SGLT2 inhibitor empagliflozin remodels pericardial fat–derived lipids-initiated ventricular ion-channel function to reduce arrhythmogenic electrical remodeling in diabetic hearts

Background Type 2 diabetes mellitus (T2DM) promotes cardiac structural and electrical remodeling, partly through pro-inflammatory and lipotoxic factors released from pericardial fat. However, the specific lipid mediators linking pericardial adipose tissue to ventricular arrhythmogenic remodeling, and how sodium–glucose cotransporter-2 inhibitors (SGLT2i) interrupt this axis, remain unclear. Methods Male db/db and control mice were treated with or without empagliflozin. Surface ECG and optical mapping were used to assess ventricular repolarization and altered action potential duration. Histology and immunohistochemistry evaluated fibrosis, antioxidant and mitochondrial proteins, and gap-junction connexins. Primary isolated cardiomyocytes were subjected to ROS and Ca2+ imaging, patch-clamp recordings, and ion-channel gene expression analysis. Lipidomics of pericardial fat identified candidate lipids, which were functionally tested in cardiomyocytes. Results Our results have shown that empagliflozin normalized diabetes-induced prolongation and dispersion of ventricular APD and improved spatial repolarization homogeneity. It reduced ventricular fibrosis and corrected aberrant Cx40 up-regulation and heterogeneous Cx43 distribution. Antioxidant (SOD1) and mitochondrial regulatory proteins (MFN2, SIRT1) were restored in diabetic myocardium. In isolated cardiomyocytes, empagliflozin decreased intracellular ROS and Ca2+ overload, and reversed diabetes-related remodeling of Ca2+ and K+ currents and their transcripts. Lipidomic profiling showed extensive pericardial fat lipidome remodeling in db/db mice that was partially normalized by empagliflozin treatment. Among dysregulated species, a bile acid metabolites 6-oxolithocholic acid (6-oxoLCA) reproduced pericardial-fat–like cardiotoxicity by inducing ROS, Ca2+ overload, K+ current suppression, and ion-channel gene modification, which were also mitigated by empagliflozin. Conclusion It showed that empagliflozin protects diabetic hearts by reprogramming pericardial fat lipids and attenuating 6-oxoLCA-driven oxidative, mitochondrial, and electrophysiological remodeling. Targeting pericardial-fat–derived lipids may represent a novel strategy to prevent arrhythmias in diabetic cardiomyopathy.