Abstract 15963: A Novel SGK1 Inhibitor (SGK1-I), Prevents Obesity-Related Atrial Fibrillation

Abstract

Introduction: Obesity is an important risk factor for atrial fibrillation. We have previously demonstrated the protective effect of genetic SGK1 inhibition in a mouse model of obesity-related atrial fibrillation (AF). SGK1-I is a novel and potent SGK1 inhibitor that has been shown to reduce late sodium current and has currently entered clinical trials as a potential treatment of long QT syndrome. Hypothesis: We sought to assess the efficacy of pharmacologic SGK1 inhibition in a mouse model of obesity-related AF. Methods: Wild type C57/Bl6 mice were fed a high fat diet containing 60% cholesterol (by calories) compounded with (HFD-SGK1i) or without (HFD) SGK1-I for 10 weeks. After feeding, the mice were assayed with invasive electrophysiology studies (EPS), optical mapping, and biochemical assays. Results: There were no significant differences in rate of weight gain, final body weight, fasting glucose, glucose tolerance, or tail-cuff blood pressure between the two groups of mice throughout the study. During EPS, there were no differences in nodal (sinus and atrio-ventricular) function or tissue (atrial/ventricular) refractory periods. However, HFD-SGK1i mice were significantly protected from obesity-related inducible AF during EPS, with a lower rate of AF inducibility (5.7% versus 1.5%, p<0.0001) and a lower total AF burden (35±54 versus 5.5±10.7 s, p=0.04). Optical mapping revealed abbreviated right (RA), but not left (LA), atrial action potential duration (APD) and attenuated inter-atrial APD differences in HFD-SGK1i mice as compared to HFD mice. In this context, Western blotting data demonstrated greater RA (versus LA) SGK1 activity/expression resulting from HFD, suggesting that SGK1 signaling may contribute to inter-atrial heterogeneity caused by HFD. Finally, protein expression of NLRP3 inflammasome components, Caspase-1 and ASC, as well as TGF-β expression were decreased in the SGK1-1 group; consistent with anti-inflammatory and anti-fibrotic signaling resulting from SGK1-I treatment. Conclusion: SGK1-I protects mice from obesity-related AF. These data further highlight SGK1 and its inhibition as a compelling target in cardiac arrhythmogenesis.