title: 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.affiliation: Division of Cardiology, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium.
authors.forename: Koen J
authors.initials: KJ
authors.lastname: Salu
authors.forename: Johan M
authors.initials: JM
authors.lastname: Bosmans
authors.forename: Yanming
authors.initials: Y
authors.lastname: Huang
authors.forename: Marc
authors.initials: M
authors.lastname: Hendriks
authors.forename: Michel
authors.initials: M
authors.lastname: Verhoeven
authors.forename: Anita
authors.initials: A
authors.lastname: Levels
authors.forename: Susan
authors.initials: S
authors.lastname: Cooper
authors.forename: Ivan K
authors.initials: IK
authors.lastname: De Scheerder
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Vrints
authors.forename: Hidde
authors.initials: H
authors.lastname: Bult
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D017023:Coronary Angiography; D023903:Coronary Restenosis / Q000378:metabolism / Q000517:prevention & control*; D015638:Cytochalasin D / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D006965:Hyperplasia; D008264:Macrophages / Q000187:drug effects; D008854:Microscopy, Electron; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D017239:Paclitaxel / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D011817:Rabbits; D011897:Random Allocation; D015607:Stents; D013552:Swine; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology*
chemical_list: D019384:Nucleic Acid Synthesis Inhibitors; D015638:Cytochalasin D; D017239:Paclitaxel