We sought to examine the effects of high volume external beam radiation (EBR) after
stent implantation on neointimal hyperplasia, smooth muscle cell (SMC) proliferation,
presence of inflammatory cells and expression of extracellular matrix (ECM).
Endovascular irradiation has been shown to reduce restenosis rates after angioplasty
in preliminary trials, but conflicting results have been reported for the effects
of external beam irradiation.
Forty-three Palmaz-Schatz stents were implanted into iliac arteries of New Zealand
White rabbits. The arteries were externally irradiated after 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 control rabbits, no radiation was applied
after stent implantation. Smooth muscle cells, macrophages and ECM were studied by
immunohistochemistry at one and 12 weeks after stent implantation. Collagen type I
and biglycan messenger ribonucleic acid (mRNA) levels were assessed by Northern blot
analysis at one week. Neointimal cell densities and arterial lumen stenosis were measured
by histomorphometry at 12 weeks.
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 augmented 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 and 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 mm2 neointima; p < 0.005 vs. control) was noted after
EBR with 16 Gy. Irradiation with 8 and 16 Gy increased arterial lumen stenosis compared
with nonirradiated control rabbits (45 +/- 7%, 55 +/- 9% vs. 33 +/- 7%; p < 0.05,
8 Gy and p < 0.001, 16 Gy vs. control).
High volume external beam radiation at doses of 8 or 16 Gy causes restenosis by augmenting
proliferative activity at and adjacent to the site of stent implantation, and by dose-dependent
up-regulation of extracellular matrix expression. The study suggests that excessive
matrix accumulation is an important determinant of failure of radiation therapy to
prevent restenosis.