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Circulation. 2007 Jan 23;115(3):377-86. Epub 2007 Jan 15.

Multimodality molecular imaging identifies proteolytic and osteogenic activities in early aortic valve disease.

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  • 1Center for Molecular Imaging Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, Mass 02129, USA. eaikawa@partners.org

Abstract

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.

Comment in

PMID:
17224478
[PubMed - indexed for MEDLINE]
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