Cellular and Transcriptional Landscape of Human Hypoplastic Left Heart Syndrome

Hypoplastic left heart syndrome (HLHS) is a congenital heart defect characterized by impaired development of the left ventricle, often managed through surgical palliation creating a single ventricle (SV). Failure of the anatomical right ventricle (RV) represents a common complication with high mortality. We used single-nucleus RNA sequencing to generate a map of the pediatric non-failing (NF) and failing (SysHF) SV. Fibroblasts and endocardial cells displayed the greatest transcriptional shifts between NF and SysHF. Notably, activated fibroblasts expanded in SysHF, and endocardial cells in NF demonstrated adaptive transcriptomic shifts absent from controls or SysHF samples. Ligand-target analysis predicted disease-state specific signaling from endocardial cells to fibroblasts: NRG3 signaling in NF and CCN2 signaling in SysHF. In silico perturbation predicted FOS, JUN, and STAT3 as regulators of fibroblast activation and endocardial adaptation. Finally, HLHS data was compared to adult human and murine RV failure to gain insight into shared pathological processes and the suitability of current animal models. These findings provide a comprehensive SV atlas and implicate cell non-autonomous signaling between endocardial cells and fibroblasts as drivers of SV systolic heart failure.