Increased apoptotic cell death in the neointima after stent-based vascularirradiation: Role of radiation-induced apoptosis for restenosis reduction

Background: Restenosis after stent implantation is a common problem faced t oday by interventional cardiologists. It is primarily caused by excessive n eointimal growth. Early clinical studies showed substantial reductions of n eointimal volumes within bodies of P-32 radioactive coronary stents. Radiot herapy induces programmed cell death (apoptosis) in tumors but there is sti ll debate whether irradiation causes apoptosis in arteries. Methods: We com pared the time course of neointimal apoptosis after implanting 7-mm long P- 32 radioactive slotted tubular stents in rabbit iliac arteries. The stents were homogeneously ion-implanted with P-32 at activity levels of 0.5 and 6 mu Ci. These stents produce continuous beta-particle emission at very low d ose rates. Neointima formation was compared with nonradioactive stents by h istomorphometry after 1, 4, and 12 weeks. Apoptosis was detected using the terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNE ) assay method and transmission electron microscopy. Results, At an early f ollow-up of 1 week after stent implantation, no changes in neointimal apopt osis were found. The P-32 stents at activities of 6 mu Ci, but not of 0.5 m u Ci, reduced neointimal cross-sectional areas and cell numbers compared wi th control stents after 4 and 12 weeks. Apoptosis in the neointima increase d after 4 weeks and was substantially elevated 12 weeks after implantation of 6 mu Ci P-32 stents compared with 0.5 mu Ci and control stents (16% vs 6 % and 3%, P < 0.01 for 6 vs 0.5 mu Ci and control stents, respectively), Co nclusions: In this study, a dose dependent decrease in neointimal thickenin g and cell density within P-32 beta-particle emitting stents was associated with an increased frequency of apoptosis. This increase in apoptosis occur red late in the time course of vascular healing after the implantation of P -32 beta-particle emitting stents. Apoptosis seems to be involved in the me chanisms by which stent-based vascular irradiation reduces neointimal hyper plasia.