Effect of thrombin inhibition with desulfatohirudin on early kinetics of cellular proliferation after balloon angioplasty in atherosclerotic rabbits.

BACKGROUND

Thrombin may have a pivotal role in restenosis after angioplasty. Hirudin, a potent thrombin inhibitor, reduces luminal narrowing by plaque after angioplasty in a rabbit model of atherosclerosis. Because cellular proliferation is believed to be an important mechanism for restenosis and thrombin has been shown to be a potent smooth muscle cell mitogen in vitro, we hypothesized that the mechanism of the effect of hirudin on limiting luminal narrowing by plaque occurs via inhibition of cellular proliferation.

METHODS AND RESULTS

Femoral atherosclerosis was induced in 108 rabbits, and balloon angioplasty was performed. At angioplasty, group 1 rabbits (n=38) were treated with a 2-hour infusion of hirudin, and group 2 rabbits (n=41) were treated with heparin. Group 3 rabbits (n=29) were treated with hirudin (n=15) or heparin (n=14) and killed at 7 or 28 days to determine cross-sectional area narrowing by plaque and cellular proliferation with the use of bromodeoxyuridine labeling. At 29, 71, or 167 hours after angioplasty, group 1 and 2 rabbits were injected with 3H-thymidine and killed 1 hour later, and labeling indexes were determined. A significant increase in the index of 3H-thymidine-labeled nuclei was observed in the intima of "ballooned" arteries compared with "nonballooned" atherosclerotic arteries at both 30 hours (0.06+/-0.05 versus 0.01+/-0.01, P<.01) and 72 hours (0.10+/-0.06 versus 0.004+/-0.004, P<.01). By 7 days, the index of labeled cells was similar to baseline (0.04+/-0.03 versus 0.01+/-0.01, P=.12). Hirudin had no effect on the 3H-thymidine labeling indexes at any of the time points studied despite the fact that hirudin treatment in group 3 rabbits resulted in less cross-sectional area narrowing by plaque at both 7 and 28 days after angioplasty (41+/-16 versus 24+/-12 at 7 days and 60+/-21 versus 44+/-17 at 28 days, heparin versus hirudin; P<.03).

CONCLUSIONS

Balloon angioplasty resulted in a marked increase in cellular proliferation that peaked at 72 hours. A 2-hour infusion of hirudin failed to reduce early 3H-thymidine labeling, suggesting that inhibition of cell proliferation within the first 7 days after angioplasty is not the predominant mechanism by which hirudin exerts its effect on limiting luminal narrowing by plaque 28 days after balloon angioplasty in this animal model.