Dapagliflozin reduces ventricular arrhythmogenesis and improves epicardial fat remodeling in a rat model of cardiometabolic HFpEF, associated with SIRT1–HIF1α-related biomarker changes

Metabolic syndrome (MetS) and obesity contribute to cardiometabolic heart failure with preserved ejection fraction (HFpEF) and ventricular arrhythmia (VA), but the effects of sodium-glucose cotransporter-2 (SGLT2) inhibition on VA remain unclear. We investigated the antiarrhythmic effects of dapagliflozin in a rat model of cardiometabolic HFpEF. Male Wistar rats were assigned to wild-type control (WT), high-fat/high-glucose diet-induced MetS (MetS), or MetS with dapagliflozin treatment (MetS-dapa) groups. VA was induced by in vivo programmed electrical stimulation, and ventricular electrophysiology was assessed by optical mapping. Dapagliflozin reduced body weight, blood pressure, epicardial fat accumulation, VA inducibility, episode frequency, and duration compared with the MetS group. Electrophysiologically, dapagliflozin shortened action potential duration at 70% repolarization (APD 70 ), reduced the maximum slope of APD restitution, and improved conduction-direction heterogeneity without significantly altering mean conduction velocity. Dapagliflozin also reduced epicardial adipose deposition, plasma free fatty acids, interstitial fibrosis, and TNF-α levels, while increasing SOD activity and KCNN2 levels. Biomarker analysis showed a modest increase in SIRT1 and a slight decrease in HIF1α after dapagliflozin treatment. These findings suggest that dapagliflozin reduces ventricular arrhythmogenesis through epicardial fat remodeling, antifibrotic and anti-inflammatory effects, and electrophysiological stabilization, accompanied by modest SIRT1–HIF1α-related biomarker changes.