SGK1 inhibition attenuates the action potential duration in reengineered heart cell models of drug-induced QT prolongation

多非利特 美西律 QT间期 医学 长QT综合征 内科学 复极 新加坡元1 诱导多能干细胞 心脏病学 药理学 电生理学 化学 胚胎干细胞 生物化学 基因 糖皮质激素
作者
Maengjo Kim,Philip T. Sager,David J. Tester,Sabindra Pradhananga,Samantha K. Hamrick,Dinesh Srinivasan,Saumya Das,Michael J. Ackerman
出处
期刊:Heart Rhythm [Elsevier BV]
卷期号:20 (4): 589-595 被引量:5
标识
DOI:10.1016/j.hrthm.2022.12.036
摘要

Drug-induced QT prolongation (DI-QTP) is a clinical entity in which administration of a human ether-à-go-go-related gene/rapid delayed rectifier potassium current blocker such as dofetilide prolongs the cardiac action potential duration (APD) and the QT interval on the electrocardiogram. Inhibition of serum and glucocorticoid regulated kinase-1 (SGK1) reduces the APD at 90% repolarization (APD90) in induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) derived from patients with congenital long QT syndrome.Here, we test the efficacy of 2 novel SGK1 inhibitors-SGK1-I1 and SGK1-I2-in iPSC-CM models of dofetilide-induced APD prolongation.Normal iPSC-CMs were treated with dofetilide to produce a DI-QTP iPSC-CM model. SGK1-I1's and SGK1-I2's therapeutic efficacy for shortening the dofetilide-induced APD90 prolongation was compared to mexiletine. The APD90 values were recorded 4 hours after treatment using a voltage-sensing dye.The APD90 was prolonged in normal iPSC-CMs treated with dofetilide (673 ± 8 ms vs 436 ± 4 ms; P < .0001). While 10 mM mexiletine shortened the APD90 of dofetilide-treated iPSC-CMs from 673 ± 4 to 563 ± 8 ms (46% attenuation; P < .0001), 30 nM of SGK1-I1 shortened the APD90 from 673 ± 8 to 502 ± 7 ms (72% attenuation; P < .0001). Additionally, 300 nM SGK1-I2 shortened the APD90 of dofetilide-treated iPSC-CMs from 673 ± 8 to 460 ± 7 ms (90% attenuation; P < .0001).These novel SGK1-Is substantially attenuated the pathological APD prolongation in a human heart cell model of DI-QTP. These preclinical data support the development of this therapeutic strategy to counter and neutralize DI-QTP, thereby increasing the safety profile for patients receiving drugs with torsadogenic potential.
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