Abstract Body (Do not enter title and authors here): BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a relatively rare but debilitating diagnosis in pediatric patients. This represents a vulnerable population who often require heart transplantation. Here, we examine the transcriptome in ventricular tissue to identify underlying cellular processes unique to pediatric HCM (pHCM).
METHODS: We performed single-nucleus RNA sequencing on explanted hearts at transplant in female patients with end-stage pHCM (n=3) and compared findings to pediatric control (n=2) and adult HCM (n=5; Figure 1A-1B).
RESULTS: We generated 91,682 single-cell transcriptomes from 8 tissue samples. Principal component analysis exhibited the largest source of transcriptional variation separated pHCM and controls (Figure 1C). We identified distinct underlying cellular processes in cardiomyocytes, fibroblasts, endothelial cells, and myeloid cells in pHCM. pHCM was enriched in cardiomyocytes with stressed signatures and pathways associated with hypertrophy (Figure 1D); we noted depletion of tissue-resident macrophages (Figure 1D) and increased vascular remodeling in endothelial cells in pHCM. Fibroblasts exhibited activation signatures and compared to adult HCM, showed heightened fibrotic processes and a unique pro-fibrotic cluster with increased metabolic stress, mitochondrial turnover, and anti-apoptotic properties (Figure 2). In cell-to-cell communication, the differential number and weight of interactions were higher in pHCM compared to controls and fibroblasts had the highest strength of outgoing interactions.
CONCLUSIONS: Our analysis provides the first single-nuclei analysis focused on pHCM. Fibroblast-mediated cellular processes contributed most to the disrupted micro-tissue environment; they had more downstream processes associated with fibrosis and may respond to metabolic stress differently compared to adult HCM. This advances our understanding of the early presentation of pHCM, providing a crucial steppingstone toward improved patient outcomes.