on January 15, 2007
Published online before print January 15, 2007, doi: 10.1161/CIRCULATIONAHA.106.654913
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Submitted on August 3, 2006
From the Center for Molecular Imaging Research (E.A., M.N., D.S., V.M.L., F.A.J., R.W.), Massachusetts General Hospital, Harvard Medical School, Charlestown, Mass; Cardiology Division (D.S., F.A.J.), Department of Medicine, Massachusetts General Hospital, Boston, Mass; Cardiovascular Division (M.A.), Department of Medicine, Brigham and Women’s Hospital, Boston, Mass; and Donald W. Reynolds Cardiovascular Clinical Research Center (E.A., M.N., F.A.J., M.A., R.W.), Harvard Medical School, Boston, Mass. * To whom correspondence should be addressed. E-mail: eaikawa{at}partners.org.
Background--Visualizing early changes in valvular cell functions in vivo may predict the future risk and identify therapeutic targets for prevention of aortic valve stenosis. Methods and Results--To test the hypotheses that (1) aortic stenosis shares a similar pathogenesis to atherosclerosis and (2) molecular imaging can detect early changes in aortic valve disease, we used in vivo a panel of near-infrared fluorescence imaging agents to map endothelial cells, macrophages, proteolysis, and osteogenesis in aortic valves of hypercholesterolemic apolipoprotein E-deficient mice (30 weeks old, n=30). Apolipoprotein E-deficient mice with no probe injection (n=10) and wild-type mice (n=10) served as controls. Valves of apolipoprotein E-deficient mice contained macrophages, were thicker than wild-type mice (P<0.001), and showed early dysfunction detected by MRI in vivo. Fluorescence imaging detected uptake of macrophage-targeted magnetofluorescent nanoparticles (24 hours after injection) in apolipoprotein E-deficient valves, which was negligible in controls (P<0.01). Valvular macrophages showed proteolytic activity visualized by protease-activatable near-infrared fluorescence probes. Ex vivo magnetic resonance imaging enhanced with vascular cell adhesion molecule-1-targeted nanoparticles detected endothelial activation in valve commissures, the regions of highest mechanical stress. Osteogenic near-infrared fluorescence signals colocalized with alkaline phosphatase activity and expression of osteopontin, osteocalcin, Runx2/Cbfa1, Osterix, and Notch1 despite no evidence of calcium deposits, which suggests ongoing active processes of osteogenesis in inflamed valves. Notably, the aortic wall contained advanced calcification. Quantitative image analysis correlated near-infrared fluorescence signals with immunoreactive vascular cell adhesion molecule-1, macrophages, and cathepsin-B (P<0.001). Conclusions--Molecular imaging can detect in vivo the key cellular events in early aortic valve disease, including endothelial cell and macrophage activation, proteolytic activity, and osteogenesis.
Accepted on November 6, 2006
Multimodality Molecular Imaging Identifies Proteolytic and Osteogenic Activities in Early Aortic Valve Disease
Elena Aikawa MD, PhD*,
Key words: valves • stenosis • inflammation • atherosclerosis • hypercholesterolemia • imaging
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