https://doi.org/10.1007/s00392-025-02625-4
1Universitätsklinikum Heidelberg Klinik für Innere Med. III, Kardiologie, Angiologie u. Pneumologie Heidelberg, Deutschland; 2Universitätsmedizin Göttingen Institut für Pharmakologie und Toxikologie Göttingen, Deutschland; 3Universitätsklinikum Heidelberg Klinik für Herzchirurgie Heidelberg, Deutschland
Background:
Sodium-glucose cotransporter 2 inhibitors (SGLT2i), initially introduced as antihyperglycemic agents, have recently gained significant relevance in treating heart failure. Despite minimal cardiac expression of SGLT2, these agents exhibit cardioprotective effects through mechanisms affecting cardiomyocyte metabolism, calcium homeostasis, inflammation, and fibroblast activity. Emerging evidence suggests that SGLT2i may also reduce the incidence of cardiac arrhythmias, such as atrial fibrillation (AF). It remains unclear whether these antiarrhythmic effects result solely from improvements in underlying heart conditions or if SGLT2i directly impact cardiac ion channels.
Sodium-glucose cotransporter 2 inhibitors (SGLT2i), initially introduced as antihyperglycemic agents, have recently gained significant relevance in treating heart failure. Despite minimal cardiac expression of SGLT2, these agents exhibit cardioprotective effects through mechanisms affecting cardiomyocyte metabolism, calcium homeostasis, inflammation, and fibroblast activity. Emerging evidence suggests that SGLT2i may also reduce the incidence of cardiac arrhythmias, such as atrial fibrillation (AF). It remains unclear whether these antiarrhythmic effects result solely from improvements in underlying heart conditions or if SGLT2i directly impact cardiac ion channels.
Objectives:
To investigate the potential antiarrhythmic effects of SGLT2i, from molecular pharmacology to cellular electrophysiology in cardiomyocytes, and up to effects observed in a large animal model.
To investigate the potential antiarrhythmic effects of SGLT2i, from molecular pharmacology to cellular electrophysiology in cardiomyocytes, and up to effects observed in a large animal model.
Methods:
Native atrial cardiomyocytes were isolated from pig and human hearts to record action potentials using the patch-clamp technique before and after dapagliflozin application. Two-dimensional cultures of atrial- and ventricular-differentiated human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were analyzed using multielectrode arrays. Action potentials and sodium current densities were measured in isolated human atrial cardiomyocytes, and automated patch-clamp studies were conducted on CHO cells transiently transfected with NaV1.5 channels, including alanine pore mutants. In vivo studies involved sedated pigs receiving intravenous dapagliflozin and a burst pacing-induced AF pig model treated with dapagliflozin or placebo over 21 days.
Native atrial cardiomyocytes were isolated from pig and human hearts to record action potentials using the patch-clamp technique before and after dapagliflozin application. Two-dimensional cultures of atrial- and ventricular-differentiated human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were analyzed using multielectrode arrays. Action potentials and sodium current densities were measured in isolated human atrial cardiomyocytes, and automated patch-clamp studies were conducted on CHO cells transiently transfected with NaV1.5 channels, including alanine pore mutants. In vivo studies involved sedated pigs receiving intravenous dapagliflozin and a burst pacing-induced AF pig model treated with dapagliflozin or placebo over 21 days.
Results:
Dapagliflozin significantly reduced the excitability and altered the morphology of action potentials in pig and human atrial cardiomyocytes, evidenced by decreased action potential amplitude and upstroke velocity. These effects were replicated in hiPSC-CMs, with a more pronounced impact on atrial-differentiated cells. Dapagliflozin inhibited peak sodium currents in human atrial cardiomyocytes and demonstrated concentration-dependent inhibition of NaV1.5 channels in transfected CHO cells. The half-maximal inhibitory concentration (IC₅₀) for dapagliflozin was only fivefold higher than that of the classical sodium channel blocker flecainide. Site-directed mutagenesis identified phenylalanine 1760 as crucial for dapagliflozin binding near the channel pore. Dapagliflozin reduced spontaneous beating frequency and conduction velocity in hiPSC-CM cultures, effects that were more pronounced in atrial cells. In sedated pigs, high-dose dapagliflozin reduced cardiac conduction velocity, particularly in the atria, and effectively cardioverted AF episodes induced by atrial burst stimulation. In the persistent AF pig model, 21-day dapagliflozin treatment prevented left atrial enlargement, prolonged atrial effective refractory periods, reduced atrial frequencies, and significantly decreased AF burden compared to controls.
Dapagliflozin significantly reduced the excitability and altered the morphology of action potentials in pig and human atrial cardiomyocytes, evidenced by decreased action potential amplitude and upstroke velocity. These effects were replicated in hiPSC-CMs, with a more pronounced impact on atrial-differentiated cells. Dapagliflozin inhibited peak sodium currents in human atrial cardiomyocytes and demonstrated concentration-dependent inhibition of NaV1.5 channels in transfected CHO cells. The half-maximal inhibitory concentration (IC₅₀) for dapagliflozin was only fivefold higher than that of the classical sodium channel blocker flecainide. Site-directed mutagenesis identified phenylalanine 1760 as crucial for dapagliflozin binding near the channel pore. Dapagliflozin reduced spontaneous beating frequency and conduction velocity in hiPSC-CM cultures, effects that were more pronounced in atrial cells. In sedated pigs, high-dose dapagliflozin reduced cardiac conduction velocity, particularly in the atria, and effectively cardioverted AF episodes induced by atrial burst stimulation. In the persistent AF pig model, 21-day dapagliflozin treatment prevented left atrial enlargement, prolonged atrial effective refractory periods, reduced atrial frequencies, and significantly decreased AF burden compared to controls.
Conclusions:
Dapagliflozin exhibits direct antiarrhythmic effects by inhibiting cardiac NaV1.5 sodium channels, leading to reduced sodium currents and altered electrophysiological properties of atrial cardiomyocytes. These findings suggest that beyond metabolic and general cardioprotective effects, SGLT2i like dapagliflozin may offer therapeutic benefits in rhythm control of AF. Further studies are necessary to fully elucidate the mechanisms underlying these antiarrhythmic effects.
Dapagliflozin exhibits direct antiarrhythmic effects by inhibiting cardiac NaV1.5 sodium channels, leading to reduced sodium currents and altered electrophysiological properties of atrial cardiomyocytes. These findings suggest that beyond metabolic and general cardioprotective effects, SGLT2i like dapagliflozin may offer therapeutic benefits in rhythm control of AF. Further studies are necessary to fully elucidate the mechanisms underlying these antiarrhythmic effects.