Abstract 14467: A Minipig Genetic Model of Hypertrophic Cardiomyopathy

Introduction: HCM is a heritable disease of heart muscle associated with increased risk of heart failure and sudden death. Mutations in genes encoding sarcomere proteins are commonly associated with HCM. However, the mechanisms by which these mutations lead to molecular, cellular and organ-level pathophysiology are uncertain, partly because of the lack of model systems amenable to integrated translational studies. Methods: Using homologous recombination and somatic cell nuclear transfer, we generated Yucatan minipigs with a heterozygous knockin of the R403Q mutation in MYH7 , a well-characterized human HCM mutation. We conducted deep phenotyping with biomechanical studies of myocardial tissue samples, circulating biomarker analysis, multi-modality cardiac imaging and histologic and multi-omic analysis of LV biopsy samples. Results: We followed a cohort of 7 R403Q pigs and 6 WT herdmates. Serum TnI was persistently elevated in R403Q vs WT pigs at ages 1 month (167.3±20.1 vs 90.5±9.9 ng/L, p=0.008), 3 months (202.0±30.6 vs 20.0±4.3 ng/L, p=0.007) and 6 months (134.5±69.6 vs 6.7±8.3 ng/L, p=0.03). Cardiac MRI revealed hypercontractility at 3 months (EF 60.5±8.6% vs. 47.8±5.3%, p=0.02). LV biopsy samples at 3 months contained fibrosis and myocardial disarray (Figure), and RNAseq and proteomic analyses showed dysregulation of modules involved in contractility and an upregulation of pro-fibrotic pathways. Consistent with studies in humans bearing HCM mutations, these abnormalities preceded a detectable increase in LV wall thickness. Conclusions: We have developed the first large-animal genetic model of HCM. Young pigs with the MYH7 R403Q mutation show functional and histologic features of the preclinical human phenotype. Our findings suggest that hypercontractility, subclinical ischemia and fibrosis contribute to the early pathogenesis of HCM. This model will be invaluable for advancing understanding of HCM and for the development of novel therapeutics.