The molecular landscape of hypertrophic cardiomyopathy across disease stages and genotypes

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Abstract
Hypertrophic cardiomyopathy (HCM) is marked by asymmetric cardiac wall thickening, hypercontractility, diastolic dysfunction, and fibrosis. Pathogenic sarcomere gene variants cause HCM, but comparable abnormalities occur in patients with unexplained disease, albeit with fewer adverse events. To investigate stage- and genotype-specific disease mechanisms, we performed single-nucleus RNA sequencing of cardiac tissues from 47 patients with HCM, spanning obstructive HCM with preserved systolic function and end-stage HCM, and compared them with nonfailing donor and dilated cardiomyopathy hearts. We identified transcriptional programs associated with cardiomyocyte hypertrophy, fibrosis, and vascular remodeling. Pathogenic variant–positive early-stage HCM samples showed reduced cardiomyocyte abundance and expansion of a proarrhythmogenic cardiomyocyte state. We identified proline-rich 16 ( PRR16 ) as a cardiomyocyte growth–associated gene in HCM and validated its increased expression by RNA in situ hybridization and in a human induced pluripotent stem cell–derived cardiomyocyte HCM model. In HCM samples, fibroblast compositional shifts were associated with profibrotic activation and adverse extracellular matrix remodeling, accompanied by reduced collagen IV ( COL4A1/COL4A2 ) expression and ultrastructural basement membrane abnormalities. HCM samples also exhibited extensive vascular alterations, including shifts in endothelial cell subpopulations, reduced pericyte abundance suggestive of microvascular dysfunction, and increased lymphangiogenic vascular endothelial growth factor C signaling. Unsupervised and supervised machine learning approaches distinguished HCM from dilated cardiomyopathy and accurately predicted genotype status in early-stage HCM from cell type–resolved transcriptional profiles, revealing widespread genotype-driven remodeling. Together, our findings uncover multicellular, genotype-associated remodeling programs in HCM, providing insight into mechanisms underlying arrhythmia, fibrosis, microvascular dysfunction, and heart failure progression.
Funding Information
  • National Science Foundation (EEC-1647837)
  • National Science Foundation (EEC-1647837)
  • National Science Foundation (EEC-1647837)
  • National Science Foundation (EEC-1647837)
  • Wellcome Trust (226083/Z/22/Z)
  • Deutsches Zentrum für Herz-Kreislaufforschung (SP/19/1/34461)
  • Deutsches Zentrum für Herz-Kreislaufforschung (SP/19/1/34461)
  • Deutsches Zentrum für Herz-Kreislaufforschung (81Z0600106)
  • Deutsches Zentrum für Herz-Kreislaufforschung (S1Z0600105)
  • Chan Zuckerberg Initiative (2019-002431)
  • Chan Zuckerberg Initiative (2019-202666)
  • Chan Zuckerberg Initiative (2019-202666)
  • Chan Zuckerberg Initiative (2019-202666)
  • Chan Zuckerberg Initiative (2019-202666)
  • Chan Zuckerberg Initiative (2021-237882)
  • British Heart Foundation (FS/CRTF/23/24444)
  • British Heart Foundation (RE/18/4/34215)
  • British Heart Foundation (RE/24/130023)
  • British Heart Foundation (BBC/F/21/220106)
  • British Heart Foundation (BBC/F/21/220106)
  • Canadian Institutes of Health Research (PJT-451105)
  • Canadian Institutes of Health Research (PJT-462950)
  • Chan Zuckerberg Initiative (2021-237882)
  • HORIZON EUROPE European Innovation Council (DCM-NEXT)
  • British Heart Foundation (FS/CRTF/23/24444)
  • British Heart Foundation (RE/24/130023)
  • British Heart Foundation (RE/18/4/34215)
  • Medical Research Council
  • Sir Jules Thorn Charitable Trust (21JTA)
  • HORIZON EUROPE European Innovation Council (DCM-NEXT)
  • Imperial College Healthcare NHS Trust (PA7460)
  • Rosetrees Trust (PGS23/100028)
  • Erich and Hanna Klessmann Foundation
  • The Beznos Family Fund
  • The Beznos Family Fund
  • Deutsche Forschungsgemeinschaft (SFB-1470 Project B03)
  • Boehringer Ingelheim Fonds
  • British Medical Association
  • British Medical Association
  • NIHR Imperial Biomedical Research Centre
  • NIHR Imperial Biomedical Research Centre
  • NIHR Imperial Biomedical Research Centre

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