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.
Itoh
Hideki
H
Department of Information Physiology, National Institute for Physiological Sciences, Myodaiji, Okazaki, Japan.
Horie
Minoru
M
Ito
Makoto
M
Imoto
Keiji
K
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