Department of Medicine, Vanderbilt University Medical Center, 2215B Garland Ave, 1285 MRBIV, Nashville, TN 37232, USA.
Departments of Medicine, Pharmacology, and Biomedical Informatics, Vanderbilt University Medical Center, 2215B Garland Ave, 1285 MRBIV, Nashville, TN 37232, USA.
Cardiovasc Res. 2024 May 29;120(7):735-744. doi: 10.1093/cvr/cvae042.
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.
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 (LOF) KCNQ1 variants. We compared the effects of pharmacologic IKs block to those of genetic KCNQ1 ablation, using JLN cells, cells homozygous for the KCNQ1 LOF 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 the pharmacologic IKs block produced no change in action potential duration at 90% repolarization (APD90). In 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, interquartile range (IQR) 100.6-391.6, n = 7] in population cells vs. 23.7 (17.3-28.7, n = 11) in JLN cells. In control cells, chronic moxifloxacin exposure (300 μM) 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.
Our data strongly suggest that KCNQ1 expression modulates baseline cardiac repolarization, and the response to IKr block, through mechanisms beyond simply generating IKs.
虽然 KCNQ1 变异是先天性长 QT 综合征的最常见原因，但我们和其他人发现，从人类诱导多能干细胞（iPSC-CMs）或人类心室肌细胞中获得的 IKs 非常小。
我们研究了人群对照 iPSC-CMs 和因复合杂合性功能丧失（LOF）KCNQ1 变异而导致 Jervell 和 Lange-Nielsen（JLN）综合征的患者来源的 iPSC-CMs。我们比较了药理学 IKs 阻断对基因敲除 KCNQ1 的影响，使用 JLN 细胞、纯合 LOF 等位基因 G643S 的 KCNQ1 细胞或降低 KCNQ1 表达的 siRNA。我们还研究了两种 IKr 阻断剂，即另一种主要的心脏复极化电流，在药理学或基因敲除 KCNQ1 时的作用：莫西沙星，与药物诱导的长 QT 风险非常低相关，以及多非利特，一种高风险药物。在对照细胞中，很容易记录到较小的 IKs，但药理学 IKs 阻断对 90%复极时动作电位持续时间（APD90）没有影响。相比之下，在基因敲除 KCNQ1（JLN）的细胞中，与对照细胞相比，基线 APD90 明显延长（469±20 与 310±16 ms）。JLN 细胞对急性 IKr 阻断的敏感性增加：延长 APD90 100 msec 所需的莫西沙星浓度（μM）在群体细胞中为 237.4[中位数，四分位距（IQR）100.6-391.6，n=7]，而在 JLN 细胞中为 23.7（17.3-28.7，n=11）。在对照细胞中，莫西沙星慢性暴露（300 μM）轻度延长 APD90（10%）并增加 IKs，而多非利特慢性暴露（5 nM）产生更大的延长（67%）而 IKs 没有增加。然而，在 siRNA 处理的细胞中，莫西沙星没有增加 IKs 并明显延长 APD90。
我们的数据强烈表明，KCNQ1 表达通过除产生 IKs 以外的机制调节心脏复极的基线，并调节 IKr 阻断的反应。
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