1. Introduction Administration Heart Failure Trial) and other trials suggest that death is disproportionately sudden in patients with Over 2 million Americans suffer from heart failure and more modest myocardial dysfunction [8]. A major caveat more than 200 000 die annually. The incidence is esti- is that the mechanism of sudden death is highly heterogemated to be 400 000 per year with a prevalence of over 4.5 neous; even if one considers only those patients with death million, numbers that will increase with the aging of the due to a tachyarrhythmia, several mechanisms may prevail. US population [1]. Despite remarkable improvements in This review will consider the cellular electrophysiologimedical therapy the prognosis of patients with myocardial cal changes that have been observed in myocardial hyfailure remains poor with over 15% of patients dying pertrophy and failure that predispose to cardiac arrhythwithin 1 year of initial diagnosis and greater than 80% 6 mias. year mortality [2]. Of the deaths in patients with heart failure, up to 50% are sudden and unexpected. The failing heart undergoes a complex series of changes 2. Cellular electrophysiology in hypertrophy and in both myocyte and non-myocyte elements. In an attempt heart failure to compensate for the reduction in cardiac function the sympathetic nervous (SNS), renin–angiotensin–aldos- 2.1. Changes in the action potential profile and duration terone (RAAS) systems and other neurohumoral mechanisms are activated. The altered signal transduction in An elementary and distinctive signature of any excitable heart failure initiates changes in gene expression that tissue is its action potential profile. Myocardial cells produce myocyte hypertrophy. Ultimately the changes in possess a characteristically long action potential (Fig. 1): gene expression that initially maintain tissue perfusion after an initial rapid upstroke, there is a plateau of prove to be maladaptive, predisposing to further myocyte maintained depolarization before repolarization. The duraloss, ventricular chamber remodeling and interstitial hy- tion of the action potential is primarily responsible for the perplasia resulting in a progressive reduction in force time course of repolarization of the heart; prolongation of development and impairment of ventricular relaxation. the action potential produces delays in cardiac repolariza-The intrinsic cardiac and peripheral responses to tion. myocardial failure adversely alter the electrophysiology of Changes in the action potential duration and profile the heart predisposing patients with heart failure to an result from alterations in the functional expression of increase in arrhythmic death. With progression of heart depolarizing and repolarizing currents. Prolongation of the failure there is an increase in the frequency and complexity action potential is characteristic of cells and tissues isoof ventricular ectopy [3, 4]. Total mortality in heart failure lated from ventricles of animals with heart failure inpatients correlates with LV function and the presence of dependent of the mechanism, which may include pressure complex ventricular ectopy [5–7]. However, there is no and/or volume overload [9–23], genetic [24–26], metabolclear correlation between SCD and LV function or ven- ic [27], ischemia/infarction [28–31] and chronic pacing tricular ectopy. In fact, data from VHeFT (Veteran’s tachycardia models [32–34]. Similarly, tissues [35–37] and cells [38, 39] from failing human ventricles exhibit action potential prolongation.