Clinica Chimica Acta 437 (2014) 19–24

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Laboratory medicine for molecular imaging of atherosclerosis Harald Mangge a,b,⁎, Gunter Almer a, Ingeborg Stelzer a, Eva Reininghaus c, Ruth Prassl d a

Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Austria BioTechMed-Graz, Austria c Department of Psychiatry, Medical University of Graz, Austria d Institute of Biophysics, Medical University of Graz, Austria b

a r t i c l e

i n f o

Article history: Received 3 April 2014 Received in revised form 24 June 2014 Accepted 30 June 2014 Available online 5 July 2014 Keywords: Laboratory medicine Molecular imaging of atherosclerosis Nanotechnology

a b s t r a c t Atherosclerotic plaques are the main cause of life threatening clinical endpoints like myocardial infarction and stroke. To prevent these endpoints, the improved early diagnosis and treatment of vulnerable atherosclerotic vascular lesions are essential. Although originally applied for anticancer treatment, recent advances have also showed the considerable potential of nanotechnology for atherosclerosis. Otherwise, one domain of laboratory medicine is the investigation of new biomarkers. Recent research activities have identified the usability of biomarker-targeted nanoparticles for molecular imaging and pharmacologic modification of vulnerable atherosclerotic lesions leading to myocardial infarction or stroke. These investigations have established a new research interface between laboratory medicine, nanotechnology, cardiology/neurology, and radiology. In this review, we discuss inflammatory pathophysiologic mechanisms and biomarkers associated with a vulnerable atherosclerotic plaque phenotype. Further, we will emphasize cardiovascular relevant functionalized nanoparticle biomarker constructs which were developed within the cooperation interface between Laboratory Medicine (anti-inflammatory biomarkers), Nano-Medicine (nanoparticle development), and Radiology (molecular imaging). © 2014 Elsevier B.V. All rights reserved.

Contents 1.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Historical background of nanomedical applications . . . . . . . . . . . . . . . 2. Atherosclerosis, inflammation and vulnerability . . . . . . . . . . . . . . . . . . . . 2.1. Early stages of AS lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Advanced stages of AS lesions . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Progression to the endpoints — myocardial infarction or stroke . . . . . . . . . . 2.4. Infection triggers? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Inflammation-related biomarkers for diagnosis of atherosclerotic perpetuation . . . . . . 3.1. Myeloperoxidase — a vulnerability marker for stroke . . . . . . . . . . . . . . 4. Selected candidate biomarkers for nanomedical targeting of AS . . . . . . . . . . . . . 4.1. Low density lipoprotein (LDL) . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. High density lipoprotein (HDL) . . . . . . . . . . . . . . . . . . . . . . . . 5. Anti-inflammatory biomarkers for nanomedical AS targeting — an underestimated strategy 5.1. Adiponectin—less adipokine, more immune modulator? . . . . . . . . . . . . . 5.2. Interleukin-10 — the anti-inflammatory “master” cytokine . . . . . . . . . . . . 6. Other relevant anti-inflammatory cytokines . . . . . . . . . . . . . . . . . . . . . . 6.1. Interleukin-13 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Interleukins -19, -27, -35, and 37 . . . . . . . . . . . . . . . . . . . . . . . 7. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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⁎ Corresponding author at: Research Unit on Lifestyle and Inflammation-associated Risk Biomarkers, Clinical Institute of Medical and Chemical Laboratory Diagnosis, Medical University of Graz, BioTechMed-Graz, Auenbruggerplatz 15, 8036 Graz, Austria. Tel.: +43 316 385 8 33 40; fax: +43 316 385 13034. E-mail address: [email protected] (H. Mangge).

http://dx.doi.org/10.1016/j.cca.2014.06.029 0009-8981/© 2014 Elsevier B.V. All rights reserved.

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1. Introduction

2. Atherosclerosis, inflammation and vulnerability

Despite diagnostic and therapeutic advances, cardiovascular endpoints are still leading causes of mortality worldwide. This is primarily due to the increasing prevalence of atherosclerosis (AS), frequently associated with the metabolic syndrome (MetS), usually caused by a sedentary, obesogenic lifestyle. Atherosclerosis is a sub-acute inflammation around lipid deposits in the vascular wall, characterized by the infiltration of macrophages and T cells interacting with one another and with the arterial wall cells [1]. The adaptive and innate immune systems are involved in the generation of vulnerability within the plaque scenario [2–6]. Currently, AS tends to be diagnosed too late at the advanced stages of the disease, either by directly measuring the degree of stenosis or by evaluating the effect of arterial stenosis on organ perfusion [7]. Recent advances in imaging techniques have provided new options for improved visualization and monitoring of AS-lesions' dynamics of progression or regression [8]. Nevertheless, a reliable, cost-effective, non-invasive technique to detect different stages of AS for the applicable, clinical characterization of AS-plaques has yet to be developed [9]. Nanomedicine applies nanotechnology for the diagnosis, therapy, and monitoring of diseases. Medical nanoparticles (NP) are typically between 1 and 300 nm in size, and resemble in scale macromolecules like proteins and DNA. Nanoparticles can consist of organic material (e.g. spherical phospholipid bilayer self-assemblies — so called liposomes), polymeric, inorganic or metallic materials (e.g. iron oxide, gold) or combinations thereof [10]. Usually, NP have a high surface-to-volume ratio, which is well suited for coating the surface with a variety of molecules, e.g. for specific targeting of pathologic key processes [11]. The investigation of new biomarkers for diagnosis, monitoring, and control of cardiovascular disease (CVD) is an exciting challenge for laboratory medicine. These biomarkers can be potentially useful molecules for coating NP to generate a selective targeting capacity for pathologic processes. Herein, we discuss these aspects in the context of improved diagnosis and treatment of the two most important clinical endpoints of AS—myocardial infarction and stroke.

Atherosclerosis is the major cause of morbidity and mortality in CVD, and represents a substantial economic burden [20]. Atherosclerotic plaques from coronary arteries cause fatal clinical endpoints after myocardial infarction, and those from carotid arteries are responsible for ischaemic stroke [21]. Chronic systemic immune-mediated inflammation is a key contributor to the pathologic process. The involvement of the toll-like receptors, TLR2 [22], TLR4 [23] and TLR7 [6] underlines the role of the innate immune response in AS. Further, endogenous danger-associated molecular patterns (DAMPs) activate the innate immune response. The DAMP proteins S100A8 and S100A9 from the S100 calgranulin family are of interest in this context. Both form a heterodimer (MRP8/14 or calprotectin), and are constitutively expressed in myeloid cells. Usually increased by traditional cardiovascular risk factors like smoking, obesity, hyperglycemia, and dyslipidemia, S100A8/A9 is an endogenous ligand of the toll-like receptor 4 (TLR4) and the receptor for advanced glycation end products (RAGE). It has been shown to correlate in humans with the extent of coronary and carotid atherosclerosis, and most importantly with a vulnerable plaque phenotype [23]. Thus, S100A8/A9 may become an interesting laboratory biomarker for the development of vulnerability in AS.

1.1. Historical background of nanomedical applications Liposomal formulations of chemotherapeutics (e.g. doxil) belong to the first clinically approved drugs based on NP. Subsequently, other nanotherapeutics have been developed, like liposomal amphotericin B for fungal infections, liposomal daunorubicin and albumin-bound NP delivering paclitaxel to treat breast cancer. The encapsulation of these cytostatic compounds in NP results in improved pharmacokinetics compared to the free drug and decreases both the drug's clearance from the blood stream as well as cardiac and liver toxicity. These effects may also be useful for a more effective treatment of atherosclerotic lesions. Apart from therapeutic application, NP have been labeled or packed with the following small molecules, chelated ions, metals or nanocrystals for visualisation by diagnostic imaging: (1) gadolinium (Gd3 +) chelates or iron oxide for magnetic resonance imaging (MRI) [12,13] (2) electron dense elements (gold or bismuth) for X-ray and computed tomography [14] (3) radiolabels (18F,64Cu, 89Zr) for positron emission tomography (PET) [15–17] (4) 111In for single-photon emission computed tomography (SPECT) imaging [18], and (5) fluorophores or quantum dots for optical imaging [19]. To summarize, although primarily applied in cancer, nanomedicine is now likely to play a substantial role in cardiovascular research, particularly for improved diagnosis and therapy of AS lesions underlying myocardial infarction and stroke. The biomarker research of laboratory medicine may substantially contribute to this important development.

2.1. Early stages of AS lesions The damage of endothelial cells is an important first step in AS. It leads to an increased penetration of lipoproteins into deeper vascular wall layers, induces the expression of chemotactic chemokines/ cytokines and adhesion molecules, and results in enhanced recruitment and accumulation of monocytes within the vascular wall [24]. The monocytes transform into macrophages and foam cells by ingestion of apolipoprotein B containing low-density lipoprotein (LDL). Effector cells of the adaptive immune response (preferentially Th1/Th17 lymphocytes) and lipoproteins accumulate in the subendothelial space [3]. Either this sequential process is self-limited by the resolution of inflammation, or it progresses to a complex scenario characterized by ingression of aggressive macrophage subtypes with foam cell development [25,26], cell apoptosis, tissue necrosis around the lipid core, bleeding, activation of metalloproteinases and neovascularization. This is accompanied by a sustained activation of the adaptive immune system (i.e. increased CD4+Th1, reduced T-regulatory cells), less interleukin-10 production [26], and increased infiltration of mature dendritic cells [27] over a period of years or even decades [28,29]. 2.2. Advanced stages of AS lesions Advanced AS lesions usually contain an extended area of lipids and necrotic cells. In normal vessels the intima is supplied with nutrients by diffusion from the lumen, distal regions from the vasa vasorum. With progression of the AS lesion, the intima thickens and local hypoxia arises. Within this scenario, neovascularization acts as a compensatory mechanism. Nevertheless, increased micro vessel density has been suggested as being critically involved in the occurrence of clinical endpoints in the context of intraplaque mast cell accumulation [30]. Thus, intensity of lipid deposition, neovascularization, increased density of mast cell chymase and tryptase, increased macrophage content, and decreased collagen deposition are important destabilizing factors [6,31]. Plaque neovascularization is strongly stimulated by inflammation. These vessels are fragile and lack mural cells, and they own ineffective endothelial cell junctions [32], which contributes to destabilization. Further, AS plaque calcification is an important issue for vulnerability. Nevertheless, its true impact remains controversial [33,34]—even a stabilizing role has been considered [34]. Albeit coronary artery calcium (CAC) score values have turned out useful to define the generic risk of acute coronary events in a population, the vulnerable plaque that needs to be treated to prevent an acute event cannot be identified by CAC scores [34].

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2.3. Progression to the endpoints — myocardial infarction or stroke

4. Selected candidate biomarkers for nanomedical targeting of AS

The rupture of AS plaques usually occurs by a breakdown of the fibrous cap that covers the lipid core, and a consecutive thrombotic occlusion causes the clinical endpoint [35,36]. Culprit lesions prone to rupture have active inflammation, a thin fibrous cap, a large lipid core, endothelial denudation with superficial platelet aggregation, fissures, and a stenosis exceeding 90% [37]. Nevertheless, few occlusions that cause acute coronary syndromes cause severe stenosis. As nonstenotic lesions, also referred to as vulnerable plaques, they remain undetected with the currently available diagnostic approaches. Hence, there is an urgent need for improved diagnosis of these lesions well before clinical events occur. This would add substantially to patients' health benefit.

4.1. Low density lipoprotein (LDL) LDL is centrally involved in the initiation and progression of AS [57]. Endogenous modification processes of LDL, primarily oxidation, enzymatic degradation and lipolysis, are important first steps. Modified LDL particles accumulate in the arterial intima, and apo-B100 binds to proteoglycans of the extracellular matrix through ionic interaction. The LDL particles undergo further oxidative modifications, aggregation, and fusion. Uptake by macrophages promotes foam cell generation, a key step in atherogenesis [58]. Hence, LDL's intrinsic properties were investigated for AS targeting by non-invasive imaging modalities, e.g. radio- or gold-labeled LDL particles or modifications thereof [59–61]. As LDL accumulates in macrophages, it may determine the content and location of macrophages within the plaque [62].

2.4. Infection triggers? 4.2. High density lipoprotein (HDL) Acute infections remain under debate as triggers of acute coronary syndrome (ACS) [38]. This is supported by observations that monocytes from patients with stable CAD show similar behavior to those from healthy individuals. Following in vitro stimulation of these monocytes with interferon-γ (INF-γ), the matrix metalloproteinase-9/tissue inhibitor of proteinase-1 production (MMP-9/TIMP-1) ratio increases to levels found in ACS [38]. Hence, acute infections may dump a labile balance of plaque monocytes by the INF-γ-mediated stimulation of certain proteinases. Thus, an association between acute infections and the development of ACS becomes more plausible. This may also be significant for stroke as shown recently [39].

3. Inflammation-related biomarkers for diagnosis of atherosclerotic perpetuation Although immune-mediated inflammation represents a doubleedged sword within the pathophysiology of AS, it is also a potentially useful target for improved diagnosis and therapy of vulnerable AS plaques [40]. Post-hoc investigations have shown that the culprit site of plaque rupture contains a high concentration of inflammatory cells [41]. In contrast to patients who died of other causes, in those who died of acute myocardial infarction, all plaques throughout the coronary system were diffusely infiltrated by inflammatory cells. This fact strongly suggests massively inflamed vasculature in cases of ACS [42]. Hence, various blood inflammatory biomarkers have been discussed as independent antecedent predictors for clinical events [43–52].

3.1. Myeloperoxidase — a vulnerability marker for stroke As 18F-Fluor-Desoxyglucose (18F-FDG) accumulates in inflammatory activated cells, 18F-FDG positron emission tomography/computed tomography (18F-FDG PET/CT) allows vessel wall inflammation to be quantified. Usually, 18F-FDG uptake correlates with macrophage content of AS-plaques [53,54]. dal-PLAQUE [55] is a multimodality imaging study to assess the efficacy and safety of dalcetrapib, a cholesterylester transfer protein (CETP) inhibitor on vascular inflammation and atherosclerotic plaque burden. Plaque progression has been investigated in this study by combining two major techniques: 18F-FDG-PET and magnetic resonance imaging (MRI). Laboratory biomarkers were correlated with mean maximum target-to-background ratio of the most diseased segment [TBRmds] of patients with coronary heart disease. This analysis identified circulating myeloperoxidase as the most promising, currently available, biomarker to detect the vulnerability of carotid plaques [46, 56]. Hence, this biomarker may become important for future stroke prevention and management.

HDLs are the smallest and most dense lipid particles with diameters from 8 to 10 nm. They contain paraoxonase and apolipoprotein A–I, both potent antioxidants [63]. The inverse correlation between blood HDL levels and CVD risk indicates the advantageous effects of HDL [64, 65]. Hence, the use of artificial HDL as a transport vehicle is attractive for therapeutic and diagnostic applications [66]. The small size of artificial HDL allows it to maneuver deeply into target organs, e.g. tumors [67], a characteristic which may also be useful for the treatment of ASlesions. Indeed, statin-loaded reconstituted HDL (rHDL) was found to inhibit plaque inflammation progression in ApoE deficient mice. A short, high-dose regimen markedly decreased the inflammation of advanced AS-plaques. Thus, statin-rHDL might represent a potent AS nanotherapy directly affecting plaque inflammation [68]. 5. Anti-inflammatory biomarkers for nanomedical AS targeting — an underestimated strategy 5.1. Adiponectin—less adipokine, more immune modulator? Adiponectin (Ad), the most important anti-inflammatory adipokine, [69], is predominantly synthesized by adipocytes [70]. It circulates at concentrations of 2–30 μg/mL [71] in three different molecular weight forms; high molecular weight (oligomer); medium molecular weight (hexamer); and low molecular weight (trimer) adiponectin [72,73]. These subfractions exert different biological functions [72–74]. Adiponectin is protective against diabetes and AS [5,72,73,75–78]. Hypoadiponectinemia was found to be a significant predictor of endothelial dysfunction in both peripheral and coronary arteries [79,80], and associated with preatherosclerotic symptoms of obese juveniles [73,77]. Waki et al. showed that leukocyte elastase from activated monocytes and/or neutrophils can cleave full length adiponectin (fAd) [81]. Thus, the 17 kDa globular fragment of adiponectin (gAd) is formed, which is found at lower levels (about 1% of total adiponectin) in the circulation [82]. Globular adiponectin increases insulin-stimulated glucose uptake and boosts ß-oxidation of fatty acids [83,84], while other functions remain controversial [85,86]. We investigated i) the role of adiponectin and subfractions in obesityassociated preatherosclerosis of humans [72,73,77,78,87] and ii) the potential of fluorescence-labeled gAd and fAd subfractions (fAd-Sfs) to bind to atherosclerotic lesions in apoE-deficient mice [5,88,89]. We found only a low binding efficiency of fAd but an inflammationmediated strong accumulation of gAd in the fibrous cap of AS-plaques [88,89]. Hence, gAd may be a promising targeting sequence for the molecular imaging of AS-lesions [88]. Further, we developed nanoconstructs between gAd and PEGylated stealth liposomes [89] which can deliver a high payload of signal-emitting molecules to AS lesions [89]. Other

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nanoconstructs between gAd and protamine-oligonucleotide NPs, called proticles [90–93] showed a particular affinity to monocytes and macrophages which may be of interest for sequential AS plaque targeting. Taken together, our results indicate the potential of gAd-targeted NPs for the molecular imaging of AS. 5.2. Interleukin-10 — the anti-inflammatory “master” cytokine A broad spectrum of proinflammatory cytokines has been reported to be involved in and to stimulate the progression of AS [4,5,94–101], whereas, more recently, few were found to potentially aid in AS regression [102–104]. Pinderski Oslund et al. found that activated T lymphocytes overexpress the anti-inflammatory cytokine IL-10, and that this event is capable of blocking AS actions in vitro and in vivo [105,106]. Xie et al. showed in a cross-sectional study that decreased serum IL-10 concentrations were significantly associated with an increased likelihood of ischemic stroke [107]. Further, IL-10 expression was found elevated in advanced and unstable AS-plaques [108]. It contributes to the regulation of the local inflammatory response, the control of apoptosis within plaques [108–111], and mediates the immunoregulatory response in conjugated linoleic acid-induced regression of AS [112]. Summarized, IL-10 is considered one of the most prominent anti-inflammatory proteins [113–115]. We have investigated the potency of IL-10 as a targeting molecule for molecular imaging of AS. This was based on the assumption that where inflammatory fire is strongly present (in vulnerable AS lesions) there is increased need for “fire water” — i.e. an up regulated antiinflammatory cascade most likely mediated by the anti-inflammatory “master” cytokine IL-10. Indeed, we could show that recombinant IL10 preferentially accumulates in AS-plaque areas. Nanoconstructs of IL-10 and PEGylated liposomes increased IL-10's stability in vivo and the specificity of target recognition [116]. Notably, no significant immune reactions have been observed when the nanoconstruct was injected into wild type mice [116]. Hence, IL-10 combined with multifunctionalized liposomes may be a promising candidate for multi-modal AS-plaque imaging [116]. Further investigations are needed to clarify if this also holds true in the human system. 6. Other relevant anti-inflammatory cytokines 6.1. Interleukin-13 Interleukin-13 is a recently discovered cytokine with antiinflammatory properties. In 2010 it was found that IL-13 induces alternative macrophage activation (M2), which results in potent antiinflammatory and tissue repair capacities [117]. Exogenous administration of IL-13 to cholesterol-fed LDL receptor-deficient mice promoted collagen formation in AS lesions, which is considered beneficial for plaque stability. In ApoE deficient mice, IL-13 has been shown to reduce vascular cell adhesion molecule-1 (VCAM-1)-dependent monocyte recruitment to AS lesions. In vitro IL-13 activated macrophages had an increased capacity for cholesterol efflux and oxidized LDL clearance without increased net foam-cell formation [118]. Thus, IL-13 promotes plaque stabilization, and seems to play a key role in halting the progression of atherogenesis. 6.2. Interleukins -19, -27, -35, and 37 Interleukin-19 promotes the Th2, rather than the Th1 response in T lymphocytes [119,120]. It is expressed in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), in injured but not in naïve arteries, and in stimulated but not in unstimulated cultured ECs and VSMCs [121,122]. LDL receptor deficient mice, fed an atherogenic diet, and injected daily with recombinant IL-19, had significantly less plaque dimensions in the aortic arch compared to controls. Thus, IL-19 appears

to be a potent inhibitor of experimental AS, by mechanisms including Th cell polarization and decreased macrophage adhesion. Future studies will show if IL-19 effects can give a basis for novel therapeutic approaches of vascular inflammation. The interleukins-27, -35, and 37 represent newcomers to the spectrum of anti-inflammatory cytokines [123]. Future studies have to improve the understanding of their complex physiological and pathogenic network. Hopefully, this will improve the treatment of chronic inflammatory diseases like AS. 7. Conclusion Diagnosing a vulnerable plaque phenotype well before fatal clinical endpoints like myocardial infarction and stroke occur is one of the most important challenges for personalized medicine. Linking laboratory medicine with radiology and nanotechnology may open new avenues towards this. We have shown here that the biomarker research of laboratory medicine can contribute significantly to this important interdisciplinary field of convergence. Interestingly, to the best of our knowledge, only few antiinflammatory biomarkers have been investigated in this context. This is astonishing because anti-inflammatory activation is always present as a negative feedback, when key processes in AS lesions perpetuate the scenario towards fatal clinical endpoints. Hence, this inflammatory “brake” may even more specifically target the scenario of vulnerable, culprit AS-lesions than the more unspecific systemic and local proinflammatory markers. Novel molecules with the ability to balance the inflammatory force, and safe, as well as specific, delivery systems for these molecules are warranted. The immune-modulating, anti-inflammatory characteristics of globular adiponectin and IL-10 are useful in this context, and will be further investigated by our group for their excellence in humans. Thus far, there is still no diagnostic approach to safely identify patients with active perpetuation of AS towards vulnerability. Most studies have so far largely dealt with single adipokines, cytokines, chemokines and their receptors measured in limited numbers of patients. Combined “omics” may effectively extend the diagnostic portfolio and introduce new avenues of personalized therapy. Potentially “druggable” microRNAs may be high interest candidates in this context [124,125]. To summarize, new innovative interdisciplinary approaches between laboratory medicine, radiology and nanotechnology provide a promising basis for important and new insights towards early diagnosis and monitoring of AS, and may finally pave the way for more effective therapeutic strategies. Acknowledgments This work is supported by funding under the European FP7 program “NanoAthero” — NMP4-LA-2012-3099820. References [1] Rocha VZ, Libby P. Obesity, inflammation, and atherosclerosis. Nat Rev Cardiol 2009;6:399–409. [2] Mallat Z, Taleb S, Ait-Oufella H, Tedgui A. The role of adaptive T cell immunity in atherosclerosis. J Lipid Res 2009;50:S364–9 [Suppl.]. [3] Ait-Oufella H, Taleb S, Mallat Z, Tedgui A. Cytokine network and T cell immunity in atherosclerosis. Semin Immunopathol 2009;31:23–33. [4] Ait-Oufella H, Taleb S, Mallat Z, Tedgui A. Recent advances on the role of cytokines in atherosclerosis. Arterioscler Thromb Vasc Biol 2011;31:969–79. [5] Mangge H, Almer G, Truschnig-Wilders M, Schmidt A, Gasser R, Fuchs D. Inflammation, adiponectin, obesity and cardiovascular risk. Curr Med Chem 2010;17:4511–20. [6] Salagianni M, Galani IE, Lundberg AM, et al. Toll-like receptor 7 protects from atherosclerosis by constraining “inflammatory” macrophage activation. Circulation 2012;126:952–62. [7] Sanz J, Fayad ZA. Imaging of atherosclerotic cardiovascular disease. Nature 2008;451:953–7.

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Laboratory medicine for molecular imaging of atherosclerosis.

Atherosclerotic plaques are the main cause of life threatening clinical endpoints like myocardial infarction and stroke. To prevent these endpoints, t...
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