Orally administered penicillamine is a potent inhibitor of neointimal and medial thickening in porcine saphenous vein-carotid artery interposition grafts.
OBJECTIVE
In patients who have undergone coronary artery bypass grafting, blood copper levels are elevated for 6 weeks after surgery. Copper is an established risk factor for cardiovascular disease and atherogenesis and promotes oxidative stress, lipid oxidation, cell proliferation, and matrix formation, all components of vein graft disease. This project therefore examined the effect of the copper chelator penicillamine on saphenous vein graft thickening in a pig model.


METHODS
Saphenous vein-carotid artery interposition grafts were carried out in Landrace pigs. Penicillamine (10 mg/kg once daily, n = 8) was administered orally incorporated into small amounts of mashed potato for 1 month (n = 8 controls). Vein grafts were then excised and fixed at 100 mm Hg, histologic sections were prepared, and morphometry and measurement of proliferating cell nuclear antigen count were carried out. In vitro studies on the effect of copper or penicillamine on human vascular smooth muscle cell replication was carried out with bromodeoxyuridine incorporation.


RESULTS
Administration of penicillamine had a potent inhibitory effect on both neointimal and medial thickness and proliferating cell nuclear antigen count but elicited a marked increase in luminal area and reduced serum copper concentrations. In vitro, copper augmented vascular smooth muscle cell proliferation, an effect blocked by penicillamine. Penicillamine alone also inhibited in vitro vascular smooth muscle cell replication.


CONCLUSIONS
The administration of penicillamine reduces vein graft thickening and promotes positive remodeling through negation of copper-induced cell proliferation. Copper chelators may therefore be therapeutically useful in preventing late vein graft failure in patients undergoing reconstructive arterial surgery.
Wan
Song
S
Department of Surgery, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong, China.
Shukla
Nilima
N
Yim
Anthony P C
AP
Johnson
Jason L
JL
Angelini
Gianni D
GD
Jeremy
Jamie Y
JY
D000284:Administration, Oral; D000714:Anastomosis, Surgical / Q000009:adverse effects / Q000379:methods; D000818:Animals; D001707:Biopsy, Needle; D017536:Carotid Artery, Common / Q000187:drug effects / Q000473:pathology / Q000637:transplantation*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006083:Graft Occlusion, Vascular / Q000473:pathology / Q000517:prevention & control*; D007150:Immunohistochemistry; D008297:Male; D010396:Penicillamine / Q000494:pharmacology*; D010784:Photomicrography; D011336:Probability; D012016:Reference Values; D012501:Saphenous Vein / Q000187:drug effects / Q000473:pathology / Q000637:transplantation*; D018709:Statistics, Nonparametric; D013552:Swine; D017539:Tunica Intima / Q000187:drug effects* / Q000473:pathology*
D010396:Penicillamine