Evaluation of matrix metalloproteinases in atherosclerosis using a novel noninvasive imaging approach.
OBJECTIVE
Despite great advances in our knowledge, atherosclerosis continues to kill more people than any other disease in the Western world. This is because our means of identifying truly vulnerable patients is limited. Prediction of atherosclerotic plaque rupture may be addressed by MRI of activated matrix metalloproteinases (MMPs), a family of enzymes that have been implicated in the vulnerability of plaques prone to rupture. This study evaluated the ability of the novel gadolinium-based MRI contrast agent P947 to target MMPs in atherosclerotic plaques.


RESULTS
The affinity of P947 toward activated MMPs was demonstrated in vitro. The affinity and specificity of P947 toward matrix metalloproteinase (MMP)-rich plaques was evaluated both in vivo using ApoE-/- mice and ex vivo in hyperlipidemic rabbits. Gadolinium content quantification and MRI showed a preferential accumulation of P947 in atherosclerotic lesions compared with the nontargeted reference compound, Gd-DOTA. The ex vivo assay on rabbit plaques revealed a higher uptake of P947. Moreover, using human carotid artery endarterectomy specimens, P947 facilitated discrimination between histologically defined MMP-rich and MMP-poor plaques. An in vivo MRI investigation in mice revealed that P947 greatly improved the ability to visualize and delineate atherosclerotic plaques.


CONCLUSIONS
P947 may be a useful tool for the detection and characterization of the MMP-rich atherosclerotic plaques.
Lancelot
Eric
E
Department of Radiology, the Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai School of Medicine, Box 1234, One Gustave L. Levy Place, New York, NY 10029, USA.
Amirbekian
Vardan
V
Brigger
Irène
I
Raynaud
Jean-Sébastien
JS
Ballet
Sébastien
S
David
Christelle
C
Rousseaux
Olivier
O
Le Greneur
Soizic
S
Port
Marc
M
Lijnen
Henri R
HR
Bruneval
Patrick
P
Michel
Jean-Baptiste
JB
Ouimet
Tanja
T
Roques
Bernard
B
Amirbekian
Smbat
S
Hyafil
Fabien
F
Vucic
Esad
E
Aguinaldo
Juan Gilberto S
JG
Corot
Claire
C
Fayad
Zahi A
ZA
D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism / Q000473:pathology*; D001057:Apolipoproteins E / Q000494:pharmacology; D050197:Atherosclerosis / Q000175:diagnosis*; D015415:Biomarkers / Q000032:analysis; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology*; D003287:Contrast Media; D004195:Disease Models, Animal; D005682:Gadolinium; D006801:Humans; D066298:In Vitro Techniques; D008279:Magnetic Resonance Imaging / Q000379:methods*; D020782:Matrix Metalloproteinases / Q000032:analysis / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D011336:Probability; D011817:Rabbits; D012680:Sensitivity and Specificity; D018709:Statistics, Nonparametric
D001057:Apolipoproteins E; D015415:Biomarkers; D003287:Contrast Media; D005682:Gadolinium; D020782:Matrix Metalloproteinases