Coronary artery disease and ACE inhibitors: from rationale to clinically proven benefits

Disordered function of the renin-angiotensin system (RAS) can certainly con tribute to atherosclerosis. Whether it is the first cause in the disease re mains unknown. Atherosclerosis is assumed to be endothelial in origin, with strong circumstantial evidence for the generalized or local overproduction of angiotensin II, or an abnormal localized response to the molecule. Thes e processes are regarded as harmful, while the vasodilator agents within th e microcirculation (bradykinin and nitric oxide, for example) are thought o f as beneficial. Long-term effects of ACE inhibitors reduce the harmful eff ects of angiotensin II while facilitating the vasodilator effects of bradyk inin and NO. Many animal models of atherosclerosis have shown beneficial effects of ACE inhibitors. These include diet-induced aortic lesions and balloon-induced n eo-intimal proliferation in a range of arteries. ACE inhibitors have genera lly inhibited the formation of these lesions, though often at rather higher doses of the drug than are licensed for use in humans. The results of ACE inhibitors in treating postangioplasty restenosis in man have not been as s uccessful, and the reasons are discussed. The efficacy of ACE inhibitors in treating heart failure has often been sho wn, and it is clear from these studies that the drugs had an important effe ct on reducing myocardial infarction. But the studies were designed to show efficacy against coronary artery disease. So three large multinational tri als (HOPE, EUROPA and PEACE) were set up to examine respectively the effect of ramipril, perindopril and trandolapril on the outcome of arterial and/o r coronary artery disease over 4-5 years. One study - HOPE has ended and sh ows significant benefits for ramipril in patients with arterial disease. Th e fall in BP produced by the drug was not considered a sufficient explanati on for the benefits: we are left with the probability that atherosclerosis (about 80% of patients had coronary artery disease) is significantly inhibi ted by the ACE inhibitor.