Complex antiarrhythmic effects of empagliflozin in non-ischemic HFrEF cardiomyocytes
- 1Department of Pharmacology, University of California
Abstract
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.
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BibTeX
@article{hegyi2026complex,
title = {{Complex antiarrhythmic effects of empagliflozin in non-ischemic HFrEF cardiomyocytes}},
author = {Bence Hegyi and Donald M. Bers},
journal = {Frontiers in Pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1955044},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1955044/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Complex antiarrhythmic effects of empagliflozin in non-ischemic HFrEF cardiomyocytes
AU - Bence Hegyi
AU - Donald M. Bers
PY - 2026
DA - 2026/10/20
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1955044
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1955044/full
AB - 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.
SN - 1663-9812
ER -