SURVIVAL AFTER MYOCARDIAL-INFARCTION IN THE RAT - ROLE OF TISSUE ANGIOTENSIN-CONVERTING ENZYME-INHIBITION

Background Chronic treatment with high doses of angiotensin-converting enzyme (ACE) inhibitors prolongs survival after myocardial infarction . Since the plasma renin-angiotensin system (RAS) is not consistently activated in the chronic phase after myocardial infarction, the benefi cial effects of ACE inhibition have been attributed, in part, to inhib ition of an activated tissue RAS. However, a relation between tissue A CE inhibition and long-term efficacy tie, concerning left ventricular [LV] hypertrophy and survival) has not been established. The present s tudy was designed to evaluate the impact of low-dose ACE inhibition (p redominant inhibition of plasma ACE) and high-dose ACE inhibition (ass ociated with substantial tissue ACE inhibition) on reversal of LV hype rtrophy and 1-year mortality after myocardial infarction in the rat. M ethods and Results Infarcted rats were randomized to placebo, low-dose lisinopril, or high-dose lisinopril (each, n=80) and compared with sh am-operated animals (n=40). In a separate group of animals, tissue ACE activity was determined after 6 weeks of therapy, demonstrating that both regimens were effective with regard to both plasma and pulmonary ACE inhibition; however, only high-dose lisinopril inhibited renal ACE , Neither dose affected LV ACE activity and ACE mRNA levels as determi ned by competitive polymerase chain reaction, whereas LV ANF mRNA leve ls were significantly reduced by high-dose lisinopril. High-dose lisin opril reduced arterial blood pressure and normalized right ventricular and LV weight and resulted in a substantial reduction of 1-year morta lity, whereas the low dose did not (1 year mortality: placebo, 56.3%; low dose, 53.3%; high dose, 22.9%, P<.0001 versus low dose and versus placebo). Conclusions Hemodynamically effective ACE inhibition is requ ired for reduction of LV hypertrophy and long-term mortality after myo cardial infarction in:the rat. Sustained inhibition of renal ACE durin g long-term therapy may contribute to the beneficial effect of high-do se lisinopril. Low-dose lisinopril, although exerting sustained inhibi tion of the plasma ACE, does not improve survival after myocardial inf arction.