AbstractObjective: To investigate whether cytochalasin D-eluting stents (CDES) suppress intimal hyperplasia in porcine coronary arteries and to compare the efficacy of paclitaxel and cytochalasin D as inhibitors of vascular smooth muscle cell (SMC) proliferation and platelet aggregation in vitro.
Methods: Rabbit platelet-rich plasma and SMC cultures derived from rabbit aortas were exposed to 10−8–10−5 M cytochalasin D or paclitaxel. Stents directly coated with 2 μg cytochalasin D (low-dose CDES, n=12) and bare stents (n=12) were randomly deployed in the right and left coronary artery of 12 pigs. Six weeks later, neointima was studied using quantitative coronary angiography (QCA) and morphometry. To examine a ten-fold higher dose, polybutyl methacrylate/polyvinyl acetate-coated stents were loaded with 20 μg cytochalasin D. High-dose CDES (n=10) and polymer-only stents (n=11) were deployed in 11 pigs.
Results: After 7 days, cytochalasin D (IC50 9.9 ± 0.4 10−8 M) and paclitaxel (IC50 1.1 ± 0.4 10−8 M) inhibited SMC proliferation in vitro (n=4). In contrast, cytochalasin D (10−6–10−5 M, n=5), but not paclitaxel, attenuated platelet shape change and aggregation induced by ADP. In vivo QCA showed less late lumen loss in low-dose CDES (0.08 ± 0.07 vs. 0.32 ± 0.08 mm, P=0.05), but morphometry demonstrated only a tendency toward a decreased intimal area. High-dose CDES inhibited both late lumen loss (0.31 ± 0.08 vs. 0.91 ± 0.06 mm, P<0.01) and intimal area (1.57 ± 0.20 vs. 2.46 ± 0.22 mm2, P<0.01). Immunohistochemistry revealed that CDES suppressed peri-strut macrophage recruitment (CD68, P=0.04) and cell proliferation (Ki67, P=0.03) as compared to polymer-only stents without interfering with endothelial cell recovery or the density of α-SMC actin staining. Thromboses or edge effects were not observed in either study.
Conclusions: CDES inhibited in-stent hyperplasia. The reduction (39%) with 20 μg CDES was equivalent to that reported for paclitaxel-eluting stents in pigs. Interference with platelet aggregation, SMC migration, SMC proliferation, and leukocyte recruitment could contribute to the benefit. The data indicate that targeting of actin microfilaments has a potential to suppress in-stent restenosis.
