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This Article Full Text Full Text (PDF) Supplemental Table and Figures All Versions of this Article: 291/6/H2692    most recent 00148.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Mandinov, L. Articles by de Muinck, E. D. Search for Related Content PubMed PubMed Citation Articles by Mandinov, L. Articles by de Muinck, E. D.

Inhibition of in-stent restenosis by oral copper chelation in porcine coronary arteries

L. Mandinov,¹ K. L. Moodie,² A. Mandinova,¹ Z. Zhuang,² F. Redican,² D. Baklanov,² V. Lindner,¹ T. Maciag,^1, M. Simons,² and E. D. de Muinck¹

¹Maine Medical Center Research Institute, Maine Medical Center, Scarborough, Maine; and ²Section of Cardiology, Angiogenesis Research Center, Dartmouth Medical School, Dartmouth-Hitchcock Medical Center, Hanover, New Hampshire

Submitted 8 February 2006 ; accepted in final form 16 May 2006

Stress-induced release of IL-1 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 mm², P < 0.05), and neointimal volume by histomorphometry was 37% less in TTM-treated animals (34.9 ± 11.5 vs. 55.2 ± 19.6 mm³, P < 0.05). We conclude that systemic copper chelation with a clinically approved chelator significantly inhibits in-stent restenosis.

inflammation; stent