Detection Of Vulnerable Atherosclerotic Plaques Research Articles

Noninvasive platelet membrane-coated Fe3O4 nanoparticles identify vulnerable atherosclerotic plaques.

Vulnerable atherosclerotic plaques serve as the primary pathological basis for fatal cardiovascular and cerebrovascular diseases. The precise identification and treatment of these vulnerable plaques hold paramount clinical importance in mitigating the incidence of myocardial infarction and stroke. Nevertheless, the identification of vulnerable plaques within the diffuse atherosclerotic plaques dispersed throughout the systemic circulation continues to pose a substantial challenge in clinical practice. Double emulsion solvent evaporation method, specifically the water-in-oil-in-water (W/O/W) technique, was employed to fabricate Fe3O4-based poly (lactic-co-glycolic acid) (PLGA) nanoparticles (Fe3O4@PLGA). Platelet membranes (PM) were extracted through hypotonic lysis, followed by ultrasound-assisted encapsulation onto the surface of Fe3O4@PLGA, resulting in the formation of PM-coated Fe3O4 nanoparticles (PM/Fe3O4@PLGA). Characterization of PM/Fe3O4@PLGA involved the use of dynamic light scattering, transmission electron microscopy, western blotting, and magnetic resonance imaging (MRI). A model of atherosclerotic vulnerable plaques was constructed by carotid artery coarctation and a high-fat diet fed to ApoE-/- (Apolipoprotein E knockout) mice. Immunofluorescence and MRI techniques were employed to verify the functionality of PM/Fe3O4@PLGA. In this study, we initially synthesized Fe3O4@PLGA as the core material. Subsequently, a platelet membrane was employed as a coating for the Fe3O4@PLGA, aiming to enable the detection of vulnerable atherosclerotic plaques through MRI. In vitro, PM/Fe3O4@PLGA not only exhibited excellent biosafety but also showed targeted collagen characteristics and MR imaging performance. In vivo, the adhesion of PM/Fe3O4@PLGA to atherosclerotic lesions was confirmed in a mouse model of vulnerable atherosclerotic plaques. Simultaneously, PM/Fe3O4@PLGA as a novel contrast agent for MRI has shown effective identification of vulnerable atherosclerotic plaques. In terms of safety profile in vivo, PM/Fe3O4@PLGA has not demonstrated significant organ toxicity or inflammatory response in the bloodstream. In this study, we successfully developed a platelet-membrane-coated nanoparticle system for the targeted delivery of Fe3O4@PLGA to vulnerable atherosclerotic plaques. This innovative system allows for the visualization of vulnerable plaques using MRI, thereby demonstrating its potential for enhancing the clinical diagnosis of vulnerable atherosclerotic plaques.

Emerging nanomaterials to enhance electrochemical impedance spectroscopy for biomedical applications

Over the last few decades, electrical impedance-based sensors have been investigated for clinical translation to detect changes in tissue conductivities, including cardiac output and pulmonary function. Recently, electrochemical impedance spectroscopy (EIS) provides metabolic measurements that occur at the electrode-tissue interface, and the 3-D EIS can be reconstructed to generate electrical impedance tomography (EIT) for detecting the impedimetric properties of the vascular wall or fatty liver disease. In both EIS and EIT applications, the electrochemical properties of the interface electrodes are essential to address the signal-to-noise ratio or sensitivity of measurements in the biological environment. To enhance the conductive properties, we will survey a series of carbon-based nanomaterials as the emerging candidates for coating the electrodes of bioimpedance sensors. In this review, we will provide a theoretical background on impedance-based measurements and highlight the current state of EIS and EIT, including their applications for cancer screening and detection of vulnerable atherosclerotic plaques. Next, we will focus on the strengths of different nanomaterials when used as an electrode coating to optimize charge transfer across the electric double layers and to enhance measurement sensitivity. We will also identify some unmet clinical needs, such as the ability to adapt to different hemodynamic conditions and blood vessel geometries, that can be realized by the novel biomaterials for the future EIS-based sensors.

Cardiovascular Imaging Techniques for Detection of Vulnerable Plaques

Abstract Various cardiovascular imaging techniques were developed for the detection of vulnerable atherosclerotic plaques, hoping to be able to predict a cardiovascular event. Plaque vulnerability results from compound pathophysiological mechanisms that lead to structural and morphological changes in lesions. The aim of this review is to present the most recent techniques for the assessment of vulnerable coronary plaques such as cardiac computed tomography angiography (CCTA), optical coherence tomography, or virtual histology intravascular ultra-sound, based on literature data from the last 3 years. CCTA permits direct visualization of the intravascular lumen, together with characterization of the arterial wall. Recent studies maintain that low-attenuation plaques, spotty calcifications, positive vessel remodeling, and the napkin-ring sign are considered main markers of plaque vulnerability and instability. Emerging analytical techniques, such as machine learning or radiomics, will probably demonstrate useful as an auxiliary diagnostic tool for vulnerable plaque detection. The data from the two imaging techniques together provide useful information, especially in patients undergoing a PCI procedure for an acute coronary syndrome. Invasive and noninvasive imaging techniques are able to deliver a large amount of scientific data to assess vulnerable coronary atheromatous plaques. Recent studies demonstrated that information defined by the two techniques is complementary, and using both methods is essential for adequate diagnosis, therapeutic strategy, and prognostic assessment.

Surface enhanced Raman spectroscopy-detection of the uptake of mannose-modified nanoparticles by macrophages in vitro: A model for detection of vulnerable atherosclerotic plaques.

Atherosclerosis is a process of thickening and stiffening of the arterial walls through the accumulation of lipids and fibrotic material, as a consequence of aging and unhealthy life style. However, not all arterial plaques lead to complications, which can lead to life-threatening events such as stroke and myocardial infarction. Diagnosis of the disease in early stages and identification of unstable atherosclerotic plaques are still challenging. It has been shown that the development of atherosclerotic plaques is an inflammatory process, where the accumulation of macrophages in the arterial walls is immanent in the early as well as late stages of the disease. We present a novel surface enhanced Raman spectroscopy (SERS)-based strategy for the detection of early stage atherosclerosis, based on the uptake of tagged gold nanoparticles by macrophages and subsequent detection by means of SERS. The results presented here provide a basis for future in vivo studies in animal models.The workflow of tracing the SERS-active nanoparticle uptake by macrophages employing confocal Raman imaging.

The Use of Biomarkers for the Early Detection of Vulnerable Atherosclerotic Plaques and Vulnerable Patients. A Review

Abstract Acute coronary syndromes represent the most severe consequences of atherosclerosis, most often triggered by the rupture of a coronary plaque, which, for various reasons, has become unstable. In many cases, these rupture-prone vulnerable plaques are difficult to diagnose, because they do not always cause significant obstruction noticeable by coronary angiography. Therefore, new methods and tools for the identification of vulnerable plaques have been proposed, many of which are currently under study. Various biomarkers have been suggested as predictors of a vulnerable plaque, as well as indicators of an increased inflammatory status associated with higher patient susceptibility for plaque rupture. Integration of such biomarkers into multiple biomarker platforms has been suggested to identify superior diagnostic algorithms for the early detection of the high-risk condition associated with an unstable plaque. The aim of this review is to summarize recent research related to biomarkers used for the early detection of vulnerable plaques and vulnerable patients.

Research progress of nuclear medicine imaging in detection of vulnerable atherosclerotic plaques

Atherosclerosis is a vascular inflammatory disease. Vulnerable atherosclerotic plaques mainly lead to severe cardiovascular and cerebrovascular diseases, such as myocardial infarction and stroke. The research on the early diagnosis of vulnerable plaques becomes currently urgent. As a noninvasive molecular modality, the nuclear medicine imaging (with specific radiolabeled probes) has been used for the detection of unstable plaques, and for the evaluation of therapeutic effect of anti-atherosclerotic drugs. Nuclear imaging techniques for detecting metabolic activity, inflammation, hypoxia, angiogenesis, apoptosis, and microcalcification in unstable plaques are summarized in this review. Key words: Plaque, atherosclerotic; Nuclear medicine; Diagnosis; Trends

Evaluation of the Effect of Intracoronary Attenuation on Coronary Plaque Measurements Using a Dual-phase Coronary CT Angiography Technique on a 320-row CT Scanner—In Vivo Validation Study

The characterization of plaques based on their computed tomography (CT) number is important for the detection of vulnerable atherosclerotic plaques. An earlier in vitro study showed that intravascular attenuation affected the attenuation of coronary atherosclerotic plaques. We attempted to validate this finding in vivo and here we introduce a dual-phase coronary CT angiography (CCTA) technique to address this issue. Institutional ethics committee approval and informed consent were obtained. Thirty patients (30 noncalcified plaques) underwent dual-phase CCTA. Two CT datasets were obtained, one with coronary artery enhancement and the other without coronary artery enhancement. The CT number of the plaque and the adjacent vessel lumen was measured in a circular region of interest on curved planar reconstruction images. The region of interest setting was consistent between the two CT datasets. We performed linear regression analysis of the changes in the CT numbers (ΔHounsfield unit), calculated by subtracting the two CT datasets, for the lumen and for the plaque. We also evaluated the relationship between plaque attenuation on nonenhanced coronary artery images and luminal attenuation with and without contrast enhancement. The ΔHounsfield unit for the plaque and the lumen showed a strong correlation (r = 0.61). There was no significant correlation between plaque attenuation on nonenhanced coronary artery images and luminal attenuation with and without contrast enhancement (r = 0.23 and 0.24, respectively). Intravascular attenuation changed the attenuation of coronary atherosclerotic plaques. Using the copy-paste technique, the CT number of identical plaques can be measured in registered dual-phase CCTA images for the evaluation of coronary plaques.

The role of near-infrared spectroscopy in the detection of vulnerable atherosclerotic plaques.

Coronary artery disease is the leading cause of mortality worldwide. Most acute coronary syndromes are caused by a rupture of a vulnerable atherosclerotic plaque which can be characterized by a lipid-rich necrotic core with an overlying thin fibrous cap. Many vulnerable plaques can cause angiographically mild stenoses due to positive remodelling, which is why the extent of coronary artery disease may be seriously underestimated. In recent years, we have witnessed a paradigm shift in interventional cardiology. We no longer focus solely on the degree of stenosis; rather, we seek to determine the true extent of atherosclerotic disease. We seek to identify high-risk plaques for improvement in risk stratification of patients and prevention. Several imaging methods have been developed for this purpose. Intracoronary near-infrared spectroscopy is one of the most promising. Here, we discuss the possible applications of this diagnostic method and provide a comprehensive overview of the current knowledge.

Diagnostic Magnetic Resonance Imaging of Atherosclerosis in Apolipoprotein E Knockout Mouse Model Using Macrophage-Targeted Gadolinium-Containing Synthetic Lipopeptide Nanoparticles.

Cardiovascular disease is the leading cause of death in Western cultures. The vast majority of cardiovascular events, including stroke and myocardial infarction, result from the rupture of vulnerable atherosclerotic plaques, which are characterized by high and active macrophage content. Current imaging modalities including magnetic resonance imaging (MRI) aim to characterize anatomic and structural features of plaques rather than their content. Previously, we reported that macrophage-targeted delivery of gadolinium (Gd)-based contrast agent (GBCA-HDL) using high density lipoproteins (HDL)-like particles significantly enhances the detection of plaques in an apolipoprotein (apo) E knockout (KO) mouse model, with an atherosclerotic wall/muscle normalized enhancement ratio (NER) of 120% achieved. These particles are comprised of lipids and synthetic peptide fragments of the major protein of HDL, apo A-I, that contain a naturally occurring modification which targets the particles to macrophages. Targeted delivery minimizes the Gd dose and thus reduces the adverse effects of Gd. The aims of the current study were to test whether varying the GBCA-HDL particle shape and composition can further enhance atherosclerotic plaque MRI and control organ clearance of these agents. We show that the optimized GBCA-HDL particles are efficiently delivered intracellularly to and uptaken by both J774 macrophages in vitro and more importantly, by intraplaque macrophages in vivo, as evidenced by NER up to 160% and higher. This suggests high diagnostic power of our GBCA-HDL particles in the detection of vulnerable atherosclerotic plaques. Further, in contrast to discoidal, spherical GBCA-HDL exhibit hepatic clearance, which could further diminish adverse renal effects of Gd. Finally, activated macrophages are reliable indicators of any inflamed tissues and are implicated in other areas of unmet clinical need such as rheumatoid arthritis, sepsis and cancer, suggesting the expanded diagnostic and prognostic use of this method.

Ultrasound-Based Carotid Elastography for Detection of Vulnerable Atherosclerotic Plaques Validated by Magnetic Resonance Imaging

Ultrasound-based carotid elastography has been developed to estimate the mechanical properties of atherosclerotic plaques. The objective of this study was to evaluate the in vivo capability of carotid elastography in vulnerable plaque detection using high-resolution magnetic resonance imaging as reference. Ultrasound radiofrequency data of 46 carotid plaques from 29 patients (74 ± 5 y old) were acquired and inter-frame axial strain was estimated with an optical flow method. The maximum value of absolute strain rate for each plaque was derived as an indicator for plaque classification. Magnetic resonance imaging of carotid arteries was performed on the same patients to classify the plaques into stable and vulnerable groups for carotid elastography validation. The maximum value of absolute strain rate was found to be significantly higher in vulnerable plaques (2.15 ± 0.79 s−1, n = 27) than in stable plaques (1.21 ± 0.37 s−1, n = 19) (p < 0.0001). Receiver operating characteristic curve analysis was performed, and the area under the curve was 0.848. Therefore, the in vivo capability of carotid elastography to detect vulnerable plaques, validated by magnetic resonance imaging, was proven, revealing the potential of carotid elastography as an important tool in atherosclerosis assessment and stroke prevention.

Towards detection of vulnerable atherosclerotic plaque: first step – A lab test platform

Towards detection of vulnerable atherosclerotic plaque: first step – A lab test platform

Noninvasive Methods of Detection of Vulnerable Atherosclerotic Plaques in Coronary Arteries

In most cases direct cause of acute coronary syndrome and sudden death is an intracoronary thrombus formed on a surface of unstable atherosclerotic plaque (UAP). The following are main characteristics of UAP: active inflammation; large lipid rich nucleus occupying a40% of plaque volume; thin (< 65 mm) fibrous cap; erosions of intima over plaque; tear of plaque cap; superficially located calcium nodules; intraplaque hemorrhage. Visualization of UAP in coronary arteries is a very important direction in diagnostics. During recent years both invasive and noninvasive methods of detection of UAP have been actively developed. In this review we present main noninvasive techniques used for detection of UAP: multislice computed tomography, magnetic resonance tomography, positron emission tomography and single-photon emission computed tomography. In the review we have covered main advantages and limitations of each invasive method of UAP detection and delineated perspectives of development of this direction.

Detection of Vulnerable Atherosclerotic Plaques in Experimental Atherosclerosis with the USPIO-Enhanced MRI.

This study's goal was to assess the diagnostic value of the USPIO-(ultra-small superparamagnetic iron oxide) enhanced magnetic resonance imaging (MRI) in detection of vulnerable atherosclerotic plaques in abdominal aorta in experimental atherosclerosis. Thirty New Zealand rabbits were randomly divided into two groups, Group A and Group B. Each group comprised 15 animals which were fed with high cholesterol diet for 8weeks and then subjected to balloon-induced endothelial injury of the abdominal aorta. After another 8weeks, animals in Group B received adenovirus carrying p53 gene that was injected through a catheter into the aortic segments rich in plaques. Two weeks later, all rabbits were challenged with the injection of Chinese Russell's viper venom and histamine. Pre-contrast images and USPIO-enhanced MRI images were obtained after pharmacological triggering with injection of USPIO for 5days. Blood specimens were taken for biochemical and serological tests at 0 and 18weeks. Abdominal aorta was histologically studied. The levels of serum ICAM-1 and VCAM-1 were quantified by ELISA. Vulnerable plaques appeared as a local hypo-intense signal on the USPIO-enhanced MRI, especially on T2*-weighted sequences. The signal strength of plaques reached the peak at 96h. Lipid levels were significantly (p<0.05) higher in both Group A and B compared with the levels before the high cholesterol diet. The ICAM-1 and VCAM-1 levels were significantly (p<0.05) higher in Group B compared with Group A. The USPIO-enhanced MRI efficiently identifies vulnerable plaques due to accumulation of USPIO within macrophages in abdominal aorta plaques.

Identifying Vulnerable Atherosclerotic Plaque in Rabbits Using DMSA-USPIO Enhanced Magnetic Resonance Imaging to Investigate the Effect of Atorvastatin.

BackgroundRupture of an atherosclerotic plaque is the primary cause of acute cardiovascular and cerebrovascular syndromes. Early and non-invasive detection of vulnerable atherosclerotic plaques (VP) would be significant in preventing some aspects of these syndromes. As a new contrast agent, dimercaptosuccinic acid (DMSA) modified ultra-small super paramagnetic iron oxide (USPIO) was synthesized and used to identify VP and rupture plaque by magnetic resonance imaging (MRI).MethodsAtherosclerosis was induced in male New Zealand White rabbits by feeding a high cholesterol diet (n = 30). Group A with atherosclerosis plaque (n = 10) were controls. VP was established in groups B (n = 10) and C (n = 10) using balloon-induced endothelial injury of the abdominal aorta. Adenovirus-carrying p53 genes were injected into the aortic segments rich in plaques after 8 weeks. Group C was treated with atorvastatin for 8 weeks. Sixteen weeks later, all rabbits underwent pharmacological triggering, and imaging were taken daily for 5 d after DMSA-USPIO infusion. At the first day and before being killed, serum MMP-9, sCD40L, and other lipid indicators were measured.ResultsDMSA-USPIO particles accumulated in VP and rupture plaques. Rupture plaques appeared as areas of hyper-intensity on DMSA-USPIO enhanced MRI, especially T2*-weighted sequences, with a signal strength peaking at 96 h. The group given atorvastatin showed few DMSA-USPIO particles and had lower levels of serum indicators. MMP-9 and sCD40L levels in group B were significantly higher than in the other 2 groups (P <0.05).ConclusionAfter successfully establishing a VP model in rabbits, DMSA-USPIO was used to enhance MRI for clear identification of plaque inflammation and rupture. Rupture plaques were detectable in this way probably due to an activating inflammatory process. Atorvastatin reduced the inflammatory response and stabilizing VP possibly by decreasing MMP-9 and sCD40L levels.

Early detection of vulnerable atherosclerotic plaque for risk reduction of acute aortic rupture and thromboemboli and atheroemboli using non-obstructive angioscopy.

The mortality rate due to rupture of aortic dissection and aortic aneurysm is approximately 90%. Acute aortic rupture can be fatal prior to hospitalization and has proven difficult to diagnose correctly or predict. The in-hospital mortality rate of ruptured aortic aneurysm ranges from 53 to 66%. Emergency surgical and endovascular treatments are the only options for ruptured aortic dissection and aortic aneurysm. No method of systematic early detection or inspection of vessel injury is available at the prevention stage. Regardless of the improvement in many imaging modalities, aortic diameter has remained a major criterion for recommending surgery in diagnosed patients. Previous reports have suggested a relationship between vulnerable plaque and atherosclerotic aortic aneurysm. Non-obstructive angioscopy is a new method for evaluating intimal injury over the whole aorta. It has been used to identify many advanced atherosclerotic plaques that were missed on traditional imaging modalities before aneurysm formation. Non-obstructive angioscopy has shown that atherosclerosis of the aorta begins before that of the coronary artery, which had been noted on autopsy "in vivo". Strong or repetitive aortic injuries might cause sudden aortic disruption. Aortic atheroma is also a risk factor of stroke and perivascular embolism. Detecting aortic vulnerable atherosclerotic plaque on non-obstructive angioscopy may not only clarify the pathogenesis of acute aortic rupture and "aortogenic" thromboemboli and atheroemboli but also play a role in the pre-emptive medicine.

Detection of Vulnerable Atherosclerotic Plaque and Prediction of Thrombosis Events in a Rabbit Model Using 18F-FDG -PET/CT

BackgroundDetection of vulnerable plaques could be clinically significant in the prevention of cardiovascular events. We aimed to compare Fluorine-18 fluorodeoxyglucose (18F-FDG) uptake in vulnerable and stable plaques, and investigate the feasibility of predicting thrombosis events using Positron Emission Tomography/Computed Tomography (PET/CT) angiography.MethodsAtherosclerosis was induced in 23 male New Zealand white rabbits. The rabbits underwent pharmacological triggering to induce thrombosis. A pre-triggered PET/CTA scan and a post-triggered PET/CTA scan were respectively performed. 18F-FDG uptake by the aorta was expressed as maximal standardized uptake value (SUVmax) and mean SUV (SUVmean). SUVs were measured on serial 7.5 mm arterial segments.ResultsThrombosis was identified in 15 of 23 rabbits. The pre-triggered SUVmean and SUVmax were 0.768±0.111 and 0.804±0.120, respectively, in the arterial segments with stable plaque, and 1.097±0.189 and 1.229±0.290, respectively, in the arterial segments with vulnerable plaque (P<0.001, respectively). The post-triggered SUVmean and SUVmax were 0.849±0.167 and 0.906±0.191, respectively in the arterial segments without thrombosis, and 1.152±0.258 and 1.294±0.313, respectively in the arterial segments with thrombosis (P<0.001, respectively). The values of SUVmean in the pre-triggered arterial segments were used to plot a receiver operating characteristic curve (ROC) for predicting thrombosis events. Area under the curve (AUC) was 0.898. Maximal sensitivity and specificity (75.4% and 88.5%, respectively) were obtained when SUVmean was 0.882.ConclusionsVulnerable and stable plaques can be distinguished by quantitative analysis of 18F-FDG uptake in the arterial segments in this rabbit model. PET/CT may be used for predicting thrombosis events and risk-stratification in patients with atherosclerotic disease.

The 10 Most Read Articles Published in Circulation Research in 2012

The 10 Most Read Articles Published in <i>Circulation Research</i> in 2012

Nanobodies Targeting Mouse/Human VCAM1 for the Nuclear Imaging of Atherosclerotic Lesions

A noninvasive tool allowing the detection of vulnerable atherosclerotic plaques is highly needed. By combining nanomolar affinities and fast blood clearance, nanobodies represent potential radiotracers for cardiovascular molecular imaging. Vascular cell adhesion molecule-1 (VCAM1) constitutes a relevant target for molecular imaging of atherosclerotic lesions. We aimed to generate, radiolabel, and evaluate anti-VCAM1 nanobodies for noninvasive detection of atherosclerotic lesions. Ten anti-VCAM1 nanobodies were generated, radiolabeled with technetium-99m, and screened in vitro on mouse and human recombinant VCAM1 proteins and endothelial cells and in vivo in apolipoprotein E-deficient (ApoE(-/-)) mice. A nontargeting control nanobody was used in all experiments to demonstrate specificity. All nanobodies displayed nanomolar affinities for murine VCAM1. Flow cytometry analyses using human human umbilical vein endothelial cells indicated murine and human VCAM1 cross-reactivity for 6 of 10 nanobodies. The lead compound cAbVCAM1-5 was cross-reactive for human VCAM1 and exhibited high lesion-to-control (4.95±0.85), lesion-to-heart (8.30±1.11), and lesion-to-blood ratios (4.32±0.48) (P<0.05 versus control C57Bl/6J mice). Aortic arch atherosclerotic lesions of ApoE(-/-) mice were successfully identified by single-photon emission computed tomography imaging. (99m)Tc-cAbVCAM1-5 binding specificity was demonstrated by in vivo competition experiments. Autoradiography and immunohistochemistry further confirmed cAbVCAM1-5 uptake in VCAM1-positive lesions. The (99m)Tc-labeled, anti-VCAM1 nanobody cAbVCAM1-5 allowed noninvasive detection of VCAM1 expression and displayed mouse and human cross-reactivity. Therefore, this study demonstrates the potential of nanobodies as a new class of radiotracers for cardiovascular applications. The nanobody technology might evolve into an important research tool for targeted imaging of atherosclerotic lesions and has the potential for fast clinical translation.

In vivo Detection of Vulnerable Atherosclerotic Plaque by MRI in a Rabbit Model

Background— The ability to identify atherosclerotic plaques with a high risk for sudden disruption before stroke or myocardial infarction would be of great utility. We used a rabbit model of controlled atherothrombosis to test whether in vivo MRI can noninvasively distinguish between plaques that disrupt after pharmacological triggering (vulnerable) and those that do not (stable). Methods and Results— Atherosclerosis was induced in male New Zealand White (n=17) rabbits by cholesterol diet and endothelial denudation of the abdominal aorta. After baseline (pretrigger) MRI with and without gadolinium contrast, the rabbits underwent 2 pharmacological triggerings to induce atherothrombosis, followed by another MRI 48 hours later (post-triggering). Atherosclerosis was identified by the pretriggered images in all rabbits, and thrombosis was identified in 9 of 17 animals (53%) by post-trigger MRI. After the animals were euthanized, 95 plaques were analyzed; 28 (29.5%) had thrombi (vulnerable) and 67 did not (stable) (70.5%). Pretriggered MRI revealed comparable stenosis in stable and vulnerable plaques, but vulnerable plaques had a larger plaque area (4.8�1.6 versus 3.0�1.0 mm 2 ; P =0.01), vessel area (9.2�3.0 versus. 15.8�4.9 mm 2 ; P =0.01), and higher remodeling ratio (1.16�0.2 versus 0.93�0.2; P =0.01) compared with stable plaques. Furthermore, vulnerable plaques more frequently exhibited (1) positive remodeling (67.8% versus 22.3%; P =0.01), in which the plaque is hidden within the vessel wall instead of occluding the lumen; and (2) enhanced gadolinium uptake (78.6% versus 20.9%; P =0.01) associated with histological findings of neovascularization, inflammation, and tissue necrosis. Conclusions— We demonstrate that in vivo MRI at 3.0 T detects features of vulnerable plaques in an animal model of controlled atherothrombosis. These findings suggest that MRI may be used as a noninvasive modality for localization of plaques that are prone to disruption.

Pre-Clinical and Clinical Evaluation of Nuclear Tracers for the Molecular Imaging of Vulnerable Atherosclerosis: An Overview

Cardiovascular diseases (CVD) are the leading cause of mortality worldwide. Despite major advances in the treatment of CVD, a high proportion of CVD victims die suddenly while being apparently healthy, the great majority of these accidents being due to the rupture or erosion of a vulnerable coronary atherosclerotic plaque. A non-invasive imaging methodology allowing the early detection of vulnerable atherosclerotic plaques in selected individuals prior to the occurrence of any symptom would therefore be of great public health benefit. Nuclear imaging could allow the identification of vulnerable patients by non-invasive in vivo scintigraphic imaging following administration of a radiolabeled tracer. The purpose of this review is to provide an overview of radiotracers that have been recently evaluated for the detection of vulnerable plaques together with the biological rationale that initiated their development. Radiotracers targeted at the inflammatory process seem particularly relevant and promising. Recently, macrophage targeting allowed the experimental in vivo detection of atherosclerosis using either SPECT or PET. A few tracers have also been evaluated clinically. Targeting of apoptosis and macrophage metabolism both allowed the imaging of vulnerable plaques in carotid vessels of patients. However, nuclear imaging of vulnerable plaques at the level of coronary arteries remains challenging, mostly because of their small size and their vicinity with unbound circulating tracer. The experimental and pilot clinical studies reviewed in the present paper represent a fundamental step prior to the evaluation of the efficacy of any selected tracer for the early, non-invasive detection of vulnerable patients.