Effects of cytochalasin D-eluting stents on intimal hyperplasia in a porcine coronary artery model.

Abstract

OBJECTIVE:

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 microg 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 microg cytochalasin D. High-dose CDES (n=10) and polymer-only stents (n=11) were deployed in 11 pigs.

RESULTS:

After 7 days, cytochalasin D (IC(50) 9.9+/-0.4 10(-8) M) and paclitaxel (IC(50) 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 mm(2), 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 alpha-SMC actin staining. Thromboses or edge effects were not observed in either study.

CONCLUSIONS:

CDES inhibited in-stent hyperplasia. The reduction (39%) with 20 mug 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.

• Authors: Koen J Salu, Johan M Bosmans, Yanming Huang, Marc Hendriks, Michel Verhoeven, Anita Levels, Susan Cooper, Ivan K De Scheerder, Chris J Vrints, Hidde Bult
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 69 Issue 2 Pg. 536-44 (Feb 01 2006) ISSN: 0008-6363 [Print] England
• PMID: 16386237 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Nucleic Acid Synthesis Inhibitors
• Cytochalasin D
• Paclitaxel

Topics

• Animals
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Cells, Cultured
• Coronary Angiography
• Coronary Restenosis (metabolism, prevention & control)
• Cytochalasin D (pharmacology, therapeutic use)
• Dose-Response Relationship, Drug
• Hyperplasia
• Macrophages (drug effects)
• Microscopy, Electron
• Models, Animal
• Muscle, Smooth, Vascular (cytology, drug effects)
• Nucleic Acid Synthesis Inhibitors (pharmacology, therapeutic use)
• Paclitaxel (pharmacology)
• Platelet Aggregation (drug effects)
• Rabbits
• Random Allocation
• Stents
• Swine
• Tunica Intima (drug effects, pathology)