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(Circulation Research. 2004;95:1216.)
© 2004 American Heart Association, Inc.

Integrative Physiology

Proarrhythmic Consequences of a KCNQ1 AKAP-Binding Domain Mutation

Computational Models of Whole Cells and Heterogeneous Tissue

Jeffrey J. Saucerman, Sarah N. Healy, Mary E. Belik, Jose L. Puglisi, Andrew D. McCulloch

From the Department of Bioengineering (J.J.S., S.N.H., M.E.B., A.D.M), Whitaker Institute of Biomedical Engineering, University of California San Diego, La Jolla; and the Department of Physiology (J.L.P.), Loyola University Chicago, Maywood, Ill.

Correspondence to Andrew D. McCulloch, Department of Bioengineering, University of California, San Diego, La Jolla, CA 92037-0412. E-mail amcculloch{at}ucsd.edu

The KCNQ1-G589D gene mutation, associated with a long-QT syndrome, has been shown to disrupt yotiao-mediated targeting of protein kinase A and protein phosphatase-1 to the I_Ks channel. To investigate how this defect may lead to ventricular arrhythmia during sympathetic stimulation, we use integrative computational models of ß-adrenergic signaling, myocyte excitation-contraction coupling, and action potential propagation in a rabbit ventricular wedge. Paradoxically, we find that the KCNQ1-G589D mutation alone does not prolong the QT interval. But when coupled with ß-adrenergic stimulation in a whole-cell model, the KCNQ1-G589D mutation induced QT prolongation and transient afterdepolarizations, known cellular mechanisms for arrhythmogenesis. These cellular mechanisms amplified tissue heterogeneities in a three-dimensional rabbit ventricular wedge model, elevating transmural dispersion of repolarization and creating other T-wave abnormalities on simulated electrocardiograms. Increasing heart rate protected both single myocyte and the coupled myocardium models from arrhythmic consequences. These findings suggest that the KCNQ1-G589D mutation disrupts a critical link between ß-adrenergic signaling and myocyte electrophysiology, creating both triggers of cardiac arrhythmia and a myocardial substrate vulnerable to such electrical disturbances.

Key Words: ß-adrenergic signaling • arrhythmia • long-QT syndrome • computational model

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