Arrhythmogenesis in the short-QT syndrome associated with combined HERG channel gating defects - A simulation study
Arrhythmogenesis in the short-QT syndrome associated with combined HERG channel gating defects - A simulation study
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DOI：
10.1253/circj.70.502
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发表时间：
2006-04-01
影响因子：
3.3
通讯作者：
Imoto, K
中科院分区：
文献类型：
--
作者：
Itoh, H;Horie, M;Imoto, K
背景本研究的目的是显示HERG通道门控缺陷如何在短QT综合征中引起危及生命的心律失常的机制，使用心室动作电位（AP）的模拟模型。方法和结果为了评估短QT综合征在心脏AP水平的电生理后果，修改野生型（WT）KCNH 2通道的马尔可夫模型以获得具有与短QT综合征相关的N588 K突变的KCNH 2通道的模型。通过改变两个参数（β i和β β），重建了N588 K突变型Markov模型，成功地再现了电压钳记录的实验结果。然后将WT和突变体模型整合到心室AP的Luo-Rudy理论模型中。出乎意料的是，单独改变1个参数（导致功能获得）可缩短AP持续时间（APD），但未能诱导早期后除极（埃兹）。结论虽然短QT综合征中KCNH 2功能的获得缩短了APD，但本模拟研究表明，EAD的发生不仅与功能的获得有关，而且与KCNH 2的加速失活有关。
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).Methods and 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 (beta i and beta beta) 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.