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(Circulation. 2008;118:1953-1960.)
© 2008 American Heart Association, Inc.

Imaging

Molecular Imaging of Activated Matrix Metalloproteinases in Vascular Remodeling

Jiasheng Zhang, MD; Lei Nie, PhD; Mahmoud Razavian, PhD; Masood Ahmed, MD; Lawrence W. Dobrucki, PhD; Abolfazl Asadi, PhD; D. Scott Edwards, PhD; Michael Azure, PhD; Albert J. Sinusas, MD; Mehran M. Sadeghi, MD

From the Raymond and Beverly Sackler Cardiovascular Molecular Imaging Laboratory, Section of Cardiovascular Medicine (J.Z., L.N., M.R., M. Ahmed, L.W.D., A.A., A.J.S., M.M.S.), Yale University School of Medicine, New Haven, Conn; VA Connecticut Healthcare System (J.Z., L.N., M.R., M. Ahmed, A.A., M.M.S.), West Haven, Conn; and Lantheus Medical Imaging (D.S.E., M. Azure), North Billerica, Mass.

Correspondence to Mehran M. Sadeghi, MD, VA Connecticut Healthcare System, 950 Campbell Ave, 111B, West Haven, CT 06516. E-mail Mehran.sadeghi{at}yale.edu

Received April 30, 2008; accepted September 9, 2008.

Background— Matrix metalloproteinase (MMP) activation plays a key role in vascular remodeling. RP782 is a novel indium ¹¹¹In–labeled tracer with specificity for activated MMPs. We hypothesized that RP782 can detect injury-induced vascular remodeling in vivo.

Methods and Results— Left common carotid artery injury was induced with a guidewire in apolipoprotein E^–/– mice. Sham surgery was performed on the contralateral artery, which served as control for imaging experiments. Carotid wire injury led to significant hyperplasia and expansive remodeling over a period of 4 weeks. MMP activity, detected by in situ zymography, increased in response to injury and was maximal by 3 to 4 weeks after injury. RP782 (11.1 MBq) was injected intravenously into apolipoprotein E^–/– mice at 1, 2, 3, and 4 weeks after left carotid injury. MicroSPECT imaging was performed at 2 hours and was followed by CT angiography to localize the carotid arteries. In vivo images revealed focal uptake of RP782 in the injured carotid artery at 2, 3, and 4 weeks. Increased tracer uptake in the injured artery was confirmed by quantitative autoradiography. Pretreatment with 50-fold excess nonlabeled tracer significantly reduced RP782 uptake in injured carotids, thus demonstrating uptake specificity. Weekly changes in the vessel-wall area closely paralleled and correlated with RP782 uptake (Spearman r=0.95, P=0.001).

Conclusions— Injury-induced MMP activation in the vessel wall can be detected by RP782 microSPECT/CT imaging in vivo. RP782 uptake tracks the hyperplastic process in vascular remodeling and provides an opportunity to track the remodeling process in vivo.

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Clinical Summaries
Circulation 2008 118: 1911-1912. [Extract] [Full Text]

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