Role of the Circulating and Tissue-Based Renin-Angiotensin System in the Development of Heart Failure: Implications for Therapy

Abstract

The renin-angiotensin system (RAS) is believed to play a central role in the pathophysiology of heart failure. However, there is a wide variability in plasma renin levels in patients with heart failure, and normal plasma renin activity has been documented in patients with mild or compensated disease. Recent evidence has demonstrated the existence of endogenous RAS in a number of tissues associated with cardiovascular homeostasis. It is possible that these tissue RAS are activated in the early stages of heart failure when plasma renin activity is normal, and therefore contribute to the progression of this condition. Angiotensin-converting enzyme (ACE) inhibitors reduce both circulating and tissue RAS activity. They are of symptomatic benefit and reduce the mortality associated with heart failure. A number of large studies initiated to investigate the effects of the ACE inhibitor enalapril in patients with all degrees of heart failure have been published recently. These studies show that addition of this drug to therapy significantly decreases patient morbidity and mortality, an effect which is most likely due to the suppression of circulating and tissue RAS activity this agent affords. The relationship of the profile of hormonal suppression seen with enalapril and drug dosage to observed beneficial effects on morbidity or mortality is unclear. Given the large range of alternative ACE inhibitors available, their variable structure, potency and duration of action, the potential for differences between agents needs further consideration. Although direct comparative studies are rare, there is a body of work suggesting that such differentiation may be present and may be of clinical significance.