Heterozygous MYH7 R403Q mutation impairs left atrial mitochondrial function in a Yucatan mini-pig model of genetic non-obstructive hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) can be caused by a MYH7 R403Q gene mutation, which drives pathological cardiac remodeling and may ultimately lead to heart failure. Here we sought to examine the effects of this mutation on cardiac mitochondrial function in a Yucatan mini-pig model of genetic HCM. Activity of key mitochondrial enzymes, citrate synthase and β-HAD, were significantly reduced in the left atria of HCM animals compared to the control group. However, left atrial mitochondrial respiration was significantly greater in HCM pigs vs controls in the following states: basal (42%, p=0.001), state 2 (47%, p=0.02) and uncoupled (p=0.003), potentiating a compensatory mechanism. Surprisingly, left ventricular mitochondrial respiration and mitochondrial enzymatic activity did not differ between the HCM model vs healthy control pigs. However, proteomic profiling revealed parallel mitochondrial dysfunction and impairment to energy metabolism processes in both chambers, such as inhibited fatty acid metabolism and mitogenesis in the left atria and increased mitochondrial dysfunction and concentration of fatty acids in the left ventricle. Collectively, the MYH7 R403Q mutation may contribute to HCM through chamber-specific mechanisms that promote mitochondrial dysfunction and impaired energy homeostasis. Further, these findings demonstrate the utility of this preclinical large animal model for identifying novel mechanisms underlying genetic heart failure with translational impact for individuals affected with HCM.