Time course of smooth muscle cell proliferation after local drug delivery of low-molecular-weight heparin using a porous balloon catheter.

Abstract

It has been reported previously that systemic application of low molecular weight heparin (LMWH) suppresses smooth muscle cell (SMC) proliferation after balloon angioplasty in experimental studies. However, the high concentration of heparin required for a beneficial effect may cause severe bleeding complications. The ideal situation to overcome the systemic side effects would be to administer LMWH locally and deep into the arterial wall, which became possible by the development of porous balloon catheters. The in vivo feasibility of local delivery of LMWH using the porous balloon has been assessed by delivering tritium-marked LMWH into rabbit carotid arteries. The efficacy of the system was investigated by using a second injury animal model. After development of an intimal plaque by electrical stimulation, 61 rabbits were treated with the porous balloon after balloon angioplasty. In 23 rabbits, local drug delivery was accomplished with a porous balloon catheter (35 holes, hole diameter 75 microns, 2.5 mm catheter diameter). LMWH was locally administered with 4 ml (solution 375 anti-Xa-units/ml) and 2 atm. To study the extent of restenosis and morphological changes, these animals were killed 3, 7, 14, 28, or 56 d after intervention. After staining (hematoxylin, van Gieson, BrdU, RAM 11, alpha-actin) procedures to quantify SMC proliferation, intimal macrophages and morphological analysis were performed. Porous balloon treatment led to an increase in intimal SMC proliferation rate in the early stage after intervention. However, during the following time period, a significant decrease of the proliferation rate as compared with the animals treated with balloon angioplasty alone could be observed, which resulted in an only moderate increase of the intimal layer after local drug delivery compared with balloon angioplasty alone.