2225-PUB: Direct Actions of the Dual SGLT1/2 Inhibitor Sotagliflozin on Functional Recovery following Global Ischemia in Diabetic and Healthy Mouse Hearts

Sotagliflozin is a dual sodium-dependent glucose transporter (SGLT) inhibitor with the potential to be cardio-protective in people with and without diabetes. Here, we used an ex vivo Langendorff reperfusion model to investigate if direct infusion with sotagliflozin in hearts from diabetic and healthy mice improves functional recovery from global ischemia. Male C57Bl/6 mice were fed either a control chow (CON) or high fat diet (HFD; 60% of calories from fat) for 46-48 weeks. Fasting blood glucose measurements were performed and body composition measured using nuclear magnetic resonance. Constant pressure Langendorff perfusion experiments were performed on hearts from each diet group. Following equilibration, hearts were infused with either sotagliflozin (90 nM) or dimethyl sulfoxide (VEH) for 10 min prior to a 25 min period of global ischemia. The infusions were recommenced for the first 15 min of 45 min reperfusion. Post ischemic recovery was assessed as % baseline recovery. HFD mice were heavier (54 vs. 34 g) with increased fat mass (42 vs. 19 %) and increased fasting blood glucose (9.6 vs. 8.0 mmol/L). Paradoxically, their functional recovery from global ischemia was, in general, better when compared with hearts from CON mice and there was no effect of sotagliflozin infusion. In CON mice, early post-ischemic coronary flow was greater with sotagliflozin infusion when compared with VEH. Functional recovery in dP/dtmax and dP/dtmin was also greater with sotagliflozin infusion when compared with VEH. In conclusion, HFD exerted a protective effect on heart function, despite inducing obesity and hyperglycemia. Ongoing studies are examining the effects of sotagliflozin in an alternative model of T2DM. In lean mice, sotagliflozin increased functional recovery from global ischemia, highlighting the potential benefits of an antidiabetic agent in acute coronary care.