Single-cell multiomic integration identifies widespread, cell-type resolved fetal reactivation in the diseased human heart

Background: As the first organ to develop in utero, the human heart undergoes extensive molecular, structural and metabolic remodeling during development and must sustain its function throughout life. Results: We generate an integrated multiomic atlas of human cardiac cells, combining newly generated and publicly available single-nucleus RNA sequencing datasets from 299 donors and single nucleus ATAC-seq datasets from 106 donors. Developmental and disease-associated processes drive far more extensive molecular remodeling than sex-associated or aging-dependent effects. Across nearly all cardiac cell types, developmental and disease-driven changes exhibit strong overlap at both the transcriptomic and epigenomic levels, revealing widespread reactivation of fetal-associated gene programs beyond cardiomyocytes. Both cardiac development and disease show convergent shifts in intercellular communication, including increased TGFβ signaling. Integration of gene expression and chromatin accessibility data reveals putative cell-type–specific transcriptional factors driving fetal reactivation in major cardiac diseases. Spatial transcriptomics data orthogonally identifies localization of this fetal reactivation signature within spatially distinct niches in ischemic and fibrotic zones of acute myocardial infarction. Finally, we construct a cell-type–resolved enhancer-to-gene linkage map that refines the association of dilated and hypertrophic cardiomyopathy genetic risk loci to downstream target genes. Conclusions: This study presents a comprehensive multimodal, cell-type–resolved atlas of the human heart, providing a foundation for understanding human cardiac gene regulation across the human lifespan and in cardiac diseases.