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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的射血分数保留的心力衰竭（HFpEF）在老年人中非常普遍，尤其是术后更年期妇女。在美国，心力衰竭影响约 7-800 万名患者，其中 HFpEF 占超过所有病例的 50%。该疾病是多种合并症（糖尿病、高血压、肥胖、肾功能障碍）。心脏和四肢肌肉是 HFpEF 患者受影响的主要器官以及疾病发生和进展的主要决定因素。老年人的内在肌细胞异常 HFpEF 患者似乎源于线粒体功能障碍。但目前尚无特定疾病 HFpEF 的治疗。目前的药物疗法对运动耐量的改善有限患者并不能解决心脏和四肢肌肉异常问题。 HFpEF 的机制发展和进展具有表型特异性，是 HFpEF 患者的一个普遍亚组由患有多种合并症（例如高血压、肥胖、胰岛素抵抗力/糖尿病）。我们开发了绝经后 HFpEF 的临床前模型，该模型概括了运动不耐受以及老年人疾病的基本心血管、肌肉和全身特征女性。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减弱，收缩/舒张功能障碍，伴有线粒体活性氧增加（ROS）和氧化应激。线粒体活性氧的增加会损害呼吸、收缩和舒张，抗疲劳能力较低。因此，过量的线粒体ROS是骨骼肌的潜在决定因素 HFpEF 异常和运动不耐受。我们的初步数据表明，过量的线粒体 ROS HFpEF 的发生是由于线粒体谷胱甘肽转运受损。一种抗氧化化合物可以增加线粒体谷胱甘肽转运和肝细胞中ROS的减少可防止线粒体的增加体外培养的肌肉细胞中 HFpEF 模拟物诱导的 ROS。因此，我们建议测试全身抗氧化治疗可恢复心脏和四肢肌肉功能和运动的假设绝经后 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和绝经后 HFpEF 的运动不耐受。这种抗氧化剂很容易为人类所利用消费并在临床环境中常规使用。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。