Localized release of perivascular heparin inhibits intimal proliferation after endothelial injury without systemic anticoagulation.

Segmental endothelial desquamation of the common carotid artery was produced in 30 rats using a balloon catheter technique which produces consistent proliferation of intimal smooth muscle cells from 5 to 20 days after injury. Immediately after endothelial injury, 15 animals were treated with periadventitial application of heparin contained in a continuous-release drug-delivery system using the polymer polyvinyl alcohol (PVA) and PVA alone applied in a similar fashion to 15 control rats. Animals were killed at 5, 10 and 20 days, respectively, after surgery by intracardiac perfusion-fixation, and vessels were prepared for light microscopy, scanning electron microscopy, and immunohistochemistry with antibodies directed against actin. At all time periods, there was a significant reduction in intimal cross-sectional area in heparin/PVA-treated vessels compared to control vessels. Scanning electron microscopy showed complete absence of endothelial cells from the luminal surface in both control and treated arteries at all time periods without evidence of significant platelet aggregation. Immunohistochemistry demonstrated the presence of immunoreactive actin in the proliferating myointimal cells. Femoral venous prothrombin time and partial thromboplastin time were unchanged in heparin/PVA-treated animals compared to controls at 1, 5, and 10 days. Continuous-release polymer drug delivery can be used to apply heparin selectively to the adventitial surface of vessels and effect changes in the vessel wall over periods of up to 3 weeks. By this means, smooth muscle proliferation and subsequent vessel narrowing after endothelial injury were inhibited without systemic anticoagulation. This technique may be applicable to both clinical and research applications related to the pathophysiology of arterial injury.