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
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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