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SGK1-inhibition restores cardiac repolarization in LQT2 rabbits and LQT3 mice by reducing late sodium current.

Year: 2026

Type: article

Abstract: Current management does not fully prevent arrhythmias in long QT syndrome (LQTS), underscoring a need for novel therapies. Here, we investigated potential beneficial effects of serum/glucocorticoid-regulated-kinase-1 (SGK1)-inhibition in different LQTS animal models. Ventricular cardiomyocytes (CMs) isolated from wild-type (WT), LQT1 (KCNQ1-Y315S) and LQT2 (KCNH2-GS628S) rabbits, and WT and LQT3 (Scn5a-1798insD+/-) mice were incubated for 2-4hours with SGK1-inhibitor (SGK1-inh, 300nM or 3μM) or vehicle to assess its effects on action potential duration (APD) and late sodium current (late INa). Whole heart experiments were performed to investigate SGK1-inh effects on QT duration (rabbits) and ventricular effective refractory periods (ERP, mice). Late INa was enhanced in LQT2 and LQT3 CMs, but not in LQT1. SGK1-inh reduced late INa in LQT2 (by 60%) and LQT3 (by 33%) CMs, but not in LQT1. Consequently, SGK1-inh shortened APD in LQT2 (by 25%) and LQT3 CMs (by 23%) restoring these to WT levels, but did not affect APD in LQT1. The proarrhythmic marker short-term-variability of APD was increased in LQT2 and LQT3, and was reduced by SGK1-inh in LQT2 (by 48%) and LQT3 (by 49%) CMs. Additionally, SGK1-inh decreased triggered APs in LQT3 CMs. Finally, SGK1-inh perfusion in ex vivo hearts shortened QT-interval in LQT2 and decreased ventricular ERP in LQT3, restoring them to WT levels. Late INa is increased in LQT2 rabbits and LQT3 mice, but not in LQT1 rabbits. SGK1-inhibition shortens APD/QT and reduces proarrhythmic risk in LQT2 and LQT3 CMs by suppressing enhanced late INa, indicating potential therapeutic benefit.

Source: Open Access CRIS of the University of Bern

DOI: 10.48620/97083

Authors: Barbieri, Miriam, Casini, Simona, Louradour, Julien, de Waal, Tanja M., Alerni, Nicolò, Verkerk, Arie O, Giannetti, Federica, Sala, Luca, Sager, Philip T, Das, Saumya, Koren, Gideon, Zehender, Manfred, Brunner, Michael, Gepstein, Lior, Crotti, Lia, Schwartz, Peter J., Wilde, Arthur A. M., Odening, Katja Elisabeth, Remme, Carol A.

Institution: Czech Academy of Sciences, Institute of Physiology

Language: English

Topic: Cardiac electrophysiology and arrhythmias

Subfield: Cardiology and Cardiovascular Medicine

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: green

OpenAlex ID: W7154997602

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