Link Between SCN5A Mutation and the Brugada Syndrome ECG Phenotype

Simulation Study

Abstract

Background The specific changes in the gating kinetics of the sodium current (I_Na) responsible for its phenotype have remained to be elucidated. In the present study the effect of changes in the gating kinetics of I_Na on early repolarization (ER) and initiation of phase 2 reentry (P2R) were evaluated in a theoretical epicardial ventricular fiber model. Methods and Results Miyoshi-I_CaL was incorporated into the modified Luo-Rudy dynamic (LRd) model. Dispersion at I_to-density was set within a theoretical fiber composed of serially arranged epicardial cells with gap junctions. The following changes in I_Na kinetics were made: (1) a -10 mV shift in steady-state inactivation, (2) a +10 mV shift in steady-state activation curve, (3) a small inactivation time constant (DEC); P2R and ER were observed. A conduction disturbance within the fiber was simulated and only when the I_Na-density was decreased did DEC, especially, show a marked increase in the likelihood of causing ER and P2R. Conduction disturbance significantly increased the likelihood causing ER or P2R. Conclusions In this one-dimension model with I_to-density dispersion, DEC-I_Na precipitates I_Na-blocker inducible ER. This suggests that the characteristic ST-segment elevation in the Brugada syndrome with SCN5A mutation can be interpreted in part by DEC-I_Na. Concomitant conduction disturbance may be required to cause P2R at physiological I_to density. (Circ J 2005; 69: 567 - 575)