Arrhythmogenesis in the short-QT syndrome associated with combined HERG channel gating defects: a simulation study.
BACKGROUND
This study aimed to show the mechanism how the HERG channel gating defects causes life-threatening arrhythmia in the short-QT syndrome, using a simulation model of ventricular action potentials (APs).


RESULTS
To evaluate the electrophysiological consequences of the short-QT syndrome at the level of the cardiac AP, the Markov model of wild-type (WT) KCNH2 channel was modified to obtain a model of the KCNH2 channel with the N588K mutation associated with the short-QT syndrome. Two parameters (betai and betabeta) were changed to reconstruct the N588K mutant Markov model, which successfully reproduced the experimental results of voltage-clamp recordings. The WT and mutant models were then integrated into the Luo-Rudy theoretical model of the cardiac ventricular AP. Unexpectedly, 1 parameter change alone, which caused gain of function, could shorten the AP duration (APD) but failed to induce early after-depolarizations (EADs). Only the condition with the combined gating defects could lead to EAD.


CONCLUSIONS
Although the gain of function for KCNH2 shortened APD in the short-QT syndrome, this simulation study suggested that arrhythmogenesis was associated not only with gain of function, but also with accelerated deactivation of KCNH2.
Department of Information Physiology, National Institute for Physiological Sciences, Myodaiji, Okazaki, Japan.
Hideki
H
Itoh
Minoru
M
Horie
Makoto
M
Ito
Keiji
K
Imoto
D000200:Action Potentials; D001145:Arrhythmias, Cardiac / Q000209:etiology* / Q000503:physiopathology*; D003198:Computer Simulation; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography; D004594:Electrophysiology; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008390:Markov Chains; D008955:Models, Cardiovascular; D009154:Mutation; D018408:Patch-Clamp Techniques; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics / Q000502:physiology*; D016276:Ventricular Function
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D024642:Potassium Channels, Voltage-Gated