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

1 Maine Medical Center Research Institute, Maine Medical Center, Scarborough, Maine; and 2 Section 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 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. inflammation; stent Address for reprint requests and other correspondence: E. D. de Muinck, Angiogenesis Research Center, Dartmouth Medical School, Borwell Research Bldg. 734E, HB 7700, 1 Medical Center Dr., Lebanon, NH 03756 (e-mail: ebo.d.demuinck{at}dartmouth.edu )