Double-barreled assault by aldosterone and salt on the heart.

Aldosterone, a mineralocorticoid hormone secreted by the adrenal zona glomerulosa, is generally regarded as the end product of the renin-angiotensin-aldosterone system. Aldosterone is a major regulator of body fluid and electrolyte homeostasis by virtue of its classic actions at renal collecting duct principal cells, mediated by mineralocorticoid receptors (MR), to induce sodium (Na ) and water reabsorption and potassium (K ) excretion. In addition to these classic effects, aldosterone induces nonclassical actions in both epithelial and nonepithelial tissues, including inflammation and fibrosis that lead to cardiac, vascular, and renal target organ damage. Indeed, a large body of evidence supports the concept that aldosterone induces deleterious effects on the cardiovascular system independently of both angiotensin II and blood pressure (1, 2). The detrimental effects of MR activation in patients with heart failure have been amply demonstrated in large clinical outcome trials. The Randomized Aldactone Evaluation Study showed that adding MR antagonist spironolactone to usual therapy in patients with moderate-severe symptoms decreased the rate of death from any cause and the risk of hospitalization for cardiovascular reasons (3). The Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy Survival Study showed that the selective MR antagonist eplerenone, added to conventional therapy, reduced the rates of death from any cause and hospitalization for cardiovascular reasons in patients with acute myocardial infarction complicated by left ventricular (LV) systolic dysfunction and heart failure (4). This year, the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure reported that eplerenone significantly reduced the risks of death and hospitalization in patients with systolic heart failure and mild symptoms (5). Impressively, in that study the number of patients with heart failure needed to treat to prevent one primary outcome was only 19, placing MR antagonist therapy at the forefront of choices for heart failure with mild symptoms (5). Recent studies have convincingly demonstrated that MR can be activated by both cortisol and aldosterone (6, 7). Cardiac MR activation contributes to infarct size after experimental myocardial infarction in rodents (7). Spironolactone not only reversed the resultant tissue damage but acted as an inverse protective agonist in the absence of the steroid receptor ligand (aldosterone or cortisol). These results encourage the initiation of human clinical trials aimed to determine whether starting MR antagonist therapy early after myocardial infarction can limit tissue damage. Taken together, the results of the animal and human studies discussed above emphasize the importance of MR in the pathophysiology of cardiac structural damage. MR are overexpressed in the failing heart and contribute to cardiac inflammation and fibrosis, and patients with even mild heart failure may have increased aldosterone and cortisol levels in spite of angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, and -blocker therapy. Both dietary Na intake and aldosterone secretion have been linked to the pathogenesis of hypertension and related cardiovascular disease. A core issue in the pathophysiology of target organ damage is the relationship of salt to aldosterone. It is clear that elevated levels of aldosterone inappropriate for Na status (high salt intake) can induce cardiovascular hypertrophy and fibrosis in a variety of experimental animal models. However, during