Aldosterone, the Mineralocorticoid Receptor, and Cardiovascular Disease in Obesity

醛固酮、盐皮质激素受体与肥胖症中的心血管疾病

• 批准号: 10024158
• 负责人: Anand Vaidya
• 金额: $ 88.68万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10024158
• 关键词: Adrenal Glands; Adult; Aldosterone; American; Blood Pressure; Blood Vessels; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Chlorthalidone; Clinical; Clinical Trials; Coronary; Development; Disease; Disease Outcome; Diuretics; Double-Blind Method; EFRAC; Enrollment; Ensure; Epidemic; Event; Fatty acid glycerol esters; Fibrosis; Foundations; Future; General Population; Heart; Heart Diseases; Heart failure; Hormonal; Hormones; Hydrocortisone; Hypertension; Image; Individual; Inflammation; Intervention; Leptin; Magnetic Resonance Imaging; Measures; Mediating; Medical; Metabolic syndrome; Methods; Mineralocorticoid Receptor; Myocardial Ischemia; Myocardial perfusion; Obesity; Obesity associated cardiovascular disease; Outcome; Outcome Study; Overweight; Oxidative Stress; Participant; Pathogenesis; Patients; Pharmaceutical Preparations; Phenotype; Physiologic pulse; Physiological; Physiology; Population; Potassium; Potassium Chloride; Prevention; Primary Hyperaldosteronism; Production; Prospective Studies; Protocols documentation; Public Health; Randomized; Receptor Activation; Renin; Research Design; Risk; Risk Factors; Severities; Stress; Stroke; Sympathetic Nervous System; adipokines; arterial stiffness; blood pressure medication; blood pressure regulation; cardiovascular disorder prevention; clinical phenotype; coronary fibrosis; cost effective; delta opioid receptor; design; eplerenone; extracellular; high risk; high risk population; improved; inflammatory marker; innovation; mortality; predicting response; prevent; public health relevance; targeted treatment; treatment guidelines; wasting

PROJECT ABSTRACT Obesity is a rapidly expanding epidemic that is arguably the leading cause of cardiovascular disease. Obese individuals have increased autonomous aldosterone production resulting in excessive activation of the mineralocorticoid receptor that increases the risk for myocardial fibrosis and ischemia, hypertension, and stroke. Since mineralocorticoid receptor antagonists are widely available and safe medications, autonomous aldosterone production represents a modifiable mechanism to prevent cardiovascular disease in obesity. We hypothesize that mineralocorticoid receptor antagonists can improve myocardial perfusion and fibrosis in obese individuals. We propose a mechanistic clinical trial that involves deep phenotyping of aldosterone physiology and cardiac MRI imaging to evaluate this hypothesis. Participants with high-risk obesity, defined as obesity with untreated hypertension and/or one or more features of the metabolic syndrome, will be enrolled. Participants will undergo a deep-phenotyping protocol to characterize aldosterone physiology, and cardiac MRI to measure myocardial perfusion reserve (to assess coronary microvascular function) and extracellular volume fraction (to assess myocardial fibrosis), before double-blinded randomization to eplerenone (a mineralocorticoid receptor antagonist and potassium-sparing diuretic) or chlorthalidone (a conventional blood pressure medication and potassium-wasting diuretic) along with potassium chloride for one year. During this year, blood pressure and potassium will be maintained in a target range to ensure outcomes are independent of these variables. Cardiac MRI-derived outcomes will be measured again after one year of the randomized intervention. It is anticipated that eplerenone therapy will improve measures of coronary microvascular function and fibrosis, independent of blood pressure, when compared to chlorthalidone with potassium. This mechanistic study is designed to investigate a targeted treatment for the prevention of cardiovascular disease in high-risk obesity using innovative hormonal phenotyping and sophisticated imaging outcomes. If our hypothesis is correct, this study may justify the early use of mineralocorticoid receptor antagonists in patients with obesity to prevent or delay the onset of cardiovascular disease, and establish a foundation for future trials to evaluate incident clinical cardiovascular outcomes.

项目摘要 肥胖是一种快速扩大的流行病，可以说是心血管疾病的主要原因。肥胖 个体增加了自主醛酮的产生，导致过度激活 矿物皮质激素受体增加了心肌纤维化和缺血，高血压和中风的风险。 由于矿物皮质激素受体拮抗剂已广泛可用且安全的药物，因此 醛固酮产量代表了预防肥胖症中心血管疾病的一种可修改机制。我们 假设盐皮质激素受体拮抗剂可以改善肥胖的心肌灌注和纤维化 个人。我们提出了一项机械临床试验，涉及醛固酮生理的深层表型 和心脏MRI成像以评估这一假设。具有高风险肥胖的参与者，定义为肥胖 未治疗的高血压和/或代谢综合征的一个或多个特征将被招募。参与者会 采用深度型型方案，以表征醛固酮生理和心脏MRI以测量 心肌灌注储备（评估冠状动脉微血管功能）和细胞外体积分数（TO 评估心肌纤维化），在与eplerenone的双盲随机分组之前（矿物皮质激素受体 拮抗剂和钾的利尿剂）或氯噻酮（常规的血压药物和 挥发钾的利尿剂）以及氯化钾一年。在今年，血压和 钾将保持在目标范围内，以确保结果与这些变量无关。心脏 在随机干预一年后，将再次测量MRI衍生的结果。预计 这种eplerenone疗法将改善冠状动脉微血管功能和纤维化的措施，与 与钾氯吡啶酮相比，血压。这项机械研究旨在 研究使用创新的高风险肥胖症预防心血管疾病的有针对性治疗方法 激素表型和复杂的成像结果。如果我们的假设正确，这项研究可能证明是合理的 肥胖患者中矿物皮质激素受体拮抗剂的早期使用以预防或延迟发作 心血管疾病，并为将来的试验建立基础，以评估事件临床心血管 结果。