e0478 Pioglitazone attenuates proinflammatory state in nondiabetic patients after coronary drugeluting stent implantation

Objectives The inflammatory response after DES placement has recently emerged as a major concern. We investigated the proinflammatory state on circulating peripheral blood mononuclear cells (MNC) after coronary polymer-based drug-eluting stent (DES) implantation in nondiabetic patients, and the benefit of pioglitazone (PIO), a peroxisome proliferator-activated receptor-g (PPAR-g) activator. Methods Twenty-eight non-diabetic patients with acute coronary syndrome were randomly assigned to pioglitazone (n=14) or placebo (n=14) treatment. From the day after DES implantation, study medication (30 mg/d) for 12 weeks was given in addition to the optimal standard drug treatment, the proinflammatory state on MNC was measured at baseline and after 12 weeks. Results PIO treatment statistically decreased plasma concentrations of interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), migration inhibitor factor (MIF), and matrix metalloproteinase-9 (MMP-9) compared with placebo (p=0.011, 0.008, 0.002 and 0.012, respectively), but standard therapy failed to restrain these factors. The mRNA expressions of IL-6, TNF-α, MIF and MMP-9 in circulating MNC decreased significantly in the PIO group (p=0.031, 0.012, 0.007 and 0.022, respectively). Interestingly, PIO prevented the loss of PPAR-γ expression in MNC after DES implantation (p=0.039). In addition, treatment with PIO enhanced the cytoplasmic IκB-β expression (p=0.003) and decreased the expression of the NF-kB p50 subunit and IκB-α (p=0.001 and 0.029, respectively). Concurrently, the NF-kB DNA binding activity in MNC was significantly inhibited by PIO treatment (p=0.004). Conclusion The inflammatory responses did not reverse after implantation of DES despite standard drug therapy, whereas PIO treatment attenuated the proinflammatory state in circulating MNC. Our results suggest that PIO treatment sequentially acts through PPAR-g activation, IkB-β induction, blockade of NF-kB activation, and inhibition of inflammatory cytokine expression. These findings demonstrate that PIO may have a novel direct protective role to modulate the local and circulating proinflammatory responses after coronary DES implantation.