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(Circulation. 2007;115:3145-3155.)
© 2007 American Heart Association, Inc.

Arrhythmia/Electrophysiology

Mechanoelectrical Feedback as Novel Mechanism of Cardiac Electrical Remodeling

Darwin Jeyaraj, MD, MRCP; Lance D. Wilson, MD; Jia Zhong, MS; Chris Flask, PhD; Jeffrey E. Saffitz, MD, PhD; Isabelle Deschênes, PhD; Xin Yu, ScD; David S. Rosenbaum, MD

From the Heart and Vascular Research Center and the Department of Biomedical Engineering, MetroHealth Campus (D.J., L.W., J.Z., I.D., X.Y., D.S.R.) and Case Center for Imaging Research (C.F.), Case Western Reserve University, Cleveland, Ohio; and Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Mass (J.E.S.).

Correspondence to David S. Rosenbaum, MD, Heart and Vascular Research Center, MetroHealth Campus, Case Western Reserve University, 2500 MetroHealth Dr, Hamman 330, Cleveland, OH 44109-1998. E-mail drosenbaum{at}metrohealth.org

Received January 8, 2007; accepted April 27, 2007.

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 (n=6) 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 (288±29 ms) compared with early-activated (250±9 ms) myocardial segments (P<0.05), 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.

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