Empagliflozin plus semaglutide at 10 nM synergistically reduced in situ expression and release of EAT-derived inflammatory mediators and inhibited pro-oxidant and pro-remodeling responses in AECs.
Does the combination of empagliflozin and semaglutide reduce pro-inflammatory and pro-oxidant responses induced by epicardial adipose tissue in atrial endothelial cells?
The combination of empagliflozin and semaglutide synergistically reduces the pro-inflammatory and pro-oxidant effects of epicardial adipose tissue on atrial endothelial cells, suggesting a potential strategy to mitigate atrial myopathy.
Abstract Background Epicardial adipose tissue (EAT) contributes to atrial myopathy and atrial fibrillation (AF) through adipokines release, endothelial dysfunction, atrial remodeling and fibrosis. Recently, it was shown that sodium-glucose co-transporter 2 inhibitors (SGLT2i) reduced AF incidence, EAT volume, and inflammation, while glucagon-like peptide-1 receptor agonists (GLP-1Ra) improved heart failure symptoms and reduced left atrial volume. Purpose This study assessed the expression of inflammatory markers, SGLT2 and GLP-1R in human EAT from AF and non-AF patients, examined the effect of EAT-derived mediators on atrial endothelial cells (AEC), and determined the effect of SGLT2i and GLP-1Ra. Methods EAT and subcutaneous AT (SAT) from 80 cardiac surgery patients were analyzed. Conditioned media (CM) from tissues were added to AECs for 24 h. Adipo-cytokines release, mRNA and protein expression levels, ROS and NO formation, platelet and monocyte adhesion and thrombin generation were determined. Results EAT showed M1 macrophage infiltration, and elevated markers of inflammation (IL-1β, IL-6, TNF-α), endothelial activation, fibrosis, thrombosis and oxidative stress, along with SGLT2 and GLP-1R compared to SAT. Oxidative stress in EAT was reduced by inhibitors of NADPH oxidases, NO synthase, AT1R, empagliflozin (SGLT2i), semaglutide (GLP-Ra), with strongest inhibition by a mixture of IL-1ß, IL-6 and TNF-aneutralizing antibodies and combination of empagliflozin plus semaglutide at low concentration (10 nM). In EAT, SGLT2 and GLP-1R were observed in adipocytes and infiltrated macrophages, while SGLT2 colocalized with microvascular endothelial cells. EAT-CM had higher levels of ICAM-1, VCAM-1, pro-inflammatory cytokines, and leptin and lower adiponectin than SAT-CM. Empagliflozin and semaglutide treatment of EAT reduced the release of pro-inflammatory mediators and increased that of adiponectin, with the strongest effect observed with their combination. Cytokines, leptin, SGLT2, GLP-1R, and ROS in EAT were elevated in AF patients compared to non-AF patients. Exposure of AECs to EAT-CM impaired NO formation, induced ROS, pro-thrombotic and pro-adhesive responses, NF-κB activation, and upregulated p53, TGF-β, and SGLT2. Empagliflozin and semaglutide inhibited these effects via the AT1R/NADPH oxidases/SGLT2 and GLP-1R/cAMP/PKA pathways, respectively in a synergistic manner. Conclusions EAT showed increased expression of pro-inflammatory mediators, SGLT2 and GLP-1R compared to SAT. This effect was more pronounced in AF patients. EAT-derived mediators promoted NO/ROS imbalance, pro-inflammatory, pro-adhesive, pro-thrombotic, and pro-fibrotic responses in AECs. Empagliflozin plus semaglutide synergically reduced in situ expression and release of EAT-derived inflammatory mediators. Thus, the combination of SGLT2i plus GLP-1Ra appears as an interesting strategy to reduce the deleterious impact of EAT on the atrium and, hence, atrial myopathy.
Fakih et al. (Sat,) conducted a other in Atrial fibrillation and non-AF in cardiac surgery patients (n=80). Empagliflozin and semaglutide vs. Subcutaneous adipose tissue (SAT) or untreated cells was evaluated on Adipo-cytokines release, mRNA and protein expression levels, ROS and NO formation, platelet and monocyte adhesion and thrombin generation. Empagliflozin plus semaglutide at 10 nM synergistically reduced in situ expression and release of EAT-derived inflammatory mediators and inhibited pro-oxidant and pro-remodeling responses in AECs.