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Preclinical models of atherosclerosis. The future of Hybrid PET/MR technology for the early detection of vulnerable plaque

Published online by Cambridge University Press:  08 April 2016

Irene Cuadrado,
Marta Saura,
Borja Castejón,
Ana María Martin,
Irene Herruzo,
Nikolaos Balatsos,
Jose Luis Zamorano and
Carlos Zaragoza
Irene Cuadrado
Affiliation:
Departmentof Physiology, University of Alcala, School of Medicine, Ctra Madrid Barcelona, Km 3,300, 28875 Alcala de Henares, Madrid, Spain
Marta Saura
Affiliation:
Departmentof Physiology, University of Alcala, School of Medicine, Ctra Madrid Barcelona, Km 3,300, 28875 Alcala de Henares, Madrid, Spain
Borja Castejón
Affiliation:
Cardiology Department, University Francisco de Vitoria/Hospital Ramón y Cajal, Ctra. Colmenar Viejo, km 9,100, 28034 Madrid, Spain
Ana María Martin
Affiliation:
Cardiology Department, University Francisco de Vitoria/Hospital Ramón y Cajal, Ctra. Colmenar Viejo, km 9,100, 28034 Madrid, Spain
Irene Herruzo
Affiliation:
Cardiology Department, University Francisco de Vitoria/Hospital Ramón y Cajal, Ctra. Colmenar Viejo, km 9,100, 28034 Madrid, Spain
Nikolaos Balatsos
Affiliation:
Department of Biochemistry and Biotechnology, University of Thessaly, Ploutonos 26, 412 21 Larissa, Greece
Jose Luis Zamorano
Affiliation:
Cardiology Department, University Francisco de Vitoria/Hospital Ramón y Cajal, Ctra. Colmenar Viejo, km 9,100, 28034 Madrid, Spain
Carlos Zaragoza*
Affiliation:
Cardiology Department, University Francisco de Vitoria/Hospital Ramón y Cajal, Ctra. Colmenar Viejo, km 9,100, 28034 Madrid, Spain
*
*Corresponding author: Carlos Zaragoza, Cardiology Department, University Francisco de Vitoria/Hospital Ramón y Cajal, Ctra. Colmenar Viejo, km 9,100, 28034 Madrid, Spain. E-mail: c.zaragoza.prof@ufv.es
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Abstract

Cardiovascular diseases are the leading cause of death in developed countries. The aetiology is currently multifactorial, thus making them very difficult to prevent. Preclinical models of atherothrombotic diseases, including vulnerable plaque-associated complications, are now providing significant insights into pathologies like atherosclerosis, and in combination with the most recent advances in new non-invasive imaging technologies, they have become essential tools to evaluate new therapeutic strategies, with which can forecast and prevent plaque rupture. Positron emission tomography (PET)/computed tomography imaging is currently used for plaque visualisation in clinical and pre-clinical cardiovascular research, albeit with significant limitations. However, the combination of PET and magnetic resonance imaging (MRI) technologies is still the best option available today, as combined PET/MRI scans provide simultaneous data acquisition together with high quality anatomical information, sensitivity and lower radiation exposure for the patient. The coming years may represent a new era for the implementation of PET/MRI in clinical practice, but first, clinically efficient attenuation correction algorithms and research towards multimodal reagents and safety issues should be validated at the preclinical level.

Information

Type
Review
Information
Expert Reviews in Molecular Medicine , Volume 18 , 2016, e6
Copyright
Copyright © Cambridge University Press 2016 

Atherosclerosis is a complex systemic multifactorial inflammatory disease, which synergistically promote lesion development. Atherosclerosis leads to the development of coronary artery disease (CAD) and carotid disease, which are two of the most common causes of mortality and morbidity worldwide (Ref. Reference Altaf1). Atherosclerotic lesions progress over decades with periods of subclinical manifestations, until atheroma plaques develop. Plaque enlargement is associated with stenosis of the arterial lumen (Ref. Reference Vaina and Stefanadis2) with subsequent alteration of blood flow, and plaque rupture and/or plaque surface erosion (Ref. Reference Romero3), leading to thrombus formation, lumen occlusion and ultimately, ischemic events (Ref. Reference Adams and Celermajer4). Traditional risk factors include high density lipoprotein-cholesterol and total cholesterol content (dyslipidemia), systolic blood pressure (hypertension), age, gender, diabetes mellitus, cigarette smoking, obesity, and left ventricle hypertrophy. However, research into a combination of additional and as yet unknown factors might help us to better understand the onset of this disease.

Factors that determine progression towards vulnerable plaque are being carefully investigated, since the early detection of vulnerable plaque may represent a big step towards increasing the life span of the population (Refs Reference Cocker5, Reference Davies6, Reference Botnar7, Reference Sadeghi8, Reference Vengrenyuk9, Reference Canet-Soulas and Letourneur10). Until now, arterial luminal diameter as detected by classical imaging technologies has been the only diagnostic procedure, and restricted to later stages of disease. However, positive remodelling, which is associated with plaque rupture, is not necessarily associated with luminal changes.

Oxidised low-density lipoproteins (oxLDL) play a major role during the onset of atherosclerosis by inducing the expression of several adhesion molecules at the cell surface of endothelial cells, promoting recruitment and adhesion, as well as internalisation of circulating monocytes from the intima layer, and internalisation to the media layer of the arteries (Refs Reference Canet-Soulas and Letourneur10, Reference Kanwar11, Reference Naghavi12). Histologically, atherosclerotic plaques can be differentiated into stable and vulnerable plaques, depending on whether they are stable or prone to rupture. Scavenger receptor-mediated uptake of ox-LDL by infiltrated monocytes causes them to differentiate into foam cells, producing significant amounts of proinflammatory cytokines and matrix metalloproteinases (MMPs), and leading to the formation of a fatty streak (Ref. Reference Li13). The lesions are composed of smooth muscle cells, cellular debris and a lipid-rich core covered by a fibrous cap (Refs Reference Majmudar14, Reference Millon15, Reference Pedersen16, Reference Ratib and Nkoulou17, Reference Rischpler, Nekolla and Beer18, Reference Bigalke19). Lesion progression continues with the formation of a necrotic core, mainly composed of apoptotic macrophages, smooth muscle cells, debris and a significant amount of free cholesterol coming from macrophages and erythrocyte membranes. The increase in free cholesterol is closely associated with lesion instability (Refs Reference Hatsukami20, Reference Jones21, Reference Xu22, Reference Cai23). Stable plaques show small necrotic cores and thick fibrous caps, whereas vulnerable plaques are composed of large necrotic cores and thin fibrous caps. The fibrous cap is mostly composed of smooth muscle cells, which produce extracellular matrix (ECM) components including collagen and elastin, hence contributing to the thickening of the fibrous cap. By contrast, those signals, which trigger smooth muscle and macrophage apoptosis will give rise to plaques with thinner fibrous caps, as shown in vulnerable atherosclerotic plaques (Fig. 1). Neoangiogenesis is another key signature of plaque vulnerability. Plaque vascularization coming from the vasa vasorum contributes a continuous influx of erythrocytes, lymphocytes and macrophages. Intraplaque vessels are immature, with a reduced number of smooth muscle cells; hence intraplaque haemorrhage also contributes to plaque rupture (Ref. Reference Heeneman24).

Figure 1.

Graphical representation of stable and vulnerable plaques.

The thinner the fibrous cap is, the more prone it is to rupture. Therefore, new non-invasive imaging approaches providing information on plaque burden and composition are needed, in order to better identify population at risk (Refs Reference Botnar7, Reference Iqbal25, Reference Dweck26, Reference Mateo27). To this end, the combination of the most recent cutting edge imaging modalities – including hybrid positron emission tomography (PET)/magnetic resonance imaging (MRI) – and preclinical models of atherosclerotic disease, has resulted in a more synergistic handling of human atherosclerosis disease, leading us closer to an effective means of tackling it.

Preclinical models of atherosclerosis

Mouse models of atherosclerosis

The use of genetically modified mouse models is, for several reasons, the most common tool for the study of atherosclerosis (Refs Reference U-King-Im28, Reference Wasserman29). Despite the differences between human and murine atherosclerosis – including vessel architecture, plaque composition and even plaque stability – and thanks to the extensive investigation in mouse models of atherosclerosis, we have a deep understanding of the mechanisms involved in atherogenesis (Refs Reference Boshuizen30, Reference Getz and Reardon31).

LDL receptor (LDLR) deficient mice develop mild atherosclerosis, in which the severity of the lesions can be accelerated when mice are fed a high-cholesterol diet (Refs Reference Li32, Reference Ru33, Reference Rensing34, Reference Marquart35, Reference Tang36, Reference Teodoro37, Reference Awan38). Aortic lesions can progress beyond the foam-cell fatty-streak stage to the fibro-proliferative intermediate stage.

The apolipoprotein E (apoE)-deficient mouse model tends to accumulate significant amounts of LDL and very LDL (VLDL), and develop atheroma plaques, which are accelerated under a high cholesterol diet, in a manner similar to that which occurs in humans, including foam cell formation and migration of smooth muscle cells to the damaged tissue (Refs Reference Bigalke19, Reference Zhao39, Reference Andrés40, Reference Higashimori41, Reference Meir and Leitersdorf42). Atheroma plaques are mainly composed of a necrotic core surrounded by proliferating smooth muscle cells and ECM components (Refs Reference Zhao39, Reference Bot43, Reference Akhtar44, Reference Fernández-Hernando45). Double apoE/class B scavenger receptor mutated animals have allowed investigators to study coronary artery atherosclerosis, thus making this double mutant murine model a valuable tool for the study of CAD (Refs Reference Vaisman46, Reference Kitayama47, Reference Zhang48, Reference Zhang49, Reference Sosnovik and Caravan50).

Mutated variants of apoE, including apoE 3Leiden, apoE2 and several single point mutated forms of the apoE gene, have also been overexpressed in mice to recreate human atherosclerosis, in which new atheroma plaque reducing drugs are tested (Refs Reference Zadelaar51, Reference Lardenoye52, Reference Lalloyer53).

Besides all the benefits of using genetically modified animals – relatively low cost, elevated sample size and ease of handling – a major limitation still remains: vulnerable atheroma plaque formation is extremely infrequent in mice when compared with other species, including humans. The recapitulation steps, beginning with the formation of large necrotic cores, the thinning of the fibrous cap and plaque vascularisation, which lead, finally, to the disruption of human atheroma plaques, are still beyond the preclinical models available. Finding a better mouse model of human vulnerable plaque could represent a big step forward in cardiovascular research. In light of the above-mentioned limitations, advances have been made in the development of mouse models suitable for the study of plaque rupture, including the following: brachiocephalic plaque disruption in aged apoE null mice fed a high fat diet (Ref. Reference Johnson54); plaque rupture in the brachiocephalic artery of mice fed a high fat diet and treated with angiotensin II, which improves the efficacy of the model (Refs Reference Katsuki55, Reference Matoba, Sato and Egashira56, Reference Sato57); mice transfected with hematopoietic stem cells overexpressing MMP-9, or uPA in macrophages (Refs Reference Gough58, Reference Hu59); plaque disruption in apoE null mice with a collar placement on the carotid artery and stimulated with lipopolysacharide and phenylephryne injection in a cold environment (Ref. Reference Ma60).

As stated above, intensive efforts to find better models of human atherosclerosis have made possible the discovery of new genes involved in human atherosclerosis. However, a crucial aspect that still deserves thorough investigation is related to the formation of occlusive thrombosis after the disruption of the fibrous cap in humans, which in the few vulnerable atheroma plaque mouse models is still missing, since mouse PAI-1 levels in plasma are lower than in humans (Ref. Reference de Witt61).

Recently, thanks to a combination of non-invasive molecular imaging technologies, including the use of MRI (Ref. Reference Desai and Lima62), we can characterise the precise location, size and the shape of atherosclerotic lesions, which enables us to discriminate between fibrous and lipid components in plaques (Refs Reference Momiyama and Fayad63, Reference Yonemura64, Reference Blum and Nahir65, Reference Oikawa66). In combination with other non-invasive imaging technologies, mouse models of atherosclerosis today also serve to test novel contrast agents and to design and target specific molecules involved in several aspects of cardiovascular diseases, and to study the molecular mechanisms governing plaque instability (Refs Reference Raman67, Reference Slevin68, Reference Winter69, Reference Cheng70).

Rabbit models of atherosclerosis

Rabbit models offer distinct advantages over mouse models, since rabbit arteries are large enough for testing endovascular therapeutic devices and for the quantification of atherosclerotic aortic components by MRI, which accurately quantifies fibrotic and lipid components, allowing serial analysis of therapeutic strategies focused on atherosclerotic plaque stabilization (Refs Reference Abran71, Reference El-Sheakh72, Reference Fan73, Reference Hyafil74, Reference Fang75, Reference Kong76, Reference Millon77, Reference Shiomi, Koike and Ito78, Reference Tian79, Reference Yanni80, Reference Johnstone81).

Rabbits have been largely used to study the influence of lipid lowering (through diet or pharmacologically) on macrophage accumulation and inflammation (Refs Reference Shiomi, Koike and Ito78, Reference Shukla82, Reference Yang83, Reference Helft84, Reference Rival85, Reference Tijburg86). To this end, a new model – in which a combination of femoral injury and induced-knee arthritis in hyperlipidemic rabbits – has been developed, allowing us to study inflammation-associated atherosclerosis (Ref. Reference Largo87).

The absence of reliable models of vulnerable plaque has been recently overcome by using a rabbit model of vulnerable atherosclerotic plaque, consisting of vascular injury in rabbits fed a hyperlipidemic diet (Refs Reference Zhao88, Reference Phinikaridou89, Reference Shimizu90, Reference Abela91). The animals developed a lipid-rich core, plaque accumulation of macrophages, and a thin fibrous cap, similar to human vulnerable plaques. In addition, another model of rabbit vulnerable plaque consists of a LDLr-deficient rabbit model: the Watanabe heritable hyperlipidemic rabbit, which resembles human familial hypercholesterolemia and shows evidence of progressive disease of the aorta (Refs Reference Shiomi, Koike and Ito78, Reference Zhang92, Reference Ito and Shiomi93).

Porcine models of atherothrombosis

Swine may represent the best preclinical model for the study of human atherosclerosis: pigs exhibit similar vessel wall architecture, respond in the same way as humans to the exposure of significant amounts of oxLDL, develop atheroma lesions in response to insulin resistance and, as in humans, pigs develop vulnerable atheroma plaques (Refs Reference Mohler94, Reference Gerrity95).

Due to the size of their vessels and the facility with which coronary artery atherosclerosis in pigs may be studied, neointimal hyperplasia and neovascularisation of the vessel have been extensively evaluated in these animals (Ref. Reference Hamada96). Pigs are also excellent models for the development and validation of coronary imaging technologies and devices, including new state of the art imaging equipment (Ref. Reference Behler97) and new generations of drug-eluting stents (Refs Reference Behler97, Reference Deuse98, Reference Virmani, Kolodgie and Farb99).

Non-invasive molecular imaging of atherosclerosis

Molecular imaging can be defined as a non-invasive in-vivo procedure to target and/or to quantify specific molecules and/or molecular pathways. In recent years, advances in biomedical sciences have been boosted by the introduction of new non-invasive imaging technologies. MRI, PET and computerised tomography (CT) are now widely used to diagnose the onset and progression of several pathologies, including atherosclerosis (Refs Reference Botnar7, Reference Beller100, Reference Nörenberg101, Reference Phinikaridou102).

A great effort is being made to find specific targets to cover all aspects of atherosclerotic disease from the initial stages, even at subclinical levels, up to the point of plaque destabilisation and rupture. To this end, several laboratories have been focusing on inflammatory macrophages, but recently specific molecules – including trans-membrane proteins, enzymes, cytokines and others – have been used to detail and to quantify, with high level of precision, specific aspects of the disease (Refs Reference Misri, Saatchi and Häfeli103, Reference Chen104, Reference Klink105, Reference Mulder106).

MRI detection of atherosclerosis

MRI provides high spatial and temporal resolution in functional assays, and allows both qualitative and quantitative discrimination of the different elements of atheroma plaques. MRI has the potential to acquire multicontrast images of the same specimen, distinguishing between blood and tissue composition within the vessel wall, and the different components of atheroma plaque, ionizing radiation free. T1-, T2-, and proton density weighted imaging sequences enable us to visualise and quantify the extension of the necrotic core, calcification, intraplaque haemorrhage and the visualisation of the fibrous cap and the presence of plaque vascularisation (Refs Reference Yonemura64, Reference Phinikaridou89). Thus, MRI is chosen for the extensive assessment of human coronary, aortic and peripheral atheroma plaques (Refs Reference Yuan107, Reference Stuber108, Reference Worthley109, Reference Fayad110, Reference Corti111, Reference Yuan112, Reference Corti113, Reference Yuan114, Reference Kramer115, Reference Di Leo116).

In combination with the use of targeted contrast agents, MRI has emerged as a powerful tool to evaluate atherosclerosis. Depending on the relaxation times (T1, T2), acquired images may reveal enhancement or inhibition of the signal, according to the probes used for the assay. T1 contrast agents incorporate Gadolinium (Gd) into micelles, immunomicelles with conjugated antibodies on the surface, and liposomes, to improve detection and sensitivity. By contrast, T2 contrast agents are usually coated with dextran, polyethylene glycol or polyvinyl alcohol, and contain an iron oxide superparamagnetic core (Refs Reference Makowski117, Reference Mulder118) (Fig. 2). According to the core size, they can be classified into ultrasmall superparamagnetic, iron-oxide (USPIO, 18–50 nm), or SPIO (100–200 nm) nanoparticles. Both particles exhibit a very large magnetic moment, leading to a quick signal loss in T2 images; thus, histological validation is highly recommended (Refs Reference Segers119, Reference Metz120, Reference Klug, Bauer and Bauer121, Reference Ma122).

Figure 2.

Schematic representation of targeted and fluorescently labelled iron oxide nanoparticles.

USPIO nanoparticles are swallowed by macrophages in vivo, a feature that makes them an excellent tool for non-invasive intraplaque detection of inflammation by MRI both in mice, rabbits and pig models of cardiovascular disease (Refs Reference Millon77, Reference Sigovan123, Reference Bjerner124, Reference Sigovan125). Alternatively, the use of T2 nanoparticles containing cell specific conjugated antibodies or peptides is another strategy for plaque detection, to quantify extension and stage of the lesion, and recently for quantification of pharmacological therapeutic effect on plaque regression. An example of this is the recently reported use of USPIOs conjugated with anti-P-selectin antibodies expressed in cells activated during the early stages of atherogenesis, as a tool for non-invasive detection of early atheroma plaque formation (Ref. Reference Jacobin-Valat126). Likewise, the use of USPIO nanoparticles with conjugated antibodies against activated platelets, which recognise αIIbβ3 integrins, within atherosclerotic lesions (Ref. Reference Burtea127), provides information about advanced atherosclerosis, intraplaque haemorrhage and inflammation, in apoE deficient mice. Iron oxide based nanoparticles conjugated with two antibodies have also been successfully used to target immune cells within the lesion. Dual-ligand microparticles of iron oxide (MPIO), targeted to P-selectin and vascular cell adhesion molecule-1 (VCAM-1) (PV-MPIO) were efficient in atherosclerotic apoE null mice at visualising by MRI the distribution of plaque macrophages closely with the burden (Ref. Reference McAteer128). The effect of statin therapy on atherosclerosis was validated by using different USPIOs in atherosclerotic rabbits (Ref. Reference Millon77) and in humans (Ref. Reference Tang129).

Iron oxide based nanoparticles have some limitations. Internalisation and compartmentalisation of iron oxide particles within cells, including macrophages, cause MR signal loss because of the generation of local magnetic field inhomogeneities that induce shortening of T2 and T2 * relaxation times, which results in a signal deficit on magnetic resonance images, rendering dark signals (Ref. Reference Sigovan123). At the same time, other factors can also induce signal loss, causing ‘blooming artifacts’, and thereby generating loss of distinction of anatomical boundaries and distortion of normal tissues. Additionally, SPIOS suffer from partial-volume effects. They lose activity because of the limited resolution of the imaging system. This is one of the main reasons for which extensive investigations are focusing on generating SPIO-specific positive contrast, namely, to distinguish the signal surrounding SPIO nanoparticles from the dark signal derived from local field inhomogeneity (Ref. Reference Diwoky130).

Gd-based T1 nanoprobes (chelates, micelles and liposomes, Fig. 3) offer the advantage of positive contrast as compared with iron oxide particles. In addition, their size facilitates endothelial crossing, offering a significant signal-to-noise ratio. However, and depending on the target, Gd-based nanoparticles are not adequate for detection of targets represented at low concentrations in living organisms. A strong correlation between macrophage density and MRI detection was found in a mouse model of atherosclerosis, by using a contrast agent consisting of Gd3+-loaded micelles targeted to the macrophage scavenger receptor (Ref. Reference Canet-Soulas and Letourneur10) and oxLDL in atheromatous plaques with MRI (Ref. Reference Kanwar11), the anti-inflammatory marker IL-10 (Ref. Reference Almer131), the adipose protein adiponectin (Ref. Reference Hansen132), or plaque rupture and thrombotic marker fibrin (Ref. Reference Andia133).

Figure 3.

Schematic representation of Gadolinium (Gd)-containing nanoparticles. (a) Target ligand conjugated to Gd chelates. (b) Target ligand conjugated to Gd containing micelles. (c) Target ligand conjugated to Gd containing liposomes. Gd, Gadolinium.

Gd-nanoprobes have been used to detect collagen, a major ECM component, which provides vessel tensile strength to the arteries (Refs Reference Chen134, Reference Spuentrup135), and elastin, the most abundant ECM component of the vessel wall (Ref. Reference Phinikaridou136). Immune foam cell expression of MMPs was also detected by Gd-based nanoparticles in mouse and rabbit models of atherosclerosis (Ref. Reference Hyafil137). MMPs are valuable markers of atherosclerosis, since they play a pivotal role in cell migration and plaque rupture. MMPs are mostly produced by foam cells, and therefore they are not suitable for detection of early atherosclerotic events. However, we found that ECM Metalloproteinase Inducer (EMMPRIN), a trans-membrane protein which induces the expression of several MMPs, is highly expressed at early stages of atherosclerosis in apoE null mice, as detected by immunoblot and by molecular imaging of apoE deficient mice with immunomicelles with conjugated anti-EMMPRIN antibodies (Fig. 4).

Figure 4.

Non-invasive molecular imaging detection of EMMPRIN by MRI in apoE null mice. (a) Composition of immunomicelles conjugated with specific anti-EMMPRIN antibody. Eight-week old apoE atherosclerotic null mice were anesthetised and injected with Gd-containing immunomicelles conjugated with anti-EMMPRIN antibody. (b) T1 4.7T MRI scan of mice at time 0 h after injection. (c) T1 4.7T MRI scans of the same mice 2 h after injection, showing Gd enhancement in the aorta (white arrow). (d and e). Ex vivo tissue sections of paraffin embedded abdominal aortas of mice injected with Gd-containing immunomicelles conjugated with anti-EMMPRIN antibody, and isolated at time 0 h (d) and 2 h (e) after injection, and visualised by confocal microscopy. Arrows represent FITC positive cells containing nanoparticles, L, lumen. apoE, apolipoprotein E; EMMPRIN, extracellular matrix metalloproteinase inducer; Gd, Gadolinium; MRI, magnetic resonance imaging.

PET detection of atherosclerosis

PET imaging is based on the use of radiolabeled tracers, providing a highly sensitive method to quantify several metabolic events, including plaque composition, inflammation, calcification and more. Unfortunately, PET images must be overlapped with images taken using better spatial resolution equipment, like MRI, since PET resolution is below the minimum threshold required in order to translate results from bench to bedside.

Radiolabeled fluorodeoxyglucose [(18F)FDG] is, among other tracers, the most common glucose analogue. (18F)FDG uptake by activated macrophages takes place in scenarios of high metabolic rates, as within atherosclerotic plaques (Refs Reference Pedersen16, Reference Millon77, Reference Zhao88, Reference Liu138, Reference Tawakol139, Reference Hag140, Reference Rosenbaum, Millon and Fayad141, Reference Calcagno142, Reference Rudd143, Reference Rudd144). In fact, a high correlation between (18F)FDG uptake and macrophage infiltration in atheroma plaque has made possible the use of (18F)FDG as a marker of vulnerable plaque (Refs Reference Chen and Dilsizian145, Reference Tawakol146). Accordingly, (18F)FDG has been used to detect important features of plaque disruption, including neovessel formation (Ref. Reference Calcagno142). In addition, (18F)FDG is an important tool for testing novel therapeutic strategies, (18F)FDG uptake in response to LXR agonist R211945 (Ref. Reference Vucic147), statin administration (Ref. Reference Davies148), the macrophage infiltration inhibitor probucol (Ref. Reference Ogawa149) and the anti-inflammatory properties of pioglitazone (Refs Reference Vucic150, Reference Lobatto151).

As shown above, (18F)FDG microPET has been extensively used to study the onset, progression and regression of atherosclerosis in mouse and rabbit models of disease. Besides, new tracers of atherosclerosis have been successfully implemented to analyse in more detail specific aspects of the disease. Such is the case of (11)C-PK11195, a PET radiotracer which labels a selective ligand of the translocator protein, which is highly expressed by activated macrophages in mice (Ref. Reference Laitinen152) and in human atherosclerosis (Ref. Reference Gaemperli153); taking this approach, via a direct and specific labelling of macrophages – rather than indirect glucose consumption, as detected by (18F)FDG – allows us to characterise and to measure inflammation in more detail. Similar approaches include the use of 18F-fluorocholine (18F-FCH), since choline is metabolised to phosphatidylcholine and incorporated into cell membranes of activated macrophages, as shown in hypercholesterolemic atherosclerotic apoE null mice (Ref. Reference Matter154). Activated macrophages are also traced with the multimodal agent 64Cu trireporter nanoparticle (64Cu-TNP), a dextranated and diethylenetriaminepentacetate (DTPA)-modified magnetofluorescent 20-nm nanoparticle, labelled with the tracer 64Cu to yield a PET, magnetic resonance and optically detectable multimodal imaging agent (Ref. Reference Nahrendorf155). Likewise, other multimodal tracers, for example the cross-linked dextran-coated iron oxide (CLIO)- 1,4,7,10-tetracarboxymethyl-1,4,7,10-tetraazacyclododecane (DOTA) (64Cu) probe or the 64Cu/Gd/TAMRA-mal-BSA tracer (Ref. Reference Bigalke19), were used in apoE null mice and in rats, respectively, to detect carotid atherosclerosis by targeting inflammatory macrophages.

Atherosclerosis is a systemic inflammatory disease, thus adhesion of circulating monocytes to the endothelial layer is a key stage of atherogenesis, in which VCAM, including the highly expressed VCAM-1, play a pivotal role (Ref. Reference Libby, DiCarli and Weissleder156). With the aim of studying early progression of atherosclerosis, a new radiotracer detecting VCAM-1 was synthesised, allowing non-invasive PET-imaging detection of early inflammation (Ref. Reference Nahrendorf157).

Additional radiotracers include 2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl) acetamide [(18F)EF5], a marker of hypoxia used to quantify plaque density, since large atherosclerotic plaques contain significant areas of hypoxia, as detected in atherosclerotic mice (Ref. Reference Silvola158). Plaque angiogenesis may be detected by targeting integrin aνβ3, a key component of the mechanism involved in the formation of new vessels, with the radiolabeled integrin binding RGD peptide radiotracer 18F-galacto-RGD (Ref. Reference Laitinen159). Activated platelets were detected in rabbit atherosclerotic lesions by using a radiotracer (18F-AppCHF-ppA), based on adenosine diphosphate-induced platelet aggregation (Ref. Reference Elmaleh160). In addition, rabbit atherosclerosis was also used to test inflammation with the C-type natriuretic factor-based tracer 64Cu-DOTA-C-ANF (Ref. Reference Liu161).

Other applications of PET in atherosclerosis include the quantification of plaque calcification through the use of (18F) sodium fluoride (Ref. Reference Chen and Dilsizian145), and fatty acid synthesis with (11)C-acetate (Ref. Reference Derlin162).

A summary of different PET tracers used to study atherosclerosis is depicted (Table 1).

Table 1.

Radiotracers to study atherosclerosis by PET

ox-LDL, oxidised low-density lipoproteins; PET, positron emission tomography; LDLr, low density lipoprotein receptor; VCAM-1, vascular cell adhesion molecule-1.

Simultaneous PET/MR technology

Three decades ago, professionals in clinical practice were faced with the momentous challenge of sequentially combining different imaging technologies in an attempt to improve the sensitivity and accuracy of diagnosis (Refs Reference Zerhouni163, Reference Skorton and Collins164). Today, multimodal imaging is a reality, and the combination of PET and CT offers unique sensitivity and anatomical information in one multimodal assay. Significant limitations of PET/CT are related to non-simultaneous data acquisition (Refs Reference Bailey165, Reference Delso, Ter Voert and Veit-Haibach166, Reference Disselhorst167). The CT scan is followed by PET acquisition. Given that CT scans take seconds, while PET images take longer, organ motion and different respiratory cycles may lead to significant artefacts (Ref. Reference Martinez-Möller168). Additionally, the radiation risk associated with CT scans, and the reduced soft tissue contrast as compared with MRI, are key concerns when applying this multimodal imaging technology (Refs Reference Martinez-Möller and Nekolla169, Reference Nappi and El Fakhri170).

PET/CT scans are traditionally used in preclinical and clinical practice to overcome poor spatial resolution exhibited by PET scans alone. In spite of the fact that it is still being studied extensively, the combination of MR with PET offers superb spatial resolution, thanks to the excellent sensitivity afforded by PET technology. In the next few years, great progress will be made in biomedical and nanoparticle research and multimodal probe design to be used in combination with this hybrid system. Simultaneous PET/MR imaging of atherosclerosis should be further studied, especially in combination with functional MR imaging techniques.

Four main challenges to combining both platforms still remain to be overcome. The first involves avoiding PET performance degradation. Photomultiplier tubes required for PET scanners are not compatible with the magnetic fields generated by MR. In this regard, several approaches have been taken, although only two of them with promising translation to clinical practice. Avalanche photodiode detectors detect gamma quanta at a 9.4 Tesla magnetic field (Refs Reference McCallum, Clowes and Welch171, Reference Maramraju172). More recently, several groups have implemented silicon photomultipliers as MR compatible PET detectors because of the fact that the timing resolution qualifies for time-of-flight PET detection mode (Ref. Reference Yoon173). With very promising results at the preclinical level, this new technological advance will be a great milestone achievement when implemented in human PET/MR scanners.

Second, there is a reduction in the quality of MRI images as a result of the radiofrequency generated by the PET insert. However, this problem has recently been overcome in a human study to assess the regional FDG uptake and transmurality of late Gd enhancement using a fully integrated whole body PET/MRI scanner in the sub-acute phase after myocardial infarction (Ref. Reference Rischpler174). Similarly, in lung disease and cancer, the performance of PET/MR versus PET/CT was also evaluated with no significant differences (Ref. Reference Schwenzer175), although the detection rate of small lung lesions is still inferior when using PET/CT (Ref. Reference Rauscher176).

Third, attenuation correction for PET/CT has already been established. However, extensive investigation in developing new PET/MR attenuation correction algorithms is crucial. Values are collected from the same CT images, in which attenuation coefficients corresponding to bone (apart from the rest of the tissues) are separated. However, magnetic resonance of bones is very similar to that of air and therefore requires improved attenuation sequences (Refs Reference Paulus, Tellmann and Quick177, Reference Mollet178).

Fourth, a main challenge in coming years will be the demand for tailored PET/MR multimodal tracers, which depict localisation of specific signals (tissue and/or molecular targets). More important, however, is the need to quantify the amount of specific particles associated with specific pathophysiological events at the molecular level, including atherosclerosis, with the possibility of non-invasively testing drug therapy and treatment. The upcoming years will be crucial for the implementation of this brand new technological achievement.

The first preclinical hybrid PET/MR scans on atherosclerotic mice, rabbits and pigs (Refs Reference Pedersen16, Reference Millon77) have shown very promising results for future clinical applications in humans, not just to follow up plaque progression, but most importantly for the new possibilities that the system offers. Since they provide concomitant anatomical, functional and chemical information about atherosclerotic plaques, these hybrid scans would therefore be useful in forecasting the outcome of plaque progression in terms of stability or vulnerability towards plaque disruption. In humans, assessment of carotid atherosclerotic plaques have recently been analysed (Ref. Reference Ripa179). Compared with PET/CT, hybrid PET/MR yields comparable (18F)FDG quantification and superior delineation of the vessel wall. However, these studies have been undertaken so far using single PET radiotracers. In the coming years when multimodal reagents are fully available, the real capabilities of this technology will come to light. To this end, rabbit atherosclerosis has been recently studied with a combination of USPIO nanoparticles and (18F)FDG, confirming the possibility of combining two functional imaging modalities in order to assess changes in the inflammation of atherosclerotic plaques by using hybrid PET/MR (Ref. Reference Millon77). In addition, the first study of rat atherosclerosis combining hybrid PET/MR with dual PET/MR nanoparticles was performed to image thrombus formation in a rat arterial thrombus model. In the study, the dual PET/MR probe was generated on the basis of EP-2104R – a well-established fibrin-targeted Gd-based MR contrast agent – by partial exchange of Gd for copper 64 (64Cu), demonstrating that fibrin-targeted dual PET/MR probe enables simultaneous, direct MR and PET imaging of thrombus (Ref. Reference Uppal180).

Outstanding research questions

Preclinical hybrid whole-body PET/MRI scanners are now a reality. In the coming years, great progress will be made in biomedical research thanks to different groups working around the world. Here we have outlined the enormous potential of hybrid PET/MR technology in cardiovascular research. When compared with CT, MR offers superior tissue resolution and functional imaging and is the best option to scan the population, thanks to the absence of ionizing radiation and the safety of the use of targeted MR contrast agents. Technically, PET motion compensation and image reconstruction are more accurate when combined with MR imaging, which in the end may offer better anatomical specificity and disease quantification. Hence, the coming years may represent a new era of PET/MRI; but first, three key issues must be addressed before its full implementation in clinical practice. First, clinically efficient attenuation correction algorithms are still under intense investigation, and worldwide standardised protocols are far from being a reality. Second, research into simultaneous multimodal reagents is now underway, and should be continued and intensified. Third, safety protocols should be investigated before transferring this cutting edge technology from bench to bedside.

Acknowledgements

Carlos Zaragoza designed the manuscript in its present form. Irene Cuadrado, Borja Castejón, Marta Saura, Ana María Martin, Irene Herruzo, Nikolaos Balatsos, Jose Luis Zamorano, and Carlos Zaragoza, drafted the manuscript in its final form. This work was supported by research grants from CZ: ‘Ministerio de Economía y Competitividad’ SAF 2011-28375, ‘Instituto de Salud Carlos III’ PI14/02022 (Plan Estatal de I+D+i 2013–2016) and co-financed by the European Development Regional Fund ‘A way to achieve Europe’ (ERDF), European COST action TD1007, and ‘Universidad Francisco de Vitoria 2014’

References

1. Altaf, N. et al. (2008) Detection of intraplaque hemorrhage by magnetic resonance imaging in symptomatic patients with mild to moderate carotid stenosis predicts recurrent neurological events. Journal of Vascular Surgery 47, 337-342 Google Scholar
2. Vaina, S. and Stefanadis, C. (2005) Detection of the vulnerable coronary atheromatous plaque. Where are we now? International Journal of Cardiovascular Intervention 7, 75-87 Google Scholar
3. Romero, J.R. et al. (2009) Carotid artery atherosclerosis, MRI indices of brain ischemia, aging, and cognitive impairment: the Framingham study. Stroke 40, 1590-1596 Google Scholar
4. Adams, M.R. and Celermajer, D.S. (1999) Detection of presymptomatic atherosclerosis: a current perspective. Clinical Science (Lond) 97, 615-624 Google Scholar
5. Cocker, M.S. et al. (2012) Imaging atherosclerosis with hybrid [18F]fluorodeoxyglucose positron emission tomography/computed tomography imaging: what Leonardo da Vinci could not see. Journal of Nuclear Cardiology 19, 1211-1225 Google Scholar
6. Davies, J.R. et al. (2005) Targeting the vulnerable plaque: the evolving role of nuclear imaging. Journal of Nuclear Cardiology 12, 234-246 Google Scholar
7. Botnar, R.M. et al. (2015) Molecular imaging in cardiovascular diseases. RoFo 36, 92-101 Google Scholar
8. Sadeghi, M.M. et al. (2010) Imaging atherosclerosis and vulnerable plaque. Journal of Nuclear Medicine 51 (Suppl 1), 51S-65S Google Scholar
9. Vengrenyuk, Y. et al. (2010) Computational stress analysis of atherosclerotic plaques in ApoE knockout mice. Annals of Biomedical Engineering 38, 738-747 CrossRefGoogle ScholarPubMed
10. Canet-Soulas, E. and Letourneur, D. (2007) Biomarkers of atherosclerosis and the potential of MRI for the diagnosis of vulnerable plaque. MAGMA 20, 129-142 Google Scholar
11. Kanwar, R.K. et al. (2012) Emerging engineered magnetic nanoparticulate probes for molecular MRI of atherosclerosis: how far have we come? Nanomedicine (Lond) 7, 899-916 Google Scholar
12. Naghavi, M. et al. (2006) From vulnerable plaque to vulnerable patient – part III: executive summary of the screening for heart attack prevention and education (SHAPE) task force report. American Journal of Cardiology 98, 2H-15H Google Scholar
13. Li, Y. et al. (2008) Effect of aging on fatty streak formation in a diet-induced mouse model of atherosclerosis. Journal of Vascular Research 45, 205-210 Google Scholar
14. Majmudar, M.D. et al. (2013) Polymeric nanoparticle PET/MR imaging allows macrophage detection in atherosclerotic plaques. Circulation Research 112, 755-761 Google Scholar
15. Millon, A. et al. (2014) Animal models of atherosclerosis and magnetic resonance imaging for monitoring plaque progression. Vascular 22, 221-237 Google Scholar
16. Pedersen, S.F. et al. (2014) Feasibility of simultaneous PET/MR in diet-induced atherosclerotic minipig: a pilot study for translational imaging. American Journal of Nuclear Medicine and Molecular Imaging 4, 448-458 Google Scholar
17. Ratib, O. and Nkoulou, R. (2014) Potential applications of PET/MR imaging in cardiology. Journal of Nuclear Medicine 55 (Suppl 2), 40S-46S Google Scholar
18. Rischpler, C., Nekolla, S.G. and Beer, A.J. (2013) PET/MR imaging of atherosclerosis: initial experience and outlook. American Journal of Nuclear Medicine and Molecular Imaging 3, 393-396 Google Scholar
19. Bigalke, B. et al. (2014) PET/CT and MR imaging biomarker of lipid-rich plaques using [64Cu]-labeled scavenger receptor (CD68-Fc). International Journal of Cardiology 177, 287-291 Google Scholar
20. Hatsukami, T.S. et al. (2000) Visualization of fibrous cap thickness and rupture in human atherosclerotic carotid plaque in vivo with high-resolution magnetic resonance imaging. Circulation 102, 959-964 Google Scholar
21. Jones, G.W. et al. (2015) Imbalanced gp130 signalling in ApoE-deficient mice protects against atherosclerosis. Atherosclerosis 238, 321-328 Google Scholar
22. Xu, L. et al. (2015) Foamy monocytes form early and contribute to nascent atherosclerosis in mice with hypercholesterolemia. Arteriosclerosis, Thrombosis, and Vascular Biology 35, 1787-1797 Google Scholar
23. Cai, J. et al. (2005) In vivo quantitative measurement of intact fibrous cap and lipid-rich necrotic core size in atherosclerotic carotid plaque: comparison of high-resolution, contrast-enhanced magnetic resonance imaging and histology. Circulation 112, 3437-3444 CrossRefGoogle ScholarPubMed
24. Heeneman, S. et al. (2008) Control of atherosclerotic plaque vulnerability: insights from transgenic mice. Frontiers in Bioscience 13, 6289-6313 Google Scholar
25. Iqbal, J. et al. (2015) Role of animal models in coronary stenting. Annals of Biomedical Engineering 44, 453-465 Google Scholar
26. Dweck, M.R. et al. (2016) MR imaging of coronary arteries and plaques. JACC: Cardiovascular Imaging 9, 306-316 Google Scholar
27. Mateo, J. et al. (2015) Magnetic resonance imaging of the atherosclerotic mouse aorta. Methods in Molecular Biology 1339, 387-394 Google Scholar
28. U-King-Im, J.M. et al. (2008) Characterisation of carotid atheroma in symptomatic and asymptomatic patients using high resolution MRI. Journal of Neurology, Neurosurgery, and Psychiatry 79, 905-912 Google Scholar
29. Wasserman, B.A. et al. (2002) Carotid artery atherosclerosis: in vivo morphologic characterization with gadolinium-enhanced double-oblique MR imaging initial results. Radiology 223, 566-573 Google Scholar
30. Boshuizen, M.C. et al. (2015) Interferon-β promotes macrophage foam cell formation by altering both cholesterol influx and efflux mechanisms. Cytokine 77, 220-226 Google Scholar
31. Getz, G.S. and Reardon, C.A. (2015) Use of mouse models in atherosclerosis research. Methods in Molecular Biology 1339, 1-16 Google Scholar
32. Li, G. et al. (2015) Hematopoietic knockdown of PPARδ reduces atherosclerosis in LDLR-/- mice. Gene Therapy 23, 78-85 Google Scholar
33. Ru, D. et al. (2015) Oxidized high-density lipoprotein accelerates atherosclerosis progression by inducing the imbalance between treg and teff in LDLR knockout mice. Acta Pathologica, Microbiologica, et Immunologica Scandinavica 123, 410-421 Google Scholar
34. Rensing, K.L. et al. (2014) Akt2/LDLr double knockout mice display impaired glucose tolerance and develop more complex atherosclerotic plaques than LDLr knockout mice. Cardiovascular Research 101, 277-287 CrossRefGoogle ScholarPubMed
35. Marquart, T.J. et al. (2013) Anti-miR-33 therapy does not alter the progression of atherosclerosis in low-density lipoprotein receptor-deficient mice. Arteriosclerosis, Thrombosis, and Vascular Biology 33, 455-458 Google Scholar
36. Tang, T. et al. (2013) Prevention of TGFβ induction attenuates angII-stimulated vascular biglycan and atherosclerosis in Ldlr-/- mice. Journal of Lipid Research 54, 2255-2264 Google Scholar
37. Teodoro, B.G. et al. (2012) Improvements of atherosclerosis and hepatic oxidative stress are independent of exercise intensity in LDLr(-/-) mice. Journal of Atherosclerosis and Thrombosis 19, 904-911 Google Scholar
38. Awan, Z. et al. (2011) The LDLR deficient mouse as a model for aortic calcification and quantification by micro-computed tomography. Atherosclerosis 219, 455-462 Google Scholar
39. Zhao, L. et al. (2008) CD44 expressed on both bone marrow-derived and non-bone marrow-derived cells promotes atherogenesis in ApoE-deficient mice. Arteriosclerosis, Thrombosis, and Vascular Biology 28, 1283-1289 Google Scholar
40. Andrés, V. et al. (2006) Atheroma development in apolipoprotein E-null mice is not affected by partial inactivation of PTEN. Frontiers in Bioscience 11, 2739-2745 Google Scholar
41. Higashimori, M. et al. (2011) Role of toll-like receptor 4 in intimal foam cell accumulation in apolipoprotein E-deficient mice. Arteriosclerosis, Thrombosis, and Vascular Biology 31, 50-57 Google Scholar
42. Meir, K.S. and Leitersdorf, E. (2004) Atherosclerosis in the apolipoprotein-E-deficient mouse: a decade of progress. Arteriosclerosis, Thrombosis, and Vascular Biology 24, 1006-1014 Google Scholar
43. Bot, I. et al. (2011) Atorvastatin inhibits plaque development and adventitial neovascularization in ApoE deficient mice independent of plasma cholesterol levels. Atherosclerosis 214, 295-300 Google Scholar
44. Akhtar, S. et al. (2013) CXCL12 promotes the stabilization of atherosclerotic lesions mediated by smooth muscle progenitor cells in Apoe-deficient mice. Arteriosclerosis, Thrombosis, and Vascular Biology 33, 679-686 Google Scholar
45. Fernández-Hernando, C. et al. (2009) Absence of Akt1 reduces vascular smooth muscle cell migration and survival and induces features of plaque vulnerability and cardiac dysfunction during atherosclerosis. Arteriosclerosis, Thrombosis, and Vascular Biology 29, 2033-2040 Google Scholar
46. Vaisman, B.L. et al. (2015) Endothelial expression of scavenger receptor class B, type I protects against development of atherosclerosis in mice. BioMed Research International 2015, 607120 CrossRefGoogle Scholar
47. Kitayama, K. et al. (2006) Blockade of scavenger receptor class B type I raises high density lipoprotein cholesterol levels but exacerbates atherosclerotic lesion formation in apolipoprotein E deficient mice. Journal of Pharmacy and Pharmacology 58, 1629-1638 Google Scholar
48. Zhang, S. et al. (2005) Diet-induced occlusive coronary atherosclerosis, myocardial infarction, cardiac dysfunction, and premature death in scavenger receptor class B type I-deficient, hypomorphic apolipoprotein ER61 mice. Circulation 111, 3457-3464 Google Scholar
49. Zhang, W. et al. (2003) Inactivation of macrophage scavenger receptor class B type I promotes atherosclerotic lesion development in apolipoprotein E-deficient mice. Circulation 108, 2258-2263 Google Scholar
50. Sosnovik, D.E. and Caravan, P. (2009) Molecular MRI of atherosclerotic plaque with targeted contrast agents. Current Cardiovascular Imaging Reports 2, 87-94 Google Scholar
51. Zadelaar, S. et al. (2007) Mouse models for atherosclerosis and pharmaceutical modifiers. Arteriosclerosis, Thrombosis, and Vascular Biology 27, 1706-1721 Google Scholar
52. Lardenoye, J.H. et al. (2000) Accelerated atherosclerosis by placement of a perivascular cuff and a cholesterol-rich diet in ApoE*3Leiden transgenic mice. Circulation Research 87, 248-253 Google Scholar
53. Lalloyer, F. et al. (2011) Peroxisome proliferator-activated receptor-alpha gene level differently affects lipid metabolism and inflammation in apolipoprotein E2 knock-in mice. Arteriosclerosis, Thrombosis, and Vascular Biology 31, 1573-1579 Google Scholar
54. Johnson, J. et al. (2005) Plaque rupture after short periods of fat feeding in the apolipoprotein E-knockout mouse: model characterization and effects of pravastatin treatment. Circulation 111, 1422-1430 Google Scholar
55. Katsuki, S. et al. (2014) Nanoparticle-mediated delivery of pitavastatin inhibits atherosclerotic plaque destabilization/rupture in mice by regulating the recruitment of inflammatory monocytes. Circulation 129, 896-906 Google Scholar
56. Matoba, T., Sato, K. and Egashira, K. (2013) Mouse models of plaque rupture. Current Opinion in Lipidology 24, 419-425 Google Scholar
57. Sato, K. et al. (2012) Dietary cholesterol oxidation products accelerate plaque destabilization and rupture associated with monocyte infiltration/activation via the MCP-1-CCR2 pathway in mouse brachiocephalic arteries: therapeutic effects of ezetimibe. Journal of Atherosclerosis and Thrombosis 19, 986-998 CrossRefGoogle ScholarPubMed
58. Gough, P.J. et al. (2006) Macrophage expression of active MMP-9 induces acute plaque disruption in apoE-deficient mice. Journal of Clinical Investigation 116, 59-69 Google Scholar
59. Hu, J.H. et al. (2010) Overexpression of urokinase by plaque macrophages causes histological features of plaque rupture and increases vascular matrix metalloproteinase activity in aged apolipoprotein e-null mice. Circulation 121, 1637-1644 Google Scholar
60. Ma, T. et al. (2013) Th17 cells and IL-17 are involved in the disruption of vulnerable plaques triggered by short-term combination stimulation in apolipoprotein E-knockout mice. Cellular & Molecular Immunology 10, 338-348 Google Scholar
61. de Witt, S.M. et al. (2014) Insights into platelet-based control of coagulation. Thrombosis Research 133 (Suppl 2), S139-S148 Google Scholar
62. Desai, M.Y. and Lima, J.A. (2006) Imaging of atherosclerosis using magnetic resonance: state of the art and future directions. Current Atherosclerosis Reports 8, 131-139 Google Scholar
63. Momiyama, Y. and Fayad, Z.A. (2007) Aortic plaque imaging and monitoring atherosclerotic plaque interventions. Topics in Magnetic Resonance Imaging 18, 349-355 Google Scholar
64. Yonemura, A. et al. (2009) Effect of lipid-lowering therapy with atorvastatin on atherosclerotic aortic plaques: a 2-year follow-up by noninvasive MRI. European Journal of Cardiovascular Prevention and Rehabilitation 16, 222-228 Google Scholar
65. Blum, A. and Nahir, M. (2013) Future non-invasive imaging to detect vascular plaque instability and subclinical non-obstructive atherosclerosis. Journal of Geriatric Cardiology 10, 178-185 Google Scholar
66. Oikawa, M. et al. (2009) Carotid magnetic resonance imaging. A window to study atherosclerosis and identify high-risk plaques. Circulation Journal 73, 1765-1773 Google Scholar
67. Raman, S.V. et al. (2008) In vivo atherosclerotic plaque characterization using magnetic susceptibility distinguishes symptom-producing plaques. JACC Cardiovascular Imaging 1, 49-57 Google Scholar
68. Slevin, M. et al. (2010) Combining nanotechnology with current biomedical knowledge for the vascular imaging and treatment of atherosclerosis. Molecular Biosystems 6, 444-450 Google Scholar
69. Winter, P.M. et al. (2003) Molecular imaging of angiogenesis in early-stage atherosclerosis with alpha(v)beta3-integrin-targeted nanoparticles. Circulation 108, 2270-2274 Google Scholar
70. Cheng, K.K. et al. (2010) Metabolomic study of the LDL receptor null mouse fed a high-fat diet reveals profound perturbations in choline metabolism that are shared with ApoE null mice. Physiological Genomics 41, 224-231 Google Scholar
71. Abran, M. et al. (2015) Validating a bimodal intravascular ultrasound (IVUS) and near-infrared fluorescence (NIRF) catheter for atherosclerotic plaque detection in rabbits. Biomedical Optics Express 6, 3989-3999 Google Scholar
72. El-Sheakh, A.R. et al. (2015) Antioxidant and anti-inflammatory effects of flavocoxid in high-cholesterol-fed rabbits. Naunyn-Schmiedeberg's Archives of Pharmacology 388, 1333-1344 Google Scholar
73. Fan, J. et al. (2015) Rabbit models for the study of human atherosclerosis: from pathophysiological mechanisms to translational medicine. Pharmacology & Therapeutics 146, 104-119 Google Scholar
74. Hyafil, F. et al. (2015) Detection of apoptotic cells in a rabbit model with atherosclerosis-like lesions using the positron emission tomography radiotracer [18F]ML-10. Molecular Imaging 14, 433-442 Google Scholar
75. Fang, D. et al. (2014) Atorvastatin suppresses Toll-like receptor 4 expression and NF-κB activation in rabbit atherosclerotic plaques. European Review for Medical and Pharmacological Sciences 18, 242-246 Google ScholarPubMed
76. Kong, L. et al. (2013) The anti-inflammatory effect of kaempferol on early atherosclerosis in high cholesterol fed rabbits. Lipids in Health and Disease 12, 115 Google Scholar
77. Millon, A. et al. (2013) Monitoring plaque inflammation in atherosclerotic rabbits with an iron oxide (P904) and (18)F-FDG using a combined PET/MR scanner. Atherosclerosis 228, 339-345 Google Scholar
78. Shiomi, M., Koike, T. and Ito, T. (2013) Contribution of the WHHL rabbit, an animal model of familial hypercholesterolemia, to elucidation of the anti-atherosclerotic effects of statins. Atherosclerosis 231, 39-47 Google Scholar
79. Tian, J. et al. (2013) Vasa vasorum and plaque progression, and responses to atorvastatin in a rabbit model of atherosclerosis: contrast-enhanced ultrasound imaging and intravascular ultrasound study. Heart 99, 48-54 Google Scholar
80. Yanni, A.E. (2004) The laboratory rabbit: an animal model of atherosclerosis research. Laboratory Animals 38, 246-256 Google Scholar
81. Johnstone, M.T. et al. (2001) In vivo magnetic resonance imaging of experimental thrombosis in a rabbit model. Arteriosclerosis, Thrombosis, and Vascular Biology 21, 1556-1560 Google Scholar
82. Shukla, K. et al. (2014) Hypolipidemic and antioxidant activity of aqueous extract of fruit of Withania coagulans (Stocks) Dunal in cholesterol-fed hyperlipidemic rabbit model. Indian Journal of Experimental Biology 52, 870-875 Google Scholar
83. Yang, X. et al. (2006) Effects of simvastatin on NF-kappaB-DNA binding activity and monocyte chemoattractant protein-1 expression in a rabbit model of atherosclerosis. Journal of Huazhong University of Science and Technology 26, 194-198 Google Scholar
84. Helft, G. et al. (2002) Progression and regression of atherosclerotic lesions: monitoring with serial noninvasive magnetic resonance imaging. Circulation 105, 993-998 Google Scholar
85. Rival, Y. et al. (2002) Anti-atherosclerotic properties of the acyl-coenzyme A: cholesterol acyltransferase inhibitor F 12511 in casein-fed New Zealand rabbits. Journal of Cardiovascular Pharmacology 39, 181-191 Google Scholar
86. Tijburg, L.B. et al. (1997) Effects of green tea, black tea and dietary lipophilic antioxidants on LDL oxidizability and atherosclerosis in hypercholesterolaemic rabbits. Atherosclerosis 135, 37-47 Google Scholar
87. Largo, R. et al. (2008) Chronic arthritis aggravates vascular lesions in rabbits with atherosclerosis: a novel model of atherosclerosis associated with chronic inflammation. Arthritis and Rheumatism 58, 2723-2734 Google Scholar
88. Zhao, Q.M. et al. (2013) Detection of vulnerable atherosclerotic plaque and prediction of thrombosis events in a rabbit model using 18F-FDG -PET/CT. PLoS ONE 8, e61140 Google Scholar
89. Phinikaridou, A. et al. (2010) In vivo detection of vulnerable atherosclerotic plaque by MRI in a rabbit model. Circulation Cardiovascular Imaging 3, 323-332 Google Scholar
90. Shimizu, T. et al. (2009) Simple rabbit model of vulnerable atherosclerotic plaque. Neurologia medico-chirurgica (Tokyo) 49, 327-332; discussion 32Google Scholar
91. Abela, G.S. et al. (1995) Triggering of plaque disruption and arterial thrombosis in an atherosclerotic rabbit model. Circulation 91, 776-784 Google Scholar
92. Zhang, J. et al. (2012) Endothelial lipase mediates HDL levels in normal and hyperlipidemic rabbits. Journal of Atherosclerosis and Thrombosis 19, 213-226 Google Scholar
93. Ito, T. and Shiomi, M. (2001) Cerebral atherosclerosis occurs spontaneously in homozygous WHHL rabbits. Atherosclerosis 156, 57-66 Google Scholar
94. Mohler, E.R. et al. (2008) Site-specific atherogenic gene expression correlates with subsequent variable lesion development in coronary and peripheral vasculature. Arteriosclerosis, Thrombosis, and Vascular Biology 28, 850-855 Google Scholar
95. Gerrity, R.G. et al. (2001) Diabetes-induced accelerated atherosclerosis in swine. Diabetes 50, 1654-1665 Google Scholar
96. Hamada, N. et al. (2010) Tacrolimus-eluting stent inhibits neointimal hyperplasia via calcineurin/NFAT signaling in porcine coronary artery model. Atherosclerosis 208, 97-103 Google Scholar
97. Behler, R.H. et al. (2009) ARFI imaging for noninvasive material characterization of atherosclerosis. Part II: toward in vivo characterization. Ultrasound in Medicine & Biology 35, 278-295 Google Scholar
98. Deuse, T. et al. (2014) Dichloroacetate prevents restenosis in preclinical animal models of vessel injury. Nature 509, 641-644 Google Scholar
99. Virmani, R., Kolodgie, F.D. and Farb, A. (2004) Drug-eluting stents: are they really safe? American Heart Hospital Journal 2, 85-88 Google Scholar
100. Beller, G.A. (2008) Cardiovascular molecular imaging: where art thou? Journal of Nuclear Cardiology 15, 611-612 Google Scholar
101. Nörenberg, D. et al. (2015) Molecular magnetic resonance imaging of atherosclerotic vessel wall disease. European Radiology 26, 910-920 Google Scholar
102. Phinikaridou, A. et al. (2013) Molecular MRI of atherosclerosis. Molecules 18, 14042-14069 CrossRefGoogle ScholarPubMed
103. Misri, R., Saatchi, K. and Häfeli, U.O. (2012) Nanoprobes for hybrid SPECT/MR molecular imaging. Nanomedicine (Lond) 7, 719-733 Google Scholar
104. Chen, W. et al. (2011) Nanoparticles as magnetic resonance imaging contrast agents for vascular and cardiac diseases. Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology 3, 146-161 Google Scholar
105. Klink, A. et al. (2010) Magnetic resonance molecular imaging of thrombosis in an arachidonic acid mouse model using an activated platelet targeted probe. Arteriosclerosis, Thrombosis, and Vascular Biology 30, 403-410 Google Scholar
106. Mulder, W.J. et al. (2008) Multimodality nanotracers for cardiovascular applications. Nature Clinical Practice. Cardiovascular Medicine 5 (Suppl 2), S103-S111 Google Scholar
107. Yuan, C. et al. (1998) Measurement of atherosclerotic carotid plaque size in vivo using high resolution magnetic resonance imaging. Circulation 98, 2666-2671 Google Scholar
108. Stuber, M. et al. (1999) Submillimeter three-dimensional coronary MR angiography with real-time navigator correction: comparison of navigator locations. Radiology 212, 579-587 Google Scholar
109. Worthley, S.G. et al. (2000) Noninvasive in vivo magnetic resonance imaging of experimental coronary artery lesions in a porcine model. Circulation 101, 2956-2961 Google Scholar
110. Fayad, Z.A. et al. (2000) Noninvasive in vivo human coronary artery lumen and wall imaging using black-blood magnetic resonance imaging. Circulation 102, 506-510 Google Scholar
111. Corti, R. et al. (2001) New understanding of atherosclerosis (clinically and experimentally) with evolving MRI technology in vivo. Annals of the New York Academy of Sciences 947, 181-195 Google Scholar
112. Yuan, C. et al. (2001) In vivo accuracy of multispectral magnetic resonance imaging for identifying lipid-rich necrotic cores and intraplaque hemorrhage in advanced human carotid plaques. Circulation 104, 2051-2056 Google Scholar
113. Corti, R. et al. (2002) Effect of percutaneous transluminal angioplasty on severely stenotic femoral lesions: in vivo demonstration by noninvasive magnetic resonance imaging. Circulation 106, 1570-1571 Google Scholar
114. Yuan, C. et al. (2002) Identification of fibrous cap rupture with magnetic resonance imaging is highly associated with recent transient ischemic attack or stroke. Circulation 105, 181-185 Google Scholar
115. Kramer, C.M. (2015) Novel magnetic resonance imaging end points for physiologic studies in peripheral arterial disease: elegance versus practicality. Circulation Cardiovascular Imaging 8, pii: e003360CrossRefGoogle ScholarPubMed
116. Di Leo, G. et al. (2015) Diagnostic accuracy of magnetic resonance angiography for detection of coronary artery disease: a systematic review and meta-analysis. European Radiology, 1-13 [Epub ahead of print]Google Scholar
117. Makowski, M.R. et al. (2009) Molecular imaging with targeted contrast agents. Topics in Magnetic Resonance Imaging 20, 247-259 Google Scholar
118. Mulder, W.J. et al. (2007) Magnetic resonance molecular imaging contrast agents and their application in atherosclerosis. Topics in Magnetic Resonance Imaging 18, 409-417 Google Scholar
119. Segers, F.M. et al. (2013) Scavenger receptor-AI-targeted iron oxide nanoparticles for in vivo MRI detection of atherosclerotic lesions. Arteriosclerosis, Thrombosis, and Vascular Biology 33, 1812-1819 Google Scholar
120. Metz, S. et al. (2011) Characterization of carotid artery plaques with USPIO-enhanced MRI: assessment of inflammation and vascularity as in vivo imaging biomarkers for plaque vulnerability. International Journal of Cardiovascular Imaging 27, 901-912 Google Scholar
121. Klug, G., Bauer, L. and Bauer, W.R. (2008) Patterns of USPIO deposition in murine atherosclerosis. Arteriosclerosis, Thrombosis, and Vascular Biology 28, E157; author reply E58-E59Google Scholar
122. Ma, Z.L. et al. (2009) Inhibited atherosclerotic plaque formation by local administration of magnetically labeled endothelial progenitor cells (EPCs) in a rabbit model. Atherosclerosis 205, 80-86 Google Scholar
123. Sigovan, M. et al. (2009) Rapid-clearance iron nanoparticles for inflammation imaging of atherosclerotic plaque: initial experience in animal model. Radiology 252, 401-409 Google Scholar
124. Bjerner, T. et al. (2000) Evaluation of nonperfused myocardial ischemia with MRI and an intravascular USPIO contrast agent in an ex vivo pig model. Journal of Magnetic Resonance Imaging 12, 866-872 Google Scholar
125. Sigovan, M. et al. (2012) Anti-inflammatory drug evaluation in ApoE-/- mice by ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging. Investigative Radiology 47, 546-552 Google Scholar
126. Jacobin-Valat, M.J. et al. (2011) MRI of inducible P-selectin expression in human activated platelets involved in the early stages of atherosclerosis. NMR in Biomedicine 24, 413-424 Google Scholar
127. Burtea, C. et al. (2008) Molecular imaging of alpha v beta3 integrin expression in atherosclerotic plaques with a mimetic of RGD peptide grafted to Gd-DTPA. Cardiovascular Research 78, 148-157 Google Scholar
128. McAteer, M.A. et al. (2012) A leukocyte-mimetic magnetic resonance imaging contrast agent homes rapidly to activated endothelium and tracks with atherosclerotic lesion macrophage content. Arteriosclerosis, Thrombosis, and Vascular Biology 32, 1427-1435 Google Scholar
129. Tang, T.Y. et al. (2009) The ATHEROMA (atorvastatin therapy: effects on reduction of macrophage activity) study. Evaluation using ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging in carotid disease. Journal of the American College of Cardiology 53, 2039-2050 Google Scholar
130. Diwoky, C. et al. (2015) Positive contrast of SPIO-labeled cells by off-resonant reconstruction of 3D radial half-echo bSSFP. NMR in Biomedicine 28, 79-88 Google Scholar
131. Almer, G. et al. (2013) Interleukin-10: an anti-inflammatory marker to target atherosclerotic lesions via PEGylated liposomes. Molecular Pharmaceutics 10, 175-186 Google Scholar
132. Hansen, T. et al. (2009) Visceral adipose tissue, adiponectin levels and insulin resistance are related to atherosclerosis as assessed by whole-body magnetic resonance angiography in an elderly population. Atherosclerosis 205, 163-167 CrossRefGoogle Scholar
133. Andia, M.E. et al. (2014) Fibrin-targeted magnetic resonance imaging allows in vivo quantification of thrombus fibrin content and identifies thrombi amenable for thrombolysis. Arteriosclerosis, Thrombosis, and Vascular Biology 34, 1193-1198 Google Scholar
134. Chen, W. et al. (2013) Collagen-specific peptide conjugated HDL nanoparticles as MRI contrast agent to evaluate compositional changes in atherosclerotic plaque regression. JACC Cardiovascular Imaging 6, 373-384 CrossRefGoogle ScholarPubMed
135. Spuentrup, E. et al. (2009) Molecular magnetic resonance imaging of myocardial perfusion with EP-3600, a collagen-specific contrast agent: initial feasibility study in a swine model. Circulation 119, 1768-1775 Google Scholar
136. Phinikaridou, A. et al. (2014) Vascular remodeling and plaque vulnerability in a rabbit model of atherosclerosis: comparison of delayed-enhancement MR imaging with an elastin-specific contrast agent and unenhanced black-blood MR imaging. Radiology 271, 390-399 Google Scholar
137. Hyafil, F. et al. (2011) Monitoring of arterial wall remodelling in atherosclerotic rabbits with a magnetic resonance imaging contrast agent binding to matrix metalloproteinases. European Heart Journal 32, 1561-1571 Google Scholar
138. Liu, Y. et al. (2013) PET imaging of chemokine receptors in vascular injury-accelerated atherosclerosis. Journal of Nuclear Medicine 54, 1135-1141 Google Scholar
139. Tawakol, A. et al. (2013) Intensification of statin therapy results in a rapid reduction in atherosclerotic inflammation: results of a multicenter fluorodeoxyglucose-positron emission tomography/computed tomography feasibility study. Journal of the American College of Cardiology 62, 909-917 Google Scholar
140. Hag, A.M. et al. (2012) (18)F-FDG PET imaging of murine atherosclerosis: association with gene expression of key molecular markers. PLoS ONE 7, e50908 Google Scholar
141. Rosenbaum, D., Millon, A. and Fayad, Z.A. (2012) Molecular imaging in atherosclerosis: FDG PET. Current Atherosclerosis Reports 14, 429-437 Google Scholar
142. Calcagno, C. et al. (2008) Detection of neovessels in atherosclerotic plaques of rabbits using dynamic contrast enhanced MRI and 18F-FDG PET. Arteriosclerosis, Thrombosis, and Vascular Biology 28, 1311-1317 Google Scholar
143. Rudd, J.H. et al. (2008) Atherosclerosis inflammation imaging with 18F-FDG PET: carotid, iliac, and femoral uptake reproducibility, quantification methods, and recommendations. Journal of Nuclear Medicine 49, 871-878 Google Scholar
144. Rudd, J.H. et al. (2007) (18)Fluorodeoxyglucose positron emission tomography imaging of atherosclerotic plaque inflammation is highly reproducible: implications for atherosclerosis therapy trials. Journal of the American College of Cardiology 50, 892-896 Google Scholar
145. Chen, W. and Dilsizian, V. (2013) Targeted PET/CT imaging of vulnerable atherosclerotic plaques: microcalcification with sodium fluoride and inflammation with fluorodeoxyglucose. Current Cardiology Reports 15, 364 Google Scholar
146. Tawakol, A. et al. (2005) Noninvasive in vivo measurement of vascular inflammation with F-18 fluorodeoxyglucose positron emission tomography. Journal of Nuclear Cardiology 12, 294-301 Google Scholar
147. Vucic, E. et al. (2012) Regression of inflammation in atherosclerosis by the LXR agonist R211945: a noninvasive assessment and comparison with atorvastatin. JACC Cardiovascular Imaging 5, 819-828 Google Scholar
148. Davies, J.R. et al. (2010) FDG-PET can distinguish inflamed from non-inflamed plaque in an animal model of atherosclerosis. International Journal of Cardiovascular Imaging 26, 41-48 Google Scholar
149. Ogawa, M. et al. (2006) Application of 18F-FDG PET for monitoring the therapeutic effect of anti-inflammatory drugs on stabilization of vulnerable atherosclerotic plaques. Journal of Nuclear Medicine 47, 1845-1850 Google Scholar
150. Vucic, E. et al. (2011) Pioglitazone modulates vascular inflammation in atherosclerotic rabbits noninvasive assessment with FDG-PET-CT and dynamic contrast-enhanced MR imaging. JACC Cardiovascular Imaging 4, 1100-1109 Google Scholar
151. Lobatto, M.E. et al. (2012) Imaging the efficacy of anti-inflammatory liposomes in a rabbit model of atherosclerosis by non-invasive imaging. Methods in Enzymology 508, 211-228 Google Scholar
152. Laitinen, I. et al. (2009) Uptake of inflammatory cell marker [11C]PK11195 into mouse atherosclerotic plaques. European Journal of Nuclear Medicine and Molecular Imaging 36, 73-80 Google Scholar
153. Gaemperli, O. et al. (2012) Imaging intraplaque inflammation in carotid atherosclerosis with 11C-PK11195 positron emission tomography/computed tomography. European Heart Journal 33, 1902-1910 Google Scholar
154. Matter, C.M. et al. (2006) 18F-choline images murine atherosclerotic plaques ex vivo. Arteriosclerosis, Thrombosis, and Vascular Biology 26, 584-589 Google Scholar
155. Nahrendorf, M. et al. (2008) Nanoparticle PET-CT imaging of macrophages in inflammatory atherosclerosis. Circulation 117, 379-387 Google Scholar
156. Libby, P., DiCarli, M. and Weissleder, R. (2010) The vascular biology of atherosclerosis and imaging targets. Journal of Nuclear Medicine 51 (Suppl 1), 33S-37S Google Scholar
157. Nahrendorf, M. et al. (2009) 18F-4V for PET-CT imaging of VCAM-1 expression in atherosclerosis. JACC Cardiovascular Imaging 2, 1213-1222 Google Scholar
158. Silvola, J.M. et al. (2011) Detection of hypoxia by [18F]EF5 in atherosclerotic plaques in mice. Arteriosclerosis, Thrombosis, and Vascular Biology 31, 1011-1015 Google Scholar
159. Laitinen, I. et al. (2009) Evaluation of alphavbeta3 integrin-targeted positron emission tomography tracer 18F-galacto-RGD for imaging of vascular inflammation in atherosclerotic mice. Circulation Cardiovascular Imaging 2, 331-338 Google Scholar
160. Elmaleh, D.E. et al. (2006) Detection of inflamed atherosclerotic lesions with diadenosine-5″,5‴-P1′,P4-tetraphosphate (Ap4A) and positron-emission tomography. Proceedings of the National Academy of Sciences of the United States of America 103, 15992-15996 Google Scholar
161. Liu, Y. et al. (2010) Molecular imaging of atherosclerotic plaque with (64)Cu-labeled natriuretic peptide and PET. Journal of Nuclear Medicine 51, 85-91 Google Scholar
162. Derlin, T. et al. (2011) Feasibility of 11C-acetate PET/CT for imaging of fatty acid synthesis in the atherosclerotic vessel wall. Journal of Nuclear Medicine 52, 1848-1854 Google Scholar
163. Zerhouni, E.A. (1990) New directions in cardiac magnetic resonance imaging. Topics in Magnetic Resonance Imaging 2, 67-71 Google Scholar
164. Skorton, D.J. and Collins, S.M. (1985) New directions in cardiac imaging. Annals of Internal Medicine 102, 795-799 Google Scholar
165. Bailey, D.L. et al. (2015) Combined PET/MRI: multi-modality multi-parametric imaging is here: summary report of the 4th international workshop on PET/MR imaging; February 23-27, 2015, Tübingen, Germany. Molecular Imaging and Biology 17, 595-608 Google Scholar
166. Delso, G., Ter Voert, E. and Veit-Haibach, P. (2015) How does PET/MR work? Basic physics for physicians. Abdominal Imaging 40, 1352-1357 Google Scholar
167. Disselhorst, J.A. et al. (2014) Principles of PET/MR imaging. Journal of Nuclear Medicine 55 (Suppl 2), 2S-10S Google Scholar
168. Martinez-Möller, A. et al. (2007) Dual cardiac-respiratory gated PET: implementation and results from a feasibility study. European Journal of Nuclear Medicine and Molecular Imaging 34, 1447-1454 Google Scholar
169. Martinez-Möller, A. and Nekolla, S.G. (2012) Attenuation correction for PET/MR: problems, novel approaches and practical solutions. Zeitschrift fur Medizinische Physik 22, 299-310 Google Scholar
170. Nappi, C. and El Fakhri, G. (2013) State of the art in cardiac hybrid technology: PET/MR. Current Cardiovascular Imaging Reports 6, 338-345 Google Scholar
171. McCallum, S., Clowes, P. and Welch, A. (2005) A four-layer attenuation compensated PET detector based on APD arrays without discrete crystal elements. Physics in Medicine and Biology 50, 4187-4207 Google Scholar
172. Maramraju, S.H. et al. (2011) Small animal simultaneous PET/MRI: initial experiences in a 9.4T microMRI. Physics in Medicine and Biology 56, 2459-2480 Google Scholar
173. Yoon, H.S. et al. (2012) Initial results of simultaneous PET/MRI experiments with an MRI-compatible silicon photomultiplier PET scanner. Journal of Nuclear Medicine 53, 608-614 Google Scholar
174. Rischpler, C. et al. (2015) PET/MRI early after myocardial infarction: evaluation of viability with late gadolinium enhancement transmurality vs. 18F-FDG uptake. European Heart Journal Cardiovascular Imaging 16, 661-669 Google Scholar
175. Schwenzer, N.F. et al. (2012) Pulmonary lesion assessment: comparison of whole-body hybrid MR/PET and PET/CT imaging – pilot study. Radiology 264, 551-558 Google Scholar
176. Rauscher, I. et al. (2014) PET/MR imaging in the detection and characterization of pulmonary lesions: technical and diagnostic evaluation in comparison to PET/CT. Journal of Nuclear Medicine 55, 724-729 Google Scholar
177. Paulus, D.H., Tellmann, L. and Quick, H.H. (2013) Towards improved hardware component attenuation correction in PET/MR hybrid imaging. Physics in Medicine and Biology 58, 8021-8040 Google Scholar
178. Mollet, P. et al. (2014) Improvement of attenuation correction in time-of-flight PET/MR imaging with a positron-emitting source. Journal of Nuclear Medicine 55, 329-336 Google Scholar
179. Ripa, R.S. et al. (2013) Feasibility of simultaneous PET/MR of the carotid artery: first clinical experience and comparison to PET/CT. American Journal of Nuclear Medicine and Molecular Imaging 3, 361-371 Google Scholar
180. Uppal, R. et al. (2011) Bimodal thrombus imaging: simultaneous PET/MR imaging with a fibrin-targeted dual PET/MR probe – feasibility study in rat model. Radiology 258, 812-820 Google Scholar
181. Kawachi, E. et al. (2013) Novel molecular imaging of atherosclerosis with gallium-68-labeled apolipoprotein A-I mimetic peptide and positron emission tomography. Circulation Journal 77, 1482-1489 Google Scholar
182. Langer, H.F. (2008) Radionuclide imaging: a molecular key to the atherosclerotic plaque. Journal of the American College of Cardiology 52, 1-12 Google Scholar
183. Pietzsch, J. et al. (2005) Catabolism of native and oxidized low density lipoproteins: in vivo insights from small animal positron emission tomography studies. Amino Acids 29, 389-404 Google Scholar
Figure 0

Figure 1.Graphical representation of stable and vulnerable plaques.

Figure 1

Figure 2.Schematic representation of targeted and fluorescently labelled iron oxide nanoparticles.

Figure 2

Figure 3.Schematic representation of Gadolinium (Gd)-containing nanoparticles. (a) Target ligand conjugated to Gd chelates. (b) Target ligand conjugated to Gd containing micelles. (c) Target ligand conjugated to Gd containing liposomes. Gd, Gadolinium.

Figure 3

Figure 4.Non-invasive molecular imaging detection of EMMPRIN by MRI in apoE null mice. (a) Composition of immunomicelles conjugated with specific anti-EMMPRIN antibody. Eight-week old apoE atherosclerotic null mice were anesthetised and injected with Gd-containing immunomicelles conjugated with anti-EMMPRIN antibody. (b) T1 4.7T MRI scan of mice at time 0 h after injection. (c) T1 4.7T MRI scans of the same mice 2 h after injection, showing Gd enhancement in the aorta (white arrow). (d and e). Ex vivo tissue sections of paraffin embedded abdominal aortas of mice injected with Gd-containing immunomicelles conjugated with anti-EMMPRIN antibody, and isolated at time 0 h (d) and 2 h (e) after injection, and visualised by confocal microscopy. Arrows represent FITC positive cells containing nanoparticles, L, lumen. apoE, apolipoprotein E; EMMPRIN, extracellular matrix metalloproteinase inducer; Gd, Gadolinium; MRI, magnetic resonance imaging.

Figure 4

Table 1.Radiotracers to study atherosclerosis by PET