Epicardial adipose tissue (EAT) is implicated in left atrial dysfunction via paracrine mechanisms, promoting endothelial dysfunction, pro-arrhythmogenic effects, and tissue remodeling, all of which favor the onset of atrial fibrillation (AF). Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have recently been shown to reduce AF incidence, EAT volume, and inflammation, but the underlying mechanisms remain unclear.

This study explores the effects of human EAT-derived mediators on atrial endothelial cell (AEC) function and evaluates the role of SGLT2 inhibition using empagliflozin (EMPA).

EAT and subcutaneous adipose tissue (SAT) samples were obtained from 70 cardiac patients at Strasbourg University Hospital. Conditioned media (CM) from these tissues were applied to AECs (24h). Tissue histology was assessed using hematoxylin and eosin staining, while protein and mRNA expression, reactive oxygen species (ROS), nitric oxide (NO) production, and pro-inflammatory cytokines levels were analyzed through Western blot, RT-qPCR, fluorescence probes, and ELISA, respectively.

Compared to SAT, EAT exhibited greater vascularization, increased infiltration of M1-like macrophages, and higher expression of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), endothelial cell markers (VCAM-1, eNOS), pro-fibrotic proteins (TGF-β), and pro-oxidant factors (NADPH oxidases NOX-1 and SGLT1/2). These changes correlated with elevated oxidative stress, mitigated by inhibitors targeting NOS, NADPH oxidases, ACE, AT1R, or SGLT2. Notably, SGLT2 and ROS levels in EAT were elevated in AF patients and increased with age. On the other hand, EAT-CM contained significantly higher concentrations of pro-inflammatory cytokines compared to SAT-CM. Exposure of AECs to highly inflamed EAT-CM (top quartile) induced oxidative stress, impaired NO production, upregulated p53 and SGLT2 expression, and triggered NF-κB nuclear translocation, whereas CM from less inflamed EAT didn’t induce these effects. EMPA prevented these effects.

In conclusion, EAT exhibits higher in situ expression and release of pro-inflammatory cytokines than SAT, contributing to oxidative stress via the AT1R/NADPH oxidases/SGLT2 pathway. Inflamed EAT-CM induces AEC dysfunction and activates NF-κB through cytokine-mediated oxidative stress and SGLT2 signaling. SGLT2 inhibitors may represent a promising strategy to reduce EAT inflammation and prevent cardiac remodeling and fibrosis.