Abstract Body (Do not enter title and authors here): Introduction: SGLT2 inhibitors improved clinical outcomes in patients with heart failure (HF), highlighting metabolism-related pathways as a therapeutic target. Genetic inhibition of SGK1, a stress activated kinase, has been previously shown to be cardioprotective, identifying SGK1 as a promising molecular target in HF.
Research Questions: Evaluate the efficacy of a potent, selective SGK1 inhibitor (THRV-1268), and empagliflozin (EMPA), and their combination in a thoracic aortic constriction (TAC) model of HF.
Methods: Male Sprague Dawley rats (5 weeks old) that underwent either TAC or sham surgery were dosed once daily via oral gavage from Day 3 until the end of the study (Day 56) with vehicle, THRV-1268 (30 mg/kg/day), EMPA (10 mg/kg/day), or THRV-1268 and EMPA (COM). Cardiac function was serially assessed by echocardiography to monitor disease progression. Tissues were stained by picrosirius red, and collagen was quantified using ImageJ software.
Results: Compared to sham, TAC rats showed impaired systolic function marked by reduced LVEF (Figure 1), and CO (103.17 ± 14.89 mL/min vs 69.37± 7.57 mL/min, p≤ 0.001), and increased LVESV (Figure 3). Ventricular hypertrophy was also observed, with elevated PWT-ED (Figure 4) and heart weight/tibia length (33.79 ± 0.0 mg/mm vs 42.91 ± 0.0 mg/mm, p=0.3). EMPA improved LVEF at Day 21 (Figure 1), but this effect was not sustained on Day 56 (Figure 1 and 2) with similar trends observed for other functional parameters. Interestingly, THRV-1268 and COM, produced sustained protection from Day 21 onward. At Day 56, higher LVEF (Figure 1), and CO (THRV-1268: 90.98 ± 4.49 mL/min, COM: 89.48 ± 10.93 mL/min, p ≤ 0.01), with lower LVESV (Figure 3) and PWT-ED (Figure 4) were observed. HW/TL also trended to lower (THRV-1268: 36.65 ± 0.0 mg/mm, COM: 37.38 ± 0.0 mg/mm). Histological analysis revealed increased fibrosis in vehicle-treated rats compared to sham, with reduced levels in treatment groups, though not statistically significant.
Conclusions: THRV-1268 demonstrated superior cardioprotective effects compared to EMPA and in combination with EMPA in the TAC-model of HF. These data support continued development of THRV-1268 as a single or additive therapeutic approach for the optimal management of HF.