BS52 Exploring the direct impact of sodium-glucose cotransporter 2 inhibitors on cardiac electrophysiology: insights from cellular models and murine hearts

Background Sodium-glucose cotransporter 2 (SGLT2) inhibitors, an effective treatment for diabetes, have recently shown significant cardiac protective properties including a potential reduction in arrhythmias. The direct effects of SGLT2 inhibitors on cardiac electrophysiology remain unclear. Understanding the impact of SGLT2 inhibitors could offer invaluable insights for patients at risk of arrhythmias. Methods Whole cell patch clamping was performed on human embryonic kidney (HEK) cells expressing Nav1.5. Cells were incubated with SGLT2 inhibitor dapagliflozin (0.1 to 10µM) for four hours, or with Dimethylsulfoxide (DMSO) as a control. Following incubation, the cardiac voltage-gated sodium current (INa) was measured. To assess effects of SGLT2 inhibitors on the whole heart electrophysiology, optical mapping was performed in the intact mouse heart loaded with potentiometric dye Di-4-ANEPPS. Hearts were recorded at baseline and following treatment with 10µM dapagliflozin, and data analysed using ElectroMap. Results When measured from a holding potential of -100 mV Dapagliflozin increased peak sodium current density. Dapagliflozin led to a more negative V50,act, compared to control (See table 1). Neither concentration of Dapagliflozin altered reversal potential (See table 1). Dapagliflozin also delayed peak INa time dependent recovery (See table 1). At a holding potential of -120 mV, Dapagliflozin increased peak INa when compared to control (-205.9± 34.68pA/pF, -208.7± 38.80 pA/pF, -235.4± 34.54 pA/pF, and -125.9 ± 19.02 pA/pF for 10uM, 1uM, 0.1uM Dapagliflozin and DMSO group respectively, p<0.05, figure 2B). However, Dapagliflozin had no effects at more physiologically relevant holding potential of -90 to-60 mV (See figure 2). Ongoing experiments are examining the effects of Dapagliflozin on INa in cardiomyocytes derived from induced pluripotent stem cells, and epicardial action potentials in the hearts of healthy mice using cardiac optical mapping. Conclusion Our findings indicate that whilst Dapagliflozin does alter biophysical properties of fast voltage gated sodium channels, these are unlikely to alter the depolarisation and conduction in a healthy myocardium, at physiological resting membrane potentials. Conflict of Interest No