Anti-arrhythmic and inotropic effects of empagliflozin following myocardial ischemia

Background: Empagliflozin (EMPA) reduces heart failure hospitalization and mortality. The benefit in terms of ventricular arrhythmia and contractility has not been explored. Objective: To determine the direct effects of EMPA on ventricular arrhythmia and cardiac contractility in an exvivo model of global ischemia-reperfusion (I/R). Methods: Langendorff-perfused rabbit hearts were subjected to 30 min of complete perfusion arrest and reperfusion. Either EMPA (1 mu M) or normal saline (controls) was then infused into the perfusate in a randomized fashion. Ten minutes following drug infusion, calcium imaging was performed. At the end of each experiment, the heart was electrically stimulated 5 times to assess the inducibility of ventricular fibrillation (VF). In a separate series of experiments, left ventricular (LV) pressure and epicardial NADH fluorescence were simultaneously recorded. LV specimens were then collected for western blotting. Results: Post-ischemia, EMPA treatment was associated with reduction in the induction of VF >10s (rate of induction: 16.7 +/- 3.3% vs. 60 +/- 8.7% in control hearts, p = 0.003), improvement of LV developed pressure (LVDP; 68.10 +/- 9.02% vs. 47.61 +/- 5.15% in controls, p = 0.03) and reduction of NADH fluorescence (87.42 +/- 2.79% vs. 112.88 +/- 2.27% in control hearts, p = 0.04) along with an increase in NAD+/NADH ratio (2.75 +/- 0.55 vs. 1.09 +/- 0.32 in the control group, p = 0.04) A higher calcium amplitude alternans threshold was also observed with EMPA-treatment (5.42 +/- 0.1 Hz vs. 4.75 +/- 0.1 Hz in controls, p = 0.006). Sodium-glucose co-transporter-2 (SGLT2) expression was not detected in LV tissues. Conclusions: EMPA treatment reduced ventricular arrhythmia vulnerability and mitigated contractile dysfunction in the global I/R model while improving calcium cycling and mitochondrial redox by SGLT2-independent mechanisms.