Referenced in: none

Automatically associated channels: Kv11.1

Title: Arrhythmogenesis in the short-QT syndrome associated with combined HERG channel gating defects: a simulation study.

Authors: Hideki Itoh, Minoru Horie, Makoto Ito, Keiji Imoto

Journal, date & volume: Circ. J., 2006 Apr , 70, 502-8

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/16565572

Abstract
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).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.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.