Frontiers in Pharmacology · Oct 20, 2026

Complex antiarrhythmic effects of empagliflozin in non-ischemic HFrEF cardiomyocytes

By Hegyi B, Bers DM

Introduction: Sodium-glucose cotransporter-2 (SGLT2) inhibitors improve clinical outcomes in heart failure with reduced ejection fraction (HFrEF) and may reduce sudden cardiac death; however, the underlying antiarrhythmic mechanisms remain incompletely understood. Methods: We investigated the cellular electrophysiological effects of the SGLT2 inhibitor empagliflozin in isolated cardiomyocytes from two non-ischemic, non-diabetic HFrEF models (rabbit and mouse). Results: Ventricular cardiomyocytes from both HFrEF models exhibited prolonged action potential duration (APD), increased short-term APD variability (STV), and greater susceptibility to APD alternans and delayed afterdepolarizations (DADs). Intracellular Ca2+ buffering with EGTA prevented DADs, attenuated APD prolongation, and reduced repolarization instability. HFrEF cardiomyocytes also showed enhanced late Na+ current (INa,L) and reduced inward rectifier K+ current (IK1). Cell pretreatment with empagliflozin (1 μmol/L, 3 h), but not acute application (3 min), attenuated proarrhythmogenic AP changes, reduced INa,L, and increased IK1 in both species. Empagliflozin had no significant electrophysiological effects in healthy control cardiomyocytes. Selective inhibition of Na+/H+ exchanger-1 (NHE-1) with cariporide (1 μmol/L, 3 h) failed to reproduce the antiarrhythmic effects of empagliflozin under our experimental conditions; however, our studies were performed with intracellular pH buffered to 7.2, where NHE-1 activity is low. Discussion: These results demonstrate that empagliflozin attenuates key proarrhythmic electrophysiological changes in non-ischemic HFrEF cardiomyocytes. The requirement for drug pretreatment supports the hypothesis that empagliflozin acts through modulation of ion channel functional expression and/or post-translational regulation rather than direct acute channel effects in non-ischemic HFrEF cardiomyocytes.

doi.org/10.3389/fphar.2026.1955044 Open access PubMed 42978803 Interventions