This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Thome, L. M. Articles by Sarembock, I. J. Search for Related Content PubMed PubMed Citation Articles by Thome, L. M. Articles by Sarembock, I. J.

(Circulation. 1998;98:2301-2306.)
© 1998 American Heart Association, Inc.

Basic Science Reports

Early Plus Delayed Hirudin Reduces Restenosis in the Atherosclerotic Rabbit More Than Early Administration Alone

Potential Implications for Dosing of Antithrombin Agents

Leonard M. Thome, MD; Lawrence W. Gimple, MD; Brian G. Bachhuber, MD; Coleen A. McNamara, MD; Michael Ragosta, MD; S. David Gertz, MD, PhD; Eric R. Powers, MD; Gary K. Owens, PhD; John E. Humphries, MD; ; Ian J. Sarembock, MB, ChB, MD

From the Cardiovascular Division and the Department of Molecular Physiology and Cellular Biophysics (G.K.O.), Department of Medicine, University of Virginia, Charlottesville, and the Department of Anatomy and Cell Biology, Hadassah Medical School, Jerusalem, Israel (S.D.G.).

Correspondence to Ian J. Sarembock, MD, Health Sciences Center, Box 158, Charlottesville, VA 22908. E-mail isarembock{at}virginia.edu

Background—A 2-hour infusion of r-hirudin at the time of balloon angioplasty limits restenosis in atherosclerotic rabbits. Because thrombin activity in the vessel wall after angioplasty remains high for 48 to 72 hours, we hypothesized that a second infusion of hirudin at 24 hours would reduce restenosis more than early treatment alone.

Methods and Results—Femoral atherosclerosis was induced in 35 rabbits by air desiccation injury and a high-cholesterol diet. At the time of angioplasty, rabbits were randomly assigned to 1 of 4 groups: controls: heparin bolus, saline infusion at 24 hours; early hirudin: hirudin bolus+2 hours' infusion, saline infusion at 24 hours; delayed hirudin: heparin bolus, hirudin infusion±bolus at 24 hours; and early+delayed hirudin: hirudin bolus+2 hours' infusion, hirudin infusion±bolus at 24 hours. Rabbits were euthanized after 28 days. The early+delayed hirudin treatment group had less loss of minimal lumen diameter by angiography at 28 days. By histomorphometry, cross-sectional area narrowing by plaque was least in the early+delayed treatment group compared with controls (P=0.0001), early hirudin (P=0.01), or delayed hirudin (P=0.001). The early+delayed hirudin group also had a significant reduction in absolute plaque area and an improvement in lumen area compared with the other groups. No differences were observed between treatment groups with respect to the cross-sectional area encompassed by the internal or external elastic laminae.

Conclusions—Combined early+delayed administration of hirudin significantly reduces angiographic restenosis and cross-sectional area narrowing by plaque compared with early or late treatment alone. These results suggest that restenosis after balloon angioplasty is markedly influenced by thrombin-mediated events not only occurring early but also extending beyond the first 24 hours in this model.

Key Words: restenosis • atherosclerosis • hirudin

This article has been cited by other articles:

				J. Kim, L. Zhang, K. Peppel, J.-H. Wu, D. A. Zidar, L. Brian, S. M. DeWire, S. T. Exum, R. J. Lefkowitz, and N. J. Freedman {beta}-Arrestins Regulate Atherosclerosis and Neointimal Hyperplasia by Controlling Smooth Muscle Cell Proliferation and Migration Circ. Res., July 3, 2008; 103(1): 70 - 79. [Abstract] [Full Text] [PDF]

				Z. H. Mnjoyan, D. Doan, J. L. Brandon, K. Felix, C. L. Sitter, A. A. Rege, T. A. Brock, and K. Fujise The critical role of the intrinsic VSMC proliferation and death programs in injury-induced neointimal hyperplasia Am J Physiol Heart Circ Physiol, May 1, 2008; 294(5): H2276 - H2284. [Abstract] [Full Text] [PDF]

				M. Kalinowski, H. Alfke, S. Bergen, K. J. Klose, J. J. Barry, and H.-J. Wagner Comparative Trial of Local Pharmacotherapy with L-Arginine, r-Hirudin, and Molsidomine to Reduce Restenosis after Balloon Angioplasty of Stenotic Rabbit Iliac Arteries Radiology, June 1, 2001; 219(3): 716 - 723. [Abstract] [Full Text] [PDF]

				C. Patterson, G. A. Stouffer, N. Madamanchi, and M. S. Runge New Tricks for Old Dogs : Nonthrombotic Effects of Thrombin in Vessel Wall Biology Circ. Res., May 25, 2001; 88(10): 987 - 997. [Abstract] [Full Text] [PDF]