doi: 10.1161/01.CIR.0000153810.81187.7D
(Circulation. 2005;111:412-419.)
© 2005 American Heart Association, Inc.
Coronary Heart Disease |
Short-Term Treatment With Atorvastatin Reduces Platelet CD40 Ligand and Thrombin Generation in Hypercholesterolemic Patients
From the Department of Experimental Medicine and Pathology (P.P., L.L., D.F., R.C., F.V.), University of Rome "La Sapienza," and the Department of Internal Medicine (V.S., A.B., M.T., R.S., R.L.), University of Rome "Tor Vergata," Rome, Italy.
Correspondence to Francesco Violi, MD, Dipartimento di Medicina Sperimentale e Patologia, Università di Roma La Sapienza, Policlinico Umberto I, 00185, Rome, Italy. E-mail francesco.violi{at}uniroma1.it
Received June 18, 2004; revision received October 16, 2004; accepted November 18, 2004.
Background— Soluble CD40L (sCD40L), a substance that maximally reflects in vivo platelet activation, is increased in patients with hypercholesterolemia. We investigated the relation between sCD40L and platelet CD4OL in hypercholesterolemic patients before and after a short-term treatment with atorvastatin.
Methods and Results— Collagen-induced platelet CD40L and plasma levels of sCD40L and prothrombin fragment F1+2, a marker of thrombin generation, were investigated in 30 hypercholesterolemic patients and 20 healthy subjects. Hypercholesterolemic patients were then randomized to either diet (n=15; group A) or atorvastatin 10 mg/d (group B); the aforementioned variables were measured at baseline and after 3 days of treatment. Compared with referents, hypercholesterolemic patients showed higher values of platelet CD40L (P<0.005), sCD40L (P<0.005), and F1+2 (P<0.003). Platelet CD40L was significantly correlated with sCD40L (P<0.001), and the latter was significantly correlated with F1+2 (P<0.001). The intervention trial showed no changes in group A but a significant decrease in platelet CD40L (P<0.01), sCD40L (P<0.002), and F1+2 (P<0.03) in group B. In vitro studies demonstrated that cholesterol enhanced platelet CD40L and CD40L-mediated clotting activation by human monocytes; also, atorvastatin dose-dependently inhibited platelet CD40L expression and clotting activation by CD40L-stimulated monocytes.
Conclusions— This study shows that, in hypercholesterolemia, platelet overexpression of CD40L may account for enhanced plasma levels of sCD40L and F1+2. Atorvastatin exerts a direct antithrombotic effect via inhibition of platelet CD40L and CD40L-mediated thrombin generation, independently of its cholesterol-lowering effect.
Key Words: platelet-derived factors • platelets • thrombin • hypercholesterolemia • statins
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