Link between SCN5A mutation and the Brugada syndrome ECG phenotype: simulation study.
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.


RESULTS
Miyoshi-I(CaL) was incorporated into the modified Luo-Rudy dynamic (LRd) model. Dispersion at Ito-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 Ito-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 Ito density.
Miyoshi
Shunichiro
S
Advanced Cardiac Therapeutics, Keio University School of Medicine, Tokyo, Japan. smiyoshi@cpnet.med.keio.ac.jp
Mitamura
Hideo
H
Fukuda
Yukiko
Y
Tanimoto
Kojiro
K
Hagiwara
Yoko
Y
Kanki
Hideaki
H
Takatsuki
Seiji
S
Murata
Mitsushige
M
Miyazaki
Toshihisa
T
Ogawa
Satoshi
S
D001145:Arrhythmias, Cardiac / Q000151:congenital / Q000235:genetics / Q000503:physiopathology*; D004562:Electrocardiography; D006801:Humans; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010641:Phenotype; D015222:Sodium Channels / Q000235:genetics
D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels