Evolving concept of cardioprotection in myocardial infarction: from SMILE-1 to SMILE-5

Abstract

Copyright © Polskie Towarzystwo Kardiologiczne INTRODUCTION The renin–angiotensin–aldosterone system (RAAS) is a central regulator of cardiovascular (CV) and renal function and plays a key role in the pathophysiology of various CV and renal diseases [1, 2]. The RAAS consists of a series of enzymatic reactions culminating in the generation of angiotensin II (Ang-II) in plasma and in various tissues, including the vessels, the heart and the kidney. Ang-II mediates most of the biological actions of RAAS through an interaction with two different types of G-protein coupled receptors — AT1 and AT2 — that can have opposing effects [1, 2]. The importance of Ang-II is supported by the widespread clinical use of angiotensin-converting enzyme (ACE) inhibitors in a wide array of CV and renal diseases. However, the RAAS is far more complex than previously understood, and several new aspects have been recently identified that have potential clinical implications. First, tissue Ang-II may be generated by non-ACE-mediated enzymes, particularly in several conditions associated with an increased CV disease risk (e.g. acute myocardial infarction [AMI]) [3]. Second, ACE can cleave and inactivate other peptides such as bradykinin, a family of potent vasodilators that counterbalance the effects of Ang-II. Importantly, all these mechanisms can be involved in the overall effects of drugs inhibiting RAAS and could help explain some aspects of the complexity of their therapeutic profile. Since their discovery more than 25 years ago, ACE inhibitors have been widely used for the treatment of CV diseases for their important cardioprotective and vasculoprotective properties [1–3]. Clinical data has demonstrated that ACE inhibitors are very effective at reducing blood pressure in a large proportion of patients with hypertension (HBP) [1, 2] when given alone or in combination. ACE inhibitors improve the clinical prognosis of patients with congestive heart failure (CHF) and AMI, particularly when complicated by overt left ventricular (LV) dysfunction [4], although their efficacy may be limited in postmyocardial patients with preserved LV function [5, 6]. ACE inhibitors are also the treatment of choice for many patients with types 1 and 2 diabetes, particularly when complicated by renal disease or proteinuria. Among the different ACE inhibitors, the efficacy of zofenopril has been proven in a wide population of patients with HBP and coronary heart disease, in particular AMI [4]. The clinical efficacy of zofenopril has been extensively studied in many subpopulations of high-risk patients where it has proven to be very effective, compared to both placebo and active treatments. Treatment with zofenopril is associated with a favourable tolerability profile as a consequence of its unique mechanism of action, which might also contribute to the additional benefits beyond ACE inhibition that have been described in patients treated with zofenopril.