Tumor necrosis factor‐α plays an important role in restenosis development

ABSTRACT 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. TNFα, 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 TNFα gene was performed. The role of TNFα in restenosis was also assessed in ApoE*3‐Leiden mice, TNFα knockout mice, and by local delivery of a TNFα biosynthesis inhibitor, thalidomide. The −238G‐1031T haplotype of the TNFα gene increased clinical and angiographic risk of restenosis ( P =0.02 and P =0.002, respectively). In a mouse model of reactive stenosis, arterial TNFα mRNA was significantly time‐dependently up‐regulated. Mice lacking TNFα 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 TNFα plays an important role in restenosis. Therefore, TNFα 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 TNFα may be an anti‐restenotic target strategy.—Monraats, P. S., Pires, N. M. M., Schepers, A., Agema, W. R. P., Boesten, L. S. M., deVries, M. R., Zwinderman, A. H., deMaat, M. P. M., Doevendans, P. A. F. M., deWinter, R. J., Tio, R. A., Waltenberger, J., 'tHart, L. M., Frants, R. R., Quax, P. H. A., van, Vlijmen, B. J. M., Havekes, L. M., van derLaarse, A., van derWall, E. E., Jukema, J. W. Tumor necrosis factor‐α plays an important role in restenosis development. FASEB J. 19, 1998–2004 (2005)