There are three aspects to consider in reviewing the contribution of angiotensin receptor biockers (ARBs) to heart failure therapy:
â¢ Pharmacologic effects.
â¢ Open issues.
A major player in the pathogenesis of heart failure is the renin-angiotensin system (RAS), an integrated enzymatic-humoral system with a fundamental role in cardiovascular homeostasis. In heart failure, there are elevated levels of circulating angiotensin II, a potent vasoconstrictor and cardiovascular growth stimulator involved in cardiac remodeling. Angiotensin II acts on tissue via two receptors. Angiotensin II type 1 receptor (AT,) promotes disease progression by mediating the effects of angiotensin II, increasing plasma aldosterone levels (thus increasing sodium retention), stimulating hypertrophy, and constricting peripheral vessels. Angiotensin II type 2 receptor (AT2), about which much less is known, appears to downmodulate or counter the effects of AT,.
At present, two pharmacologic strategies have been developed to counter the effects of angiotensin II in heart failure. The first is the use of angiotensin-converting enzyme (ACE) inhibitors, which block the enzymatic conversion of angiotensin I to angiotensin II and also prevent the inactivation of bradykinin. The accumulation of bradykinin, which promotes nitric oxide release, is believed to be responsible for their tissue benefits (delayed post-ischemic remodeling, regression of hypertrophy).
However, angiotensin II accumulates despite ACE inhibition via an alternative chymase-mediated synthetic pathway.
The second strategy is to use ARBs, drugs that selectively and competitively bind to AT, receptors, thus inhibiting the various adverse tissue effects mediated by this receptor.
To date, RAS blockade has been achieved mainly with ACE inhibitors. The European Society of Cardiology proposes ARBs for patients with symptomatic heart failure who do not tolerate ACE inhibitors, whether due to cough, symptomatic hypotension, deteriorating renal function, and/or angioedema. ARBs appear better tolerated than ACE inhibitors. However, the Evaluation of Losartan In the Elderly (ELITE) study found no difference in the incidence of renal dysfunction at 1-year follow-up between losartan and capto-pril. With ARBs too, therefore, renal function should be closely monitored.
It is unclear whether ARBs are as effective as ACE inhibitors in lowering mortality. The Valsartan Heart Failure Trial (Val-HeFT) found no difference in overall mortality, but valsartan decreased the combined end point of all-cause mortality and hospitalization. The Losartan Heart Failure Survival Study (ELITE II) and Val-HeFT suggest that caution is required in establishing regimens based on the combined use of ARBs, ACE inhibitors, and (3-blockers, as this combination could have adverse effects.