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INTERVENTIONAL CARDIOLOGY

Cilostazol inhibits leukocyte integrin Mac-1, leading to a potential reduction in restenosis after coronary stent implantation

Teruo Inoue, MD, FACC^*,,*, Toshihiko Uchida, MD, Masashi Sakuma, MD, Yoshitaka Imoto, Yasushi Ozeki, PhD, Yukio Ozaki, MD, Yutaka Hikichi, MD^* and Koichi Node, MD^*

^* Department of Cardiovascular and Renal Medicine, Saga University Faculty of Medicine, Saga, Japan
Department of Cardiology, Koshigaya Hospital, Dokkyo University School of Medicine, Koshigaya, Japan
Yufu Itonaga Company, Tokyo, Japan
Department of Laboratory Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Tamaho, Japan

Manuscript received May 12, 2004; revised manuscript received June 23, 2004, accepted June 29, 2004.

^* Reprint requests and correspondence: Dr. Teruo Inoue, Department of Cardiovascular and Renal Medicine, Saga University Faculty of Medicine, 5-1-1 Nabeshima, Saga 849-8501, Japan (Email: inouete{at}med.saga-uc.ac.jp).

OBJECTIVES: The aim of this study was to confirm clinically a hypothesis that cilostazol inhibits leukocyte Mac-1, leading to prevention of post-stent restenosis.

BACKGROUND: The platelet phosphodiesterase III inhibitor called cilostazol also inhibits alpha-granule release of P-selectin in platelets. The P-selectin–mediated platelet-leukocyte interaction promotes activation and upregulation of leukocyte Mac-1 after coronary stenting, which plays a key role on the mechanism of restenosis. Thus, cilostazol's potential inhibition of this process may lead to prevention of restenosis.

METHODS: Using flow cytometric analysis of whole blood obtained from the coronary sinus, the expression of platelet membrane glycoproteins and neutrophil adhesion molecules was observed in 70 consecutive patients undergoing coronary stenting. The patients were randomly assigned to either a cilostazol or ticlopidine group before stent placement.

RESULTS: The restenosis rate was lower (15% vs. 31%, p < 0.05) in the cilostazol group (n = 34) than in the ticlopidine group (n = 32). A stent-induced increase in platelet P-selectin (CD62P) expression and an increase in neutrophil Mac-1 (CD11b) expression were suppressed in the cilostazol group compared with the ticlopidine group. Angiographic late lumen loss was correlated with the relative changes in platelet P-selectin and neutrophil Mac-1 at 48 h after coronary stenting.

CONCLUSIONS: Cilostazol may have effects on suppression of P-selectin–mediated platelet activation, platelet-leukocyte interaction, and subsequent Mac-1–mediated leukocyte activation, which might lead to a reduced restenosis rate after coronary stent implantation.

Abbreviations and Acronyms   cAMP = cyclic adenosine monophosphate   CREST = Cilostazol for REStenosis Trial   DMSO = dimethyl sulfoxide   FITC = fluorescein isothiocyanate   FMLP = formyl-methyonyl leucyl phenylalanine   MFI = mean channel fluorescence intensity   PBS = phosphate-buffered saline   PCI = percutaneous coronary intervention   PDE = phosphodiesterase   PSGL = P-selectin glycoprotein ligand

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