Abnormal Progenitor Cell Differentiation And Cardiomyocyte Proliferation In Hypoplastic Right Heart Syndrome

Pulmonary atresia with intact ventricular septum (PA-IVS) is a rare (4-8 per 100,000 live births) type of hypoplastic right heart syndrome (HRHS) where the right-sided structures in the heart are malformed. In PA-IVS, the pulmonary valve that acts to regulate the unidirectional flow of blood from the right ventricle (RV) to the lungs does not open, resulting in no connection between the RV and the pulmonary arteries. After surgical or catheter-based intervention, PA-IVS patients have clinical outcomes that range from single-ventricle palliation to a biventricular repair. Mechanisms underlying the spectrum of RV hypoplasia in PA-IVS are difficult to fully ascribe to an atretic pulmonary valve. There are no reliable animal models available for studying disease mechanisms of PA-IVS. In this study, we leverage patient-specific induced pluripotent stem cells (iPSCs) and single-cell RNA sequencing to elucidate cellular etiologies of ventricular hypoplasia in PA-IVS. PA-IVS iPSC-derived cardiomyocytes are less proliferative compared to controls under both static and cyclic stretch, suggesting that genetic factors may contribute to a spectrum of ventricular hypoplasia in PA-IVS. Single-cell transcriptomic analysis reveals that cell lineage determination towards second heart progenitors is suppressed, with enhanced differentiation into first heart field and epicardial lineages during cardiac differentiation. Additionally, biological pathways associated with cell proliferation and cell cycle progression are downregulated whereas mitochondrial activities are elevated in early cardiomyocytes originated from PA-IVS patients. In conclusion, abnormal cell lineage differentiation and cardiomyocyte proliferation may underlie the cellular and developmental etiologies of ventricular hypoplasia in HRHS.