International guidelines recommend ICD implantation in patients with severe left ventricular dysfunction of any origin only after careful optimization of medical therapy. Indeed, major randomized clinical trials suggest that suboptimal use of fundamental drugs, such as ACE inhibitors (ACE-i) and beta-blockers, may affect ICD shock-free survival, sudden cardiac death (SCD), and overall mortality. While solid evidence in favour of pharmacological therapy based on ACE-i with or without beta-blockers is available, data on SCD in HF patients treated with angiotensin receptor blockers (ARBs) are limited. The present paper systematically analyses the impact of ARBs on SCD in HF and reviews the contributory role of the renin-angiotensin system (RAS) to the establishment of arrhythmic substrates. The following hypothesis is supported: (1) the RAS is a critical component of the electrical remodelling of the failing myocardium, (2) RAS blockade reduces the risk of SCD, and (3) ARBs represent a powerful tool to improve overall survival and possibly reduce the risk of SCD provided that high doses are employed to achieve optimal AT1-receptor blockade. 1. Introduction Heart failure (HF) affects 15 million people in Europe, with a prevalence of 2-3% in the general population and 10–20% in 70- to 80-year-old subjects. It represents the common ending of different cardiovascular diseases and is characterized by high short-term mortality in advanced stages (up to 50% at 1 year for NYHA class IV patients) [1–4]. Death in HF occurs either from circulatory failure due to progressive left ventricular (LV) dysfunction or sudden cardiac death (SCD). This latter accounts for approximately half of all HF deaths, the underlying mechanism being sudden onset of ventricular tachycardia (VT) or ventricular fibrillation (VF). Despite decades of research for the evaluation of hundred compounds, there are no antiarrhythmic drugs that definitely prevent SCD in HF patients on already optimized therapy with β-blockers and ACE inhibitors [5]. In contrast, the implantable cardioverter-defibrillator (ICD) prevents SCD and improves survival in both primary and secondary prevention patients treated with optimal medical therapy, including beta-blockers and either ACE inhibitors or angiotensin receptor blockers (ARBs) [6–8]. Based on data from multiple randomized primary prevention trials, current guidelines recommend ICD implantation in patients with symptomatic and severe LV dysfunction of any origin on already optimized medical therapy [9]. However, the concept of optimal drug treatment in ICD
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