title: Tumor necrosis factor-alpha 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. TNFalpha, 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 TNFalpha gene was performed. The role of TNFalpha in restenosis was also assessed in ApoE*3-Leiden mice, TNFalpha knockout mice, and by local delivery of a TNFalpha biosynthesis inhibitor, thalidomide. The -238G-1031T haplotype of the TNFalpha gene increased clinical and angiographic risk of restenosis (P=0.02 and P=0.002, respectively). In a mouse model of reactive stenosis, arterial TNFalpha mRNA was significantly time-dependently up-regulated. Mice lacking TNFalpha 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 TNFalpha plays an important role in restenosis. Therefore, TNFalpha 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 TNFalpha may be an anti-restenotic target strategy.
authors.affiliation: Department of Cardiology, Leiden University Medical Center, The Netherlands.
authors.forename: Pascalle S
authors.initials: PS
authors.lastname: Monraats
authors.forename: Nuno M M
authors.initials: NM
authors.lastname: Pires
authors.forename: Abbey
authors.initials: A
authors.lastname: Schepers
authors.forename: Willem R P
authors.initials: WR
authors.lastname: Agema
authors.forename: Lianne S M
authors.initials: LS
authors.lastname: Boesten
authors.forename: Margreet R
authors.initials: MR
authors.lastname: de Vries
authors.forename: Aeilko H
authors.initials: AH
authors.lastname: Zwinderman
authors.forename: Moniek P M
authors.initials: MP
authors.lastname: de Maat
authors.forename: Pieter A F M
authors.initials: PA
authors.lastname: Doevendans
authors.forename: Robbert J
authors.initials: RJ
authors.lastname: de Winter
authors.forename: René A
authors.initials: RA
authors.lastname: Tio
authors.forename: Johannes
authors.initials: J
authors.lastname: Waltenberger
authors.forename: Leen M
authors.initials: LM
authors.lastname: 't Hart
authors.forename: Rune R
authors.initials: RR
authors.lastname: Frants
authors.forename: Paul H A
authors.initials: PH
authors.lastname: Quax
authors.forename: Bart J M
authors.initials: BJ
authors.lastname: van Vlijmen
authors.forename: Louis M
authors.initials: LM
authors.lastname: Havekes
authors.forename: Arnoud
authors.initials: A
authors.lastname: van der Laarse
authors.forename: Ernst E
authors.initials: EE
authors.lastname: van der Wall
authors.forename: J Wouter
authors.initials: JW
authors.lastname: Jukema
mesh_terms: D000368:Aged; D000483:Alleles; D000787:Angina Pectoris / Q000235:genetics / Q000628:therapy; D000792:Angiography; D015906:Angioplasty, Balloon, Coronary / Q000379:methods; D000818:Animals; D003251:Constriction, Pathologic; D017023:Coronary Angiography; D003327:Coronary Disease / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D023903:Coronary Restenosis; D004195:Disease Models, Animal; D005260:Female; D005263:Femoral Artery / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007249:Inflammation; D007511:Ischemia; D015810:Linkage Disequilibrium; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008875:Middle Aged; D015999:Multivariate Analysis; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D012044:Regression Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D013792:Thalidomide / Q000494:pharmacology; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D013792:Thalidomide