HLHS is the fourth most common congenital heart lesion to present within the first year of life, accounting for 1.4% to 3.8% of congenital heart disease. With a birth prevalence described by the New England Regional Infant Cardiac Program of 0.163 per 1,000 live births, more than 1,000 infants with HLHS are expected to be born in the United States each year.

As many as 28% of patients with HLHS may have a definable genetic or extracardiac abnormality. Both autosomal recessive and multifactorial inheritance patterns have been suggested. HLHS has been reported in siblings, with a recurrence rate of 0.5% for HLHS and 2.2% for any congenital heart lesion. First-degree relatives have a 12% prevalence of cardiac abnormalities, with a particularly high incidence of bicuspid aortic valves. Many syndromes, including Turner syndrome, Noonan syndrome, Smith-Lemli-Opitz syndrome, and Holt-Oram syndrome, have a known association with HLHS. Numerous chromosomal abnormalities have been and continue to be reported in children with HLHS and include the following: trisomy 9, 13, 18, and 21; duplication of 12p and 16q; chromosomal deletions 2q-, 4p-, 4q-, 7q-, 11q-, 18p-, and 22q11-; and balanced 3:7 translocation. Abnormalities of the central nervous system are the most common extracardiac malformation, with one series reporting a 29% incidence of major or minor neurologic abnormalities, including microcephaly, microencephaly, abnormal cortical mantle, agenesis of the corpus callosum, and holoprosencephaly.

HLHS is characterized by significant hypoplasia of left heart structures, including the left atrium, LV, mitral and aortic valves, and ascending aorta. Most (85%) neonates with HLHS have a combination of aortic and mitral valve atresia or stenosis. The remainder (15%) typically present with a right ventricle
(RV)–dominant complete atrioventricular canal defect with malalignment of the ventricular septum, aortic atresia, and significant LV hypoplasia. Infrequently, patients with HLHS may have other associated cardiac lesions, including ventricular inversion or double-outlet RV. The degree of LV hypoplasia in HLHS is variable depending on the relative patency of the aortic and mitral valves. The LV cavity may be slit-like or absent, severely hypoplastic with prominent endocardial fibroelastosis, or even normal or nearly normal in size. The size of the ascending aorta varies depending on the patency of the aortic valve. An additional discrete juxtaductal coarctation often is found in 70% to 80% of infants with HLHS.

Right-sided heart structures, including the right atrium, RV, and pulmonary arteries characteristically are dilated. The left atrium in neonates with HLHS is significantly hypoplastic with thickened endocardium. A mildly restrictive interatrial communication typically is present, with a patent foramen ovale or small secundum atrial septal defect most commonly identified. An intact atrial septum is found in 10% of patients with HLHS and likely represents premature closure of the fossa ovalis in utero or a congenitally absent fossa ovalis. Pulmonary venous return to the hypoplastic left atrium usually is normal; however, anomalous pulmonary venous connections often occur in neonates with a significantly restrictive interatrial communication.

Although HLHS has a heterogeneous anatomic substrate, the pathophysiologic manifestations are similar. Because oxygenation occurs in the placenta and the RV provides systemic output, fetuses with HLHS typically have normal in utero development. After birth, survival depends on the continued patency of intracardiac shunts at both atrial and ductal levels to maintain adequate systemic oxygenation and perfusion. Pulmonary venous return is shunted from the hypoplastic left atrium to the right atrium via a patent foramen ovale, where it mixes with systemic venous return. Systemic cardiac output from the RV must traverse a patent ductus arteriosus to provide antegrade blood flow to the body and vital organs via the descending aorta and retrograde blood flow to the aortic arch to supply the brachiocephalic vessels, ascending aorta, and coronary arteries.

Shortly after birth, normal physiologic changes can result in severe hemodynamic compromise. In the infant with HLHS, the systemic and pulmonary circulations run in parallel rather than in series. The proportion of systemic versus pulmonary blood flow is dependent on the relative resistances between the two circuits. The typical fall in neonatal pulmonary vascular resistance occurring after birth predisposes the infant with HLHS to increased pulmonary blood flow at the expense of adequate peripheral systemic perfusion. Improved oxygen saturation may obscure the underlying hemodynamic implications of this fall in pulmonary vascular resistance, leading to worsening systemic perfusion, metabolic acidosis, and congestive heart failure. Subsequent constriction of the ductus arteriosus further impairs systemic output, leading to profound metabolic acidosis, tissue hypoxemia, shock, and eventual death.