Background and Objective: Inhibitors of the sodium/glucose cotransporter-2 (SGLT2i) have recently surprised with additional clinical benefits beyond their anti-hyperglycemic effects. Several large randomized trials have consistently shown that SGLT2i exert beneficial effects on cardiovascular outcomes regardless of the presence or absence of diabetes. In addition, SGLT2i treatment has been shown to be associated with a significantly reduced risk of atrial arrhythmias and sudden cardiac death, raising the question of whether SGLT2i might have additional direct antiarrhythmic effects. Thus, the aim of this project was to employ a translational large animal model of atrial fibrillation (AF) to systematically investigate whether SGLTi affect atrial electrophysiologyand arrhythmogenesis.

Method: Persistent AF was induced in n = 10 German landrace pigs over 18 d by application of atrial burst stimulation via implanted pacemakers using a biofeedback algorithm. Dapagliflozin (3 mg /Kg) or solvent control was administered intravenously (i.v.) once per day. Electrophysiological studies and echocardiography were performed before and after the pharmacological treatment period. Finally, isolated atrial cardiomyocytes were subjected to patch-clamp measurements.

Results: The high dose dapagliflozin i.v. therapy was well tolerated, resulting in no significant differences between the solvent control and the treatment group in terms of weight gain, behavior, and standard blood tests. Echocardiography revealed that in the control group AF induction was associated with a trend towards an increase in right and left atrial diameters which was not present in animals with high dose dapagliflozin therapy. Under control conditions, 18 d of AF induction shortened atrial effective refractory periods (AERP_300ms) from 158.3 ± 6.0 ms to 80.0 ± 5.8 ms (p = 0.03). In the group with high dose dapagliflozin administration, this was successfully prevented and the AERP_300ms was 170.0 ± 11.8 ms. Daily surface ECG recordings revealed that the animals under dapagliflozin administration showed a markedly reduced AF burden. Sinus node functionality parameters were unchanged. At the ventricular level, a discrete but statistically significant shortening of QT time was observed under dapagliflozin therapy that was accompanied by a slight reduction in effective ventricular refractory periods (VERP_500ms). Patch-clamp experiments on isolated atrial cardiomyocytes could reproduce the antiarrhythmic effect of dapagliflozin on atrial electrophysiology. 

Conclusion: High dose dapagliflozin therapy exerts in vivo antiarrhythmic effects that can be employed for rhythm control of AF in a translational porcine large animal model.