Prevalence

Congenital heart disease occurs in approximately 0.8% of live births. The incidence is higher in stillborns (3-4%), spontaneous abortuses (10-25%), and premature infants (about 2% excluding patent ductus arteriosus [PDA]). This overall incidence does not include mitral valve prolapse, PDA of preterm infants, and bicuspid aortic valves (present in 1-2% of adults). Congenital cardiac defects have a wide spectrum of severity in infants: about 2-3 in 1,000 newborn infants will be symptomatic with heart disease in the 1st yr of life. The diagnosis is established by 1 wk of age in 40-50% of patients with congenital heart disease and by 1 mo of age in 50-60% of patients. With advances in both palliative and corrective surgery, the number of children with congenital heart disease surviving to adulthood has increased dramatically. Despite these advances, congenital heart disease remains the leading cause of death in children with congenital malformations. Table 418-1 summarizes the relative frequency of the most common congenital cardiac lesions.

Table 418-1 RELATIVE FREQUENCY OF MAJOR CONGENITAL HEART LESIONS*

* Excluding patent ductus arteriosus in preterm neonates, bicuspid aortic valve, physiologic peripheral pulmonic stenosis, and mitral valve prolapse.

Most congenital defects are well tolerated in the fetus because of the parallel nature of the fetal circulation. Even the most severe cardiac defects (e.g., hypoplastic left heart syndrome) can usually be well compensated for by the fetal circulation. In this example, the entire fetal cardiac output would be ejected by the right ventricle via the ductus arteriosus into both the descending and ascending aortae (the latter filling in a retrograde fashion), so that fetal organ blood flow would be minimally perturbed. Since the placenta provides for gas exchange and the normal fetal circulation has mixing between more highly and more poorly oxygenated blood, fetal organ oxygen delivery is also not dramatically affected. It is only after birth when the fetal pathways (ductus arteriosus and foramen ovale) begin to close that the full hemodynamic impact of an anatomic abnormality becomes apparent. One notable exception is the case of severe regurgitant lesions, most commonly of the tricuspid valve. In these lesions (e.g., Ebstein anomaly or severe right ventricular outflow obstruction [Chapter 424.7]), the parallel fetal circulation cannot compensate for the volume load imposed on the right side of the heart. In utero heart failure, often with fetal pleural and pericardial effusions, and generalized ascites (nonimmune hydrops fetalis) may occur.

Although the most significant transitions in circulation occur in the immediate perinatal period, the circulation continues to undergo changes after birth, and these later changes may also have a hemodynamic impact on cardiac lesions and their apparent incidence. As pulmonary vascular resistance falls in the 1st several weeks of life, left-to-right shunting through intracardiac defects increases and symptoms become more apparent. Thus, in patients with a ventricular septal defect (VSD), heart failure is often first noticed between 1 and 3 mo of age (Chapter 420.6). The severity of various defects can also change dramatically with growth; some VSDs may become smaller and even close as the child ages. Alternatively, stenosis of the aortic or pulmonary valve, which may be only moderate in the newborn period, may become worse if valve orifice growth does not keep pace with patient growth (Chapter 421.5). The physician should always be alert for associated congenital malformations, which can adversely affect the patient’s prognosis (see Table 416-2).

Etiology

The cause of most congenital heart defects is unknown. Most cases of congenital heart disease were thought to be multifactorial and result from a combination of genetic predisposition and environmental stimulus. A small percentage of congenital heart lesions are related to chromosomal abnormalities, in particular, trisomy 21, 13, and 18 and Turner syndrome; heart disease is found in more than 90% of patients with trisomy 18, 50% of patients with trisomy 21, and 40% of those with Turner syndrome. Other genetic factors may have a role in congenital heart disease; certain types of VSDs (supracristal) are more common in Asian children. The risk of recurrence of congenital heart disease increases if a 1st-degree relative (parent or sibling) is affected.

A growing list of congenital heart lesions has been associated with specific chromosomal abnormalities, and several have even been linked to specific gene defects. Fluorescent in situ hybridization analysis allows clinicians rapid screening of suspected cases once a specific chromosomal abnormality has been identified, although clinical laboratory tests for specific gene defects are still uncommon.

A well-characterized genetic cause of congenital heart disease is the deletion of a large region (1.5-3 Mb) of chromosome 22q11.2, known as the DiGeorge critical region. At least 30 genes have been mapped to the deleted region; Tbx1, a transcription factor involved in early outflow tract development has been implicated as a cause of DiGeorge syndrome. The estimated prevalence of 22q11.2 deletions is 1/4,000 live births. Cardiac lesions associated with 22q11.2 deletions are most often seen in association with either the DiGeorge syndrome or the Shprintzen (velocardiofacial) syndrome. The acronym CATCH 22 has been used to summarize the major components of these syndromes (cardiac defects, abnormal facies, thymic aplasia, cleft palate, and hypocalcemia). The specific cardiac anomalies are conotruncal defects (tetralogy of Fallot, truncus arteriosus, double-outlet right ventricle, subarterial VSD) and branchial arch defects (coarctation of the aorta, interrupted aortic arch, right aortic arch). Congenital airway anomalies such as tracheomalacia and bronchomalacia are sometimes present. Although the risk of recurrence is extremely low in the absence of a parental 22q11.2 deletion, it is 50% if 1 of the parents carries the deletion. More than 90% of patients with DiGeorge syndrome have a microdeletion at 22q11.2. A 2nd genetic locus on the short arm of chromosome 10 (10p13p14) has also been identified, the deletion of which shares some but not all phenotypic characteristics with the 22q11.2 deletion; patients with del(10p) have an increased incidence of sensorineural hearing loss.

Other structural heart lesions that have been associated with specific chromosomal abnormalities include familial secundum atrial septal defect associated with heart block (the transcription factor NKX2.5 on chromosome 5q35), familial atrial septal defect without heart block (the transcription factor GATA4), Alagille syndrome (Jagged1 on chromosome 20p12), and Williams syndrome (elastin on chromosome 7q11). Of interest, patients with ventricular septal defects (VSDs) and atrioventricular septal defects (AVSDs) have been found to have multiple NKX2.5 mutations in cells isolated from diseased heart tissues, but not from normal heart tissues or from circulating lymphocytes, indicating a potential role for somatic mutations leading to mosaicism in the pathogenesis of congenital heart defects. A compilation of known genetic causes of congenital heart disease is presented in Table 418-2.

Table 418-2 GENETICS OF CONGENITAL HEART DISEASE

AS, aortic stenosis; ASD, atrial septal defect; AV, atrioventricular; PDA, patent ductus arteriosus; PS, pulmonic stenosis; RBBB, right bundle branch block; RV, right ventricular; TAPVR, total anomalous pulmonary venous return.

* In many cases, mutation of a single gene has been closely linked to a specific cardiovascular disease, for example, by finding a high incidence of mutations or deletions of that gene in a large group of patients. These findings are often confirmed by studies in mice in which deletion or alteration of the gene induces a similar cardiac phenotype to the human disease. In others, mutation of a gene may increase the risk of cardiovascular disease, but with decreased penetrance, suggesting that modifier genes or environmental factors play a role. Finally, in some cases, gene mutations have only been identified in a small number of pedigrees, and confirmation awaits screening of larger numbers of patients.

Great progress in identifying the genetic origin of cardiovascular disease has been made in hypertrophic cardiomyopathy. Mutations in 11 genes have been implicated, most of which encode protein components of the cardiac sarcomere, either components of the thick or thin fibers or associated regulatory subunits, although 2 are mutations in mitochondrial t-RNAs (transfer RNAs). Mutations of the cardiac β-myosin heavy-chain gene (chromosome 14q1) and the myosin-binding protein C gene (chromosome 11q11) are the most common (see Tables 418-2 and 433-2), with less common mutations including the cardiac troponin T and I genes, α-tropomyosin, regulatory and essential myosin light chains, titin, and the α-myosin heavy chain. Over 200 mutations have been identified in these genes, and some patients may carry mutations in more than 1 gene. Clinical laboratory tests are now available for the most common of these mutations.

Progress has also been made in identifying the genetic basis of dilated cardiomyopathy, which is familial in 20-50% of cases. Autosomal dominant inheritance is most commonly encountered and, to date, 16 genes have been identified (see Table 418-2). X-linked inheritance accounts for 5-10% of cases of familial dilated cardiomyopathy. Mutations in the dystrophin gene (chromosome Xp21) are the most common in this group. Mutations in the gene encoding tafazzin are associated with Barth syndrome and some cases of isolated non-compaction of the left ventricle. Autosomal recessive inheritance has been associated with a mutation in cardiac troponin I. Mitochondrial myopathies may be due to mutations of enzymes of the electron transport chain encoded by nuclear DNA (in which inheritance will follow mendelian genetic patterns) or enzymes of fatty acid oxidation encoded by mitochondrial DNA (which is inherited solely from the mother).

The genetic basis of heritable arrhythmias, most notably the long Q-T syndromes, has been linked to mutations of genes coding for subunits of cardiac potassium and sodium channels (see Table 418-2). Other heritable arrhythmias include arrhythmogenic right ventricular dysplasia (ARVD), familial atrial fibrillation, familial complete heart block, and Brugada syndrome.

Of all cases of congenital heart disease, 2-4% are associated with known environmental or adverse maternal conditions and teratogenic influences, including maternal diabetes mellitus, phenylketonuria, or systemic lupus erythematosus; congenital rubella syndrome; and maternal ingestion of drugs (lithium, ethanol, warfarin, thalidomide, antimetabolites, vitamin A derivatives, anticonvulsant agents) (see Table 416-2). Associated noncardiac malformations noted in identifiable syndromes may be seen in as many as 25% of patients with congenital heart disease (see Table 416-1).

Gender differences in the occurrence of specific cardiac lesions have been identified. Transposition of the great arteries and left-sided obstructive lesions are slightly more common in boys (≈65%), whereas atrial septal defect, VSD, PDA, and pulmonic stenosis are more common in girls. No racial differences in the occurrence of congenital heart lesions as a whole have been noted; for specific lesions such as transposition of the great arteries, a higher occurrence is seen in white infants.

Genetic Counseling

Parents who have a child with congenital heart disease require counseling regarding the probability of a cardiac malformation occurring in subsequent children (Chapter 77). With the exception of syndromes known to be due to mutation of a single gene, most congenital heart disease is still relegated to a multifactorial inheritance pattern, which should result in a low risk of recurrence. As more genetic etiologies are identified, however, these risks will need constant updating. The incidence of congenital heart disease in the normal population is ≈0.8%, and this incidence increases to 2-6% for a 2nd pregnancy after the birth of a child with congenital heart disease or if a parent is affected. This recurrence risk is highly dependent on the type of lesion in the 1st child. When 2 1st-degree relatives have congenital heart disease, the risk for a subsequent child may reach 20-30%. When a 2nd child is found to have congenital heart disease, it will tend to be of a similar class as the lesion in their 1st-degree relative (conotruncal lesions, left-sided obstructive lesions, right-sided obstructive lesions, atrioventricular septation defects). The degree of severity may be variable, as is the presence of associated defects. Careful echocardiographic screening of 1st-degree relatives will often uncover mild forms of congenital heart disease that were clinically silent. For example, the incidence of bicuspid aortic valve is more than double (5% vs 2% in the general population) in the relatives of children with left ventricular outflow obstructions (aortic stenosis, coarctation of the aorta, or hypoplastic left heart syndrome). Given the rapid advancements in the field of cardiovascular genetics, consultation with a knowledgeable genetic counselor is the most reliable way of providing the family with up-to-date information regarding the risk of recurrence.

Fetal echocardiography improves the rate of detection of congenital heart lesions in high-risk patients (Chapter 90). The resolution and accuracy of fetal echocardiography are excellent, but not perfect; families should be counseled that a normal fetal echocardiogram does not guarantee the absence of congenital heart disease. Congenital heart lesions may evolve in the course of the pregnancy; moderate aortic stenosis with a normal-sized left ventricle at 18 wk of gestation may evolve into aortic atresia with a hypoplastic left ventricle by 34 wk because of decreased flow through the atria, ventricle, and aorta in the latter half of gestation. This progression has prompted initial clinical trials of interventional treatment, such as fetal aortic balloon valvuloplasty, for the prevention of hypoplastic left heart syndrome (Chapter 417.7).

The major factor in determining whether a woman with congenital heart disease, either unoperated or operated, will be able to carry a fetus to term is the mother’s cardiovascular status. In the presence of a mild congenital heart defect or after successful repair of a more severe lesion, normal childbearing is likely. In a woman with poor cardiac function, however, the increased hemodynamic burden imposed by pregnancy may result in a significantly increased risk to both the mother and fetus. The incidence of spontaneous abortion in the presence of severe congenital heart disease is high, especially when the mother is cyanotic. The maternal risk in these situations is also high, and these pregnancies should be managed by an experienced perinatologist in conjunction with a cardiologist with expertise in adult congenital heart disease (Chapter 428.1). It is important to discuss various methods of birth control with young women who have repaired or palliated congenital heart lesions. Antibiotic prophylaxis against endocarditis may also be indicated at the time of delivery.