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Modeling of I_K1 mutations in human left ventricular myocytes and tissue

Gunnar Seemann,¹ Frank B. Sachse,^2,3 Daniel L. Weiss,¹ Louis J. Ptáek,⁴ and Martin Tristani-Firouzi^2,5

¹Institut für Biomedizinische Technik, Universität Karlsruhe (TH), Karlsruhe, Germany; ²Nora Eccles Harrison Cardiovascular Research and Training Institute and ³Bioengineering Department, University of Utah, Salt Lake City, Utah; ⁴Howard Hughes Medical Institute, Department of Neurology, University of California, San Francisco, California; and ⁵Division of Pediatric Cardiology, University of Utah, Salt Lake City, Utah

Submitted 30 June 2006 ; accepted in final form 22 August 2006

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 inward rectifier potassium channel (K_ir)2.1 that cause Andersen-Tawil syndrome (ATS). ATS is an autosomal dominant disorder associated with ventricular arrhythmias that uncommonly degenerate into the lethal arrhythmia torsade de pointes. We simulated the cellular and tissue effects of a potent disease-causing mutation D71V K_ir2.1 with mathematical models of human ventricular myocytes and a bidomain model of transmural conduction. The D71V K_ir2.1 mutation caused significant action potential duration prolongation in subendocardial, midmyocardial, and subepicardial myocytes but did not significantly increase transmural dispersion of repolarization. Simulations of the D71V mutation at shorter cycle lengths induced stable action potential alternans in midmyocardial, but not subendocardial 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 the low frequency of torsade de pointes arrhythmia in ATS.

Andersen-Tawil syndrome; K_ir2.1 mutation; ion channel modeling

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