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(Circulation. 2005;111:1841-1846.)
© 2005 American Heart Association, Inc.

Vascular Medicine

Simvastatin Blunts Endotoxin-Induced Tissue Factor In Vivo

Sabine Steiner, MD; Walter S. Speidl, MD; Johannes Pleiner, MD; Daniela Seidinger, MTA; Gerlinde Zorn, MTA; Christoph Kaun, CTA; Johann Wojta, PhD; Kurt Huber, MD; Erich Minar, MD; Michael Wolzt, MD; Christoph W. Kopp, MD

From the Second Department of Medicine, Divisions of Angiology (S.S., D.S., E.M., C.W.K.) and Cardiology (W.S.S, G.Z., C.K., J.W.), and the Department of Clinical Pharmacology (J.P., M.W.), Medical University of Vienna, and the Department of Medicine, Cardiology, and Emergency Medicine (K.H.), Wilhelminenhospital, Vienna, Austria.

Correspondence to Christoph W. Kopp, MD, Second Department of Medicine, Division of Angiology, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria. E-mail christoph.kopp{at}univie.ac.at

Received August 14, 2004; revision received November 22, 2004; accepted November 24, 2004.

Background— Beyond lipid lowering, various antiinflammatory properties have been ascribed to statins. Moreover, in vitro studies have suggested the presence of anticoagulant effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, as lipopolysaccharide (LPS)-induced monocyte tissue factor (TF) was suppressed. In this study, we examined the role of statins in experimental endotoxemia on inflammatory and procoagulant responses in vivo.

Methods and Results— In this double-blind, placebo-controlled, parallel-group study, 20 healthy, male subjects were randomized to receive either simvastatin (80 mg/d) or placebo for 4 days before intravenous administration of LPS (20 IU/kg IV). Plasma high-sensitive C-reactive protein (hsCRP), monocyte chemoattractant protein (MCP-1), sCD40L, sCD40, and prothrombin fragment F1+2 (F1.2) were determined by ELISAs at baseline and at 4 and 8 hours after LPS administration. Monocyte TF expression and monocyte-platelet aggregates were measured by whole-blood flow cytometry over the same time course. The increases in hsCRP and MCP-1, both known inducers of TF, were significantly suppressed by statin treatment after LPS challenge. Statin premedication blunted the increase of monocyte TF expression in response to LPS. In parallel, endotoxin-induced formation of F1.2 was significantly reduced by simvastatin after 4 and 8 hours. LPS infusion affected neither the formation and activation of monocyte-platelet aggregates nor plasma levels of sCD40 and sCD40L.

Conclusions— Simvastatin suppresses the inflammatory response to endotoxin and blunts monocyte TF expression but does not affect platelet activation.

Key Words: statins • inflammation • thrombosis

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