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Cardiovascular Research 2007 73(3):607-617; doi:10.1016/j.cardiores.2006.11.015
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Copyright © 2006, European Society of Cardiology

Short- and long-term effects of cytochalasin D, paclitaxel and rapamycin on wall thickening in experimental porcine vein grafts

Gavin J. Murphy1, Thomas W. Johnson1, Martin H. Chamberlain, S. Imran Rizvi, Marcie Wyatt, Sarah J. George, Gianni D. Angelini, Karl R. Karsch, Martin Oberhoff1 and Andrew C. Newby*,1

Bristol Heart Institute, University of Bristol, Bristol, U.K., BS2 8HW, UK

* Corresponding author. Tel.: +44 1179283583; fax: +44 1179283581. Email address: a.newby{at}bris.ac.uk

Objectives: Neointima formation and wall thickening caused by smooth muscle cell proliferation compromise long-term patency of human aorto-coronary vein-grafts. We investigated short- and long-term effects of anti-proliferative pharmacological agents on experimental pig vein-grafts with similar dimensions and kinetics to human coronary grafts.

Methods and results: Saphenous veins were treated for 1 h ex vivo with vehicle or concentrations of cytochalasin D, paclitaxel or rapamycin found to be anti-proliferative in preliminary studies. Vehicle and treated veins were implanted contralaterally, end-to-end into the carotid arteries of pigs. Cytochalasin D 2.5 µg/ml non-significantly reduced neointima formation in 4-week vein-grafts (mean±standard error, 2.5±0.6 vs. 3.3±0.6 mm2, n=10, p=NS), whilst paclitaxel 10 µM produced significant inhibition (1.7±0.2 vs. 3.0±0.3 mm2, n=8, p<0.01) as did rapamycin 0.1 mg/ml (0.6±0.3 vs. 1.7±0.5 mm2, n=8, p<0.02). Similar effects were found on total wall cross-sectional area but medial area was unaffected. PCNA staining of 1-week vein grafts confirmed in vivo anti-proliferative effects of paclitaxel (21±2 vs. 36±3%, n=5, p<0.01) and rapamycin (32±1 vs. 57±6%, n=6, p<0.005); neither agent stimulated loss of endothelium at these concentrations. Neointima and total wall area increased significantly between 4- and 12-weeks in all vein-grafts such that there was no longer a significant effect on neointima formation of either paclitaxel (7.5±1.3 vs. 8.9±1.9 mm2 in control, n=5, p=NS) or rapamycin (6.0±0.9 vs. 7.9±1.1 mm2 in control, n=9, p=NS) or on total wall area in 12-week grafts.

Conclusions: Pre-treatment of saphenous vein with anti-proliferative agents paclitaxel or rapamycin reduced neointima and total wall area after 4 weeks but continued growth abolished differences by 12 weeks. These results may help to understand the failure of clinical studies using anti-proliferative treatments in vein-grafts.

KEYWORDS Vein-grafts; Paclitaxel; Rapamycin; Neointima

1 These authors contributed equally.

Time for primary review 48 days


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