Mineralocorticoid Receptors: An Appealing Target to Treat Coronary Microvascular Dysfunction in Diabetes

Cardiovascular disease (CVD), particularly coronary vascular disease, is a primary contributor to diabetes-related morbidity and mortality worldwide. Specifically, dysfunction of coronary microcirculation is common in this patient population, often occurring in the absence of or preceding epicardial coronary atherosclerosis, thereby leading to impaired coronary blood flow (CBF) regulation and increased risk of myocardial ischemia/infarct. Clinically, coronary microvascular function can be assessed by determination of coronary flow reserve (CFR) (ratio of maximal hyperemic to basal CBF), and impaired CFR is a powerful independent correlate of cardiac mortality in diabetic patients (1). Importantly, recent evidence revealed that diabetic patients with preserved CFR (above the median) have cardiac event rates similar to nondiabetic patients (1). Thus, treatment strategies designed to restore CFR (i.e., coronary microvascular function) hold promise to reduce acute and long-term cardiac mortality in patients with diabetes.Diabetes is associated with increased activation of the renin-angiotensin-aldosterone system (RAAS), and evidence suggests that the aldosterone-binding mineralocorticoid receptor (MR) contributes to obesity and diabetes-related vascular dysfunction (2,3). Even modest elevations in circulating aldosterone levels correlate with increased acute ischemic events and cardiovascular death in diabetic patients with coronary artery disease (4). Furthermore, accumulating evidence demonstrates that inhibition of angiotensin II (AngII) action, via ACE inhibition or angiotensin receptor blockade (ARB), does not appreciably lower circulating aldosterone levels, suggesting a residual role for MR activation in CVD pathogenesis (5). This is consistent with initial clinical trials demonstrating reduced mortality with MR antagonist treatment in …