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Multimodality and molecular imaging of matrix metalloproteinase activation in calcific aortic valve disease
Journal article   Open access   Peer reviewed

Multimodality and molecular imaging of matrix metalloproteinase activation in calcific aortic valve disease

Jae-Joon Jung, Mahmoud Razavian, Azariyas A Challa, Lei Nie, Reza Golestani, Jiasheng Zhang, Yunpeng Ye, Kerry S Russell, Simon P Robinson, Donald D Heistad, …
The Journal of nuclear medicine (1978), Vol.56(6), pp.933-938
06/2015
DOI: 10.2967/jnumed.114.152355
PMCID: PMC4454445
PMID: 25908827
url
https://doi.org/10.2967/jnumed.114.152355View
Published (Version of record) Open Access

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. 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. 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. 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.
 Animals Aortic Valve - diagnostic imaging Aortic Valve - enzymology Aortic Valve - pathology Aortic Valve Stenosis - diagnosis Aortic Valve Stenosis - diagnostic imaging Aortic Valve Stenosis - pathology Apolipoproteins E - genetics Calcinosis - diagnosis Calcinosis - diagnostic imaging Calcinosis - pathology Diet, High-Fat Echocardiography Heart Defects, Congenital - diagnosis Heart Defects, Congenital - diagnostic imaging Heart Defects, Congenital - enzymology Heart Valve Diseases - diagnosis Heart Valve Diseases - diagnostic imaging Heart Valve Diseases - enzymology Humans Matrix Metalloproteinases - metabolism Mice Mice, Transgenic Molecular Imaging Multimodal Imaging Technetium - chemistry Tomography, Emission-Computed, Single-Photon Tomography, X-Ray Computed

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