Comparability of the external vs internal location of radiation in inhibiting neointimal hyperplasia

One of the most controversial issues in utilizing radiation to inhibit restenosis is the importance of the location of the radiation source. The experimental results from using external forms of radiation have been contradictory and conflicting. In this study, we undertook to externally place a brachytherapy catheter source and to determine if a dose-response effect could be observed, as has been demonstrated with endovascular locations.

Neointimal hyperplasia was created in a rat carotid artery model by a balloon catheter technique. Immediately following injury, treatment groups received irradiation via an externally located high-dose rate (HDR) 192Ir brachytherapy catheter. This system allows for a more uniform dose delivery compared with endovascular radiation sources. Radiation was delivered to a 2-cm length of the injured vessel at doses of 5, 10, or 15 Gy and the animals were sacrificed at various time points following treatment (24 h to 6 months). Serial sections of tissue were stained immunohistochemically with primary antibodies for CD11b, platelet-derived growth factor (PDGF), and alpha-smooth muscle actin.

Radiation doses of 5, 10, and 15 Gy inhibited the appearance of neointimal hyperplasia in a dose- and time-dependent manner. That is, doses of 5-15 Gy allowed for varying degrees of neointimal hyperplasia at 3 weeks posttreatment, with a greater resurgence of monocyte/macrophage activity at 5 Gy than at 10 or 15 Gy, where an absence of macrophage activity and PDGF expression was noted. From 2 to 6 months, the 10 and 15 Gy doses were again more suppressive of neointimal hyperplasia than 5 Gy, and at 6 months posttreatment the doses were approximately 25% and 50% effective, respectively.

The demonstrated effectiveness of external brachytherapy provides "proof of principle," that it is the radiation dose delivered to the arterial wall, and not the location of the source, which is critical to a successful outcome. Ablation of the resident monocyte/macrophage population (or prevention of their activation) occurs with low to moderate doses of irradiation, leading to the absence of a cytokine cascade as evi denced by a lack of PDGF expression. A favorable therapeutic ratio exists, therefore, for radiation treatment of the arterial vasculature to prevent neointimal hyperplasia postangioplasty.