EFFECT OF THROMBIN INHIBITION WITH DESULFATOHIRUDIN ON EARLY KINETICSOF CELLULAR PROLIFERATION AFTER BALLOON ANGIOPLASTY IN ATHEROSCLEROTIC RABBITS

Background Thrombin may have a pivotal role in restenosis after angiop lasty. Hirudin, a potent thrombin inhibitor, reduces luminal narrowing by plaque after angioplasty in a rabbit model of atherosclerosis. Bec ause cellular proliferation is believed to be an important mechanism f or restenosis and thrombin has been shown to be a potent smooth muscle cell mitogen in vitro, we hypothesized that the mechanism of the effe ct of hirudin on limiting luminal narrowing by plaque occurs via inhib ition of cellular proliferation. Methods and Results Femoral atheroscl erosis was induced in 108 rabbits, and balloon angioplasty was perform ed. 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 hepa rin. Group 3 rabbits (n=29) were treated with hirudin (n=15) or hepari n (n=14) and killed at 7 or 28 days to determine cross-sectional area narrowing by plaque and cellular proliferation with the use of bromode oxyuridine labeling. At 29, 71, or 167 hours after angioplasty, group 1 and 2 rabbits were injected with H-3-thymidine and killed 1 hour lat er, and labeling indexes were determined. A significant increase in th e index of H-3-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 ind ex of labeled cells was similar to baseline (0.04+/-0.03 versus 0.01+/ -0.01, P=.12). Hirudin had no effect on the H-3-thymidine labeling ind exes at any of the time points studied despite the fact that hirudin t reatment in group 3 rabbits resulted in less cross-sectional area narr owing by plaque at both 7 and 28 days after angioplasty (41+/-16 versu s 24+/-12 at 7 days and 60+/-21 versus 44+/-17 at 28 days, heparin ver sus hirudin; P<.03). Conclusions Balloon angioplasty resulted in a mar ked increase in cellular proliferation that peaked at 72 hours. A 2-ho ur infusion of hirudin failed to reduce early H-3-thymidine labeling, suggesting that inhibition of cell proliferation within the first 7 da ys after angioplasty is not the predominant mechanism by which hirudin exerts its effect on limiting luminal narrowing by plaque 28 days aft er balloon angioplasty in this animal model.