Objective  To clarify the subtype-specific molecular mechanisms of hy-pertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and arrhythmogenic cardiomyopathy (ACM) in terms of cellular composition, transcriptional features, and intercellular interactions.

Methods  The single-nucleus RNA sequencing (snRNA-seq) data from publicly available human heart tissue samples were integrated. Among them, HCM, DCM, and non-heart failure control samples were obtained from the Single Cell Portal database, whereas ACM samples were obtained from the European Genome-phenome Archive database. Data quality control, batch correction, clustering and annotation, differential expression and pathway enrichment analyses, cell-cell communication analysis, and spatial transcriptomics validation were performed to systematically characterize the cellular composition and molecular features of different cardiomyopathy subtypes.

Results  At the cellular composition level, all three cardiomyopathy subtypes exhibited reduced cardiomyocytes along with increased fibroblasts and smooth muscle cells, with the most pronounced changes observed in DCM. Subtype-specific differences were also evident: endothelial cells were increased in HCM and DCM but decreased in ACM; pericytes were markedly reduced in HCM, whereas both pericytes and neuronal cells were increased in ACM. At the molecular pathway level, HCM showed activation of the PI3K– AKT– mTOR pathway; DCM exhibited enhanced angiogenesis signaling; and ACM displayed significantly upregulated oxidative phosphorylation. Regarding key cellular subpopulations, HCM was enriched for Endothelial_c0-PIK3R3 and Fibro-blast_c0-POSTN subsets; DCM showed increases in Myeloid_ c0- C20orf194 and Fibro-blast_c0-POSTN; while ACM was characterized by elevated Cardiomyocyte_ c2-CDIN1, and Pericyte_c1-LOC644135 subsets. Furthermore, the pathway activities of Endotheli-al_c0-PIK3R3 in HCM and Fibroblast_c0-POSTN in DCM were validated using spatial tran-scriptomics.

Conclusion  This study systematically delineates subtype-specific cellular compositions and molecular functional features of cardiomyopathies, providing novel single-nucleus transcriptomic evidence for understanding the pathological mechanisms of HCM, DCM and ACM, and laying a foundation for precision diagnosis and therapeutic strategies for cardiomyopathies.

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