Sun Zhuoqian, Milos Patrice M, Thompson John F, Lloyd David B, Mank-Seymour Amy, Richmond Jodi, Cordes Jason S, Zhou Jun
Department of Safety Pharmacology, World-Wide Safety Sciences, Eastern Point Road, Groton, CT 06340, USA.
J Mol Cell Cardiol. 2004 Nov;37(5):1031-9. doi: 10.1016/j.yjmcc.2004.09.001.
Various drugs are reported to prolong the QT-interval on the surface ECG, thereby increasing the risk of developing a potentially fatal arrhythmia known as Torsades de Pointes (TdP). TdP case reports for these drugs have often been associated with risk factors such as overdosing, concomitant drugs and/or existing pathophysiological conditions. A few cases appear to be devoid of these factors. To determine what role genetic variation in the hERG gene plays in drug-induced arrhythmias, we screened DNA samples collected from 105 atrial-fibrillation patients treated with dofetilide for polymorphisms, seven of whom developed TdP. An uncommon missense change, R1047L, was identified in two of seven patients who experienced TdP as compared with five of 98 individuals who were free of TdP. Included in the affected individuals was the only subject homozygous for this SNP. Cellular electrophysiological studies revealed a 10-mV positive shift in the steady-state activation curve of the 1047L hERG channel stably expressed in HEK-293 cells as compared with the wild-type (WT) channel. The activation and inactivation kinetics of the 1047L current were significantly slower than the WT (P < 0.05) at given membrane potentials. A computer simulation using a rabbit ventricular myocyte model indicated that same extent of changes in the I(Kr) channel may result in an approximately 15% prolongation in the action potential duration. Our study suggests that 1047L leads to a functional impairment of the hERG channel, which may contribute to the higher incidence of TdP in 1047L carriers when challenged with a channel blocker.
据报道，多种药物可延长体表心电图的QT间期，从而增加发生一种称为尖端扭转型室性心动过速（TdP）的潜在致命性心律失常的风险。这些药物的TdP病例报告通常与诸如用药过量、合并用药和/或现有病理生理状况等危险因素相关。少数病例似乎不存在这些因素。为了确定人乙醚相关基因（hERG）的基因变异在药物诱导的心律失常中所起的作用，我们对105例接受多非利特治疗的心房颤动患者采集的DNA样本进行了多态性筛查，其中7例发生了TdP。在7例发生TdP的患者中，有2例发现了一种罕见的错义改变R1047L，而在98例未发生TdP的个体中，有5例出现了这种改变。受影响的个体中包括该单核苷酸多态性（SNP）的唯一纯合子。细胞电生理研究显示，与野生型（WT）通道相比，在HEK - 293细胞中稳定表达的1047L hERG通道的稳态激活曲线有10 mV的正向偏移。在给定膜电位下，1047L电流的激活和失活动力学明显慢于WT（P < 0.05）。使用兔心室肌细胞模型进行的计算机模拟表明，I(Kr)通道相同程度的变化可能导致动作电位持续时间延长约15%。我们的研究表明，1047L导致hERG通道功能受损，这可能是1047L携带者在受到通道阻滞剂挑战时TdP发生率较高的原因。
