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Tumor necrosis factor- plays an important role in restenosis development

Pascalle S. Monraats^*,,1, Nuno M. M. Pires^*,,1, Abbey Schepers^,, Willem R. P. Agema^*,, Lianne S. M. Boesten^,||, Margreet R. de Vries, Aeilko H. Zwinderman^¶, Moniek P. M. de Maat^**, Pieter A. F. M. Doevendans, Robbert J. de Winter, René A. Tio^¶¶, Johannes Waltenberger^#, Leen M. ’t Hart^##, Rune R. Frants^***, Paul H. A. Quax^,, Bart J. M. van Vlijmen^*, Louis M. Havekes^*,,||, Arnoud van der Laarse^*, Ernst E. van der Wall^* and J. Wouter Jukema^*,,2

^* Department of Cardiology,
Department of Surgery,
^## Department of Molecular Cell Biology,
^*** Department of Human Genetics, Center for Human and Clinical Genetics,
^|| Department of General Internal Medicine, Leiden University Medical Center, The Netherlands;
Interuniversity Cardiology Institute of The Netherlands (ICIN), Utrecht, The Netherlands;
Gaubius Laboratory, TNO-Quality of Life, Leiden, The Netherlands;
^¶ Department of Medical Statistics, Academic Medical Center, Amsterdam, The Netherlands;
^** Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands;
Department of Cardiology, University Medical Center Utrecht, The Netherlands;
Department of Cardiology, Academic Medical Center, Amsterdam, The Netherlands;
^¶¶ Department of Cardiology, Academic Hospital Groningen, The Netherlands; and
^# Department of Cardiology, Academic Hospital Maastricht, The Netherlands

²Correspondence: Leiden University Medical Center, Department of Cardiology, 5-P, P.O. Box 9600, 2300 RC Leiden, The Netherlands. E-mail: j.w.jukema{at}lumc.nl

Genetic factors appear to be important in the restenotic process after percutaneous coronary intervention (PCI), as well as in inflammation, a pivotal factor in restenosis. TNF, a key regulator of inflammatory responses, may exert critical influence on the development of restenosis after PCI. The GENetic DEterminants of Restenosis (GENDER) project included 3104 patients who underwent a successful PCI. Systematic genotyping for six polymorphisms in the TNF gene was performed. The role of TNF in restenosis was also assessed in ApoE*3-Leiden mice, TNF knockout mice, and by local delivery of a TNF biosynthesis inhibitor, thalidomide. The –238G-1031T haplotype of the TNF gene increased clinical and angiographic risk of restenosis (P=0.02 and P=0.002, respectively). In a mouse model of reactive stenosis, arterial TNF mRNA was significantly time-dependently up-regulated. Mice lacking TNF or treated locally with thalidomide showed a reduction in reactive stenosis (P=0.01 and P=0.005, respectively). Clinical and preclinical data indicate that TNF plays an important role in restenosis. Therefore, TNF genotype may be used as a risk marker for restenosis and may contribute to individual patient screening prior to PCI in clinical practice. Inhibition of TNF may be an anti-restenotic target strategy.—Monraats, P. S., Pires, N. M. M., Schepers, A., Agema, W. R. P., Boesten, L. S. M., de Vries, M. R., Zwinderman, A. H., de Maat, M. P. M., Doevendans, P. A. F. M., de Winter, R. J., Tio, R. A., Waltenberger, J., ’t Hart, L. M., Frants, R. R., Quax, P. H. A., van Vlijmen, B. J. M., Havekes, L. M., van der Laarse, A., van der Wall, E. E., Jukema, J. W. Tumor necrosis factor- plays an important role in restenosis development.

Key Words: TNF • inflammation • transgenic mice • haplotype

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