Modulated dispersion of activation and repolarization by premature beats in patients with cardiomyopathy at risk of sudden death

Abstract

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...

Ventricular stimulus site influences dynamic dispersion of repolarization in the intact human heart

“…This is consistent with previously published data in human and animal studies (6, 13, 19, 26, 32, 40, 42, 47, 48, 53). Thus the heterogeneity in ARI results in regional repolarization wavefronts that are opposite to the wavefront of activation, consistent with the concept of negative AT/ARI coupling, as shown in Table 1, and consistent with previous in vivo experimental data (23, 52). Our study shows that this homogenization of total repolarization within localized regions of the heart occurs over a range of cycle lengths and may be protective against localized reentry during normal physiological working parameters of the ventricle, particularly sinus tachycardia.…”

“…The spatial variation in restitution properties and AT-APD coupling in the intact human heart has largely only been studied in situations where global AT is relatively short, such as in sinus rhythm or right ventricular (RV) apical pacing, when early engagement of the Purkinje network occurs (52, 62). This homogenizes total AT, while maintaining a normal endocardial-to-epicardial activation sequence.…”

“…Little is known about the role of varying the activation site in relation to the spatial restitution and AT-APD coupling properties of the RV and left ventricle (LV). In the intact human ventricle, negative coupling between AT-APD has been demonstrated during RV apical pacing (24, 52, 61). However, to continually maintain negative AT-ARI (activation recovery interval) coupling for varying stimulus sites, and, therefore, limit RT dispersion, regional APD would have to adapt to varying AT sequences.…”

Role of abnormal repolarization in the mechanism of cardiac arrhythmia

“…Therefore, with a given intrinsic difference in APD between the two myocardial regions, a spatial disparity in the final repolarization time could be either amplified or attenuated depending on whether these regions are activated at the same time point, or the activation in one region is postponed relative to the other. High‐resolution mapping of ventricular depolarization in human subjects and various animal models (dog, rabbit, pig, and rat) suggests the presence of close relationships between the sequence of electrical activation and the distribution of APD along the propagation path. Under physiological conditions, the impulse propagation from the site of earliest activation is associated with progressive shortening of APD, which is attributed to electrotonic interactions between adjacent cardiac cells.…”

“…The presence of the activation–repolarization coupling has been validated by reconstructing the epicardial, endocardial, and transmural maps of ventricular activation. Quantitatively, it could be assessed by plotting APD 90 values measured in distinct ventricular recording sites vs. corresponding activation times (Fig.…”