Preface

Congenital heart defect (CHD) may be defined as an anatomic malformation of the heart or great vessels which occurs during intrauterine development, irrespective of the age at presentation. Ventricular septal defect and coarctation of the aorta are typical examples of CHDs. The reported incidence of congenital cardiac defects varies between 0.6% and 0.8% of live births. This would result in the birth of 30 to 35,000 infants with CHD each year in the United States alone. Congenital heart defects are more common than well-known congenital anomalies such as congenital pyloric stenosis, cleft lip, Down syndrome, and congenital dislocation of the hip. Nearly 50% of these babies can be managed with simple medications, observation, and follow-up without any major therapeutic intervention. However, the remaining 50%, in the past, required surgical intervention, some under cardiopulmonary bypass. Since the advent of transcatheter techniques, 50% of these babies (i.e., 25% of the total) can be managed with less invasive, percutaneous, transcatheter techniques.

Developments such as early detection of the neonates with serious heart disease and their rapid transport to tertiary care centers, availability of highly sensitive noninvasive diagnostic tools, advances in neonatal care and anesthesia, progress in transcatheter interventional procedures, and extension of complicated surgical procedures to the neonate and infant have advanced to such a degree that almost all congenital cardiac defects can be diagnosed and "corrected". The defects that could not be corrected could be effectively palliated. For achieving excellence in cardiac care, however, close interaction and collaboration of the pediatric cardiologists with neonatologists, pediatricians, general/family practitioners (who care for children with CHD), internists (who care for adults with CHD), anesthesiologists, and cardiac surgeons is mandatory. Education of physicians caring for children and adults with CHD continues to be important in achieving optimal care for the patients with heart disease.

Because of vastness of the subject, all issues related to congenital heart defects cannot be discussed in their entirety and therefore, only selected aspects will be included in this book. The book is divided into several sections, which include an overview of congenital heart defects, prevalence and etiology, some individual heart defects, management of some of the congenital heart defects, international issues, and miscellaneous issues. While there are significant advances in the understanding

#### X Preface

molecular mechanisms of cardiac development and of the etiology of CHD, these have not progressed to such a degree so as to be useful in preventing CHD at this time. Consequently, several chapters were devoted to this subject.

Preface XI

in the mice model. Then, they describe the BMP signaling pathways in general and specific to heart development, including that of the mesoderm, myocardial wall formation, valve development, chamber septation, and outflow tract morphogenesis. The authors conclude that BMP signaling pathways are critical regulators of heart development in several species, including humans, and that mutations in the BMP pathway have been identified in humans with CHD. This insight may help develop diagnostic tests and therapeutic options for CHD in the future. Vogler et al of Sanford-Burnham Medical Research Institute in La Jolla, California, describe recent advances and findings gained from a Drosophila model for CHD. They begin with comparing Drosophila to vertebrate cardiogenesis and point out their similarities. They then allude to the lessons learned from studying Drosophila heart morphogenesis. This is followed by a discussion of manipulating the heart and genome of a fly. They also suggest that the Drosophila model is useful in elucidating the molecular mechanisms of CHD and cardiomyopathy. They conclude that development of technologies such as time-lapse analysis of heart formation, and optical techniques to study function suggest that further studies using this system will provide insights into fundamental

In the next section, three individual cardiac defects are reviewed. Flack and Graham from Vanderbilt University, Nashville, Tennessee, USA, describe incidence, natural history, clinical and laboratory features, and management of congenitally corrected transposition of the great arteries (CCTGA). The authors allude to the problems associated with dysfunction of left-sided, morphologic right ventricle with or without Ebstein's type of malformation of the morphologic tricuspid valve. Conventional medical management and cardiac resynchronization are discussed. Role of conventional surgical therapy and double-switch operation are also detailed. Followup recommendations and pregnancy outcomes are also discussed. They conclude that outcomes, based on long-term follow-up of physiologic vs. anatomic repair for CCTGA, favor anatomic correction. Ríos-Méndez of "El Cruce" Hospital in Buenos Aires, Argentina, present four cases of a double-chambered right ventricle from their institution, discuss the significance of these findings and present a literature review. The author concludes that the double-chambered right ventricle is a rare cardiac anomaly, ventricular septal defect is the most commonly-associated defect. Echocardiography (transthoracic or transesophageal), performed by a cardiologist familiar with congenital heart disease, is the method of choice for diagnosing this condition, and surgical treatment is effective with low morbidity. Pierre et al of Bichat Hospital in Paris, France, reviews features of anomalous connections of coronary arteries (ANOCOR), presents a simple classification, points out low prevalence of about 1% in the general population, discusses anatomical patterns associated with a risk of sudden death, and explores prevention of sport-related fatalities and modalities of cost-effective screening. Additionally, Pierre et al advocates multidetector CT angiography with three-dimensional reconstruction as an accurate diagnostic tool, supports surgery by the unroofing technique in ANOCOR arising from the aorta (and direct aortic implantation for ANOCOR connected with the pulmonary artery), deplores lack of long-term follow-up evaluation after surgery and support setting up

cellular mechanisms underlying heart function and disease.

In the first section on the overview of congenital heart defects, I present a brief review of incidence, etiology and classification of CHD, and an overview of the nine most common congenital cardiac anomalies and their management. The exact etiology of CHD is not known, and the majority of cardiac defects can be explained by multifactorial inheritance hypothesis. The CHD may be classified as acyanotic and cyanotic defects, the former being further divided into obstructive and left-to-right shunt lesions. Pathologic, physiologic, clinical, and laboratory features of the nine most common CHD were distinctively described. Methods of management for each of these defects include transcatheter techniques for most of the acyanotic defects and by and large surgery for the cyanotic defects. Based on this review, it appears that while the etiology of CHD is not clearly identified, their recognition by clinical evaluation and non-invasive laboratory tests is possible, and their treatment with currently available transcatheter and surgical methods is feasible, effective, and safe.

In the next section on prevalence and etiology, Sayasathid and Associates from Naresuan University, Thailand, discuss epidemiology and etiology of CHD including preventative guidelines for pregnant mothers. They suggest that the number of patients with CHD continues to increase, and that epidemiology studies reveal that cases of CHD are underestimated. Huang and Liang of Guangxi Traditional Chinese Medical College in Nanning, China explore molecular mechanisms of congenital heart disease. The authors review normal cardiac development and recent discoveries of the genetic causes of CHD. They provide possible strategies for exploring these new developments to improve understanding of the genetic basis of CHD. They support the use of animal biomedical models to understand normal and abnormal function from gene to phenotype, and to provide a basis for preventive or therapeutic intervention in human diseases. In the next chapter, Minamisawa and Yokoyama from Waseda University, Japan, present recent advances in the molecular mechanism of patent ductus arteriosus (PDA). The authors describe acute and functional closure of the ductus, and discuss complex molecular mechanisms involved in ductal closure. The remodelling is reviewed, which includes the differentiation of vascular smooth muscle cells (SMCs) and endothelial cells, accumulation of extracellular matrix, vascular SMC migration into the sub endothelial region, impaired elastogenesis, and eventually fibrotic changes due to apoptosis and necrosis. The role of PGE2-EP4-cAMP signal pathway, oxygen, and calcium channels. Multiple vasoreactive stimulations in the modulator of vascular remodelling of the ductus arteriosus is also discussed. The authors conclude that this knowledge may help develop novel therapeutic strategies for patients with PDA and ductal dependent cardiac anomalies. Harmelink and Jiao of the University of Alabama in Birmingham, USA, describe bone morphogenetic protein (BMP) signaling pathways in heart development and disease. They review evidence from multiple experimental models that demonstrates the role of BMP signaling pathways in the heart development. Initially, they describe normal heart development in the mice model. Then, they describe the BMP signaling pathways in general and specific to heart development, including that of the mesoderm, myocardial wall formation, valve development, chamber septation, and outflow tract morphogenesis. The authors conclude that BMP signaling pathways are critical regulators of heart development in several species, including humans, and that mutations in the BMP pathway have been identified in humans with CHD. This insight may help develop diagnostic tests and therapeutic options for CHD in the future. Vogler et al of Sanford-Burnham Medical Research Institute in La Jolla, California, describe recent advances and findings gained from a Drosophila model for CHD. They begin with comparing Drosophila to vertebrate cardiogenesis and point out their similarities. They then allude to the lessons learned from studying Drosophila heart morphogenesis. This is followed by a discussion of manipulating the heart and genome of a fly. They also suggest that the Drosophila model is useful in elucidating the molecular mechanisms of CHD and cardiomyopathy. They conclude that development of technologies such as time-lapse analysis of heart formation, and optical techniques to study function suggest that further studies using this system will provide insights into fundamental cellular mechanisms underlying heart function and disease.

X Preface

molecular mechanisms of cardiac development and of the etiology of CHD, these have not progressed to such a degree so as to be useful in preventing CHD at this time.

In the first section on the overview of congenital heart defects, I present a brief review of incidence, etiology and classification of CHD, and an overview of the nine most common congenital cardiac anomalies and their management. The exact etiology of CHD is not known, and the majority of cardiac defects can be explained by multifactorial inheritance hypothesis. The CHD may be classified as acyanotic and cyanotic defects, the former being further divided into obstructive and left-to-right shunt lesions. Pathologic, physiologic, clinical, and laboratory features of the nine most common CHD were distinctively described. Methods of management for each of these defects include transcatheter techniques for most of the acyanotic defects and by and large surgery for the cyanotic defects. Based on this review, it appears that while the etiology of CHD is not clearly identified, their recognition by clinical evaluation and non-invasive laboratory tests is possible, and their treatment with currently

available transcatheter and surgical methods is feasible, effective, and safe.

In the next section on prevalence and etiology, Sayasathid and Associates from Naresuan University, Thailand, discuss epidemiology and etiology of CHD including preventative guidelines for pregnant mothers. They suggest that the number of patients with CHD continues to increase, and that epidemiology studies reveal that cases of CHD are underestimated. Huang and Liang of Guangxi Traditional Chinese Medical College in Nanning, China explore molecular mechanisms of congenital heart disease. The authors review normal cardiac development and recent discoveries of the genetic causes of CHD. They provide possible strategies for exploring these new developments to improve understanding of the genetic basis of CHD. They support the use of animal biomedical models to understand normal and abnormal function from gene to phenotype, and to provide a basis for preventive or therapeutic intervention in human diseases. In the next chapter, Minamisawa and Yokoyama from Waseda University, Japan, present recent advances in the molecular mechanism of patent ductus arteriosus (PDA). The authors describe acute and functional closure of the ductus, and discuss complex molecular mechanisms involved in ductal closure. The remodelling is reviewed, which includes the differentiation of vascular smooth muscle cells (SMCs) and endothelial cells, accumulation of extracellular matrix, vascular SMC migration into the sub endothelial region, impaired elastogenesis, and eventually fibrotic changes due to apoptosis and necrosis. The role of PGE2-EP4-cAMP signal pathway, oxygen, and calcium channels. Multiple vasoreactive stimulations in the modulator of vascular remodelling of the ductus arteriosus is also discussed. The authors conclude that this knowledge may help develop novel therapeutic strategies for patients with PDA and ductal dependent cardiac anomalies. Harmelink and Jiao of the University of Alabama in Birmingham, USA, describe bone morphogenetic protein (BMP) signaling pathways in heart development and disease. They review evidence from multiple experimental models that demonstrates the role of BMP signaling pathways in the heart development. Initially, they describe normal heart development

Consequently, several chapters were devoted to this subject.

In the next section, three individual cardiac defects are reviewed. Flack and Graham from Vanderbilt University, Nashville, Tennessee, USA, describe incidence, natural history, clinical and laboratory features, and management of congenitally corrected transposition of the great arteries (CCTGA). The authors allude to the problems associated with dysfunction of left-sided, morphologic right ventricle with or without Ebstein's type of malformation of the morphologic tricuspid valve. Conventional medical management and cardiac resynchronization are discussed. Role of conventional surgical therapy and double-switch operation are also detailed. Followup recommendations and pregnancy outcomes are also discussed. They conclude that outcomes, based on long-term follow-up of physiologic vs. anatomic repair for CCTGA, favor anatomic correction. Ríos-Méndez of "El Cruce" Hospital in Buenos Aires, Argentina, present four cases of a double-chambered right ventricle from their institution, discuss the significance of these findings and present a literature review. The author concludes that the double-chambered right ventricle is a rare cardiac anomaly, ventricular septal defect is the most commonly-associated defect. Echocardiography (transthoracic or transesophageal), performed by a cardiologist familiar with congenital heart disease, is the method of choice for diagnosing this condition, and surgical treatment is effective with low morbidity. Pierre et al of Bichat Hospital in Paris, France, reviews features of anomalous connections of coronary arteries (ANOCOR), presents a simple classification, points out low prevalence of about 1% in the general population, discusses anatomical patterns associated with a risk of sudden death, and explores prevention of sport-related fatalities and modalities of cost-effective screening. Additionally, Pierre et al advocates multidetector CT angiography with three-dimensional reconstruction as an accurate diagnostic tool, supports surgery by the unroofing technique in ANOCOR arising from the aorta (and direct aortic implantation for ANOCOR connected with the pulmonary artery), deplores lack of long-term follow-up evaluation after surgery and support setting up of registries to determine the outcome of children and young adults (≤ 30-year old) with high-risk ANOCOR.

Preface XIII

mass spectrometry to accurately measure oxygen consumption, and discuss the postoperative physiology following Norwood operation and its management. Itoi from Kyoto Prefectural University of Medicine in Kyoto, Japan, discusses myocardial use of energy substrates in young patients with atrial (ASD) and ventricular septal defects (VSD) and patent ductus arteriosus, (PDA) and presents their data. They conclude that myocardial energy metabolism in acyanotic CHD was sustained by fatty acid oxidation irrespective of workload. There was accelerated glucose use with overload. Lactate seemed to play an important role in maintain lactate-pyruvate redox potential. When mild myocardial workload (as in ASD), the NADH demand was complemented by lactate oxidation, while with higher workload (as in pulmonary hypertension) lactate production was accelerated to maintain the cellular redox state. Okuneva et al from E.N. Meshalkin Research Institute of Circulation Pathology and A.V. Nikolayev Institute of Inorganic Chemistry in Russia describes the results of their study to investigate the structure of cardiomyocytes, and the content of chemical elements (CE) in infants with transposition of the great arteries (TGA). They found that pathologic hypertrophy of myocardium in TGA is reflected by the decreased Zn, Br, Cr, Cl and Se content in myocardium (also Ca) and excess of Copper. They recommend that pregnant women and nursing mothers should get the optimum quantity of microelements Cr, Zn, Sr, Ni, Rb, Br, and most impotently Se (to protect the myocardium from lipid peroxidation). Se also prevents development of congenital heart diseases, including TGA, although no data to support this recommendation was

There are significant advances in the understanding of the molecular mechanisms of cardiac development and of the etiology of CHD. However, these have not evolved to such a degree so as to be useful in preventing CHD at this time. Treatment of the majority of acyanotic and simpler cyanotic heart defects with currently available transcatheter and surgical techniques is feasible, effective and safe. Recent advances in medical and surgical therapy, particularly the application of staged total cavopulmonary connection (Fontan) have markedly improved the long-term outlook of children who have one functioning ventricle. There are a number of other developments, some of which were reviewed in this book. It is my hope that these discussions will give a fund of information to the practicing physician caring for infants, children and adults with congenital heart defects, helping them provide

> **P. Syamasundar Rao, MD, FAAP, FACC, FSCAI**  University of Texas at Houston Medical School

> > Houston, Texas,

USA

presented.

optimal care for their patients.

Management of congenital heart disease was discussed in the next section. Hadzimuratovic discusses evaluation and emergency treatment of critically ill neonates with cyanosis and respiratory distress. The author reviews some important aspects of normal and abnormal findings in physical examination, ECG, and chest xray films of the neonate, and suggested approaches to diagnose and treat neonates with central cyanosis. The author then discusses management of several neonatal issues, namely, heart failure in the newborn infant, hypoplastic left heart syndrome, premature neonates with a large PDA, persistent pulmonary hypertension of the newborn, and transient myocardial ischemia. Guzman et al from Cardiovascular Clinic Santa Maria in Medellin, Colombia present the results of Fontan Surgery performed at their institution. They state that management strategies for functional single ventricles have evolved into staged procedures with a goal to obtain normal ventricular pressures, volumes, and normal systemic arterial saturation. They examined the results of total cavo-pulmonary connection (Fontan operation) and conclude that the Fontan operation performed at their institution is safe with a mortality rate of 14.3%, comparable to a previously published large series.

In the next section on international issues, Bode-Thomas at the University of Jos in Nigeria reviews practical problems encountered in the diagnosis, treatment, and prevention of congenital heart diseases in the developing countries. The author initially points out that there is a paucity of data on the incidence or birth prevalence of congenital heart disease in most developing countries. This under-estimates the burden of congenital heart disease, undermining arguments for more resource allocation in the face of the many other competing health care needs. A discussion of peculiarities and challenges of CHD diagnosis and treatment in developing regions follows with a suggestion for establishing treatment centers in developing countries.

The final section includes several miscellaneous issues. Chalajour et al of Stanford University in Stanford, California, USA, discusses dynamics of myocardial cell populations following birth, and the role of cardiac progenitor cells (CPC) in neonatal myocardial tissue expansion and heart growth, as well as therapeutic strategies for congenital heart defects. The authors conclude that the presence of resident CPC in myocardium is well supported. However, controversies continue regarding the origin of CPC. Methods for activating resident CPC are still in the early discovery phase, and the potential applications of CPC-focused therapies in congenital heart disease treatment are likely in the future. Li from the University of Alberta, Canada, in a chapter on "Accurate measurement of systemic oxygen consumption in ventilated children with congenital heart disease" points out inaccuracies of using estimated oxygen consumption values (calculated by predictive equations developed by several workers in the past) in the Fick principle. These inaccuracies were found particularly in children younger than 3 years of age, whether it be in the Catheterization Laboratory or in the ICU postoperatively. The author describes the use of respiratory mass spectrometry to accurately measure oxygen consumption, and discuss the postoperative physiology following Norwood operation and its management. Itoi from Kyoto Prefectural University of Medicine in Kyoto, Japan, discusses myocardial use of energy substrates in young patients with atrial (ASD) and ventricular septal defects (VSD) and patent ductus arteriosus, (PDA) and presents their data. They conclude that myocardial energy metabolism in acyanotic CHD was sustained by fatty acid oxidation irrespective of workload. There was accelerated glucose use with overload. Lactate seemed to play an important role in maintain lactate-pyruvate redox potential. When mild myocardial workload (as in ASD), the NADH demand was complemented by lactate oxidation, while with higher workload (as in pulmonary hypertension) lactate production was accelerated to maintain the cellular redox state. Okuneva et al from E.N. Meshalkin Research Institute of Circulation Pathology and A.V. Nikolayev Institute of Inorganic Chemistry in Russia describes the results of their study to investigate the structure of cardiomyocytes, and the content of chemical elements (CE) in infants with transposition of the great arteries (TGA). They found that pathologic hypertrophy of myocardium in TGA is reflected by the decreased Zn, Br, Cr, Cl and Se content in myocardium (also Ca) and excess of Copper. They recommend that pregnant women and nursing mothers should get the optimum quantity of microelements Cr, Zn, Sr, Ni, Rb, Br, and most impotently Se (to protect the myocardium from lipid peroxidation). Se also prevents development of congenital heart diseases, including TGA, although no data to support this recommendation was presented.

XII Preface

with high-risk ANOCOR.

of registries to determine the outcome of children and young adults (≤ 30-year old)

Management of congenital heart disease was discussed in the next section. Hadzimuratovic discusses evaluation and emergency treatment of critically ill neonates with cyanosis and respiratory distress. The author reviews some important aspects of normal and abnormal findings in physical examination, ECG, and chest xray films of the neonate, and suggested approaches to diagnose and treat neonates with central cyanosis. The author then discusses management of several neonatal issues, namely, heart failure in the newborn infant, hypoplastic left heart syndrome, premature neonates with a large PDA, persistent pulmonary hypertension of the newborn, and transient myocardial ischemia. Guzman et al from Cardiovascular Clinic Santa Maria in Medellin, Colombia present the results of Fontan Surgery performed at their institution. They state that management strategies for functional single ventricles have evolved into staged procedures with a goal to obtain normal ventricular pressures, volumes, and normal systemic arterial saturation. They examined the results of total cavo-pulmonary connection (Fontan operation) and conclude that the Fontan operation performed at their institution is safe with a

mortality rate of 14.3%, comparable to a previously published large series.

In the next section on international issues, Bode-Thomas at the University of Jos in Nigeria reviews practical problems encountered in the diagnosis, treatment, and prevention of congenital heart diseases in the developing countries. The author initially points out that there is a paucity of data on the incidence or birth prevalence of congenital heart disease in most developing countries. This under-estimates the burden of congenital heart disease, undermining arguments for more resource allocation in the face of the many other competing health care needs. A discussion of peculiarities and challenges of CHD diagnosis and treatment in developing regions follows with a suggestion for establishing treatment centers in developing countries.

The final section includes several miscellaneous issues. Chalajour et al of Stanford University in Stanford, California, USA, discusses dynamics of myocardial cell populations following birth, and the role of cardiac progenitor cells (CPC) in neonatal myocardial tissue expansion and heart growth, as well as therapeutic strategies for congenital heart defects. The authors conclude that the presence of resident CPC in myocardium is well supported. However, controversies continue regarding the origin of CPC. Methods for activating resident CPC are still in the early discovery phase, and the potential applications of CPC-focused therapies in congenital heart disease treatment are likely in the future. Li from the University of Alberta, Canada, in a chapter on "Accurate measurement of systemic oxygen consumption in ventilated children with congenital heart disease" points out inaccuracies of using estimated oxygen consumption values (calculated by predictive equations developed by several workers in the past) in the Fick principle. These inaccuracies were found particularly in children younger than 3 years of age, whether it be in the Catheterization Laboratory or in the ICU postoperatively. The author describes the use of respiratory There are significant advances in the understanding of the molecular mechanisms of cardiac development and of the etiology of CHD. However, these have not evolved to such a degree so as to be useful in preventing CHD at this time. Treatment of the majority of acyanotic and simpler cyanotic heart defects with currently available transcatheter and surgical techniques is feasible, effective and safe. Recent advances in medical and surgical therapy, particularly the application of staged total cavopulmonary connection (Fontan) have markedly improved the long-term outlook of children who have one functioning ventricle. There are a number of other developments, some of which were reviewed in this book. It is my hope that these discussions will give a fund of information to the practicing physician caring for infants, children and adults with congenital heart defects, helping them provide optimal care for their patients.

> **P. Syamasundar Rao, MD, FAAP, FACC, FSCAI**  University of Texas at Houston Medical School Houston, Texas, USA

**Part 1** 

**Overview of Congenital Hear Defects** 

**Part 1** 

**Overview of Congenital Hear Defects** 

**1** 

*USA* 

P. Syamasundar Rao

**Congenital Heart Defects – A Review** 

Congenital heart defect (CHD) may be defined as an anatomic malformation of the heart or great vessels which occurs during intrauterine development, irrespective of the age at presentation. Ventricular septal defect and coarctation of the aorta are typical examples of CHDs. In this chapter, a brief review of incidence, etiology and classification of CHD, and an overview of the most common congenital cardiac anomalies and their management will be presented. Cardiac abnormalities, generally considered not congenital in origin but important cardiac problems in children, namely rheumatic heart disease, Kawasaki syndrome and cardiomyopathy will not be discussed in this review. Also, discussion of important symptoms/findings/issues with which the children are referred to pediatric cardiologists such as cardiac murmur, chest pain, syncope/dizziness, palpitation, arrhythmia, hypertension, clearance for participation in sports, coronary risk factors, bacterial endocarditis prophylaxis, ADHD medication use, clearance for non-cardiac

The reported incidence of congenital cardiac defects varies between 0.47 to 1.17% of live births, but 0.6% to 0.8% of live births is considered typical. This would result in birth of 25,000 to 35,000 infants with CHD each year in the United States alone. Congenital heart defects are more common than well-known congenital anomalies such as congenital pyloric

The exact cause of all congenital cardiac defects is not known. The majority of the defects can be explained by multifactorial inheritance hypothesis (Nora 1968) which states that a predisposed fetus, when exposed to a given environmental trigger (to which the fetus is sensitive) during the critical period of cardiac morphogenesis will develop the disease. This genetic and environmental interaction is most likely to be pathogenetic mechanism of congenital heart defects. Calculations based on this hypothesis predict the frequency of occurrence of the disease in first degree relatives to be square root of its frequency in the

A variety of factors have statistical association with certain heart defects and these may be termed risk factors. Maternal rubella appears to have causative association with heart defects. Significantly higher incidence of serologic evidence for Coxsackie B virus infection

surgery and others will not be included in the this chapter.

stenosis, cleft lip, Down syndrome and congenital dislocation of the hip.

population; this fits the congenital heart disease figures (Nora 1968).

**Incidence of congenital heart defects** 

**1. Introduction** 

**2. Etiology** 

*University of Texas at Houston Medical School, Houston* 
