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Abstract 11027: SGK1 Inhibition and Attenuation of the Action Potential Duration in Re-Engineered Heart Cell Models of Drug-Induced QT Prolongation
- Source :
- Circulation (Ovid); November 2022, Vol. 146 Issue: Supplement 1 pA11027-A11027, 1p
- Publication Year :
- 2022
-
Abstract
- Background:Drug-induced QT prolongation (DI-QTP) is a clinical entity in which administration of a HERG/IKrblocker such as dofetilide prolongs the cardiac action potential duration (APD) at the cellular level and the QT interval clinically, and increases the risk for a potentially lethal, QT-triggered ventricular arrhythmia. There may be a role for inhibition of INaLto counter DI-QTP. Recently, we have shown that inhibition of serum and glucocorticoid regulated kinase-1 (SGK1) reduces the APD90 in induced pluripotent stem cell derived cardiomyocytes (iPSC-CM) from patients with LQT3 and ameliorates increases in INaL.Objective:To test the efficacy of novel SGK1 inhibitors (SGK-I) in re-engineered cardiomyocyte models of dofetilide-induced APD prolongation.Methods:Normal iPSC-CMs were treated with dofetilide [5 nM] to produce a DI-QTP iPSC-CM model. The SGK1-I’s therapeutic efficacy for shortening the dofetilide-induced APD90 prolongation was compared to mexiletine. The APD90 values were recorded 4 hours after treatment using FluoVolt, a voltage-sensitive fluorescent dye.Results:The APD90 was significantly prolonged in normal iPSC-CMs treated with dofetilide (673 ± 8 ms with dofetilide vs 436 ± 4 ms with DMSO, p<0.0001). While 10 μM mexiletine shortened the average APD90 of dofetilide-treated normal iPSC-CMs from 673 ± 4 ms to 563 ± 8 ms (46% attenuation, p<0.0001), 30 nM of SGK-I shortened the APD90 from 673 ± 4 ms to 478 ± 10 ms (82% attenuation, p<0.0001).Conclusions:Therapeutically inhibiting SGK1 effectively shortens the cardiomyocyte APD in a human heart cell model of DI-QTP. The novel SGK1 inhibitor normalized the pathological APD prolongation almost fully (> 80%) in the iPSC-CM model treated with dofetilide. This pre-clinical data supports further development of this therapeutic strategy to counter and neutralize the threat of DI-QTP.
Details
- Language :
- English
- ISSN :
- 00097322 and 15244539
- Volume :
- 146
- Issue :
- Supplement 1
- Database :
- Supplemental Index
- Journal :
- Circulation (Ovid)
- Publication Type :
- Periodical
- Accession number :
- ejs61505799
- Full Text :
- https://doi.org/10.1161/circ.146.suppl_1.11027