Circulation, Vol 89, 770-776, Copyright © 1994 by American Heart Association
ER Edelman and MJ Karnovsky
BACKGROUND: Heparin inhibits proliferation of smooth muscle cells in
culture and intimal hyperplasia in experimental animals but paradoxically
exacerbates vascular injury in clinical trials. To determine whether the
difference in the means by which heparin was administered explained the
benefit in animals and aggravation in humans, we examined the vascular
effects of a range of heparin treatments. METHODS AND RESULTS: When
laboratory rats were injected subcutaneously with heparin (55.5 IU,
approximately 1.0 mg/kg) per clinical trial protocols, intimal hyperplasia
after arterial injury was exacerbated rather than alleviated. The intima to
media area ratio was increased 22.5% with every-other-day injections and
was increased 16.8% with daily injections. When the daily dose of heparin
was increased to 7.2 mg/kg or when injections were initiated a week before
injury, intimal hyperplasia was made even worse (52.2% and 59.9% above
control). Twice-daily heparin, 7 and 17 hours apart, had no demonstrable
effect one way or the other, and it was not until the heparin was
administered at 12-hour intervals that intimal hyperplasia and cell
proliferation were lessened (44.6% decrease). The greatest reduction in
intimal hyperplasia was obtained when the heparin was administered
continuously. The continuous osmotic pump intravenous infusion of heparin
inhibited 62.5% of the expected proliferation, and perivascular polymeric
device release of heparin blocked the response by 74.2%. While subcutaneous
injections transiently increased activated partial thromboplastin time,
neither mode of continuous delivery altered coagulation. CONCLUSIONS: We
might reconsider the use of heparin in vascular diseases and not neglect
this promising compound because of inappropriate extrapolation from the
laboratory to clinical use.
ARTICLES
Contrasting effects of the intermittent and continuous administration of heparin in experimental restenosis
Department of Medicine (Cardiovascular Division, Brigham and Women's Hospital), Boston, MA 02115.
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