Local and systemic delivery of low molecular weight heparin stimulates the reendothelialization after balloon angioplasty.
OBJECTIVE
Recent investigations revealed the importance of endothelial cell integrity and function in the pathogenesis of restenosis after angioplasty. Agents which stimulate reendothelialization may prevent restenosis after interventional procedures. The results of in vitro studies suggested that heparin and low molecular weight heparin administration may enhance the recovery of the endothelium. In this study the extent of endothelial denudation and the occurrence and time course of endothelial regeneration after experimental balloon angioplasty followed by subcutaneous or local delivery of low molecular weight heparin was 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 balloon angioplasty. Thirty-two rabbits received no further medical treatment. Twenty-five rabbits received subcutaneous low molecular weight heparin reviparin (400 anti-Xa-units/day) during the following 7 days. In 25 animals the dilated arterial segments were treated locally with reviparin (1500 anti-Xa-units/4 ml, 2 atm) using a porous balloon (2.5 mm, 35 holes, diameter 75 microns). Twenty animals served as control group without intervention. The vessels were excised 3, 7, 14, 28 and 56 days following intervention. Sections were stained with an antibody against 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 addition, morphometric analysis of the intimal and medial area was performed.


RESULTS
Three days after balloon angioplasty histomorphological analysis showed a reduction of about 60% of the preinterventional endothelial cell number in all three groups. Already one week after intervention there was a significantly higher number of endothelial cells in both groups of low molecular weight heparin treated animals compared to the untreated group (s.c. group 144 +/- 33, local group 142 +/- 32 versus untreated 79 +/- 17 endothelial cells, p < or = 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 s.c. and local reviparin treated animals and a subsequent reduction of intimal thickening.


CONCLUSIONS
Local delivery of low molecular weight heparin promotes reendothelialization and contributes to the inhibition of smooth muscle cell proliferation.
Oberhoff
M
M
Department of Medicine, University of Tübingen, Germany.
Novak
S
S
Herdeg
C
C
Baumbach
A
A
Kranzhöfer
A
A
Bohnet
A
A
Horch
B
B
Hanke
H
H
Haase
K K
KK
Karsch
K R
KR
D000279:Administration, Cutaneous; D000287:Administration, Topical; D000800:Angioplasty, Balloon / Q000009:adverse effects*; D000818:Animals; D001161:Arteriosclerosis / Q000473:pathology / Q000628:therapy; D002339:Carotid Arteries / Q000473:pathology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000293:injuries* / Q000473:pathology; D005343:Fibrinolytic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D006495:Heparin, Low-Molecular-Weight / Q000008:administration & dosage* / Q000627:therapeutic use; D006652:Histological Techniques; D007091:Image Processing, Computer-Assisted; D008297:Male; D008855:Microscopy, Electron, Scanning; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology; D011817:Rabbits; D012038:Regeneration; D013268:Stimulation, Chemical
D005343:Fibrinolytic Agents; D006495:Heparin, Low-Molecular-Weight; C094240:reviparin