Renin-angiotensin system in human failing hearts: message from nonmyocyte cells to myocytes.

Abstract

The survival benefit conferred by angiotensin-converting enzyme (ACE) inhibitors in patients with heart failure has led to an intense interest in the mechanisms underlying the action of angiotensin II.1 2 However, ACE inhibition therapy does not completely block angiotensin II production, and in some patients angiotensin II remains elevated, in part because of the conversion of angiotensin I to angiotensin II by chymase activity.3 The main two receptors for angiotensin II, AT1 receptor (AT1R) and AT2 receptor (AT2R), are present in the myocardium. Most angiotensin II functions in the cardiovascular system are mediated by AT1R. AT2R has anti-AT1R effects, such as negative chronotropic action or inhibition of interstitial fibrosis, which may play a protective role in development of heart failure.4 Presently, no therapeutic agents that specifically act on AT2R are approved for clinical trials. However, AT1R blockers are available that could shunt the activity of the cardiac renin-angiotensin system toward selective stimulation of beneficial AT2R. Two separate clinical approaches (ELITE-II and RESOLVD) compared ACE inhibitors with AT1R blockers in patients with heart failure.5 6 No significant differences were observed in the beneficial effect of these two classes of agents, and the cardioprotective role of AT2R remains to be determined. The cardioprotective action of ACE inhibitors and AT1R blockers depends on the expression level of myocardial AT1R …