Gliflozin therapy attenuates persistent systemic inflammation and monocyte metabolic dysfunction post-ACS: a comparative study across the CAD spectrum
A Mroueh, W Fakih, A Trimaille, A Granier, D S Gong, M Choi, A Nicolas, C Aboueddahab, G Ndiaye, A Carmona, L Jesel, V Schini-Kerth, O MorelAbstract
Background
Chronic inflammation and cellular metabolic stress often persist following an acute coronary syndrome (ACS) event despite guideline-therapy. SGLT2 inhibitors (gliflozins) exhibit potent cardio-protection, but their ability to modulate long-term systemic inflammation and monocyte function post-ACS is poorly defined. This work investigated systemic inflammatory markers and monocyte metabolic activity across coronary artery disease (CAD) spectrum and evaluated the long-term anti-inflammatory effect of gliflozin therapy post-ACS event.
Methods
Blood samples from healthy subjects (H; n=20), individuals with cardiovascular risk factors without coronary lesion (CVD, n=20), stable CAD and no history of ACS event (CAD, n=60), acute STEMI (n=30), 3-6 months post-STEMI (ACS, n=35), and 3-6 months post- STEMI treated with gliflozin for > 4 weeks due to other clinical indication (n=25) were collected. Plasma IL-6, TNF-α, MCP-1, ICAM-1, and VCAM-1 along with monocyte oxidative stress, glucose uptake and adhesion activity were assessed. Primary comparisons evaluated inflammatory progression from healthy to acute STEMI, post-ACS recovery and the impact of gliflozin therapy. Patient groups were comparable in age, sex distribution, BMI, smoking and cardiovascular risk profile, whereas healthy subjects differed.
Results
Across the CAD spectrum, a stepwise increase in systemic IL-6, TNF-α, MCP-1, ICAM-1, and VCAM-1 were observed, reaching peak levels during acute STEMI. In parallel, PBMCs metabolic activity increased progressively, with oxidative stress reaching 3.1-fold, glucose uptake reaching 2.9-fold and adhesion to endothelial cells reaching 4.7-fold increase in STEMI, compared to their activity in healthy state. At 3-6 months post-STEMI, TNF-α (13.5 ± 1.3 vs 8.5 ± 1.2 pg/mL) and ICAM-1 (397.3 ± 19.8 vs 241.1 ± 11.4 ng/mL) remained elevated compared to stable CAD patients with no history of ACS. Consistently, monocytes oxidative stress, glucose uptake and adhesion capacity remained significantly higher by 16.3%, 12.7% and 28.1% than in stable CAD. In patients treated with gliflozin, TNF-α (7.7 ± 0.9 pg/mL) and ICAM-1 (243.6 ± 15.6 ng/mL) were significantly decreased to levels no longer different from stable CAD, accompanied by a reduction in PBMC oxidative stress, glucose uptake and adhesion to endothelial cells by 20.6%, 20.8% and 53.7% respectively, restoring metabolic activity to levels comparable to stable CAD.
Conclusion
Inflammatory and endothelial activation markers increase progressively across the CAD spectrum and peak during acute STEMI. While most markers decline after the acute phase, TNF-α, ICAM-1 and monocyte metabolic activation remain persistently elevated months post-ACS. On the other hand, gliflozin therapy significantly attenuates persistent inflammation and monocyte oxidative/metabolic activation, restoring values to those observed prior to ACS.