Modeling of IK1 mutations in human left ventricular myocytes and tissue.
Modeling of IK1 mutations in human left ventricular myocytes and tissue.
复制标题
人类左心室肌细胞和组织中 IK1 突变的建模。
DOI：
10.1152/ajpheart.00701.2006
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发表时间：
2007
期刊：
影响因子：
--
通讯作者：
M. Tristani
中科院分区：
文献类型：
--
作者：
G. Seemann;F. Sachse;D. Weiß;L. Ptáček;M. Tristani
由于研究人类心脏组织的固有困难，阐明离子通道病中心律失常的细胞学基础是复杂的。因此，我们使用计算机模拟方法来研究内向整流钾通道(K(Ir))2.1突变导致Andersen-Tawil综合征(ATS)所引起的细胞功能障碍的机制。ATS是一种常染色体显性遗传性疾病，与室性心律失常相关，罕见地退化为致命性心律失常尖端扭转性心律失常。我们模拟了一个强大的致病突变D71V K(Ir)2.1的细胞和组织效应，并用人体心肌细胞的数学模型和跨壁传导的双项模型进行了模拟。D71V K(Ir)2.1突变导致心内膜下、心肌中和心外膜下心肌细胞动作电位时程显著延长，但并未显著增加跨壁复极离散度。在较短周期长度下模拟D71V突变，可在心肌中诱导稳定的动作电位交替，但不能诱导心内膜下或心外膜下细胞。动作电位交替在跨壁心电图上表现为一种缩略的QRS波群，是中层心肌组织动作电位传播失败的结果。此外，我们对D71V突变的模拟概括了ATS的几个关键的心电图特征，包括QT延长、T波平坦和QRS增宽。因此，我们的建模方法真实地概括了ATS的几个特征，并为ATS中尖端扭转性心律失常的低频率提供了机制解释。
Elucidation of the cellular basis of arrhythmias in ion channelopathy disorders is complicated by the inherent difficulties in studying human cardiac tissue. Thus we used a computer modeling approach to study the mechanisms of cellular dysfunction induced by mutations in inward rectifier potassium channel (K(ir))2.1 that cause Andersen-Tawil syndrome (ATS). ATS is an autosomal dominant disorder associated with ventricular arrhythmias that uncommonly degenerate into the lethal arrhythmia torsade de pointes. We simulated the cellular and tissue effects of a potent disease-causing mutation D71V K(ir)2.1 with mathematical models of human ventricular myocytes and a bidomain model of transmural conduction. The D71V K(ir)2.1 mutation caused significant action potential duration prolongation in subendocardial, midmyocardial, and subepicardial myocytes but did not significantly increase transmural dispersion of repolarization. Simulations of the D71V mutation at shorter cycle lengths induced stable action potential alternans in midmyocardial, but not subendocardial or subepicardial cells. The action potential alternans was manifested as an abbreviated QRS complex in the transmural ECG, the result of action potential propagation failure in the midmyocardial tissue. In addition, our simulations of D71V mutation recapitulate several key ECG features of ATS, including QT prolongation, T-wave flattening, and QRS widening. Thus our modeling approach faithfully recapitulates several features of ATS and provides a mechanistic explanation for the low frequency of torsade de pointes arrhythmia in ATS.
影响因子：
5.5
作者：
Tsuboi, M;Antzelevitch, C
通讯作者：
Antzelevitch, C
影响因子：
3.4
作者：
Kurata, Y;Hisatome, I;Shibamoto, T
通讯作者：
Shibamoto, T