The molecular landscape of hypertrophic cardiomyopathy across disease stages and genotypes

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.

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Journal
Science Translational Medicine
Published
2026-09-16
DOI
https://doi.org/10.1126/scitranslmed.aea2747
Primary Topic
Cardiomyopathy and Myosin Studies
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article
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article

The molecular landscape of hypertrophic cardiomyopathy across disease stages and genotypes

Carolyn Y. Ho, Joshua Gorham, Christine E. Seidman, Kemar Brown et al.
Science Translational Medicine
Cardiomyopathy and Myosin Studies
article

The molecular landscape of hypertrophic cardiomyopathy across disease stages and genotypes

Carolyn Y. Ho, Joshua Gorham, Christine E. Seidman, Kemar Brown, Matthias Heinig, Jan Gummert, Gavin Y. Oudit, Jan Haas, Sam N. Barnett, Martin Beyer, Robert F. Padera, James S. Ware, Corinna Losert, Jonathan G. Seidman, Jan Lukas Robertus, Syndi Barish, Sean L. Zheng, Qian Wei, Jorge Ruiz‐Orera, Eric L. Lindberg, Anissa Viveiros, Lukáš Mach, Meraj Neyazi, Michela Noseda, Henrike Maatz, Anna Myronova, Nikolay Shvetsov, Neal K. Lakdawala, Hendrik Milting, Norbert Hübner, Eleonora Adami, Richard N. Mitchell, Christoph Lippert, Giannino Patone, Abhilash Suresh, Sharlene M. Day, Anna Gaertner, Amanda Adam, Barbara McDonough, Viktoria Strohmenger, Daniel Reichart, Michael Lee, Yuri Kim, Qi Shi, Huachen Chen, Fabio De Robertis, L A Liebig, Natalia López Anguita, Antonis Pantazis, Benjamin Meder, Gabriela Venturini, David Saul, Norbert Frey
article en

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.

Science Translational MedicineVol. 18(867)
Brigham and Women's Hospital (US), Helmholtz Association of German Research Centres (DE), Harvard University (US), Hasso Plattner Institute (DE), University of Alberta (CA), Universität Hamburg (DE), Max Delbrück Center (DE), Heidelberg University (DE), General Medical Council (GB), Royal Brompton & Harefield NHS Foundation Trust (GB), Heart and Diabetes Center North Rhine-Westphalia (DE), Helmholtz Zentrum München (DE), LMU Klinikum (DE), British Heart Foundation (GB), Massachusetts General Hospital (US), Precisis (Germany) (DE), University Medical Center Hamburg-Eppendorf (DE), German Center for Infection Research (DE), German Centre for Cardiovascular Research (DE), Centre of Experimental Medicine of the Slovak Academy of Sciences (SK), Imperial College London (GB), Technical University of Munich (DE), Heidelberg Institute for Theoretical Studies (DE), Charité - Universitätsmedizin Berlin (DE), University of Pennsylvania (US), Ludwig-Maximilians-Universität München (DE), Medical Research Council (GB), Icahn School of Medicine at Mount Sinai (US)
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Cardiomyopathy and Myosin Studies
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