Hypoplastic left heart syndrome: anatomical spectrum, clinical management, and brain defects

Hypoplastic left heart syndrome (HLHS) is a complex congenital heart disease (CHD) involving hypoplasia of the left ventricle (LV) and the aorta (Ao), along with aortic and mitral valve stenosis/atresia with or without coarctation. It is a physiologically single-ventricle lesion, previously uniformly fatal, but now survivable with a 3-stage surgical palliation ending with the Fontan circulation, a circulation for only one working ventricle. In the classical definition of HLHS, the ventricular septum is intact; however, HLHS variants have been described with similar single-ventricle pathophysiology in which the hypoplastic LV is not hemodynamically coupled to the aortic outflow. Evidence for a genetic etiology for HLHS is indicated by its high recurrence risk, the association with various chromosomal abnormalities, and the demonstration of mutations in mice causing HLHS. Despite surgical advances allowing survival of patients with HLHS, there is still high morbidity and mortality after their first-stage palliation. The causes of such high morbidity and mortality are not well understood, but most deaths are likely related to cardiovascular/hemodynamic causes. Studies in the animal models of HLHS show that this cardiac lesion arises early in embryogenesis, decreases left-sided inflow, and is associated with metabolic dysfunction, cell proliferation, and differentiation defects. Findings indicate HLHS is also associated with intrinsic cell deficits, deficits that may also contribute to the high risk of heart failure and adverse neurodevelopment. In this article, we update a previous review by describing the basic pathophysiology; pertinent pre- and postoperative management of HLHS and its anatomical variants; and novel insights from the HLHS mouse model on the causes of HLHS-associated heart failure and poor neurodevelopment, as well as potential therapeutic strategies.