Relationship of soluble CD40 ligand to vascular endothelial growth factor, angiopoietins, and tissue factor in atrial fibrillation: a link among platelet activation, angiogenesis, and thrombosis?

BACKGROUND: The precise pathophysiologic processes underlying the prothrombotic or hypercoagulable state in patients with atrial fibrillation (AF) remain uncertain. We hypothesized a relationship among abnormal platelet activation, angiogenic factors, and coagulation, thereby contributing to increased thrombogenecity. METHODS: Plasma levels of soluble CD40 ligand (sCD40L [an index of platelet activation]) and tissue factor (TF [an index of coagulation]), as well as the angiogenic factors, vascular endothelial growth factor (VEGF), angiopoietin (Ang)-1, and Ang-2, were measured by enzyme-linked immunosorbent assay in 59 patients with chronic AF. Data were compared to 40 age-matched and sex-matched healthy control subjects who were in sinus rhythm. RESULTS: AF patients had significantly higher levels of sCD40L (p = 0.038), VEGF (p = 0.023), and Ang-2 (p <0.001), but not Ang-1 (p = 0.363), compared to control subjects. In non-anticoagulated AF patients (n = 28), TF levels were also higher (p = 0.043), in addition to high sCD40L, VEGF, and Ang-2, compared to control subjects. Among AF patients, sCD40L levels correlated strongly with levels of VEGF (r = 0.919; p <0.001) and Ang-2 (r = 0.546; p = 0.002). VEGF levels were significantly correlated with levels of Ang-2 (r = 0.490; p <0.001) and TF (r = 0.298; p = 0.044). In multivariate regression analysis, sCD40L levels were independently associated with levels of VEGF (p = 0.003) and Ang-2 (p = 0.005). CONCLUSIONS: Plasma levels of sCD40L are elevated in patients with AF, and are related to levels of VEGF, Ang-2, and TF. This interaction among platelets, angiogenic markers, and TF may play a role in the generation of the prothrombotic state associated with AF.