1Universitätsklinikum Heidelberg Klinik für Innere Med. III, Kardiologie, Angiologie u. Pneumologie Heidelberg, Deutschland
Background and Objective: Atrial arrhythmias, especially atrial fibrillation (AF), affect a large number of patients worldwide, and therefore represent a particularly relevant disease for which new specific treatment options are urgently needed. Inhibitors of the sodium-glucose linked transporter 2 (SGLT2i), initially used as an antidiabetic drug, have demonstrated effects extending beyond anti-hyperglycemic properties. While SGLT2i have become an indispensable part of heart failure therapy, some studies point towards additional benefits for rhythm control in AF. To gain further insight into how the SGLT2i dapagliflozin affects atrial electrophysiology translational large animal models of acute AF episodes and persistent AF were utilized.
Methods: Following ablation of the atrioventricular node, pacemakers were implanted in n = 12 German Landrace pigs to induce persistent AF over a period of 3 weeks. AF induction was accomplished by atrial burst pacing using a biofeedback algorithm. Half of the pigs received elevated-dose dapagliflozin treatment (3 mg/kg body weight) once daily via a central venous catheter, the other half received the same amount of the respective solvent. Electrophysiological studies, a 12-lead ECG and echocardiography were performed before and after the 3 week experimental phase. Moreover, acute AF episodes were induced in n = 4 additional pigs via right atrial burst stimulation and time to cardioversion was monitored after administration of dapagliflozin 3 mg/kg body weight or the respective solvent.
Results: Under intermittent atrial burst stimulation, the pigs developed persistent AF which was endogenously propagated. Over the course of the 3 weeks, the left atrial diameter showed a significant increase in the control-treated AF pigs that was not observed in the SGLT2i group. Electrophysiological studies revealed that the induction of AF shortened the atrial effective refractory periods (AERP500) from 179.2 ± 6.1 ms to 85.0 ± 10.8 ms (p = 0.0003) and that this could be prevented by the administration of SGLT2i: In the dapagliflozin treatment group, the AERP500 was 190.8 ± 14.1 ms. Further, a slight decrease in ventricular effective refractory periods (VERP500) was observed in the SGLT2i group. Importantly, sinus node recovery times (SNRT) remained unchanged in both groups, suggesting that no side effects on sinus node function are to be expected. Animals administered SGLT2i showed a tendency towards reduced AF burden with fewer prolonged episodes. Upon acute intraoperative administration of SGLT2i, spontaneous cardioversion to sinus rhythm within the first 10 minutes after application was observed.
Conclusion: Elevated-dose treatment with the SGLT2i dapagliflozin displays antiarrhythmic effects that can be employed for both, acute or long-term rhythm management of atrial fibrillation in a translational porcine large animal model.