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


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 mug/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 microM 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 mm(2), 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.
Murphy
Gavin J
GJ
Bristol Heart Institute, University of Bristol, Bristol, BS2 8HW, UK.
Johnson
Thomas W
TW
Chamberlain
Martin H
MH
Rizvi
S Imran
SI
Wyatt
Marcie
M
George
Sarah J
SJ
Angelini
Gianni D
GD
Karsch
Karl R
KR
Oberhoff
Martin
M
Newby
Andrew C
AC
D000818:Animals; D019072:Antibiotic Prophylaxis; D015415:Biomarkers / Q000032:analysis; D049109:Cell Proliferation / Q000187:drug effects; D015638:Cytochalasin D / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D023421:Models, Animal; D009924:Organ Culture Techniques; D017239:Paclitaxel / Q000494:pharmacology*; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D012501:Saphenous Vein / Q000473:pathology / Q000637:transplantation*; D020123:Sirolimus / Q000494:pharmacology*; D013194:Staining and Labeling; D013552:Swine; D013995:Time; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology*
D015415:Biomarkers; D018809:Proliferating Cell Nuclear Antigen; D015638:Cytochalasin D; D017239:Paclitaxel; D020123:Sirolimus