LOCAL-DELIVERY INFUSION PRESSURE IS A KEY DETERMINANT OF VASCULAR DAMAGE AND INTIMAL THICKENING

Local drug delivery following percutaneous transluminal coronary angio plasty (PTCA) may prevent restenosis by achieving higher local tissue concentrations of drugs than systemic administration. However, it rema ins unknown whether vascular damage and the ensuing intimal thickening is associated with the degree of infusion pressure achieved by local delivery. Therefore, local delivery of normal saline was performed usi ng a channeled balloon catheter (Transport(TM)) to the rabbit iliac ar tery with different infusion pressures of 0, 3, 5, 7, and 12 atm (n = 4 for each). The extent of vascular damage and the development of inti mal thickening were determined histopathologically 14 days after the p rocedure. In 10 additional rabbits, to assess the degree of vessel pen etration, local delivery of indocyanine green dye solution was perform ed in a similar fashion. After 1 h, the green dye penetrated deeply at the higher infusion pressures of 7 and 12 atm. The incidence of inter nal elastic lamina laceration and occurrence of total occlusion as a r esult of thrombus formation demonstrated an increase proportional to t he degree of local infusion pressure. When the vascular injury score i n each arterial section was plotted against the infusion pressure, a s ignificant relation was observed (r = 0.717, p < 0.0001). At 0, 3, 5, 7, and 12 atm, neointimal areas of 0.160 +/- 0.005, 0.163 +/- 0.008, 0 .189 +/- 0.017, 0.260 +/- 0.027, and 0.329 +/- 0.033 mm(2), respective ly, were observed. Smooth muscle cell (SMC) proliferative activity als o increased in proportion to the local infusion pressure. We have demo nstrated for the first time that local delivery infusion pressure itse lf is related to the severity of vascular damage, resulting in the dev elopment of intimal thickening and an associated increase in SMC proli ferative activity. Therefore, we suggest that infusion pressure is a k ey determinant of vascular injury during local drug delivery, with low er pressure causing the least neointimal response.