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[Abstract]

Calcific aortic valve disease (CAVD) is the most common cause of aortic stenosis. Matrix metalloproteinases (MMPs) are upregulated in CAVD and contribute to valvular remodeling and calcification. We investigated the feasibility and correlates of MMP-targeted molecular imaging for detection of valvular biology in CAVD.

METHODS: Apolipoprotein E-deficient (apoE(-/-)) mice were fed a Western diet (WD) for 3, 6, and 9 mo (n = 108) to induce CAVD. Wild-type mice served as the control group (n = 24). The development of CAVD was tracked with CT, echocardiography, MMP-targeted small-animal SPECT imaging using (99m)Tc-RP805, and histologic analysis.

RESULTS: Key features of CAVD-leaflet thickening and valvular calcification-were noted after 6 mo of WD and were more pronounced after 9 mo. These findings were associated with a significant reduction in aortic valve leaflet separation and a significant increase in transaortic valve flow velocity. On in vivo SPECT/CT images, MMP signal in the aortic valve area was significantly higher at 6 mo in WD mice than in control mice and decreased thereafter. The specificity of the signal was demonstrated by blocking, using an excess of nonlabeled precursor. Similar to MMP signal, MMP activity as determined by in situ zymography and valvular inflammation by CD68 staining were maximal at 6 mo. In vivo (99m)Tc-RP805 uptake correlated significantly with MMP activity (R(2) = 0.94, P < 0.05) and CD68 expression (R(2) = 0.98, P < 0.01) in CAVD.

CONCLUSION: MMP-targeted imaging detected valvular inflammation and remodeling in a murine model of CAVD. If this ability is confirmed in humans, the technique may provide a tool for tracking the effect of emerging medical therapeutic interventions and for predicting outcome in CAVD.

© 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

[Author information]

Jung JJ1, Razavian M1, Challa AA1, Nie L1, Golestani R1, Zhang J1, Ye Y1, Russell KS2, Robinson SP3, Heistad DD4, Sadeghi MM5.

1 Section of Cardiovascular Medicine and Cardiovascular Research Center, Yale University School of Medicine, New Haven, Connecticut VA Connecticut Healthcare Systems, West Haven, Connecticut.

2 Section of Cardiovascular Medicine and Cardiovascular Research Center, Yale University School of Medicine, New Haven, Connecticut.

3 Lantheus Medical Imaging, North Billerica, Massachusetts; and.

4 Division of Cardiovascular Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa.

5 Section of Cardiovascular Medicine and Cardiovascular Research Center, Yale University School of Medicine, New Haven, Connecticut VA Connecticut Healthcare Systems, West Haven, Connecticut mehran.sadeghi@yale.edu.