September 17, 2026Science Translational Medicine
The molecular landscape of hypertrophic cardiomyopathy across disease stages and genotypes
Key result
Single-nucleus RNA sequencing in HCM maps genotype-linked remodeling driving arrhythmia, fibrosis, and vascular dysfunction.
- n=47
Key Points
- To identify stage- and genotype-specific transcriptional mechanisms underlying hypertrophic cardiomyopathy across varying degrees of disease progression.
- Conducted single-nucleus RNA sequencing on cardiac tissue from N=47 patients with hypertrophic cardiomyopathy (spanning obstructive and end-stage disease), comparing them with nonfailing donor and dilated cardiomyopathy controls.
- Validated candidate growth genes using RNA in situ hybridization and human induced pluripotent stem cell-derived cardiomyocyte models.
- Implemented unsupervised and supervised machine learning algorithms to classify disease etiology and predict sarcomere variant status from single-cell transcriptomic profiles.
- Pathogenic variant-positive early-stage samples exhibited lower cardiomyocyte abundance, expansion of a proarrhythmogenic cardiomyocyte subpopulation, and upregulation of the cardiomyocyte growth regulator PRR16.
- Fibroblast activation correlated with profibrotic extracellular matrix remodeling, diminished COL4A1/COL4A2 basement membrane expression, endothelial subpopulation shifts, pericyte loss, and increased VEGF-C signaling.
- Machine learning models successfully separated hypertrophic cardiomyopathy from dilated cardiomyopathy and accurately predicted genotype status in early-stage disease based on cell type-specific gene expression.
Study Design
Type
Observational (n=47)
Structured PICO
P
Population
47 patients with hypertrophic cardiomyopathy, spanning obstructive and end-stage disease, compared with nonfailing donor and dilated cardiomyopathy hearts.
E
Exposure
Single-nucleus RNA sequencing and machine learning analysis
C
Comparator
Nonfailing donor hearts and dilated cardiomyopathy hearts
O
Outcome
Transcriptional programs associated with cardiomyocyte hypertrophy, fibrosis, and vascular remodelingsurrogate
Single-nucleus RNA sequencing reveals multicellular, genotype-associated remodeling programs in HCM, providing insights into the molecular mechanisms underlying arrhythmia, fibrosis, microvascular dysfunction, and heart failure progression.
Discussion
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Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“It has long been known that HCM patients with a known genetic cause tend to suffer more severe disease, yet the molecular mechanisms accounting for this have remained unknown. We show that these patients have a distinct pattern of gene activity in their hearts.”
“This was interesting, because cardiomyopathies are usually thought of as diseases of heart muscle cells only.”
“It was intriguing to see that the unbiased multiomics factor analysis revealed that so many different cell types contribute to the signatures that distinguish between patient groups and controls.”
Implication
Genotype-linked programs may enable precision risk stratification in HCM; leaves open therapeutic translation pending functional validation.
Cite This Study
Adami et al. (2026) conducted an observational in Hypertrophic cardiomyopathy (n=47). Hypertrophic cardiomyopathy and pathogenic sarcomere gene variants vs. Nonfailing donor and dilated cardiomyopathy hearts was evaluated on Transcriptional programs associated with cardiomyocyte hypertrophy, fibrosis, and vascular remodeling. Single-nucleus RNA sequencing of cardiac tissues from 47 HCM patients identified multicellular, genotype-associated remodeling programs underlying arrhythmia, fibrosis, and microvascular dysfunction.