Systemic antioxidant treatment for cardiomyopathy, muscle weakness, and exercise intolerance in postmenopausal HFpEF

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Abstract Heart failure with preserved ejection fraction (HFpEF) is highly prevalent in the elderly, especially post- menopausal women. Heart failure affects ~7-8 million patients in the United States, with HFpEF accounting for more than 50% of all cases. The disease is a consequence of multiple comorbidities (diabetes, hypertension, obesity, and renal dysfunction). Cardiac and limb muscles are the main organs affected in patients with HFpEF and the main determinants of disease development and progression. Intrinsic myocyte abnormalities in older patients with HFpEF appear to stem from mitochondrial dysfunction. However, there is no disease-specific treatment for HFpEF. Current pharmacotherapies provide limited improvements in exercise tolerance in patients and do not resolve the cardiac and limb muscle abnormalities. The mechanisms of HFpEF development and progression are phenotype-specific, and a prevalent subgroup of patients with HFpEF consists of older postmenopausal women with multiple comorbidities (e.g., hypertension, obesity, insulin resistance/diabetes). We have developed a preclinical model of postmenopausal HFpEF that recapitulates the exercise intolerance and essential cardiovascular, muscle, and systemic features of the disease in older women. Data from our lab and others show diminished cardiac and limb muscle mitochondrial respiration and contraction/relaxation dysfunction, which are accompanied by increased mitochondrial reactive oxygen species (ROS) and oxidative stress. Increases in mitochondrial ROS impair respiration, contraction and relaxation, and lower fatigue resistance. Therefore, excess mitochondrial ROS is a potential determinant of skeletal muscle abnormalities and exercise intolerance in HFpEF. Our preliminary data suggest that excess mitochondrial ROS in HFpEF is due to impaired mitochondrial glutathione transport. An antioxidant compound shown to increase mitochondrial glutathione transport and decrease ROS in hepatocytes prevents the increase in mitochondrial ROS induced by in vitro mimics of HFpEF in cultured muscle cells. Therefore, we propose to test the hypothesis that systemic antioxidant treatment restores cardiac and limb muscle function and exercise tolerance in a model of postmenopausal HFpEF. This is a novel approach to treat cardiac and limb myopathy and exercise intolerance in postmenopausal HFpEF. The antioxidant is readily available for human consumption and routinely used in the clinical setting. Hence, positive effects in our pre-clinical studies can be translated immediately to clinical trials in patients.