External beam radiation after stent implantation increases neointimal hyperplasia by augmenting smooth muscle cell proliferation and extracellular matrix accumulation

OBJECTIVES We sought to examine the effects of high volume external beam ra diation (EBR) after stent implantation on neointimal hyperplasia, smooth mu scle cell(SMC) proliferation, presence of inflammatory cells and expression of extracellular matrix (ECM). BACKGROUND Endovascular irradiation has been shown to reduce restenosis rat es after angioplasty in preliminary trials, but conflicting results have be en reported for the effects of external beam irradiation. METHODS Forty-three Palmaz-Schatz stents were implanted into iliac arteries of New Zealand White rabbits. The arteries were externally irradiated afte r stent implantation with a single dose of 8 Gy (at day 3) or 16 Gy in two fractions (8 Gy at days 3 and 4) by means of a linear accelerator. In the c ontrol rabbits, no radiation was applied after stent implantation. Smooth m uscle cells, macrophages and ECM were studied by immunohistochemistry at on e and 12 weeks after stent implantation. Collagen type I and biglycan messe nger ribonucleic acid (mRNA) levels were assessed by Northern blot analysis at one week. Neointimal cell densities and arterial lumen stenosis were me asured by histomorphometry at 12 weeks. RESULTS At 1 week, SMC proliferation at the site of stent implantation was increased after EBR with 8 and 16 Gy (26 +/- 5%, 32 +/- 3% vs. 17 +/- 8%; p < 0.01, 16 Gy vs. control). External beam radiation with 8 and 16 Gy augme nted SMC proliferation proximal and distal to the angioplasty site (11 +/- 3%, 14 +/- 3 vs. 6 +/- 1%; p < 0.01, 16 Gy vs. control). Collagen type I an d biglycan mRNA levels were elevated in stented arteries after EBR with 16 Gy. At 12 weeks, a marked decrease in neointimal cell density(248 +/- 97 vs . 498 +/- 117 SMCs/0.1 mm(2) neointima; p < 0.005 vs. control) was noted af ter EBR with 16 Gy. Irradiation with 8 and 16 Gy increased arterial lumen s tenosis compared with nonirradiated control rabbits (45 +/- 7%, 55 +/- 9% v s. 33 +/- 7%; p < 0.05, 8 Gy and p < 0.001, 16 Gy vs. control). CONCLUSIONS High volume external beam radiation at doses of 8 or 16 Gy caus es restenosis by augmenting proliferative activity at and adjacent to the s ite of stent implantation, and by dose-dependent up-regulation of extracell ular matrix expression. The study suggests that excessive matrix accumulati on is an important determinant of failure of radiation therapy to prevent r estenosis. (C) 1999 by the American College of Cardiology.