SGK1 inhibition normalizes action potential duration in transgenic LQT2 rabbits but not in LQT1, suggesting a novel gene-specific therapeutic approach in long QT syndrome

Abstract

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): SNSF (Swiss National Science Fundation) Background Increasing evidence suggests that secondary remodeling in Na+ and Ca2+ homeostasis may further enhance the propensity to develop arrhythmias in K-channelopathies LQT1 and LQT2 syndrome. In this context, the Serum and Glucocorticoid regulated Kinase-1 (SGK-1) was recently identified as a major regulator of sodium channels in cardiomyocytes. It is mainly activated in pathological conditions, leading to increased INaLate, prolongation of action potential duration (APD) and increased susceptibility to ventricular arrhythmias, recapitulating LQTS phenotype. SGK1 inhibition might hence be a novel therapeutic target also in genetic LQTS subtypes. Methods In cardiomyocytes (CM) isolated from wild type (WT), LQT1 and LQT2 adult rabbits patch-clamp experiments were performed to record AP with SGK1-inhibitor(SGK1-inh, 3 µM) or DMSO vehicle control. Results In the perforated patch configuration at 37°C, 3 μM of SGK1-inh shortened APD90 in LQT2 CMs at 1 Hz (DMSO-control [ms]: 477.3 vs treated cells[ms]: 362.8 p < 0.0001) and at 2 Hz (DMSO-cells: 325.7 vs treated cells:295.4,p <0.05). In contrast, in WT and LQT1 CMs, no effect on APD90 was observed neither at 1 Hz (WT, DMSO-cells: 329.2 vs treated cells: 301.6 p=ns; LQT1, DMSO-cells: 429.8 vs treated cells: 431.6, p=ns) nor at 2 Hz (WT, DMSO-cells:256.8 vs treated cells:242 p=ns; LQT1,DMSO cells:310.4 vs treated cells: 315.8,p=ns). Importantly, the SGK1-inhibitor effect in LQT2 rabbit CMs was so pronounced that it normalized APD to the wildtype level (LQT2+SGK1-Inh: 362.8 vs WT:329.2, ps=ns). Furthermore, short-term-variability in APD was markedly reduced by SGK1-Inh in LQT2, indicating an antiarrhythmic effect. Conclusions SGK1-inhibition exerts a beneficial APD-shortening effect only in LQT2, indicating a gene-specific efficacy. The underlying mechanism is still unclear. We hypothesize that the SGK1 pathway/INaLate activation in LQT1 might not be as active as in LQT2. We are currently conducting more experiments on potential genotype differences in SGK1 activity and SGK1-mediated INaLate inhibition to further elucidate the differences.Effects of SGK1-inh on AP characteristic