Aldosterone, the Mineralocorticoid Receptor, and Cardiovascular Disease in Obesity

项目摘要 肥胖是一种迅速蔓延的流行病，可以说是心血管疾病的主要原因。肥胖 个体增加了自主的醛固酮产生，导致过度激活 盐皮质激素受体，增加心肌纤维化和缺血、高血压和中风的风险。 由于盐皮质激素受体拮抗剂是广泛可用且安全的药物， 醛固酮的产生代表了一种可修改的机制，可以预防肥胖引起的心血管疾病。我们 盐皮质激素受体拮抗剂可改善肥胖患者心肌灌注和纤维化的假说 个人。我们建议进行一项机械性的临床试验，包括对醛固酮生理学进行深入的表型分析。 和心脏MRI成像来评估这一假说。患有高危肥胖的参与者，定义为肥胖和 未经治疗的高血压和/或代谢综合征的一个或多个特征将被登记。参与者将 进行深入的表型鉴定以确定醛固酮的生理学特征，并通过心脏核磁共振来测量 心肌灌注储备(用于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)，在双盲随机使用依普利酮(一种盐皮质激素受体)之前 拮抗剂和保钾利尿剂)或氯苯吡酮(一种传统的降压药和 浪费钾的利尿剂)和氯化钾一起服用一年。在这一年，血压和 钾将保持在目标范围内，以确保结果不受这些变量的影响。心脏 在随机干预一年后，将再次测量MRI得出的结果。这是意料之中的 依普利酮治疗将改善冠状动脉微血管功能和纤维化的指标，独立于 血压，与含钾的氯替利酮相比。这项机械研究的目的是 使用创新技术研究预防高危肥胖患者心血管疾病的靶向治疗 荷尔蒙表型和复杂的成像结果。如果我们的假设是正确的，这项研究可能会证明 肥胖患者早期应用盐皮质激素受体拮抗剂预防或延缓高血压的发生 心血管疾病，并为未来评估心血管事件的临床试验奠定基础 结果。

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.