Role of ACE inhibition or AT₁ blockade in the remodeling following myocardial infarction

Abstract

Ventricular remodeling following nonfatal myocardial infarction includes an excentric hypertrophy of the surviving myocardium, associated with hemodynamic overload. Disseminated cardiomyocyte apoptosis and phenotype changes of the surviving myocardium, such as a labile calcium homeostasis of the hypertrophied cardiomyocytes, impaired β-adrenergic signal transduction, interstitial fibrosis, and reduced coronary reserve are typical features of the overloaded, distended ventricular wall. They are considered as relevant for the myocardial dysfunction progressing to overt cardiac failure and for the enhanced mortality risk. Hemodynamic load and trophic angiotensin effects are assumed to cause this excentric hypertrophy, since systemic and local angiotensin formation in the overloaded myocardium is activated. In isolated rat cardiomyocytes, cultured on distensible membranes, overload is mimicked by distension, and causes enhanced formation and release of angiotensin II, which results in AT₁ receptor mediated trophic reactions of distended neonatal cardiomyocytes and in AT₁-mediated apoptosis in distended adult cardiomyocytes.

In experimental models of post-infarct remodeling, therapy with ACE inhibition or with AT₁ blockade similarly normalizes myocardial hypertrophy, interstitial fibrosis, and impaired coronary reserve. In patients with terminal heart failure, a reduction of apoptotic signs and a normalization of antiapoptotic gene expression is obtained by myocardial unloading under ventricular assist devices or by treatment with ACE inhibitors, and the latter therapy has been shown to improve survival. In contrast to general assumptions and to predictions from data in vitro, the improvements obtained by AT₁ blocker therapy in vivo are mediated by bradykinin, as are those obtained under ACE inhibitors. Under AT₁ blockade, bradykinin is probably activated due to stimulation of AT₂ and other AT receptors.