Lack of association between soluble CD40L and risk in a large cohort of patients with acute coronary syndrome in OPUS TIMI-16

Background Previous studies have suggested that elevated soluble CD40 ligand (sCD40L) levels predict adverse cardiovascular outcomes in patients with acute coronary syndromes (ACS). Recently, questions have been raised regarding the influence of pre-analytical and analytical conditions on measurement of sCD40L, and additional studies have had conflicting findings regarding the prognostic value of this marker. Methods and Results We measured levels of sCD40L in citrated plasma using an analytically validated automated immunoassay (Roche Diagnostics) in a large cohort of ACS patients (n = 2403) from the placebo arm of the OPUS TIMI-16 trial. No association was observed between elevated sCD40L levels and risk of death or myocardial infarction (MI) (Quartile 1, 8.0%; Quartile 2, 11.7%; Quartile 3, 8.2%; Quartile 4, 6.8%; P = 0.54) or risk of death, MI or heart failure at 10 months (Quartile 1, 9.9%; Quartile 2, 14.2%; Quartile 3, 10.9%; Quartile 4, 8.3%; P = 0.55). A comparison of plasma vs. serum measurements of sCD40L was performed on samples from a nested case-control analysis (n = 42) from within this cohort. Median sCD40L levels did not differ between cases and controls using plasma (0.23 ng/ml vs. 0.27 ng/ml, respectively; P = 0.82) or serum samples (0.64 vs. 0.77, respectively; P = 0.85). Serum samples consistently yielded elevated sCD40L measurements compared to plasma samples (median value 0.72 ng/ml vs. 0.25 ng/ml, respectively, P < 0.001). Conclusions The absence of an association between sCD40L and cardiovascular outcomes in a large cohort of patients with ACS raises concern regarding the reproducibility of clinical results with this novel biomarker. Despite a plausibly important role in the pathobiology of atherothrombosis, pre-analytic sources of variability may limit the practical clinical application of sCD40L.