Elsevier

Heart Rhythm

Volume 20, Issue 4, April 2023, Pages 589-595
Heart Rhythm

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

https://doi.org/10.1016/j.hrthm.2022.12.036Get rights and content

Background

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.

Objective

Here, we test the efficacy of 2 novel SGK1 inhibitors—SGK1-I1 and SGK1-I2—in iPSC-CM models of dofetilide-induced APD prolongation.

Methods

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.

Results

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).

Conclusion

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.

Introduction

Long QT syndrome (LQTS) is characterized by delayed repolarization of the myocardium resulting in pathological prolongation of the ventricular cardiomyocyte’s action potential duration (APD) that manifests as a prolonged QT interval on the 12-lead electrocardiogram (ECG). Patients with LQTS may present with syncope/seizures, sudden cardiac arrest, or sudden cardiac death (SCD).1 LQTS may be congenital or acquired.

The prevalence of congenital LQTS (cLQTS) occurs in ∼1 in 2000 and is typically inherited as an autosomal dominant monogenetic disorder.2 Approximately 80% of cLQTS results from either loss-of-function (LOF) or gain-of-function pathogenic variants in 1 of 3 LQTS-susceptibility genes: KCNQ1-encoded slow delayed rectifier potassium current (Kv7.1, LOF, LQTS type 1 [LQT1]) potassium channel, KCNH2-encoded rapid delayed rectifier potassium current (IKr) (human ether-à-go-go–related gene [HERG], Kv11.1, LOF, LQTS type 2 [LQT2]) potassium channel, or SCN5A-encoded INa (Nav1.5, gain-of-function, LQTS type 3 [LQT3]) sodium channel.1

Acquired LQTS is more common than cLQTS, with the vast majority of acquired LQTS occurring because of drug-induced QT prolongation (DI-QTP), also referred to as drug-induced LQTS, a clinical entity in which administration of a drug produces a marked prolongation of the QT interval on the patient’s ECG,3, 4, 5 usually by inhibition of the LQT2-associated Kv11.1 channel (ie, HERG-related current). While the incidence of DI-QTP can be difficult to ascertain, at least 1 study has suggested that 5%–7% of reports of ventricular tachycardia, ventricular fibrillation, or SCD were associated with DI-QTP.4,6 DI-QTP and the risk of torsades de pointes represent a leading cause for early termination of drugs in the development or withdrawal of marketed drugs despite their potential benefits.4

Many different classes of drugs including antiarrhythmics, antipsychotics, antibiotics, oncologic medications, and antihistamines have been associated with DI-QTP.3 Those Food and Drug Administration–approved medications with a documented increased risk of DI-QTP and those with an additional increased risk of DI-QTP and subsequent DI-SCD are maintained and updated at www.crediblemeds.org. The predominant mechanism of DI-QTP is as a HERG blocker.3,4 However, recent studies have demonstrated that potent IKr blockers such as dofetilide, a common antiarrhythmic drug used in the treatment of atrial fibrillation, may also enhance late sodium current (INa-L) on prolonged drug exposure.7,8

Serum and glucocorticoid regulated kinase-1 (SGK1) is an important regulator of SCN5A-encoded Nav1.5-mediated INa in the heart.9,10 Recently, Bezzerides et al11 provided a proof-of-concept for a SGK1 inhibitor (SGK1-I)–based therapeutic for LQT3 by demonstration of an APD shortening effect on a patient-specific induced pluripotent stem cell–derived cardiomyocyte (iPSC-CM) model of the LQT3-causing SCN5A-N406K variant after treatment with a novel SGK1-I by preferentially reducing INa-L.

Given that small molecule SGK1-Is may be antiarrhythmic in cardiac diseases through correction of abnormal INa-L, SGK1-Is could potentially be used in combination therapy with DI-QTP–associated IKr-blocking drugs to counter the unwanted side effect of APD prolongation and thereby reduce or eliminate that drug’s DI-SCD potential.10,11 Here, we test the efficacy of 2 potent and selective SGK1-Is (SGK1-I1 and SGK1-I2) in a human iPSC-CM model of dofetilide-induced APD prolongation.

Section snippets

Methods

The authors declare that all supporting data are available in the article. The research reported in this article adhered to Helsinki Declaration as revised in 2013 guidelines.

Generation of a human normal iPSC-CM model

A normal iPSC line was generated by CRISPR/Cas9–based gene correction of the P1332L variant in SCN5A that caused a rate-corrected QT interval of 583 ms on the ECG of a female patient. The normal iPSC line had a normal female karyotype (Figure 1). The genetic correction of the SCN5A-P1332L variant to wild type in the normal iPSC line (Figure 1B) was confirmed by Sanger sequencing. The pluripotency of undifferentiated normal iPSCs was demonstrated by immunofluorescence staining of pluripotent

Discussion

Lethal arrhythmic events associated with QT prolongation is a potential risk during treatment with some antiarrhythmic drugs and more importantly with many noncardiac drugs due to off-target HERG inhibition.3,5 Because of their potential off-target proarrhythmic effect, many otherwise promising drugs have had their development terminated while clinically beneficial drugs have been removed from the market or had their use in potentially lifesaving applications (eg, oncology) terminated during a

Conclusion

Therapeutically inhibiting SGK1 effectively shortens the cardiomyocyte’s APD in a human heart cell model of DI-QTP. Whether SGK1-Is can reverse the APD-prolonging effects of other IKr blockers and other drugs associated with APD prolongation remains to be tested. These preclinical data support further development of this therapeutic strategy to counter and neutralize DI-QTP, thereby decreasing or eliminating the threat of DI-SCD altogether.

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Funding Sources: This work was supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program and Thryv Therapeutics, Inc.

Disclosures: Dr Ackerman is a consultant for Abbott, Boston Scientific, Bristol Myers Squibb, Daiichi Sankyo, InVitae, Thryv Therapeutics, and Medtronic. Dr Ackerman and Mayo Clinic are involved in an equity/royalty relationship with AliveCor, Anumana, ARMGO Pharma, Pfizer, and UpToDate. These relationships are all modest, and none of these entities have contributed to this study in any manner. Dr Das is a scientific founder and has received equity for Thryv Therapeutics and Switch Therapeutics and has a consulting relationship with Thryv Therapeutics and Renovacor. Dr Sager is a scientific founder and has received equity from Thryv Therapeutics where he is an employee. The rest of the authors report no conflicts of interest.

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