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.

抽象的 在老年人中，心力衰竭和保留的射血分数（HFPEF）非常普遍 更年期的妇女。心力衰竭在美国影响约7-8万患者，HFPEF占 所有情况中有50％以上。该疾病是多种合并症的结果（糖尿病，高血压， 肥胖和肾功能障碍）。心脏和肢体肌肉是HFPEF患者受影响的主要器官 以及疾病发展和进展的主要决定因素。老年的内在心肌异常 HFPEF患者似乎来自线粒体功能障碍。但是，没有特定疾病的 HFPEF的治疗。当前的药物治疗提供了有限的运动耐受性 患者并且不能解决心脏和肢体肌肉异常。 HFPEF的机制 发育和进展是表型特异性的，HFPEF患者的普遍亚组 由多种合并症的绝经后妇女组成（例如高血压，肥胖，胰岛素 阻力/糖尿病）。我们已经开发了绝经后HFPEF的临床前模型，该模型概括了 运动不耐受和疾病的必要心血管，肌肉和全身特征 女性。来自我们实验室和其他实验室的数据显示心脏和肢体肌肉线粒体呼吸减少 收缩/松弛功能障碍，伴随着线粒体活性氧的增加 （ROS）和氧化应激。线粒体ROS的增加损害呼吸，收缩和放松，以及 降低疲劳性。因此，多余的线粒体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线粒体ROS过多 在HFPEF中是由于线粒体谷胱甘肽运输受损。显示出增加的抗氧化剂化合物 线粒体谷胱甘肽的传输并减少肝细胞中的ROS可防止线粒体的增加 由培养的肌肉细胞中HFPEF的体外模仿诱导的ROS。因此，我们建议测试 系统性抗氧化剂治疗可恢复心脏和肢体肌肉功能和运动 绝经后HFPEF模型中的公差。这是一种治疗心脏和肢体肌病的新方法 并在绝经后HFPEF中运动不耐受。抗氧化剂很容易适合人类 消费和通常在临床环境中使用。因此，我们的临床前研究中的积极影响可能是 立即翻译成患者的临床试验。