This Article Figures Only Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hehrlein, C. Articles by Kübler, W. Search for Related Content PubMed PubMed Citation Articles by Hehrlein, C. Articles by Kübler, W.

EXPERIMENTAL STUDIES

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

Christoph Hehrlein, MD^*, Simone Kaiser, BS^*, Reimer Riessen, MD, J.ürgen Metz, MD, Peter Fritz, MD and Wolfgang Kübler, MD^*

^* Department of Cardiology, University of Heidelberg, Heidelberg, Germany
Department of Anatomy and Cell Biology, University of Heidelberg, Heidelberg, Germany
Department of Clinical Radiology, University of Heidelberg, Heidelberg, Germany
Department of Cardiology, University of Tübingen, Tübingen, Germany

Manuscript received August 6, 1998; revised manuscript received March 19, 1999, accepted April 19, 1999.

Reprint requests and correspondence: Dr. Christoph Hehrlein, Associate Director, Heart Institute, Cardiovascular Research, Borgess Medical Center, 1521 Gull Road, Kalamazoo, Michigan 49001

OBJECTIVES

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).

BACKGROUND

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.

METHODS

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.

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 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).

CONCLUSIONS

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.

Abbreviations and Acronyms   CIA = common iliac artery   EBR = external beam radiation   ECM = extracellular matrix   EIA = external iliac artery   MAC = macrophage   mRNA = messenger ribonucleic acid   SMC = smooth muscle cell

This article has been cited by other articles:

				A. N Cheema, N. Nili, C. W Li, H. A Whittingham, J. Linde, R. J van Suylen, M. R Eskandarian, A. P Wong, B. Qiang, J.-F. Tanguay, et al. Effects of intravascular cryotherapy on vessel wall repair in a balloon-injured rabbit iliac artery model Cardiovasc Res, July 1, 2003; 59(1): 222 - 233. [Abstract] [Full Text] [PDF]

				E. Regar, K. Kozuma, G. Sianos, V.L.M.A. Coen, W.J. van der Giessen, D. Foley, P. de Feyter, B. Rensing, P. Smits, J. Vos, et al. Routine intracoronary beta-irradiation. Acute and one year outcome in patients at high risk for recurrence of stenosis Eur. Heart J., July 1, 2002; 23(13): 1038 - 1044. [Abstract] [Full Text] [PDF]

				I. P. Kay, A. J. Wardeh, K. Kozuma, G. Sianos, E. Regar, M. Knook, W. J. van der Giessen, A. Thury, J. M. R. Ligthart, V. M. A. Coen, et al. The pattern of restenosis and vascular remodelling after cold-end adioactive stent implantation Eur. Heart J., August 1, 2001; 22(15): 1311 - 1317. [Abstract] [PDF]