Synergistic anti-inflammatory effect: simvastatin and pioglitazone reduce inflammatory markers of plasma and epicardial adipose tissue of coronary patients with metabolic syndrome

Background: The inappropriate secretion of adipocytokines plays a critical role in chronic inflammatory states associated with obesity-linked type 2 diabetes and atherosclerosis. The pleiotropic actions of simvastatin and pioglitazone on epicardial adipose tissue (EAT) are unknown. This study assessed the anti-inflammatory actions of simvastatin and pioglitazone on EAT in patients with coronary artery disease (CAD) and metabolic syndrome (MS). Methods: A total of 73 patients with multivessel CAD who underwent elective bypass grafting were non-randomly allocated to one of four subgroups: Control (n = 17), simvastatin (20 mg/day, n = 20), pioglitazone (15 mg or 30 mg/day, n = 18), or simvastatin + pioglitazone (20 mg/day + 30 mg/day, respectively, n = 18); 20 valvar patients were also included. EAT samples were obtained during surgery. The infiltration of macrophages and lymphocytes and cytokines secretion were investigated using immunohistochemical staining and compared to plasma inflammatory biomarkers. Results: Simvastatin significantly reduced plasma interleukin-6, leptin, resistin and monocyte chemoattractant protein-1 (p < 0.001 for all); pioglitazone reduced interleukin-6, tumoral necrose factor-alpha, resistin and matrix metalloproteinase-9 (p < 0.001 for all). Simvastatin + pioglitazone treatment further reduced plasmatic variables, including interleukin-6, tumoral necrose factor-alpha, resistin, asymmetric dimethylarginine and metalloproteinase-9 vs. the control group (p < 0.001). Higher plasma adiponectin and lower high sensitivity C-reactive protein concentrations were found simultaneously in the combined treatment group. A positive correlation between the mean percentage systemic and tissue cytokines was observed after treatments. T-and B-lymphocytes and macrophages clusters were observed in the fat fragments of patients treated with simvastatin for the first time. Conclusions: Pioglitazone, simvastatin or combination treatment substantially reduced EAT and plasma inflammatory markers in CAD and MS patients. These tissue effects may contribute to the control of coronary atherosclerosis progression.