Background: The positive results of several cardiovascular endpoint studies have helped the substance class of sodium-glucose cotransporter 2 (SGLT2) inhibitors (SGLT2i) to rapidly enter the pharmacotherapy of heart failure (HF) patients. Therefore, SGLT2i are already routinely used in HF patients. Since this patient group has a high prevalence of atrial fibrillation (AF), the question of antiarrhythmic effects of SGLT2i is frequently debated. Interestingly, therapy with SGLT2i in patients with type 2 diabetes mellitus was indeed associated with a significantly reduced risk of atrial arrhythmias and sudden cardiac death. The underlying molecular mode of action remains, however, unclear.

Purpose: Investigating the antiarrhythmic potential of SGLT2i on a molecular and cellular level by characterizing direct electrophysiological effects of SGLT2i on human atrial ion channels and action potential (AP) parameters.

Methods: Effects of dapa-, empa-, cana- and ertugliflozin on atrial ion channels, heterologously expressed in Xenopus laevis oocytes and CHO cells were assessed using the two-electrode voltage-clamp and the patch-clamp method. APs were recorded from isolated human and porcine atrial cardiomyocytes (CM) obtained from patients and pigs with either sinus rhythm (SR) or AF using the patch-clamp technique.

Results: A comprehensive screening of SGLT2i effects on human atrial ion currents in Xenopus laevis oocytes revealed strong inhibition of the voltage-gated sodium channel Na_V1.5 by SGLT2i. In CHO cells, heterologously expressing human Na_V1.5 channel subunits, dapagliflozin (100 µM) decreased peak sodium currents by 74.3 % with an IC₅₀ value of 1.7 µM. Dapagliflozin (100 µM) further suppressed AP formation in isolated human and porcine left and right atrial CM. It significantly reduced action potential amplitude (APA), AP upstroke velocity, APD₅₀ and APD₉₀. APA was reduced by 38.4 % and APA inhibition was significantly pronounced in atrial CM obtained from patients and pigs with AF as compared to SR controls.

Conclusion: Dapagliflozin exhibits class I antiarrhythmic effects which suppress AP formation in isolated human and porcine atrial CM.