1. SGK1 inhibition attenuates the action potential duration in reengineered heart cell models of drug-induced QT prolongation.
- Author
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Kim, Maengjo, Sager, Philip T., Tester, David J., Pradhananga, Sabindra, Hamrick, Samantha K., Srinivasan, Dinesh, Das, Saumya, and Ackerman, Michael J.
- Abstract
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. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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