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

  1. Koen J. Salua,
  2. Johan M. Bosmansa,
  3. Yanming Huangc,
  4. Marc Hendriksd,
  5. Michel Verhoevend,
  6. Anita Levelsd,
  7. Susan Coopere,
  8. Ivan K. De Scheerderc,
  9. Chris J. Vrintsa and
  10. Hidde Bultb,*
  1. aDivision of Cardiology, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium
  2. bDivision of Pharmacology, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium
  3. cInterventional Cardiology, University Hospital Gasthuisberg, Leuven, Belgium
  4. dMedtronic Bakken Research Center, Maastricht, The Netherlands
  5. eDepartment of Anatomical Pathology, University of the Orange Free State, Bloemfontein, South Africa
  1. *Corresponding author. Tel.: +32 38202738; fax: +32 38202567. Email address: hidde.bult{at}ua.ac.be
  • Received June 20, 2005.
  • Revision received October 31, 2005.
  • Accepted November 10, 2005.

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 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.

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    1. Cardiovasc Res (2006) 69 (2): 536-544. doi: 10.1016/j.cardiores.2005.11.012
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