A Population-Scale Single-Cell Atlas of the Human Heart Reveals Cellular Remodeling and Cell–Cell Communication in Aging and Cardiac Disease

Previous single-cell and single-nucleus heart atlases, often limited by small sample sizes, lack the statistical power needed for phenotype association analysis, particularly for cardiovascular diseases and cardiac aging. To address this, we integrated data from 436 samples across 12 single-cell studies, harmonized the corresponding sample metadata, and constructed a comprehensive heart atlas comprising 355,762 cells and 1,436,719 nuclei. Consensus annotation identified 10 broad cell types and 54 fine-grained subsets. Associating gene expression patterns and cell type proportions with phenotypic data, we identified NRG1 -expressing endocardial cells linked to multiple cardiac diseases and found that interferon (IFN) response signatures mark aging in multiple heart cell types. Importantly, we also developed PopComm, a novel computational method for inferring ligand–receptor (LR) interactions from population-scale single-cell data and quantifying interaction strength for individual samples. Using PopComm, we revealed a close association between the IFN response state and altered cell–cell communication during cardiac aging.