title: Multimodality and molecular imaging of matrix metalloproteinase activation in calcific aortic valve disease.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Section of Cardiovascular Medicine and Cardiovascular Research Center, Yale University School of Medicine, New Haven, Connecticut VA Connecticut Healthcare Systems, West Haven, Connecticut.
authors.forename: Jae-Joon
authors.initials: JJ
authors.lastname: Jung
authors.affiliation: Section of Cardiovascular Medicine and Cardiovascular Research Center, Yale University School of Medicine, New Haven, Connecticut VA Connecticut Healthcare Systems, West Haven, Connecticut.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Razavian
authors.affiliation: Section of Cardiovascular Medicine and Cardiovascular Research Center, Yale University School of Medicine, New Haven, Connecticut VA Connecticut Healthcare Systems, West Haven, Connecticut.
authors.forename: Azariyas A
authors.initials: AA
authors.lastname: Challa
authors.affiliation: Section of Cardiovascular Medicine and Cardiovascular Research Center, Yale University School of Medicine, New Haven, Connecticut VA Connecticut Healthcare Systems, West Haven, Connecticut.
authors.forename: Lei
authors.initials: L
authors.lastname: Nie
authors.affiliation: Section of Cardiovascular Medicine and Cardiovascular Research Center, Yale University School of Medicine, New Haven, Connecticut VA Connecticut Healthcare Systems, West Haven, Connecticut.
authors.forename: Reza
authors.initials: R
authors.lastname: Golestani
authors.affiliation: Section of Cardiovascular Medicine and Cardiovascular Research Center, Yale University School of Medicine, New Haven, Connecticut VA Connecticut Healthcare Systems, West Haven, Connecticut.
authors.forename: Jiasheng
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Section of Cardiovascular Medicine and Cardiovascular Research Center, Yale University School of Medicine, New Haven, Connecticut VA Connecticut Healthcare Systems, West Haven, Connecticut.
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Ye
authors.affiliation: Section of Cardiovascular Medicine and Cardiovascular Research Center, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Kerry S
authors.initials: KS
authors.lastname: Russell
authors.affiliation: Lantheus Medical Imaging, North Billerica, Massachusetts; and.
authors.forename: Simon P
authors.initials: SP
authors.lastname: Robinson
authors.affiliation: Division of Cardiovascular Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa.
authors.forename: Donald D
authors.initials: DD
authors.lastname: Heistad
authors.affiliation: 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.
authors.forename: Mehran M
authors.initials: MM
authors.lastname: Sadeghi
mesh_terms: D000818:Animals; D001021:Aortic Valve / Q000000981:diagnostic imaging* / Q000201:enzymology / Q000473:pathology*; D001024:Aortic Valve Stenosis / Q000175:diagnosis* / Q000000981:diagnostic imaging* / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics; D000082882:Bicuspid Aortic Valve Disease; D002114:Calcinosis / Q000175:diagnosis* / Q000000981:diagnostic imaging* / Q000473:pathology; D059305:Diet, High-Fat; D004452:Echocardiography; D006330:Heart Defects, Congenital / Q000175:diagnosis* / Q000000981:diagnostic imaging / Q000201:enzymology; D006349:Heart Valve Diseases / Q000175:diagnosis* / Q000000981:diagnostic imaging / Q000201:enzymology; D006801:Humans; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D057054:Molecular Imaging; D064847:Multimodal Imaging; D013667:Technetium / Q000737:chemistry; D015899:Tomography, Emission-Computed, Single-Photon; D014057:Tomography, X-Ray Computed
chemical_list: D001057:Apolipoproteins E; D013667:Technetium; D020782:Matrix Metalloproteinases
keywords: aortic valve; calcification; inflammation; matrix metalloproteinases; molecular imaging