**2. Etiology**

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

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

Congenital Heart Defects – A Review 5

25%

40%

20%

The obstruction can be at valvar, subvalvar or supravalvar sites or in the branch pulmonary arteries (Rao 2000a). Valvar stenosis is the most common type and will be discussed in this section. Valvar pulmonary stenosis (PS) constitutes 7.5% to 9.0% of all CHDs. The pathologic features of valvar stenosis vary, but the most commonly found pathology is what is described as "dome shaped" pulmonary valve with fusion of the thickened pulmonary valve leaflets. Hypertrophy of the right ventricle (proportional to the degree of obstruction) and dilatation of main pulmonary artery (not related to the severity of obstruction) are also seen.

Children with PS usually present with asymptomatic murmurs, although they can present with signs of systemic venous congestion (usually interpreted as congestive heart failure) due to severe right ventricular dysfunction or cyanosis because of right-to-left shunt across

The right ventricular and the right ventricular outflow tract impulses are increased and a heave may be felt at the left lower and upper sternal borders. A thrill may be felt at the left upper sternal border and/or in the suprasternal notch. The first heart sound may be normal or loud. The second heart sound is variable, depending upon the degree of obstruction and will be detailed later in this section. An ejection systolic click is heard in most cases of valvar stenosis. The click is heard best at the left lower, mid and upper sternal borders and varies with respiration (decreases or disappears with inspiration). An ejection systolic murmur (Figure 1, top) is heard best at the left upper sternal border and it radiates into infraclavicular regions, axillae and back. The intensity of the murmur may vary between grades II-V/VI; the intensity is not necessarily related to the severity of the

**Type of Defect % incidence** 

Acyanotic 65%

Transposition of the great arteries

Table 1. Classification of Congenital Heart Defects

Obstructive Lesions

Cyanotic

**4.1 Pulmonary stenosis** 

**4.1.1 Symptoms** 

the atrial septum.

stenosis.

**4.1.2 Physical findings** 

Pulmonary stenosis Aortic stenosis

Left-to-right shunt lesions Atrial septal defect Ventricular septal defect Patent ductus arteriosus

Tetralogy of Fallot

Tricuspid atresia

Coarctation of the aorta

during pregnancy in mothers of infants with congenital heart defects than in matchedcontrol women suggested causative relationship between Coxsackie B infection and congenital heart defects, but this evidence is neither conclusive nor confirmed. Among drugs, maternal ingestion of thalidomide during pregnancy is associated with high incidence heart defects in the offspring. Similar association has been reported for some anticonvulsant drugs (particularly dilantin and trimethadione), alcohol (excessive), Lithium, sex hormones, diazepam, carticosteroids, phenolhiazine, folic acid antagonists, cocaine and dextromethamphetamines. A higher incidence of cardiac abnormalities with maternal diabetes is well known. Gross chromosomal anomalies such as trisomy 21 (Down syndrome), trisomy D and E syndromes, Turner's syndrome (XO), partial deletion of chromosome 22 and cri-du-chat (partial dilation of the short arm of chromosome 5) are associated with a higher incidence of heart defects than normal population and are likely be responsible for the congenital heart defects. Some generalized syndromes, secondary to a single mutant gene (for example, Marfan) involving multiple organ systems are associated with cardiovascular defects peculiar to that particular syndrome (Rao 1977a). Both autosomal (dominant and recessive) and sex-linked (dominant and recessive) single mutant gene syndromes have been reported with CHD. Finally, less than 1% of congenital heart defects can be explained by simple Mendelian inheritance. Autosomal dominant transmission other than single mutant gene syndrome has been reported with atrial septal defect, patent ductus arteriosus, aortic stenosis, pulmonary stenosis, tetralogy of Fallot and hypertrophic cardiomyopathy. Autosomal recessive inheritance may be present in some forms of endocardial fibroelastosis. To the best of my knowledge, sex-linked transmission has not been reported with CHD. However, recently questions have been raised as to the mitochondrial inheritance in which maternal transmission to almost all offspring occurs. In the presence of family history of congenital heart defect (parent or sibling) the probability of CHD in the offspring is higher than that seen in general population.

In summary, the cause of congenital heart defects is largely unknown and the majority of them may be explained by multifactorial inheritance hypothesis. Extensive research on gene mapping that is currently in progress may unravel previously unknown genetic mechanisms for CHD. Also, several chapters to follow address the issues related to causation of CHD.
