SGK1 inhibition shortens action potential duration and exerts anti-arrhythmic effects in LQT3 mice and LQT2 rabbits by reducing enhanced late sodium current

Abstract Background Serum and glucocorticoid regulated kinase 1 (SGK1) activation during pathological conditions has been shown to increase late sodium current (INa), prolong action potential duration (APD), and induce ventricular arrhythmias, thus recapitulating a long QT syndrome (LQTS) phenotype. Hence, pharmacological SGK1 inhibition may be a novel therapeutic approach in inherited LQTS. Aim We aimed to investigate potential beneficial effects of SGK1 inhibition in animal models of different LQTS subtypes and underlying mechanisms. Methods Cardiomyocytes (CMs) isolated from wild-type (WT) and LQT3 mice (Scn5a-1798insD) as well as from WT, LQT1 (KCNQ1-Y315S) and LQT2 (KCNH2-G628S) rabbits, were incubated for 3-5 hours with SGK1-inhibitor (SGK1-inh, 300 nM-3 μM) or DMSO (vehicle). Patch-clamp experiments were performed to assess action potential (AP) properties, short-term variability (STV) of APD, triggered activity and late INa. Result SGK1-inh incubation significantly shortened the prolonged APD90 in LQT3 CMs by 23% and in LQT2 CMs by 25% (restoring them towards the WT level), without affecting other AP properties. In contrast, in WT and LQT1 CMs, no significant effect of SGK1-inh on APD90 was observed. Furthermore, short-term-variability (STV) of APD, a measure of pro-arrhythmia, was pathologically increased in LQT3 (5.6±0.2 ms vs WT 2.7±0.3 ms, p<0.05) and LQT2 (14.7±2.8 ms vs WT 5.9 ±1.1 ms, p<0.0001), but not in LQT1. SGK1-Inh significantly reduced STV in LQT3 and LQT2 CMs, but had no effect in WT and LQT1 CMs. Finally, SGK1-inh treatment significantly decreased the number of triggered APs recorded after a fast pacing stimulation protocol (20 pulses at 5 Hz followed by a 10 s pause) in LQT3 CMs. While enhanced late INa was previously demonstrated in LQT3 CMs, we now also observed increased late INa in LQT2 CMs as compared to WT (-0.14 ± 0.02 pA/pF vs WT -0.08 ± 0.02 pA/pF, p< 0.005), but not in LQT1 CMs. SGK1-Inh significantly reduced late INa in LQT3 (by 32%) and LQT2 CMs (by 43%), confirming that SGK1-inh directly targets late INa. Conclusion SGK1-inhibition exerts a beneficial APD-shortening and anti-arrhythmic effect in LQT3 and LQT2 by reducing the enhanced late INa associated with these LQTS genetic subtypes. These findings furthermore underscore the contribution of increased late INa to the LQT2 and LQT3 phenotypes.