Why the study?
The mechanisms by which sarcomere-associated gene variants lead to hypertrophic cardiomyopathy phenotype are uncertain due to lack of suitable model systems for integrated translational studies.
A novel Yucatan minipig model with a heterozygous knockin of the human MYH7 R403Q variant successfully recapitulates the structural, physiological, and transcriptomic features of human hypertrophic cardiomyopathy.
Porcine MYH7 R403Q model recapitulates human HCM hypertrophy; leaves open mechanistic and therapeutic translation pending human validation.
Hypertrophic cardiomyopathy (HCM) is a disease of heart muscle commonly caused by variants in genes encoding sarcomere-associated proteins. The mechanisms by which these variants lead to the phenotype are uncertain, partly because of the lack of model systems amenable to integrated translational studies. We generated Yucatan minipigs with heterozygous knockin of the human HCM R403Q variant in MYH7. MYH7 R403Q pigs exhibited hypertrophy similar to humans on cardiac imaging. Relative to wild-type, MYH7 R403Q pigs showed increased interstitial fibrosis, increased myocyte disarray, lower capillary density, and intimal hyperplasia of intramyocardial arterioles with decreased luminal diameters. Bulk RNA sequencing and single nuclear RNA sequencing analyses showed upregulation of profibrotic and proinflammatory pathways. MYH7 R403Q hearts showed hypercontractility, elevated end-diastolic pressures, blunted β-adrenergic enhancement of systolic and diastolic function, and increased Ca
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Green et al. (2026) studied Hypertrophic cardiomyopathy (HCM). Heterozygous knockin of the human HCM R403Q variant in MYH7 vs. Wild-type was evaluated on Cardiac hypertrophy, structural changes, and physiological parameters.
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