Left Ventricular Structural, Physiological, and Transcriptomic Abnormalities in a Novel Porcine Hypertrophic Cardiomyopathy Model.

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 Ca2+ sensitivity. The cardiac myosin inhibitor MYK-581 reduced hypercontractility and improved diastolic function. Data from this large animal genetic model of HCM strengthen the mechanistic link between genetic variants and in vivo phenotypes and elucidate the mechanisms of myofilament-targeted therapies.