Mechanoelectrical Feedback as Novel Mechanism of Cardiac Electrical Remodeling

Abstract

Background-Altered electrical activation of the heart by pacing or disease induces profound ventricular electrical remodeling (VER), manifested electrocardiographically as T-wave memory and ultimately as deleterious mechanical remodeling from heterogeneous strain. Although T-wave memory is associated with altered expression of sarcolemmal ion channels, the biophysical mechanisms responsible for triggering remodeling of cardiac ion channels are unknown. Methods and Results-To test the hypothesis that mechanoelectrical feedback triggered by regional strain is a mechanism for VER, dogs (nϭ6) underwent 4 weeks of ventricular pacing to induce VER. Multisegment transmural optical action potential imaging of left ventricular wedges revealed profound and selective prolongation of action potential duration in late-activated (288Ϯ29 ms) compared with early-activated (250Ϯ9 ms) myocardial segments (PϽ0.05), providing the first experimental evidence that amplification of repolarization gradients between segments of left ventricle is the electrophysiological basis for T-wave memory. In vivo tagged magnetic resonance imaging revealed a 2-fold and preferential increase in circumferential strain in late-activated segments of myocardium, which exactly coincided with segments undergoing VER. VER could not be attributed to structural remodeling because it occurred without any histological evidence of cellular hypertrophy. Conclusions-The mechanism responsible for triggering remodeling of ion channel function in VER was locally enhanced circumferential strain. These data suggest a novel mechanoelectrical feedback mechanism for inducing physiological and potentially deleterious electrical heterogeneities in the heart. (Circulation. 2007;115:3145-3155.)

Mechanoelectric Feedback as a Trigger Mechanism for Cardiac Electrical Remodeling: A Model Study

“…In case electrical remodeling is controlled by W tot , the q n are increased for the later-activated segments, which results in more shortening during ejection. The large differences in strain during ejection between early and later-activated segments are in agreement with the large differences in peak systolic strains measured by Jeyaraj et al 26 after 4 weeks of ventricular pacing. Prolongation of the APD occurs for both early and later-activated segments, but not for intermediate segments (Fig.…”

“…Fiber A represents normal ventricular depolarization and Fiber B represents ventricular depolarization after epicardial pacing. Fiber C is included to compare our simulation results with the experimental results of Jeyaraj et al, 26 who report a dispersion in depolarization time of 180 ms. In all cases, the cardiac cycle was simulated with T rest = 0.5 kPa, T preload = 1 kPa, and T afterload = 10 kPa.…”

“…41 Libbus et al 42 suggest that remodeling of I to may be explained by changes in electrotonic load. Jeyaraj et al 26 recently proposed mechanoelectric feedback as a mechanism for electrical remodeling. Based on their observation that APD is prolonged near the site of stimulation and also in remote regions, it is unlikely that electrical remodeling is explained by electrotonic interactions.…”

“…7 At present, it is unclear what mechanism drives electrical remodeling after changing the activation sequence. Based on experimental observations, Jeyaraj et al 26 suggest mechanoelectric feedback as a mechanism for electrical remodeling. Recently, Sosunov et al 62 found that electrical remodeling can be inhibited either by reducing mechanical load or by reducing contractility.…”

Coupling of ventricular action potential duration and local strain patterns during reverse remodeling in responders and nonresponders to cardiac resynchronization therapy

“…It has been shown that increased regional dispersion of repolarization varied between responders and non-responders. 33,34 It would be of interest to see how this regional change related to the global LV repolarization time and dispersion as depending on the extent of the region exhibiting the changes; there might be either pro-or antiarrhythmic effects. We are unable to comment on the initial response because no LV strain measurements were acquired immediately after CRT implant due to clinical constraints of patient discomfort.…”