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: The substance class of SGLT2 inhibitors has become an integral part in the pharmacotherapy of heart failure. The cardioprotective effects are pleiotropic and underlying mechanisms have been investigated, focusing mainly on the metabolic and structural levels. However, less is known about potential electrophysiological effects of SGTL2 inhibitors. Here, we aimed to augment our understanding of the molecular mechanisms, by which SGLT2 inhibitors could directly act on cardiomyocyte (CM) electrophysiology. Since there is an urgent need for improved treatment of atrial arrhythmias, we placed special emphasis on the atria and assessed the effects of dapagliflozin on the cellular electrophysiological level.
Purpose: To investigate acute electrophysiological effects of dapagliflozin and thereby assess a potential new role of SGLT2 inhibitors in the treatment of atrial arrhythmias.
Methods: A total of n = 36 patients undergoing open heart surgery were included in the study, after giving written informed consent. Atrial CM were isolated from fresh tissue samples, and subjected to patch clamp recordings of atrial action potentials (AP), inward sodium currents (INa) and outward potassium currents (IKur and Ito), before and upon acute administration of the SGLT2 inhibitor dapagliflozin. Human induced pluripotent stem cell (hiPSC)-derived CM (hiPSC-CM) were used to further characterize the effects of dapagliflozin on atrial and ventricular cells, using automated patch clamp (APC) and multi-electrode array (MEA) measurements.
Results: In human atrial CM, the AP inducibility (percentage of current pulses evoking an AP), the AP amplitude, and the upstroke velocity were reduced by acute dapagliflozin treatment in a concentration-dependent manner (1, 10, 100 µmol/L; n/N = 14–28/5–13). Hypothesizing that dapagliflozin affects the fast depolarisation of the AP, INa, IKur, and Ito currents were investigated in human atrial CM before and after administration of dapagliflozin (100 µmol/L; n/N = 5–17/4–9). Here, we found a significant decrease of the peak INa density by 53.6 ± 6.9 % (p < 0.0001), while IKur and Ito currents were not affected significantly. The inhibitory effects on the INa current and the AP formation could be reproduced in hiPSC-CM. Interestingly, the effects were clearly pronounced in atrial compared to ventricular cells. In single atrial hiPSC-CM, we compared the inhibitory effect of dapagliflozin on INa to the class I antiarrhythmic flecainide, and the IC50 values were 15.2 µmol/L and 3.0 µmol/L, respectively. In monolayers of atrial hiPSC-CM, acute dapagliflozin treatment led to a concentration-dependent decrease in the conduction velocity as well as the spontaneous beating frequency. Our experiments suggest a direct electrophysiological effect of dapagliflozin that replicates the action of a class I antiarrhythmic drug. Very interestingly, acute dapagliflozin effects seem to be atrial-predominant.
Conclusion: The SGLT2 inhibitor dapagliflozin resembles the action of a class I antiarrhythmic agent, and acutely lowers the excitability of atrial CM by inhibiting fast inward sodium currents. Our data suggest a potential new indication for dapagliflozin in the treatment of atrial arrhythmias. Additional opportunities in combining chronic and acute SGLT2 inhibitor treatment might arise from the knowledge about chronic pleiotropic and acute antiarrhythmic effects.