Aldosterone, the Mineralocorticoid Receptor, and Cardiovascular Disease in Obesity

Obesity is a dominant risk factor for the development of cardiovascular disease (CVD). The public health relevance of this relationship is underscored by the fact that 40% (93 million) of adult Americans are obese.

Activation of the mineralocorticoid receptor (MR) is a major mechanism implicated in the pathogenesis of obesity-associated CVD. MR activation causes vascular stiffness, inflammation, and fibrosis, and MR antagonists improve clinical outcomes in heart failure with reduced ejection fraction, especially in obesity. However, even in the absence of heart failure, multiple mechanisms of CVD in obesity are mediated by excessive activation of the MR. These mechanisms include: autonomous aldosterone production, increased cortisol action, high sympathetic nervous system activity, increased leptin, inflammation, and oxidative stress.

Autonomous aldosterone production is a highly prevalent and poorly recognized disorder that causes CVD independent of blood pressure (BP). Autonomous aldosterone production manifests across a wide severity spectrum, ranging from mild/subclinical (rarely recognized) to overt (primary aldosteronism). The investigators' work has characterized autonomous aldosterone production as a phenotype of non-physiologic, non-suppressible, and renin-independent aldosterone production that is highly prevalent in the general population of the U.S.A..

Autonomous aldosterone production and MR activation are especially enriched in obesity, particularly among obese/overweight individuals with hypertension and/or metabolic syndrome. Current treatment guidelines do not recommend the early use of MR antagonists in obesity or hypertension, thereby delaying or omitting a targeted therapy that may specifically mitigate the mechanism of CVD in this high-risk population.

The investigators have validated cardiac MRI methods to measure coronary microvascular function and myocardial fibrosis, both strong surrogates for CVD that correlate with aldosterone production and that improve with MR antagonist therapy.