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

全身抗氧化治疗绝经后 HFpEF 患者的心肌病、肌无力和运动不耐受

• 批准号: 10593536
• 负责人: Leonardo Ferreira
• 金额: $ 22.88万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2023-08-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10593536
• 关键词: Accounting; Adult; Affect; Angiotensin II; Animals; Antioxidants; Biopsy; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular system; Clinical; Clinical Trials; Complex; Consumption; Cultured Cells; Cytosol; Data; Degenerative polyarthritis; Development; Diabetes Mellitus; Diet; Disease; Disease Marker; Disease Progression; EFRAC; Echocardiography; Elderly; Electron Transport; Enzymes; Exercise Tolerance; Fatigue; Fatty acid glycerol esters; Functional disorder; Glutathione; Goals; Heart failure; Hepatocyte; Human; Hypertension; Impairment; In Vitro; Inbred WKY Rats; Individual; Insulin Resistance; Isometric Exercise; Kidney; Lead; Left; Life; Limb structure; Liquid substance; Liver; Liver diseases; Measures; Membrane; Membrane Fluidity; Mental disorders; Metabolic; Metabolism; Mitochondria; Mitochondrial Matrix; Modeling; Morbidity - disease rate; Morphology; Muscle; Muscle Cells; Muscle Mitochondria; Muscle Weakness; Muscle function; Myopathy; Nutrient; OGTT; Obesity; Organ; Ovariectomy; Oxidative Stress; Oxygen; Palmitates; Patients; Persons; Pharmacotherapy; Phenotype; Pilot Projects; Plasma; Postmenopause; Pre-Clinical Model; Property; Publishing; Randomized; Rattus; Reactive Oxygen Species; Relaxation; Resistance; Respiration; Rodent; Rodent Model; Running; S-Adenosylhomocysteine; S-Adenosylmethionine; Severity of illness; Skeletal Muscle; Source; Symptoms; Testing; Thinness; Translating; Translations; United States; Ventricular; Woman; biophysical properties; comorbidity; cytokine; exercise intolerance; experimental study; fluidity; high reward; high risk; human data; hypertensive; improved; in vivo; kidney dysfunction; male; mitochondrial dysfunction; mortality; normotensive; novel strategies; older patient; older women; patient subsets; preclinical study; preservation; prevent; stem; sugar; uptake

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.

摘要 射血分数正常的心力衰竭（HFpEF）在老年人中非常普遍，尤其是在术后， 更年期女性。心力衰竭影响美国约700 - 800万患者，其中HFpEF占 超过50%的病例。该疾病是多种合并症（糖尿病，高血压， 肥胖和肾功能障碍）。心脏和肢体肌肉是HFpEF患者的主要受累器官 以及疾病发展和进展的主要决定因素。老年人内源性肌细胞异常 HFpEF患者似乎源于线粒体功能障碍。然而，没有疾病特异性 治疗HFpEF。目前的药物治疗对运动耐量的改善有限， 患者，并没有解决心脏和肢体肌肉异常。HFpEF的机制 发生和进展具有表型特异性，HFpEF患者的一个流行亚组 包括具有多种合并症的绝经后老年妇女（例如，高血压，肥胖，胰岛素 抵抗/糖尿病）。我们已经开发了一种绝经后HFpEF的临床前模型， 运动不耐症和老年人疾病的基本心血管、肌肉和全身特征 妇女来自我们实验室和其他实验室的数据显示，心肌和四肢肌肉线粒体呼吸减少， 收缩/舒张功能障碍，伴有线粒体活性氧增加 (ROS)和氧化应激。线粒体ROS的增加损害呼吸、收缩和舒张， 抗疲劳性较低。因此，过量的线粒体ROS是骨骼肌的潜在决定因素 HFpEF中的异常和运动不耐受。我们的初步数据表明过量的线粒体活性氧 在HFpEF是由于受损的线粒体谷胱甘肽转运。一种抗氧化化合物， 线粒体谷胱甘肽转运和肝细胞中ROS的减少阻止了线粒体谷胱甘肽转运的增加。 体外模拟HFpEF在培养的肌细胞中诱导的ROS。因此，我们建议测试 假设全身抗氧化剂治疗恢复心脏和四肢肌肉功能和运动 绝经后HFpEF模型中的耐受性。这是一种治疗心脏和肢体肌病的新方法 绝经后HFpEF患者的运动不耐受。这种抗氧化剂对人类来说是很容易获得的 消费和常规用于临床环境。因此，在我们的临床前研究中， 立即转化为临床试验。