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.

译文

:由于研究人类心脏组织的固有困难,阐明离子性通道病疾病中的心律不齐的细胞基础变得复杂。因此,我们使用一种计算机建模方法来研究由引起Andersen-Tawil综合征(ATS)的内向整流钾通道(K(ir))2.1突变引起的细胞功能障碍的机制。 ATS是与室性心律失常相关的常染色体显性遗传疾病,通常退化为致命性心律失常扭转性尖端。我们用人心室肌细胞的数学模型和跨壁传导的双域模型模拟了强力致病突变D71V K(ir)2.1的细胞和组织作用。 D71V K(ir)2.1突变导致心内膜下,心肌中层和心外膜下心肌细胞的动作电位持续时间显着延长,但并未明显增加跨壁的复极分散。 D71V突变在更短的周期长度上的模拟在心肌中层而不是心内膜下或心外膜下的细胞中诱导了稳定的动作电位交替蛋白。动作电位交替素表现为跨壁ECG中的QRS缩略语,是动作电位在心肌中部组织中传播失败的结果。此外,我们对D71V突变的模拟概括了ATS的几个重要ECG功能,包括QT延长,T波展平和QRS展宽。因此,我们的建模方法忠实地概括了ATS的几个功能,并为ATS的扭转性点性心律失常的低频率提供了机械的解释。

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