LOCAL AND SYSTEMIC DELIVERY OF LOW-MOLECULAR-WEIGHT HEPARIN STIMULATES THE REENDOTHELIALIZATION AFTER BALLOON ANGIOPLASTY

Objective: Recent investigations revealed the importance of endothelia l cell integrity and function in the pathogenesis of restenosis after angioplasty. Agents which stimulate reendothelialization may prevent r estenosis after interventional procedures. The results of in vitro stu dies suggested that heparin and low molecular weight heparin administr ation may enhance the recovery of the endothelium. In this study the e xtent of endothelial denudation and the occurrence and time course of endothelial regeneration after experimental balloon angioplasty follow ed by subcutaneous or local delivery of low molecular weight heparin w as investigated. Methods: A total of 102 rabbits were included in the study. An atheromatous plaque was induced by electrical stimulation in the right carotid artery of the animals. All animals underwent balloo n angioplasty. Thirty-two rabbits received no further medical treatmen t. Twenty-five rabbits received subcutaneous low molecular weight hepa rin reviparin (400 anti-Xa-units/day) during the following 7 days. In 25 animals the dilated arterial segments were treated locally with rev iparin (1500 anti-Xa-units/4 ml, 2 atm) using a porous balloon (2.5 mm , 35 holes, diameter 75 mu m). Twenty animals served as control group without intervention. The vessels were excised 3, 7, 14, 28 and 56 day s following intervention. Sections were stained with an antibody again st von Willebrand factor and PECAM 1 to confirm the endothelial origin of the lining cells. After bromodeoxyuridine labeling, the extent of proliferation was determined by using a monoclonal antibody. In additi on, morphometric analysis of the intimal and medial area was performed . Results: Three days after balloon angioplasty histomorphological ana lysis showed a reduction of about 60% of the preinterventional endothe lial cell number in all three groups. Already one week after intervent ion there was a significantly higher number of endothelial cells in bo th groups of low molecular weight heparin treated animals compared to the untreated group (sc group 144 +/- 33, local group 142 +/- 32 versu s untreated 79 +/- 17 endothelial cells, p less than or equal to 0.05) . This significant difference was maintained during the following four weeks and demonstrated a 2-fold increase in endothelial proliferation in the heparin treated animals compared with the untreated group. In addition, immunohistological examination showed a significant decrease in smooth muscle cell proliferation in the sc and local reviparin tre ated animals and a subsequent reduction of intimal thickening. Conclus ion: Local delivery of low molecular weight heparin promotes reendothe lialization and contributes to the inhibition of smooth muscle cell pr oliferation. (C) 1998 Elsevier Science B.V. All rights reserved.