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1 Institut für Biomedizinische Technik, Universität Karlsruhe (TH), Karlsruhe, Germany
2 CVRTI, University of Utah, Salt Lake City, Utah, United States; Bioengineering, University of Utah, Salt Lake City, Utah, United States
3 Institut für Biomedizinische Technik, Universität Karlsruhe (TH), United States
4 Neurology, Howard Hughes Medical Institute, San Francisco, California, United States
5 CVRTI, University of Utah, Salt Lake City, Utah, United States
* To whom correspondence should be addressed. E-mail: fs{at}cvrti.utah.edu.
Elucidation of the cellular basis of arrhythmias in ion channelopathy disorders is complicated by the inherent difficulties in studying human cardiac tissue. Thus, we used a computer modeling approach to study the mechanisms of cellular dysfunction induced by mutations in Kir2.1 that cause Andersen-Tawil Syndrome (ATS). ATS is an autosomal dominant disorder associated with ventricular arrhythmias that uncommonly degenerate into the lethal arrhythmia, torsades de pointes. We simulated the cellular and tissue effects of a potent disease-causing mutation D71V Kir2.1 using mathematical models of human ventricular myocytes and a bidomain model of transmural conduction. The D71V Kir2.1 mutation caused significant action potential duration prolongation in subendo-, midmyo- and subepicardial myoctes, but did not significantly increase transmural dispersion of repolarization. Simulations of the D71V mutation at shorter cycle lengths induced stable action potential alternans in the midmyocardial cell, but not subendo- or subepicardial cells. The action potential alternans was manifested as an abbreviated QRS complex in the transmural ECG, the result of action potential propagation failure in the midmyocardial tissue. In addition, our simulations of D71V mutation recapitulate several key ECG features of ATS, including QT prolongation, T wave flattening and QRS widening. Thus, our modeling approach faithfully recapitulates several features of ATS and provides a mechanistic explanation for low frequency of torsades de pointes arrhythmia in ATS.
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