Genotype- and Stage-Specific Molecular Remodeling Programs Identified in Hypertrophic Cardiomyopathy

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Summary of  Science Translational Medicine https://doi.org/10.1126/scitranslmed.aea2747 
Dr. Eleonora Adami et al.

Points

Harvard Medical School and Max Delbrück Center researchers mapped nearly one million cardiac cells using single nucleus RNA sequencing across forty seven patients with hypertrophic cardiomyopathy.
Genetic hypertrophic cardiomyopathy samples exhibited significantly reduced cardiomyocyte density and expanded proarrhythmogenic cell states compared with nongenetic disease presentations and healthy donor tissue.
Investigators identified proline rich 16 expression as a central molecular driver of cardiomyocyte hypertrophy, validating its upregulation through in situ hybridization and stem cell models.
Fibroblasts in early stage disease displayed profibrotic activation and reduced collagen four expression, leading to basement membrane ultrastructural abnormalities and extracellular matrix destabilization.
Machine learning algorithms successfully distinguished hypertrophic cardiomyopathy from dilated cardiomyopathy and predicted genetic status using transcriptional profiles derived exclusively from cardiac fibroblasts.

Summary

This study evaluated the cellular and molecular transcriptomic landscape of hypertrophic cardiomyopathy (HCM) across different clinical stages and genetic backgrounds. Led by researchers from Harvard Medical School, Brigham and Women’s Hospital, and the Max Delbrück Center, the investigation characterized stage- and genotype-specific disease mechanisms to inform targeted therapies. Given that HCM is defined by asymmetric wall thickening, hypercontractility, and fibrosis, mapping near-million-cell transcriptional profiles provides critical insights into pathways driving arrhythmias, microvascular dysfunction, and heart failure progression.

Using single-nucleus RNA sequencing on cardiac tissues from 47 HCM patients—spanning early-stage obstructive disease with preserved systolic function to end-stage heart failure—the researchers profiled nearly 1,000,000 individual cells. Profiles were compared against nonfailing donor hearts and dilated cardiomyopathy controls. Pathogenic variant–positive early-stage samples demonstrated reduced cardiomyocyte density and expansion of a proarrhythmogenic state. Proline-rich 16 (PRR16) was identified as a key driver of cardiomyocyte hypertrophy, validated via RNA in situ hybridization and human induced pluripotent stem cell models. Fibroblast activation showed reduced collagen IV (COL4A1/COL4A2) expression and basement membrane ultrastructural abnormalities, alongside increased lymphangiogenic VEGF-C signaling.

Supervised and unsupervised machine learning models accurately differentiated HCM from dilated cardiomyopathy and predicted genotype status in early-stage disease using single-cell transcriptional profiles, including those derived solely from cardiac fibroblasts. The authors conclude that HCM involves widespread multicellular, genotype-driven remodeling beyond cardiomyocytes alone. These findings establish a high-resolution molecular foundation for developing stage- and genotype-specific precision therapeutics to prevent disease progression.

Link to the article: https://www.science.org/doi/10.1126/scitranslmed.aea2747?referrer=https%3A%2F%2Fmedicalxpress.com%2F

References

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, E. Q., Adam, A., Suresh, A., Reichart, D., Lindberg, E., Brown, K. J., Strohmenger, V., … Seidman, C. E. (2026). The molecular landscape of hypertrophic cardiomyopathy across disease stages and genotypes. Science Translational Medicine, 18(867), eaea2747. https://doi.org/10.1126/scitranslmed.aea2747