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

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.