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(Circulation. 2000;101:1192.)
© 2000 American Heart Association, Inc.

Basic Science Reports

Cellular Arrhythmogenic Effects of Congenital and Acquired Long-QT Syndrome in the Heterogeneous Myocardium

Prakash C. Viswanathan, PhD; Yoram Rudy, PhD

From the Cardiac Bioelectricity Research and Training Center, Department of Physiology and Biophysics (P.C.V., Y.R.), and the Department of Biomedical Engineering (Y.R.), Case Western Reserve University, Cleveland, Ohio.

Correspondence to Yoram Rudy, PhD, Cardiac Bioelectricity Research and Training Center, 505 Wickenden Bldg, Case Western Reserve University, Cleveland, OH 44106-7207. E-mail yxr{at}po.cwru.edu

Background—Certain alterations by mutations or drugs of the potassium currents I_Ks and I_Kr and the sodium current I_Na give rise to several types of the long-QT syndrome. I_Ks is heterogeneously distributed across the ventricular wall.

Methods and Results—We investigated the effects of reducing I_Ks or I_Kr or enhancing late I_Na (to simulate the 3 forms of long-QT syndrome) on action potential duration (APD) in the context of I_Ks heterogeneity. We introduced I_Ks heterogeneity in the Luo-Rudy dynamic cell model to simulate epicardial, endocardial, and midmyocardial (M) cells. Results demonstrated higher susceptibility of M cells to the development of arrhythmogenic early afterdepolarizations (EADs) in isolated cells and poorly coupled tissue. An important observation is that I_Kr block or late I_Na acts to increase APD differences between the cell types, whereas I_Ks block minimizes such differences. Also, for normal transverse coupling, EADs develop in the endocardial region rather than in the M region as the result of strong electrotonic interaction.

Conclusions—I_Ks heterogeneity and intercellular coupling strongly influence EAD development during interventions or disorders that prolong APD. M cells in isolation or in poorly coupled tissue are more susceptible to EAD development than epicardial or endocardial cells. In well-coupled myocardium, EAD formation in the subendocardium can be the source of focal arrhythmias or provide the trigger for reentrant excitation. The efficacy of I_Ks block in minimizing APD dispersion could have important implications for antiarrhythmic therapy.

Key Words: action potentials • cells • long-QT syndrome • arrhythmia

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