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European Heart Journal Advance Access published online on June 29, 2009
European Heart Journal, doi:10.1093/eurheartj/ehp259
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org

Rapamycin promotes arterial thrombosis in vivo: implications for everolimus and zotarolimus eluting stents

Giovanni G. Camici1,2, Jan Steffel1,2,3, Ilijana Amanovic1,2, Alexander Breitenstein1,2,3, Janette Baldinger1,2, Stephan Keller1,2, Thomas F. Lüscher1,2,3 and Felix C. Tanner1,2,3,*

1 Cardiovascular Research, Physiology Institute, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
2 Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
3 Cardiology, Cardiovascular Center, University Hospital Zürich, Zurich, Switzerland

Received 7 January 2009; revised 21 April 2009; accepted 25 May 2009 * Corresponding author. Tel: +41 44 635 6469, Fax: +41 44 635 6827, Email: felix.tanner{at}access.uzh.ch

Aims: Drug-eluting stents (DES) may be associated with an increased risk for stent thrombosis when compared with bare-metal stents. In endothelial cells, rapamycin induces tissue factor (TF) by inhibiting the mammalian target of rapamycin (mTOR). However, the effect of mTOR inhibition on TF activity and thrombus formation in vivo has not yet been studied. Moreover, it is unclear whether second-generation DES substances everolimus and zotarolimus have an effect on endothelial TF expression.

Methods and results: In a mouse carotid artery photochemical injury model, rapamycin (182 ± 27.5 µg/L) decreased time to thrombotic occlusion by 40%, increased TF activity, and abrogated p70S6K phosphorylation when compared with controls. In vitro, rapamycin, everolimus, and zotarolimus (each 10–7 mol/l) enhanced TNF-{alpha}-induced TF expression by 2.2-, 1.7-, and 2.4-fold, respectively, which was paralleled by an increase in TF surface activity. Similar to rapamycin, everolimus and zotarolimus abrogated TNF-{alpha}-induced p70S6K phosphorylation under these conditions.

Conclusion: Rapamycin increases TF activity and promotes arterial thrombosis in vivo at concentrations relevant in patients undergoing DES implantation; this effect may increase the thrombogenicity of DES. Since everolimus and zotarolimus augment endothelial TF expression and activity in vitro in a similar manner as rapamycin, these findings may also be relevant for second generation DES.

Key Words: Drug-eluting stents • Thrombosis • Tissue factor

This paper was guest edited by Prof. Van de Werf, Department of Cardiology, University Hospitals Leuven, Belgium


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