title: Long-term clopidogrel administration following severe coronary injury reduces proliferation and inflammation via inhibition of nuclear factor-kappaB and activator protein 1 activation in pigs.
abstract: BACKGROUND
  The optimal duration of clopidogrel treatment following percutaneous coronary intervention (PCI) and the patient population that would benefit most are still unknown. In a porcine coronary injury model, we tested two different durations of clopidogrel treatment on severely or moderately injured arteries and examined the arterial response to injury. To understand the molecular mechanism, we also investigated the effects on transcription factors nuclear factor-kappaB (NF-kappaB) and activator protein 1 (AP-1).
  
  
  METHODS
  In 24 cross-bred pigs, one coronary artery was only moderately injured by percutaneous transluminal coronary angioplasty (PTCA) and one coronary artery was severely injured by PTCA and subsequent beta-irradiation (Brachy group). Animals received 325 mg aspirin daily for 3 months and 75 mg clopidogrel daily for either 28 days [short-term (ST) clopidogrel group] or 3 months [long-term (LT) clopidogrel group].
  
  
  RESULTS
  After 3 months, the number of proliferating cells per cross-section differed significantly between ST and LT in both injury groups (PTCA(ST) 90.2 +/- 10.3 vs. PTCA(LT )19.2 +/- 4.7, P < 0.05; Brachy(ST) 35.8 +/- 8.4 vs. Brachy(LT) 7.5 +/- 2.0, P < 0.05). Similar results were seen for inflammatory cells (CD3(+) cells): PTCA(ST) 23.5 +/- 3.55 vs. PTCA(LT )4.67 +/- 0.92, P < 0.05; Brachy(ST) 83.17 +/- 11.17 vs. Brachy(LT) 20 +/- 4.82, P < 0.05). Long-term administration also reduced the activity of NF-kappaB and AP-1 by 62-64% and 42-58%, respectively. However, the effects of different durations of clopidogrel administration on artery dimensions were not statistically significant.
  
  
  CONCLUSIONS
  Regarding inflammation and transcription factor activity at the PCI site, long-term clopidogrel administration is superior to short-term administration, especially in severely injured arteries. Transferring our results to the human situation, patients with more severely diseased arteries may benefit from a prolonged clopidogrel medication after PCI.
authors.affiliation: Charité- Campus Benjamin Franklin, Berlin, Germany. klaus.pels@charite.de
authors.forename: K
authors.initials: K
authors.lastname: Pels
authors.forename: P L
authors.initials: PL
authors.lastname: Schwimmbeck
authors.forename: P
authors.initials: P
authors.lastname: Rosenthal
authors.forename: C
authors.initials: C
authors.lastname: Loddenkemper
authors.forename: C
authors.initials: C
authors.lastname: Dang-Heine
authors.forename: U
authors.initials: U
authors.lastname: Rauch
authors.forename: H
authors.initials: H
authors.lastname: Martens
authors.forename: H-P
authors.initials: HP
authors.lastname: Schultheiss
authors.forename: R
authors.initials: R
authors.lastname: Dechend
authors.forename: C
authors.initials: C
authors.lastname: Deiner
mesh_terms: D000818:Animals; D001241:Aspirin / Q000008:administration & dosage*; D000077144:Clopidogrel; D023903:Coronary Restenosis / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D016328:NF-kappa B / Q000378:metabolism*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage*; D013223:Statistics as Topic; D034421:Sus scrofa / Q000293:injuries; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D010975:Platelet Aggregation Inhibitors; D018808:Transcription Factor AP-1; D000077144:Clopidogrel; D013988:Ticlopidine; D001241:Aspirin