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CD40 ligand (CD40L), a transmembrane glycoprotein belonging to the tumor necrosis factor family and expressed by a variety of cells, is involved in the basic mechanisms of inflammation, atherosclerosis and thrombosis. Some studies suggest that the soluble form of CD40L (sCD40L) is a predictor of major cardiovascular events and mortality in a variety of clinical settings, but data from literature are conflicting. We studied consecutive patients with acute (ACS) or chronic (CCS) coronary syndrome who underwent percutaneous coronary artery intervention (PCI). Blood samples for sCD40L dosage were taken at baseline immediately before PCI. We tested the relation between sCD40L and pre-specified outcome measures consisting of new ACS, clinical restenosis and all-cause mortality. We recruited 3,841 patients (mean age 64 ± 11 years, 79% men) with ACS (n=2,383) or CCS (n=1,458). During a mean follow-up of two years (±0.6 years), 642 patients developed ACS, 409 developed restenosis (≥70% of at least one of the previously treated coronary segments) and 175 died. For each 1-standard deviation increase in sCD40L (0.80 ng/mL), the hazard ratios (HRs) for ACS, restenosis, and mortality were 1.11 (95% confidence interval [CI]: 1.05 to 1.18, p<0.0001), 1.10 (95% CI: 1.02 to 1.19, p=0.010), and 1.00 (95% CI: 0.86 to 1.16, p=0.983), respectively. In multivariable Cox regression models with adjustment for several potential confounders including age, acute or chronic coronary syndrome, multi-vessel disease, stent placement, diabetes, previous coronary events and dyslipidemia, sCD40L remained an independent predictor of ACS and coronary restenosis. There were no interactions between sCD40L and acute or chronic coronary syndrome or stent placement. Among patients with ACS or CCS who undergo PCI, higher levels of sCD40L predict an increased risk of acute coronary events and coronary restenosis, but not of mortality. [ABSTRACT FROM AUTHOR]