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| Item Type: | Article |
|---|---|
| Title: | The molecular landscape of hypertrophic cardiomyopathy across disease stages and genotypes |
| Creators: |
Adami, Eleonora  ORCID: https://orcid.org/0000-0002-1813-6681, Kim, Yuri ORCID: https://orcid.org/0000-0001-5978-5779, Zheng, Sean L. ORCID: https://orcid.org/0000-0002-5762-6392, Shvetsov, Nikolay ORCID: https://orcid.org/0000-0001-9526-7637, Losert, Corinna ORCID: https://orcid.org/0000-0002-5997-4702, Maatz, Henrike ORCID: https://orcid.org/0000-0002-9232-6272, Barish, Syndi ORCID: https://orcid.org/0009-0004-0874-6752, Venturini, Gabriela, López-Anguita, Natalia López ORCID: https://orcid.org/0000-0003-3373-7191, Shi, Qi, Neyazi, Meraj, Beyer, Martin ORCID: https://orcid.org/0000-0003-0925-7067, Wei, Eric Q. ORCID: https://orcid.org/0000-0001-5948-0174, Adam, Amanda, Suresh, Abhilash ORCID: https://orcid.org/0009-0009-4964-4222, Reichart, Daniel ORCID: https://orcid.org/0000-0002-8559-5888, Lindberg, Eric ORCID: https://orcid.org/0000-0002-2979-433X, Brown, Kemar J. ORCID: https://orcid.org/0000-0002-2184-4654, Strohmenger, Viktoria ORCID: https://orcid.org/0000-0001-7972-6098, Saul, David ORCID: https://orcid.org/0009-0007-0701-0040, Gärtner, Anna ORCID: https://orcid.org/0000-0001-6899-7693, Lee, Michael ORCID: https://orcid.org/0000-0002-0186-4439, Mach, Lukas ORCID: https://orcid.org/0000-0001-7824-4468, Robertus, Jan Lukas ORCID: https://orcid.org/0000-0003-0433-7965, Gorham, Joshua M. ORCID: https://orcid.org/0000-0001-5969-4690, Haas, Jan ORCID: https://orcid.org/0000-0002-8040-8289, Liebig, Laura A. ORCID: https://orcid.org/0009-0000-9282-0775, Lippert, Christoph ORCID: https://orcid.org/0000-0001-6363-2556, Meder, Benjamin, Myronova, Anna ORCID: https://orcid.org/0000-0003-2886-2588, Patone, Giannino ORCID: https://orcid.org/0000-0002-7242-0341, Barnett, Sam N. ORCID: https://orcid.org/0000-0002-8968-4319, Ware, James S. ORCID: https://orcid.org/0000-0002-6110-5880, de Robertis, Fabio, Pantazis, Antonis, Gummert, Jan ORCID: https://orcid.org/0000-0002-6956-9110, Viveiros, Anissa ORCID: https://orcid.org/0000-0001-9452-1082, Chen, Huachen, Ruiz-Orera, Jorge ORCID: https://orcid.org/0000-0002-8317-0034, Frey, Norbert, McDonough, Barbara A. ORCID: https://orcid.org/0000-0002-4257-8623, Mitchell, Richard N. ORCID: https://orcid.org/0000-0002-0329-7618, Padera, Robert F. ORCID: https://orcid.org/0000-0002-4571-5494, Day, Sharlene M. ORCID: https://orcid.org/0000-0001-9802-7188, Ho, Carolyn Y. ORCID: https://orcid.org/0000-0002-7334-7924, Lakdawala, Neal K ORCID: https://orcid.org/0000-0001-6458-5421, Milting, Hendrik ORCID: https://orcid.org/0000-0001-9722-0007, Heinig, Matthias ORCID: https://orcid.org/0000-0002-5612-1720, Oudit, Gavin Y. ORCID: https://orcid.org/0000-0002-9154-9028, Noseda, Michela ORCID: https://orcid.org/0000-0002-9553-5029, Seidman, Jonathan G. ORCID: https://orcid.org/0000-0002-9082-3566, Hübner, Norbert ORCID: https://orcid.org/0000-0002-1218-6223 and Seidman, Christine E. ORCID: https://orcid.org/0000-0001-6380-1209
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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. |
| Keywords: | Cardiac Myocytes, Dilated Cardiomyopathy, Extracellular Matrix, Fibroblasts, Fibrosis, Genotype, Hypertrophic Cardiomyopathy |
| Source: | Science Translational Medicine |
| ISSN: | 1946-6234 |
| Publisher: | American Association for the Advancement of Science |
| Volume: | 18 |
| Number: | 867 |
| Page Range: | eaea2747 |
| Date: | 16 September 2026 |
| Official Publication: | https://doi.org/10.1126/scitranslmed.aea2747 |
| PubMed: | View item in PubMed |
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