Immune-epicardial adiposity, associated with coronary artery disease, is modulated by semaglutide

Background

The interplay between epicardial adipogenesis and immune cell infiltration promotes the transition from metabolically active adipose tissue to inflamed epicardial adipose tissue (1) (EAT), increasing mortality risk in patients with coronary artery disease (CAD) (2). However, the mechanisms underlying immune–adiposity remodelling in EAT, and the ability of semaglutide to regulate this process remain unknown.

Purpose

To investigate immune–adiposity remodelling in epicardial fat, its association with CAD, and its modulation by semaglutide.

Methods

EAT biopsies were collected from patients undergoing cardiac surgery (n=199), after written informed consent. Adiposity- and neutrophil-associated markers were quantified by RT-qPCR. Stromal cells isolated from EAT (EAT-ST, n=10) were differentiated into preadipocytes for 15 days using an adipogenic cocktail in the presence or absence of semaglutide (1 nM). Neutrophil-like dHL60 cell adhesion to adipogenized stromal cells was assessed by RT-qPCR. The paracrine effects of conditioned media from non-adipogenised (IDMTb) or adipogenised (IDMTad) EAT stromal cells treated with or without semaglutide (n=8) were evaluated in human coronary artery endothelial cells (HCAECs) using a real-time wound healing assay.

Results

Consistent with previous cardiac CT findings, EAT from CAD patients exhibited reduced expression of lipid transport proteins FABP4 (p = 0.019) and CD36 (p < 0.001), alongside increased neutrophil-related markers CD16 (p = 0.018), DEFA3 (p = 0.028), and CXCR2 (p = 0.039), despite similar BMI. An inverse association between adiposity- and neutrophil-related markers (r = −0.29, p < 0.001) suggests a remodelling transition from a metabolic to an inflamed phenotype.

These findings were validated in a preclinical model, where enhanced epicardial adipogenesis was associated with increased neutrophil attachment, demonstrated by a strong correlation between the neutrophil marker CD11b and the adiposity marker FABP4 (r = 0.63, p = 0.003), as well as elevated expression of CD11b (p = 0.012) and S100A9 (p = 0.020). Semaglutide significantly attenuated neutrophil attachment to adipogenised epicardial stromal cells (p = 0.024) and improved coronary re-endothelialisation (p = 0.018).

Conclusion

Epicardial fat from CAD patients exhibits a low-adiposity, highly inflamed transcriptional profile. Semaglutide modulates immune–adiposity remodeling by reducing neutrophil attachment to epicardial adipogenized cells, with beneficial effects on coronary endothelial repair.