Mineralocorticoid receptor antagonists for the treatment of hypertension and the metabolic syndrome.

I ncreasing evidence suggests a link between the metabolic syndrome and aldosterone. Patients with obesity and the metabolic syndrome have been found to have increased adrenal production of aldosterone and increased cortisol levels , whereas weight reduction is associated with a decrease in aldosterone. 6 A high-fat diet has been shown to lead to an upregulation of mineralocorticoid expression, and adipocytes produce aldosterone through angiotensin II–mediated aldoste-rone synthase, which is regulated by calcineurin. 7 Increased levels of aldosterone are associated with brown fat dysfunction and inflammation of white fat, 8 as well as several other adverse cardiovascular and renal effects including mitochondrial dys-function, an increase in reactive oxygen species, macrophage infiltration and inflammatory cytokine activation, myocardial and vascular fibrosis and hypertrophy, endothelial dysfunc-tion, mesangial cell inflammation and fibrosis, podocyte loss, albuminuria, progressive renal dysfunction, insulin resistance, pancreatic β-cell dysfunction, sympathetic nervous system activation, ventricular and atrial arrhythmias, as well as sodium retention, potassium loss, and hypertension. Mineralocorticoid receptor antagonists (MRAs) have been shown to decrease inflammation and myocardial fibrosis in patients with obesity 9 and the metabolic syndrome, as well as to provide target organ protection in patients with hypertension independent of a drop in blood pressure and to reduce total mortality and total hospitalizations in patients with chronic heart failure and a reduced left ventricular ejection fraction. One can therefore postulate that aldosterone and activation of the MR play a critical role in the cardiovascular and renal consequences of the metabolic syndrome and that MRAs would have a beneficial effect in preventing these consequences. In this issue of Hypertension, Buglioni et al 10 report on the measurement of plasma aldosterone levels in a random sample (n=1674, ≥45 years of age) of the general population from Olmsted county, MN. They noted that aldosterone levels were associated with hypertension, central obesity, chronic renal disease, the metabolic syndrome, as well as increased triglyc-eride levels, concentric left ventricular hypertrophy, and atrial fibrillation after adjusting for age and sex. Aldosterone levels in the highest tertile correlated with lower naturetic peptide levels and mortality. Although most of these associations remained significant after excluding patients with an aldoste-rone level above the normal range, the association with mortality did not remain significant. Of interest was the finding that aldosterone levels were significantly higher in those patients with hypertension treated with antihypertensive medications, likely reflecting aldosterone breakthrough or escape in those treated with a renin–angiotensin–aldosterone system inhibi-tor. The …