INHIBITION OF CELLULAR PROLIFERATION AFTER EXPERIMENTAL BALLOON ANGIOPLASTY BY LOW-MOLECULAR-WEIGHT HEPARIN

Background. The proliferative response induced by balloon angioplasty is known to be an important factor in the development of restenosis after successful coronary angioplasty. Methods and Results. To study the effects of low-molecular-weight heparin (LMWH) on cellular proliferation after experimental balloon angioplasty, LMWH (3.9 kd, 400 anti-Xa units/kg/day) was given to 20 male New Zealand White rabbits. After an intimal fibromuscular plaque was induced by electrical stimulation in the right carotid artery, LMWH was applied during the 7 days after balloon dilatation. As the control group, 20 other rabbits underwent balloon angioplasty without application of LMWH. The vessels were excised 3, 7, 14, and 28 days after balloon treatment. During the final 18 hours before the rabbits were killed, bromodeoxyuridine was applied. Intimal wall thickness increased from 13 +/- 5 cell layers (preangioplasty control group) to 20 +/- 6 cell layers in the LMWH-treated group at 28 days (p < 0.05). In contrast, histological examination of control animals 28 days after angioplasty revealed a significant increase to 35 +/- 15 cell layers (p < 0.01). Immunohistological quantification showed a significant increase (p < 0.001) of cells undergoing DNA synthesis at 3 (10.2 +/- 4.2%) and 7 (7.7 +/- 4.8%) days after balloon dilatation in control animals. In contrast, at 3 and 7 days after balloon treatment, the percentage of cells undergoing DNA synthesis in LMWH-treated rabbits was lower (3 days, 2.7 +/- 1.8%; 7 days, 1.9 +/- 0.3%) than the corresponding untreated controls but showed a significant increase (p < 0.01) compared with the preangioplasty controls. The differences between the two groups were statistically significant, however (3 days, p < 0.01; 7 days, p < 0.05). As early as 14 days after angioplasty, the extent of cellular proliferation was normalized and was comparable to the preintervention levels in both groups. Conclusions. Our data indicate that the proliferative response after balloon angioplasty can be reduced in vivo by early treatment with LMWH and thus encourage further clinical investigations.