Copyright © 2007, European Society of Cardiology
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b and AP-1 activation is associated with late lumen loss after porcine coronary angioplasty and antiproliferative beta-irradiation
aInstitute of Veterinary Physiology, Faculty of Veterinary Medicine, FU Berlin, Berlin, Germany
bDepartment of Cardiology, Charité — Campus Buch Franz Volhard Klinik, HELIOS Klinikum Berlin, Germany
cDepartment of Cardiology, Klinikum Leverkusen, Leverkusen, Germany
dDepartment of Radiation Therapy and Oncology, Charité — Campus Benjamin Franklin, Berlin, Germany
eDepartment of Pathology, Charité — Campus Benjamin Franklin, Berlin, Germany
fDepartment of Cardiology, Charité — Campus Benjamin Franklin, Berlin, Germany
* Corresponding author. Department of Cardiology, Charité — Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany. Tel.: +49 30 8445 2068; fax: +49 30 8445 4648. klaus.pels{at}charite.de
Objective Despite the success of antiproliferative therapies, restenosis remains a common problem after percutaneous transluminal coronary angioplasty (PTCA). Longer-term clinical results of brachytherapy (intracoronary radiation), the lack of long-term clinical results after implantation of drug eluting stents, and the occurrence of late thrombosis after both procedures leave room for skepticism. Neointimal proliferation is not substantially inhibited at late time points after brachytherapy, and late lumen loss with a "catch-up" proliferation can occur. We hypothesized that the transcription factors nuclear factor-{kappa}B (NF-
B) and activator protein-1 (AP-1) are involved in these processes. We addressed the role of these mediators in a porcine model of coronary restenosis.
Methods Thirty-nine pigs underwent PTCA in two major coronary arteries. One of the two balloon-injured arteries was randomly assigned to receive immediate 20 Gy beta-irradiation (Brachy group) using a noncentered source train (90Sr/Y Beta-Cath, Novoste). Animals were sacrificed after 1 day, 14 days, or 28 days. Proliferating cells were labeled prior to euthanasia.
Results At late time points, lumen area was significantly smaller and the inflammatory response was more pronounced in the Brachy group than in the PTCA group. These findings coincided with sustained activation of MMP-9 and transcription factors like NF-B and AP-1. Initially, cell proliferation was reduced in the Brachy group; however, at late time points, differences between the two treatment groups were no longer significant.
Conclusions Brachytherapy initially inhibits cell proliferation; however, cellular and molecular inflammatory processes (e.g. activation of NF–B) are enhanced within the arterial wall. This proinflammatory side effect may be responsible for the observed delayed proliferation and the resulting lumen loss.
KEYWORDS Restenosis; Inflammation; Proliferation; Brachytherapy; Lumen loss; NF-B; AP-1; Transcription factors; Porcine; Coronary arteries; Beta-irradiation