Molecular imaging of matrix metalloproteinases in atherosclerotic plaques

Review Article
Schattauer 2012
Molecular imaging of matrix metalloproteinases in atherosclerotic
plaques
Sébastien Lenglet1; Aurélien Thomas2; Pierre Chaurand2; Katia Galan1; François Mach1; Fabrizio Montecucco1
1Cardiology Division, Foundation for Medical Research, Department of Medical Specialties, University of Geneva, Geneva, Switzerland; 2Department of Chemistry, Montréal
University, Montréal, Québec, Canada
MMP might be of pivotal relevance in the evaluation of the risk of rup- Ischaemic stroke and myocardial infarction often result from the ture. New imaging approaches, focused on the visualisation of inflam-sudden rupture of an atherosclerotic plaque. The subsequent arterial mation in the vessel wall and plaque, may emerge as tools for individ-thrombosis occluding the vessel lumen has been widely indicated as ualised risk assessment and prevention of events. In this review, we the crucial acute event causing peripheral tissue ischaemia. A complex summarize experimental findings of the currently available invasive cross-talk between systemic and intraplaque inflammatory mediators and noninvasive imaging techniques, used to detect the presence and has been shown to regulate maturation, remodeling and final rupture activity of MMPs in atherosclerotic plaques. of an atherosclerotic plaque. Matrix metalloproteinases (MMPs) are proteolytic enzymes (released by several cell subsets within athero- Keywords
sclerotic plaques), which favour atherogenesis and increase plaque vul- Matrix metalloproteinase, atherosclerosis, inflammation nerability. Thus, the assessment of intraplaque levels and activity of Correspondence to:
Financial support:
This research was funded by EU FP7, Grant number 201668, AtheroRemo to Dr. F. Mach. This work was also supported by the Swiss National Science Foundation Grants Faculty of Medicine, University of Geneva to Dr. F. Mach (#310030–118245) and Dr. Montecucco (#32002B-134963/1). This Avenue de la Roseraie 64, 1211 Geneva 4, Switzerland work was also funded by a grant from the Swiss Heart Foundation and Novartis Foun- Tel.: +41 22 372 71 92, Fax: +41 22 382 72 45 dation to Dr. F. Mach. This work was funded by the “Sir Jules Thorn Trust Reg” fund and Gustave and Simone Prévot fund to Dr. F. Montecucco. Received: October 18, 2011 Accepted after minor revision: December 9, 2011 Prepublished online: January 25, 2012 doi:10.1160/TH11-10-0717
Thromb Haemost 2012; 107: 409–416
Introduction: Inflammation in atherosclerotic able plaques can suddenly rupture this cap and expel their throm-
plaques
bogenic content into the blood stream. The subsequent acute formation of a thrombus/embolus occluding the arterial lumen The main pathologic feature of atherosclerosis is the athero- and provoking tissue ischaemia represents the most dangerous pa- sclerotic plaque (also called “atheroma”), which is characterised by thophysiological event for terminal organs. The morphological the inflammatory response of the vessel wall to the initial endothe- traits typically associated with rupture-prone plaques include a lial dysfunction. Atherosclerotic factors (such as hypercholestero- large eccentric necrotic core and a thin fibrous cap heavily infil- laemia or hypertension) might trigger the initial endothelial injury trated with macrophages and inflammatory cells, spotty calcifi- that, if not neutralised, favours the establishment of a chronic in- cation and vasa vorum proliferation (2). The plaque rupture flammation in the vessel wall. During this phase, both inflamma- mainly occurs in their shoulder, where active macrophages ac- tory and vascular cells are recruited and activated within the in- cumulate to phagocytate apoptotic cells and release proteolytic flamed arterial sub-intimal space. In particular, they attempt to enzymes (such as matrix metalloproteinases [MMPs]). However, phagocytate the oxidised lipids or apoptotic bodies. To improve atherosclerotic plaques have been described as very heterogeneous this response, these cells also release several soluble mediators, tissues, characterised by different vulnerabilities depending on which attract other inflammatory cells from the blood stream and portions upstream or downstream the blood flow (3). Therefore, increase intraplaque injury. The atherosclerotic lesion can progress the selective assessment of MMP release and activity within the to more advanced lesions composed of activated macrophages, T different plaque regions might be a very promising approach to lymphocytes, foam cells and mast cells around a necrotic lipid-rich better evaluate cardiovascular vulnerability (4). core (1), separated from the blood stream by a fibrous cap. Vulner- Downloaded from www.thrombosis-online.com on 2012-04-09 | IP: 77.122.21.216 For personal or educational use only. No other uses without permission. All rights reserved.
Lenglet et al. Imaging of matrix metalloproteases
Enzyme Substrates
Author (year) [ref.]
Table 1: MMP substrates and localisation
in atherosclerotic plaques.
Collagen I, II, III, IV, V, VII, X and XI, Neutrophils, macrophages, fibronectin, laminin, MMP-7,-8,-11 phages, T-lymphocytes Fu (2001) [20] Halpert (1996) [20] Newby (2007) [12] muscle cells, endothelial cells, Johnson (2005) [18] T-lymphocytes Newby (2007) [12] Schönbeck (1999) [24] Busti (2010) [15] Newby (2007) [12] Ray (2004) [28] Schneider (2008) [29] Role of MMPs in atherosclerotic plaque
control system of their protein degrading function. Firstly, MMP vulnerability
expression might be regulated at the level of the gene transcription and translation. The second control level is represented by the ac- MMPs are a family of endopeptidases consisting of more than 28 tivation of the pro-MMP by the proteolytic cleavage. Finally, MMP structurally related members that share a Zn2+-based or Ca2+ cata- might be also blocked after their activation via the interaction with lytic sites (5). The majority of MMPs is synthesised and secreted as specific inhibitors (called tissue inhibitors of MMPs [TIMPs]) (8). inactive pro-enzymes (pro-MMPs) or zymogens. In general, the The misregulation of this complex system is a common patho-activation of these enzymes occurs via the proteolytic cleavage of physiological process of several diseases, such as rheumatoid ar-the pro-peptide domain by other MMPs (6). Considering their thritis, periodontal disease, multiple sclerosis, cancer and athero-structure and specific substrates (major extracellular matrix sclerosis (5). In a normal artery, pro-MMP2, TIMP-1 and TIMP-2 [ECM] components), MMPs have been also classified into differ- are well detectable and appropriately balanced. Within human ent groups (including collagenases, gelatinases, stromelysins, atherosclerotic plaques, MMP control systems might be pathologi-membrane-type MMPs [MT-MMPs], and others) (5, 7). The bio- cally down regulated (9). In particular, TIMP-1 intraplaque ex- logical relevance of activated MMPs is modulated by an articulated pression has been shown as reduced in symptomatic plaque speci- Downloaded from www.thrombosis-online.com on 2012-04-09 | IP: 77.122.21.216 For personal or educational use only. No other uses without permission. All rights reserved.
Lenglet et al. Imaging of matrix metalloproteases
Table 2: Characteristics of the foremost
Technique Advantage
Disadvantage
Reference
molecular imaging techniques used for the
identification of MMPs in atherosclerotic
plaques.
ground ratio) Limited spatial resolution Restricted to animal studies and ex vivo human artery plaques * SPECT: single photon emission computed tomography. † PET: positron emission tomography. ‡ HR-MRI: high-resolution magnetic resonance imaging. § NIRF: near-infrared fluorescence. mens (9). Conversely, TIMP-1 serum levels were not altered in vul- Single photon emission computed tomography
nerable patients with acute myocardial infarction (10) or is-chaemic stroke (11), when compared with asymptomatic controls. Radiographic scintigraphic technique, such as single photon These studies indicate that the intraplaque (instead of systemic) emission computed tomography (SPECT), is designed to image regulation of MMP inhibitory mediators is substantially associ- systemic disorders such as atherosclerosis. It offers the opportunity ated with plaque vulnerability and its potential acute rupture. The to specifically identify the various components of inflammation in final result is a dramatic increase of the intraplaque activity of cer- atherosclerotic plaques (for instance macrophage infiltration, tain MMPs, such as interstitial collagenases (MMP-1, -8 and -13) apoptosis or foam cell generation) (31). The first studies were con-and gelatinases (MMP-2 and -12). In vulnerable plaques, pro-in- ducted on New Zealand white rabbits, in which atherosclerosis flammatory soluble mediators have been shown to sustain MMP lesions were induced by balloon de-endothelisation of the ab-expression and release. These processes are crucial mechanisms dominal aorta followed by a high-fat and high-cholesterol diet (32, driving plaque progression and destabilisation, till its final rupture 33). After intravenous administration, the matrix metalloprotei-(12). The source of MMPs within atherosclerotic plaques is also a nase inhibitor (MPI) uptake in atherosclerosis lesions was clearly matter of debate. Foam cells, macrophages, vascular smooth visualised by micro SPECT imaging. The results were confirmed by muscle cells (VSMC) and endothelial cells (EC) can release numer- immunohistochemical characterisation and zymography, reveal- ous MMPs that are capable of digesting ECM proteins (13). More ing that the radiotracer uptake correlated with macrophage infil-recently, neutrophilic MMPs have been also detected within tration as well as with the expression and activity of MMP-2 and atherosclerotic plaque, suggesting that several vascular and inflam- –9. Furthermore, the MPI uptake was lowered in animals after die- matory cells might modulate MMP-related plaque vulnerability tary modification and statin treatment, thus confirming previous (14). The functions and the cellular sources of MMPs involved in observations that these treatments substantially decrease the MMP atherogenesis are summarised in ǠTable 1. activity in atherosclerotic lesions. These first studies patently dem- The molecular imaging modalities for MMP activity would onstrate that in vivo quantification is feasible by non-invasive tar- ideally provide the plaque phenotype, thus helping researchers to geted imaging. MMP activity has been also studied in rodents with further clarify the inflammatory pathophysiology of the vulner- 99mtechnetium-labelled broad MMP inhibitors (MPI). Oshima et al. conducted the same type of experiments in two transgenic mouse models, namely ApoE-/- and LDLR-/- mice (34). These animals exhibit spontaneous hyperlipidaemia and the de-velopment of extensive atherosclerosis in the aorta and large ar- Imaging of MMPs in atherosclerotic plaques
teries (35, 36). In these animals, the MPI radiotracer uptake was highest in the most advanced lesions and strongly correlated with In this part, we provide an overview of the currently available im- the extent of plaque infiltration and quantitative expression of aging techniques used to detect MMPs in atherosclerotic plaques. MMP-2 and -9. So, MPI imaging could be used to detect high-risk, Each technique described below possesses its own strengths and unstable lesions since the plaque morphology in these mice is simi-drawbacks, which are summarised in ǠTable 2. On the other lar to that of human atherosclerosis (35–38). hand, ǠTable 3 summarises the results of the available imaging Kuge et al. suggested that the membrane MMP (MT1-MMP or techniques targeting MMPs to assess atherosclerotic plaque in- MMP-14) have a role in the destabilisation of atherosclerotic flammation and associated vulnerability. plaques (39). Expression of MT1-MMP has also been found with- Downloaded from www.thrombosis-online.com on 2012-04-09 | IP: 77.122.21.216 For personal or educational use only. No other uses without permission. All rights reserved.
412 Lenglet et al. Imaging of matrix metalloproteases
Table 3: Summary of MMP molecular imaging techniques in atherosclerotic plaques.
Technique Author
Molecular Agent/Probe Study
subjects Results
Reduced uptake in the diet withdrawal and statin groups Immunohistochemical correlation between MPI uptake and the macrophage infiltration and MMP-2 and MMP-9 expression Imaging of MMP activity in atherosclerotic plaques in vivo Reduced uptake after statin treatment and diet withdra- Higher MPI uptake in atherosclerotic lesions of mice (both genotypes) fed with a high-cholesterol diet in comparison with mice fed with a normal chow Significant correlation between MPI and MMP-2 and MMP-9 Watanabe heritable Accumulation of MT1-MMP in Watanabe rabbit aortas is hyperlipidaemic rab- 5.4-fold higher than that of control rabbits bits Histological grade of lesions (atheromatous > fibroatheromatous > collagen-rich > neomintimal) In vivo heterogenous uptake of tracer along the aorta Significant reduction in RP782 uptake after the diet with-drawal MMP-2 and MMP-9 activity are detected in vivo and ex Human symptomatic Ex vivo topographic distribution of MMPs in an athero- In vivo signal of MMPs activity increases in carotid plaques in the HCD group Pioglitazone reduces MMPs target-to-background ratio versus HCD Detection of MMP activity in complicated areas with ulceration and haemorrhage in comparison with non-complicated areas Weak correlation between the protease activity and the stenosis degree Human symptomatic High resolution mapping of MMP activity in ex vivo vulnerable plaque of intact human carotid specimens Attenuation of MMP-related NIRF signal intensities in aortas (ex vivo) from mice exercising versus sedentary mice Good affinity of P947 to human MMP-rich carotid plaques In vivo detection of atherosclerotic plaques in ApoE-/- Watanabe heritable Accumulation of P947 in atherosclerotic plaques from hyperlipidaemic rab- rabbit aortas, correlation with the immunohischemical bits In vivo signal enhancement in the aortic walls Correlation with MM2, MMP3 and MMP-9 stainings Ex vivo detection of the specific footprint associated with MMP-2 and -9 in atherosclerotic plaque cap * SPECT: single photon emission computed tomography.† MMPs: matrix metalloproteases. ‡ MPI: matrix metalloproteinase inhibitor. § NIRF: near- infrared fluorescence. || MRI: magnetic resonance imaging. # TR-LIFS: time-resolved laser-induced fluorescence spectroscopy. Downloaded from www.thrombosis-online.com on 2012-04-09 | IP: 77.122.21.216 For personal or educational use only. No other uses without permission. All rights reserved.
Lenglet et al. Imaging of matrix metalloproteases
in human atherosclerotic plaques (40), suggesting that its detec- To image MMP activity, Deguchi et al. have used a gelatinase tion may be useful for the assessment of atherosclerotic plaque vul- probe conjugated with NIRF fluorochromes (48). MMP-2 and –9 nerability. Therefore, Kuge et al. recently designed a 99mTc-labelled recognise and cleave this protease-activable agent and augment the anti-MT1-MMP monoclonal IgG as a radio-probe for imaging probe’s fluorescence in vitro by 200-fold (49). In this study, ApoE-/- atherosclerosis (41). In a rabbit model of atherosclerosis, they mice fed with a high-cholesterol diet received the gelatinase NIRF showed a significantly higher 99mTc-MT1-MMP mAb accumu- agent. After 24 hours, fluorescence molecular tomography reveal- lation in atherosclerotic rabbit aortas as compared to controls. ed increased NIRF signals in the aortic root and arch, known sites Moreover, the radiotracer mainly accumulates in atheromatous of atherosclerosis in ApoE-/- mice. Sites of increased gelatinase ac-lesions (type IV according to the classification scheme of the tivity visualised by NIRF co-localised with macrophage accumu-American Heart Association; [42, 43]). This lesion type (consider- lation, immunoreactive MMP-2 and –9 and gelatinolytic activity ed to be very similar to human vulnerable plaques) is characterised detected by in situ zymography. Thus, these results validate the use by fibrous connective tissue and a dense accumulation of extracel- of this gelatinase probe to monitor MMP activity in vivo. lular lipid and foam cells (44). The study shows that nuclear im- The first application of NIRF in human carotid artery plaques aging of MT1-MMP could provide a new diagnostic tool for better was reported by Wallis de Vries et al. (50). They incubated athero-identifying vulnerable atherosclerotic plaques. sclerotic plaques from endarterectomy with a new activable NIRF Recently, Razavian et al. used micro-SPECT and 111In-RP782, a agent, the MMPsense 680, and analysed the topographic distribu- radiotracer that specifically targets the MMP activation epitope, to tion of MMPs by applying multispectral NIRF imaging. Within the evaluate anatomic localisation of MMPs in aortas of ApoE-/- mice specimen, the NIRF signals resulted in the identification of cold under high-fat diet (45). The authors also showed a heterogeneous spots (with low NIRF intensity) and hot spots (with high NIRF in-distribution of RP782 uptake along the aorta and this pattern was tensity). In situ zymography and quantitative PCR from excised confirmed by ex vivo autoradiography. Interestingly, RP782 uptake hot and cold spots demonstrated that the gelatinase most abun-heterogeneity along the aorta was more pronounced in athero- dantly present and enzymatically active is therefore most likely sclerotic plaques over time progression and the withdrawal of the MMP-9. Thus, this study attests the possibility to detect differential high-fat diet induced a significant reduction in aortic MMP acti- topographic NIRF signals within an excised atherosclerotic vation detected by RP782 imaging. Although the relevance of these plaque. In addition, the possibility of identifying the more vulner- observations in human beings remains to be determined, these re- able plaques (to improve the selection criteria for surgical inter- sults highlight the importance of the in vivo assessment of MMP ventions) was also demonstrated. activity that can be achieved by molecular imaging. The MMP activity in a bigger cohort of patients undergoing ca- Although the nuclear imaging technique SPECT is a leading rotid endarterectomy or carotid stenting (captured emboli) has modality for the detection of MMP, radiation exposure with the been analysed with a fluoregenic cleavable decapeptide (51). Be-radiotracers cited above will limit its widespread use for the moni- sides the detection of MMP activity within or around complicated toring of patients with atherosclerotic risk factors. Further clinical areas (ulceration and haemorrhage) of the carotid atheroma, this studies are needed to demonstrate the diagnostic accuracy of this study demonstrates that the degree of carotid stenosis was weakly technique and also investigate the risk-benefit ratio. positively correlated with the inflammatory proteolytic enzyme-related signal unlike histological imaging. In other words, some in-formative divergence between anatomic and molecular imaging might exist. Thus, this NIRF probe is likely yielding information Near-infrared fluorescence
more applicable to the pathophysiology of a plaque rupture than conventional imaging (such as immunochemistry, which does not Another new and promising tool to image proteolytic activity in always distinguish active proteases from inactive precursors). atherosclerotic plaques is the near-infrared fluorescence (NIRF) mo- Until now, the planar fluorescence methods used can only pro- lecular imaging. This technique operates in the near-infrared spec- vide a qualitative indication of the existence of MMP activity trum of light and uses biocompatible probes that provide fluorescent rather than an accurate assessment of it specific localisation and images to detect enzymatic action of MMPs. In its unprocessed distribution. To improve this characteristic, Razansky et al. have form, the probe is designed so that signals from the closely posi- used the multispectral optoacoustic tomography (MSOT) to pro- tioned fluorochromes are quenched. Once the probe is cleaved by the vide volumetric images of MMPsense 680 probe distribution ex active MMP, the released fluorochrome emits light in the near-in- vivo within intact human plaques (52). This technology coupled frared range when excited. Since one enzyme can cleave multiple with tomographic reconstruction and spectral processing allows probes, this approach results in an amplified fluorescence. indeed three-dimensional imaging of biomarkers in small animals Considering that the inhibitors used in SPECT bind the MMP (53). MMPsense 680 was applied to human carotid plaques from enzyme in a 1:1 fashion and thereby provide no signal amplifi- symptomatic patients and MSOT method had simultaneously cation, the NIRF probe offers a relevant improvement. provided maps of both activated and inactive probe distribution in Another advantage of this modality is the possibility of NIRF these tissues. The MSOT signals were correlated with the inflam- signals to penetrate tissue up to several centimeters, thus enabling matory activities, the macrophage influx and the MMP activity by in vivo imaging (46, 47). epifluorescence imaging of cryosections, zymography and immu- Downloaded from www.thrombosis-online.com on 2012-04-09 | IP: 77.122.21.216 For personal or educational use only. No other uses without permission. All rights reserved.
414 Lenglet et al. Imaging of matrix metalloproteases
nohistochemistry experiments. On the basis of these results and caps of human carotid plaques using TR-LIFS derived spectro-the successful use of MSOT for whole-body imaging of living mice scopic variables in wavelength bands (59). Importantly, these (54), molecular and morphological characterisation of plaques by amounts of MMPs correlated with the changes in collagen, elastin MSOT with NIRF probes could be a promising method to non-in- and lipid content in plaques. This approach is very attractive be- cause TR-LIFS allows the assessment of MMPs content in human plaques without labelling or destroying the measured tissues. Moreover, TR-LIFS interrogation of arteries can be conducted via fiberoptic catheters, which are now in an advanced stage of devel- Magnetic resonance imaging
opment for the in vivo intravascular use in conjunction with in-travascular ultrasound catheters (61). On the other hand, the main Magnetic resonance imaging (MRI) can provide information on limitation of this study is that only the MMP expression was as-both plaque volume and composition in multiple arterial territori- sessed, and not the activity which is primordial for a potential es (55). It has been shown that MRI of the carotid artery can differ- entiate several plaque components including fibrous cap, lipid- To complete this review on imaging techniques of MMP, we rich/necrotic core, intraplaque hemorrhage and calcification (56). want to include the imaging mass spectrometry (IMS), which is an The correlation between clinical symptoms and features of vulner- emergent and innovative tool for direct analysis of tissue section able plaque raises the possibility that MRI of the carotid arteries (62, 63). In addition to the MS capacities for monitoring and iden-may have a potential role in the management of symptomatic caro- tifying biomolecules, IMS will lead to information on the spatial tid artery disease. Recently, the development of targeted molecular localisation of the target proteins in tissue or individual cells (64). contrast agents has permitted to identify the molecular consti- Furthermore, it might be possible to map at the same time the evol- tuents of individual plaques. Among them, the novel MRI contrast ution of the expression profiles of thousands of potential biom-agent P947 (an MMP inhibitor coupled to a gadolinium chelate) arkers in an unbiased and specific way (65, 66). IMS might be per-binds with an affinity at a micromolar range human soluble formed in the same tissue used for other examination procedures, MMP-1,-2,-3,-8,-9 and -13. In human carotid arteries, the ex vivo thus potentially providing unprecedented molecular information P947 concentration is significantly higher in the MMP-rich than in and enhancing our knowledge and our ability to predict and to the MMP-poor plaques (57). These results suggest that P947 ac- treat disease (67, 68). The first study on MMP expression was re- cumulates within human plaques and is capable of identifying vul- cently assessed by Muruganatham et al. (69), who have sprayed a nerable plaques. In the same study, authors have also showed in synthetic Förster resonance energy transfer (FRET) substrate spe-vivo in ApoE-/- mice that P947 might delineate plaques with a pat- cific for MMPs on rat tissue sections and have used matrix-assisted tern consistent with that in studies of MMP expression in athero- laser desorption/ionisation to directly visualising the spatial locali- sclerotic plaques. Indeed, higher signal intensity at the fibrous cap, sation of MMP-9 activity. Their results showed a better selectivity the shoulder regions and the outer layers of plaques were observed. than fluorescence imaging and constituted a first approach to the Accordingly, a smaller enhancement in the lipid-rich core regions specific IMS analysis of MMP in tissue section.
of plaques was also shown. Amirbekian et al., using confocal laser
scanning microscopy with a fluorescent tagged P947 (Eu-P947),
have confirmed the colocalisation of specific MMPs and the signals
observed with P947 (58). Furthermore, in situ MMP zymography Clinical translation
experiments on atherosclerotic aortic sections from ApoE-/- mice
have revealed that the fluorescence is due to activated MMPs. Although these new imaging techniques have the capacity to ident-
Thereby, MRI with the P947 agent may become a useful imaging ify MMP activity in vivo, two major limitations remain regarding
tool for noninvasive detection of MMP activity in the evaluation of the short-term clinical use. Firstly, the agents and probes described
atherosclerosis.
in this review will need a full characterisation of their toxic effects, pharmacokinetics and pharmacodynamics. Indeed, radiolabelled antibodies used in nuclear imaging (SPECT) have a relatively slow Other imaging strategies for detecting protease
clearance from the blood and tissues surrounding the target lesions and accumulate in the liver and the kidneys (41). In MRI studies activity
using the new contrast agent P947, no data regarding potential toxicity of this probe have been sought (57, 58). At last, among the An original approach based on a label-free imaging technique has NIRF dyes available, only one (indocyanine green) has been ap-been recently proposed for evaluating MMP-2 and -9 contents proved by the US Food and Drug Administration (FDA) for the use (59). Time-resolved laser-induced fluorescence spectroscopy (TR- in patients (77, 78). In brief, the in vivo application of these tools LIFS) is a technique recently shown to be capable of recognising will be impeded until additional research will be conducted on several components associated with plaque vulnerability with high their toxicity and novel agents/probes developed. specificity and sensitivity (60). Phipps et al. demonstrated that The second limitation for the clinical translation is represented there are distinct levels of MMP-2 and -9, discernible in the fibrotic by the difficulty for imaging the MMP activity in human coronary Downloaded from www.thrombosis-online.com on 2012-04-09 | IP: 77.122.21.216 For personal or educational use only. No other uses without permission. All rights reserved.
Lenglet et al. Imaging of matrix metalloproteases
arteries because of their small size and their deep localisation. In- 10. Tanindi A, Sahinarslan A, Elbeg S, et al. Association of matrix metalloprotei- deed, the MRI approach is inadequate to image small vessels be- nase-1, matrix metalloproteinase-9, tissue inhibitor of matrix metalloprotei-nase-1, and interleukin-6 with epicardial and myocardial perfusion. Coron Artery cause of its low sensitivity (58). Since NIRF signal has a limited depth penetration and quantification, its detection might be more 11. Montecucco F, Di Marzo V, da Silva RF, et al. The activation of the cannabinoid re-accessible in superficial vessels (such as arteries carotids) than in ceptor type 2 (CB2) reduces neutrophilic protease-mediated vulnerability in atherosclerotic plaques. Eur Heart J 2011; epub ahead of print. aorta or coronary arteries. To address this need, the development 12. Newby AC. Metalloproteinases and vulnerable atherosclerotic plaques. Trends of a catheter-based intravascular detection platform will be necess- ary. An intravascular in vivo approach with a flexible and narrow- 13. Halvorsen B, Otterdal K, Dahl TB, et al. Atherosclerotic plaque stability--what de- diameter NIRF catheter has been successfully demonstrated in termines the fate of a plaque? Prog Cardiovasc Dis 2008; 51: 183–194. 14. Peeters W, Moll FL, Vink A, et al. Collagenase matrix metalloproteinase-8 express- rabbits for one-dimensional intravascular detection of a protease ed in atherosclerotic carotid plaques is associated with systemic cardiovascular activity (cathepsin B) (79). We believe that this study will set the outcome. Eur Heart J 2011; 32: 2314–2325. basis for future clinical applications of this promising technology. 15. Busti C, Falcinelli E, Momi S, et al. Matrix metalloproteinases and peripheral ar- terial disease. Intern Emerg Med 2010; 5: 13–25. 16. Lemaître V, O'Byrne TK, Borczuk AC, et al. ApoE knockout mice expressing human matrix metalloproteinase-1 in macrophages have less advanced athero-sclerosis. J Clin Invest 2001; 107: 1227–1234. Conclusion
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