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.