Key result
Simulation using a heterogeneous model of the ventricular wall showed that homogeneous models cannot adequately reproduce the effects of loss of Na+ channel functions on the vulnerable period.
Physiological transmural heterogeneity in computational models reveals that proarrhythmic effects of Na+ channel mutations may not be driven by an extended vulnerable period, challenging findings from homogeneous models.
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Challenges proarrhythmic mechanisms from homogeneous models; heterogeneous simulations required to clarify Na+ channel mutation risks.
In this study we compare the effects of Na/sup +/ channel mutations on vulnerable period (VP) in hetero- versus homogeneous model of ventricular wall. According to several articles, some Na/sup +/ channel mutations and class I antiarrhythmics prolong VP in homogeneous models and increase risk of reentrant arrhythmias. Here more realistic model is used by introducing physiological transmural heterogeneity into a one-dimensional cable of the Luo-Rudy model cells. We propose a generalized formula for VP and describe new phenomena pertaining to VP not reported with the uniform models. Our simulation results show that the homogeneous models cannot adequately reproduce the effects of loss of Na/sup +/ channel functions on VP. Differences in results are significant both qualitatively and quantitatively. The proarrhythmic effect may not be, therefore, due to extended VP.
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Kapela et al. (2005) studied Cardiac sodium channel mutations. Heterogeneous model of ventricular wall vs. Homogeneous model of ventricular wall was evaluated on Vulnerable period (VP). Simulation using a heterogeneous model of the ventricular wall showed that homogeneous models cannot adequately reproduce the effects of loss of Na+ channel functions on the vulnerable period.
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