Aims While variants in KCNQ1 are the commonest cause of the congenital long QT syndrome, we and others find only a small IKs in cardiomyocytes from human induced pluripotent stem cells (iPSC-CMs) or human ventricular myocytes. Methods and Results We studied population control iPSC-CMs and iPSC-CMs from a patient with Jervell and Lange-Nielsen (JLN) syndrome due to compound heterozygous loss of function KCNQ1 variants. We compared the effects of pharmacologic IKs block to those of genetic KCNQ1 ablation, using JLN cells, cells homozygous for the KCNQ1 loss of function allele G643S, or siRNAs reducing KCNQ1 expression. We also studied the effects of two blockers of IKr, the other major cardiac repolarizing current, in the setting of pharmacologic or genetic ablation of KCNQ1: moxifloxacin, associated with a very low risk of drug-induced long QT, and dofetilide, a high-risk drug. In control cells, a small IKs was readily recorded but pharmacologic IKs block produced no change in action potential duration at 90% repolarization (APD90). By contrast, in cells with genetic ablation of KCNQ1 (JLN), baseline APD90 was markedly prolonged compared with control cells (469 ± 20 vs. 310 ± 16 ms). JLN cells displayed increased sensitivity to acute IKr block: the concentration (μM) of moxifloxacin required to prolong APD90 100 msec was 237.4 (median, IQR 100.6-391.6, n = 7) in population cells versus 23.7 (17.3-28.7, n = 11) in JLN cells. In control cells, chronic moxifloxacin exposure (300μM) mildly prolonged APD90 (10%) and increased IKs, while chronic exposure to dofetilide (5 nM) produced greater prolongation (67%) and no increase in IKs. However, in the siRNA-treated cells, moxifloxacin did not increase IKs, and markedly prolonged APD90. Conclusion Our data strongly suggest that KCNQ1 expression modulates baseline cardiac repolarization, and the response to IKr block, through mechanisms beyond simply generating IKs. Translational Perspective Mutations in KCNQ1 – whose expression generates IKs – are the major cause of long QT syndrome. We report here that while pharmacologic IKs block in human cardiomyocytes generates minimal change in repolarization, suppressing KCNQ1 expression markedly increases both baseline repolarization duration and sensitivity to some (but not all) specific IKr blockers. Thus, beyond simply generating IKs, KCNQ1 subserves critical additional role(s) in repolarization control at baseline and in response to IKr block. Our findings imply that assessment of arrhythmic risk in individual patients and by drugs requires a framework that extends beyond a simple one gene-one ion current paradigm.

中文翻译：

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KCNQ1 的电生理效应超出了 IK 的表达范围：来自遗传和药理学阻断的证据

目的 虽然 KCNQ1 变异是先天性长 QT 综合征的最常见原因，但我们和其他人在人类诱导多能干细胞 (iPSC-CM) 或人类心室肌细胞的心肌细胞中仅发现少量 IK。方法和结果 我们研究了群体对照 iPSC-CM 和来自因 KCNQ1 复合杂合功能丧失而导致的 Jervell 和 Lange-Nielsen (JLN) 综合征患者的 iPSC-CM。我们使用 JLN 细胞、KCNQ1 功能丧失等位基因 G643S 的纯合细胞或减少 KCNQ1 表达的 siRNA，比较了药理 IK 阻断与遗传 KCNQ1 消除的效果。我们还研究了另一种主要心脏复极电流 IKr 的两种阻滞剂在 KCNQ1 药物或基因消融情况下的作用：莫西沙星（与药物引起的长 QT 风险极低相关）和多非利特（一种高风险药物。在对照细胞中，很容易记录小 IK，但药物 IK 阻滞不会导致 90% 复极 (APD90) 时的动作电位持续时间发生变化。相比之下，在 KCNQ1 (JLN) 基因消除的细胞中，与对照细胞相比，基线 APD90 显着延长（469 ± 20 vs. 310 ± 16 ms）。JLN 细胞对急性 IKr 阻断的敏感性增加：群体细胞中将 APD90 延长 100 毫秒所需的莫西沙星浓度 (μM) 为 237.4（中位数，IQR 100.6-391.6，n = 7），而群体细胞中为 23.7（17.3-28.7，n = 11） ）在 JLN 细胞中。在对照细胞中，长期暴露于莫西沙星 (300μM) 会轻微延长 APD90 (10%) 并增加 IK，而长期暴露于多非利特 (5 nM) 会产生更大的延长 (67%)，并且 IK 不会增加。然而，在 siRNA 处理的细胞中，莫西沙星并没有增加 IK，并且显着延长了 APD90。结论 我们的数据强烈表明，KCNQ1 表达通过不仅仅是生成 IK 的机制来调节基线心脏复极以及对 IKr 阻滞的反应。KCNQ1 的翻译视角突变（其表达产生 IK）是长 QT 综合征的主要原因。我们在此报告，虽然药物 IK 阻断人类心肌细胞中的复极变化极小，但抑制 KCNQ1 表达却显着增加基线复极持续时间和对某些（但不是全部）特定 IKr 阻滞剂的敏感性。因此，除了简单地生成 IK 之外，KCNQ1 在基线复极控制和响应 IKr 阻滞方面还发挥着关键的附加作用。我们的研究结果表明，评估个体患者和药物的心律失常风险需要一个超越简单的单基因一离子电流范式的框架。