Published online before print October 20, 2008, doi: 10.1161/CIRCULATIONAHA.108.789743
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(Circulation. 2008;118:1953-1960.)
© 2008 American Heart Association, Inc.
Imaging |
Molecular Imaging of Activated Matrix Metalloproteinases in Vascular Remodeling
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.
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Abstract |
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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.
Key Words: imaging • metalloproteinases • remodeling
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Introduction |
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Vascular disease remains a major cause of morbidity and mortality in developed (and increasingly, developing) countries. Advances in vascular biology in the past 2 decades have translated into the discovery of novel therapies, which in turn have led to a reduction in morbidity and mortality. It is well recognized that the lack of in vivo imaging modalities for detection of molecular events in the vessel wall has limited vascular biology research and the ability to detect early, presumably easier-to-treat vascular disease. Molecular imaging targeted at biologically relevant molecules or markers of vascular disease provides an opportunity to study pathogenesis, detect early disease, and track therapeutic interventions.
Clinical Perspective p 1960
Matrix metalloproteinases (MMPs) are a multigene family of endopeptidases that play a key role in normal vascular homeostasis and pathogenesis.1,2 Expression, activation, and inhibition by tissue inhibitor of matrix metalloproteinases (TIMPs) are the main regulatory mechanisms of MMP activity. Imaging MMP activation can provide novel insight into the pathogenesis of vascular disease and serve as a clinical tool for tracking vascular pathology. Here, we demonstrate the feasibility of MMP-targeted in vivo hybrid imaging of vascular remodeling, a common feature of many vasculopathies, including in-stent restenosis, graft arteriosclerosis, and aneurysm formation. RP782, an indium 111In–labeled tracer with specificity for activated MMPs,3 is used to detect injury-induced MMP activation in murine carotid arteries. High-resolution imaging with accurate localization of the target artery is achieved through microSPECT imaging in combination with CT angiography. Finally, the biological significance of RP782 uptake in injury-induced vascular remodeling is addressed.
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Methods |
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Reagents
Reagents were from Sigma (St Louis, Mo), unless otherwise specified. RP782, an 111In-labeled tracer with specificity for activated MMPs,3 was provided by Lantheus Medical Imaging (North Billerica, Mass).
Animal Model
Left common carotid injury was induced in apolipoprotein E (apoE)–/– mice (n=59) as described previously.4,5 Briefly, 6- to 8-week old female apoE–/– mice (Jackson Laboratory, Bar Harbor, Me) were fed high-cholesterol (1.25% cholesterol, Harlan Teklad, Madison, Wis) chow ad libitum. After 1 week, the common carotid and external carotid arteries were exposed by blunt-end dissection under anesthesia (ketamine 100 mg/kg and xylazine 10 mg/kg IP), and the left common carotid artery was injured with 6 passes of a 0.014-inch guidewire introduced through the external carotid artery. The opposite carotid artery was approached but not injured and served as control. Buprenorphine (0.05 mg/kg SC) was used for postoperative analgesia. Experiments were performed according to regulations of Yale University’s Animal Care Committee.
Histology, Morphometry, Immunofluorescent, and In Situ Zymography Studies
Groups of 4 animals were anesthetized before and at 1, 2, 3, or 4 weeks after injury (supplemental Figure I). After perfusion with normal saline, carotid arteries were harvested, embedded in OCT compound, snap-frozen, and stored at –80°C until further use. Immunofluorescent staining was performed with standard techniques on 5-µm-thick cryostat sections. Primary antibodies included anti-mouse MMP-2 and MMP-9 (Chemicon, Temecula, Calif), smooth muscle 
-actin (Sigma), and CD31 (BD Pharmingen, San Jose, Calif). Isotype-matched antibodies were used as control. Nuclei were detected with DAPI. For morphometric analysis, microscopic measurements were performed on cryostat sections at 250 µm below the carotid bifurcation with NIH ImageJ software (National Institutes of Health, Bethesda, Md), as described previously.5 Changes in morphometric indices were calculated by subtracting from measurements at any time point those of the preceding time point. MMP activation was assessed by in situ zymography. Frozen sections were placed on Zymo-Film (Wako, Richmond, Va) and incubated at room temperature for 3 minutes. The film was then immersed in Ponceau to stain the gelatin membrane. Protease activity was manifested as a white area. Specificity for MMPs was demonstrated in the presence of 1,10-phenanthroline, an MMP inhibitor.
Imaging
For imaging experiments, RP782 (11.1 MBq) was administered to groups of 5 to 7 animals at 1, 2, 3, and 4 weeks after injury through an inferior vena cava intravenous catheter. Animals were imaged after 2 hours with a dedicated high-resolution small animal imaging system (X-SPECT, Gamma Medica-Ideas, Northridge, Calif) with 1-mm medium-energy pinhole collimators. In micro-Jaszczak phantom studies, this system has a resolution of 0.8 and 2 mm for 99mTC and 111In, respectively. Anesthetized mice (with isoflurane) were placed in a fixed position on the animal bed. A point source of known activity (
1 µCi) was placed in the field of view but outside the body to quantify uptake and to verify the accuracy of image fusions. MicroSPECT imaging was performed in a step-and-shoot manner with the following acquisition parameters: 64 projections, 30 seconds/projection (35-minute image acquisition), with 174 and 242 keV photopeaks ±10% window. After completion of microSPECT imaging, animals were injected with a continuous infusion of iodinated CT contrast (iohexol 100 µL/min) over 2 minutes, and CT imaging was performed (energy 75 kV/280 µA, matrix 512x512) to identify anatomic structure. The imaging protocol lasted 1 hour, after which (3 hours after tracer administration) different tissues were harvested for gamma counting and autoradiography. MicroSPECT images were reconstructed through iterative reconstruction (5 iterations, 4 subsets) with system software (FLEX SPECT, Gamma Medica-Ideas). CT projection images were reconstructed with commercial software (Cobra, Exxim Computing Corp, Pleasanton, Calif) that implements a cone-beam reconstruction algorithm. Reconstructed microSPECT images were reoriented according to the CT anatomic images, fused, and exported in the Interfile format for further processing with Amide’s Medical Imaging Data Examiner.6 When necessary, image fusion was adjusted manually with the help of a fiducial marker and anatomic landmarks. For quantitative analysis of tracer uptake, cylindrical regions of interest were drawn at the level of carotid artery bifurcation (2x2x2 mm). A region of interest immediately posterior to both carotids (1x1x1 mm) served as background.
Autoradiography
After imaging, carotids were harvested for autoradiography at 3 hours after tracer administration (n=24). An additional group of animals (n=12) were used for autoradiography and biodistribution studies at 6 hours. Blocking experiments were performed at 6 hours in 3 animals in the presence of 50-fold excess nonlabeled RP782, which was administered 5 minutes before RP782 administration. Samples were exposed to high-sensitivity, x-radiographic X-OMAT Kodak Scientific Imaging Film (Eastman Kodak, Rochester, NY) for various times to optimize detection. Tracer uptake was quantified by quantitative autoradiography with a standard curve and was expressed as millibecquerels per pixel. Background-corrected signal intensities in the regions of interest were measured on high-resolution images with Kodak 1D image analysis software (Carestream Health, Inc, New Haven, Conn). A standard curve was derived from a series of standards with known activity deposited on Whatman paper (Whatman/GE Healthcare, Florham Park, NJ) and exposed to the same film. Multiple exposures for each film were obtained, the linear range was determined, and the films were used for quantitative analysis of tracer uptake in the target artery.
Gamma Counting
Samples were weighed, and gamma counting was performed on a gamma counter (Cobra, Perkin-Elmer, Shelton, Conn). The values were corrected for background, decay, and weight.
Assay for Activated MMP Specificity
Five-micrometer-thick sections of the left carotid artery at 3 weeks after injury were exposed to 1,10-phenanthroline, a broad-spectrum MMP inhibitor (10 mmol/L; Invitrogen, San Diego, Calif), or control buffer for 10 minutes at 37°C. Next, RP782 (3.7 kBq) was added for 20 minutes, samples were washed 3 times, and the tissue was transferred to a tube for gamma counting.
Statistical Analysis
All data are presented as mean±SD. Morphometric data and tracer uptake specificity were analyzed by Mann–Whitney test. A paired t test after logarithmic transformation (ratio t test) was used to examine the statistical significance of the difference in tracer uptake between the right and left carotid arteries. The nonparametric Spearman correlation was used to test the association between 2 variables. Significance was set at the 0.05 level.
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
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Results |
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MMP Activation in Vascular Remodeling
We used an established model of wire injury to the arterial wall in apoE–/– mice as the prototypical example of vascular remodeling. Left common carotid artery injury led to significant vessel-wall hyperplasia and expansive remodeling over a period of 4 weeks (Figure 1). The left carotid artery neointima and media area increased from 12 677±2424 µm2 before injury to 176 352±14 198 µm2 at 4 weeks after injury (n=4; P=0.028). Concomitantly, there was a compensatory enlargement of the artery, with the total cross-sectional vessel area increasing from 75 354±22 180 µm2 in noninjured arteries to 206 541±18 336 µm2 at 4 weeks after injury (P=0.028). Over the same period of time, the cross-sectional luminal area decreased from 62 677±21 841 µm2 to 30 189±17 289 µm2 (P=0.057). Although partial ligation of the carotid artery can potentially lead to changes in flow and structural changes in the contralateral artery,7 the morphometry of the sham-operated right common carotid artery remained unchanged from baseline.
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MMP-2 and MMP-9 play a key role in vascular remodeling.2 Therefore, we focused our ex vivo studies of vascular remodeling on these 2 members of the MMP family. Immunostaining of sham-operated carotid arteries demonstrated little constitutive MMP-2 and MMP-9 expression, predominantly confined to the media. Concomitant with the changes in vessel size and composition in response to wire injury, there was a marked increase in MMP-2 and MMP-9 expression levels, which was detectable at 1 week and peaked at 2 to 3 weeks after injury (Figure 2). Coimmunostaining with cell-specific markers demonstrated MMP-2 colocalization with -actin–positive vascular smooth muscle cells (VSMCs) and CD31-positive endothelial cells (Figure 3). MMP-9 colocalized with -actin–positive VSMCs (not shown).
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Next, we assessed MMP-2 and MMP-9 protease activity by in situ gelatinase zymography in normal and injured carotid arteries. Despite the constitutive MMP-2 (and to a lesser degree MMP-9) expression, we did not detect any gelatinase activity in normal carotid arteries (Figure 4). Wire injury led to an increase in gelatinase activity that was detectable as early as 1 week after injury and became more prominent by 3 weeks. The MMP specificity of this gelatinase activity was demonstrated by the marked reduction in proteolysis in the presence of a specific MMP inhibitor, 1,10-phenanthroline.
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MicroSPECT/CT Imaging of MMP Activation in Vascular Remodeling
As a prelude to imaging studies, we addressed the biodistribution of RP782, a novel 111In-labeled tracer that specifically targets activated MMPs,3 in apoE–/– mice. Tissue uptake was quantified by gamma well counting at 3 and 6 hours (n=3 in each group) after intravenous administration of the tracer (11.1 MBq), which demonstrated rapid renal clearance and favorable pharmacokinetics for in vivo imaging (supplemental Figure II). The blood pool activity was 2.5±0.4% and 0.2±0.0% injected dose per gram, respectively, at 3 and 6 hours. Because of the small size of the carotid arteries, their weights could not be measured accurately. We used morphometric estimates of the carotid artery volume to assess the ratio of carotid artery to blood uptake (3.3±1.6 for the right carotid and 11.9±6.1 for the injured left carotid artery at 3 hours, n=6, 2 to 4 weeks after surgery; P=0.004).
Next, we used a hybrid microSPECT/CT system to image MMP activation and localize it to remodeling murine arteries identified by angiography. RP782 (11.1 MBq) was administered to apoE–/– mice (n=24) at 1, 2, 3, and 4 weeks after left common carotid artery injury. MicroSPECT imaging was started at 2 hours after injection and was followed by CT angiography to localize carotid arteries. Tracer uptake in injured carotid arteries was visually detectable on microSPECT/CT images at 2, 3, and 4 weeks after injury (Figure 5A, 5B, and 5C; supplemental Movie). Quantitative analysis of image-derived tracer uptake demonstrated a significant difference in target-to-background activity between the injured left and control right carotid arteries (1.62±0.36 and 1.29±0.20 for left and right carotid arteries, P<0.0001). Background-corrected tracer uptake in the injured left carotid artery was significantly higher than uptake in the right carotid artery at 2 (P=0.004) and 3 (P=0.03) weeks after injury (Figure 5D). In some of the animals, tracer uptake was also detectable at the surgical site.
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Autoradiographic RP782 Uptake Quantitation and Specificity
RP782 uptake in carotid arteries was further assessed by quantitative autoradiography. Consistent with in vivo imaging results, tracer uptake was significantly higher in the injured than in the contralateral control arteries at all time points after injury (Figure 6A), with the uptake intensity increasing from 478±337, 550±356, 504±118, and 642± 344 mBq/pixel in the noninjured right carotid to 1123±475, 2389±1013, 2093±941, and 1946±867 mBq/pixel in the injured left carotid artery at 1, 2, 3, and 4 weeks after injury, respectively (n=5 to 7 in each group, P=0.004 for the right carotid versus left carotid at 1 week, <0.001 at 2, 3, and 4 weeks; Figure 6B). Similar results were obtained when carotid uptake was analyzed at 6 hours after injection (data not shown).
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RP782 uptake specificity was addressed in a group of animals at 2 to 3 weeks after carotid injury. Animals were pretreated with 50-fold excess nonlabeled tracer. Six hours after RP782 administration (11.1 MBq), tracer uptake in the left carotid artery was markedly reduced in animals pretreated with excess nonlabeled tracer, which demonstrates the specificity of RP782 uptake (from 720±255 to 44±8 mBq/pixel, n=6 without and 3 with blocking, P=0.02; Figure 7A and 7B).
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RP782 specificity for activated MMPs in the vessel wall was addressed on sections of the left carotid artery at 3 weeks after injury. A broad-spectrum MMP inhibitor, 1,10-phenanthroline (10 mmol/L), significantly inhibited RP782 binding to carotid artery (from 37.8±40.4 to 4.1±7.3 cpm per section, n=8; P=0.002), which demonstrates the activated MMP specificity of RP782 binding (Figure 7C).
Biological Significance of RP782 Uptake
MMP activation, detectable by RP782 imaging, plays a pivotal role in several aspects of vascular remodeling, including vascular cell proliferation/migration, as well as reorganization of the matrix scaffold. To define the biological significance of RP782 uptake in injury-induced vascular remodeling, we assessed the correlation between morphometric indices of vascular remodeling, namely, hyperplasia and expansive remodeling, and RP782 uptake. There was an excellent correlation between RP782 uptake and weekly changes in the vessel wall (neointima plus media) cross-sectional area (Spearman’s r=0.95, P=0.001; Figure 8) but not with changes in the total vessel (r=0.59, P=0.13) or luminal (r=–0.09, P=0.84) areas.
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Discussion |
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In the present study, we demonstrated the feasibility of high-sensitivity, high-resolution microSPECT/CT molecular imaging of MMP activation in injury-induced vascular remodeling using a novel activated MMP-specific tracer. Furthermore, we established a potential application of imaging MMP activation in the tracking of vessel-wall hyperplasia in vivo. MMPs are a multigene family of at least 23 secreted or transmembrane zinc- and calcium-dependent endopeptidases that selectively digest individual components of the extracellular matrix. MMPs are biosynthesized either as secreted or transmembrane proenzymes. The secreted MMPs are released into the extracellular space in a latent or proenzyme state (pro-MMP). Activation of these latent MMPs is achieved through enzymatic cleavage of the propeptide domain. Activated MMPs degrade extracellular matrix (and other) proteins8,9 at highly specific peptide sequences.10 In the normal blood vessel, MMPs are involved in maintaining the integrity of the vessel by breaking down extracellular matrix while new matrix is being synthesized. Among many MMPs expressed in vascular tissue,11 MMP-2 and MMP-912–14 play an important role in vascular pathology. Normal arteries express MMP-2, TIMP-1, and TIMP-2, which are produced constitutively by endothelial cells and VSMCs; however, there is no detectable in situ MMP enzymatic activity in normal arteries.2 MMP activation is a key mediator of vascular remodeling. Vascular remodeling, a persistent change in blood vessel size or composition, is a common feature of many vasculopathies, including atherosclerosis and aneurysm formation. Endothelial cells, VSMCs, and inflammatory cells are the main sources of MMP production in vascular remodeling.2,15
The strength of molecular imaging in tracking molecular events is dependent on the development of highly specific probes that can be detected by an appropriate imaging technology.16 In recent years, there has been considerable progress toward the development of novel molecular imaging approaches for detection of cancer;17–19 however, the application of the same concepts to vascular imaging has proved highly challenging.20 The small size of the target (in the submillimeter range in mice) and immediate vicinity to the blood pool are major limiting factors for in vivo detection of molecular and cellular events in blood vessels. As such, vascular molecular imaging is highly dependent on the availability of high-resolution, high-sensitivity imaging systems. Light-based imaging modalities21–24 are limited by the depth of penetration and are not (as yet) quantitative in vivo.25,26 Scintigraphic imaging can provide the high sensitivity required for in vivo imaging;19 however, it is somewhat limited in the ability to localize the target signal to a specific anatomic structure.27–29 An example of this limitation can be seen in a recent study on imaging MMP activation in ligated carotid arteries by planar imaging, which could not discriminate uptake in the surgical wound from that in the target artery.30 Recent technological advances have somewhat improved this limitation of scintigraphic imaging (whether positron emission tomography or single-photon emission CT) with regard to spatial resolution. Despite these improvements, identification of the target artery may only be achieved through concomitant use of high-resolution CT angiography (or MRI). This hybrid imaging approach enabled us to clearly identify the arterial tree and localize the RP782 signal to the injured carotid arteries, distinguishing it from the more superficial surgical wound uptake.
A number of MMP-targeted radiotracers have been developed and evaluated for the imaging of cancer,31–33 ventricular remodeling,3 and vascular pathology.30 A common feature of these agents and the RP782 used in the present study is their broad spectrum of MMP targets.3 Although we focused our evaluation of MMP activation on gelatinases, several other MMPs are involved in vascular pathology and may play an equally important role in vascular remodeling.2,15 Imaging specific members of the MMP family would be of great significance as a research tool. This is dependent on the development of novel, highly specific tracers, which may be based on the structure of specific inhibitors currently under development. It is uncertain whether broadly or more narrowly specific tracers will better serve as clinical diagnostic tools in specific situations, such as vulnerable plaque and aneurysm rupture, in which MMP activation plays a key role.
The 2 components of vascular remodeling, geometric remodeling (expansive remodeling in the case of wire injury) and hyperplasia, play complementary yet distinct roles in vascular remodeling. MMPs are key mediators of vascular cell differentiation, migration, proliferation, and survival, as well as reorganization of the matrix scaffold. There are conflicting data on the biological significance of MMP-2 and MMP-9 expression and activation in vascular remodeling. VSMC migration in the balloon-injured rat carotid artery is reduced by the administration of a nonselective MMP inhibitor, GM6001;34,35 however, this inhibition is not associated with a reduction in the size of neointima. Adenoviral expression of TIMP-1 inhibits VSMC migration and neointima formation in the balloon-injured rat carotid artery.36 MMP-9 overexpression in VSMCs leads to expansive remodeling and thinning of the intima in the rat carotid arteries,37 and geometric remodeling and neointima formation induced by endothelial denudation or carotid ligation are reduced in both MMP-2 knockout and MMP-9 knockout mice.14,38,39 There is a relative paucity of information on the activation state of MMPs in vascular remodeling. This is due in part to the absence of appropriate in vivo measures of MMP activation. The availability of an activation-specific MMP-targeted tracer provided us with the opportunity to track MMP activation in vivo. Given the active role of MMPs in the pathogenesis of vascular remodeling, it is reasonable to assume that MMP activation correlates with temporal changes in morphometric indices of vascular remodeling. Although both the expansive remodeling and neointima formation are dependent on MMP function, a significant correlation could be shown with changes in the neointima and media area (which parallels vascular cell proliferation5) but not changes in the total vessel area. This may indicate that MMP activation plays a more pivotal role in the hyperplastic response to injury and that other non-MMP proteolytic systems, such as the plasminogen/plasmin system,15 are the predominant regulators of geometric remodeling.
Clinical Relevance
Although valuable as an investigational tool for preclinical studies, MMP-targeted imaging also allows for the tracking of MMP activation in humans. MMP activation plays a key role in vascular morbidity and mortality.2 Protease-mediated disruption of the thin fibrous cap of vulnerable plaque can lead to myocardial infarction and death. Similarly, MMP activation is a key mediator of aneurysm expansion and rupture. As such, MMP-targeted imaging potentially may identify high-risk patients, eg, those at risk for acute coronary syndromes or prone to aneurysm rupture. Neointimal hyperplasia is the predominant pathological feature of in-stent restenosis, graft arteriosclerosis, and diabetic vasculopathy. The ability to track vessel-wall hyperplasia noninvasively may lead to early detection, for example, in graft arteriosclerosis, which is often detected in the late stages when therapeutic interventions are not effective. Finally, given the causal role of MMP activation in pathogenesis, MMP-targeted imaging of vascular remodeling may provide a clinical tool to track the effect of therapeutic interventions in vascular disease.
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Acknowledgments |
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We thank Dr Barry Zaret for his valuable comments in preparing this manuscript.
Sources of Funding
This work was supported by National Institutes of Health program project HL070295, R01 HL085093, American Heart Association grant 0435053N, and a Department of Veterans Affairs Merit Award to Dr Sadeghi.
Disclosures
Drs Edwards and Azure are employees of Lantheus Medical Imaging. Drs Sinusas and Sadeghi receive experimental tracers from Lantheus Medical Imaging. In addition, Dr Sinusas has received research grants from Lantheus Medical Imaging. The other authors report no conflicts.
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The online-only Data Supplement is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.108.789743/DC1.
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