Background:Prior epidemiological studies demonstrated that the p.D85N-Potassium voltage-gated channel subfamily E member 1 (KCNE1) common variant reduces repolarization reserve and predisposes to drug-induced QT prolongation/torsades de pointes. We sought to develop a cellular model for drug-induced long QT syndrome using a patient-specific induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM).Methods:p.D85N-KCNE1 iPSCs were generated from a 23-year-old female with an exaggerated heart rate-corrected QT interval response to metoclopramide (ΔQTc of 160 ms). Clustered regularly interspaced short palindromic repeats-associated 9 technology was used to generate gene-corrected isogenic iPSCs. Field potential duration and action potential duration (APD) were measured from iPSC-CMs.Results:At baseline, p.D85N-KCNE1 iPSC-CMs displayed significantly longer field potential duration (281±15 ms, n=13 versus 223±8.6 ms, n=14, P<0.01) and action potential duration at 90% repolarization (APD90; 579±22 ms, n=24 versus 465±33 ms, n=26, P<0.01) than isogenic-control iPSC-CMs. Dofetilide at a concentration of 2 nM increased significantly field potential duration (379±20 ms, n=13, P<0.01) and APD90 (666±11 ms, n=46, P<0.01) in p.D85N-KCNE1 iPSC-CMs but not in isogenic-control. The effect of dofetilide on APD90 (616±54 ms, n=7 versus 526±54 ms, n=10, P<0.05) was confirmed by Patch-clamp. Interestingly, treatment of p.D85N-KCNE1 iPSC-CMs with estrogen at a concentration of 1 nM exaggerated further dofetilide-induced APD90 prolongation (696±9 ms, n=81, P<0.01) and caused more early afterdepolarizations (11.7%) compared with isogenic control (APD90: 618±8 ms, n=115 and early afterdepolarizations: 2.6%, P<0.05).Conclusions:This iPSC-CM study provides further evidence that the p.D85N-KCNE1 common variant in combination with environmental factors such as QT prolonging drugs and female sex is proarrhythmic.

中文翻译：

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药物诱导的长 QT 综合征患者特异性 p.D85N-钾电压门控通道 E 成员 1 诱导多能干细胞衍生心肌细胞模型的开发

背景：先前的流行病学研究表明，p.D85N-钾电压门控通道亚家族 E 成员 1 (KCNE1) 常见变体降低了复极储备并易患药物诱导的 QT 延长/尖端扭转型室速。我们试图使用患者特异性诱导多能干细胞衍生的心肌细胞 (iPSC-CM) 开发药物诱导的长 QT 综合征的细胞模型。方法：p.D85N-KCNE1 iPSCs 由一名 23 岁的女性产生对甲氧氯普胺的心率校正 QT 间期反应过大（ΔQTc 为 160 ms）。聚集规则间隔短回文重复相关 9 技术用于生成基因校正的等基因 iPSC。从 iPSC-CM 测量场电位持续时间和动作电位持续时间 (APD)。结果：在基线，p。P <0.01) 和 90% 复极时的动作电位持续时间 (APD90; 579±22 ms, n=24 vs 465±33 ms, n=26, P <0.01) 比等基因对照 iPSC-CMs。浓度为 2 nM 的多非利特显着增加p.D85N-KCNE1 iPSC- 中的场电位持续时间 (379±20 ms, n=13, P <0.01) 和 APD90 (666±11 ms, n=46, P <0.01) CMs 但不在等基因对照中。膜片钳证实了多非利特对 APD90 的影响（616±54 ms，n=7 对 526±54 ms，n=10，P <0.05）。有趣的是，用 1 nM 浓度的雌激素处理 p.D85N-KCNE1 iPSC-CMs 进一步夸大了多非利特诱导的 APD90 延长（696±9 ms，n=81，P<0.01) 并引起更多的早期后除极 (11.7%) 与等基因对照 (APD90: 618±8 ms, n=115 和早期后除极: 2.6%, P <0.05)。结论：这项 iPSC-CM 研究提供了进一步的证据，即p.D85N-KCNE1 常见变体与 QT 延长药物和女性性等环境因素相结合是致心律失常的。