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Adami, E.* ; Kim, Y.* ; Zheng, S.L.* ; Shvetsov, N.* ; Losert, C. ; Maatz, H.* ; Barish, S.* ; Venturini, G.* ; Anguita, N.L.* ; Shi, Q.* ; Neyazi, M.* ; Beyer, M.* ; Wei, Q.* ; Adam, A.* ; Suresh, A.* ; Reichart, D.* ; Lindberg, E.L.* ; Brown, K.* ; Strohmenger, V.* ; Saul, D.* ; Gaertner, A.* ; Lee, M.* ; Mach, L.* ; Robertus, J.L.* ; Gorham, J.* ; Haas, J.* ; Liebig, L.A.* ; Lippert, C.* ; Meder, B.* ; Myronova, A.* ; Patone, G.* ; Barnett, S.N.* ; Ware, J.S.* ; Robertis, F.D.* ; Pantazis, A.* ; Gummert, J.* ; Viveiros, A.* ; Chen, H.* ; Ruiz‐Orera, J.* ; Frey, N.* ; McDonough, B.* ; Mitchell, R.N.* ; Padera, R.F.* ; Day, S.M.* ; Ho, C.Y.* ; Lakdawala, N.K.* ; Milting, H.* ; Heinig, M. ; Oudit, G.Y.* ; Noseda, M.* ; Seidman, J.G.* ; Hübner, N.* ; Seidman, C.E.*

The molecular landscape of hypertrophic cardiomyopathy across disease stages and genotypes.

Sci. Transl. Med. 18:eaea2747 (2026)
DOI PMC
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Hypertrophic Cardiomyopathy ; Induced Pluripotent Stem Cell ; Sarcomere ; Extracellular Matrix ; Cardiomyopathy ; Myocyte ; Heart Failure ; In Situ Hybridization ; Gene Expression; Cardiac Fibrosis; Heart; Proliferation; Transcription; Variants; Platform; Muscle; Growth
ISSN (print) / ISBN 1946-6234
e-ISSN 1946-6242
Zeitschrift Science Translational Medicine
Quellenangaben Band: 18, Heft: 867, Seiten: , Artikelnummer: eaea2747 Supplement: ,
Verlag American Association for the Advancement of Science (AAAS)
Verlagsort 1200 New York Ave, Nw, Washington, Dc 20005 Usa
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Computational Biology (ICB)
Förderungen Wellcome Trust
Chan Zuckerberg Initiative
Canadian Institutes of Health Research
British Medical Association Foundation Josephine Lansdell Grant
Deutsches Zentrum fuer Herz-Kreislauf-Forschung
British Heart Foundation Centre for Research Excellence, Imperial College London
British Heart Foundation
Boehringer Ingelheim Fonds
Engineering Research Centers Program of the National Science foundation
Rosetrees Trust
Pathfinder Cardiogenomics Programme of the European Innovation Council of the European Union (DCM-NEXT)
Sir Jules Thorn Charitable Trust
NIHR Imperial Biomedical Research Centre
Medical Research Council UK
National Science Foundation Engineering Research Center on Cellular Metamaterials
Imperial College Healthcare NHS Trust Biomedical Research Centre Funding
Deutsches Zentrum fuer Herz-Kreislauf-Forschung DZHK (German Center for Cardiovascular Research)
German Research Foundation
Erich and Hanna Klessmann Foundation
Beznos Family Fund