Monitoring of arterial wall remodelling in atherosclerotic rabbits with a magnetic resonance imaging contrast agent binding to matrix metalloproteinases.
OBJECTIVE
P947 is a gadolinium-based magnetic resonance imaging (MRI) contrast agent with high affinity for several matrix metalloproteinases (MMPs) involved in arterial wall remodelling. We tested whether the intensity of enhancement detected in vivo in the arterial wall with P947 and MRI correlates with actual tissue MMP-related enzymatic activity measured in a rabbit atherosclerotic model subjected to dietary manipulations.


RESULTS
Aortas of 15 rabbits in which atherosclerotic lesions were induced by balloon angioplasty and 4 months of hypercholesterolaemic diet were imaged at 'baseline' with P947-enhanced MRI. Atherosclerotic rabbits were divided into three groups: five rabbits were sacrificed ('baseline' group); five rabbits continued to be fed a lipid-supplemented diet ('high-fat' group); and five rabbits were switched from atherogenic to a purified chow diet ('low-fat' group). Four months later, a second P947-enhanced MRI was acquired in the 10 remaining rabbits. A significantly lower signal was detected in the aortic wall of rabbits from the 'low-fat' group as compared with rabbits from the 'high-fat' group (21 ± 6 vs. 46 ± 3%, respectively; P = 0.04). Such differences were not detected with the contrast agent P1135, which lacks the MMP-specific peptide sequence. In addition, the intensity of aortic wall enhancement detected with MRI after injection of P947 strongly correlated with actual MMP-2 gelatinolytic activity measured in corresponding aortic segments using zymography (r = 0.87).


CONCLUSIONS
P947-enhanced MRI can distinguish dietary-induced variations in MMP-related enzymatic activity within plaques in an experimental atherosclerotic model, supporting its utility as a clinical imaging tool for in vivo detection of arterial wall remodelling.
Translational and Molecular Imaging Institute, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA.
Fabien
F
Hyafil
Esad
E
Vucic
Jean-Christophe
JC
Cornily
Rahul
R
Sharma
Vardan
V
Amirbekian
Francis
F
Blackwell
Eric
E
Lancelot
Claire
C
Corot
Valentin
V
Fuster
Zorina S
ZS
Galis
Laurent J
LJ
Feldman
Zahi A
ZA
Fayad
D000818:Animals; D001012:Aorta, Abdominal; D001018:Aortic Diseases / Q000473:pathology*; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology*; D002784:Cholesterol / Q000378:metabolism; D003287:Contrast Media; D018752:Diet, Fat-Restricted; D059305:Diet, High-Fat; D006571:Heterocyclic Compounds / Q000378:metabolism; D018810:Magnetic Resonance Angiography; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D009942:Organometallic Compounds / Q000378:metabolism; D058226:Plaque, Atherosclerotic / Q000378:metabolism / Q000473:pathology; D011817:Rabbits
D003287:Contrast Media; D006571:Heterocyclic Compounds; D009942:Organometallic Compounds; D002784:Cholesterol; C050823:gadolinium 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetate; D020782:Matrix Metalloproteinases