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

• Published in: American journal of physiology. Heart and circulatory physiology Vol. 291; no. 6; p. H2692
• Main Authors: Mandinov, L, Moodie, K L, Mandinova, A, Zhuang, Z, Redican, F, Baklanov, D, Lindner, V, Maciag, T, Simons, M, de Muinck, E D
• Format: Journal Article
• Language: English
• Published: United States 01-12-2006
• Subjects: Animals; Ceruloplasmin - metabolism; Chelating Agents - metabolism; Chelating Agents - pharmacology; Chelation Therapy - methods; Copper - metabolism; Coronary Angiography; Coronary Restenosis - pathology; Coronary Restenosis - physiopathology; Coronary Restenosis - prevention & control; Coronary Vessels - diagnostic imaging; Coronary Vessels - pathology; Coronary Vessels - physiopathology; Disease Models, Animal; Male; Molybdenum - metabolism; Molybdenum - pharmacology; Stents; Swine; Time Factors; Tunica Intima - drug effects; Tunica Intima - pathology; Ultrasonography, Interventional
• ISSN: 0363-6135
• DOI: 10.1152/ajpheart.00148.2006

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.