Abstract 4142850: SGK1 inhibition attenuated left ventricular thickening and diastolic dysfunction in a mouse model of Heart Failure with Preserved Ejection Fraction

Background: Heart failure with preserved ejection fraction (HFpEF) is growing in prevalence and expected to become the dominant form of heart failure in the future. Given its significant burden, it is important that novel therapeutic options are explored to identify potential drug targets. Serum and glucocorticoid regulated kinase 1 (SGK1) is a PI3-kinase-dependent kinase and lies downstream of insulin signaling pathways. Hypothesis: Given the association between HFpEF and insulin resistance, we hypothesized that SGK1 activation is involved in HFpEF pathogenesis, and that SGK1 inhibition may have therapeutic potential. Methods: In this study, we utilized a mouse model of HFpEF, derived by combining obesity and increased afterload.C57BL6/J mice (age 10 weeks) were either fed with control chow and control water (CTL, N=5) or high fat diet (HFD) and Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME, 0.5g/L in drinking water) (HFpEF, N=8) or HFD chow with an incorporated SGK1 inhibitor as well as L-NAME in drinking water (SGK1I, N=6). After treatment for 15 weeks, the mice underwent tail-cuff blood pressure measurements as well as transthoracic echocardiography (TTE) to assess cardiac structural parameters, systolic function, and diastolic function. Results: After 15 weeks of treatment, the two groups of mice fed HFD had increased body weight and higher systolic and diastolic tail-cuff BPs than the control group. There were no differences in LV chamber size or systolic function as determined by LVEF or fractional shortening. The HFpEF group had significantly higher diastolic posterior wall thickness (HFpEF: 1.2±0.06, CTL: 1.08±0.04 mm p=0.001), but these differences were attenuated in the SGK1I group (1.09±0.05, p=NS compared to CTL). HFpEF mice, when compared to controls, had a significantly lower early diastolic mitral annular septal tissue velocity (e’) (CTL:37.5±3.2; HFpEF: 24.8±4.2; p=0.002), as well as a significantly higher ratio of E/e’ (CTL: 23±1.2; HFpEF 32.4±6.6; p=0.01). Treatment with SGK1I mitigated HFD+L-NAME induced diastolic dysfunction (e’: 31±8.1; E/e’ 28±4.6; p=NS compared to control for both). Conclusions: SGK1 inhibition attenuated left ventricular thickening and diastolic dysfunction in mice treated with HFD and L-NAME. Further investigation is warranted to determine the underlying mechanisms and assess for translational promise.