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

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). 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]. 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. 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.