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Transl. Med."],"published-print":{"date-parts":[[2026,9,16]]},"abstract":"<jats:p>\n                    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\u2013positive early-stage HCM samples showed reduced cardiomyocyte abundance and expansion of a proarrhythmogenic cardiomyocyte state. We identified\n                    <jats:italic toggle=\"yes\">proline-rich 16<\/jats:italic>\n                    (\n                    <jats:italic toggle=\"yes\">PRR16<\/jats:italic>\n                    ) as a cardiomyocyte growth\u2013associated gene in HCM and validated its increased expression by RNA in situ hybridization and in a human induced pluripotent stem cell\u2013derived cardiomyocyte HCM model. In HCM samples, fibroblast compositional shifts were associated with profibrotic activation and adverse extracellular matrix remodeling, accompanied by reduced collagen IV (\n                    <jats:italic toggle=\"yes\">COL4A1\/COL4A2<\/jats:italic>\n                    ) 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\u2013resolved 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.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.aea2747","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T17:58:11Z","timestamp":1789581491000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["The molecular landscape of hypertrophic cardiomyopathy across disease stages and genotypes"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1813-6681","authenticated-orcid":true,"given":"Eleonora","family":"Adami","sequence":"first","affiliation":[{"name":"Cardiovascular and Metabolic Sciences, Max Delbr\u00fcck Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin 13125, Germany."},{"name":"German Center for Cardiovascular Research (DZHK), Partner Site Berlin. Berlin 13125, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5978-5779","authenticated-orcid":true,"given":"Yuri","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Brigham and Women\u2019s Hospital, Boston, MA 02115, USA."},{"name":"Division of Genetics, Brigham and Women\u2019s Hospital, Boston, MA 02115, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5762-6392","authenticated-orcid":true,"given":"Sean L.","family":"Zheng","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Imperial College London, London SW3 6LY, UK."},{"name":"Medical Research Council Laboratory of Medical Sciences, London W12 0NN, UK."},{"name":"British Heart Foundation Centre of Regenerative Medicine, British Heart Foundation Centre of Research Excellence, Imperial College London, London W12 0NN, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9526-7637","authenticated-orcid":true,"given":"Nikolay","family":"Shvetsov","sequence":"additional","affiliation":[{"name":"Cardiovascular and Metabolic Sciences, Max Delbr\u00fcck Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin 13125, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5997-4702","authenticated-orcid":true,"given":"Corinna","family":"Losert","sequence":"additional","affiliation":[{"name":"Institute of Computational Biology, German Research Center for Environmental Health, Helmholtz Zentrum M\u00fcnchen, Neuherberg 85764, Germany."},{"name":"Department of Computer Science, School of Computation, Information and Technology, Technical University of Munich, Garching 85748, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9232-6272","authenticated-orcid":true,"given":"Henrike","family":"Maatz","sequence":"additional","affiliation":[{"name":"Cardiovascular and Metabolic Sciences, Max Delbr\u00fcck Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin 13125, Germany."},{"name":"German Center for Cardiovascular Research (DZHK), Partner Site Berlin. Berlin 13125, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0874-6752","authenticated-orcid":true,"given":"Syndi","family":"Barish","sequence":"additional","affiliation":[{"name":"Department of Genetics, Harvard Medical School, Boston, MA 02115, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela","family":"Venturini","sequence":"additional","affiliation":[{"name":"Department of Genetics, Harvard Medical School, Boston, MA 02115, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia L\u00f3pez","family":"Anguita","sequence":"additional","affiliation":[{"name":"Cardiovascular and Metabolic Sciences, Max Delbr\u00fcck Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin 13125, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Shi","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Imperial 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