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Introduction: HCM is a disease of heart muscle associated with heart failure and sudden death, usually caused by mutations in sarcomere protein genes. The mechanisms by which mutations cause disease are uncertain, partly because of the lack of model systems amenable to integrated translational studies. Methods: We generated Yucatan minipigs with heterozygous knockin of the human HCM MYH7 R403Q mutation. We conducted serial serum biomarker analyses, cardiac imaging and histologic and omic analyses of LV biopsy samples of wildtype and R403Q pigs (n =14/group). Results: Cardiac MRI (CMR) and echocardiography showed heterogeneity in the pattern of hypertrophy in R403Q pigs (concentric vs asymmetric), similar to humans. Histology showed lower capillary density (x102/mm2) in R403Q vs WT pigs (13.0±0.0.9 vs 10.1±0.4, p <0.01). CMR showed regional myocardial flow reserve (FR) in response to dipyridamole was decreased in R403Q pigs and was negatively correlated with the severity of hypertrophy (Figure: Panel A shows a plot of all pigs; Panel B shows an R403Q pig with greater impairment of FR in the hypertrophic septum than the relatively normal posterior wall). Serum TnI (ng/L) was elevated in R403Q vs WT pigs at ages 1 month (167.3±20.1 vs 90.5±9.9, p <0.01), 3 months (202.0±30.6 vs 20.0±4.3, p <0.01), 6 months (134.5±69.6 vs 6.7±8.3, p <0.01), and 9 months (206.1±66.8 vs 0.0±0.0, p <0.001). There was increased fibrosis (% area) in R403Q vs WT pigs at ages 3 months (11.4±5.2 vs 2.9±3.1, p <0.01) and 9 months (15.7±8.5 vs 3.5±3.1, p <0.01), with increased myocyte disarray. Intramyocardial arterioles in R403Q pigs showed intimal hyperplasia with decreased luminal diameters. RNAseq and proteomic analyses showed upregulation of pro-fibrotic pathways. Conclusions: This first large-animal genetic model of HCM allows studies such as FR not possible in rodents. Our data suggest that a limitation in perfusion of hypertrophic myocardium leads to chronic injury and fibrosis. [ABSTRACT FROM AUTHOR]