External Application of Rapamycin-Eluting Film at Anastomotic Sites Inhibits Neointimal Hyperplasia in a Canine Model

doi:10.1016/j.athoracsur.2007.02.034

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Original Articles: Cardiovascular

External Application of Rapamycin-Eluting Film at Anastomotic Sites Inhibits Neointimal Hyperplasia in a Canine Model

Satoshi Kawatsu, MD^a^,_*, Katsuhiko Oda, MD^a, Yoshikatsu Saiki, MD^a, Yasuhiko Tabata, PhD, DMedSci^b, Koichi Tabayashi, MD^a

^a Department of Cardiovascular Surgery, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Japan
^b Department of Biomaterials, Field of Tissue Engineering, Institute for Frontier Medical Science, Kyoto University, Sankyo-ku, Kyoto, Japan

Accepted for publication February 15, 2007.

^_* Address correspondence to Dr Kawatsu, Department of Cardiovascular Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Japan 980-8574 (Email: kawa2{at}mail.tains.tohoku.ac.jp).

Presented at the Forty-third Annual Meeting of The Society of Thoracic Surgeons, San Diego, CA, Jan 29–31, 2007.

Background: Stenosis at a vascular anastomotic site has been a significantclinical issue. We tested the hypothesis that rapamycin-elutingbiodegradable poly L-lactic acid and epsilon-caprolactone copolymer(PLA-CL) film applied externally can inhibit neointimal hyperplasiain a canine vascular anastomosis model.

Methods: Femoral artery graft interposition was performed in 25 beagles.Beagles were divided into five groups (five in each): graftinterposition without PLA-CL film (control); with PLA-CL filmonly; and PLA-CL containing rapamycin 8 µg, 80 µg,and 800 µg. Orthotopic arterial graft interposition wasperformed on the left side and vein graft from the ipsilateralfemoral vein was interposed on the right. Morphometric and immunochemicalanalyses were performed at four-week intervals.

Results: In arterial graft models, the ratio of intimal area (intimalarea divided by the entire vessel area) was significantly reducedin all the three rapamycin-eluting film groups compared withcontrol (0.19, 0.07, 0.05, and 0.38 in 8 µg, 80 µg,800 µg groups and control, respectively, p < 0.05).In vein graft models, the ratio of intimal area was significantlydecreased only in the 800 µg rapamycin group comparedwith control (0.33 vs 0.54, p < 0.05). Inhibition of neointimalgrowth was associated with reduced cell proliferation, as evidencedby proliferating cell nuclear antigen immunostaining and diminishedalpha-actin positive vascular smooth muscle cells.

Conclusions: Rapamycin-eluting biodegradable PLA-CL film applied externallycan inhibit neointimal hyperplasia of arterial and vein graftsin a canine model. The inhibitory effect of rapamycin-elutingfilm against neointimal growth is more pronounced in the arterialgraft than the vein graft.

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