Abstract 16: A Minipig Genetic Model Of Hypertrophic Cardiomyopathy

Introduction: Hypertrophic cardiomyopathy (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 knock-in 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, cardiac imaging and histologic and multi-omic analysis of LV biopsy samples. Results: We followed a cohort of 22 R403Q pigs and 6 WT herdmates. Juvenile animals (3 months) showed early signs of HCM with elevated serum troponin I, increased myocardial contractility in muscle fibers and hearts and interstitial fibrosis and myocyte disarray. At late adolescence (9 months), disarray and fibrosis had progressed, but contractility had normalized with some pigs progressing to systolic dysfunction. Across the cohort, end-diastolic pressure was increased with evidence of diastolic dysfunction and elevation in B-type natriuretic peptide. Transcriptomic analysis at both 3 and 9 months showed dysregulation of metabolic modules and an upregulation of pro-fibrotic pathways. By one year of age, 11 of 22 R403Q pigs had suffered sudden cardiac death, whereas all wildtype pigs survived. 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, and late adolescent animals have signs of advanced disease with an increased rate of sudden cardiac death. These data suggest that our minipig model may yield insights throughout the natural history of HCM from preclinical to end-stage disease. This model will thus be invaluable for advancing understanding of HCM and for the development of novel therapeutics.