Settings of increased aldosterone activity – obesity, advanced age and disease
The MR is expressed in adipose tissue, driving stem cell differentiation and leptin secretion and contributes to Metabolic Syndrome in obesity. Leptin induces release of aldosterone in a positive feedback loop and may be a significant mediator of obesity-associated hyper-aldosteronism. MR-driven hypertrophic adipocytes, especially in visceral and perivascular fat, modulate vascular health and disease through release of proinflammatory cytokines, IL-1, Il-6, TNFa and monocyte-chemotactic-protein-1 (MCP-1) and pro-thrombotic factor plasminogen activator inhibitor type-1 (PAI-1). (11,12)
Aging is characterized by a transition from physiological aldosterone regulation to a pattern of renin-independent secretion. The adrenal gland shows increasing non-neoplastic foci of aldosterone-producing cells while cortisol-mediated MR activation increases. MR expression has also been shown to be increased in the vasculature with aging. Thus, the elderly may have increased risk of autonomous aldosterone production, cortisol-mediated MR activation, and increased MR expression, all contributing to increased aldosterone-mediated pathogenesis.
Evidence continues to accrue confirming chronic Ang II/aldosterone/MR hyper-activation in several cardiovascular disorders, including hypertension, coronary artery disease, ventricular hypertrophy, atrial fibrillation, congestive heart failure and related diseases such as chronic kidney disease, diabetes, stroke and Metabolic Syndrome. (13) In these disease settings the affected tissues are in a heightened state of oxidative and inflammatory stress with persistent interactive up-regulation promoting disease progression. The homeostatic response to chronic RAAS stress is up-regulation of ACE2 and atrial and brain natriuretic factors. The most common medical interventions include ACE inhibitors (ACEI), ATR blockers (ARB) and statins, with MR blockers (MRB) reserved for end-stage disease. Abrupt discontinuation of these medications is associated with rapid increase in disease and death in patients after myocardial infarction or in cardiac failure. During acute events such as myocardial infarction and viral pneumonia, attenuating the RAAS stress response has been shown to be protective.