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

摘要 心力衰竭伴保留射血分数(HFpEF)在老年人中非常普遍，尤其是 更年期女性。在美国，心力衰竭影响到约700-800万患者，其中HFpEF占 超过50%的案例。这种疾病是多种合并症(糖尿病、高血压、 肥胖和肾功能障碍)。心脏和四肢肌肉是影响HFpEF患者的主要器官 以及疾病发展和进展的主要决定因素。老年人固有的心肌细胞异常 HFpEF患者似乎源于线粒体功能障碍。然而，没有特定于疾病的 高血压性肺功能衰竭的治疗。目前的药物治疗在运动耐量方面的改善有限 患者并不能解决心脏和四肢肌肉的异常。高频脉冲电场的作用机制 发展和进展是表型特有的，并且是HFpEF患者的一个流行亚群 由患有多种并发症(如高血压、肥胖症、胰岛素)的绝经后老年妇女组成 抵抗力/糖尿病)。我们已经开发了一个绝经后HFpEF的临床前模型，它概括了 运动不耐受与老年人心血管、肌肉和全身疾病的基本特征 女人。来自我们实验室和其他实验室的数据显示，心脏和四肢肌肉线粒体呼吸和 收缩/松弛功能障碍，伴有线粒体活性氧增加 (ROS)和氧化应激。线粒体ROS的增加会损害呼吸、收缩和放松，而且 抗疲劳性较低。因此，线粒体过量的ROS是骨骼肌的一个潜在决定因素。 HFpEF的异常和运动不耐受。我们的初步数据表明，过量的线粒体ROS 在HFpEF中，是由于线粒体谷胱甘肽运输受损。一种抗氧化剂化合物被证明可以增加 肝细胞线粒体谷胱甘肽转运和ROS减少可阻止线粒体增加 体外模拟HFpEF在培养肌肉细胞中诱导ROS。因此，我们建议测试 全身抗氧化剂治疗可恢复心脏和四肢肌肉功能和运动的假说 绝经后HFpEF模型的耐受性。这是一种治疗心脏和肢体肌病的新方法。 绝经后HFpEF与运动耐量有关。这种抗氧化剂对人类来说很容易买到 在临床环境中使用和常规使用。因此，我们的临床前研究的积极影响可以是 立即转化为患者的临床试验。

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.