Gene- and variant-specific efficacy of serum/glucocorticoid-regulated kinase 1 inhibition in long QT syndrome types 1 and 2.

Abstract

AIMS:

Current long QT syndrome (LQTS) therapy, largely based on beta-blockade, does not prevent arrhythmias in all patients; therefore, novel therapies are warranted. Pharmacological inhibition of the serum/glucocorticoid-regulated kinase 1 (SGK1-Inh) has been shown to shorten action potential duration (APD) in LQTS type 3. We aimed to investigate whether SGK1-Inh could similarly shorten APD in LQTS types 1 and 2.

METHODS AND RESULTS:

Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and hiPSC-cardiac cell sheets (CCS) were obtained from LQT1 and LQT2 patients; CMs were isolated from transgenic LQT1, LQT2, and wild-type (WT) rabbits. Serum/glucocorticoid-regulated kinase 1 inhibition effects (300 nM-10 µM) on field potential durations (FPD) were investigated in hiPSC-CMs with multielectrode arrays; optical mapping was performed in LQT2 CCS. Whole-cell and perforated patch clamp recordings were performed in isolated LQT1, LQT2, and WT rabbit CMs to investigate SGK1-Inh (3 µM) effects on APD. In all LQT2 models across different species (hiPSC-CMs, hiPSC-CCS, and rabbit CMs) and independent of the disease-causing variant (KCNH2-p.A561V/p.A614V/p.G628S/IVS9-28A/G), SGK1-Inh dose-dependently shortened FPD/APD at 0.3-10 µM (by 20-32%/25-30%/44-45%). Importantly, in LQT2 rabbit CMs, 3 µM SGK1-Inh normalized APD to its WT value. A significant FPD shortening was observed in KCNQ1-p.R594Q hiPSC-CMs at 1/3/10 µM (by 19/26/35%) and in KCNQ1-p.A341V hiPSC-CMs at 10 µM (by 29%). No SGK1-Inh-induced FPD/APD shortening effect was observed in LQT1 KCNQ1-p.A341V hiPSC-CMs or KCNQ1-p.Y315S rabbit CMs at 0.3-3 µM.

CONCLUSION:

A robust SGK1-Inh-induced APD shortening was observed across different LQT2 models, species, and genetic variants but less consistently in LQT1 models. This suggests a genotype- and variant-specific beneficial effect of this novel therapeutic approach in LQTS.

• Authors: Federica Giannetti, Miriam Barbieri, Assad Shiti, Simona Casini, Philip T Sager, Saumya Das, Sabindra Pradhananga, Dinesh Srinivasan, Saranda Nimani, Nicolò Alerni, Julien Louradour, Manuela Mura, Massimiliano Gnecchi, Paul Brink, Manfred Zehender, Gideon Koren, Antonio Zaza, Lia Crotti, Arthur A M Wilde, Peter J Schwartz, Carol Ann Remme, Lior Gepstein, Luca Sala, Katja E Odening
• Journal: Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology (Europace) Vol. 25 Issue 5 (05 19 2023) ISSN: 1532-2092 [Electronic] England
• PMID: 37099628 (Publication Type: Journal Article)
• Copyright: © The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.

Chemical References

• Glucocorticoids
• KCNQ1 Potassium Channel

Topics

• Animals
• Humans
• Rabbits
• Glucocorticoids
• KCNQ1 Potassium Channel (genetics)
• Long QT Syndrome (drug therapy, genetics)
• Arrhythmias, Cardiac (genetics)
• Myocytes, Cardiac (physiology)
• Action Potentials (physiology)
• Induced Pluripotent Stem Cells