Department of Molecular Pharmacology and Therapeutics, Columbia University Irving Medical Center, Vagelos College of Physicians and Surgeons, Columbia, NY, USA.
Channels (Austin). 2022 Dec;16(1):173-184. doi: 10.1080/19336950.2022.2106025.
The congenital long QT syndrome (LQTS), one of the most common cardiac channelopathies, is characterized by delayed ventricular repolarization underlying prolongation of the QT interval of the surface electrocardiogram. LQTS is caused by mutations in genes coding for cardiac ion channels or ion channel-associated proteins. The major therapeutic approach to LQTS management is beta blocker therapy which has been shown to be effective in treatment of LQTS variants caused by mutations in K channels. However, this approach has been questioned in the treatment of patients identified as LQTS variant 3(LQT3) patients who carry mutations in , the gene coding for the principal cardiac Na channel. LQT3 mutations are gain of function mutations that disrupt spontaneous Na channel inactivation and promote persistent or late Na channel current (I) that delays repolarization and underlies QT prolongation. Clinical investigation of patients with the two most common LQT3 mutations, the ΔKPQ and the E1784K mutations, found beta blocker treatment a useful therapeutic approach for managing arrhythmias in this patient population. However, there is little experimental data that reveals the mechanisms underlying these antiarrhythmic actions. Here, we have investigated the effects of the beta blocker propranolol on I expressed by ΔKPQ and E1784K channels in induced pluripotent stem cells derived from patients carrying these mutations. Our results indicate that propranolol preferentially inhibits I expressed by these channels suggesting that the protective effects of propranolol in treating LQT3 patients is due in part to modulation of I.
先天性长 QT 综合征(LQTS)是最常见的心脏离子通道病之一,其特征是心室复极延迟,导致体表心电图 QT 间期延长。LQTS 是由编码心脏离子通道或离子通道相关蛋白的基因突变引起的。LQTS 管理的主要治疗方法是β受体阻滞剂治疗,该方法已被证明对由 K 通道基因突变引起的 LQTS 变异型有效。然而,这种方法在治疗被认为是 LQT3 变异型的患者时受到了质疑,这些患者携带编码主要心脏 Na 通道的基因的基因突变。LQT3 突变是功能获得性突变,会破坏 Na 通道的自发失活,并促进持续或晚期 Na 通道电流(I),从而延迟复极并导致 QT 间期延长。对具有两种最常见 LQT3 突变(ΔKPQ 和 E1784K 突变)的患者进行临床研究发现,β受体阻滞剂治疗是管理该患者群体心律失常的有用治疗方法。然而,很少有实验数据揭示这些抗心律失常作用的机制。在这里,我们研究了β受体阻滞剂普萘洛尔对携带这些突变的患者来源诱导多能干细胞中 ΔKPQ 和 E1784K 通道表达的 I 的影响。我们的结果表明,普萘洛尔优先抑制这些通道表达的 I,这表明普萘洛尔在治疗 LQT3 患者中的保护作用部分归因于 I 的调节。