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 个体增加了自发性醛固酮产生，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预防肥胖症心血管疾病的可改变机制。我们 假设盐皮质激素受体拮抗剂可以改善肥胖患者心肌灌注和纤维化 个体我们提出了一个机制的临床试验，涉及深表型的醛固酮生理学 和心脏核磁共振成像来评估这一假设。高风险肥胖的参与者，定义为肥胖， 未经治疗的高血压和/或代谢综合征的一种或多种特征。参与者将 进行深度表型分析以表征醛固酮生理学，并进行心脏MRI以测量 心肌灌注储备（用于评估冠状动脉微血管功能）和细胞外容积分数（用于 评估心肌纤维化），然后双盲随机分配至依普利酮（盐皮质激素受体 拮抗剂和保钾利尿剂）或氯噻酮（一种常规的血压药物， 钾消耗利尿剂）与氯化钾一起沿着一年。在这一年里，血压和 钾将维持在目标范围内，以确保结果与这些变量无关。心脏 将在随机干预一年后再次测量MRI衍生结局。预计 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， 血压，当与氯噻酮钾相比。这项机制研究旨在 研究一种有针对性的治疗方法，用于预防高危肥胖症患者的心血管疾病， 激素表型和复杂的成像结果。如果我们的假设是正确的，这项研究可能证明 肥胖患者早期使用盐皮质激素受体拮抗剂，预防或延迟 心血管疾病，并为未来的试验建立基础，以评估事件临床心血管疾病 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.