Hypoplastic left heart syndrome occurs in up to 3% of all infants born with congenital heart disease and is a leading cause of death in this population. Although there is strong evidence for a genetic component, a specific genetic cause is only known in a small subset of patients, consistent with a multifactorial etiology for the syndrome. There is controversy surrounding the mechanisms underlying the syndrome, which is likely due, in part, to the phenotypic variability of the disease. The most commonly held view is that the “decreased” growth of the left ventricle is due to a decreased flow during a critical period of ventricular development. Research has also been hindered by what has been, up until now, a lack of genetically engineered animal models that faithfully reproduce the human disease. There is a growing body of evidence, nonetheless, indicating that the hypoplasia of the left ventricle is due to a primary defect in ventricular development. In this review, we discuss the evidence demonstrating that, at least for a subset of cases, the chamber hypoplasia is the consequence of hyperplasia of the contained cardiomyocytes. In this regard, hypoplastic left heart syndrome could be viewed as a neonatal form of cardiomyopathy. We also discuss the role of the endocardium in the development of the ventricular hypoplasia, which may provide a mechanistic basis for how impaired flow to the developing ventricle leads to the anatomical changes seen in the syndrome.

Aims: Thinning of the compact myocardium is a major contributor to adverse outcomes in ventricular non-compaction, the third most common form of cardiomyopathy. Endothelial-specific deletion of Ets1, a gene associated with Jacobsen syndrome, causes ventricular non-compaction with reduced compact myocardium. However, the mechanisms by which pathological cardiac endothelium impairs compact myocardium growth remain poorly understood. Methods and results: To uncover the mechanisms underlying compact myocardium thinning and identify therapeutic endothelial-secreted factors, we performed single-cell RNA sequencing. Aberrant cardiomyocyte and endothelial cell states were observed in non-compacted ventricles. Conditional deletion of Ets1 in either the endocardium or coronary endothelium impaired compact myocardial growth. In endocardium, Ets1 deficiency suppressed Notch1 signaling by upregulating Dlk1 and downregulating Dll4, both direct Ets1 targets. In coronary endothelium, Ets1 deficiency reduced the expression of its direct targets Hmcn1, Slit2, and Col18a1, three extracellular matrix (ECM) components that promote compact myocardial proliferation. Notably, treatment with these ECM proteins or the Notch1 effector Nrg1 restored the impaired compact myocardial proliferation. Conclusion: These findings highlight Ets1-regulated endothelial-secreted factors as essential for compact myocardium development and suggest novel therapeutic targets for ventricular non-compaction.