CARDIOVASCULAR GENOMIC MEDICINE
Molecular and Cellular Imaging of Atherosclerosis
Emerging Applications
Farouc A. Jaffer, MD, PhD*, , ,*,
Peter Libby, MD, FACC*, , and
Ralph Weissleder, MD, PhD*,,1
* Center for Molecular Imaging Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts
Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
Donald W. Reynolds Cardiovascular Clinical Research Center, Harvard Medical School, Boston, Massachusetts.
Manuscript received August 23, 2005;
revised manuscript received November 9, 2005,
accepted November 20, 2005.
* Reprint requests and correspondence: Dr. Farouc A. Jaffer, MGH-CMIR, 149 13th Street, Room 5406, Charlestown, Massachusetts 02129. (Email: fjaffer{at}partners.org).
 |
Abstract
|
|---|
Molecular imaging studies have shed light on important biological aspects of atherosclerosis, and are now entering the clinical arena for the detection of clinical atheroma. This review first discusses fundamental principles regarding the rationale for and development of molecular imaging technologies for investigating atherosclerosis. Next, we highlight clinically promising imaging strategies that illuminate key biological aspects of atherosclerosis, including macrophage activity, protease activity, lipoprotein presence, apoptosis, and angiogenesis. We envision that several molecular imaging approaches will become important adjuncts to the clinical management of high-risk atherosclerosis.
|
Abbreviations and Acronyms
| | FDG = fluorodeoxyglucose | | LDL = low-density lipoprotein | | MMP = matrix metalloproteinase | | MNP = magnetic nanoparticles (dextran-coated) | | MPO = myeloperoxidase | | MRI = magnetic resonance imaging | | NIRF = near-infrared fluorescence or fluorochrome | | PET = positron emission tomography | | SPECT = single-photon emission computed tomography | | VCAM = vascular cell adhesion molecule |
|
Molecular imaging is a rapidly evolving discipline that aims to develop imaging agents and technologies to visualize specific molecular processes in vivo. With a considerable track record in the biological sciences and drug discovery (1–7), molecular imaging is now poised to make significant contributions to clinical imaging of atherosclerosis (8). Advances in atherosclerosis biology (9–13), imaging agent chemistry (nanotechnology, chemical biology screens), and imaging platforms (magnetic resonance imaging [MRI], integrated nuclear-computed tomography imaging, optical imaging, and ultrasound imaging) continue to drive this progress from bench to bedside.
In this review, we present recent developments in molecular and cellular imaging of atherosclerotic vascular disease. The discussion comprises several sections. First, we provide a rationale for employing molecular imaging strategies in the detection of clinical atheromata. Next, we provide a biological framework for designing atherosclerosis-targeted imaging agents, and briefly summarize various technical aspects of molecular agent development. We then consider a few clinically promising applications of molecular imaging for high-risk atherosclerosis.
|
Molecular imaging: Detection of atherosclerosis beyond anatomy
|
|---|
Via its sequelae of myocardial infarction and stroke, atherosclerotic vascular disease threatens to become a leading cause of death worldwide by the year 2020 (14). As high-risk or vulnerable plaques are often unrecognized before causing clinical events, there is an unmet need to identify these plaques before the onset of symptoms (15–17). This recognition has motivated the development of a number of noninvasive and invasive diagnostic imaging strategies to permit identification of high-risk individuals, based on the presence of high-risk anatomical or structural features of plaques (18–20). Recognizing that the multiplicity of so-called vulnerable plaques necessitates both local and global treatment strategies (21), the present discussion emphasizes the role of atherosclerosis imaging in the identification and management of the high-risk patient rather than solely individual lesions.
In contrast with existing imaging approaches that primarily aim to assess structural components of atherosclerosis (e.g., fibrous cap thickness, the size of the lipid core), molecular and cellular imaging aims to image biological properties of atherosclerotic plaques in vivo (6–8,22–27). The fundamental motivation for this approach stems from the recognition that molecular and cellular processes govern all phases of atherogenesis, including plaque progression and plaque rupture (10). The ability to visualize specific biological aspects of atherosclerotic lesions could have utility in a number of different clinical scenarios, such as: 1) providing new diagnostic imaging capabilities for detecting high-risk plaques before symptom onset; 2) offering the potential of personalized medicine (28) to guide the initiation and titration of molecularly based atherosclerotic therapies (e.g., a measure of plaque macrophage activity could direct novel antimacrophage molecular therapies); and 3) supplying imaging end points for clinical trials to assess the efficacy of novel atherosclerotic therapeutics, as a prelude to costly and time-consuming outcome studies. Similar to serum biomarker discovery for atherosclerosis risk assessment (29), specific molecular markers provide a foundation for the construction of atherosclerosis-targeted imaging agents. Table 1 summarizes promising targets, shown in the context of the biology of atherosclerosis in Figure 1.
View larger version (47K):
[in this window]
[in a new window]
|
Figure 1 The biology of atherosclerosis initiation, progression, and complications. This road map identifies important targets for molecular imaging (Table 1). Imaging agents are available for a range of targets and imaging modalities, and several agents have been tested in clinical studies. Modified by permission from reference 10. CCR2 = chemokine (CC motif) receptor 2; MCP = monocyte chemoattractant protein; M-CSF = monocyte colony-stimulating factor; MMP = matrix metalloproteinase; ROS = reactive oxygen species; VCAM = vascular cell adhesion molecule.
|
|
|
The biology of atherosclerosis provides a basis for imaging agent development
|
|---|
The past two decades have witnessed major advances in the underlying molecular and cellular mechanisms of atherogenesis and lesion progression (9–13). Fundamentally, the process of inflammation regulates atherosclerosis (10,13) (Fig. 1). In particular, the macrophage has emerged as the key cellular mediator of inflammation in atheroma, and participates in all phases of atherogenesis, including lesion initiation, progression, and complication. Initially recruited to the artery wall as monocytes, these cells mature into macrophages. Once resident, macrophages ingest oxidized lipoproteins via scavenger receptors, becoming foam cells, and contribute to atheroma expansion. A subset of macrophages can die within the atheroma, via oncosis and/or apoptosis (programmed cell death), leading to the development of a paucicellular lipid core. In addition to imbibing lipid, macrophages produce and/or secrete a number of proteases, such as cathepsins and matrix metalloproteinases (MMP) that can degrade the extracellular matrix comprising the fibrous cap. Macrophages also secrete various reactive oxygen species (e.g., products of NAD[P]H oxidases or myeloperoxidase [MPO]) that can further modify lipoproteins, setting up a vicious cycle of additional monocyte/macrophage recruitment. Finally, autopsy studies have demonstrated prominent macrophage accumulation in ruptured atherosclerotic lesions (30). These findings underscore a key role for macrophages in plaque complications (15).
The endothelium also contributes importantly to atherogenesis. Via their recruitment of monocytes, endothelial cells regulate early lesion development. Under inflammatory conditions, endothelial cells express adhesion molecules such as vascular cell adhesion molecule (VCAM)-1; VCAM-1 can mediate the recruitment both monocytes and T lymphocytes into the nascent atheroma to foster lesion evolution (10). In addition, the fragile endothelium in angiogenic vessels, typically associated with  vß3 integrin (31), can promote lesion progression via intraplaque hemorrhage (32) and may produce plaque complications (15).
Thus, biological insights provide the foundation for the development of atherosclerosis-targeted imaging agents (Fig. 1, Table 1). The past two decades have witnessed tremendous growth in atherosclerosis imaging, and recent review articles summarize some of the experimental data (6–8,22–27). Many promising imaging agents, already undergoing experimental validation, may emerge in the clinical arena.
|
New atherosclerosis imaging agents: Windows into in vivo biology
|
|---|
A molecular imaging agent (or imaging reporter) typically consists of two components: 1) a detection moiety, such as a radioisotope, magnetic compound, fluorochrome, or sonic enhancer; and 2) a molecule-specific or cell-specific affinity ligand, such as an antibody, peptide, or small molecule (e.g., derived from diversity oriented synthesis). Clinically useful molecular imaging agents report on specific biological processes, generate a strong signal (ideally when recognized by its target), possess favorable pharmacokinetics and biodistribution, and exhibit an excellent safety profile. For these reasons not all biomarkers associated with atherosclerosis (29) furnish promising imaging targets. For example, secreted proteins or stationary receptors with low abundance are difficult to target. Conversely, internalizing receptors, abundant extracellular markers, and low-background enzyme-sensing quenched substrates can provide high-yield imaging strategies (Table 1).
Reporter imaging agent technology has dovetailed advances in chemical biology, and now incorporates screening approaches using phage-display (33–35), nanoparticle libraries (36), and combinatorial chemistry (37). Equally important, amplification strategies can enhance target signal generation and/or minimize background signal (6,38). Such "smart" agents (e.g., protease-activatable [39–42], or incorporating oligomerization of signal-producing substrates [43], cellular trapping of phosphorylated substrates [44], and covalent binding [45]) can provide high contrast-to-noise ratios and thus prove particularly well suited for in vivo imaging.
|
Emerging clinical applications
|
|---|
With the recent advances in biology and imaging technology, molecular imaging studies now offer the ability to visualize key biological signatures of atherosclerosis in vivo. We anticipate that molecular imaging studies of atherosclerosis will prove useful in the following four clinical scenarios: 1) identifying patients at high-risk for cardiovascular events (death, myocardial infarction, stroke) not identified by routine clinical evaluation (e.g., history, physical exam, electrocardiogram, lipid profile, C-reactive protein, exercise treadmill testing); 2) characterizing the vulnerability of lesions in high-risk areas of the coronary vasculature (e.g., the proximal third of each of the coronary arteries [46])—lesions deemed particularly high-risk could eventually justify novel local therapies such as intracoronary drug-eluting stents; 3) evaluating novel atherosclerotic therapies that target biology rather than the lipid profile (e.g., peroxisome proliferator-activated receptors [47]); and 4) selecting individualized treatment strategies based on the molecular profile of vulnerable plaques identified in particular patients. Several promising atherosclerosis-targeted imaging agents have already undergone testing in the clinic or are on the clinical horizon (Table 1).
Cellular imaging of macrophage activity.
Receptor-mediated uptake
Most clinically tested magnetic nanoparticles (MNP) have carbohydrate coatings (dextrans or starch derivatives) that bind to and undergo endocytosis by macrophages, presumably through dextran receptors (48) or scavenger receptors. Long circulating MNP that targeted tissue macrophages were first developed in the late 1980s (49) and subsequently proved biocompatible and able to effect strong MRI contrast (R2 > R1) in cells and in vivo (50,51). In atherosclerosis, preclinical studies with magnetofluorescent dextranated nanoparticles have demonstrated preferential uptake of dextranated MNP by lesional macrophages, with concomitant but much lower uptake by endothelial cells and smooth muscle cells (52). Recently, Kooi et al. (53) and Trivedi et al. (54) have demonstrated that long-circulating MNP (e.g., ferumoxtran, Advanced Magnetics, Cambridge, Massachusetts) can accumulate in macrophage-rich human carotid endarterectomy specimens. Symptomatic patients (n = 19) scheduled for carotid endarterectomy underwent pre-contrast carotid MRI and then received an intravenous injection of ferumoxtran (2.6 mg Fe/kg iron). After 24 h (and in one study serially up to 72 h), patients underwent repeat carotid MRI. Black-blood T2*-weighted imaging showed focal negative signal enhancement (darkening) within carotid atherosclerotic lesions (Fig. 2) (53,54). Histopathological correlation demonstrated colocalization between macrophages and iron deposition as detected by immunohistochemistry (Fig. 2) as well as electron microscopy. Slight uptake was noted in other cells such as smooth muscle cells and endothelial cells, and specimens from control patients without MNP showed minimal iron deposition (53). A recent experimental study extended these results by quantifying the cellular distribution of MNP in atherosclerosis using a multimodality MRI and near-infrared fluorescence (NIRF) magnetofluorescent nanoparticle (52).
View larger version (113K):
[in this window]
[in a new window]
|
Figure 2 Cellular magnetic resonance image of macrophage (Mac) endocytosis in clinical (53,54) and experimental (52) atherosclerosis using magnetic nanoparticles. (A) Dextranated magnetic nanoparticle injection (ferumoxtran, 2.6 mg/kg) produces focal signal loss within a carotid plaque of a neurologically symptomatic patient (top, "Pre" and [57] "Post" images, arrow). Histological examination of the carotid endarterectomy specimen demonstrates colocalization of macrophages (C, anti-CD68 macrophage antibody, original magnification x100), and iron (Fe) (D, Perls iron stain, neutral red counterstain; original magnification x400). Images provided courtesy of Dr. Jonathan Gillard, Dr. Rikin Trivedi, Dr. Simon Howarth, and Dr. Martin Graves, Addenbrooke’s Hospital, Cambridge, United Kingdom. Reproduced by permission from reference 8. (B) Multimodality magnetic resonance image and near infrared fluorescent imaging of murine atherosclerosis using a magnetofluorescent nanoparticle (MFNP) (52). (E) In vivo 9.4-T electrocardiogram- and respiratory-gated magnetic resonance image of an apolipoprotein E–/–-deficient mouse. Injection of a clinical-type near infrared fluorescent dextranated magnetic nanoparticle (15 mg/kg of iron, 24 h circulation time) produces focal signal loss (arrow) in the aortic root, a known site of atherosclerosis in the apo E–/– mouse. (F) Fluorescence reflectance imaging of the resected aorta confirms a focal near-infrared fluorescent signal within the aortic root (arrow). (G) On fluorescence microscopy, the near-infrared fluorescent MFNP accumulates in intimal macrophages (red, arrow) within aortic root plaque sections (original magnification x200). In contrast, smooth muscle cells (stained here with a spectrally distinct -actin fluorescent antibody, green) modestly colocalize with the MFNP.
|
|
Together these results demonstrate that MNP-enhanced MRI can identify macrophage-rich atheromata. To become useful for coronary plaque imaging, post-MNP magnetic resonance images will require higher resolution and signal-to-noise ratios, possibly via intravascular magnetic resonance coils (55,56) or novel pulse sequences (57). Alternatively, newer MNP, such as those that permit concomitant NIRF imaging (52), may allow sequential optical imaging of coronary plaque macrophages, possibly via intravascular NIRF catheters (58). Finally, newer derivatized MNP (i.e., those with affinity ligands conjugated to the dextran coat [35,59]) offer the potential to improve substantially the sensitivity and specificity of MNP uptake by activated macrophages (59).
Metabolism
18Fluorodeoxyglucose (18FDG), a positron emission tomography (PET) radiotracer, competes with glucose for uptake into metabolically active cells including macrophages in atheromata (44). Fluorodeoxyglucose is trapped inside cells after phosphorylation. Rudd et al. (44) employed 18FDG to image plaque inflammation in patients with symptomatic carotid atherosclerosis (Fig. 3). Patients (n = 8) who had experienced a recent carotid arterial ischemic event and had an internal carotid artery lesion >70% stenosis received an intravenous injection of 18FDG, and then underwent PET imaging 3 h later. Rigorous co-registration with subsequently acquired cranial computed tomography images demonstrated focal 18FDG uptake in carotid plaques (Fig. 3). Examination of the surgically resected plaque specimens demonstrated heavy macrophage infiltration. Corroborating microautoradiography experiments revealed focal uptake of tritiated deoxyglucose, an analog of 18FDG, into macrophage-rich plaque sections, with minimal uptake in other areas of plaques or in control sections. It still remains unsettled whether appreciable background 18FDG signal is present in other metabolically active arterial cells (e.g., smooth muscle cells) in vulnerable plaque.
View larger version (124K):
[in this window]
[in a new window]
|
Figure 3 Cellular imaging of macrophage metabolism using 18F-fluorodeoxyglucose (18FDG) (44). (A) Positron emission tomography (left), contrast computed tomography (middle), and offline co-registered positron emission tomography/computed tomography (right) images of a neurologically symptomatic patient who received an intravenous bolus of 18FDG (dose 370 Mbq). The positron emission tomography image demonstrates focal 18FDG uptake by a right carotid plaque (arrow), corroborated by the computed tomography angiogram and co-registered positron emission tomography/computed tomography images. (B) Relatively weaker 18FDG accumulation is seen in the carotid plaque of an asymptomatic patient. (C, D) A surgically resected carotid plaque from a symptomatic patient was incubated with tritiated deoxyglucose, an analogue of 18FDG. Autoradiography (C, original magnification x100) shows colocalization of silver grains with plaque macrophages (D, anti-CD68 antibody, x200) in areas of the fibrous cap and lipid core. Images provided courtesy of Dr. James Rudd and Dr. Peter Weissberg, Addenbrooke’s Hospital, Cambridge, United Kingdom. Reproduced by permission from reference 44.
|
|
18Fluorodeoxyglucose uptake occurred variably in the contralateral asymptomatic plaques in six of eight patients, and did not occur in normal carotid arteries. These findings demonstrate that 18FDG PET could be useful in identifying inflamed subclinical carotid lesions. The advent of integrated PET-computed tomography scanners should further improve image quality with the 18FDG method. However, this approach will likely prove less suitable for detecting coronary atheromata due to high 18FDG cardiac uptake by metabolically active cardiomyocytes (25). Alternative PET tracers for imaging macrophages include the benzodiazepine receptor-targeted agent 11C(R)-PK11195 (60), as well as a number of experimental agents under development such as tagged affinity peptides.
Molecular imaging of protease activity.
Cathepsins
The cathepsin family includes cysteine proteases overexpressed in human and experimental atherosclerosis (61). Produced by macrophages, endothelial cells, and smooth muscle cells, cathepsins S and K can degrade extracellular matrix via their elastase and/or collagenase properties and therefore may participate in plaque destabilization (62). Recently, Chen et al. (41) optically imaged cathepsin B activity in experimental atherosclerosis in vivo. The authors employed an NIRF-activatable imaging agent that became brightly fluorescent after enzymatic cleavage by cathepsin B (39). Using noninvasive fluorescence-mediated tomography (63) co-registered with MRI, atherosclerotic lesions in mice became brightly fluorescent 24 h after receiving a systemic injection of the agent (Fig. 4). Ex vivo fluorescence reflectance imaging confirmed focal NIRF signal in atheroma, and correlative fluorescence microscopy revealed cathepsin B and macrophage colocalization with NIRF signal in microscopic sections.
View larger version (79K):
[in this window]
[in a new window]
|
Figure 4 Molecular imaging of cathepsin B protease activity in atherosclerosis using an injectable protease-activatable near-infrared fluorescent (NIRF) agent (41). (A) In vivo murine magnetic resonance image of an aortic plaque (arrow) co-registers with NIRF signal enhancement on (B) in vivo fluorescence mediated tomography, a three-dimensional noninvasive and quantitative fluorescence imaging method (63). (C) Sudan IV-stained lipid-rich aortic lesions correlate well with (D) protease-generated NIRF signal within plaques. (E) Immunoreactive cathepsin B enzyme (x200 original magnification) correlates with (F) focal NIRF signal on microscopic sections, consistent with cathepsin-B–mediated activation of the imaging agent. Reproduced by permission from reference 41.
|
|
This study demonstrated that protease activity could serve as a useful imaging biomarker for detecting inflammation in atherosclerosis. A version of this agent is under development for clinical trials (8), and may offer an approach to detect inflamed plaques. Although depth penetration limits certain optical imaging methods, near-infrared photons can be tomographically reconstructed, offering the potential for deep tissue imaging in vivo (38). In addition, NIRF imaging catheters (58) and handheld reflectance devices are undergoing rapid translation into the clinic. In concert with protease activatable imaging agents, these devices could identify inflamed coronary and carotid plaques in vivo. Additional protease-activatable NIRF agents, for example for cathepsin K (62), may provide new inflammatory readouts for atherosclerosis (64).
MMPs
Members of the MMP family of zinc-dependent endopeptidases can also degrade extracellular matrix macromolecules including elastin and collagen. Heightened activity of MMPs in human plaques and experiments in genetically altered mice suggest a causative role for MMPs in plaque destabilization, particularly in lesions with positive (expansive, outward, compensatory) remodeling (65–68). Recently, Schäfers et al. (69) performed an in vivo single-photon emission computed tomography (SPECT) biodistribution imaging study of a broad-spectrum MMP inhibitor. The 123I- or 125I-radiolabeled imaging agent derived from a compound that binds to the active catalytic site of MMPs (70). Using atherosclerotic apolipoprotein E-deficient (apo E –/–) mice, the authors demonstrated focal signal enhancement of carotid plaques in animals receiving an intravenous injection of the agent, validated by 125I autoradiography in situ. Animals pre-treated with the unlabeled MMP inhibitor parent compound showed minimal signal. Further studies may help to determine the precise relationship between the radiolabeled active site ligand and MMP activity.
Imaging of MMP activity in atherosclerosis therefore offers another method for detecting inflamed atherosclerotic lesions. With the typical resolution of clinical SPECT systems ( 10 mm), 123I scintigraphy of MMP-rich carotid plaques may prove feasible using Schäfers’ agent, particularly in concert with integrated SPECT-computed tomography systems. A gelatinase MMP-activatable NIRF agent (71) may furnish another option for imaging of MMP activity at higher resolution in vivo (72).
Imaging of MPO activity.
Myeloperoxidase, a member of the heme peroxidase superfamily capable of generating the oxidant species hypochlorous acid, is biologically and clinically linked to atherosclerosis (73,74). Myeloperoxidase localizes within human atherosclerotic plaques (75,76), and its products may promote atherogenesis by modifying low-density lipoproteins (LDL) to an atherogenic form, functionally inactivating high-density lipoproteins, activating MMPs, causing endothelial cell apoptosis and tissue factor release, and inactivating nitric oxide (73,77). A number of MRI and nuclear imaging substrates for MPO are now available (78–82). Myeloperoxidase-induced oligomerization of these substrates produces high target-to-background signal levels via chemical amplification (e.g., enhanced relaxivity of paramagnetic [78–80] or superparamagnetic compounds [81]) and/or biological amplification (e.g., enhanced accumulation of larger substrates [82]) strategies. Ongoing investigation in atherosclerotic animals will determine the utility of these and novel MPO sensors.
Imaging of lipoproteins.
LDL
Low-density lipoprotein contributes importantly to atherosclerosis initiation and progression (9,10), and the presence of a large lipid core is a high-risk feature of coronary plaques (15). When modified to an oxidized form (e.g., by MPO products, as discussed in the preceding text), oxidized LDL particles become proinflammatory and can promote recruitment and activation of monocytes in evolving atheromata. Low-density lipoprotein was recognized as a scintigraphic imaging target over 20 years ago, and reached clinical evaluation using 99mTc-labeled LDL (83). However, insufficient target-to-background ratios limited its applicability for coronary-sized lesions (24). Newer imaging targets include oxidized LDL epitopes, recently shown to be associated with coronary artery disease (84). Tsimikas et al. (85) have developed radiolabeled oxidation-specific antibodies to target oxidized LDL in experimental atheroma in vivo (86,87). Further studies will determine the potential of these agents (or perhaps magnetic and/or fluorescent analogs) and new lipoprotein-targeted agents (88,89) for the clinical detection of lipoprotein-rich plaques.
Imaging of apoptosis.
Apoptosis or programmed cell death may contribute to atherosclerotic plaque vulnerability (10,15,90,91). During the process of apoptosis, phosphatidylserine, a phospholipid normally residing on the inner cell membrane of viable cells, becomes exteriorized and thus available to affinity ligands such as annexin V. Several scintigraphic imaging agents have been developed based on annexin V (e.g., 99mTc- and 123I-labeled annexin V for SPECT imaging, and 124I- and 18F-labeled annexin V for PET imaging). In an experimental atherosclerosis imaging study, Kolodgie et al. (92) demonstrated strong uptake of radiolabeled 99mTc annexin V in the balloon-injured aortas of cholesterol-fed rabbits. A good correlation was seen between lesional radiotracer uptake and macrophage content. In vivo however, annexin V can also bind necrotic cells and platelets, and can enter macrophages, thereby diminishing the specificity for apoptotic cells that the agent exhibits in vitro (93).
In a clinical extension of this work, Kietselaer et al. (94) recently demonstrated in vivo uptake of radiolabeled annexin A5 (renamed from annexin V) into carotid plaques containing markers of instability, including macrophages, infiltrates, and intraplaque hemorrhage (Fig. 5). Two carotid plaques with stable histological features did not appreciably take up the imaging agent. Radiolabeled annexin A5 thus provides another clinical option for imaging carotid atheroma. For imaging of apoptotic coronary plaques, higher resolution imaging agents such as an annexin V magnetofluorescent nanoparticle for MRI (95) may offer additional apoptosis imaging capabilities.
View larger version (91K):
[in this window]
[in a new window]
|
Figure 5 Molecular imaging of apoptosis in atherosclerosis using radiolabeled annexin (94). 99mTc-radiolabeled annexin A5 accumulates in a carotid lesion (A, single-photon emission computed tomography images, arrows) of a patient with a recent transient ischemic attack (TIA). (B, D) Annexin A5 in sections of the resected plaque stains strongly (B, anti-annexin A5 polyclonal antibody, original magnification x400) in a macrophage-rich area. In contrast, minimal annexin A5 signal (C) appears in the carotid artery of a patient with a remote TIA. (D) Annexin A5 immunoreactivity is at a background level in the corresponding smooth muscle cell-rich lesion. Images provided courtesy of Dr. Bas Kietselaer and Dr. Leonard Hofstra, University Hospital of Maastricht, Maastricht, the Netherlands. Reproduced by permission from reference 94. ant = anterior; l = left.
|
|
Imaging of angiogenesis.
VCAM-1
Due to their potential to promote intraplaque hemorrhage and subsequent cholesterol deposition and plaque growth (96), plaque neovessels may mark plaque vulnerability (15,90). Microvessels in human atheromata can overexpress the leukocyte adhesion molecule VCAM-1, a ligand for the 4ß1 integrin very late antigen-4, and indicate ongoing inflammation within plaques (97). Recently, two new VCAM-1–targeted imaging agents have been investigated in atherosclerosis (35,98). Kelly et al. (35) identified a novel VCAM-1 peptide affinity ligand from phage display that is actively internalized by cells expressing VCAM-1. Conjugation of the ligand to a magnetofluorescent nanoparticle enabled direct MRI and NIRF imaging of VCAM-1 expression in murine atherosclerosis, validated by correlative NIRF microscopy and immunohistochemistry. Hamilton et al. (98) synthesized VCAM-1–targeted echogenic immunoliposomes using a commercially available VCAM-1 antibody as an affinity ligand. Intravascular ultrasound imaging of the VCAM-1–targeted agent in balloon-injured carotid arteries of cholesterol-fed swine demonstrated intimal signal enhancement after agent injection. Further studies may determine its specificity for atheroma compared to nondiseased arterial segments (99).
Integrin vß3
Neovascular endothelial cells also characteristically express integrin vß3, a heterodimeric protein that localizes to human atherosclerotic plaques, particularly within the vasa vasorum and intraplaque microvessels (100). To image vß3 expression in early atherosclerosis, Winter et al. (101) conjugated an arginine-glycine-aspartic acid (RGD) peptidometic to a gadolinium-coated (>90,000 molecules) perfluorocarbon. Using cholesterol-fed rabbits with intimal hyperplasia, the vß3-targeted agent showed durable plaque signal enhancement on in vivo MRI. Histological examination revealed colocalization of vß3 with endothelial cells lining the vasa vasorum. Magnetic resonance imaging of vß3 expression may therefore permit detection of atherosclerotic lesions with abundant neovessels. Further investigation to determine whether the augmented vß3 signal in atherosclerotic plaques suffices to distinguish plaques from normal coronary arteries that express vß3 at baseline (100). Other vß3-targeted imaging agents have been designed for ultrasound (102), PET (103), SPECT (104,105), NIRF (106), and MRI (107), and could also be applied to atherosclerosis. Finally, another promising strategy for imaging angiogenesis targets the extra-domain B of fibronectin, an extracellular matrix protein found in advanced atherosclerotic lesions (108).
|
Outlook
|
|---|
Molecular imaging studies can now elucidate biological aspects of atherosclerosis in vivo, and the field is moving rapidly toward the clinical detection of high-risk atheroma (Table 1). Targeted and activatable imaging agents now under development use a variety of imaging platforms including MRI, nuclear, NIRF, and ultrasound. To achieve clinical utility for the evaluation of atherosclerotic plaques, molecular imaging studies must: 1) provide outcome information beyond that of clinical (e.g., Framingham risk score) and emerging biomarker (e.g., C-reactive protein) risk assessments; 2) be compared to imaging methods that address plaque anatomy (e.g., noncontrast-enhanced MRI, intravascular ultrasound, optical coherence tomography, near infrared spectroscopy); and 3) accurately report on the biological process targeted by the agent. These requirements will undoubtedly require prospective clinical trials that evaluate novel imaging agents with histological end points (e.g., carotid endarterectomy specimens retrieved after agent injection), imaging end points (e.g., statin-mediated reductions in macrophage or protease activity), and, ultimately, clinical end points (e.g., new-onset angina, myocardial infarction, stroke, or death).
Patients likely recruited for such trials include those with indications for invasive procedures such as carotid endarterectomy (atheroma specimen retrieval) and cardiac catheterization (nonculprit lesion assessment after culprit lesion percutaneous coronary intervention) as well as patients with very high Framingham risk scores (e.g., 10-year risk of nonfatal myocardial infarction or death >20%), particularly if noninvasive molecular imaging options are available. Initial molecular imaging trials likely will focus on imaging agent validation in atheroma specimens, primarily by correlating plaque imaging signals with the histological presence of the expected biological target. Secondary trials will then determine the ability of a given molecular imaging agent to predict cardiovascular risk in outcome-driven, natural history studies of vulnerable plaques.
Although likely to require substantial effort and cost, completion of such trials will be of pivotal importance to patients and apparently healthy individuals at high risk for the consequences of atheroma progression and rupture. If predictive beyond conventional risk assessment, we envision that molecular imaging of atherosclerosis, in concert with anatomical imaging techniques, will prove instrumental in guiding the detection, risk stratification, systemic therapy (e.g., optimal medications and doses), and local treatment (e.g., intracoronary stenting) of this disease.
|
Appendix
|
|---|
For a glossary of terms, please see the online version of this article.
|
Footnotes
|
|---|
Supported by NIH UO1-HL080731, NIH R01 HL078641, and the Donald W. Reynolds Foundation.
1 Dr. Weissleder is a shareholder and one of the founding members of VisenMedical, a privately held company in Woburn, Massachusetts. Dr. Weissleder is the inventor of several imaging patents, all of which have been assigned to Massachusetts General Hospital. Cardiovascular Genomic Medicine series edited by Geoffrey S. Ginsburg, MD, PhD. 
|
References
|
|---|
1. Weissleder R. Scaling down imagingmolecular mapping of cancer in mice. Nat Rev Cancer 2002;2:11-18.[CrossRef][Web of Science][Medline]2. Rudin M, Weissleder R. Molecular imaging in drug discovery and development Nat Rev Drug Discov 2003;2:123-131.[CrossRef][Web of Science][Medline] 3. Massoud TF, Gambhir SS. Molecular imaging in living subjectsseeing fundamental biological processes in a new light. Nat Rev Drug Discov 2003;17:545-580. 4. Blasberg RG, Tjuvajev JG. Molecular-genetic imagingcurrent and future perspectives. J Clin Invest 2003;111:1620-1629.[CrossRef][Web of Science][Medline] 5. Herschman HR. Molecular imaginglooking at problems, seeing solutions. Science 2003;302:605-608.[Abstract/Free Full Text] 6. Jaffer FA, Weissleder R. Seeing withinmolecular imaging of the cardiovascular system. Circ Res 2004;94:433-445.[Abstract/Free Full Text] 7. Choudhury RP, Fuster V, Fayad ZA. Molecular, cellular and functional imaging of atherothrombosis Nat Rev Drug Discov 2004;3:913-925.[CrossRef][Web of Science][Medline] 8. Jaffer FA, Weissleder R. Molecular imaging in the clinical arena JAMA 2005;293:855-862.[Abstract/Free Full Text] 9. Glass CK, Witztum JL. Atherosclerosis. The road ahead Cell 2001;104:503-516.[CrossRef][Web of Science][Medline] 10. Libby P. Inflammation in atherosclerosis Nature 2002;420:868-874.[CrossRef][Medline] 11. Dzau VJ, Braun-Dullaeus RC, Sedding DG. Vascular proliferation and atherosclerosisnew perspectives and therapeutic strategies. Nat Med 2002;8:1249-1256.[CrossRef][Web of Science][Medline] 12. Binder CJ, Chang MK, Shaw PX, et al. Innate and acquired immunity in atherogenesis Nat Med 2002;8:1218-1226.[CrossRef][Web of Science][Medline] 13. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease N Engl J Med 2005;352:1685-1695.[Free Full Text] 14. Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990–2020Global Burden of Disease study. Lancet 1997;349:1498-1504.[CrossRef][Web of Science][Medline] 15. Naghavi M, Libby P, Falk E, et al. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: part I Circulation 2003;108:1664-1672.[Abstract/Free Full Text] 16. Naghavi M, Libby P, Falk E, et al. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: part II Circulation 2003;108:1772-1778.[Abstract/Free Full Text] 17. Schaar JA, Muller JE, Falk E, et al. Terminology for high-risk and vulnerable coronary artery plaques. Report of a meeting on the vulnerable plaque, June 17 and 18, 2003, Santorini, Greece Eur Heart J 2004;25:1077-1082.[Abstract/Free Full Text] 18. Fayad ZA, Fuster V. Clinical imaging of the high-risk or vulnerable atherosclerotic plaque Circ Res 2001;89:305-316.[Abstract/Free Full Text] 19. MacNeill BD, Lowe HC, Takano M, Fuster V, Jang IK. Intravascular modalities for detection of vulnerable plaquecurrent status. Arterioscler Thromb Vasc Biol 2003;23:1333-1342.[Abstract/Free Full Text] 20. Madjid M, Zarrabi A, Litovsky S, Willerson JT, Casscells W. Finding vulnerable atherosclerotic plaquesis it worth the effort?. Arterioscler Thromb Vasc Biol 2004;24:1775-1782.[Abstract/Free Full Text] 21. Libby P. Act local, act globalinflammation and the multiplicity of "vulnerable" coronary plaques. J Am Coll Cardiol 2005;45:1600-1602.[Free Full Text] 22. Tsimikas S. Noninvasive imaging of oxidized low-density lipoprotein in atherosclerotic plaques with tagged oxidation-specific antibodies Am J Cardiol 2002;90:22L-27L.[CrossRef][Web of Science][Medline] 23. Wickline SA, Lanza GM. Nanotechnology for molecular imaging and targeted therapy Circulation 2003;107:1092-1095.[Free Full Text] 24. Strauss HW, Grewal RK, Pandit-Taskar N. Molecular imaging in nuclear cardiology Semin Nucl Med 2004;34:47-55.[CrossRef][Web of Science][Medline] 25. Davies JR, Rudd JH, Weissberg PL. Molecular and metabolic imaging of atherosclerosis J Nucl Med 2004;45:1898-1907.[Abstract/Free Full Text] 26. Lindner JR. Microbubbles in medical imagingcurrent applications and future directions. Nat Rev Drug Discov 2004;3:527-532.[CrossRef][Web of Science][Medline] 27. Dobrucki LW, Sinusas AJ. Cardiovascular molecular imaging Semin Nucl Med 2005;35:73-81.[CrossRef][Web of Science][Medline] 28. Pollard TD. The future of biomedical researchfrom the inventory of genes to understanding physiology and the molecular basis of disease. JAMA 2002;287:1725-1727.[Free Full Text] 29. Ridker PM, Brown NJ, Vaughan DE, Harrison DG, Mehta JL. Established and emerging plasma biomarkers in the prediction of first atherothrombotic events Circulation 2004;109:IV6-IV19. 30. Davies MJ, Richardson PD, Woolf N, Katz DR, Mann J. Risk of thrombosis in human atherosclerotic plaquesrole of extracellular lipid, macrophage, and smooth muscle cell content. Br Heart J 1993;69:377-381.[Abstract/Free Full Text] 31. Brooks PC, Montgomery AM, Rosenfeld M, et al. Integrin alpha v beta 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels Cell 1994;79:1157-1164.[CrossRef][Web of Science][Medline] 32. Virmani R, Kolodgie FD, Burke AP, et al. Atherosclerotic plaque progression and vulnerability to ruptureangiogenesis as a source of intraplaque hemorrhage. Arterioscler Thromb Vasc Biol 2005;25:2054-2061.[Abstract/Free Full Text] 33. Landon LA, Deutscher SL. Combinatorial discovery of tumor targeting peptides using phage display J Cell Biochem 2003;90:509-517.[CrossRef][Web of Science][Medline] 34. Arap W, Kolonin MG, Trepel M, et al. Steps toward mapping the human vasculature by phage display Nat Med 2002;8:121-127.[CrossRef][Web of Science][Medline] 35. Kelly KA, Allport JR, Tsourkas A, Shinde-Patil VR, Josephson L, Weissleder R. Detection of vascular adhesion molecule-1 expression using a novel multimodal nanoparticle Circ Res 2005;96:327-336.[Abstract/Free Full Text] 36. Weissleder R, Kelly K, Sun EY, Shtatland T, Josephson L. Cell-specific targeting of nanoparticles by multivalent attachment of small molecules Nat Biotechnol 2005;23:1418-1423.[CrossRef][Web of Science][Medline] 37. Schreiber SL. Target-oriented and diversity-oriented organic synthesis in drug discovery Science 2000;287:1964-1969.[Abstract/Free Full Text] 38. Weissleder R, Ntziachristos V. Shedding light onto live molecular targets Nat Med 2003;9:123-128.[CrossRef][Medline] 39. Weissleder R, Tung CH, Mahmood U, Bogdanov Jr A. In vivo imaging of tumors with protease-activated near-infrared fluorescent probes Nat Biotechnol 1999;17:375-378.[CrossRef][Web of Science][Medline] 40. Louie AY, Huber MM, Ahrens ET, et al. In vivo visualization of gene expression using magnetic resonance imaging Nat Biotechnol 2000;18:321-325.[CrossRef][Web of Science][Medline] 41. Chen J, Tung CH, Mahmood U, et al. In vivo imaging of proteolytic activity in atherosclerosis Circulation 2002;105:2766-2771.[Abstract/Free Full Text] 42. Jaffer FA, Tung CH, Gerszten RE, Weissleder R. In vivo imaging of thrombin activity in experimental thrombi with thrombin-sensitive near-infrared molecular probe Arterioscler Thromb Vasc Biol 2002;22:1929-1935.[Abstract/Free Full Text] 43. Bogdanov Jr. A, Matuszewski L, Bremer C, Petrovsky A, Weissleder R. Oligomerization of paramagnetic substrates results in signal amplification and can be used for MR imaging of molecular targets Mol Imaging 2002;1:16-23.[CrossRef][Medline] 44. Rudd JH, Warburton EA, Fryer TD, et al. Imaging atherosclerotic plaque inflammation with [18F]-fluorodeoxyglucose positron emission tomography Circulation 2002;105:2708-2711.[Abstract/Free Full Text] 45. Jaffer FA, Tung CH, Wykrzykowska JJ, et al. Molecular imaging of factor XIIIa activity in thrombosis using a novel, near-infrared fluorescent contrast agent that covalently links to thrombi Circulation 2004;110:170-176.[Abstract/Free Full Text] 46. Wang JC, Normand SL, Mauri L, Kuntz RE. Coronary artery spatial distribution of acute myocardial infarction occlusions Circulation 2004;110:278-284.[Abstract/Free Full Text] 47. Li AC, Palinski W. Peroxisome proliferator-activated receptorshow their effects on macrophages can lead to the development of a new drug therapy against atherosclerosis. Annu Rev Pharmacol Toxicol 2006;46:1-39.[CrossRef][Web of Science][Medline] 48. Nagaoka K, Takahara K, Tanaka K, et al. Association of SIGNR1 with TLR4-MD-2 enhances signal transduction by recognition of LPS in gram-negative bacteria Int Immunol 2005;17:827-836.[Abstract/Free Full Text] 49. Weissleder R, Elizondo G, Wittenberg J, Rabito CA, Bengele HH, Josephson L. Ultrasmall superparamagnetic iron oxidecharacterization of a new class of contrast agents for MR imaging. Radiology 1990;175:489-493.[Abstract/Free Full Text] 50. Weissleder R, Elizondo G, Wittenberg J, Lee AS, Josephson L, Brady TJ. Ultrasmall superparamagnetic iron oxidean intravenous contrast agent for assessing lymph nodes with MR imaging. Radiology 1990;175:494-498.[Abstract/Free Full Text] 51. Harisinghani MG, Barentsz J, Hahn PF, et al. Noninvasive detection of clinically occult lymph-node metastases in prostate cancer N Engl J Med 2003;348:2491-2499.[Abstract/Free Full Text] 52. Jaffer FA, Nahrendorf M, Sosnovik DE, Kelly KA, Aikawa E, Weissleder R. Cellular imaging of inflammation in atherosclerosis using magnetofluorescent nanomaterials Mol Imaging. 2006In press. 53. Kooi ME, Cappendijk VC, Cleutjens KB, et al. Accumulation of ultrasmall superparamagnetic particles of iron oxide in human atherosclerotic plaques can be detected by in vivo magnetic resonance imaging Circulation 2003;107:2453-2458.[Abstract/Free Full Text] 54. Trivedi RA, U-King-Im JM, Graves MJ, et al. In vivo detection of macrophages in human carotid atheromatemporal dependence of ultrasmall superparamagnetic particles of iron oxide-enhanced MRI. Stroke 2004;35:1631-1635.[Abstract/Free Full Text] 55. Schneiderman J, Wilensky RL, Weiss A, et al. Diagnosis of thin-cap fibroatheromas by a self-contained intravascular magnetic resonance imaging probe in ex vivo human aortas and in situ coronary arteries J Am Coll Cardiol 2005;45:1961-1969.[Abstract/Free Full Text] 56. Larose E, Yeghiazarians Y, Libby P, et al. Characterization of human atherosclerotic plaques by intravascular magnetic resonance imaging Circulation 2005;112:2324-2331.[Abstract/Free Full Text] 57. Cunningham CH, Arai T, Yang PC, McConnell MV, Pauly JM, Conolly SM. Positive contrast magnetic resonance imaging of cells labeled with magnetic nanoparticles Magn Reson Med 2005;53:999-1005.[CrossRef][Web of Science][Medline] 58. Zhu B, Jaffer FA, Ntziachristos V, Weissleder R. Development of a near infrared fluorescence catheteroperating characteristics and feasibility for atherosclerotic plaque detection. J Phys D Appl Phys 2005;38:2701-2707.[CrossRef] 59. Weissleder R, Kelly K, Sun E, Shtatland T, Josephson L. Cell-specific targeting of nanoparticles by multivalent attachment of small molecules Nat Biotechnol 2005;23:1418-1423.[CrossRef][Web of Science][Medline] 60. Venneti S, Lopresti BJ, Wang G, et al. PET imaging of brain macrophages using the peripheral benzodiazepine receptor in a macaque model of neuroAIDS J Clin Invest 2004;113:981-989.[CrossRef][Web of Science][Medline] 61. Liu J, Sukhova GK, Sun JS, Xu WH, Libby P, Shi GP. Lysosomal cysteine proteases in atherosclerosis Arterioscler Thromb Vasc Biol 2004;24:1359-1366.[Abstract/Free Full Text] 62. Sukhova GK, Shi GP, Simon DI, Chapman HA, Libby P. Expression of the elastolytic cathepsins S and K in human atheroma and regulation of their production in smooth muscle cells J Clin Invest 1998;102:576-583.[Web of Science][Medline] 63. Ntziachristos V, Tung CH, Bremer C, Weissleder R. Fluorescence molecular tomography resolves protease activity in vivo Nat Med 2002;8:757-760.[CrossRef][Medline] 64. Kim DE, Jaffer FA, Quinti L, et al. Imaging of cathepsin K activity in atherosclerosis using a protease-activatable near infrared fluorescence agent (abstr) Circulation 2005;112:II206. 65. Galis Z, Sukhova G, Lark M, Libby P. Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques J Clin Invest 1994;94:2493-2503.[Web of Science][Medline] 66. Sukhova GK, Schonbeck U, Rabkin E, et al. Evidence for increased collagenolysis by interstitial collagenases-1 and -3 in vulnerable human atheromatous plaques Circulation 1999;99:2503-2509.[Abstract/Free Full Text] 67. Fukumoto Y, Deguchi JO, Libby P, et al. Genetically determined resistance to collagenase action augments interstitial collagen accumulation in atherosclerotic plaques Circulation 2004;110:1953-1959.[Abstract/Free Full Text] 68. Deguchi JO, Aikawa E, Libby P, et al. Matrix metalloproteinase-13/collagenase-3 deletion promotes collagen accumulation and organization in mouse atherosclerotic plaques Circulation 2005;112:2708-2715.[Abstract/Free Full Text] 69. Schafers M, Riemann B, Kopka K, et al. Scintigraphic imaging of matrix metalloproteinase activity in the arterial wall in vivo Circulation 2004;109:2554-2559.[Abstract/Free Full Text] 70. Hidalgo M, Eckhardt SG. Development of matrix metalloproteinase inhibitors in cancer therapy J Natl Cancer Inst 2001;93:178-193.[Abstract/Free Full Text] 71. Bremer C, Tung CH, Weissleder R. In vivo molecular target assessment of matrix metalloproteinase inhibition Nat Med 2001;7:743-748.[CrossRef][Web of Science][Medline] 72. Deguchi J, Aikawa M, Tung CH, et al. In vivo detection of activity of gelatinases (MMP-2/9) in atherosclerotic mice (abstr) Circulation 2004;110:III139. 73. Nicholls SJ, Hazen SL. Myeloperoxidase and cardiovascular disease Arterioscler Thromb Vasc Biol 2005;25:1102-1111.[Abstract/Free Full Text] 74. Brennan ML, Penn MS, Van Lente F, et al. Prognostic value of myeloperoxidase in patients with chest pain N Engl J Med 2003;349:1595-1604.[Abstract/Free Full Text] 75. Daugherty A, Dunn JL, Rateri DL, Heinecke JW. Myeloperoxidase, a catalyst for lipoprotein oxidation, is expressed in human atherosclerotic lesions J Clin Invest 1994;94:437-444.[Web of Science][Medline] 76. Sugiyama S, Okada Y, Sukhova GK, Virmani R, Heinecke JW, Libby P. Macrophage myeloperoxidase regulation by granulocyte macrophage colony-stimulating factor in human atherosclerosis and implications in acute coronary syndromes Am J Pathol 2001;158:879-891.[Abstract/Free Full Text] 77. Sugiyama S, Kugiyama K, Aikawa M, Nakamura S, Ogawa H, Libby P. Hypochlorous acid, a macrophage product, induces endothelial apoptosis and tissue factor expressioninvolvement of myeloperoxidase-mediated oxidant in plaque erosion and thrombogenesis. Arterioscler Thromb Vasc Biol 2004;24:1309-1314.[Abstract/Free Full Text] 78. Chen JW, Pham W, Weissleder R, Bogdanov Jr A. Human myeloperoxidasea potential target for molecular MR imaging in atherosclerosis. Magn Reson Med 2004;52:1021-1028.[CrossRef][Web of Science][Medline] 79. Chen JW, Querol M, Bogdanov Jr. A, Weissleder R. Imaging myeloperoxidase using novel amplifiable paramagnetic substrates Radiology. 2006In press. 80. Querol M, Chen JW, Yudina A, Weissleder R, Bogdanov Jr. A. Myeloperoxidase-sensitive paramagnetic contrast agent for atherosclerotic plaque MR imaging J Am Chem Soc 2006In press. 81. Perez JM, Simeone FJ, Saeki Y, Josephson L, Weissleder R. Peroxidase substrate nanosensors for MR imaging Nano Lett 2004;4:119-122. 82. Querol Sans M, Chen JW, Weissleder R, Bogdanov Jr. A. Myeloperoxidase activity imaging using (67)Ga labeled substrate Mol Imaging Biol 2006In press. 83. Ginsberg HN, Goldsmith SJ, Vallabhajosula S. Noninvasive imaging of 99mtechnetium-labeled low density lipoprotein uptake by tendon xanthomas in hypercholesterolemic patients Arteriosclerosis 1990;10:256-262.[Abstract/Free Full Text] 84. Tsimikas S, Brilakis ES, Miller ER, et al. Oxidized phospholipids, Lp(a) lipoprotein, and coronary artery disease N Engl J Med 2005;353:46-57.[Abstract/Free Full Text] 85. Tsimikas S, Shortal BP, Witztum JL, Palinski W. In vivo uptake of radiolabeled MDA2, an oxidation-specific monoclonal antibody, provides an accurate measure of atherosclerotic lesions rich in oxidized LDL and is highly sensitive to their regression Arterioscler Thromb Vasc Biol 2000;20:689-697.[Abstract/Free Full Text] 86. Shaw PX, Horkko S, Tsimikas S, et al. Human-derived anti-oxidized LDL autoantibody blocks uptake of oxidized LDL by macrophages and localizes to atherosclerotic lesions in vivo Arterioscler Thromb Vasc Biol 2001;21:1333-1339.[Abstract/Free Full Text] 87. Torzewski M, Shaw PX, Han KR, et al. Reduced in vivo aortic uptake of radiolabeled oxidation-specific antibodies reflects changes in plaque composition consistent with plaque stabilization Arterioscler Thromb Vasc Biol 2004;24:2307-2312.[Abstract/Free Full Text] 88. Frias JC, Williams KJ, Fisher EA, Fayad ZA. Recombinant HDL-like nanoparticlesa specific contrast agent for MRI of atherosclerotic plaques. J Am Chem Soc 2004;126:16316-16317.[CrossRef][Web of Science][Medline] 89. Mitsumori LM, Ricks JL, Rosenfeld ME, Schmiedl UP, Yuan C. Development of a lipoprotein based molecular imaging MR contrast agent for the noninvasive detection of early atherosclerotic disease Int J Cardiovasc Imaging 2004;20:561-567.[CrossRef][Web of Science][Medline] 90. Libby P. The molecular bases of the acute coronary syndromes Circulation 1995;91:2844-2850.[Free Full Text] 91. Geng Y-J, Libby P. Evidence for apoptosis in advanced human atheroma. Co-localization with interleukin-1 beta-converting enzyme Am J Pathol 1995;147:251-266.[Abstract] 92. Kolodgie FD, Petrov A, Virmani R, et al. Targeting of apoptotic macrophages and experimental atheroma with radiolabeled annexin Va technique with potential for noninvasive imaging of vulnerable plaque. Circulation 2003;108:3134-3139.[Abstract/Free Full Text] 93. Lahorte CM, Vanderheyden JL, Steinmetz N, Van de Wiele C, Dierckx RA, Slegers G. Apoptosis-detecting radioligandscurrent state of the art and future perspectives. Eur J Nucl Med Mol Imaging 2004;31:887-919.[CrossRef][Web of Science][Medline] 94. Kietselaer BL, Reutelingsperger CP, Heidendal GA, et al. Noninvasive detection of plaque instability with use of radiolabeled annexin A5 in patients with carotid-artery atherosclerosis N Engl J Med 2004;350:1472-1473.[Free Full Text] 95. Sosnovik DE, Schellenberger EA, Nahrendorf M, et al. Magnetic resonance imaging of cardiomyocyte apoptosis with a novel magneto-optical nanoparticle Magn Reson Med 2005;54:718-724.[CrossRef][Web of Science][Medline] 96. Virmani R, Kolodgie FD, Burke AP, et al. Atherosclerotic plaque progression and vulnerability to ruptureangiogenesis as a source of intraplaque hemorrhage. Arterioscler Thromb Vasc Biol 2005;15:1-8. 97. O’Brien KD, Allen MD, McDonald TO, et al. Vascular cell adhesion molecule-1 is expressed in human coronary atherosclerotic plaques. Implications for the mode of progression of advanced coronary atherosclerosis J Clin Invest 1993;92:945-951.[Web of Science][Medline] 98. Hamilton AJ, Huang SL, Warnick D, et al. Intravascular ultrasound molecular imaging of atheroma components in vivo J Am Coll Cardiol 2004;43:453-460.[Abstract/Free Full Text] 99. Kaul S, Lindner JR. Visualizing coronary atherosclerosis in vivothinking big, imaging small. J Am Coll Cardiol 2004;43:461-463.[Free Full Text] 100. Hoshiga M, Alpers CE, Smith LL, Giachelli CM, Schwartz SM. Alpha-v beta-3 integrin expression in normal and atherosclerotic artery Circ Res 1995;77:1129-1135.[Abstract/Free Full Text] 101. Winter PM, Morawski AM, Caruthers SD, et al. Molecular imaging of angiogenesis in early-stage atherosclerosis with alpha(v)beta3-integrin-targeted nanoparticles Circulation 2003;108:2270-2274.[Abstract/Free Full Text] 102. Ellegala DB, Leong-Poi H, Carpenter JE, et al. Imaging tumor angiogenesis with contrast ultrasound and microbubbles targeted to alpha(v)beta3 Circulation 2003;108:336-341.[Abstract/Free Full Text] 103. Haubner R, Weber WA, Beer AJ, et al. Noninvasive visualization of the activated alphavbeta3 integrin in cancer patients by positron emission tomography and [18F]Galacto-RGD PLoS Med 2005;2:e70.[CrossRef][Medline] 104. Meoli DF, Sadeghi MM, Krassilnikova S, et al. Noninvasive imaging of myocardial angiogenesis following experimental myocardial infarction J Clin Invest 2004;113:1684-1691.[CrossRef][Web of Science][Medline] 105. Hua J, Dobrucki LW, Sadeghi MM, et al. Noninvasive imaging of angiogenesis with a 99mTc-labeled peptide targeted at alphavbeta3 integrin after murine hindlimb ischemia Circulation 2005;111:3255-3260.[Abstract/Free Full Text] 106. Sunkuk K, Shi K, Houston JP, et al. Imaging dose-dependent pharmacokinetics of an RGD-fluorescent dye conjugate targeted to alpha(v)beta(3) receptor expressed in Kaposi’s sarcoma Mol Imaging 2005;4:75-87.[Medline] 107. Sipkins DA, Cheresh DA, Kazemi MR, Nevin LM, Bednarski MD, Li KC. Detection of tumor angiogenesis in vivo by alphaVbeta3-targeted magnetic resonance imaging Nat Med 1998;4:623-626.[CrossRef][Web of Science][Medline] 108. Matter CM, Schuler PK, Alessi P, et al. Molecular imaging of atherosclerotic plaques using a human antibody against the extra-domain B of fibronectin Circ Res 2004;95:1225-1233.[Abstract/Free Full Text]
This article has been cited by other articles:
|
|
|
|
 
R. P. Choudhury and E. A. Fisher
Molecular Imaging in Atherosclerosis, Thrombosis, and Vascular Inflammation
Arterioscler. Thromb. Vasc. Biol.,
July 1, 2009;
29(7):
983 - 991.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Zeng, A. Zampetaki, A. Margariti, A. E. Pepe, S. Alam, D. Martin, Q. Xiao, W. Wang, Z.-G. Jin, G. Cockerill, et al.
Sustained activation of XBP1 splicing leads to endothelial apoptosis and atherosclerosis development in response to disturbed flow
PNAS,
May 19, 2009;
106(20):
8326 - 8331.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Ishino, T. Mukai, Y. Kuge, N. Kume, M. Ogawa, N. Takai, J. Kamihashi, M. Shiomi, M. Minami, T. Kita, et al.
Targeting of Lectinlike Oxidized Low-Density Lipoprotein Receptor 1 (LOX-1) with 99mTc-Labeled Anti-LOX-1 Antibody: Potential Agent for Imaging of Vulnerable Plaque
J. Nucl. Med.,
October 1, 2008;
49(10):
1677 - 1685.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
O C Raffel, T Akasaka, and I-K Jang
Cardiac optical coherence tomography
Heart,
September 1, 2008;
94(9):
1200 - 1210.
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. F. Langer, R. Haubner, B. J. Pichler, and M. Gawaz
Radionuclide imaging a molecular key to the atherosclerotic plaque.
J. Am. Coll. Cardiol.,
July 1, 2008;
52(1):
1 - 12.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. H. Choi, A. Chae, E. Miller, M. Messig, F. Ntanios, A. N. DeMaria, S. E. Nissen, J. L. Witztum, and S. Tsimikas
Relationship Between Biomarkers of Oxidized Low-Density Lipoprotein, Statin Therapy, Quantitative Coronary Angiography, and Atheroma Volume Observations From the REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) Study.
J. Am. Coll. Cardiol.,
July 1, 2008;
52(1):
24 - 32.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Burtea, S. Laurent, O. Murariu, D. Rattat, G. Toubeau, A. Verbruggen, D. Vansthertem, L. Vander Elst, and R. N. Muller
Molecular imaging of {alpha}v{beta}3 integrin expression in atherosclerotic plaques with a mimetic of RGD peptide grafted to Gd-DTPA
Cardiovasc Res,
April 1, 2008;
78(1):
148 - 157.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. F. Padera Jr. and F. J. Schoen
Pathology of Cardiac Surgery
Card. Surg. Adult,
January 1, 2008;
3(2008):
111 - 178.
[Full Text]
|
|
|
|
|
|
|
M. A. McAteer, J. E. Schneider, Z. A. Ali, N. Warrick, C. A. Bursill, C. von zur Muhlen, D. R. Greaves, S. Neubauer, K. M. Channon, and R. P. Choudhury
Magnetic Resonance Imaging of Endothelial Adhesion Molecules in Mouse Atherosclerosis Using Dual-Targeted Microparticles of Iron Oxide
Arterioscler. Thromb. Vasc. Biol.,
January 1, 2008;
28(1):
77 - 83.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. G. Spagnoli, E. Bonanno, G. Sangiorgi, and A. Mauriello
Role of Inflammation in Atherosclerosis
J. Nucl. Med.,
November 1, 2007;
48(11):
1800 - 1815.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. A. Jaffer, P. Libby, and R. Weissleder
Molecular Imaging of Cardiovascular Disease
Circulation,
August 28, 2007;
116(9):
1052 - 1061.
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. A. Beller
Noninvasive Screening for Coronary Atherosclerosis and Silent Ischemia in Asymptomatic Type 2 Diabetic Patients: Is it Appropriate and Cost-Effective?
J. Am. Coll. Cardiol.,
May 15, 2007;
49(19):
1918 - 1923.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. A. Jaffer, D.-E. Kim, L. Quinti, C.-H. Tung, E. Aikawa, A. N. Pande, R. H. Kohler, G.-P. Shi, P. Libby, and R. Weissleder
Optical Visualization of Cathepsin K Activity in Atherosclerosis With a Novel, Protease-Activatable Fluorescence Sensor
Circulation,
May 1, 2007;
115(17):
2292 - 2298.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. E. Sosnovik, M. Nahrendorf, and R. Weissleder
Molecular Magnetic Resonance Imaging in Cardiovascular Medicine
Circulation,
April 17, 2007;
115(15):
2076 - 2086.
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y.-W. Wu, H.-L. Kao, M.-F. Chen, B.-C. Lee, W.-Y. I. Tseng, J.-S. Jeng, K.-Y. Tzen, R.-F. Yen, P.-J. Huang, and W.-S. Yang
Characterization of Plaques Using 18F-FDG PET/CT in Patients with Carotid Atherosclerosis and Correlation with Matrix Metalloproteinase-1
J. Nucl. Med.,
February 1, 2007;
48(2):
227 - 233.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. N. DeMaria, O. Ben-Yehuda, G. K. Feld, G. S. Ginsburg, B. H. Greenberg, W. Y.W. Lew, J. A.C. Lima, A. S. Maisel, J. Narula, D. J. Sahn, et al.
Highlights of the Year in JACC 2006
J. Am. Coll. Cardiol.,
January 30, 2007;
49(4):
509 - 527.
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Waxman, F. Ishibashi, and J. E. Muller
Detection and Treatment of Vulnerable Plaques and Vulnerable Patients: Novel Approaches to Prevention of Coronary Events
Circulation,
November 28, 2006;
114(22):
2390 - 2411.
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Nahrendorf, F. A. Jaffer, K. A. Kelly, D. E. Sosnovik, E. Aikawa, P. Libby, and R. Weissleder
Noninvasive Vascular Cell Adhesion Molecule-1 Imaging Identifies Inflammatory Activation of Cells in Atherosclerosis
Circulation,
October 3, 2006;
114(14):
1504 - 1511.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
Top
Abstract
Molecular imaging: Detection of...