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Effects of Na⁺ channel and cell coupling abnormalities on vulnerability to reentry: a simulation study

¹Cardiovascular Research Laboratory, Departments of ²Medicine (Cardiology), ³Physiology, and ⁴Physiological Science, and ⁵Division of Cardiology, Cedars-Sinai Research Institute, David Geffen School of Medicine, University of California, Los Angeles, California 90095

Submitted 16 June 2003 ; accepted in final form 19 November 2003

The role of dynamic instabilities in the initiation of reentry in diseased (remodeled) hearts remains poorly explored. Using computer simulations, we studied the effects of altered Na⁺ channel and cell coupling properties on the vulnerable window (VW) for reentry in simulated two-dimensional cardiac tissue with and without dynamic instabilities. We related the VW for reentry to effects on conduction velocity, action potential duration (APD), effective refractory period dispersion and restitution, and concordant and discordant APD alternans. We found the following: 1) reduced Na⁺ current density and slowed recovery promoted postrepolarization refractoriness and enhanced concordant and discordant APD alternans, which increased the VW for reentry; 2) uniformly reduced cell coupling had little effect on cellular electrophysiological properties and the VW for reentry. However, randomly reduced cell coupling combined with decoupling promoted APD dispersion and alternans, which also increased the VW for reentry; 3) the combination of decreased Na⁺ channel conductance, slowed Na⁺ channel recovery, and cellular uncoupling synergistically increased the VW for reentry; and 4) the VW for reentry was greater when APD restitution slope was steep than when it was flat. In summary, altered Na⁺ channel and cellular coupling properties increase vulnerability to reentrant arrhythmias. In remodeled hearts with altered Na⁺ channel properties and cellular uncoupling, dynamic instabilities arising from electrical restitution exert important influences on the VW for reentry.

vulnerable window; action potential duration alternans; remodeling; computer simulation

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