Abstract 4138799: SGK1 inhibition shortens action potential duration in LQT3 mice and LQT2 rabbits via inhibition of late sodium current

Background: Serum and glucocorticoid regulated kinase 1 (SGK1) activation during pathological conditions has been shown to increase late sodium current, 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 effects of SGK1 inhibition in animal models of different LQTS subtypes, and the potential involvement of late I Na inhibition. 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 AP properties, short-term variability (STV) of APD and late I Na . Result: SGK1-inh incubation significantly shortened the prolonged APD 90 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 effect of SGK1-inh on APD 90 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 markedly reduced STV in LQT3 (to 2.9±0.1 ms) and LQT2 CMs (to 7.2± 1.2 ms), but had no effect in WT and LQT1 CMs. While enhanced late I Na was previously demonstrated in LQT3 CMs, we now also observed increased late I Na 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 I Na in LQT3 (by 32%) and LQT2 CMs (by 43%), but not in LQT1 CMs, confirming that SGK1-inh directly targets late I Na . Conclusion: SGK1-inhibition exerts a beneficial APD-shortening and anti-arrhythmic effect in LQT3 and LQT2 by reducing the enhanced late I Na associated with these LQTS genetic subtypes. These findings furthermore underscore the contribution of increased late I Na to the LQT2 phenotype.