Inhibition of in-stent restenosis by oral copper chelation in porcine coronary arteries.
Stress-induced release of IL-1alpha and fibroblast growth factor-1 is dependent on intracellular copper and is a major driver of neointimal hyperplasia. Therefore, we assessed the effect of tetrathiomolybdate (TTM), a clinically proven copper chelator, on in-stent restenosis. Nine pigs were treated with TTM (5 mg/kg po) twice daily for 2 wk before stent implantation and for 4 wk thereafter, and nine pigs served as controls. In-stent restenosis was assessed by quantitative coronary angiography (QCA), intravascular ultrasound (IVUS), and histomorphometry. Serum ceruloplasmin activity was used as a surrogate marker of copper bioavailability. In TTM-treated animals, ceruloplasmin dropped 70 +/- 10% below baseline levels. Baseline characteristics were comparable in TTM-treated and control animals. At 4-wk follow-up, all parameters relevant to in-stent restenosis were significantly reduced in TTM-treated animals: minimal lumen diameter by QCA was 2.03 +/- 0.57 and 1.47 +/- 0.45 mm in TTM-treated and control animals, respectively (P < 0.05), percent stenosis diameter was 39% less in TTM-treated animals (27.1 +/- 16.6% vs. 44.5 +/- 16.1%, P < 0.05), minimal lumen area by IVUS was 60% larger in TTM-treated animals (4.27 +/- 1.56 vs. 2.67 +/- 1.19 mm(2), P < 0.05), and neointimal volume by histomorphometry was 37% less in TTM-treated animals (34.9 +/- 11.5 vs. 55.2 +/- 19.6 mm(3), P < 0.05). We conclude that systemic copper chelation with a clinically approved chelator significantly inhibits in-stent restenosis.
Mandinov
L
L
Maine Medical Center Research Institute, Scarborough, USA.
Moodie
K L
KL
Mandinova
A
A
Zhuang
Z
Z
Redican
F
F
Baklanov
D
D
Lindner
V
V
Maciag
T
T
Simons
M
M
de Muinck
E D
ED
D000818:Animals; D002570:Ceruloplasmin / Q000378:metabolism; D002614:Chelating Agents / Q000378:metabolism / Q000494:pharmacology*; D015913:Chelation Therapy / Q000379:methods; D003300:Copper / Q000378:metabolism*; D017023:Coronary Angiography; D023903:Coronary Restenosis / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D003331:Coronary Vessels / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D008297:Male; D008982:Molybdenum / Q000378:metabolism / Q000494:pharmacology*; D015607:Stents; D013552:Swine; D013997:Time Factors; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology; D018084:Ultrasonography, Interventional
D002614:Chelating Agents; D003300:Copper; D008982:Molybdenum; C020809:tetrathiomolybdate; D002570:Ceruloplasmin