16p13.11 18q11.1–18q11.2 19p13.3

1414–2903 308–6118 52–805

Gain Gain Gain, loss

11–14 1–28 1–34

Xp22.2

509–615

Gain

2–4

MYH11 GATA6 MIER2, CNN2, FSTL3, PTBP1, WDR18, GNA11, S1PR4 MID1

TOF DORV, TAPVC, AVSD TOF TOF TOF HLHS, Ebstein AVSD, VSD, TOF, ASD, BAV TOF, COA, HLHS DILV, AS TOF, TAPVC, VSD, BAV COA, ASD, VSD, TAPVC, complex left-sided malformations HLHS VSD TOF TOF, AVSD

AS, aortic stenosis; ASD, atrial septal defect; AVSD, atrioventricular septal defect; BAV, bicuspid aortic valve; CNV, copy number variant; COA, coarctation of the aorta; DILV, double inlet left ventricle; HLHS, hypoplastic left heart syndrome; PA, pulmonary atresia; TAPVC, total anomalous pulmonary venous connection; TOF, tetralogy of Fallot; VSD, ventricular septal defect. Source: Adapted from [10].

responsible gene. “Reverse genetics” takes the opposite approach, in which a gene of interest is mutated and the associated phenotype is interrogated. Although both techniques provide insight into causality, both also have limitations. Forward genetic approaches rely on statistical associations and may fail to provide robust mechanistic insights. Similarly, reverse genetic approaches provide a more robust association of gene function and phenotype, but until recently were not experiments that could be performed in humans and therefore lacked the complexity of other approaches. In general, if one wants to understand humans, it is necessary to study humans. Prior to the sequencing of the human genome and the subsequent development of the International HapMap project, very little was known about the underlying contribution of genetic variation to CHD [17]. Although obvious associations between large chromosomal aneuploidies such as Trisomy 21 and CHD were well known (Table 2.1), the pedigrees of classic multigenerational families that were necessary to determine genetic linkage were simply not available. Except for relatively minor phenotypes such as atrial septal defects and familial patent arterial duct, cardiac-related complications invariably led to death during childhood, thus preventing the

accumulation of affected individuals in families [18,19]. When data from the HapMap project became available in 2005, for the first time scientists had the tools to begin to understand the underlying genetic architecture of CHD as it is known today. The HapMap was the first attempt to categorize the genetic diversity of humans using the millions of single-nucleotide variants that are found throughout the human genome [17]. Large-scale sequencing technology was limited to microarrays, so this map of genetic variants could be based only on sequence variation found commonly throughout the human population and was limited in resolution. These single-nucleotide polymorphisms (SNPs) were usually found at a population frequency of at least 5%. Importantly, although 5% seems relatively infrequent, in genetic language it was the operational definition of a common variant at the time (now more often described as >1%). Studies that determined the association of common variation to complex traits or diseases were termed genome-wide association studies (GWAS), and received a tremendous amount of interest as the first significant validation of the Human Genome Project [20]. GWAS specifically refer to studies involving common variants in contrast to the study of rare variants,

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Table 2.3 Single genes associated with congenital heart disease. Gene

Protein

Phenotypes*

ANKRD1 CITED2 FOG2/ZFPM2 GATA4 GATA6 HAND2 IRX4 MED13L NKX2-5/NKX2.5

Ankyrin repeat domain c-AMP responsive element-binding protein Friend of GATA GATA4 transcription factor GATA6 transcription factor Helix-loop-helix transcription factor Iroquois homeobox 4 Mediator complex subunit 13-like Homeobox containing transcription factor

NKX2-6 TBX1 TBX5 TBX20 TFAP2B ZIC3

Homeobox containing transcription factor T-Box 1 transcription factor T-Box 5 transcription factor T-Box 20 transcription factor Transcription factor AP-2 beta Zinc finger transcription factor

ACVR1/ALK2 ACVR2B ALDH1A2 CFC1/CRYPTIC CRELD1 FOXH1 GDF1 GJA1 JAG1 LEFTY2 NODAL

BMP receptor Activin receptor Retinaldehyde dehydrogenase Cryptic protein Epidermal growth factor-related proteins Forkhead activin signal transducer Growth differentiation factor-1 Connexin 43 Jagged-1 ligand Left–right determination factor Nodal homolog (TGF-beta superfamily)

NOTCH1 PDGFRA SMAD6 TAB2 TDGF1 VEGF ACTC ELN MYH11 MYH6 MYH7

NOTCH1 (ligand of JAG1) platelet-derived growth factor receptor alpha MAD-related protein TGF-beta activated kinase Teratocarcinoma-derived growth factor 1 Vascular endothelial growth factor Alpha cardiac actin Elastin Myosin heavy chain 11 Alpha myosin heavy chain Beta myosin heavy chain

TAPVC ASD; VSD TOF, DORV ASD, PS, VSD, TOF, AVSD, PAPVC ASD, TOF, PS, AVSD, PDA, OFT defects, VSD TOF VSD TGA ASD, VSD, TOF, HLH, COA, TGA, DORV, IAA, OFT defects PTA TOF, (22q11 deletion syndromes) AVSD, ASD, VSD (Holt-Oram syndrome) ASD, MS, VSD PDA (Char syndrome) TGA, PS, DORV, TAPVC, ASD, HLH, VSD, dextrocardia, L–R axis defects AVSD PS, DORV, TGA, dextrocardia, TOF TOF; TGA; AVSD; ASD; VSD; IAA; DORV ASD; AVSD TOF, TGA Heterotaxy, TOF, TGA, DORV ASD, HLH, TAPVC, (oculodentodigital dysplasia) PAS, TOF, (Alagille syndrome) TGA, AVSD, IAA, COA, L-R axis defects, IVC defects TGA, PA, TOF, DORV, dextrocardia, IVC defect, TAPVC, AVSD BAV, AS, COA, HLH TAPVC BAV, COA, AS OFT defects TOF, VSD COA, OFT defects ASD SVAS, PAS, PS, AS (Williams-Beuren syndrome) PDA, aortic aneurysm ASD, TA, AS, PFO, TGA Ebstein anomaly, ASD, NVM

AS, aortic stenosis; ASD, atrial septal defect; AV, aortic valve; AVSD, atrioventricular septal defect; BAV, bicuspid aortic valve; COA, coarctation of the aorta; DORV, double outlet right ventricle; HCM, hypertrophic cardiomyopathy; HLH, hypoplastic left heart; IAA, interrupted aortic arch; IVC, inferior caval vein; LVOT, left ventricular outflow tract; MS, mitral stenosis; MV, mitral valve; NVM, neovascular membrane; OFT, outflow tract; PAPVC, partial anomalous pulmonary venous connection; PAS, pulmonary artery stenosis; PDA, patent arterial duct; PFO, patent foramen ovale; PS, pulmonary stenosis; RBBB, right bundle branch block; TAPVC, total anomalous pulmonary venous connection; SVAS, supravalvular aortic stenosis; TA, temporal arteritis; TGA, transposition of the great arteries; TOF, tetralogy of Fallot; SV, single ventricle; VSD, ventricular septal defect. Source: Adapted from [10].

Genetics of Congenital Heart Disease

which at the time was limited by technology. SNPs and common single-nucleotide variants are one and the same, whereas rare single-nucleotide variants that occur at very low frequencies, usually well below 1%, are considered mutations rather than polymorphisms or SNPs. In both candidate gene association studies and GWAS, the association of common variants and CHD is not strongly associated with CHD [21–24].

Common Variants as Gene Modifiers A subsequent iteration of the HapMap, the 1000 Genomes Project, confirmed that >95% of variation within an individual genome is common. This does not mean that individual genomes are overwhelmingly similar, but rather that most genetic variants are found repeated in human populations. This population frequency has important implications for the effects of the variant on health. Unlike highly detrimental and rare genetic variants that are likely to reduce reproductive fitness, benign polymorphisms survive through generations and can accumulate within a population. If a gene mutation leads to a serious congenital abnormality, like most CHD, the affected individual is unlikely to live long enough to reproduce and pass the mutation on to his or her offspring. Only genetic variants that allow an individual to live long enough to reproduce or are otherwise advantageous are likely to accumulate within human populations. Thus, although they contribute >95% of the variability between individual genomes, the majority of common polymorphisms are unlikely to contribute to CHD. Although unlikely to be the primary cause of CHD phenotypes affecting reproductive fitness, background common variation is relevant to CHD. Both human and animal studies suggest that common variants are important modifiers of CHD phenotype expression and are critical contributors to the variable expressivity and incomplete penetrance that are hallmarks of CHD [5,25]. Variable expression occurs when identical genetic variants are associated with different disease phenotypes. Incomplete penetrance is a form of the carrier state, or the extreme version of expressivity in which there is no overt phenotype despite the presence of the causative mutation [26,27]. An important example was identified in early patient cohorts expressing inactivating mutations of the highly conserved cardiac transcription factor NKX2-5. Identical mutations resulted in highly pleomorphic phenotypes such as the extent of left ventricular outflow tract obstruction (interrupted aortic arch vs. hypoplastic aortic arch) or other times with carriers having structurally normal hearts. Other examples exist where a variety of disparate heart defects including complete heart block, atrial septal defects, ventricular septal

29

defects, and tetralogy of Fallot are all associated with mutations in NKX2-5 [28,29]. Polymorphic alleles within individual genetic backgrounds likely modified the phenotypic expression of the causative mutant. Experimental work in transgenic mouse models further corroborated this observation, as dominant NKX2-5 mutations have been shown to have preferential expression of different anatomic phenotypes when bred onto different inbred mouse backgrounds [25,30]. Although causal genetic variants associated with CHD are held to low frequency, the same does not hold true for noncausative alleles that contribute to biologic systems essential to CHD outcomes against which there is no strong selection. One example is the family of enzymes that comprise the cytochrome P450 drug metabolism pathway. Unlike the modest effects that common polymorphisms usually have on complex trait susceptibility, polymorphic alleles of the cytochrome P450 2D6 enzyme can result in large differences in a patient’s ability to metabolize medications [31,32]. More than 25% of all known clinically utilized drugs can be affected, including up to a fivefold change in dosing requirements for common cardiac medications such as metoprolol and procainamide [33,34]. One study utilizing this common variant approach focused on polymorphic alleles of the Alzheimer’s disease-associated gene Apolipoprotein E (ApoE). An association of the ApoE 𝜀2 allele was correlated with a reduction in neurodevelopmental testing scores following complex congenital cardiac surgery [35,36]. Although the effect was modest, it served as an important proof of principle experiment that common polymorphism may impact disease outcome by modifying biologic systems important to treatment strategies for CHD. Other work has demonstrated that genotypes common to CHD populations impacting the renin-angiotensin-aldosterone system are associated with adverse ventricular remodeling. Following second-stage single-ventricle palliation, infants homozygous for two SNPs, rs833069 in VEGFA and rs2758331 in the SOD2 allele, have a combined 16-fold increased risk of death or heart transplantation after cardiac surgery [37,38].

Rare de novo Variants and Whole-Exome Sequencing By 2010, capacity for whole-exome sequencing technology matured sufficiently to permit cost-effective genome-wide discovery of rare sequence variants [39]. Unlike prior candidate gene approaches in which potential gene targets need to be identified a priori, all ∼20,000 expressed genes that comprise the human exome could be evaluated for sequence variability and tested agnostically for disease association. Prior whole-genome approaches

30

Pediatric Cardiac Surgery

such as GWAS did not directly evaluate gene sequence, but rather identified variants through polymorphic markers scattered throughout the genome, using linkage for association. Although the exome only represents 1% of the human genome, it is critically important. By 2018, sequencing methods for examining the genome outside of the exome, or whole-genome sequencing (WGS), had become commonplace [40,41]. Although there are many advantages, such as identifying potential important regulatory sites, the WGS approach has yet to be used extensively for CHD [42]. To account for the tremendous volume of benign and noncausative variability between individual genomes, investigators in the National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)– supported Pediatric Cardiac Genomics Consortium (PCGC) took the approach of exome sequencing proband trios, which consist of not only the affected proband, but also his or her unaffected parents. De novo mutations that are found in the affected child but are absent from the parental genomes are strong candidates for causing disease. After further restricting candidate genes to those that were both predicted to be damaging as well as highly expressed in the developing heart, the PCGC demonstrated a 7.5-fold excess of damaging, rare de novo mutations in CHD cohorts. They further estimated that these rare sequence mutations account for ∼10% of CHD, predicting ∼400 likely pathogenic CHD genes [8]. Among the newly identified mutations, far more than expected involved chromatin remodeling genes related to histone H3K4. These genes regulate the active transcription of many developmental genes and are hypothesized to serve as intermediaries between environmental stimuli and gene expression. These chromatin remodeling genes were similar to genes found in previous genome-wide studies, previous candidate gene studies, and early animal knockout studies, and highlight two general principles involving CHD genomic mutations [43,44]. First, CHD mutations commonly impact transcriptional regulatory proteins and cell signaling pathways rather than structural proteins [26,45,46]. This finding is in contrast to CHD-related conditions such as inherited cardiomyopathies, inherited arrhythmias, and thoracic vascular disease, for which structural rather than regulatory protein mutations appear to predominate. As signaling cascades are not only dependent upon multiple component proteins, but also are themselves intertwined with multiple other development systems, it becomes readily understandable why CHD is genetically heterogeneous, or that seemingly disparate gene mutations result in phenotypically similar CHD. The biologic redundancy of these cell signaling pathways and the shared use of common transcription factors throughout the development of multiple organ systems, such as the heart, the

brain, and the gastrointestinal tract, may also help explain the frequent occurrence of extracardiac features in CHD patients [47–49]. Second, mutations in CHD genes usually result in altered gene dosage or haploinsufficiency of the affected gene. Unlike oncologic conditions where mechanisms of uncontrolled growth or gene expression predominate, in CHD mutations that result in increased gene expression are exceedingly rare. Instead, CHD mutations are more commonly associated with the loss of gene function analogous to the heterozygous knockdown of a single disease allele in mutant mouse models [30]. What has yet to be extensively evaluated is the contribution of mosaicism and somatic mutations to the architecture of CHD [50,51]. The architectural characteristics of the mutations appear independent of the affected gene, predicting that de novo CHD may occur as a random event. Supporting this is the observation that there are essentially equal numbers of de novo mutations between CHD patients and controls, with both groups accumulating slightly more than one exonic mutation per patient per generation. This suggests that CHD genomes are not inherently more unstable or prone to mutation. In addition, there is no evidence that pathogenic genes have an intrinsically higher mutation rate; the genes that lead to CHD are not themselves particularly hypermutable, prone to DNA injury, or found in areas likely to undergo mutation. Last, despite epidemiologic evidence that suggests a higher incidence of CHD in Asia, there is no robust evidence of racial or anatomic clustering of identified variants [52]. Taken together, it appears that one de novo mutation occurs randomly in the exome every generation and CHD occurs when that mutation arises in a gene or gene pathway critical to heart development by chance alone. Although the contribution of de novo mutations to CHD is significant, it is notable that these mutations only represent a fraction of the observed cases of CHD. As enabled by the technological advances described above, only recently have rare inherited variants been amenable to study. One recent study used a candidate gene sequencing approach in 610 syndromic and 1281 nonsyndromic CHD patients to determine if inherited rare damaging mutations with presumed incomplete penetrance could account for additional heritability. Despite finding a significantly increased burden of inherited rare damaging variants in nonsyndromic patients, these variants only accounted for disease in just over 1% of nonsyndromic CHD patients [53]. As an extension of its earlier studies, the PCGC recently completed a more comprehensive analysis, examining the effect of recessive inherited variants. In this study of 2871 CHD probands, including 2645 parent–offspring trios, whole-exome sequencing identified rare inherited mutations in 1.8% of patients. As in its prior study, the PCGC found de novo

Genetics of Congenital Heart Disease

mutations in 8% of cases, including 28% with both neurodevelopmental and extracardiac congenital anomalies. The significant overlap between genes with damaging de novo mutations in probands with CHD and autism suggests shared developmental mechanisms [7]. While several syndromic forms of CHD have been characterized and causative genes identified, multiple studies screening nonsyndromic CHD patients for mutations in these genes have been unrewarding. It is likely that the approach of screening coding regions of syndromic CHD genes for causative mutations in isolated CHDs is fundamentally flawed. One would predict that mutations in the coding region would be present in all cells of the organism and expressed in all tissues where the gene is expressed. More likely, in nonsyndromic patients mutations would be found in regulatory elements that control expression of these genes in the developing heart. Alterations in regulatory elements of genes involved in syndromic forms of congenital heart defects will likely result in isolated congenital heart defects through cardiac-specific spatiotemporal disruption of expression. For most genes, the region immediately upstream of the minimal promoter contains the most important transcription factor binding sites. However, for many genes multiple cis-acting distal elements (enhancers, repressors, and insulators) are required for correct spatiotemporal expression [54,55]. These regulatory elements may be located upstream, downstream, or within introns, and can reside greater than 1 Mb from the target gene [56]. Disruption of these long-range regulatory interactions can result in human disease phenotypes either through global or partial tissue-specific loss or gain of expression. Distal regulatory elements have been shown to be key tissue-specific regulators of cardiac development in animal models as well, and to be highly evolutionarily conserved in humans [57,58].

Copy Number Variants Common and rare de novo mutations are important types of sequence variation that contribute to human disease. However, larger structural variations that result from aberrant meiotic recombination are called copy number variants (CNVs). Although commonly defined to exceed 1000 base pairs in size, most CNVs are substantially larger, with some containing millions of bases that may code for over 150 genes. CNVs are the dominant form of intermediate structural variation known to significantly impact human disease and multiple studies have now been published demonstrating the association of damaging CNVs with ∼10% of CHD cases [59–61]. Notably, CNVs comprise well-recognized deletion syndromes, including DiGeorge and Williams syndrome or 7q11.23

31

deletion syndrome. When 22q11.2 deletion patients are included in the analysis, up to ∼15% of CHD patients are associated with pathogenic CNVs. As with individual genes with single-nucleotide variants (SNVs), there are significant differences between the pathogenicity of specific intermediate genomic variants that impact disease inheritance and phenotypic expression. This observation enables hypotheses about the nature of genetic disease in CHD independent of specific anatomic classification. In CHD patients with seemingly isolated disease without the presence of extracardiac defects, the major detectable genetic abnormality is a CNV. Approximately 8% of isolated patients will have an identifiable CNV of which the majority is likely to be de novo; half may have recessive inheritance. Damaging de novo SNVs demonstrate no enrichment in nonsyndromic proband cohorts, and although recent evidence suggests that inherited SNVs are mildly enriched in isolated CHD patients, this represents the minority of patients [62]. These data suggest that despite increasingly aggressive clinical genetic screening for CHD, sequencing for isolated CHD is likely to be low yield [63–65]. In CHD patients with extracardiac anomalies and/or neurodevelopmental delay, ∼20–30% of syndromic CHD patients will have a damaging de novo SNV. Inherited (recessive) SNVs have not been found to be enriched in syndromic CHD patient cohorts. An additional ∼2–3% of CHD patients may harbor a damaging CNV, of which half may be inherited. Del 22q11.2 may comprise an additional ∼5% of patients, of which the majority are overwhelming likely to be de novo. Syndromic CHD patients may benefit from chromosomal microarray testing for the detection of 22q11, and appear to be the target population that would most benefit from clinical whole-exome sequencing. Due to the high proportion of de novo mutations, sibling recurrence is likely to be low, although the risk of an affected offspring may be considerable due to the high transmission rate of de novo mutations [66,67]. The clinical implications of these genetic discoveries are now becoming clearer. The presence of a pathologic CNV is associated with serious adverse clinical consequences, including reduced somatic growth, neurodevelopmental delay, and a 2.5-fold increase in death following cardiac surgery [37,68]. This result was somewhat unanticipated, implying that CNV burden results in shared adverse effects independent from the causative gene sets within the affected segment. Alternatively, the mechanisms that underlie these disparate clinical outcomes may overlap in ways not currently understood. Pathologic CNVs specific to CHD have been found throughout the genome in association with a wide variety of anatomically diverse CHDs. It is not intuitive that a CNV resulting in a truncus lesion and a CNV located elsewhere

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in the genome associated with heterotaxy would share a common adverse impact on survival [42,69].

Conclusion Over the last decade, there has been exponential growth in our capacity to decipher the genetic underpinnings of CHD. Enabled by significant advances in sequencing technology and the dramatic reduction in sequencing costs, the basic genomic pathways that contribute to CHD have only recently become evident. However, using existing technologies, fully 60–70% of CHD cannot be currently explained using a genetic focus. It may be that the combination of a detailed understanding of noncoding variants with combinatorial and recessive gene effects can further elucidate the genetic and epigenetic landscape of CHD, with the remainder due to nongenetic etiologies. In summary, well-described chromosomal aneuploidies such as Trisomy 21 comprise ∼10% of CHD. Other genetic forms of CHD result from different classes of genomic alterations involving a common set of ∼400 causative genes that play roles in transcriptional regulation or cell signaling pathways. The majority of known mutations are rare de novo SNVs (∼10%) and CNVs (∼10%) that lead to haploinsufficiency or altered dosage. An additional small percentage of SNVs are inherited from incompletely penetrant parents, as well as a higher percentage of CNVs. Common sequence polymorphisms or SNPs do not contribute strongly to CHD risk, but likely modify the penetrance of causative rare mutations playing a significant accessory role in CHD pathogenesis and clinical outcomes. Finally, patients with isolated CHD are less likely to harbor a de novo SNV than patients with associated neurodevelopmental delay and extracardiac anomalies.

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Genetics of Congenital Heart Disease 24. Stevens KN, Hakonarson H, Kim CE, et al. Common variation in ISL1 confers genetic susceptibility for human congenital heart disease. PLoS One. 2010;5(5):e10855. 25. Winston JB, Erlich JM, Green CA, et al. Heterogeneity of genetic modifiers ensures normal cardiac development. Circulation. 2010;121:1313–1321. 26. Prendiville T, Jay PY, Pu WT. Insights into the genetic structure of congenital heart disease from human and murine studies on monogenic disorders. Cold Spring Harb Perspect Med. 2014;4(10):a013946. 27. Rogers MS, D’Amato RJ. The effect of genetic diversity on angiogenesis. Exp Cell Res. 2006;312:561–574. 28. Abou Hassan OK, Fahed AC, Batrawi M, et al. NKX2-5 mutations in an inbred consanguineous population: genetic and phenotypic diversity. Sci Rep. 2015;5:8848. 29. McElhinney DB, Geiger E, Blinder J, Benson DW, Goldmuntz E. NKX2.5 mutations in patients with congenital heart disease. J Am Coll Cardiol. 2003;42:1650–1655. 30. Bruneau BG, Nemer G, Schmitt JP, et al. A murine model of Holt-Oram syndrome defines roles of the T-box transcription factor Tbx5 in cardiogenesis and disease. Cell. 2001;106:709–721. 31. Gao J, Tian X, Zhou J, et al. From genotype to phenotype: Cytochrome P450 2D6-mediated drug clearance in humans. Mol Pharm. 2017;14:649–657. 32. Ur Rasheed MS, Mishra AK, Singh MP. Cytochrome P450 2D6 and Parkinson’s disease: polymorphism, metabolic role, risk and protection. Neurochem Res. 2017;42:3353–3361. 33. Lessard E, Fortin A, Bélanger PM, et al. Role of CYP2D6 in the N-hydroxylation of procainamide. Pharmacogenetics. 1997;7:381–390. 34. Mottet F, Vardeny O, de Denus S. Pharmacogenomics of heart failure: a systematic review. Pharmacogenomics. 2016;17:1817–1858. 35. Gaynor JW, Kim DS, Arrington CB, et al. Validation of association of the apolipoprotein E epsilon2 allele with neurodevelopmental dysfunction after cardiac surgery in neonates and infants. J Thorac Cardiovasc Surg. 2014;148:2560–2566. 36. Gaynor JW, Nord AS, Wernovsky G, et al. Apolipoprotein E genotype modifies the risk of behavior problems after infant cardiac surgery. Pediatrics. 2009;124:241–250. 37. Kim DS, Kim JH, Burt AA, et al. Patient genotypes impact survival after surgery for isolated congenital heart disease. Ann Thorac Surg. 2014;98:104–111. 38. Mital, S, Chung WK, Colan SD, et al. Renin-angiotensinaldosterone genotype influences ventricular remodeling in infants with single ventricle. Circulation. 2011;123: 2353–2362. 39. Teer JK, Mullikin JC. Exome sequencing: the sweet spot before whole genomes. Hum Mol Genet. 2010;19(R2): R145–R151. 40. Cirulli ET, Goldstein DB. Uncovering the roles of rare variants in common disease through whole-genome sequencing. Nat Rev Genet. 2010;11:415–425. 41. Veeramah KR, Hammer MF. The impact of whole-genome sequencing on the reconstruction of human population history. Nat Rev Genet. 2014;15:149–162..

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42. Chung JH, Cai J, Suskin BG, et al. Whole-genome sequencing and integrative genomic analysis approach on two 22q11.2 deletion syndrome family trios for genotype to phenotype correlations. Hum Mutat. 2015;36:797–807. 43. Krupp DR, Barnard RA, Duffourd Y, et al., Exonic mosaic mutations contribute risk for autism spectrum disorder. Am J Hum Genet. 2017;101:369–390. 44. Menezes J, Acquadro F, Wiseman M, et al. Exome sequencing reveals novel and recurrent mutations with clinical impact in blastic plasmacytoid dendritic cell neoplasm. Leukemia. 2014;28:823–829. 45. Andersen TA, Troelsen K de L, Larsen LA. Of mice and men: molecular genetics of congenital heart disease. Cell Mol Life Sci. 2014;71:1327–1352. 46. Stallmeyer B, Fenge H, Nowak-Göttl U, Schulze-Bahr E. Mutational spectrum in the cardiac transcription factor gene NKX2.5 (CSX) associated with congenital heart disease. Clin Genet. 2010;78:533–540. 47. Dewey FE, Perez MV, Wheeler MT, et al. Gene coexpression network topology of cardiac development, hypertrophy, and failure. Circ Cardiovasc Genet. 2011;4:26–35. 48. Lage K, Greenway SC, Rosenfeld JA, et al. Genetic and environmental risk factors in congenital heart disease functionally converge in protein networks driving heart development. Proc Natl Acad Sci U S A. 2012;109(35): 14035–14040. 49. Sperling SR. Systems biology approaches to heart development and congenital heart disease. Cardiovasc Res. 2011;91:269–278. 50. Esposito G, Butler TL, Blue GM, et al. Somatic mutations in NKX2-5, GATA4, and HAND1 are not a common cause of tetralogy of Fallot or hypoplastic left heart. Am J Med Genet A. 2011;155A(10):2416–2421. 51. Zheng J, Li F, Liu J, et al. Investigation of somatic NKX2-5 mutations in Chinese children with congenital heart disease. Int J Med Sci. 2015;12:538–543. 52. van der Linde D, Konings EE, Slager MA, et al. Birth prevalence of congenital heart disease worldwide: a systematic review and meta-analysis. J Am Coll Cardiol. 2011;58:2241–2247. 53. Sifrim A, Hitz MP, Wilsdon A, et al. Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing. Nat Genet. 2016;48:1060–1065. 54. Kleinjan DA, van Heyningen V. Long-range control of gene expression: emerging mechanisms and disruption in disease. Am J Hum Genet. 2005;76:8–32. 55. West AG, Fraser P, Remote control of gene transcription. Hum Mol Genet. 2005;14(spec. 1):R101–R111. 56. Velagaleti GV, Bien-Willner GA, Northup JK, et al. Position effects due to chromosome breakpoints that map approximately 900 Kb upstream and approximately 1.3 Mb downstream of SOX9 in two patients with campomelic dysplasia. Am J Hum Genet. 2005;76:652–662. 57. Saitsu H, Shiota K, Ishibashi M. Analysis of fibroblast growth factor 15 cis-elements reveals two conserved enhancers which are closely related to cardiac outflow tract development. Mech Dev. 2006;123:665–673.

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58. Strahle U, Rastegar S. Conserved non-coding sequences and transcriptional regulation. Brain Res Bull. 2008;75(2–4): 225–230. 59. Carey AS, Liang L, Edwards J, et al. Effect of copy number variants on outcomes for infants with single ventricle heart defects. Circ Cardiovasc Genet. 2013;6:444–451. 60. Glessner JT, Bick AG, Ito K, et al. Increased frequency of de novo copy number variants in congenital heart disease by integrative analysis of single nucleotide polymorphism array and exome sequence data. Circ Res. 2014;115: 884–896. 61. Warburton D, Ronemus M, Kline J, et al. The contribution of de novo and rare inherited copy number changes to congenital heart disease in an unselected sample of children with conotruncal defects or hypoplastic left heart disease. Hum Genet. 2014;133:11–27. 62. Gelb BD, Chung WK. Complex genetics and the etiology of human congenital heart disease. Cold Spring Harb Perspect Med. 2014;4(7):a013953. 63. Cowan JR, Ware SM. Genetics and genetic testing in congenital heart disease. Clin Perinatol. 2015;42(2):373–393, ix.

64. Geng J, Picker J, Zheng Z, et al. Chromosome microarray testing for patients with congenital heart defects reveals novel disease causing loci and high diagnostic yield. BMC Genomics. 2014;15:1127. 65. Miller DT, Adam MP, Aradhya S, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010;86:749–764. 66. Arndt AK, MacRae CA. Genetic testing in cardiovascular diseases. Curr Opin Cardiol. 2014;29:235–240. 67. Landis BJ, Ware SM. The current landscape of genetic testing in cardiovascular malformations: opportunities and challenges. Front Cardiovasc Med. 2016;3:22. 68. Aiyagari R, Rhodes JF, Shrader P., et al. Impact of pre-stage II hemodynamics and pulmonary artery anatomy on 12-month outcomes in the Pediatric Heart Network Single Ventricle Reconstruction trial. J Thorac Cardiovasc Surg. 2014;148:1467–1474. 69. Tomita-Mitchell A, Mahnke DK, Struble CA, et al. Human gene copy number spectra analysis in congenital heart malformations. Physiol Genomics. 2012;44:518–541.

CH A P T E R

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Fetal Cardiac Physiology and Fetal Cardiac Intervention Timothy S. Lancaster, Jacob R. Miller, and Pirooz Eghtesady Washington University School of Medicine, St. Louis Children’s Hospital, St. Louis, MO, USA

Physiology of the Fetal Circulation History of Fetal Circulation Research Our current understanding of fetal cardiovascular physiology derives largely from the pioneering work of a group of South African researchers who relocated to the University of California San Francisco in the mid-1960s. Notable among them were Dr. Abraham Rudolph and Dr. Michael Heymann, who wrote an earlier version of this chapter [1]. Together they made novel use of radionuclide-labeled microspheres to quantitatively study cardiac output and organ blood flow in the undisturbed, conscious fetus, typically using the fetal lamb model [2–4]. These techniques, with variations, remain widely used for in vivo measurement of total and regional perfusion.

Fetal Circulation In a normal adult blood flow is in series; that is, a sequential flow of blood from the systemic venous system to the right heart, to the lungs, and to the left heart, where well-oxygenated blood is eventually pumped back into the systemic circulation. Fetal circulation is in parallel, where the right and left hearts control different proportions of the total blood volume. The total fetal cardiac output is thus a sum of both ventricles’ output – the combined ventricular output (CVO) or the biventricular output. The general pattern favors the streaming of well-oxygenated blood from the placenta to the heart and the brain; and the less oxygenated blood streams into the umbilical arteries and, finally, back to the placenta. A number of elegant studies, including more recently with bold imaging using magnetic resonance imaging, have shown this differential blood oxygen content in

different regions of the fetal circulation [5]. Nevertheless, the fetus at best lives in a hypoxic environment and a number of genes and molecular processes based on hypoxia-inducible factor (1 and 2) have been shown to be affected by the relative hypoxia (e.g., expression of Erythropoietin gene in the fetal liver). How altered anatomy (e.g., transposition of great arteries) impacts the differential tissue oxygen delivery and consequences for altered biology (e.g., less oxygenated blood going to the brain or the myocardium instead) is under investigation.

Fetal Intra- and Extracardiac Shunts Three shunts that are critical to carrying out streaming of blood in the fetal circulatory system are (i) the ductus venosus (DV), (ii) the foramen ovale (FO), and (iii) the patent arterial duct (Figure 3.1). About half of the oxygenated placental blood returning via the umbilical vein (UV) is diverted directly into the inferior caval vein (IVC) via the DV, thus bypassing the liver parenchyma [4]. When this well-oxygenated blood reaches the right atrium (RA) it is preferentially shunted across the atrial septum to the left atrium (LA) via the FO, thus making its way via the left ventricle (LV) to the coronary and cerebral circulations. The deoxygenated venous return from these circulations and the upper body drains via the superior caval vein (SVC) into the RA, streaming directly into the right ventricle (RV) with almost no blood traversing the FO thus minimizing mixing with the oxygenated blood going from the IVC to the LA [4]. The RV then pumps this relatively deoxygenated blood into the main pulmonary artery (PA), the majority of it flowing into the descending aorta via the arterial duct and from there supplying the abdominal viscera, the lower body, and the umbilical arteries, with reoxygenation occurring

Pediatric Cardiac Surgery, Fifth Edition. Edited by Constantine Mavroudis and Carl L. Backer. © 2023 John Wiley & Sons Ltd. Published 2023 by John Wiley & Sons Ltd.

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21

43 S V C

45 RPV

RPA 53

DA

LA

AAo

70

53 LPA

53

LPV 45

MPT

FO

RPV

5

10 S RPA 5 57 V DA C LA AAO FO MPT

RA

RV

40-83

I V C

55

73 63

55

UA PV 35

IVC

UV

RV 4 DAo

P

LHV D V 83 PS

40

LV

65

67

RHV

67

60

DAo

LPV

35

53

I V C

3 4

27 RA

LV

LPA 3

83

Figure 3.1 Diagrammatic representation of normal fetal circulation, major flow patterns, and blood hemoglobin oxygen saturations. AAo, ascending aorta; DAo, descending aorta; DV, ductus venosus; FO, foramen ovale; IVC, inferior caval vein; LA, left atrium; LHV, left hepatic vein; LPA, left pulmonary artery; LPV, left pulmonary veins; LV, left ventricle; MPT, main pulmonary trunk; P, placenta; PS, portal sinus; PV, portal vein; RA, right atrium; RHV, right hepatic vein; RPA, right pulmonary artery; RPV, right pulmonary veins; RV, right ventricle; UA, umbilical arteries; UV, umbilical vein. Source: Mavroudis C, Backer CL 2003 / with permission of Elsevier.

at the placenta. The lower-body venous return is via the IVC to the RA, being split between the shunt across the FO and the normal flow via the tricuspid valve to the RV [6]. Figure 3.2 illustrates flows in the main vessels, shunts, and chambers as a proportion of the biventricular output. Note that the lungs receive minimal flow in the fetus, but quickly transition to receive the full cardiac output in the neonate.

Venous Return The richly oxygenated UV blood splits in half as it enters the liver, being distributed equally between the DV and the liver parenchyma [7]. The DV blood flows into the suprahepatic IVC, streaming dorsal and leftward to that of the blood returning from the lower body, facilitating its

Figure 3.2 Representative values for percentages of fetal cardiac output (combined ventricular output) returning to and leaving the heart in normal fetal lambs. AAo, ascending aorta; DAo, descending aorta; DV, ductus venosus; FO, foramen ovale; IVC, inferior caval vein; LA, left atrium; LHV, left hepatic vein; LPA, left pulmonary artery; LPV, left pulmonary veins; LV, left ventricle; MPT, main pulmonary trunk; P, placenta; PS, portal sinus; PV, portal vein; RA, right atrium; RHV, right hepatic vein; RPA, right pulmonary artery; RPV, right pulmonary veins; RV, right ventricle; UA, umbilical arteries; UV, umbilical vein. Source: Mavroudis C, Backer CL 2003 / with permission of Elsevier.

preferential shunting across the FO and into the LA and, hence, to the brain and myocardium [8]. The other half of UV blood flow enters the liver preferentially via the portal sinus and left portal vein, representing about 80% of total hepatic blood flow. The remaining 20% of hepatic blood flow arrives from the portal vein (15%) and hepatic arteries (5%) [7]. The crista dividens, the lower border of the septum secundum, forms the cephalad margin of the FO lying to the right of the atrial septum, overriding the IVC orifice. It splits the IVC stream into an anterior and rightward portion flowing into the RA and a posterior and leftward stream that flows into the LA. The latter stream is predominantly composed of the UV return that flowed via the DV. Some mixing does occur, in that some DV blood flows into the RA and some deoxygenated IVC blood flows into the LA, but the net result is that the left atrium has a significantly higher oxygen saturation than the right (Figure 3.1). Blood returning to the heart via the SVC is preferentially streamed into the tricuspid orifice by the crista interveniens, situated in the posterolateral wall of the RA. The coronary sinus flow is also directed toward the tricuspid valve and, hence, the RV. The pulmonary venous return is to the LA, mixing with blood crossing the FO.

Cardiac Output, Oxygenation, and Distribution The RV is the dominant ventricle in the fetus. It predominantly perfuses the lower body, the abdominal organs,

Fetal Cardiac Physiology and Fetal Cardiac Intervention

and the placenta. As illustrated in Figure 3.2, the RV contributes approximately 65% of CVO, while the LV contributes only 35% [9]. The RV output is composed of venous return from the SVC, coronary sinus, and the predominantly lower-body return from the IVC, and is pumped mostly to the descending aorta via the arterial duct, with only 8% of the RV output reaching the lungs. This preferentially distributes deoxygenated venous return to the placenta for reoxygenation. With progression of gestation, the relative proportion of blood that travels to the fetal lungs increases and by the third trimester it is much greater than previously thought. There are also clinical case reports now of increasing this blood flow through maternal hyperoxygenation, which can serve as both therapeutic means as well as diagnostic (e.g., to assess pulmonary venous obstruction in response to increased pulmonary blood flow). The latter findings suggest that the third trimester is key in the development of the pulmonary vasculature, relevant to the care of fetuses with intact atrial septum. While the LV pumps a relatively small percentage of the total CVO, it serves to preferentially deliver the oxygen-enriched blood from the UV and FO to the brain and myocardium. Blood streaming into the LV has a relatively high oxygen saturation of 60% and perfuses the ascending aorta, resulting in 21% of the CVO reaching the brain and upper body via the arch branches, 4% reaching the coronary arteries, and 10% reaching the descending aorta via the isthmus. Hence, some saturated blood from the LV entering the descending aorta may perfuse the placenta, contributing to the physiological “left-to-right” shunt equivalent in the fetus [10]. Individual organ

Table 3.1 Normal fetal pH and blood gas data.

Value

Umbilical vein

Descending aorta

Ascending aorta

pH PO2 (mmHg) PCO2 (mmHg)

7.40–7.45 28–33 45–50

7.35–7.40 20–24 48–53

7.37–7.42 22–26 46–51

Source: Heymann 2003 / with permission of Elsevier.

blood flows are shown in Figure 3.3 [4] as proportions of the CVO. Table 3.1 shows some representative fetal blood gas values. Although the systemic arterial partial pressure of oxygen (pO2 ) in the fetus is low, hemoglobin O2 saturation is higher in the fetus than the adult because of fetal hemoglobin and the consequent left shift of the oxyhemoglobin dissociation curve. Fetal O2 consumption is significantly less, as the work of breathing is absent and thermoregulation requirements in utero are far less [11].

Intracardiac and Vascular Pressures Fetal vascular pressures (shown in Figure 3.4) also reflect the blood streaming patterns described previously. The high flow from the placenta results in the UV having a 3–5 mmHg higher pressure than the IVC. The RA pressure is higher than the LA and, along with the kinetic energy of blood streaming via the IVC, contributes to the shunting of blood across the FO [6]. The arterial duct 55

RPV

Placenta

3 S V C

Lower body RA

Upper body Brain

I V C

Heart

3

Lungs Kidneys Liver Spleen

0

10

20

30

40

50

Figure 3.3 Average combined cardiac output distributed to different organs or parts in eight different fetal animals. Source: Adapted from [4].

37

35 42

RPA DA

LPA

LA AAo 2 FO MPT 57 37 44 57 3

LPV

55 2 LV

RV DAo 55

35 42

Figure 3.4 Representative values for vascular pressures in normal fetal lambs. AAo, ascending aorta; DAo, descending aorta; DV, ductus venosus; FO, foramen ovale; IVC, inferior caval vein; LA, left atrium; LHV, left hepatic vein; LPA, left pulmonary artery; LPV, left pulmonary veins; LV, left ventricle; MPT, main pulmonary trunk; P, placenta; PS, portal sinus; PV, portal vein; RA, right atrium; RHV, right hepatic vein; RPA, right pulmonary artery; RPV, right pulmonary veins; RV, right ventricle; UA, umbilical arteries; UV, umbilical vein. Source: Mavroudis C, Backer CL 2003 / with permission of Elsevier.

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offers little resistance to flow and pressures in the RV and the main pulmonary trunk are only slightly higher (1–2 mmHg) than in the aorta and the LV. High resistance in the pulmonary vascular bed, in contrast, serves to limit blood flow through the fetal lungs and also directs blood to the systemic circulation via the arterial duct.

Circulatory Changes at Birth The Transition At birth, the pattern of circulation changes from the fetal “parallel” type to the adult “series” type, leading to more efficient oxygen uptake and delivery [12]. This happens with rapid establishment of pulmonary circulation, loss of placental circulation, and the closure of the ductus vein, the FO, and eventually the arterial duct. There is a rapid increase in O2 consumption, probably related to the work of breathing and thermoregulation, with an increase in cardiac output, a decrease in pulmonary vascular resistance, and an increase in pulmonary blood flow. The consequent increase in pulmonary venous return to the LA coupled with a decrease in IVC flow to the RA from cessation of placental UV return reverses the pressure difference between the LA and the RA, closing the flap valve of the FO. Pressures are also reversed across the ductus arteriosus (DA), with a left-to-right flow reversal being established before it closes.

Closure of the Arterial Duct In the fetus, the patency of the arterial duct is maintained by prostaglandin E2 (PGE2 ) and prostacyclin (PGI2 ) [13]. The initial functional closure that occurs within 12 hours of birth is thought to be mediated by the increase in systemic pO2 , though other vasoactive substances may also contribute [14]. A reduction in circulating prostaglandin levels is implicated in persistent ductal closure. Eventually there is fibrous replacement of the musculature of the arterial duct with formation of the arterial ligament.

Pulmonary Circulation The high fetal pulmonary vascular resistance (PVR) is attributed to vasoconstriction in the thick medial layer of the small branches [15]. With increasing gestation there is growth of new arteries, an increase in the cross-sectional area of the vascular bed, a drop in the PVR, and a slight increase in pulmonary blood flow [15]. Hypoxia is a major vasoconstrictive factor, as are acidosis and the leukotrienes [16,17]. A diverse group of vasoactive substances cause fetal and perinatal pulmonary vasodilatation – bradykinin, histamine, acetylcholine, PGE1 , PGE2 , prostaglandin D2 (PGD2), PGI2 , and catecholamines, to name a few.

Their effects are mediated by the endothelial release of secondary substances like nitric oxide (NO). A baseline relaxation of the fetal pulmonary vasculature has been attributed to NO [18]. Ventilation causes a mechanical stretch-induced production of PGI2 in the fetal lung, with a drop in PVR that is accentuated with oxygen [19]. A calcium-dependent potassium channel activation has been hypothesized to mediate this effect of oxygen [20]. At birth, a combination of ventilatory stretch, increased alveolar oxygen tension, local NO, and PGI2 production blend to produce a dramatic fall in PVR and a resultant striking increase in pulmonary blood flow. A role for ventilation-induced local mast cell degranulation and release of histamine and PGD2 has also been suggested in contributing to postnatal pulmonary vasodilation [21].

Myocardial Performance The immature fetal myocardium displays significant structural and hence functional differences from that of the adult. Not only are myocardial cells smaller, smooth, and rounded as opposed to being rod-shaped as in the adult, the cytoplasm has proportionately more water and lower myofibril content and myocardial cells are not all arranged parallel to the cellular axis. This may account for the differences in force generation and in the fetal myocardium being stiffer and less compliant. The Frank–Starling mechanism is intact in the fetus, at least at low atrial pressures, but studies have differed on ventricular performance at higher atrial filling pressures [22–25]. Increases in arterial pressure significantly depress cardiac function in the fetus [25]. It does appear that in the fetus the preload and afterload are interrelated. The enhancement in stroke volume occurring after increasing the filling pressure by volume loading is stifled by a simultaneous augmentation in the afterload. It remains a matter of great interest how the neonatal LV transitions from a low-pressure, low-output chamber to functioning at systemic pressures controlling a full cardiac output abruptly at birth. Changes in contractility, increase in beta adrenergic receptor density, and postnatal thyroid hormone changes have been suggested to aid in this transition [26,27].

Fetal Cardiac Intervention Rationale for Fetal Cardiac Intervention The utility of fetal cardiac intervention is based on the fundamental principle that congenital heart disease evolves in utero, and that intervention in the fetus may beneficially alter the natural progression of the disease [28,29]. From a historical perspective, the concept

Fetal Cardiac Physiology and Fetal Cardiac Intervention

of fetal intervention stemmed from early attempts to treat fetal erythroblastosis by transfusion of red blood cells into the abdomen of the fetus. Remarkably, this crude technique worked and was the impetus for the early attempts at intervention. Subsequently others, in particular Dr. Michael Harrison, considered by many as the father of fetal surgery, extended the concept of fetal intervention to noncardiac lesions such as congenital diaphragmatic hernia and other lesions where in utero injury from unfettered pathophysiology could be altered [30]. Today, treatment of myelomeningocele is an accepted intervention at a number of select centers and still other unique pathologies are being addressed by both minimally invasive as well as open fetal surgery. From the cardiac standpoint, fetal cardiac intervention similarly evolved from the notion that hemodynamic effects of certain congenital lesions may cause progression in utero to ventricular hypoplasia, or to myocardial injury leading to congestive heart failure, arrhythmias, or fetal hydrops. Fetal pulmonary and neurologic development may also be affected [29,31]. Such in utero progression has become more evident through intentional study of the natural history of congenital lesions throughout gestation, which in turn has been enabled through advances in fetal cardiac imaging. Detrimental progression of structural heart disease in utero has been demonstrated for several lesions, including critical valvar aortic stenosis, obstructive left heart lesions with intact atrial septum, and critical valvar pulmonary stenosis or pulmonary atresia. In each of these lesions, fetal intervention may theoretically alleviate flow restriction enough to limit its progression in utero, thereby reducing morbidity at birth and facilitating further surgical care. Both surgical and catheter-based techniques for fetal cardiac intervention have been proposed; however, closed heart interventional techniques have the greatest clinical promise and are the only methods in current clinical use in humans.

Limitations for Success of Fetal Cardiac Surgery Several decades of experimental work have been invested in the development of fetal open-heart surgery; however, a number of important challenges have so far limited its clinical application. These include fetal bypass and its related placental dysfunction, fetal myocardial protection, postoperative fetal support, risk of pregnancy loss and preterm labor, and risk to the mother. Beginning in the 1970s, the group led by Drs Rudolph and Heymann pioneered early research into fetal cardiac surgery by creating fetal lamb models of congenital lesions, including banding of the ascending aorta to simulate stenosis and placement of a left atrial balloon to create inflow limitation [32]. Fetal lamb models of aortic

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and pulmonary banding and closed-heart techniques for surgical repair were also reported [33,34]. However, repair of fetal intracardiac lesions would require fetal cardiopulmonary bypass (CPB), into which extensive research followed, mostly using near-term and earlier-gestation lamb models as well as primate models. Fetal CPB is challenged primarily by a characteristic and often inevitable physiologic response known as placental dysfunction. This is a progressive circulatory derangement consisting of increased placental vascular resistance, decreased placental blood flow, and impaired placental gas exchange, leading to fetal hypercarbia, hypoxia, acidosis, and frequently fetal demise [35]. Placental blood flow is diminished both during bypass and after separation, leading to progressive deterioration of the fetus in the postbypass period. The mechanisms of placental dysfunction occur by a redistribution of fetal blood flow, with preservation of fetal cardiac output but an increase in placental vascular resistance causing shunting of blood away from the placenta, resulting in persistent impairment of fetal gas exchange [36]. Although still not fully understood, proposed initiators of the altered placental vascular resistance include exposure of the placenta to lower volume or nonpulsatile blood flow, hyperoxia, endothelial dysfunction, or release of vasoactive agents such as catecholamines, angiotensin, vasopressin, nitric oxide, or prostaglandins [36–38]. Reductions in maternal uterine artery blood flow also occur in response to fetal CPB, suggesting a localized maternal–fetal placental interaction perhaps mediated by a fetal vasoactive substance [39]. Through clinical experience with the EXIT procedure (Ex Utero Intrapartum Therapy), treatment of certain lesions prior to delivery, where the fetus is exposed through maternal laparotomy and hysterotomy (incision different from standard C-section) and gas exchange is maintained via placental support, have to be completed within 30 minutes. Adherence to this 30-minute time frame is necessary so that placental and, secondarily, fetal myocardial function does not deteriorate. While the EXIT procedures are carried out at near term (vs. fetal surgery at 28 weeks or sooner), it is believed that similar principles are in play. Many strategies have been investigated in an attempt to mitigate the development and progression of placental dysfunction, including variable bypass flow rates [40–42] and variable temperature conditions [35]. Modifications to the bypass circuit have been reported, including exclusion of an external oxygenator (thereby using the placenta as the sole oxygenator) [39,43], exclusion of the placenta (by umbilical cord occlusion during bypass) [44], vacuum-assisted venous drainage [43], use of pulsatile flow pumps [45], miniaturization of the bypass pump and circuit [46–49], and modifications to prime volumes and

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composition [50,51]. Attention has also been paid to limiting the fetal stress response to surgery, which is thought to contribute to the release of vasoconstrictive agents and thereby increased placental vascular resistance [52]. The use of high spinal anesthesia in the fetal lamb resulted in a reduction of the fetal stress release of catecholamines and improved placental perfusion during bypass [53]. Administration of either indomethacin or high-dose steroids to the fetus to counteract the stress release of prostaglandins also limited placental dysfunction [54,55]. Appropriate fetal fluid resuscitation has been shown to be important for postoperative fetal support after CPB [56]. Many of these modifications to the conduct of experimental fetal CPB have had modest impacts on delaying the onset or lessening the severity of placental dysfunction. In fact, high rates of healthy survival to term have been demonstrated for fetal lambs that underwent CPB at a late gestational age (120–130 days, where term gestation is 148 days) using a combination of the above methods [47,57]. However, the relevant clinical window for fetal cardiac intervention in humans (21–29 weeks’ gestation) corresponds to a mid-gestation animal model (90–110 days gestation for sheep) [58], and immature fetuses of this age are even more sensitive to the disturbance of CPB. More recently, our laboratory showed the potential for carrying out simple fetal atrial septostomy (as a proof of concept for fetuses with intact atrial septum) with successful completion to term pregnancy in mid-gestation sheep fetuses. The primary reason for the success of these cases was simplicity and rapid conduct of the procedures, with a focus on getting in and out as quickly as possible. While all these were normal healthy sheep fetuses (quite distinct from the clinical situation), it served as a possible marker of feasibility in the future. We had also attempted creation of artificial veins of Marshall by creating a bypass graft from the right to left atrium, but the length of the procedures (due to the delicate nature of the atrial tissue in sheep) and the thrombosis of the grafts made the approach not viable in our hands, despite its attractive nature (off bypass). Notwithstanding the extensive body of knowledge gained to date, myocardial and placental dysfunction continues to plague studies of fetal CPB in mid-gestation lambs [48,52,59] and the first primate study of fetal CPB using baboon fetuses under 1000g [60]. One single attempt at fetal cardiac surgery was carried out by Hanley and Reddy nearly a decade ago without success in a fetus with tricuspid dysplasia and presumed functional pulmonary atresia (Reddy, personal communication). With the persistent challenges facing fetal open-heart surgery and the growing feasibility and clinical application of closed-heart interventional techniques, it appears that the latter will be the primary mode of fetal cardiac intervention for the foreseeable future. However, experimental work

into surgical techniques continues and recent reports of success in immature fetal lambs with a specially designed miniature bypass pump [49] and using total extracorporeal circulation [61] demonstrate continued progress in this arena. A deeper understanding of the placental microcirculation, the maternal and fetal response to surgical stress, methods for fetal myocardial protection, and advances in fetal extracorporeal support would facilitate its translation from the laboratory to clinical reality. Similarly, perhaps further comfort with surgeries in micro, premature, and small for gestational age patients will augment interest in this area, although other advances may negate the need for such invasive procedures, at least in the form traditionally contemplated.

Clinical Outcomes of Fetal Cardiac Intervention Closed-heart, catheter-based interventional techniques were developed in parallel with the experimental surgical work described above, and reached clinical practice with the first reported fetal balloon aortic valvuloplasty in 1989 [62]. Although still limited to very specialized heart centers and highly selected patients, closed-heart interventional procedures have come to the forefront of clinically relevant fetal cardiac intervention, and currently include aortic valvuloplasty, atrial septoplasty/stenting, and pulmonary valvuloplasty. The technique for these procedures most commonly involves ultrasound-guided, percutaneous access with both maternal and fetal anesthesia, although a limited maternal laparotomy may be used if adequate fetal positioning cannot be obtained for percutaneous access [63]. Usually, a transuterine and fetal transventricular or transatrial puncture is performed to obtain wire access to the cardiac chambers, and a balloon catheter is used for dilation (Figure 3.5) [64]. Uterine hysterotomy is avoided. Alternative techniques for access have been proposed, including recent reports of fetal transhepatic catheterization in a lamb model [65].

Fetal Aortic Valvuloplasty Fetal aortic valvuloplasty is the most commonly performed fetal cardiac intervention, and is primarily indicated for critical valvar aortic stenosis with evolving hypoplastic left heart syndrome (HLHS). Among fetuses diagnosed with valvar aortic stenosis at mid-gestation, some will maintain adequate LV growth and function to support a biventricular circulation at birth, while others will develop hypoplasia of the left heart structures, severe mitral regurgitation, or LV failure and hydrops [29,66–68]. Several echocardiographic features have been reported to predict progression of fetal valvar AS to LV hypoplasia

Fetal Cardiac Physiology and Fetal Cardiac Intervention

41

maternal abdominal wall uterine wall

Needle

Echocardiography Transducer fetal chest wall

needle left ventricle

dilating balloon through aortic valve

guide wire

aorta

spine

Figure 3.5 Illustration of ideal fetal positioning and ultrasound-guided, percutaneous technique for fetal balloon aortic valvuloplasty. Source: Republished with permission of

Wolters Kluwer Health, Inc., from Balloon Dilation of Severe Aortic Stenosis in the Fetus, Tworetzky W, Wilkins-Haug L, Jennings RW et al, permission conveyed through Copyright Clearance Center, Inc.

during gestation, including retrograde flow in the transverse aortic arch, severe LV dysfunction, monophasic mitral valve inflow, and left-to-right flow across the FO [68]. These findings are currently used to guide selection of fetuses with valvar aortic stenosis who may benefit from fetal aortic valvuloplasty. The rationale for fetal intervention is that relieving LV outflow obstruction may mitigate the ongoing process of LV myocardial damage and improve left heart growth and function, improving the likelihood of biventricular circulation after birth [69]. The largest experience with fetal aortic valvuloplasty comes from the group at Children’s Hospital Boston, who have reported results of 100 fetuses treated with this technique. Technical success, defined as crossing of the aortic valve and balloon inflation with clearly increased flow and/or new aortic regurgitation (AR), was achieved in 70–80% of patients after an initial learning curve [69,70]. Factors contributing to technical failure included unfavorable fetal position or difficulty achieving optimal fetal position, difficulty puncturing the LV (smaller, thicker ventricles), suboptimal cannula trajectory, inability to cross the valve with the wire (most likely due to aortic atresia), and fetal hemodynamic instability [69]. Fetal hemodynamic changes such as bradycardia and ventricular dysfunction were common during fetal cardiac intervention (45% of fetuses), and usually resolved with medical management [71]. Other complications included hemopericardium, sometimes requiring drainage, and development of moderate to severe AR in nearly 40% of fetuses, which improved to mild AR by birth in all

but one. There were 11 fetal deaths after valvuloplasty (11% fetal mortality), 4 occurring within 24 hours of the procedure, and no significant maternal complications. Relative to comparable fetuses not undergoing intervention, those receiving successful aortic valvuloplasty had improved growth of the aortic valve, ascending aorta, and mitral valve throughout the remainder of gestation. Improvement in LV physiologic measures in these studies has been put forth as evidence of benefit to LV function after successful valvuloplasty; however, to date no difference has been seen in actual LV growth between groups, and all surviving patients required postnatal intervention, which was usually surgical and usually multiple. Of the 70 patients in the study who had technically successful fetal intervention and proceeded to live birth, 50% achieved a biventricular outcome either from birth or with conversion after a stage 1 procedure [72,73]. It should be noted that, in this experience, the adoption of fetal aortic valvuloplasty to preserve left heart function and the aggressive tracking of patients to a biventricular pathway are based on the assumption that biventricular circulation will yield superior long-term survival and function over a univentricular circulation. While these outcomes are encouraging, little experience exists to demonstrate the long-term function of borderline left ventricles rehabilitated to a biventricular circulation, especially those requiring fetal intervention. Survival in the first seven years after birth was superior for the biventricular cohort compared to the HLHS cohort, after which point survival curves converged to equivalence [70].

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Pediatric Cardiac Surgery

Little functional assessment of this cohort has been reported to date, although a recent study showed that neurodevelopmental outcomes of children who underwent fetal aortic valvuloplasty were not better than HLHS patients without fetal intervention [74]. Further, for those with persistent elevated left-sided pressures, the option of heart transplantation is curtailed due to injury to the pulmonary vasculature. Many suffer from elevated antibody titers and sensitization, which abrogate the potential for rescue with transplantation. Further studies are warranted to show the potential utility and impact on long-term outcome for these babies and the associated procedures.

statistically significant) higher survival to first hospital discharge in patients who had successful fetal intervention [84]. However, more sobering data pertain to the outcome of these fetuses: approximately only 35% of all fetuses (and this was the largest cohort reported to date with nearly 90 fetuses with IAS included) survived to hospital discharge, whether having undergone a hybrid approach (∼25%) or Norwood Stage I palliation (∼30%). Overall, less than 19% survived “long term,” consistent with other reports including from the Single Ventricle Reconstruction Trial and other single-institution series [83]. This cohort of patients remain the most likely candidates for fetal intervention if the trajectory and natural history of lung injury can be altered with such measures.

Fetal Atrial Septoplasty/Stenting HLHS and other obstructive left heart lesions usually feature left-to-right shunting across the FO. In a high-risk subset of patients with restrictive or intact atrial septum (HLHS/IAS), however, the resulting left atrial hypertension can lead to pulmonary vascular hypertension with evolving pulmonary vascular disease, parenchymal disease, and lymphangiectasia throughout gestation [75,76]. Despite successful emergent neonatal management for atrial obstruction, infants born with HLHS/IAS have higher mortality than other HLHS patients, owing largely to their pulmonary maldevelopment [75,77,78]. The rationale for fetal atrial intervention in HLHS/IAS is therefore to relieve atrial obstruction in utero, prevent the development of pulmonary vascular disease and its consequences, and ease initial neonatal management. Fetal atrial intervention can consist of either balloon atrial septal dilation (septoplasty) or atrial septal stent placement. Patients selected for intervention typically have established HLHS/IAS (