Evolution of angiotensin-converting enzyme inhibition in hypertension, heart failure, and vascular protection

Over 100 years of scientific investigation has established that angiotensin-converting enzyme (ACE) plays an important role in both the renin–angiotensin system and the kinin–kallekrein system. ACE inhibitors—which stem the production of angiotensin II, a potent vasoconstrictor—have proved to be useful agents in the management of hypertension, in the prevention and treatment of heart failure, and in the improvement of endothelial function. Generally, ACE inhibitors are as efficacious as β blockers and thiazide diuretics in reducing blood pressure and also induce regression of left ventricular hypertrophy. Many trials—including the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS), the Veteran’s Administration Cooperative Vasodilator–Heart Failure Trial (V-HeFT I), the Studies of Left Ventricular Dysfunction (SOLVD), and the Survival and Ventricular Enlargement (SAVE) trial—have demonstrated the ability of ACE inhibitors to reduce mortality within a wide range of heart failure, from asymptomatic left ventricular dysfunction to severe heart failure. The SAVE trial specifically evaluated the effects on post-myocardial infarction mortality and remodeling and found that ACE inhibitors were effective in reducing both. Further studies are assessing the potential additional antiatherosclerotic aspects of ACE inhibitors. Initial research indicates a reversal of endothelial dysfunction in atherosclerotic animals, and subsequent clinical trials, including the Trial on Reversing ENdothelial Dysfunction (TREND), support the likelihood of a similar effect in humans. Beneficial effects in hypertension or heart failure may also be gained with other interruptors of the renin–angiotensin system, such as angiotensin receptor blockers. Results from studies assessing these receptor blockers will bring greater understanding to the mechanism of action of ACE inhibitors.