The effect of intracoronary β-radiation on neointimal formation and vascular remodeling in balloon-injured porcine coronary arteries: Effect of dose rate

Background: Neointimal formation and vascular remodeling are major mechanisms contributing to coronary restenosis after percutaneous transluminal coronary angioplasty. Intracoronary γ- and β-radiation have been shown to inhibit neointimal formation in balloon-injured porcine coronary arteries. However, the effects of intracoronary radiation (ICR) dose and dose rate on vascular remodeling versus inhibition of neointimal formation have not been evaluated. Methods and Results: Forty-one Hanford Miniature swine were subjected to oversized balloon injury in the left anterior descending and right coronary artery. A spiral centering catheter with perfusion capabilities was placed in the injured segment for circumferentially uniform radiation dose delivery to the vessel wall. Each artery was randomly afterloaded with a dummy wire or an active wire with the ³²P source encapsulated in either a short (3 mm) or long (27 mm) segment at the distal end of the wire. The 3-mm source wire was used to deliver 650, 1,300, and 1,900 cGy while the 27-mm source wire was used to deliver 1,200 and 3,500 cGy of β-radiation to the adventitia (≃ 0.5 mm into the vessel wall). The dose rate for 1CR varied from 2.5 to 140 cGy/sec, depending on the mCi strength of the ³²p source at the time of endovascular radiation. One month later, repeat coronary angiography and intravascular ultrasound (IVUS) to measure the external elastic lamina (EEL) area were done. The animals were sacrificed and the coronary vasculature was perfusion fixed. Morphometric, quantitative coronary angiographic, and IVUS analyses were carried out in a blinded fashion. A significant reduction in percent area stenosis (PAS) and neointimal area (NA) was observed on morphometry in coronary arteries treated with 3,500 cGy of β-radiation. The PAS and NA was 44% ± 13% and 0.96 ± 0.25 mm² in the control groups versus 19% ± 14% and 0.30 ± 0.23 mm² in the 3,500-cGy group (P < 0.02). There was no significant difference on morphometry between the control and the other four β-radiation-treated groups. There was no significant improvement in the change in minimum lumen diameter (ΔMLD) between the control and the five radiation-treated groups. Further analysis of angiographic data revealed that the apparent lack of beneficial effect on angiography was due to significant reductions in lumen diameter in the subgroups of arteries subjected to 1CR at a dose rate > 50 cGy/sec with the 3-mm source wire only. The ΔMLD was -1.39 ± 0.49, -1.79 ± 0.64, and - 1.79 ± 0.39 mm in the 650-, 1,300-, and 1,900-cGy groups treated with a dose rate > 50 cGy/sec versus -0.56 ± 0.95 in control (P < 0.05). This reduction in lumen diameter on angiography was associated with a significant reduction in vessel (EEL) area especially in the groups treated with the 3 mm source at a dose rate > 50 cGy/sec. The EEL area was 8.8 ± 1.7, 9.9 ± 1.7, and 8.9 ± 0.6 mm² in the 650, 1,300, and 1,900 cGy groups treated at a dose rate > 50 cGy/sec compared to 11.7 ± 1.6 mm² in control arteries (P < 0.001). Conclusions: Endovascular β-radiation at high doses (3,500 cGy to adventitia) and dose rate < 50 cGy/sec inhibits restenosis after balloon injury in the porcine model of coronary restenosis. This dose and dose rate is associated with a neutral effect on vascular remodeling. While lower doses of ICR did not worsen the PAS, a reduction in MLD and EEL area were observed. However, this adverse effect on angiographic restenosis and vascular remodeling appears to be largely limited to the subgroups treated at dose rates > 50 cGy/sec.