Tumor necrosis factor-alpha plays an important role in restenosis development.
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.
Monraats
Pascalle S
PS
Department of Cardiology, Leiden University Medical Center, The Netherlands.
Pires
Nuno M M
NM
Schepers
Abbey
A
Agema
Willem R P
WR
Boesten
Lianne S M
LS
de Vries
Margreet R
MR
Zwinderman
Aeilko H
AH
de Maat
Moniek P M
MP
Doevendans
Pieter A F M
PA
de Winter
Robbert J
RJ
Tio
René A
RA
Waltenberger
Johannes
J
't Hart
Leen M
LM
Frants
Rune R
RR
Quax
Paul H A
PH
van Vlijmen
Bart J M
BJ
Havekes
Louis M
LM
van der Laarse
Arnoud
A
van der Wall
Ernst E
EE
Jukema
J Wouter
JW
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
D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D013792:Thalidomide