Aldosterone antagonism in addition to angiotensin-converting enzyme inhibitors in heart failure.

Although the role of the systemic renin-angiotensin-aldosterone system in the pathophysiology of heart failure is well-known for years, the impact of a local cardiac aldosterone system has been recognized recently. Aldosterone promotes cardiac hypertrophy and fibrosis in hypertension and heart failure and is involved in left ventricular remodeling after myocardial infarction. Plasma aldosterone levels in patients with heart failure are an indicator of a worse prognosis. Although ACE inhibitor therapy in these patients reduces plasma aldosterone levels, this effect is only transitory, a phenomenon referred to as "aldosterone escape". Even maximally recommended doses of ACE inhibitors do not completely prevent ACE-mediated formation of angiotensin II in chronic heart failure, and those patients with increased aldosterone levels during ACE inhibition have impaired exercise capacity. The RALES study has demonstrated convincingly that in patients with heart failure, addition of the mineralocorticoid receptor antagonist spironolactone (25 mg/d) to ACE inhibition markedly reduces mortality and prevents worsening heart failure. While reduction of excessive extracellular matrix turnover leading to decreased fibrosis appears to be the most important effect of spironolactone in heart failure, other mechanisms such as regression of hypertrophy, improvement of endothelial function, enhanced renal sodium excretion and antiarrhythmic actions may contribute. In RALES, low-dose spironolactone did not confer a substantial risk of hyperkalemia, however, with broader use of spironolactone in heart failure, cases of hyperkalemia associated with the use of this drug increase. Close control of serum potassium and creatinine and estimation of creatinine clearance are mandatory, especially in the presence of additional factors impairing renal function. The new and more selective aldosterone antagonist eplerenone which is devoid of some side effects of spironolactone, has been shown to be effective in hypertension and holds great promise as future therapeutic agent in patients with heart failure.