Subramanian A, Suszko A, Selvaraj RJ, Nanthakumar K, Ivanov J, Chauhan VS. Modulated dispersion of activation and repolarization by premature beats in patients with cardiomyopathy at risk of sudden death. Am J Physiol Heart Circ Physiol 300: H2221-H2229, 2011. First published March 25, 2011; doi:10.1152/ajpheart.01050.2010.-Premature beats can trigger ventricular arrhythmias in heart disease, but the mechanisms are not well defined. We studied the effect of premature beats on activation and repolarization dispersion in seven patients with cardiomyopathy (57 Ϯ 10 yr, left ventricular ejection fraction 31 Ϯ 7%). Activation time (AT), activation-recovery interval (ARI), and total repolarization time (TRT) were measured from 26 unipolar electrograms during right ventricle (RV) endocardial (early) to left ventricle epicardial (late) activation in response to RV apical extrastimulation (S1S2). Early TRT dispersion increased significantly with shorter S1S2 (1.0 Ϯ 0.2 to 2.3 Ϯ 0.4 ms/mm, P Ͻ 0.0001), with minimal change in late TRT dispersion (0.8 Ϯ 0.1 to 1.0 Ϯ 0.3 ms, P ϭ 0.02). This was associated with an increase in early AT dispersion (1.0 Ϯ 0.1 to 1.5 Ϯ 0.2 ms/mm, P ϭ 0.05) but no change in late AT dispersion (0.6 Ϯ 0.1 to 0.7 Ϯ 0.2 ms/mm, P ϭ 0.4). Early and late ARI dispersion did not change with shorter S1S2. AT restitution slopes were similar between early and late sites, as was slope heterogeneity. ARI restitution slope was greater in early vs. late sites (1.3 Ϯ 0.6 vs. 0.8 Ϯ 0.6, P ϭ 0.03), but slope heterogeneity was similar. With shorter S1S2, AT-ARI slopes became less negative (flattened) at both early (Ϫ0.4 Ϯ 0.1 to ϩ0.04 Ϯ 0.2) and late (Ϫ1.5 Ϯ 0.2 to ϩ0.3 Ϯ 0.2) sites, implying less activation-repolarization coupling. There was no difference in AT-ARI slopes between early and late sites at short S1S2. In conclusion, high-risk patients with cardiomyopathy have greater TRT dispersion at tightly coupled S1S2 due to greater AT dispersion and activation-repolarization uncoupling. Modulated dispersion is more pronounced at early vs. late activated sites, which may predispose to reentrant ventricular arrhythmias. restitution; congestive heart failure FREQUENT PREMATURE VENTRICULAR beats are associated with an increased risk of sudden cardiac death in patients with left ventricular dysfunction (18). Critically timed premature beats can initiate ventricular tachycardia and fibrillation by providing a depolarizing trigger during the vulnerable period of cardiac repolarization. Premature beats can also modulate activation and repolarization gradients, creating zones of slow conduction and prolonged refractoriness, leading to unidirectional conduction block and reentry (8, 11). These gradients have been evaluated in response to programmed ventricular extrastimulation in patients with preserved ventricular function along the endocardium during percutaneous intervention (9,15,24,25) and the epicardium during intraoperative mapping (7, 17). Based on these clinical studies, repolarization heterogeneity is minimized by...