Published online before print November 4, 2004, doi: 10.1161/01.RES.0000150055.06226.4e
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Submitted on August 18, 2004
Revised on October 13, 2004
Accepted on October 27, 2004
Proarrhythmic Consequences of a KCNQ1 AKAP-Binding Domain Mutation. Computational Models of Whole Cells and Heterogeneous Tissue
Jeffrey J. Saucerman ;
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.
* To whom correspondence should be addressed. 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 IKs channel. To investigate how this defect may lead to ventricular arrhythmia during sympathetic stimulation, we use integrative computational models of 
-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 -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 -adrenergic signaling and myocyte electrophysiology, creating both triggers of cardiac arrhythmia and a myocardial substrate vulnerable to such electrical disturbances.
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