Submitted on February 8, 2006
Accepted on May 16, 2006
Inhibition of In-Stent Restenosis by Oral Copper Chelation in Porcine Coronary Arteries
Lazar Mandinov1, Karen L Moodie2, Anna Mandinova1, Zhenwu Zhuang2, Francis Redican2, Dmitri Baklanov2, Volkhard Lindner1, Thomas Maciag1, Michael Simons3, and Ebo D de Muinck2*
1 Maine Medical Center Research Institute, Maine Medical Center, Scarborough, Maine, United States
2 Angiogenesis Research Center, Dartmouth Medical School, Hanover, New Hampshire, United States
3 Section Of Cardiology, Angiogenesis Research Center, Dartmouth Medical School, Dartmouth-Hitchcock Medical Center, Hanover, New Hampshire, United States
* To whom correspondence should be addressed. E-mail: ebo.d.demuinck{at}dartmouth.edu.
OBJECTIVE. Stress-induced release of interleukin-1
and fibroblast growth factor 1, is dependent upon intra-cellular copper, and is a major driver of neo-intimal hyperplasia. Therefore, we assessed the effect of tetrathiomolybdate (TTM) - a clinically proven copper chelator - on in-stent restenosis. METHODS. Nine pigs (Gr.1) received 5mg/kg TTM p.o. twice daily for 2 weeks before stent implantation and 4 weeks thereafter, and 9 pigs (Gr.2) 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. RESULTS. In Gr.1 ceruloplasmin dropped 70±10% below baseline levels. The groups were comparable regarding baseline characteristics. At 4 weeks follow-up all parameters relevant to in-stent restenosis were significantly reduced in Gr.1: minimal lumen diameter by QCA was 2.03±0.57 mm in Gr.1 vs. 1.47±0.45 mm in Gr.2, (p<0.05); percent diameter stenosis was 39% less in Gr.1 (27.1±16.6% vs. 44.5±16.1%, p<0.05); minimal lumen area by IVUS was 60% larger in Gr.1 (4.27±1.56 mm2 vs. 2.67±1.19 mm2, p<0.05), and neointima volume by histomorphometry was 37% less in Gr.1 (34.9±11.5 mm3 vs. 55.2±19.6 mm3, p<0.05). CONCLUSIONS. Systemic copper chelation with a clinically approved chelator significantly inhibits in-stent restenosis.
