Low-Dose Radioactive Endovascular Stents Prevent Smooth Muscle Cell Proliferation and Neointimal Hyperplasia in Rabbits

Abstract

Background Restenosis induced by smooth muscle cell (SMC) migration and proliferation and neointimal thickening limits the clinical success of balloon angioplasty and stent implantation. In this study, the long-term effect of endovascular irradiation via low-dose radioactive stents on neointima formation was compared with conventional stent implantation in a rabbit model. Methods and Results Palmaz-Schatz stents were made radioactive in a cyclotron. The stents had a very low activity (maximum, 35 μCi), and thus, manipulation did not require extensive radiation protection. One, 4, 12, and 52 weeks after the implantation of nonradioactive stents and radioactive stents in rabbit iliac arteries, neointimal thickening was analyzed by quantitative histomorphometry. Immunostaining for endothelial cell von Willebrand factor, macrophages, SMC α-actin, collagen type I, and proliferating cell nuclear antigen (PCNA) was performed to determine radiation-induced changes in the arterial wall. SMC proliferation was quantified by computer-assisted cell counting of PCNA-immunoreactive cells. Neointima formation was markedly suppressed by the implantation of radioactive stents in a dose-dependent fashion at all observed time points. At peak proliferative activity of SMCs 1 week after nonradioactive stent implantation, 30±2% of SMCs in the neointima were proliferating, compared with 0.5±0.1% of SMCs after implantation of stents with an initial activity of 35 μCi ( P <.001). The neointima covering radioactive stents was characterized by decreased smooth muscle cellularity and increased extracellular matrix formation. Further, we observed a delayed endothelialization depending on the radiation dose. No difference in vascular thrombosis was found after nonradioactive and radioactive stent implantation. Conclusions The results of this study clearly indicate that low-dose radioactive endovascular stents potently inhibit SMC proliferation and neointimal hyperplasia in rabbits.