A large-scale single-nucleus resource reveals a cardiomyocyte-like fibroblast and stage-specific remodeling across cardiomyopathies.
basic_science · Level V
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- Record sourced from PubMed, PMID 42243863.
- Also identified by DOI 10.1186/s12916-026-04954-1.
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Abstract
Cardiomyopathies represent a heterogeneous group of myocardial disorders with distinct phenotypes and outcomes, yet their cell-type-specific mechanisms and differences remain incompletely defined. Here, we present the Cardiac Cell Atlas, a large-scale single-nucleus transcriptomic atlas of 525 cardiac tissue samples (20 newly generated and 505 publicly available) spanning dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), left ventricular non-compaction (LVNC), and non-failing controls, integrating > 2 million nuclei. This resource delineates both shared remodeling signatures and divergent trajectories across cardiomyopathies. We identified a previously unrecognized fibroblast (FB) subpopulation expressing cardiomyopathy genes (TNNT2, RYR2, MYBPC3), positioned between fibroblasts and ventricular cardiomyocytes (VCM) and segregating into FB-like (SORBS2<sup>-</sup>) and ventricular VCM-like (SORBS2<sup>+</sup>) states, the latter with reparative potential. Notably, HCM was dominated by compensatory hypertrophic remodeling, whereas DCM showed progressive cardiomyocyte loss and maladaptive FB expansion, consistent with their distinct clinical outcomes. Left ventricular ejection fraction (LVEF)-associated pseudotime staging revealed dynamic remodeling: early HCM showed enriched VCM-FB-endothelial(EC) signaling and effective compensation, while early DCM lacked EC involvement, predisposing to dysfunction. At mid-stage, signaling declined in HCM but intensified in DCM as ECs became active remodelers, whereas late-stage disease in both subtypes exhibited global signaling loss, with residual maladaptive extracellular matrix(ECM)-receptor activity persisting in DCM. Together, the Cardiac Cell Atlas provides a comprehensive reference for human cardiac cell states and interactions, advancing mechanistic understanding and informing clinical strategies for risk stratification, stage-specific intervention, and improved outcomes in HCM and DCM. The web portal of Cardiac Cell Atlas together with all the datasets are publicly available at http://113.54.15.143:8000/app/index/.