Advances in Molecular Imaging of Atherosclerosis and Myocardial

Articles in PresS. Am J Physiol Heart Circ Physiol (October 12, 2012). doi:10.1152/ajpheart.00583.2012
ͳ
Advances in Molecular Imaging of Atherosclerosis and Myocardial Infarction: Shedding New
ʹ
Light on In-vivo Cardiovascular Biology
͵
Ͷ
Alkystis Phinikaridou1,4, Marcelo Andia1,2,4, Ajay M. Shah3,4, and René M. Botnar
1,4,5
ͷ
͸
1
Division of Imaging Science and Biomedical Engineering, King’s College London, London, UK
͹ 2 Radiology Department, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile
ͺ
3
ͻ
Cardiovascular Division, King’s College London, United Kingdom
4
ͳͲ
5
BHF Centre of Excellence, King’s College London, United Kingdom
Wellcome Trust and EPSRC Medical Engineering Center, King’s College London, United Kingdom
ͳͳ
ͳʹ
ͳ͵
ͳͶ
Correspondence address:
ͳͷ
Alkystis Phinikaridou, PhD
ͳ͸
King’s College London, Division of Imaging Sciences and Biomedical Engineering
ͳ͹
The Rayne Institute, 4th Floor, Lambeth Wing, St Thomas’ Hospital
ͳͺ
London SE1 7EH, United Kingdom
ͳͻ
Tel: 020 7188 8386
ʹͲ
Fax: 020 7188 5442
ʹͳ
Email: alkystis.1.phinikaridou@kcl.ac.uk
ʹʹ
ʹ͵
ʹͶ
ʹͷ
ʹ͸
ʹ͹
ʹͺ
ʹͻ
͵Ͳ
͵ͳ
͵ʹ
ͳ
Copyright © 2012 by the American Physiological Society.
͵͵
Abstract
͵Ͷ
Molecular imaging of the cardiovascular system heavily relies on the development of new imaging
͵ͷ
probes and technologies to facilitate visualization of biological processes underlying or preceding
͵͸
disease. Molecular imaging is a highly active research discipline that has seen tremendous growth
͵͹
over the past decade. It has broadened our understanding of oncologic, neurologic, and
͵ͺ
cardiovascular diseases (CVD) by providing new insights into the in vivo biology of disease
͵ͻ
progression and therapeutic interventions. As it allows for the longitudinal evaluation of biological
ͶͲ
processes it is ideally suited for monitoring treatment response. In this review, we will concentrate on
Ͷͳ
the major accomplishments and advances in the field of molecular imaging of atherosclerosis and
Ͷʹ
myocardial infarction, with a special focus on magnetic resonance imaging (MRI).
Ͷ͵
ͶͶ
PART A: Imaging of Atherosclerosis
Ͷͷ
Atherosclerosis related cardiovascular complications, primarily myocardial infarction and stroke, are
Ͷ͸
estimated to become the leading cause of death worldwide by the year 2020 (117). As “high-risk
Ͷ͹
vulnerable plaques” are often undetected until they cause life-threatening adverse events, an
Ͷͺ
increasing effort has been made to better understand plaque biology and vulnerability with a special
Ͷͻ
focus on the development of new targeted molecular imaging agents. Such agents may allow in vivo:
ͷͲ
1) monitoring of plaque progression, 2) detecting of vulnerable plaque, 3) monitoring of the
ͷͳ
effectiveness of interventions, and 4) guiding of patient-specific medical treatment. Currently, a
ͷʹ
plethora of targeted imaging agents are available for the visualization of the major biological
ͷ͵
processes involved in atherosclerosis both for experimental and clinical utilization. Some of these
ͷͶ
applications are summarized in Figure 1.
ͷͷ
ͷ͸
Endothelial permeability and activation
ͷ͹
Increased endothelial cell permeability, dysfunction, and expression of surface adhesion molecules
ͷͺ
(E- and P-selectin) are considered to be the initiating events in atherogenesis. Increased endothelial
ͷͻ
leakage allows circulating low-density lipoprotein particles (LDL) (73) to passively diffuse into the
ʹ
͸Ͳ
vessel wall whereas expression of adhesion molecules is responsible for the receptor-mediated
͸ͳ
recruitment of leukocytes (30). Additionally, endothelial dysfunction defined as the decrease in the
͸ʹ
bioavailability of nitric oxide promotes platelet activation and smooth muscle cell (SMC) proliferation
͸͵
(30). Functionally, endothelial dysfunction is associated with a paradoxical vasoconstriction in
͸Ͷ
response to acetylcholine both in humans (98) and ApoE-/- mice (7, 28). It precedes angiographic
͸ͷ
evidence of coronary artery disease (207) and is a predictor of future cardiovascular events (52).
͸͸
Recently, contrast-enhanced MRI with gadofosveset has been used to image endothelial permeability
͸͹
in an ApoE-/- mouse model of accelerated atherosclerosis (139) (Figure 1). Gadofosveset is a
͸ͺ
clinically approved gadolinium-based contrast agent that reversibly binds to serum albumin, resulting
͸ͻ
in a prolonged vascular presence and a 5-10 fold increase in relaxivity (r1) (16, 92). Gadofosveset
͹Ͳ
uptake was associated with mechanically damaged endothelium in a swine model of coronary injury
͹ͳ
(138), atherosclerosis-associated endothelial damage in ApoE-/- mice (139) (Figure 1), and leaky
͹ʹ
neovessels in human carotid and rabbit aortic plaque (96, 97). Furthermore, VHSPNKK-modified
͹͵
magnetofluorescent particles (VNP) targeting the VCAM-1 receptor (74, 121) and microparticles of
͹Ͷ
iron oxide (MPIO) (103, 104) (Figure 1) targeting the VCAM-1 receptor and/or P-selectin have been
͹ͷ
used to image activated endothelium in murine atherosclerotic plaque. Imaging of VCAM-1 leucocyte
͹͸
recruitment has also been achieved with a hybrid positron emission tomography/computed
͹͹
tomography (PET-CT) system using an
͹ͺ
has also been used to assess endothelial vasomotor responses in humans before and after
͹ͻ
administration of endothelial stressors (55, 128, 185). Interestingly, the extent of endothelial
ͺͲ
dysfunction correlated with local plaque burden (55, 185).
18
F-labeled small VCAM-1 affinity ligand (122). Finally, MRI
ͺͳ
ͺʹ
Macrophage, metabolism and lipoproteins
ͺ͵
Inflammatory macrophages participate in all phases of atherogenesis, including lesion initiation,
ͺͶ
progression, and complications (105). Initially recruited to the vessel wall as monocytes, resident
ͺͷ
macrophages uptake oxidized LDL via the scavenger receptor and subsequently transform into foam
ͺ͸
cells contributing to atheroma expansion. Macrophages also secrete several proteolytic enzymes and
͵
ͺ͹
extracellular matrix proteins (e.g., elastin) that both increase plaque burden and destabilize the lesion.
ͺͺ
Finally, macrophage apoptosis (programmed cell death) leads to the development of an acellular lipid
ͺͻ
core. The ability of macrophages to endocytose foreign objects has been used as the basis of their
ͻͲ
imaging. Iron-oxide based magnetic nanoparticles (MNP) of variable size (SPIO, USPIO, VSOP) and
ͻͳ
stabilized with different surface coating materials (e.g. dextran or citrate) have been shown to be non-
ͻʹ
specifically endocytosed by macrophages in hyperlipidemic rabbits (35, 57, 66, 88, 114, 152, 155,
ͻ͵
158, 164, 214), mice (Figure 1) (100) and human carotid plaques (64, 87, 181, 182, 188-190), and
ͻͶ
are used to image macrophage density. These nanoparticles are biocompatible and able to exert a
ͻͷ
strong T2 and T2* effect (R2>R1) resulting in a signal drop visible on T2-weighted (T2W) and T2*-
ͻ͸
weighted (T2*W) MR images 24-48h after administration. Histological correlation showed co-
ͻ͹
localization of the MNPs with macrophage-rich regions of the plaque whereas little uptake was
ͻͺ
observed in SMCs and endothelial cells. Magenotofluorescent nanoparticles that combine MRI with
ͻͻ
optical imaging properties by additionally carrying a fluorescent moiety (e.g., near-infrared fluorescent,
ͳͲͲ
[NIRF]) are also available and have been used to quantify the cellular distribution of nanoparticles
ͳͲͳ
(70).
ͳͲʹ
(N1177) for CT imaging (65) of macrophages. Receptor-based macrophage imaging has also been
ͳͲ͵
achieved by using gadolinium-loaded micelles targeting the macrophage scavenger receptor (Figure
ͳͲͶ
1) (3), the cannabinoid receptor (CB2-R), and neutrophil gelatinase-associated lipocalin 2 (NGAL) in
ͳͲͷ
murine plaques (3, 116, 183, 184).
64
Cu-labeled nanoparticles allowed for PET/CT imaging (127) and crystalline iodinated particles
ͳͲ͸
On a functional level, the glucose analogue [18]-fluorodeoxyglucose (18FDG), that competes
ͳͲ͹
with glucose for uptake into metabolically active cells, has been used to image inflammatory cell
ͳͲͺ
activity non-invasively by PET, with or without complementary CT or MRI scans, in humans (151, 159)
ͳͲͻ
and rabbits (13). Experiments in humans showed that the net
ͳͳͲ
(plaque/integral plasma) in symptomatic lesions was 27% higher than in the contralateral
ͳͳͳ
asymptomatic lesions. There was no measurable
ͳͳʹ
arteries. Autoradiography of excised plaques confirmed accumulation of deoxyglucose in
ͳͳ͵
macrophage-rich areas of the plaque.
Ͷ
18
FDG accumulation rate
18
FDG uptake in angiographically normal carotid
ͳͳͶ
Imaging plaque lipids is also essential as lipid-rich plaques are more likely to rupture.
ͳͳͷ
labeled LDL particles have been used to image subjects with large tendon xanthomas secondary to
ͳͳ͸
homozygous familial hypercholesterolemia or sitosterolemia over 20 years ago (47). On the molecular
ͳͳ͹
level, gadolinium-loaded LDL-based nanoparticles (GdDO3A-OA-LDL) (Figure 1) (213) and
ͳͳͺ
recombinant HDL-like nanoparticles (Figure 1) (25, 41) have also been developed to image
ͳͳͻ
atherosclerosis in mice. Furthermore, the oxidized LDL receptor (LOX-1) and oxidized plaque LDL
ͳʹͲ
particles have been imaged using antibodies that bind to the LOX-1 receptor (94) and oxidation
ͳʹͳ
specific epitopes (11, 186, 191) using single photon emission computed tomography (SPECT), CT,
ͳʹʹ
and MRI. Finally, diffusion weighted imaging (DWI) that generates endogenous contrast between
ͳʹ͵
plaque components based on the characteristic diffusion coefficients of water molecules has been
ͳʹͶ
used to visualize plaque components including lipids both in vivo and ex vivo (Figure 1) (143, 187).
99m
Tc-
ͳʹͷ
ͳʹ͸
Enzymatic activity and apoptosis
ͳʹ͹
Matrix metalloproteinases (MMPs) degrade extracellular matrix proteins including elastin and
ͳʹͺ
collagen and therefore participate in plaque destabilization (43, 50, 163, 179). MMP expression was
ͳʹͻ
show to be increased in vulnerable atherosclerotic plaque undergoing positive arterial remodeling
ͳ͵Ͳ
(136, 156). In vivo SPECT using a
ͳ͵ͳ
to the active catalytic site of MMPs (58) demonstrated focal signal enhancement of carotid plaque in
ͳ͵ʹ
atherosclerotic ApoE-/- mice (154). In vivo and ex vivo MRI for the detection of MMP-rich plaques was
ͳ͵͵
achieved with the use of a gadolinium-based MMP sensitive contrast agent (P947) (91). Gadolinium
ͳ͵Ͷ
quantification and MRI showed a preferential accumulation of P947 in rabbit atherosclerotic lesions
ͳ͵ͷ
compared
ͳ͵͸
endarterectomy specimens, P947 facilitated discrimination between histologically defined MMP-rich
ͳ͵͹
and MMP-poor plaques.
with
the
123
non-targeted
I- or
125
I-radiolabeled agent derived from a compound that binds
compound,
Gd-DOTA.
Moreover,
using
human
carotid
ͳ͵ͺ
Myeloperoxidase (MPO) is secreted by activated macrophages at multiple stages of plaque
ͳ͵ͻ
development and generates the oxidant species hydrochlorous acid (10, 29, 129, 177, 178) that
ͳͶͲ
modifies LDL, activates MMPs, induces endothelial cell apoptosis, inactivates nitric oxide, and triggers
ͷ
ͳͶͳ
tissue factor release. In vivo MR imaging of MPO has been achieved with the development of a
ͳͶʹ
gadolinium-based MO sensor bis-5HT-DTPA(Gd) [MPO(Gd)] in rabbit atherosclerotic plaques (Figure
ͳͶ͵
1) (144, 150).
ͳͶͶ
Cathepsins expressed by plaque macrophages, endothelial cells, and SMCs, can also
ͳͶͷ
degrade extracellular matrix proteins via their elastase and/or collagenase properties and promote
ͳͶ͸
plaque destabilization (180). In vivo imaging of cathepsin B was achieved with protease-activated
ͳͶ͹
NIRF probes (20, 130, 206). NIRF imaging, using this probe, and in combination with MRI showed
ͳͶͺ
that murine atherosclerotic lesions were fluorescently labeled 24h post injection and the signal
ͳͶͻ
colocalized with cathepsin B and macrophage immunopositive regions. Recently, a new 2D
ͳͷͲ
intravascular NIRF pullback catheter combined with a cysteine protease-activatable probe (ProSense)
ͳͷͳ
provided high-resolution in vivo mapping of arterial inflammation in coronary-sized arteries and
ͳͷʹ
revealed increased inflammation in atheromata and in stent-induced arterial injury (69).
ͳͷ͵
Lastly, cellular apoptosis is also a key feature of plaque progression and stability. Imaging of
ͳͷͶ
apoptosis is mainly based on targeting annexinA5 that binds to phosphatidylserine, a membrane
ͳͷͷ
phospholipid that becomes externalized on the extracellular leaflet of the cell membrane in apoptotic
ͳͷ͸
cells. Apoptosis has been visualized ex vivo with 99mTc-annexin injected in atherosclerotic rabbits (86).
ͳͷ͹
Quantitative annexin uptake was 9.3-fold higher in lesion versus non-lesion areas and the uptake
ͳͷͺ
paralleled lesion severity and macrophage burden. No correlation was observed with SMCs. In vivo
ͳͷͻ
detection of plaque instability using
ͳ͸Ͳ
atherosclerosis 6h post injection of the tracer (77). Higher tracer uptake correlated with
ͳ͸ͳ
histopathological features characteristic of unstable plaque, including substantial macrophage
ͳ͸ʹ
infiltration and intraplaque hemorrhage. Immunohistochemical analysis demonstrated specific binding
ͳ͸͵
of annexinA5 to macrophage cell membranes. Recently, MRI and fluorescence imaging of apoptosis
ͳ͸Ͷ
has been achieved using annexinA5-functionalized bimodal nanoparticles in murine atherosclerotic
ͳ͸ͷ
plaques (Figure 1) (196). In vivo T1-weighted (T1W) MRI of the abdominal aorta revealed enhanced
ͳ͸͸
uptake of the annexinA5-micelles as compared to control-micelles, which corroborated with ex vivo
ͳ͸͹
NIRF images of the excised aortas. Confocal laser scanning microscopy demonstrated that the
99m
Tc-annexinA5 was also shown in patients with carotid-artery
͸
ͳ͸ͺ
targeted agent was associated with macrophages and apoptotic cells, whereas the non-specific
ͳ͸ͻ
control agent showed no clear uptake by such cells.
ͳ͹Ͳ
ͳ͹ͳ
Neovascularization
ͳ͹ʹ
Neovascularization is also considered a vulnerability component as it can promote intraplaque
ͳ͹͵
haemorrhage and cholesterol deposition (113, 201). Dynamic contrast enhanced MRI using
ͳ͹Ͷ
extravascular non-specific gadolinium contrast agents e.g., Gd-DTPA (14, 75, 76) and intravascular
ͳ͹ͷ
agents (B-22956/1, gadofosveset) (26, 95, 97) was shown to correlate with plaque neovascularization.
ͳ͹͸
In addition to VCAM-1, described above, endothelial cells of neovessels express integrin Įvȕ3 (63).
ͳ͹͹
Imaging of plaque neovessels has been achieved with gadolinium-coated perfluorocarbon
ͳ͹ͺ
nanoparticles conjugated with an arginine-glycine-aspartic acid (RGD) peptidometic molecule. In vivo
ͳ͹ͻ
MRI experiments performed in cholesterol-fed rabbits with intimal hyperplasia, showed signal
ͳͺͲ
enhancement after administration of the Įvȕ3-targeting particles that colocalized with Įvȕ3 endothelial
ͳͺͳ
cells lining the vasa vasorum. The same particles have been used as vehicles for antiangiogenic drug
ͳͺʹ
delivery in rabbit aortas (211, 212). A low-molecular weight peptidomimetic of Arg-Gly-Asp (mimRGD)
ͳͺ͵
grafted to gadolinium diethylenetriaminepentaacetate (Gd-DTPA-g-mimRGD) has also been used to
ͳͺͶ
image neovascularization in ApoE-/- mice (Figure 1) (12). Additionally, Įvȕ3 imaging in cancer and MI
ͳͺͷ
was also feasible using ultrasound (36), PET (54), SPECT (106), NIRF (90), and MRI (161) agents.
ͳͺ͸
ͳͺ͹
Extracellular matrix and vascular remodeling
ͳͺͺ
The balance between the production and degradation of extracellular matrix proteins (collagen,
ͳͺͻ
elastin, proteoglycans) is essential for atheroma expansion and stability. Multi-contrast in vivo MRI
ͳͻͲ
has been used to evaluate the thickness and integrity of the fibrous cap in human carotid disease (53,
ͳͻͳ
109, 217). The recent development of a small molecular weight gadolinium based elastin-targeting
ͳͻʹ
contrast agent, enabled in vivo MR imaging of atherosclerosis progression in the brachiocephalic
ͳͻ͵
artery of ApoE-/- mice (Figure 1) (101) and visualization of vascular remodeling after stent-induced
ͳͻͶ
coronary injury in a swine model (202). Furthermore, CNA-35 functionalized nanoparticles have been
͹
ͳͻͷ
used to image aortic aneurysm progression (84) and atherosclerosis (31, 195). Ex vivo application of
ͳͻ͸
magnetization transfer (MT) was shown to discriminate the collagenous fibrous cap and the media
ͳͻ͹
from the lipid core and adventitia in human endarterectomy samples (Figure 1) (133, 142).
ͳͻͺ
The direction of vascular remodeling (expansive versus constrictive) and its association with
ͳͻͻ
plaque vulnerability has recently been explored. Traditionally, positive remodeling defined as the
ʹͲͲ
increase of the outer vessel wall area was considered advantageous as it prevents luminal obstruction
ʹͲͳ
(48). However, additional evidence showed that it is also associated with plaque vulnerability (137)
ʹͲʹ
and may lead to clinical sequelae including myocardial infarction (MI) and stroke. In vivo assessment
ʹͲ͵
of vascular remodeling in humans has been primarily achieved with intravascular ultrasound (IVUS)
ʹͲͶ
and CT [66-68]. Importantly, recent prospective studies using IVUS and/or CT have identified plaque
ʹͲͷ
burden and positive arterial remodelling as a good surrogate marker for high-risk plaques (15, 115,
ʹͲ͸
174). Non-invasive imaging of vascular remodeling by MRI has also been feasible in pre-clinical
ʹͲ͹
models of atherosclerosis (141, 173), patients with coronary (81, 107) and carotid artery disease (5,
ʹͲͺ
194).
ʹͲͻ
ʹͳͲ
Intraplaque hemorrhage and thrombus
ʹͳͳ
Intraplaque hemorrhage is a major contributor to plaque vulnerability, and mural thrombosis is the
ʹͳʹ
end-point of plaque rupture that may initiate myocardial injury due to acute vessel occlusion. Non-
ʹͳ͵
contrast enhanced MR imaging of red-blood cell rich thrombus or hemorrhage relies on the changes
ʹͳͶ
of T1 and T2 relaxation times of different oxygenation states of hemoglobin in erythrocytes. This
ʹͳͷ
approach has been used to visualize and estimate the age of hematoma (24, 49), venous thrombosis
ʹͳ͸
(112, 145), intraplaque hemorrhage (111), arterial thrombus (27, 200), and intracoronary thrombus
ʹͳ͹
(Figure 1) (71). Detection of thrombus size and protein content has also been achieved by
ʹͳͺ
magnetization transfer and diffusion weighted MRI applied ex vivo and in vivo (80, 140, 199, 200).
ʹͳͻ
Moreover, the development of targeted contrast agents for fibrin (Figure 1) (8, 9, 38, 72, 162, 168-
ʹʹͲ
171, 175, 210), platelets (72, 85, 155), and Į2-Įntiplasmin (108) significantly improved the detection
ʹʹͳ
and age-characterization of thrombus. Activated platelets have additionally been targeted via their
ͺ
ʹʹʹ
gpIIb/IIIa receptor for non-invasive molecular imaging of intravascular thrombosis (4, 203, 204). These
ʹʹ͵
contrasts agents should ideally help to better visualize thrombus, and also differentiate between acute
ʹʹͶ
and chronic thrombus, and therefore guide further medical interventions.
ʹʹͷ
ʹʹ͸
PART B: Imaging of Myocardial Infarction
ʹʹ͹
Acute myocardial infarction (AMI) is still one of the main causes of morbidity in Western countries
ʹʹͺ
(208). Myocardial ischemia progresses with the duration of coronary occlusion, and the delay in time
ʹʹͻ
to reperfusion determines the extent of irreversible necrosis extending from the sub-endocardial
ʹ͵Ͳ
layers towards the epicardium. MRI is an extremely powerful modality for the assessment of function,
ʹ͵ͳ
perfusion, and tissue characterization in AMI in a single examination. In particular, it can detect the
ʹ͵ʹ
location and extent of necrosis (147), infarct size, myocardial edema (myocardium at risk),
ʹ͵͵
microvascular obstruction leading to intramyocardial hemorrhage (44), and assess ventricular
ʹ͵Ͷ
volumes and function for the evaluation of post-infarction remodeling (51). In this section we will focus
ʹ͵ͷ
on the use of MRI in the detection of the area at risk, infarct size, and salvaged myocardium.
ʹ͵͸
ʹ͵͹
Detection of myocardial ischemia (area at risk, infarct size, salvaged myocardium)
ʹ͵ͺ
The area at risk is defined as the myocardial area related to an occluded coronary artery with
ʹ͵ͻ
complete absence of blood flow whereas the infarct size represents the sub-region within the area at
ʹͶͲ
risk that undergoes irreversible damage and progresses to complete tissue necrosis. Subsequently,
ʹͶͳ
the salvaged myocardium corresponds to the region of the area at risk that experiences reversible
ʹͶʹ
damage. Studies have shown that the duration of ischemia is the major factor determining the fraction
ʹͶ͵
of the area at risk that progresses to become irreversibly damaged infarcted region (147, 148).
ʹͶͶ
Traditionally, the myocardium at risk has been measured by SPECT, using the injection of a
ʹͶͷ
technetium-based tracer (160), and by contrast echocardiography (68). Over the last years, both
ʹͶ͸
preclinical and clinical studies have shown that T2W MRI sequences, which are sensitive to the
ʹͶ͹
concentration of water-bound protons can be used to visualize and quantify the area at risk. The high
ʹͶͺ
signal intensity on the T2W images is indicative of higher tissue water content and may reflect
ͻ
ʹͶͻ
myocardial inflammation and tissue edema (Figure 2) (42). In an early experimental study in dogs the
ʹͷͲ
mean T2 relaxation time for one-day old infarcted regions was significantly higher from that of the
ʹͷͳ
remote myocardium. Concomitantly, the percent water content of the infarcted area was significantly
ʹͷʹ
greater than that of normal regions. Such changes resulted in a linear correlation between the T2
ʹͷ͵
relaxation time and percent water content (59). Later studies in animal models verified the correlation
ʹͷͶ
of the area at risk measured by T2W MRI images with corresponding histological sections in swine
ʹͷͷ
(46) and canine (2) models of MI. The latter study also demonstrated that the T2 hyperintense area
ʹͷ͸
more closely resembled the hypokinetic zone identified on displacement encoding with stimulated
ʹͷ͹
echoes (DENSE) systolic strain maps. Interestingly, some of these hypokinetic areas showed a partial
ʹͷͺ
recovery of function on follow up studies of chronic MI. Moreover, quantitative T2 mapping reliably
ʹͷͻ
identified myocardial edema without the limitations encountered by T2W short tau inversion recovery
ʹ͸Ͳ
imaging (T2-STIR), and may therefore be clinically more robust in showing acute ischemic injury
ʹ͸ͳ
(198).
ʹ͸ʹ
For diagnostic purposes it is essential to accurately identify not only the area at risk but also
ʹ͸͵
the actual infarct size and salvaged myocardium in order to differentiate between irreversible (infarct)
ʹ͸Ͷ
and reversible (edema, ischemia) areas of myocardial damage. Longer durations of ischemia
ʹ͸ͷ
generally produce more transmural infarcts as opposed to infarcts with increasing circumferential
ʹ͸͸
extent. Thus, the transmural extent of the infarction is inversely related to the extent of salvaged
ʹ͸͹
myocardium. The extent of the salvaged area at risk contains prognostic information and may serve
ʹ͸ͺ
as a therapeutic target. A better differentiation between the areas of reversible and irreversible
ʹ͸ͻ
damage can be achieved using delayed enhancement imaging with non-specific gadolinium contrast
ʹ͹Ͳ
agents (e.g., Gd-DTPA). Contrast-enhanced images can be acquired early or late after contrast
ʹ͹ͳ
administration.
ʹ͹ʹ
ʹ͹͵
Early gadolinium enhancement (EGE) for measuring area at risk
ʹ͹Ͷ
The hyperenhanced region on EGE, taken about 2 minutes after contrast administration, was shown
ʹ͹ͷ
to correlate with the area at risk derived from T2W images in patients with successfully reperfused
ͳͲ
ʹ͹͸
AMI who underwent an MRI examination within 4 days after the event (102). The hyperenhanced
ʹ͹͹
region on EGE extended transmurally and was consistently larger than that on late gadolinium
ʹ͹ͺ
enhancement MRI. The relative peri-infarct zone was calculated as the difference in hyperenhanced
ʹ͹ͻ
regions between EGE and LGE, and normalized to the individual infarct size. The relative peri-infarct
ʹͺͲ
zone was inversely correlated with the transmurality of infarction and the time from symptom to
ʹͺͳ
reperfusion. Furthermore, a pre-clinical study in rats (132) showed that the enhanced region
ʹͺʹ
overestimated infarct size immediately after the injection of Gd-DTPA (5-7 minutes), although 40
ʹͺ͵
minutes post injection the area of enhancement decreased and matched the infarct size.
ʹͺͶ
ʹͺͷ
Late gadolinium enhancement (LGE) for measuring infarct size and salvaged myocardium
ʹͺ͸
Preclinical studies in dogs demonstrated that LGE distinguishes between reversible and irreversible
ʹͺ͹
ischemic injury independent of wall motion and infarct age (37, 78). Non-viable infarcted tissue is
ʹͺͺ
usually seen as an area of “hyperenhancement” after contrast injection. This work was further
ʹͺͻ
validated when higher gadolinium concentrations were measured in the infarcted area by regional
ʹͻͲ
electrolyte concentrations using electron probe x-ray microanalysis (146). Contrast uptake in acute MI
ʹͻͳ
occurs because of the expansion of the extracellular space due to edema and inflammation, and
ʹͻʹ
cellular breakdown that allow the contrast agent to enter the intracellular space. The clinical value of
ʹͻ͵
LGE is that: (i) the transmural extent of the infarct on day 3 was shown to be a better predictor of
ʹͻͶ
improvement in contractile function than the actual occlusion time in animal models (61), and (ii) the
ʹͻͷ
transmurality of the infarct was also shown to predict myocardial viability and recovery of contractile
ʹͻ͸
function after revascularization in humans (Figure 2) (22, 79, 157).
ʹͻ͹
Finally, a combination of T2W, LGE, and perfusion MRI imaging has been used. A pig model
ʹͻͺ
of reperfused MI showed that first pass perfusion MRI most accurately reflected the infarct area, and
ʹͻͻ
that the high signal intensity on T2W images reflects both irreversibly and reversibly injured, but
͵ͲͲ
essentially viable, peri-infarct zone (23). An imaging approach combining LGE and T2W MRI in
͵Ͳͳ
patients with acute MI and successful reperfusion 3 +/- 3 days after the event showed that the high
͵Ͳʹ
signal intensity on T2W MRI reflected reversible myocardial damage and LGE reflected irreversibly
ͳͳ
͵Ͳ͵
injured myocardium (42). Combination of T2W MRI and LGE was also used to accurately differentiate
͵ͲͶ
acute from chronic MI (1). Although chronic infarcts are relatively acellular they also enhance with
͵Ͳͷ
gadolinium agents because of increased extracellular space due to fibrosis and decrease in the
͵Ͳ͸
washout kinetics of the contrast agent due to the collagenous nature of the remodeled myocardium.
͵Ͳ͹
͵Ͳͺ
MRI versus SPECT imaging of myocardial infarction
͵Ͳͻ
The main advantage of MRI LGE is its spatial resolution of 1–2 mm (in plane) contrary to about 10
͵ͳͲ
mm with SPECT scans (205). The superior spatial resolution makes LGE MRI more suitable for the
͵ͳͳ
detection of sub-endocardial infarcts when perfusion by SPECT appears unaltered or when the
͵ͳʹ
infarcts themselves were undetected by SPECT (67, 82, 205). Furthermore, comparisons between
͵ͳ͵
P7F WHWURIRVPLQ perfusion
͵ͳͶ
patients with ST-segment elevation myocardial infarction provided the most direct validation that T2
͵ͳͷ
abnormalities represent the area at risk (18).
SPECT imaging and T2W short tau inversion recovery (T2-STIR) MRI in
͵ͳ͸
͵ͳ͹
MRI versus PET imaging of myocardial infarction
͵ͳͺ
The main advantage of MRI LGE is its spatial resolution of 1-2 mm (in plane) contrary to about 2-4
͵ͳͻ
mm with PET scans. Similarly to SPECT, PET images are also less sensitive in identifying sub-
͵ʹͲ
endocardial infarcts compared to LGE MRI (83, 89).
͵ʹͳ
͵ʹʹ
Targeted molecular imaging of myocardial infarction
͵ʹ͵
Although anatomic, functional, perfusion, and infarct size imaging has been validated and the
͵ʹͶ
prognostic value of these measurements is widely accepted, the application of molecular imaging
͵ʹͷ
using targeted contrast agents may enable the identification of pathologically altered biological
͵ʹ͸
processes that would allow early intervention before the disease progresses to the symptomatic
͵ʹ͹
stage. In the next section we will focus on the biological processes involved in myocardial infarction
͵ʹͺ
and post infarct remodeling and discuss the availability of molecular targets allowing their
ͳʹ
͵ʹͻ
visualization. Representative imaging examples of these biological processes are summarized in
͵͵Ͳ
Figure 2.
͵͵ͳ
͵͵ʹ
Apoptosis and necrosis in MI
͵͵͵
Hours after the onset of ischemia, cardiomyocyte death occurs via two distinct pathways; apoptosis
͵͵Ͷ
and necrosis. Although LGE MRI, described above, provides an accurate measure of infarct size, it
͵͵ͷ
does not differentiate between these biological processes. It is evident that cells that show early
͵͵͸
features of an apoptotic program may have the potential to be salvaged if they could be detected
͵͵͹
early. Similarly to atherosclerosis, imaging of apoptosis in MI is mainly based on targeting either
͵͵ͺ
annexinA5 or exposed DNA fragments. Imaging of annexinA5 and/or differentiation of apoptosis from
͵͵ͻ
necrosis has been achieved with 99Tc-SPECT (40, 62, 153) fluorescence imaging (34), and MRI (165,
͵ͶͲ
166). The spatial and temporal presence of macrophages in the infarcted region has been imaged
͵Ͷͳ
with different modalities. Magnetofluorescent cross-linked iron-oxide nanoparticles (CLIO-Cy5.5)
͵Ͷʹ
injected intravenously two days after experimental MI were detected two days later in the infarcted
͵Ͷ͵
region of the heart using T2*W MRI (Figure 2) (165). Recently, a DNA-binding Gd chelate for the
͵ͶͶ
detection of cell death by MRI has also been developed (45).
͵Ͷͷ
͵Ͷ͸
Inflammation and wound healing in MI
͵Ͷ͹
Activation of the vascular endothelium is crucial for leucocyte recruitment. PET/CT imaging of
͵Ͷͺ
vascular adhesion molecule-1 (VCAM-1) expressed on endothelial cells has been achieved using a
͵Ͷͻ
tetrameric peptide
͵ͷͲ
PET image, delayed hyperenhancement after iodine injection in the CT image, and a high signal on
͵ͷͳ
autoradiography. Monocytes recruited to the injured myocardium (tissue monocytes/macrophages)
͵ͷʹ
from the spleen and bone marrow reservoirs play a central role in infarct healing (123). In a mouse
͵ͷ͵
model of MI, it has been shown that the recruitment involves a biphasic process in which Ly6-Chigh
͵ͷͶ
monocytes dominate the first 4 days after the event to remove cellular debris whereas Ly6-Clow
F-4V (Figure 2) (122). 7KH infarcted myocardium showed a strong signal in the
18
ͳ͵
͵ͷͷ
appear between days 5-10 days to promote tissue repair and resolution of inflammation (126).
͵ͷ͸
Insufficient or excessive recruitment of monocytes into the infarcted area has been shown to impair
͵ͷ͹
wound healing in preclinical (135) and clinical studies (192).
͵ͷͺ
dependent infiltration of injected biochemically inert nanoemulsions of perfluorocarbons (PFCs) into
͵ͷͻ
the border zone of infarcted areas in murine injury models, and histology demonstrated a co-
͵͸Ͳ
localization of PFCs with cells of the monocyte/macrophage system (Figure 2) (39). Myocardial
͵͸ͳ
inflammation was also visualized with
͵͸ʹ
signal showed significantly increased uptake in the infarcts of mice on day 5 after coronary ligation
͵͸͵
(standardized uptake value 2.7 r 0.1) when compared with myocardium in control mice (1.3 r 0.2; p
͵͸Ͷ
< 0.01). On day 14, the
͵͸ͷ
Interestingly, there were differences between the activity in non-infarcted remote myocardium on day
͵͸͸
5 after MI and control hearts (percent injected dose/gram of tissue, remote 8.9 r 0.5; control 5.1 r
͵͸͹
1.0; p < 0.05). The MRI component of hybrid datasets enabled the precise definition of the infarct area
͵͸ͺ
and analysis of anatomic and functional parameters (93). In addition to imaging resident macrophages
͵͸ͻ
using iron-particels by T2*W MRI (Figure 2), other studies showed the feasibility of tracking the
͵͹Ͳ
distribution of iron-labeled macrophages by injecting the contrast agent prior to MI and then imaging
͵͹ͳ
the animals post-MI (110, 216). These studies demonstrated that pre-loaded macrophages infiltrate in
͵͹ʹ
the infarcted myocardium up to day 4 post-MI, consistent with histological studies validating the
͵͹͵
presence of CD68 macrophages. However, MPIOs showed persistent localization in the infarct even
͵͹Ͷ
14 days post-MI whereas histological studies showed a progressive decrease of macrophage content
͵͹ͷ
4 days post-MI (215). A combination of fluorescence molecular tomography (FMT-CT) and physiologic
͵͹͸
MRI imaging was used to specifically image Ly6-Chigh monocytes and their role in infarct healing
͵͹͹
(135).
18
18
FDG-PET
18
FDG signal approached control values (MI 1.6 r 0.1; remote 1.4 r 0.1).
Enzymatic activity in MI
H/(19)F MRI at 9.4 T revealed a time-
FDG-PET (Figure 2) (6, 93). The time course of
͵͹ͺ
͵͹ͻ
(1)
ͳͶ
͵ͺͲ
Monocytes/macrophages are active cells secreting a variety of enzymes and cytokines.
͵ͺͳ
Myeloperoxidase (MPO) is an inflammatory enzyme abundantly expressed in neutrophils that induces
͵ͺʹ
production of hypochlorous acid (HOCl) which is cytotoxic. MPO is released post-MI (126) and
͵ͺ͵
although it does not significantly affect tissue necrosis it has a profound adverse effect on LV
͵ͺͶ
remodeling and function (197). MPO in MI has been imaged using an activable MPO-Gd contrast
͵ͺͷ
agent (Figure 2) (21, 124) that is first radicalized by MPO and then either spontaneously oligomerizes
͵ͺ͸
or binds to matrix proteins, all leading to enhanced r1 relaxivity and delayed washout kinetics. In a
͵ͺ͹
serial imaging study, MPO activity in the myocardium peaked 2 days after coronary ligation in mice.
͵ͺͺ
Finally, a fluorogenic sensor for monitoring peroxynitrite (ONOO(-)) and myeloperoxidase-mediated
͵ͺͻ
hypochlorous acid (HOCl/OCl(-)) production has been developed and utilized for ex vivo imaging of
͵ͻͲ
reactive oxygen/nitrogen species in myocardial ischemia (134). Another enzyme family actively
͵ͻͳ
involved in myocardial healing is matrix metalloproteinases that are capable of degrading all types of
͵ͻʹ
extracellular matrix proteins. In myocardial ischemia increased MMP activity may lead to infarct
͵ͻ͵
expansion that contributes to ventricular rupture and dilation. Imaging of MMPs and cathepsin activity
͵ͻͶ
(ProSense) has been achieved with SPECT using a
͵ͻͷ
and fluorescent modalities (Figure 2) (19, 93, 125).
99m
Tc-labeled radiotracer (99mTc-RP805) (176)
͵ͻ͸
͵ͻ͹
Neovascularization in MI
͵ͻͺ
Angiogenesis occurs naturally after MI to restore perfusion with oxygen and nutrients to the ischemic
͵ͻͻ
myocardium. Several imaging modalities have been developed to image angiogenesis mainly by
ͶͲͲ
targeting the Įvȕ3 integrin, expressed on the cell surface of proliferating endothelial cells and the
ͶͲͳ
vascular endothelial growth factor (VEGF). Serial in vivo dual-isotope SPECT imaging with an
ͶͲʹ
labeled Įvȕ3-targeted agent demonstrated focal radiotracer uptake in hypoperfused regions of canine
ͶͲ͵
myocardium where angiogenesis was stimulated. There was a 4-fold increase in myocardial
ͶͲͶ
radiotracer uptake in the infarcted region associated with histological evidence of angiogenesis and
ͶͲͷ
increased expression of the Įvȕ3 integrin (106). A novel compound called Regioselectivity
ͶͲ͸
Addressable Functionalized Template-RGD (RAFT-RGD) is composed of four cyclo(RGDfK)
ͳͷ
111
In-
ͶͲ͹
sequences tethered on a cyclodecapeptide that specifically binds to the Įvȕ3 integrin and is co-
ͶͲͺ
internalized with the receptor, suggesting increased affinity of the peptide scaffold for the Įvȕ3 integrin.
ͶͲͻ
Tthe infarcted area was readily visible in vivo in a rat model of reperfused MI by SPECT with the
ͶͳͲ
99m
Ͷͳͳ
Moreover, a PET (18F-Galakto-RGD) agent, carrying the cyclic Arg-Gly-Asp (cRGD) peptidic
Ͷͳʹ
sequence that specifically binds to the Įvȕ3-targeting agent was used to assess the time course of
Ͷͳ͵
post-MI angiogenesis in rats (60). In this model, focal accumulation in the infarcted area started at
ͶͳͶ
day 3, peaked between 1 and 3 weeks, and decreased to baseline at 6 months after reperfusion (60).
Ͷͳͷ
The feasibility for translating the preclinical work in the clinical setting was demonstrated when the
Ͷͳ͸
same agent was later used in a patient two weeks after MI and PCI (99). Another PET tracer (64Cu-
Ͷͳ͹
DOTA-VEGF121) showed minimal baseline myocardial uptake that increased significantly at day 3
Ͷͳͺ
after MI and remained elevated for 2 weeks post-MI, after which it returned to baseline levels (Figure
Ͷͳͻ
2) (149). Finally, cyclic Asn-Gly-Arg (cNGR)–labeled paramagnetic quantum dots (pQDs) have been
ͶʹͲ
developed for MRI imaging of angiogenesis (131). The tripeptide cNGR homes specifically to CD13,
Ͷʹͳ
an aminopeptidase that is strongly upregulated during myocardial angiogenesis. Injection of cNGR-
Ͷʹʹ
pQDs resulted in a strong negative contrast that was located mainly in the infarcted myocardium of
Ͷʹ͵
mice 7 days after surgery and up to 2 hours after intravenous contrast agent administration. This
ͶʹͶ
negative contrast was significantly less in MI mice injected with unlabeled pQDs and in sham-
Ͷʹͷ
operated mice injected with cNGR-pQDs. Validation with ex vivo 2-photon laser scanning microscopy
Ͷʹ͸
revealed a strong colocalization of cNGR-pQDs with vascular endothelial cells.
Tc-RAFT-RGD compound but not with the negative control
99m
Tc-RAFT-RAD (Figure 2) (32).
Ͷʹ͹
Ͷʹͺ
Extracellular matrix in MI
Ͷʹͻ
The extracellular matrix plays a fundamental and increasingly more appreciated role in acute MI and
Ͷ͵Ͳ
infarct healing (33). During the inflammatory phase (rodents: 1h-48h, larger animals: 1h-4d), cytokines
Ͷ͵ͳ
and adhesion molecules become upregulated leading to leukocyte recruitment to the infarct zone.
Ͷ͵ʹ
Simultaneously, protease activation increases resulting in degradation of matrix proteins and
Ͷ͵͵
generation of low molecular weight fragments that exert potent pro-inflammatory effects. Later on, as
ͳ͸
Ͷ͵Ͷ
the acute inflammatory response subsides, mesenchymal cells infiltrate the infarct marking the
Ͷ͵ͷ
transition to the proliferative phase (rodents: 48h-5d, larger animals: 4d-14d) when myofibroblasts
Ͷ͵͸
secret extracellular matrix and angiogenesis occurs. During the maturation phase (rodents: 5d-28d,
Ͷ͵͹
larger animals: 14d-2months) the cellularity of the infarct decreases and lysyl-oxidase becomes
Ͷ͵ͺ
upregulated inducing matrix cross-linking and formation of a dense collagen-based scar. Formation of
Ͷ͵ͻ
a stable cross-linked extracellular matrix may shield the myofibroblasts from mechanical tension
ͶͶͲ
promoting quiescence. Conversely, overabundant collagen is also harmful because it hinders diastolic
ͶͶͳ
function and predisposes to arrhythmia. A type I collagen-specific peptide was identified using phage
ͶͶʹ
display and subsequently modified to improve affinity for collagen (17). The peptide conjugated to
ͶͶ͵
gadolinium (EP-3533) enabled in vivo molecular MR imaging of fibrosis in a murine model of healed
ͶͶͶ
post infarction myocardial scarring (Figure 2) (56) and perfusion in a swine model (172). In the murine
ͶͶͷ
MI model, dynamic T1W MRI revealed that the washout time for EP-3533 was significantly longer
ͶͶ͸
(195 minutes) than those for Gd-DTPA (25 minutes) in regions of scarring. The area of enhancement
ͶͶ͹
correlated with the histological presence of collagen. The gadolinium concentration in scar was
ͶͶͺ
twofold higher compared to that of remote myocardium fifty minutes after EP-3533 injection. Another
ͶͶͻ
collagen specific peptide (collagelin) has been identified and used for SPECT imaging in a rat model
ͶͷͲ
of healed MI. Scintigraphic imaging following injection of
Ͷͷͳ
of the probe occurred in rats with MI, but not in controls (118).
99m
Tc-labelled-collagelin showed that uptake
Ͷͷʹ
Newly synthesized collagen fibers in the ischemic myocardium become cross-linked into
Ͷͷ͵
interconnected matrix. In addition to lysyl-oxidase, tissue and plasma transglutaminate (FXIII) are
ͶͷͶ
involved in this process (120). The in vivo enzyme activity of FXIII within the infarct was assessed
Ͷͷͷ
using an
Ͷͷ͸
the probe as a substrate and cross-links it to extracellular matrix proteins, leading to local entrapment
Ͷͷ͹
of
Ͷͷͺ
was associated with increased left ventricular dilation post-MI. Conversely, FXIII-treated mice showed
Ͷͷͻ
increased FXII activity and a faster resolution of the neutrophil response, enhanced macrophage
Ͷ͸Ͳ
recruitment, increased collagen content and augmented angiogenesis in the healing infarct. Finally,
111
111
Indium-labelled affinity peptide (111In-DOTA-FXIII) (Figure 2) (119, 193). FXIII recognizes
In-DOTA-FXIII in the healing infarct. Decreased FXIII SPECT signal enhancement in the infarct
ͳ͹
Ͷ͸ͳ
an MRI elastin-specific contrast agent showed increased deposition of elastin 7 days post-MI and
Ͷ͸ʹ
enabled visualization of myocardial remodeling in a mouse model of coronary ligation (209). The CNR
Ͷ͸͵
peaked at 45 minutes post injection and it was significantly higher than for Gd-DTPA at 30 minutes.
Ͷ͸Ͷ
Changes in myocardial microstructure are important components of the tissue response to
Ͷ͸ͷ
infarction but are difficult to resolve with current imaging techniques. A novel technique, diffusion
Ͷ͸͸
spectrum MRI tractography (DSI tractography), has been shown to resolve 3D myofiber architecture.
Ͷ͸͹
Meshlike networks of orthogonal myofibers in infarcted myocardium may resist mechanical
Ͷ͸ͺ
remodeling but also probably increase the risk for lethal reentrant arrhythmias (167).
Ͷ͸ͻ
Ͷ͹Ͳ
Outlook
Ͷ͹ͳ
Extensive progress in the field of molecular imaging of atherosclerosis and myocardial infarction has
Ͷ͹ʹ
enabled the in vivo detection of several biological processes involved in disease progression and
Ͷ͹͵
resolution, and monitoring of interventions both in the preclinical and clinical setting using MRI and
Ͷ͹Ͷ
other imaging modalities. Developments of novel imaging agents with improved signal detection
Ͷ͹ͷ
properties, sensitivity, specificity, and favourable pharmacokinetics together with improvements in
Ͷ͹͸
MRI acquisition and image processing protocols have elucidated disease biology and therapeutic
Ͷ͹͹
mechanisms and shed more light on the longitudinal processes of atherosclerotic plaque progression
Ͷ͹ͺ
and instability, myocardial infarct healing, regeneration and repair. Translation of these new imaging
Ͷ͹ͻ
methods in the clinical arena is a very challenging aspect of molecular imaging, as it requires clinical
ͶͺͲ
trials with histological and clinical end-points that demonstrate utility of the complimentary information
Ͷͺͳ
to that already clinically available. However, if successful, it may revolutionize medicine as it may
Ͷͺʹ
allow more accurate disease assessment and personalized care in patients with atherosclerosis or
Ͷͺ͵
after myocardial infarction.
ͶͺͶ
Ͷͺͷ
Ͷͺ͸
Ͷͺ͹
ͳͺ
Ͷͺͺ
Ͷͺͻ
Figure Legends
ͶͻͲ
Figure 1: Examples of available imaging modalities and targets for atherosclerosis.
Ͷͻͳ
Endothelium, Molecular MRI imaging of increased endothelial permeability in the brachiocephalic
Ͷͻʹ
artery of atherosclerotic ApoE-/- mice using gadofosveset and complementary Evan’s blue staining
Ͷͻ͵
(139). MRI detection of endothelial adhesion molecules (VCAM-1 and P-selectin) in the aortic root of
ͶͻͶ
ApoE-/- mice using dual-targeted microparticles of iron oxide (MPIO)(103). Inflammation
Ͷͻͷ
(macrophages), MRI of macrophage content in the brachiocephalic artery of ApoE-/- mice after
Ͷͻ͸
administration of very small iron oxide particles (VSOP) using susceptibility gradient mapping (100).
Ͷͻ͹
MRI of macrophages in the abdominal aorta of ApoE-/- mice using immunomicelles targeting the
Ͷͻͺ
macrophage scavenger receptor (3). Copyright (2007) National Academy of Sciences, U.S.A. Lipids,
Ͷͻͻ
MRI of plaque lipid using recombinant LDL-like gadolinium-based nanoparticles in the thoracic aorta
ͷͲͲ
of ApoE-/- mice (213) - Reproduced by permission of The Royal Society of Chemistry. MRI of plaque
ͷͲͳ
lipid using recombinant HDL-like gadolinium-based nanoparticles in the abdominal aorta of ApoE-/-
ͷͲʹ
mice (41). Ex vivo MRI detection of lipids in human endarterectomy plaque using diffusion-weighted
ͷͲ͵
imaging (DWI) (143). Enzymes, MRI of myeloperoxidase activity in atherosclerotic plaque of
ͷͲͶ
cholesterol-fed rabbits using an enzyme-sensitive gadolinium-based contrast agent [bis-5HT-
ͷͲͷ
DTPA(Gd) [MPO(Gd)] (150). Apoptosis, MRI of apoptosis in the abdominal plaque of ApoE-/- mice
ͷͲ͸
using
ͷͲ͹
angiogenesis in ApoE-/- mice using a low-molecular weight peptidomimetic of Arg-Gly-Asp (mimRGD)
ͷͲͺ
grafted to gadolinium diethylenetriaminepentaacetate (Gd-DTPA-g-mimRGD) (12). Extracellular
ͷͲͻ
matrix (elastin), MRI of intraplaque elastin in the brachiocephalic artery of ApoE-/- mice using a low-
ͷͳͲ
molecular weight gadolinium-based contrast agent (101). Extracellular matrix (collagen), Ex vivo
ͷͳͳ
MRI detection of collagen-rich fibrous cap in human endarterectomy plaques using magnetization
ͷͳʹ
transfer (142). Thrombus, MRI direct thrombus imaging (MRDTI) due to the T1 shortening effect of
ͷͳ͵
methemoglobin (71). MRI of thrombus associated with plaque rupture in a rabbit model using a fibrin-
annexinA5-functionalized
bimodal
nanoparticles
ͳͻ
(196).
Neovascularization,
MRI
of
ͷͳͶ
binding gadolinium-labeled peptide (EP-1873) (9). All images were reprinted and/or adopted with
ͷͳͷ
permission.
ͷͳ͸
ͷͳ͹
Figure 2: Examples of available imaging modalities and targets for myocardial infarction
ͷͳͺ
Edema, MRI detection of edema using T2W images in a subject 3 days after reperfused MI (42).
ͷͳͻ
Necrosis, Gadolinium-contrast enhanced MRI using Gd-DTPA detects irreversible myocardial
ͷʹͲ
ischemic injury due to increased extracellular space (79). Apoptosis, MRI detection of myocyte
ͷʹͳ
apoptosis using T2*W MRI after injection of annexin-based iron loaded nanoparticles (165).
ͷʹʹ
Inflammation (VCAM-1), PET/CT imaging of vascular adhesion molecule-1 (VCAM-1) expressed on
ͷʹ͵
endothelial cells using the tetrameric peptide 18F-4V (122).Inflammation (Macrophages), 1H/19F-MRI
ͷʹͶ
detection of macrophages in cardiac ischemia after injection of perfluorocarbon nanoemulsions. Photo
ͷʹͷ
courtesy of Dr. Flogel.
ͷʹ͸
myocardium 7days post-MI (6). MRI detection of macrophage infiltration in infarcted myocardium
ͷʹ͹
using T2*W MRI after injection of very small very small iron oxide particles (VSOP). Photo courtesy of
ͷʹͺ
Dr. Protti. Enzymatic activity (MPO), MRI of MPO activity 2 days after MI in mice (124). Enzymatic
ͷʹͻ
activity (MMP), Fluorescence reflectance image shows higher matrix metalloproteinase sensor
ͷ͵Ͳ
activation in MI (red color) compared to the remote (yellow box) 6 days after the surgery (93).
ͷ͵ͳ
Neovascularization, SPECT imaging of myocardial angiogenesis in rats using the Įvȕ3 integrin-
ͷ͵ʹ
targeted tracer
ͷ͵͵
using a
ͷ͵Ͷ
inversion recovery MRI detection of myocardial scarring in mice using a gadolinium-based collagen-
ͷ͵ͷ
binding contrast agent (EP-3533) (56). Extracellular matrix (transglutaminase), SPECT imaging of
ͷ͵͸
transglutaminase activity using an
ͷ͵͹
images were reprinted and/or adopted with permission.
18
FDG-PET detection of metabolically active macrophages in the murine
99m
Tc-RAFT-RGD (32). PET imaging of the VEGF receptor in rat myocardial infarct
64
Cu-DOTA-VEGF121 tracer (149). Extracellular matrix (collagen), Delayed enhancement
111
Indium labeled affinity peptide (111In-DOTA-FXIII) (119). All
ͷ͵ͺ
ʹͲ
ͷ͵ͻ
References
ͷͶͲ
ͷͶͳ
ͷͶʹ
ͷͶ͵
ͷͶͶ
ͷͶͷ
ͷͶ͸
ͷͶ͹
ͷͶͺ
ͷͶͻ
ͷͷͲ
ͷͷͳ
ͷͷʹ
ͷͷ͵
ͷͷͶ
ͷͷͷ
ͷͷ͸
ͷͷ͹
ͷͷͺ
ͷͷͻ
ͷ͸Ͳ
ͷ͸ͳ
ͷ͸ʹ
ͷ͸͵
ͷ͸Ͷ
ͷ͸ͷ
ͷ͸͸
ͷ͸͹
ͷ͸ͺ
ͷ͸ͻ
ͷ͹Ͳ
ͷ͹ͳ
ͷ͹ʹ
ͷ͹͵
ͷ͹Ͷ
ͷ͹ͷ
ͷ͹͸
ͷ͹͹
ͷ͹ͺ
ͷ͹ͻ
ͷͺͲ
ͷͺͳ
ͷͺʹ
ͷͺ͵
ͷͺͶ
ͷͺͷ
ͷͺ͸
ͷͺ͹
ͷͺͺ
ͷͺͻ
ͷͻͲ
ͷͻͳ
ͷͻʹ
ͷͻ͵
ͷͻͶ
1.
Abdel-Aty H, Zagrosek A, Schulz-Menger J, Taylor AJ, Messroghli D, Kumar A, Gross M, Dietz R,
and Friedrich MG. Delayed enhancement and T2-weighted cardiovascular magnetic resonance imaging
differentiate acute from chronic myocardial infarction. Circulation 109: 2411-2416, 2004.
2.
Aletras AH, Tilak GS, Natanzon A, Hsu LY, Gonzalez FM, Hoyt RF, Jr., and Arai AE. Retrospective
determination of the area at risk for reperfused acute myocardial infarction with T2-weighted cardiac magnetic
resonance imaging: histopathological and displacement encoding with stimulated echoes (DENSE) functional
validations. Circulation 113: 1865-1870, 2006.
3.
Amirbekian V, Lipinski MJ, Briley-Saebo KC, Amirbekian S, Aguinaldo JG, Weinreb DB, Vucic E,
Frias JC, Hyafil F, Mani V, Fisher EA, and Fayad ZA. Detecting and assessing macrophages in vivo to
evaluate atherosclerosis noninvasively using molecular MRI. Proc Natl Acad Sci U S A 104: 961-966, 2007.
4.
Andrews RK and Berndt MC. Platelet adhesion: a game of catch and release. J Clin Invest 118: 30093011, 2008.
5.
Astor BC, Sharrett AR, Coresh J, Chambless LE, and Wasserman BA. Remodeling of carotid
arteries detected with MR imaging: atherosclerosis risk in communities carotid MRI study. Radiology 256: 879886, 2010.
6.
Berr SS, Xu Y, Roy RJ, Kundu B, Williams MB, and French BA. Images in cardiovascular medicine.
Serial multimodality assessment of myocardial infarction in mice using magnetic resonance imaging and micropositron emission tomography provides complementary information on the progression of scar formation.
Circulation 115: e428-429, 2007.
7.
Bonthu S, Heistad DD, Chappell DA, Lamping KG, and Faraci FM. Atherosclerosis, vascular
remodeling, and impairment of endothelium-dependent relaxation in genetically altered hyperlipidemic mice.
Arteriosclerosis, Thrombosis, and Vascular Biology 17: 2333-2340, 1997.
8.
Botnar RM, Buecker A, Wiethoff AJ, Parsons EC, Jr., Katoh M, Katsimaglis G, Weisskoff RM,
Lauffer RB, Graham PB, Gunther RW, Manning WJ, and Spuentrup E. In vivo magnetic resonance imaging
of coronary thrombosis using a fibrin-binding molecular magnetic resonance contrast agent. Circulation 110:
1463-1466, 2004.
9.
Botnar RM, Perez AS, Witte S, Wiethoff AJ, Laredo J, Hamilton J, Quist W, Parsons EC, Jr.,
Vaidya A, Kolodziej A, Barrett JA, Graham PB, Weisskoff RM, Manning WJ, and Johnstone MT. In vivo
molecular imaging of acute and subacute thrombosis using a fibrin-binding magnetic resonance imaging
contrast agent. Circulation 109: 2023-2029, 2004.
10.
Brennan ML, Penn MS, Van Lente F, Nambi V, Shishehbor MH, Aviles RJ, Goormastic M, Pepoy
ML, McErlean ES, Topol EJ, Nissen SE, and Hazen SL. Prognostic value of myeloperoxidase in patients with
chest pain. The New England journal of medicine 349: 1595-1604, 2003.
11.
Briley-Saebo KC, Shaw PX, Mulder WJ, Choi SH, Vucic E, Aguinaldo JG, Witztum JL, Fuster V,
Tsimikas S, and Fayad ZA. Targeted molecular probes for imaging atherosclerotic lesions with magnetic
resonance using antibodies that recognize oxidation-specific epitopes. Circulation 117: 3206-3215, 2008.
12.
Burtea C, Laurent S, Murariu O, Rattat D, Toubeau G, Verbruggen A, Vansthertem D, Vander Elst
L, and Muller RN. Molecular imaging of alpha v beta3 integrin expression in atherosclerotic plaques with a
mimetic of RGD peptide grafted to Gd-DTPA. Cardiovasc Res 78: 148-157, 2008.
13.
Calcagno C, Cornily JC, Hyafil F, Rudd JH, Briley-Saebo KC, Mani V, Goldschlager G, Machac J,
Fuster V, and Fayad ZA. Detection of neovessels in atherosclerotic plaques of rabbits using dynamic contrast
enhanced MRI and 18F-FDG PET. Arteriosclerosis, thrombosis, and vascular biology 28: 1311-1317, 2008.
14.
Calcagno C, Cornily JC, Hyafil F, Rudd JH, Briley-Saebo KC, Mani V, Goldschlager G, Machac J,
Fuster V, and Fayad ZA. Detection of neovessels in atherosclerotic plaques of rabbits using dynamic contrast
enhanced MRI and 18F-FDG PET. Arterioscler Thromb Vasc Biol 28: 1311-1317, 2008.
15.
Calvert PA, Obaid DR, O'Sullivan M, Shapiro LM, McNab D, Densem CG, Schofield PM, Braganza
D, Clarke SC, Ray KK, West NE, and Bennett MR. Association between IVUS findings and adverse outcomes
in patients with coronary artery disease: the VIVA (VH-IVUS in Vulnerable Atherosclerosis) Study. JACC
Cardiovascular imaging 4: 894-901, 2011.
16.
Caravan P, Cloutier NJ, Greenfield MT, McDermid SA, Dunham SU, Bulte JW, Amedio JC, Jr.,
Looby RJ, Supkowski RM, Horrocks WD, Jr., McMurry TJ, and Lauffer RB. The interaction of MS-325 with
human serum albumin and its effect on proton relaxation rates. J Am Chem Soc 124: 3152-3162, 2002.
17.
Caravan P, Das B, Dumas S, Epstein FH, Helm PA, Jacques V, Koerner S, Kolodziej A, Shen L,
Sun WC, and Zhang Z. Collagen-targeted MRI contrast agent for molecular imaging of fibrosis. Angew Chem
Int Ed Engl 46: 8171-8173, 2007.
ʹͳ
ͷͻͷ
ͷͻ͸
ͷͻ͹
ͷͻͺ
ͷͻͻ
͸ͲͲ
͸Ͳͳ
͸Ͳʹ
͸Ͳ͵
͸ͲͶ
͸Ͳͷ
͸Ͳ͸
͸Ͳ͹
͸Ͳͺ
͸Ͳͻ
͸ͳͲ
͸ͳͳ
͸ͳʹ
͸ͳ͵
͸ͳͶ
͸ͳͷ
͸ͳ͸
͸ͳ͹
͸ͳͺ
͸ͳͻ
͸ʹͲ
͸ʹͳ
͸ʹʹ
͸ʹ͵
͸ʹͶ
͸ʹͷ
͸ʹ͸
͸ʹ͹
͸ʹͺ
͸ʹͻ
͸͵Ͳ
͸͵ͳ
͸͵ʹ
͸͵͵
͸͵Ͷ
͸͵ͷ
͸͵͸
͸͵͹
͸͵ͺ
͸͵ͻ
͸ͶͲ
͸Ͷͳ
͸Ͷʹ
͸Ͷ͵
͸ͶͶ
͸Ͷͷ
͸Ͷ͸
͸Ͷ͹
͸Ͷͺ
͸Ͷͻ
͸ͷͲ
͸ͷͳ
͸ͷʹ
18.
Carlsson M, Ubachs JF, Hedstrom E, Heiberg E, Jovinge S, and Arheden H. Myocardium at risk
after acute infarction in humans on cardiac magnetic resonance: quantitative assessment during follow-up and
validation with single-photon emission computed tomography. JACC Cardiovasc Imaging 2: 569-576, 2009.
19.
Chen J, Tung CH, Allport JR, Chen S, Weissleder R, and Huang PL. Near-infrared fluorescent
imaging of matrix metalloproteinase activity after myocardial infarction. Circulation 111: 1800-1805, 2005.
20.
Chen J, Tung CH, Mahmood U, Ntziachristos V, Gyurko R, Fishman MC, Huang PL, and
Weissleder R. In vivo imaging of proteolytic activity in atherosclerosis. Circulation 105: 2766-2771, 2002.
21.
Chen JW, Querol Sans M, Bogdanov A, Jr., and Weissleder R. Imaging of myeloperoxidase in mice
by using novel amplifiable paramagnetic substrates. Radiology 240: 473-481, 2006.
22.
Choi KM, Kim RJ, Gubernikoff G, Vargas JD, Parker M, and Judd RM. Transmural extent of acute
myocardial infarction predicts long-term improvement in contractile function. Circulation 104: 1101-1107, 2001.
23.
Choi SI, Jiang CZ, Lim KH, Kim ST, Lim CH, Gong GY, and Lim TH. Application of breath-hold T2weighted, first-pass perfusion and gadolinium-enhanced T1-weighted MR imaging for assessment of myocardial
viability in a pig model. J Magn Reson Imaging 11: 476-480, 2000.
24.
Clark RA, Watanabe AT, Bradley WG, Jr., and Roberts JD. Acute hematomas: effects of
deoxygenation, hematocrit, and fibrin-clot formation and retraction on T2 shortening. Radiology 175: 201-206,
1990.
25.
Cormode DP, Chandrasekar R, Delshad A, Briley-Saebo KC, Calcagno C, Barazza A, Mulder WJ,
Fisher EA, and Fayad ZA. Comparison of synthetic high density lipoprotein (HDL) contrast agents for MR
imaging of atherosclerosis. Bioconjugate chemistry 20: 937-943, 2009.
26.
Cornily JC, Hyafil F, Calcagno C, Briley-Saebo KC, Tunstead J, Aguinaldo JG, Mani V, Lorusso V,
Cavagna FM, and Fayad ZA. Evaluation of neovessels in atherosclerotic plaques of rabbits using an albuminbinding intravascular contrast agent and MRI. Journal of magnetic resonance imaging : JMRI 27: 1406-1411,
2008.
27.
Corti R, Osende JI, Fayad ZA, Fallon JT, Fuster V, Mizsei G, Dickstein E, Drayer B, and Badimon
JJ. In vivo noninvasive detection and age definition of arterial thrombus by MRI. J Am Coll Cardiol 39: 13661373, 2002.
28.
Crauwels HM, Van Hove CE, Holvoet P, Herman AG, and Bult H. Plaque-associated endothelial
dysfunction in apolipoprotein E-deficient mice on a regular diet. Effect of human apolipoprotein AI.
Cardiovascular Research 59: 189-199, 2003.
29.
Daugherty A, Dunn JL, Rateri DL, and Heinecke JW. Myeloperoxidase, a catalyst for lipoprotein
oxidation, is expressed in human atherosclerotic lesions. The Journal of clinical investigation 94: 437-444, 1994.
30.
Davignon J and Ganz P. Role of endothelial dysfunction in atherosclerosis. Circulation 109: III27-32,
2004.
31.
de Smet M, van Bochove GS, Sanders HM, Arena F, Mulder JW, Krams R, Merkx M, Strijkers GJ,
and Nicolay K. Contrast-enhanced MRI of atherosclerosis with collagen targeted CNA35-micelles. Proc Intl Soc
Mag Reson Med 16, 2008.
32.
Dimastromatteo J, Riou LM, Ahmadi M, Pons G, Pellegrini E, Broisat A, Sancey L, Gavrilina T,
Boturyn D, Dumy P, Fagret D, and Ghezzi C. In vivo molecular imaging of myocardial angiogenesis using the
alpha(v)beta3 integrin-targeted tracer 99mTc-RAFT-RGD. J Nucl Cardiol 17: 435-443, 2010.
33.
Dobaczewski M, Gonzalez-Quesada C, and Frangogiannis NG. The extracellular matrix as a
modulator of the inflammatory and reparative response following myocardial infarction. J Mol Cell Cardiol 48:
504-511, 2010.
34.
Dumont EA, Reutelingsperger CP, Smits JF, Daemen MJ, Doevendans PA, Wellens HJ, and
Hofstra L. Real-time imaging of apoptotic cell-membrane changes at the single-cell level in the beating murine
heart. Nat Med 7: 1352-1355, 2001.
35.
Durand E, Raynaud JS, Bruneval P, Brigger I, Al Haj Zen A, Mandet C, Lancelot E, and Lafont A.
Magnetic resonance imaging of ruptured plaques in the rabbit with ultrasmall superparamagnetic particles of
iron oxide. Journal of vascular research 44: 119-128, 2007.
36.
Ellegala DB, Leong-Poi H, Carpenter JE, Klibanov AL, Kaul S, Shaffrey ME, Sklenar J, and
Lindner JR. Imaging tumor angiogenesis with contrast ultrasound and microbubbles targeted to alpha(v)beta3.
Circulation 108: 336-341, 2003.
37.
Fieno DS, Kim RJ, Chen EL, Lomasney JW, Klocke FJ, and Judd RM. Contrast-enhanced magnetic
resonance imaging of myocardium at risk: distinction between reversible and irreversible injury throughout
infarct healing. J Am Coll Cardiol 36: 1985-1991, 2000.
38.
Flacke S, Fischer S, Scott MJ, Fuhrhop RJ, Allen JS, McLean M, Winter P, Sicard GA, Gaffney PJ,
Wickline SA, and Lanza GM. Novel MRI contrast agent for molecular imaging of fibrin: implications for
detecting vulnerable plaques. Circulation 104: 1280-1285, 2001.
ʹʹ
͸ͷ͵
͸ͷͶ
͸ͷͷ
͸ͷ͸
͸ͷ͹
͸ͷͺ
͸ͷͻ
͸͸Ͳ
͸͸ͳ
͸͸ʹ
͸͸͵
͸͸Ͷ
͸͸ͷ
͸͸͸
͸͸͹
͸͸ͺ
͸͸ͻ
͸͹Ͳ
͸͹ͳ
͸͹ʹ
͸͹͵
͸͹Ͷ
͸͹ͷ
͸͹͸
͸͹͹
͸͹ͺ
͸͹ͻ
͸ͺͲ
͸ͺͳ
͸ͺʹ
͸ͺ͵
͸ͺͶ
͸ͺͷ
͸ͺ͸
͸ͺ͹
͸ͺͺ
͸ͺͻ
͸ͻͲ
͸ͻͳ
͸ͻʹ
͸ͻ͵
͸ͻͶ
͸ͻͷ
͸ͻ͸
͸ͻ͹
͸ͻͺ
͸ͻͻ
͹ͲͲ
͹Ͳͳ
͹Ͳʹ
͹Ͳ͵
͹ͲͶ
͹Ͳͷ
͹Ͳ͸
͹Ͳ͹
͹Ͳͺ
39.
Flogel U, Ding Z, Hardung H, Jander S, Reichmann G, Jacoby C, Schubert R, and Schrader J. In
vivo monitoring of inflammation after cardiac and cerebral ischemia by fluorine magnetic resonance imaging.
Circulation 118: 140-148, 2008.
40.
Fonge H, de Saint Hubert M, Vunckx K, Rattat D, Nuyts J, Bormans G, Ni Y, Reutelingsperger C,
and Verbruggen A. Preliminary in vivo evaluation of a novel 99mTc-labeled HYNIC-cys-annexin A5 as an
apoptosis imaging agent. Bioorg Med Chem Lett 18: 3794-3798, 2008.
41.
Frias JC, Williams KJ, Fisher EA, and Fayad ZA. Recombinant HDL-like nanoparticles: a specific
contrast agent for MRI of atherosclerotic plaques. J Am Chem Soc 126: 16316-16317, 2004.
42.
Friedrich MG, Abdel-Aty H, Taylor A, Schulz-Menger J, Messroghli D, and Dietz R. The salvaged
area at risk in reperfused acute myocardial infarction as visualized by cardiovascular magnetic resonance. J Am
Coll Cardiol 51: 1581-1587, 2008.
43.
Galis ZS, Sukhova GK, Lark MW, and Libby P. Increased expression of matrix metalloproteinases
and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin Invest 94: 24932503, 1994.
44.
Ganame J, Messalli G, Dymarkowski S, Rademakers FE, Desmet W, Van de Werf F, and Bogaert
J. Impact of myocardial haemorrhage on left ventricular function and remodelling in patients with reperfused
acute myocardial infarction. Eur Heart J 30: 1440-1449, 2009.
45.
Garanger E, Hilderbrand SA, Blois JT, Sosnovik DE, Weissleder R, and Josephson L. A DNAbinding Gd chelate for the detection of cell death by MRI. Chem Commun (Camb): 4444-4446, 2009.
46.
Garcia-Dorado D, Oliveras J, Gili J, Sanz E, Perez-Villa F, Barrabes J, Carreras MJ, Solares J, and
Soler-Soler J. Analysis of myocardial oedema by magnetic resonance imaging early after coronary artery
occlusion with or without reperfusion. Cardiovasc Res 27: 1462-1469, 1993.
47.
Ginsberg HN, Goldsmith SJ, and Vallabhajosula S. Noninvasive imaging of 99mtechnetium-labeled
low density lipoprotein uptake by tendon xanthomas in hypercholesterolemic patients. Arteriosclerosis 10: 256262, 1990.
48.
Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, and Kolettis GJ. Compensatory
enlargement of human atherosclerotic coronary arteries. N Engl J Med 316: 1371-1375, 1987.
49.
Gomori JM, Grossman RI, Goldberg HI, Zimmerman RA, and Bilaniuk LT. Intracranial hematomas:
imaging by high-field MR. Radiology 157: 87-93, 1985.
50.
Gough PJ, Gomez IG, Wille PT, and Raines EW. Macrophage expression of active MMP-9 induces
acute plaque disruption in apoE-deficient mice. J Clin Invest 116: 59-69, 2006.
51.
Grothues F, Moon JC, Bellenger NG, Smith GS, Klein HU, and Pennell DJ. Interstudy reproducibility
of right ventricular volumes, function, and mass with cardiovascular magnetic resonance. Am Heart J 147: 218223, 2004.
52.
Halcox JP, Schenke WH, Zalos G, Mincemoyer R, Prasad A, Waclawiw MA, Nour KR, and
Quyyumi AA. Prognostic value of coronary vascular endothelial dysfunction. Circulation 106: 653-658, 2002.
53.
Hatsukami TS, Ross R, Polissar NL, and Yuan C. Visualization of fibrous cap thickness and rupture in
human atherosclerotic carotid plaque in vivo with high-resolution magnetic resonance imaging. Circulation 102:
959-964, 2000.
54.
Haubner R, Weber WA, Beer AJ, Vabuliene E, Reim D, Sarbia M, Becker KF, Goebel M, Hein R,
Wester HJ, Kessler H, and Schwaiger M. Noninvasive visualization of the activated alphavbeta3 integrin in
cancer patients by positron emission tomography and [18F]Galacto-RGD. PLoS Med 2: e70, 2005.
55.
Hays AG, Hirsch GA, Kelle S, Gerstenblith G, Weiss RG, and Stuber M. Noninvasive visualization of
coronary artery endothelial function in healthy subjects and in patients with coronary artery disease. J Am Coll
Cardiol 56: 1657-1665, 2010.
56.
Helm PA, Caravan P, French BA, Jacques V, Shen L, Xu Y, Beyers RJ, Roy RJ, Kramer CM, and
Epstein FH. Postinfarction myocardial scarring in mice: molecular MR imaging with use of a collagen-targeting
contrast agent. Radiology 247: 788-796, 2008.
57.
Herborn CU, Vogt FM, Lauenstein TC, Dirsch O, Corot C, Robert P, and Ruehm SG. Magnetic
resonance imaging of experimental atherosclerotic plaque: comparison of two ultrasmall superparamagnetic
particles of iron oxide. Journal of magnetic resonance imaging : JMRI 24: 388-393, 2006.
58.
Hidalgo M and Eckhardt SG. Development of matrix metalloproteinase inhibitors in cancer therapy. J
Natl Cancer Inst 93: 178-193, 2001.
59.
Higgins CB, Herfkens R, Lipton MJ, Sievers R, Sheldon P, Kaufman L, and Crooks LE. Nuclear
magnetic resonance imaging of acute myocardial infarction in dogs: alterations in magnetic relaxation times. Am
J Cardiol 52: 184-188, 1983.
ʹ͵
͹Ͳͻ
͹ͳͲ
͹ͳͳ
͹ͳʹ
͹ͳ͵
͹ͳͶ
͹ͳͷ
͹ͳ͸
͹ͳ͹
͹ͳͺ
͹ͳͻ
͹ʹͲ
͹ʹͳ
͹ʹʹ
͹ʹ͵
͹ʹͶ
͹ʹͷ
͹ʹ͸
͹ʹ͹
͹ʹͺ
͹ʹͻ
͹͵Ͳ
͹͵ͳ
͹͵ʹ
͹͵͵
͹͵Ͷ
͹͵ͷ
͹͵͸
͹͵͹
͹͵ͺ
͹͵ͻ
͹ͶͲ
͹Ͷͳ
͹Ͷʹ
͹Ͷ͵
͹ͶͶ
͹Ͷͷ
͹Ͷ͸
͹Ͷ͹
͹Ͷͺ
͹Ͷͻ
͹ͷͲ
͹ͷͳ
͹ͷʹ
͹ͷ͵
͹ͷͶ
͹ͷͷ
͹ͷ͸
͹ͷ͹
͹ͷͺ
͹ͷͻ
͹͸Ͳ
͹͸ͳ
͹͸ʹ
͹͸͵
͹͸Ͷ
͹͸ͷ
60.
Higuchi T, Bengel FM, Seidl S, Watzlowik P, Kessler H, Hegenloh R, Reder S, Nekolla SG, Wester
HJ, and Schwaiger M. Assessment of alphavbeta3 integrin expression after myocardial infarction by positron
emission tomography. Cardiovasc Res 78: 395-403, 2008.
61.
Hillenbrand HB, Kim RJ, Parker MA, Fieno DS, and Judd RM. Early assessment of myocardial
salvage by contrast-enhanced magnetic resonance imaging. Circulation 102: 1678-1683, 2000.
62.
Hofstra L, Liem IH, Dumont EA, Boersma HH, van Heerde WL, Doevendans PA, De Muinck E,
Wellens HJ, Kemerink GJ, Reutelingsperger CP, and Heidendal GA. Visualisation of cell death in vivo in
patients with acute myocardial infarction. Lancet 356: 209-212, 2000.
63.
Hoshiga M, Alpers CE, Smith LL, Giachelli CM, and Schwartz SM. Alpha-v beta-3 integrin
expression in normal and atherosclerotic artery. Circulation research 77: 1129-1135, 1995.
64.
Howarth SP, Tang TY, Trivedi R, Weerakkody R, J UK-I, Gaunt ME, Boyle JR, Li ZY, Miller SR,
Graves MJ, and Gillard JH. Utility of USPIO-enhanced MR imaging to identify inflammation and the fibrous
cap: a comparison of symptomatic and asymptomatic individuals. Eur J Radiol 70: 555-560, 2009.
65.
Hyafil F, Cornily J-C, Feig JE, Gordon R, Vucic E, Amirbekian V, Fisher EA, Fuster V, Feldman LJ,
and Fayad ZA. Noninvasive detection of macrophages using a nanoparticulate contrast agent for computed
tomography. Nat Med 13: 636, 2007.
66.
Hyafil F, Laissy JP, Mazighi M, Tchetche D, Louedec L, Adle-Biassette H, Chillon S, Henin D,
Jacob MP, Letourneur D, and Feldman LJ. Ferumoxtran-10-enhanced MRI of the hypercholesterolemic rabbit
aorta: relationship between signal loss and macrophage infiltration. Arteriosclerosis, thrombosis, and vascular
biology 26: 176-181, 2006.
67.
Ibrahim T, Bulow HP, Hackl T, Hornke M, Nekolla SG, Breuer M, Schomig A, and Schwaiger M.
Diagnostic value of contrast-enhanced magnetic resonance imaging and single-photon emission computed
tomography for detection of myocardial necrosis early after acute myocardial infarction. J Am Coll Cardiol 49:
208-216, 2007.
68.
Iliceto S, Marangelli V, Marchese A, Amico A, Galiuto L, and Rizzon P. Myocardial contrast
echocardiography in acute myocardial infarction. Pathophysiological background and clinical applications. Eur
Heart J 17: 344-353, 1996.
69.
Jaffer FA, Calfon MA, Rosenthal A, Mallas G, Razansky RN, Mauskapf A, Weissleder R, Libby P,
and Ntziachristos V. Two-dimensional intravascular near-infrared fluorescence molecular imaging of
inflammation in atherosclerosis and stent-induced vascular injury. J Am Coll Cardiol 57: 2516-2526, 2011.
70.
Jaffer FA, Nahrendorf M, Sosnovik D, Kelly KA, Aikawa E, and Weissleder R. Cellular imaging of
inflammation in atherosclerosis using magnetofluorescent nanomaterials. Mol Imaging 5: 85-92, 2006.
71.
Jansen CH, Perera D, Makowski MR, Wiethoff AJ, Phinikaridou A, Razavi RM, Marber MS, Greil
GF, Nagel E, Maintz D, Redwood S, and Botnar RM. Detection of intracoronary thrombus by magnetic
resonance imaging in patients with acute myocardial infarction. Circulation 124: 416-424, 2011.
72.
Johansson LO, Bjornerud A, Ahlstrom HK, Ladd DL, and Fujii DK. A targeted contrast agent for
magnetic resonance imaging of thrombus: implications of spatial resolution. J Magn Reson Imaging 13: 615618, 2001.
73.
Kao CH, Chen JK, Kuo JS, and Yang VC. Visualization of the transport pathways of low density
lipoproteins across the endothelial cells in the branched regions of rat arteries. Atherosclerosis 116: 27-41,
1995.
74.
Kelly KA, Allport JR, Tsourkas A, Shinde-Patil VR, Josephson L, and Weissleder R. Detection of
vascular adhesion molecule-1 expression using a novel multimodal nanoparticle. Circ Res 96: 327-336, 2005.
75.
Kerwin W, Hooker A, Spilker M, Vicini P, Ferguson M, Hatsukami T, and Yuan C. Quantitative
magnetic resonance imaging analysis of neovasculature volume in carotid atherosclerotic plaque. Circulation
107: 851-856, 2003.
76.
Kerwin WS, Oikawa M, Yuan C, Jarvik GP, and Hatsukami TS. MR imaging of adventitial vasa
vasorum in carotid atherosclerosis. Magn Reson Med 59: 507-514, 2008.
77.
Kietselaer BL, Reutelingsperger CP, Heidendal GA, Daemen MJ, Mess WH, Hofstra L, and Narula
J. Noninvasive detection of plaque instability with use of radiolabeled annexin A5 in patients with carotid-artery
atherosclerosis. The New England journal of medicine 350: 1472-1473, 2004.
78.
Kim RJ, Fieno DS, Parrish TB, Harris K, Chen EL, Simonetti O, Bundy J, Finn JP, Klocke FJ, and
Judd RM. Relationship of MRI delayed contrast enhancement to irreversible injury, infarct age, and contractile
function. Circulation 100: 1992-2002, 1999.
79.
Kim RJ, Wu E, Rafael A, Chen EL, Parker MA, Simonetti O, Klocke FJ, Bonow RO, and Judd RM.
The use of contrast-enhanced magnetic resonance imaging to identify reversible myocardial dysfunction. N Engl
J Med 343: 1445-1453, 2000.
ʹͶ
͹͸͸
͹͸͹
͹͸ͺ
͹͸ͻ
͹͹Ͳ
͹͹ͳ
͹͹ʹ
͹͹͵
͹͹Ͷ
͹͹ͷ
͹͹͸
͹͹͹
͹͹ͺ
͹͹ͻ
͹ͺͲ
͹ͺͳ
͹ͺʹ
͹ͺ͵
͹ͺͶ
͹ͺͷ
͹ͺ͸
͹ͺ͹
͹ͺͺ
͹ͺͻ
͹ͻͲ
͹ͻͳ
͹ͻʹ
͹ͻ͵
͹ͻͶ
͹ͻͷ
͹ͻ͸
͹ͻ͹
͹ͻͺ
͹ͻͻ
ͺͲͲ
ͺͲͳ
ͺͲʹ
ͺͲ͵
ͺͲͶ
ͺͲͷ
ͺͲ͸
ͺͲ͹
ͺͲͺ
ͺͲͻ
ͺͳͲ
ͺͳͳ
ͺͳʹ
ͺͳ͵
ͺͳͶ
ͺͳͷ
ͺͳ͸
ͺͳ͹
ͺͳͺ
ͺͳͻ
ͺʹͲ
ͺʹͳ
ͺʹʹ
80.
Kim SE, Treiman GS, Roberts JA, Jeong EK, Shi X, Hadley JR, and Parker DL. In vivo and ex vivo
measurements of the mean ADC values of lipid necrotic core and hemorrhage obtained from diffusion weighted
imaging in human atherosclerotic plaques. Journal of magnetic resonance imaging : JMRI 34: 1167-1175, 2011.
81.
Kim WY, Stuber M, Bornert P, Kissinger KV, Manning WJ, and Botnar RM. Three-dimensional
black-blood cardiac magnetic resonance coronary vessel wall imaging detects positive arterial remodeling in
patients with nonsignificant coronary artery disease. Circulation 106: 296-299, 2002.
82.
Kitagawa K, Sakuma H, Hirano T, Okamoto S, Makino K, and Takeda K. Acute myocardial
infarction: myocardial viability assessment in patients early thereafter comparison of contrast-enhanced MR
imaging with resting (201)Tl SPECT. Single photon emission computed tomography. Radiology 226: 138-144,
2003.
83.
Klein C, Nekolla SG, Bengel FM, Momose M, Sammer A, Haas F, Schnackenburg B, Delius W,
Mudra H, Wolfram D, and Schwaiger M. Assessment of myocardial viability with contrast-enhanced magnetic
resonance imaging: comparison with positron emission tomography. Circulation 105: 162-167, 2002.
84.
Klink A, Heynens J, Herranz B, Lobatto ME, Arias T, Sanders HM, Strijkers GJ, Merkx M, Nicolay
K, Fuster V, Tedgui A, Mallat Z, Mulder WJ, and Fayad ZA. In vivo characterization of a new abdominal aortic
aneurysm mouse model with conventional and molecular magnetic resonance imaging. J Am Coll Cardiol 58:
2522-2530, 2011.
85.
Klink A, Lancelot E, Ballet S, Vucic E, Fabre JE, Gonzalez W, Medina C, Corot C, Mulder WJ,
Mallat Z, and Fayad ZA. Magnetic resonance molecular imaging of thrombosis in an arachidonic Acid mouse
model using an activated platelet targeted probe. Arterioscler Thromb Vasc Biol 30: 403-410, 2010.
86.
Kolodgie FD, Petrov A, Virmani R, Narula N, Verjans JW, Weber DK, Hartung D, Steinmetz N,
Vanderheyden JL, Vannan MA, Gold HK, Reutelingsperger CP, Hofstra L, and Narula J. Targeting of
apoptotic macrophages and experimental atheroma with radiolabeled annexin V: a technique with potential for
noninvasive imaging of vulnerable plaque. Circulation 108: 3134-3139, 2003.
87.
Kooi ME, Cappendijk VC, Cleutjens KB, Kessels AG, Kitslaar PJ, Borgers M, Frederik PM,
Daemen MJ, and van Engelshoven JM. Accumulation of ultrasmall superparamagnetic particles of iron oxide
in human atherosclerotic plaques can be detected by in vivo magnetic resonance imaging. Circulation 107:
2453-2458, 2003.
88.
Korosoglou G, Weiss RG, Kedziorek DA, Walczak P, Gilson WD, Schar M, Sosnovik DE,
Kraitchman DL, Boston RC, Bulte JW, Weissleder R, and Stuber M. Noninvasive detection of macrophagerich atherosclerotic plaque in hyperlipidemic rabbits using "positive contrast" magnetic resonance imaging. J Am
Coll Cardiol 52: 483-491, 2008.
89.
Kuhl HP, Beek AM, van der Weerdt AP, Hofman MB, Visser CA, Lammertsma AA, Heussen N,
Visser FC, and van Rossum AC. Myocardial viability in chronic ischemic heart disease: comparison of
contrast-enhanced magnetic resonance imaging with (18)F-fluorodeoxyglucose positron emission tomography.
J Am Coll Cardiol 41: 1341-1348, 2003.
90.
Kwon S, Ke S, Houston JP, Wang W, Wu Q, Li C, and Sevick-Muraca EM. Imaging dose-dependent
pharmacokinetics of an RGD-fluorescent dye conjugate targeted to alpha v beta 3 receptor expressed in
Kaposi's sarcoma. Molecular imaging 4: 75-87, 2005.
91.
Lancelot E, Amirbekian V, Brigger I, Raynaud JS, Ballet S, David C, Rousseaux O, Le Greneur S,
Port M, Lijnen HR, Bruneval P, Michel JB, Ouimet T, Roques B, Amirbekian S, Hyafil F, Vucic E,
Aguinaldo JG, Corot C, and Fayad ZA. Evaluation of matrix metalloproteinases in atherosclerosis using a
novel noninvasive imaging approach. Arterioscler Thromb Vasc Biol 28: 425-432, 2008.
92.
Lauffer RB, Parmelee DJ, Ouellet HS, Dolan RP, Sajiki H, Scott DM, Bernard PJ, Buchanan EM,
Ong KY, Tyeklar Z, Midelfort KS, McMurry TJ, and Walovitch RC. MS-325: a small-molecule vascular
imaging agent for magnetic resonance imaging. Acad Radiol 3 Suppl 2: S356-358, 1996.
93.
Lee WW, Marinelli B, van der Laan AM, Sena BF, Gorbatov R, Leuschner F, Dutta P, Iwamoto Y,
Ueno T, Begieneman MP, Niessen HW, Piek JJ, Vinegoni C, Pittet MJ, Swirski FK, Tawakol A, Di Carli M,
Weissleder R, and Nahrendorf M. PET/MRI of inflammation in myocardial infarction. J Am Coll Cardiol 59:
153-163, 2012.
94.
Li D, Patel AR, Klibanov AL, Kramer CM, Ruiz M, Kang BY, Mehta JL, Beller GA, Glover DK, and
Meyer CH. Molecular imaging of atherosclerotic plaques targeted to oxidized LDL receptor LOX-1 by
SPECT/CT and magnetic resonance. Circ Cardiovasc Imaging 3: 464-472.
95.
Lobbes MB, Heeneman S, Passos VL, Welten R, Kwee RM, van der Geest RJ, Wiethoff AJ,
Caravan P, Misselwitz B, Daemen MJ, van Engelshoven JM, Leiner T, and Kooi ME. Gadofosvesetenhanced magnetic resonance imaging of human carotid atherosclerotic plaques: a proof-of-concept study.
Investigative radiology 45: 275-281, 2010.
ʹͷ
ͺʹ͵
ͺʹͶ
ͺʹͷ
ͺʹ͸
ͺʹ͹
ͺʹͺ
ͺʹͻ
ͺ͵Ͳ
ͺ͵ͳ
ͺ͵ʹ
ͺ͵͵
ͺ͵Ͷ
ͺ͵ͷ
ͺ͵͸
ͺ͵͹
ͺ͵ͺ
ͺ͵ͻ
ͺͶͲ
ͺͶͳ
ͺͶʹ
ͺͶ͵
ͺͶͶ
ͺͶͷ
ͺͶ͸
ͺͶ͹
ͺͶͺ
ͺͶͻ
ͺͷͲ
ͺͷͳ
ͺͷʹ
ͺͷ͵
ͺͷͶ
ͺͷͷ
ͺͷ͸
ͺͷ͹
ͺͷͺ
ͺͷͻ
ͺ͸Ͳ
ͺ͸ͳ
ͺ͸ʹ
ͺ͸͵
ͺ͸Ͷ
ͺ͸ͷ
ͺ͸͸
ͺ͸͹
ͺ͸ͺ
ͺ͸ͻ
ͺ͹Ͳ
ͺ͹ͳ
ͺ͹ʹ
ͺ͹͵
ͺ͹Ͷ
ͺ͹ͷ
ͺ͹͸
ͺ͹͹
ͺ͹ͺ
ͺ͹ͻ
96.
Lobbes MB, Heeneman S, Passos VL, Welten R, Kwee RM, van der Geest RJ, Wiethoff AJ,
Caravan P, Misselwitz B, Daemen MJ, van Engelshoven JM, Leiner T, and Kooi ME. Gadofosvesetenhanced magnetic resonance imaging of human carotid atherosclerotic plaques: a proof-of-concept study.
Invest Radiol 45: 275-281, 2010.
97.
Lobbes MB, Miserus RJ, Heeneman S, Passos VL, Mutsaers PH, Debernardi N, Misselwitz B,
Post M, Daemen MJ, van Engelshoven JM, Leiner T, and Kooi ME. Atherosclerosis: contrast-enhanced MR
imaging of vessel wall in rabbit model--comparison of gadofosveset and gadopentetate dimeglumine. Radiology
250: 682-691, 2009.
98.
Ludmer PL, Selwyn AP, Shook TL, Wayne RR, Mudge GH, Alexander RW, and Ganz P.
Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries. N Engl J Med 315:
1046-1051, 1986.
99.
Makowski MR, Ebersberger U, Nekolla S, and Schwaiger M. In vivo molecular imaging of
angiogenesis, targeting alphavbeta3 integrin expression, in a patient after acute myocardial infarction. Eur Heart
J 29: 2201, 2008.
100.
Makowski MR, Varma G, Wiethoff AJ, Smith A, Mattock K, Jansen CH, Warley A, Taupitz M,
Schaeffter T, and Botnar RM. Noninvasive assessment of atherosclerotic plaque progression in ApoE-/- mice
using susceptibility gradient mapping. Circulation Cardiovascular imaging 4: 295-303, 2011.
101.
Makowski MR, Wiethoff AJ, Blume U, Cuello F, Warley A, Jansen CH, Nagel E, Razavi R, Onthank
DC, Cesati RR, Marber MS, Schaeffter T, Smith A, Robinson SP, and Botnar RM. Assessment of
atherosclerotic plaque burden with an elastin-specific magnetic resonance contrast agent. Nature medicine 17:
383-388, 2011.
102.
Matsumoto H, Matsuda T, Miyamoto K, Shimada T, Mikuri M, and Hiraoka Y. Peri-infarct zone on
early contrast-enhanced CMR imaging in patients with acute myocardial infarction. JACC Cardiovasc Imaging 4:
610-618, 2011.
103.
McAteer MA, Mankia K, Ruparelia N, Jefferson A, Nugent HB, Stork LA, Channon KM, Schneider
JE, and Choudhury RP. A leukocyte-mimetic magnetic resonance imaging contrast agent homes rapidly to
activated endothelium and tracks with atherosclerotic lesion macrophage content. Arteriosclerosis, thrombosis,
and vascular biology 32: 1427-1435, 2012.
104.
McAteer MA, Schneider JE, Ali ZA, Warrick N, Bursill CA, von zur Muhlen C, Greaves DR,
Neubauer S, Channon KM, and Choudhury RP. Magnetic resonance imaging of endothelial adhesion
molecules in mouse atherosclerosis using dual-targeted microparticles of iron oxide. Arterioscler Thromb Vasc
Biol 28: 77-83, 2008.
105.
McNeill E, Channon KM, and Greaves DR. Inflammatory cell recruitment in cardiovascular disease:
murine models and potential clinical applications. Clin Sci (Lond) 118: 641-655, 2010.
106.
Meoli DF, Sadeghi MM, Krassilnikova S, Bourke BN, Giordano FJ, Dione DP, Su H, Edwards DS,
Liu S, Harris TD, Madri JA, Zaret BL, and Sinusas AJ. Noninvasive imaging of myocardial angiogenesis
following experimental myocardial infarction. J Clin Invest 113: 1684-1691, 2004.
107.
Miao C, Chen S, Macedo R, Lai S, Liu K, Li D, Wasserman BA, Vogel-Claussen J, Lima JA, and
Bluemke DA. Positive remodeling of the coronary arteries detected by magnetic resonance imaging in an
asymptomatic population: MESA (Multi-Ethnic Study of Atherosclerosis). J Am Coll Cardiol 53: 1708-1715,
2009.
108.
Miserus RJ, Herias MV, Prinzen L, Lobbes MB, Van Suylen RJ, Dirksen A, Hackeng TM,
Heemskerk JW, van Engelshoven JM, Daemen MJ, van Zandvoort MA, Heeneman S, and Kooi ME.
Molecular MRI of early thrombus formation using a bimodal alpha2-antiplasmin-based contrast agent. JACC
Cardiovascular imaging 2: 987-996, 2009.
109.
Mitsumori LM, Hatsukami TS, Ferguson MS, Kerwin WS, Cai J, and Yuan C. In vivo accuracy of
multisequence MR imaging for identifying unstable fibrous caps in advanced human carotid plaques. J Magn
Reson Imaging 17: 410-420, 2003.
110.
Montet-Abou K, Daire JL, Hyacinthe JN, Jorge-Costa M, Grosdemange K, Mach F, Petri-Fink A,
Hofmann H, Morel DR, Vallee JP, and Montet X. In vivo labelling of resting monocytes in the
reticuloendothelial system with fluorescent iron oxide nanoparticles prior to injury reveals that they are mobilized
to infarcted myocardium. Eur Heart J 31: 1410-1420, 2010.
111.
Moody AR, Murphy RE, Morgan PS, Martel AL, Delay GS, Allder S, MacSweeney ST, Tennant WG,
Gladman J, Lowe J, and Hunt BJ. Characterization of complicated carotid plaque with magnetic resonance
direct thrombus imaging in patients with cerebral ischemia. Circulation 107: 3047-3052, 2003.
112.
Moody AR, Pollock JG, O'Connor AR, and Bagnall M. Lower-limb deep venous thrombosis: direct
MR imaging of the thrombus. Radiology 209: 349-355, 1998.
ʹ͸
ͺͺͲ
ͺͺͳ
ͺͺʹ
ͺͺ͵
ͺͺͶ
ͺͺͷ
ͺͺ͸
ͺͺ͹
ͺͺͺ
ͺͺͻ
ͺͻͲ
ͺͻͳ
ͺͻʹ
ͺͻ͵
ͺͻͶ
ͺͻͷ
ͺͻ͸
ͺͻ͹
ͺͻͺ
ͺͻͻ
ͻͲͲ
ͻͲͳ
ͻͲʹ
ͻͲ͵
ͻͲͶ
ͻͲͷ
ͻͲ͸
ͻͲ͹
ͻͲͺ
ͻͲͻ
ͻͳͲ
ͻͳͳ
ͻͳʹ
ͻͳ͵
ͻͳͶ
ͻͳͷ
ͻͳ͸
ͻͳ͹
ͻͳͺ
ͻͳͻ
ͻʹͲ
ͻʹͳ
ͻʹʹ
ͻʹ͵
ͻʹͶ
ͻʹͷ
ͻʹ͸
ͻʹ͹
ͻʹͺ
ͻʹͻ
ͻ͵Ͳ
ͻ͵ͳ
ͻ͵ʹ
ͻ͵͵
ͻ͵Ͷ
ͻ͵ͷ
113.
Moreno PR, Purushothaman KR, Fuster V, Echeverri D, Truszczynska H, Sharma SK, Badimon
JJ, and O'Connor WN. Plaque neovascularization is increased in ruptured atherosclerotic lesions of human
aorta: implications for plaque vulnerability. Circulation 110: 2032-2038, 2004.
114.
Morishige K, Kacher DF, Libby P, Josephson L, Ganz P, Weissleder R, and Aikawa M. Highresolution magnetic resonance imaging enhanced with superparamagnetic nanoparticles measures
macrophage burden in atherosclerosis. Circulation 122: 1707-1715, 2010.
115.
Motoyama S, Sarai M, Harigaya H, Anno H, Inoue K, Hara T, Naruse H, Ishii J, Hishida H, Wong
ND, Virmani R, Kondo T, Ozaki Y, and Narula J. Computed tomographic angiography characteristics of
atherosclerotic plaques subsequently resulting in acute coronary syndrome. Journal of the American College of
Cardiology 54: 49-57, 2009.
116.
Mulder WJ, Strijkers GJ, Briley-Saboe KC, Frias JC, Aguinaldo JG, Vucic E, Amirbekian V, Tang
C, Chin PT, Nicolay K, and Fayad ZA. Molecular imaging of macrophages in atherosclerotic plaques using
bimodal PEG-micelles. Magn Reson Med 58: 1164-1170, 2007.
117.
Murray CJ and Lopez AD. Alternative projections of mortality and disability by cause 1990-2020:
Global Burden of Disease Study. Lancet 349: 1498-1504, 1997.
118.
Muzard J, Sarda-Mantel L, Loyau S, Meulemans A, Louedec L, Bantsimba-Malanda C, Hervatin F,
Marchal-Somme J, Michel JB, Le Guludec D, Billiald P, and Jandrot-Perrus M. Non-invasive molecular
imaging of fibrosis using a collagen-targeted peptidomimetic of the platelet collagen receptor glycoprotein VI.
PLoS One 4: e5585, 2009.
119.
Nahrendorf M, Aikawa E, Figueiredo JL, Stangenberg L, van den Borne SW, Blankesteijn WM,
Sosnovik DE, Jaffer FA, Tung CH, and Weissleder R. Transglutaminase activity in acute infarcts predicts
healing outcome and left ventricular remodelling: implications for FXIII therapy and antithrombin use in
myocardial infarction. Eur Heart J 29: 445-454, 2008.
120.
Nahrendorf M, Hu K, Frantz S, Jaffer FA, Tung CH, Hiller KH, Voll S, Nordbeck P, Sosnovik D,
Gattenlohner S, Novikov M, Dickneite G, Reed GL, Jakob P, Rosenzweig A, Bauer WR, Weissleder R, and
Ertl G. Factor XIII deficiency causes cardiac rupture, impairs wound healing, and aggravates cardiac
remodeling in mice with myocardial infarction. Circulation 113: 1196-1202, 2006.
121.
Nahrendorf M, Jaffer FA, Kelly KA, Sosnovik DE, Aikawa E, Libby P, and Weissleder R.
Noninvasive vascular cell adhesion molecule-1 imaging identifies inflammatory activation of cells in
atherosclerosis. Circulation 114: 1504-1511, 2006.
122.
Nahrendorf M, Keliher E, Panizzi P, Zhang H, Hembrador S, Figueiredo JL, Aikawa E, Kelly K,
Libby P, and Weissleder R. 18F-4V for PET-CT imaging of VCAM-1 expression in atherosclerosis. JACC
Cardiovasc Imaging 2: 1213-1222, 2009.
123.
Nahrendorf M, Pittet MJ, and Swirski FK. Monocytes: protagonists of infarct inflammation and repair
after myocardial infarction. Circulation 121: 2437-2445, 2010.
124.
Nahrendorf M, Sosnovik D, Chen JW, Panizzi P, Figueiredo JL, Aikawa E, Libby P, Swirski FK,
and Weissleder R. Activatable magnetic resonance imaging agent reports myeloperoxidase activity in healing
infarcts and noninvasively detects the antiinflammatory effects of atorvastatin on ischemia-reperfusion injury.
Circulation 117: 1153-1160, 2008.
125.
Nahrendorf M, Sosnovik DE, Waterman P, Swirski FK, Pande AN, Aikawa E, Figueiredo JL, Pittet
MJ, and Weissleder R. Dual channel optical tomographic imaging of leukocyte recruitment and protease
activity in the healing myocardial infarct. Circ Res 100: 1218-1225, 2007.
126.
Nahrendorf M, Swirski FK, Aikawa E, Stangenberg L, Wurdinger T, Figueiredo JL, Libby P,
Weissleder R, and Pittet MJ. The healing myocardium sequentially mobilizes two monocyte subsets with
divergent and complementary functions. J Exp Med 204: 3037-3047, 2007.
127.
Nahrendorf M, Zhang H, Hembrador S, Panizzi P, Sosnovik DE, Aikawa E, Libby P, Swirski FK,
and Weissleder R. Nanoparticle PET-CT imaging of macrophages in inflammatory atherosclerosis. Circulation
117: 379-387, 2008.
128.
Nguyen PK, Meyer C, Engvall J, Yang P, and McConnell MV. Noninvasive assessment of coronary
vasodilation using cardiovascular magnetic resonance in patients at high risk for coronary artery disease.
Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic
Resonance 10: 28, 2008.
129.
Nicholls SJ and Hazen SL. Myeloperoxidase and cardiovascular disease. Arteriosclerosis, thrombosis,
and vascular biology 25: 1102-1111, 2005.
130.
Ntziachristos V, Tung CH, Bremer C, and Weissleder R. Fluorescence molecular tomography
resolves protease activity in vivo. Nature medicine 8: 757-760, 2002.
ʹ͹
ͻ͵͸
ͻ͵͹
ͻ͵ͺ
ͻ͵ͻ
ͻͶͲ
ͻͶͳ
ͻͶʹ
ͻͶ͵
ͻͶͶ
ͻͶͷ
ͻͶ͸
ͻͶ͹
ͻͶͺ
ͻͶͻ
ͻͷͲ
ͻͷͳ
ͻͷʹ
ͻͷ͵
ͻͷͶ
ͻͷͷ
ͻͷ͸
ͻͷ͹
ͻͷͺ
ͻͷͻ
ͻ͸Ͳ
ͻ͸ͳ
ͻ͸ʹ
ͻ͸͵
ͻ͸Ͷ
ͻ͸ͷ
ͻ͸͸
ͻ͸͹
ͻ͸ͺ
ͻ͸ͻ
ͻ͹Ͳ
ͻ͹ͳ
ͻ͹ʹ
ͻ͹͵
ͻ͹Ͷ
ͻ͹ͷ
ͻ͹͸
ͻ͹͹
ͻ͹ͺ
ͻ͹ͻ
ͻͺͲ
ͻͺͳ
ͻͺʹ
ͻͺ͵
ͻͺͶ
ͻͺͷ
ͻͺ͸
ͻͺ͹
ͻͺͺ
ͻͺͻ
ͻͻͲ
ͻͻͳ
131.
Oostendorp M, Douma K, Wagenaar A, Slenter JM, Hackeng TM, van Zandvoort MA, Post MJ,
and Backes WH. Molecular magnetic resonance imaging of myocardial angiogenesis after acute myocardial
infarction. Circulation 121: 775-783, 2010.
132.
Oshinski JN, Yang Z, Jones JR, Mata JF, and French BA. Imaging time after Gd-DTPA injection is
critical in using delayed enhancement to determine infarct size accurately with magnetic resonance imaging.
Circulation 104: 2838-2842, 2001.
133.
Pachot-Clouard M, Vaufrey F, Darrasse L, and Toussainti JF. Magnetization transfer characteristics
in atherosclerotic plaque components assessed by adapted binomial preparation pulses. Magma 7: 9-15, 1998.
134.
Panizzi P, Nahrendorf M, Wildgruber M, Waterman P, Figueiredo JL, Aikawa E, McCarthy J,
Weissleder R, and Hilderbrand SA. Oxazine conjugated nanoparticle detects in vivo hypochlorous acid and
peroxynitrite generation. J Am Chem Soc 131: 15739-15744, 2009.
135.
Panizzi P, Swirski FK, Figueiredo JL, Waterman P, Sosnovik DE, Aikawa E, Libby P, Pittet M,
Weissleder R, and Nahrendorf M. Impaired infarct healing in atherosclerotic mice with Ly-6C(hi) monocytosis.
J Am Coll Cardiol 55: 1629-1638, 2010.
136.
Pasterkamp G, Schoneveld AH, Hijnen DJ, de Kleijn DP, Teepen H, van der Wal AC, and Borst C.
Atherosclerotic arterial remodeling and the localization of macrophages and matrix metalloproteases 1, 2 and 9
in the human coronary artery. Atherosclerosis 150: 245-253, 2000.
137.
Pasterkamp G, Schoneveld AH, van der Wal AC, Haudenschild CC, Clarijs RJ, Becker AE, Hillen
B, and Borst C. Relation of arterial geometry to luminal narrowing and histologic markers for plaque
vulnerability: the remodeling paradox. J Am Coll Cardiol 32: 655-662, 1998.
138.
Pedersen SF, Thrysoe SA, Paaske WP, Thim T, Falk E, Ringgaard S, and Kim WY. CMR
assessment of endothelial damage and angiogenesis in porcine coronary arteries using gadofosveset. Journal
of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance
13: 10, 2011.
139.
Phinikaridou A, Andia ME, Protti A, Indermuehle A, Shah A, Smith A, Warley A, and Botnar RM.
Noninvasive magnetic resonance imaging evaluation of endothelial permeability in murine atherosclerosis using
an albumin-binding contrast agent. Circulation 126: 707-719, 2012.
140.
Phinikaridou A, Qiao Y, Giordano N, and Hamilton JA. Detection of thrombus size and protein
content by ex vivo magnetization transfer and diffusion weighted MRI. Journal of cardiovascular magnetic
resonance : official journal of the Society for Cardiovascular Magnetic Resonance 14: 45, 2012.
141.
Phinikaridou A, Ruberg FL, Hallock KJ, Qiao Y, Hua N, Viereck J, and Hamilton JA. In vivo
detection of vulnerable atherosclerotic plaque by MRI in a rabbit model. Circ Cardiovasc Imaging 3: 323-332,
2009.
142.
Qiao Y, Hallock KJ, and Hamilton JA. Magnetization Transfer Magnetic Resonance of Human
Atherosclerotic Plaques ex vivo Detects Areas of High Protein Density. Journal of cardiovascular magnetic
resonance : official journal of the Society for Cardiovascular Magnetic Resonance 13: 73, 2011.
143.
Qiao Y, Ronen I, Viereck J, Ruberg FL, and Hamilton JA. Identification of atherosclerotic lipid
deposits by diffusion-weighted imaging. Arterioscler Thromb Vasc Biol 27: 1440-1446, 2007.
144.
Querol M, Chen JW, and Bogdanov AA, Jr. A paramagnetic contrast agent with myeloperoxidasesensing properties. Org Biomol Chem 4: 1887-1895, 2006.
145.
Rapoport S, Sostman HD, Pope C, Camputaro CM, Holcomb W, and Gore JC. Venous clots:
evaluation with MR imaging. Radiology 162: 527-530, 1987.
146.
Rehwald WG, Fieno DS, Chen EL, Kim RJ, and Judd RM. Myocardial magnetic resonance imaging
contrast agent concentrations after reversible and irreversible ischemic injury. Circulation 105: 224-229, 2002.
147.
Reimer KA and Jennings RB. The "wavefront phenomenon" of myocardial ischemic cell death. II.
Transmural progression of necrosis within the framework of ischemic bed size (myocardium at risk) and
collateral flow. Lab Invest 40: 633-644, 1979.
148.
Reimer KA, Lowe JE, Rasmussen MM, and Jennings RB. The wavefront phenomenon of ischemic
cell death. 1. Myocardial infarct size vs duration of coronary occlusion in dogs. Circulation 56: 786-794, 1977.
149.
Rodriguez-Porcel M, Cai W, Gheysens O, Willmann JK, Chen K, Wang H, Chen IY, He L, Wu JC,
Li ZB, Mohamedali KA, Kim S, Rosenblum MG, Chen X, and Gambhir SS. Imaging of VEGF receptor in a rat
myocardial infarction model using PET. J Nucl Med 49: 667-673, 2008.
150.
Ronald JA, Chen JW, Chen Y, Hamilton AM, Rodriguez E, Reynolds F, Hegele RA, Rogers KA,
Querol M, Bogdanov A, Weissleder R, and Rutt BK. Enzyme-sensitive magnetic resonance imaging targeting
myeloperoxidase identifies active inflammation in experimental rabbit atherosclerotic plaques. Circulation 120:
592-599, 2009.
ʹͺ
ͻͻʹ
ͻͻ͵
ͻͻͶ
ͻͻͷ
ͻͻ͸
ͻͻ͹
ͻͻͺ
ͻͻͻ
ͳͲͲͲ
ͳͲͲͳ
ͳͲͲʹ
ͳͲͲ͵
ͳͲͲͶ
ͳͲͲͷ
ͳͲͲ͸
ͳͲͲ͹
ͳͲͲͺ
ͳͲͲͻ
ͳͲͳͲ
ͳͲͳͳ
ͳͲͳʹ
ͳͲͳ͵
ͳͲͳͶ
ͳͲͳͷ
ͳͲͳ͸
ͳͲͳ͹
ͳͲͳͺ
ͳͲͳͻ
ͳͲʹͲ
ͳͲʹͳ
ͳͲʹʹ
ͳͲʹ͵
ͳͲʹͶ
ͳͲʹͷ
ͳͲʹ͸
ͳͲʹ͹
ͳͲʹͺ
ͳͲʹͻ
ͳͲ͵Ͳ
ͳͲ͵ͳ
ͳͲ͵ʹ
ͳͲ͵͵
ͳͲ͵Ͷ
ͳͲ͵ͷ
ͳͲ͵͸
ͳͲ͵͹
ͳͲ͵ͺ
ͳͲ͵ͻ
ͳͲͶͲ
ͳͲͶͳ
ͳͲͶʹ
ͳͲͶ͵
ͳͲͶͶ
ͳͲͶͷ
ͳͲͶ͸
ͳͲͶ͹
151.
Rudd JHF, Warburton EA, Fryer TD, Jones HA, Clark JC, Antoun N, Johnstrom P, Davenport AP,
Kirkpatrick PJ, Arch BN, Pickard JD, and Weissberg PL. Imaging Atherosclerotic Plaque Inflammation With
[18F]-Fluorodeoxyglucose Positron Emission Tomography. Circulation 105: 2708-2711, 2002.
152.
Ruehm SG, Corot C, Vogt P, Kolb S, and Debatin JF. Magnetic resonance imaging of atherosclerotic
plaque with ultrasmall superparamagnetic particles of iron oxide in hyperlipidemic rabbits. Circulation 103: 415422, 2001.
153.
Sarda-Mantel L, Michel JB, Rouzet F, Martet G, Louedec L, Vanderheyden JL, Hervatin F, Raguin
O, Vrigneaud JM, Khaw BA, and Le Guludec D. (99m)Tc-annexin V and (111)In-antimyosin antibody uptake
in experimental myocardial infarction in rats. Eur J Nucl Med Mol Imaging 33: 239-245, 2006.
154.
Schafers M, Riemann B, Kopka K, Breyholz HJ, Wagner S, Schafers KP, Law MP, Schober O, and
Levkau B. Scintigraphic imaging of matrix metalloproteinase activity in the arterial wall in vivo. Circulation 109:
2554-2559, 2004.
155.
Schmitz SA, Winterhalter S, Schiffler S, Gust R, Wagner S, Kresse M, Coupland SE, Semmler W,
and Wolf KJ. USPIO-enhanced direct MR imaging of thrombus: preclinical evaluation in rabbits. Radiology 221:
237-243, 2001.
156.
Schoenhagen P, Vince DG, Ziada KM, Kapadia SR, Lauer MA, Crowe TD, Nissen SE, and Tuzcu
EM. Relation of matrix-metalloproteinase 3 found in coronary lesion samples retrieved by directional coronary
atherectomy to intravascular ultrasound observations on coronary remodeling. Am J Cardiol 89: 1354-1359,
2002.
157.
Selvanayagam JB, Kardos A, Francis JM, Wiesmann F, Petersen SE, Taggart DP, and Neubauer
S. Value of delayed-enhancement cardiovascular magnetic resonance imaging in predicting myocardial viability
after surgical revascularization. Circulation 110: 1535-1541, 2004.
158.
Sigovan M, Boussel L, Sulaiman A, Sappey-Marinier D, Alsaid H, Desbleds-Mansard C, Ibarrola
D, Gamondes D, Corot C, Lancelot E, Raynaud JS, Vives V, Lacledere C, Violas X, Douek PC, and CanetSoulas E. Rapid-clearance iron nanoparticles for inflammation imaging of atherosclerotic plaque: initial
experience in animal model. Radiology 252: 401-409, 2009.
159.
Silvera SS, Aidi He, Rudd JHF, Mani V, Yang L, Farkouh M, Fuster V, and Fayad ZA. Multimodality
imaging of atherosclerotic plaque activity and composition using FDG-PET/CT and MRI in carotid and femoral
arteries. Atherosclerosis In Press, Corrected Proof.
160.
Sinusas AJ, Trautman KA, Bergin JD, Watson DD, Ruiz M, Smith WH, and Beller GA.
Quantification of area at risk during coronary occlusion and degree of myocardial salvage after reperfusion with
technetium-99m methoxyisobutyl isonitrile. Circulation 82: 1424-1437, 1990.
161.
Sipkins DA, Cheresh DA, Kazemi MR, Nevin LM, Bednarski MD, and Li KC. Detection of tumor
angiogenesis in vivo by alphaVbeta3-targeted magnetic resonance imaging. Nature medicine 4: 623-626, 1998.
162.
Sirol M, Aguinaldo JG, Graham PB, Weisskoff R, Lauffer R, Mizsei G, Chereshnev I, Fallon JT,
Reis E, Fuster V, Toussaint JF, and Fayad ZA. Fibrin-targeted contrast agent for improvement of in vivo acute
thrombus detection with magnetic resonance imaging. Atherosclerosis 182: 79-85, 2005.
163.
Sluijter JPG, Pulskens WPC, Schoneveld AH, Velema E, Strijder CF, Moll F, de Vries J-P,
Verheijen J, Hanemaaijer R, de Kleijn DPV, and Pasterkamp G. Matrix Metalloproteinase 2 Is Associated
With Stable and Matrix Metalloproteinases 8 and 9 With Vulnerable Carotid Atherosclerotic Lesions: A Study in
Human Endarterectomy Specimen Pointing to a Role for Different Extracellular Matrix Metalloproteinase Inducer
Glycosylation Forms. Stroke 37: 235-239, 2006.
164.
Smith BR, Heverhagen J, Knopp M, Schmalbrock P, Shapiro J, Shiomi M, Moldovan NI, Ferrari M,
and Lee SC. Localization to atherosclerotic plaque and biodistribution of biochemically derivatized
superparamagnetic iron oxide nanoparticles (SPIONs) contrast particles for magnetic resonance imaging (MRI).
Biomed Microdevices 9: 719-727, 2007.
165.
Sosnovik DE, Garanger E, Aikawa E, Nahrendorf M, Figuiredo JL, Dai G, Reynolds F, Rosenzweig
A, Weissleder R, and Josephson L. Molecular MRI of cardiomyocyte apoptosis with simultaneous delayedenhancement MRI distinguishes apoptotic and necrotic myocytes in vivo: potential for midmyocardial salvage in
acute ischemia. Circ Cardiovasc Imaging 2: 460-467, 2009.
166.
Sosnovik DE, Schellenberger EA, Nahrendorf M, Novikov MS, Matsui T, Dai G, Reynolds F,
Grazette L, Rosenzweig A, Weissleder R, and Josephson L. Magnetic resonance imaging of cardiomyocyte
apoptosis with a novel magneto-optical nanoparticle. Magn Reson Med 54: 718-724, 2005.
167.
Sosnovik DE, Wang R, Dai G, Wang T, Aikawa E, Novikov M, Rosenzweig A, Gilbert RJ, and
Wedeen VJ. Diffusion spectrum MRI tractography reveals the presence of a complex network of residual
myofibers in infarcted myocardium. Circ Cardiovasc Imaging 2: 206-212, 2009.
ʹͻ
ͳͲͶͺ
ͳͲͶͻ
ͳͲͷͲ
ͳͲͷͳ
ͳͲͷʹ
ͳͲͷ͵
ͳͲͷͶ
ͳͲͷͷ
ͳͲͷ͸
ͳͲͷ͹
ͳͲͷͺ
ͳͲͷͻ
ͳͲ͸Ͳ
ͳͲ͸ͳ
ͳͲ͸ʹ
ͳͲ͸͵
ͳͲ͸Ͷ
ͳͲ͸ͷ
ͳͲ͸͸
ͳͲ͸͹
ͳͲ͸ͺ
ͳͲ͸ͻ
ͳͲ͹Ͳ
ͳͲ͹ͳ
ͳͲ͹ʹ
ͳͲ͹͵
ͳͲ͹Ͷ
ͳͲ͹ͷ
ͳͲ͹͸
ͳͲ͹͹
ͳͲ͹ͺ
ͳͲ͹ͻ
ͳͲͺͲ
ͳͲͺͳ
ͳͲͺʹ
ͳͲͺ͵
ͳͲͺͶ
ͳͲͺͷ
ͳͲͺ͸
ͳͲͺ͹
ͳͲͺͺ
ͳͲͺͻ
ͳͲͻͲ
ͳͲͻͳ
ͳͲͻʹ
ͳͲͻ͵
ͳͲͻͶ
ͳͲͻͷ
ͳͲͻ͸
ͳͲͻ͹
ͳͲͻͺ
ͳͲͻͻ
ͳͳͲͲ
ͳͳͲͳ
ͳͳͲʹ
ͳͳͲ͵
ͳͳͲͶ
ͳͳͲͷ
168.
Spuentrup E, Botnar RM, Wiethoff AJ, Ibrahim T, Kelle S, Katoh M, Ozgun M, Nagel E, Vymazal J,
Graham PB, Gunther RW, and Maintz D. MR imaging of thrombi using EP-2104R, a fibrin-specific contrast
agent: initial results in patients. European radiology 18: 1995-2005, 2008.
169.
Spuentrup E, Buecker A, Katoh M, Wiethoff AJ, Parsons EC, Jr., Botnar RM, Weisskoff RM,
Graham PB, Manning WJ, and Gunther RW. Molecular magnetic resonance imaging of coronary thrombosis
and pulmonary emboli with a novel fibrin-targeted contrast agent. Circulation 111: 1377-1382, 2005.
170.
Spuentrup E, Fausten B, Kinzel S, Wiethoff AJ, Botnar RM, Graham PB, Haller S, Katoh M,
Parsons EC, Jr., Manning WJ, Busch T, Gunther RW, and Buecker A. Molecular magnetic resonance
imaging of atrial clots in a swine model. Circulation 112: 396-399, 2005.
171.
Spuentrup E, Katoh M, Wiethoff AJ, Parsons EC, Jr., Botnar RM, Mahnken AH, Gunther RW, and
Buecker A. Molecular magnetic resonance imaging of pulmonary emboli with a fibrin-specific contrast agent.
Am J Respir Crit Care Med 172: 494-500, 2005.
172.
Spuentrup E, Ruhl KM, Botnar RM, Wiethoff AJ, Buhl A, Jacques V, Greenfield MT, Krombach
GA, Gunther RW, Vangel MG, and Caravan P. Molecular magnetic resonance imaging of myocardial
perfusion with EP-3600, a collagen-specific contrast agent: initial feasibility study in a swine model. Circulation
119: 1768-1775, 2009.
173.
Steen H, Lima JA, Chatterjee S, Kolmakova A, Gao F, Rodriguez ER, and Stuber M. Highresolution three-dimensional aortic magnetic resonance angiography and quantitative vessel wall
characterization of different atherosclerotic stages in a rabbit model. Invest Radiol 42: 614-621, 2007.
174.
Stone GW, Maehara A, Lansky AJ, de Bruyne B, Cristea E, Mintz GS, Mehran R, McPherson J,
Farhat N, Marso SP, Parise H, Templin B, White R, Zhang Z, and Serruys PW. A prospective natural-history
study of coronary atherosclerosis. The New England journal of medicine 364: 226-235, 2011.
175.
Stracke CP, Katoh M, Wiethoff AJ, Parsons EC, Spangenberg P, and Spuntrup E. Molecular MRI of
cerebral venous sinus thrombosis using a new fibrin-specific MR contrast agent. Stroke; a journal of cerebral
circulation 38: 1476-1481, 2007.
176.
Su H, Spinale FG, Dobrucki LW, Song J, Hua J, Sweterlitsch S, Dione DP, Cavaliere P, Chow C,
Bourke BN, Hu XY, Azure M, Yalamanchili P, Liu R, Cheesman EH, Robinson S, Edwards DS, and
Sinusas AJ. Noninvasive targeted imaging of matrix metalloproteinase activation in a murine model of
postinfarction remodeling. Circulation 112: 3157-3167, 2005.
177.
Sugiyama S, Kugiyama K, Aikawa M, Nakamura S, Ogawa H, and Libby P. Hypochlorous acid, a
macrophage product, induces endothelial apoptosis and tissue factor expression: involvement of
myeloperoxidase-mediated oxidant in plaque erosion and thrombogenesis. Arteriosclerosis, thrombosis, and
vascular biology 24: 1309-1314, 2004.
178.
Sugiyama S, Okada Y, Sukhova GK, Virmani R, Heinecke JW, and Libby P. Macrophage
myeloperoxidase regulation by granulocyte macrophage colony-stimulating factor in human atherosclerosis and
implications in acute coronary syndromes. The American journal of pathology 158: 879-891, 2001.
179.
Sukhova GK, Schonbeck U, Rabkin E, Schoen FJ, Poole AR, Billinghurst RC, and Libby P.
Evidence for increased collagenolysis by interstitial collagenases-1 and -3 in vulnerable human atheromatous
plaques. Circulation 99: 2503-2509, 1999.
180.
Sukhova GK, Shi GP, Simon DI, Chapman HA, and 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 102: 576583, 1998.
181.
Tang T, Howarth SP, Miller SR, Trivedi R, Graves MJ, King-Im JU, Li ZY, Brown AP, Kirkpatrick
PJ, Gaunt ME, and Gillard JH. Assessment of inflammatory burden contralateral to the symptomatic carotid
stenosis using high-resolution ultrasmall, superparamagnetic iron oxide-enhanced MRI. Stroke; a journal of
cerebral circulation 37: 2266-2270, 2006.
182.
Tang TY, Howarth SP, Miller SR, Graves MJ, JM UK-I, Trivedi RA, Li ZY, Walsh SR, Brown AP,
Kirkpatrick PJ, Gaunt ME, and Gillard JH. Comparison of the inflammatory burden of truly asymptomatic
carotid atheroma with atherosclerotic plaques contralateral to symptomatic carotid stenosis: an ultra small
superparamagnetic iron oxide enhanced magnetic resonance study. J Neurol Neurosurg Psychiatry 78: 13371343, 2007.
183.
te Boekhorst BC, Bovens SM, Hellings WE, van der Kraak PH, van de Kolk KW, Vink A, Moll FL,
van Oosterhout MF, de Vries JP, Doevendans PA, Goumans MJ, de Kleijn DP, van Echteld CJ,
Pasterkamp G, and Sluijter JP. Molecular MRI of murine atherosclerotic plaque targeting NGAL: a protein
associated with unstable human plaque characteristics. Cardiovascular research 89: 680-688, 2011.
184.
te Boekhorst BC, Bovens SM, Rodrigues-Feo J, Sanders HM, van de Kolk CW, de Kroon AI,
Cramer MJ, Doevendans PA, ten Hove M, Pasterkamp G, and van Echteld CJ. Characterization and in vitro
and in vivo testing of CB2-receptor- and NGAL-targeted paramagnetic micelles for molecular MRI of vulnerable
͵Ͳ
ͳͳͲ͸
ͳͳͲ͹
ͳͳͲͺ
ͳͳͲͻ
ͳͳͳͲ
ͳͳͳͳ
ͳͳͳʹ
ͳͳͳ͵
ͳͳͳͶ
ͳͳͳͷ
ͳͳͳ͸
ͳͳͳ͹
ͳͳͳͺ
ͳͳͳͻ
ͳͳʹͲ
ͳͳʹͳ
ͳͳʹʹ
ͳͳʹ͵
ͳͳʹͶ
ͳͳʹͷ
ͳͳʹ͸
ͳͳʹ͹
ͳͳʹͺ
ͳͳʹͻ
ͳͳ͵Ͳ
ͳͳ͵ͳ
ͳͳ͵ʹ
ͳͳ͵͵
ͳͳ͵Ͷ
ͳͳ͵ͷ
ͳͳ͵͸
ͳͳ͵͹
ͳͳ͵ͺ
ͳͳ͵ͻ
ͳͳͶͲ
ͳͳͶͳ
ͳͳͶʹ
ͳͳͶ͵
ͳͳͶͶ
ͳͳͶͷ
ͳͳͶ͸
ͳͳͶ͹
ͳͳͶͺ
ͳͳͶͻ
ͳͳͷͲ
ͳͳͷͳ
ͳͳͷʹ
ͳͳͷ͵
ͳͳͷͶ
ͳͳͷͷ
ͳͳͷ͸
ͳͳͷ͹
ͳͳͷͺ
ͳͳͷͻ
ͳͳ͸Ͳ
ͳͳ͸ͳ
ͳͳ͸ʹ
atherosclerotic plaque. Molecular imaging and biology : MIB : the official publication of the Academy of
Molecular Imaging 12: 635-651, 2010.
185.
Terashima M, Nguyen PK, Rubin GD, Iribarren C, Courtney BK, Go AS, Fortmann SP, and
McConnell MV. Impaired coronary vasodilation by magnetic resonance angiography is associated with
advanced coronary artery calcification. JACC Cardiovascular imaging 1: 167-173, 2008.
186.
Torzewski M, Shaw PX, Han KR, Shortal B, Lackner KJ, Witztum JL, Palinski W, and Tsimikas S.
Reduced in vivo aortic uptake of radiolabeled oxidation-specific antibodies reflects changes in plaque
composition consistent with plaque stabilization. Arteriosclerosis, thrombosis, and vascular biology 24: 23072312, 2004.
187.
Toussaint JF, Southern JF, Fuster V, and Kantor HL. Water diffusion properties of human
atherosclerosis and thrombosis measured by pulse field gradient nuclear magnetic resonance. Arterioscler
Thromb Vasc Biol 17: 542-546, 1997.
188.
Trivedi RA, JM UK-I, Graves MJ, Horsley J, Goddard M, Kirkpatrick PJ, and Gillard JH. MRIderived measurements of fibrous-cap and lipid-core thickness: the potential for identifying vulnerable carotid
plaques in vivo. Neuroradiology 46: 738-743, 2004.
189.
Trivedi RA, JM UK-I, Graves MJ, Kirkpatrick PJ, and Gillard JH. Noninvasive imaging of carotid
plaque inflammation. Neurology 63: 187-188, 2004.
190.
Trivedi RA, Mallawarachi C, JM UK-I, Graves MJ, Horsley J, Goddard MJ, Brown A, Wang L,
Kirkpatrick PJ, Brown J, and Gillard JH. Identifying inflamed carotid plaques using in vivo USPIO-enhanced
MR imaging to label plaque macrophages. Arteriosclerosis, thrombosis, and vascular biology 26: 1601-1606,
2006.
191.
Tsimikas S, Shortal BP, Witztum JL, and 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. Arteriosclerosis, thrombosis, and vascular biology 20: 689-697,
2000.
192.
Tsujioka H, Imanishi T, Ikejima H, Kuroi A, Takarada S, Tanimoto T, Kitabata H, Okochi K, Arita Y,
Ishibashi K, Komukai K, Kataiwa H, Nakamura N, Hirata K, Tanaka A, and Akasaka T. Impact of
heterogeneity of human peripheral blood monocyte subsets on myocardial salvage in patients with primary
acute myocardial infarction. J Am Coll Cardiol 54: 130-138, 2009.
193.
Tung CH, Ho NH, Zeng Q, Tang Y, Jaffer FA, Reed GL, and Weissleder R. Novel factor XIII probes
for blood coagulation imaging. Chembiochem 4: 897-899, 2003.
194.
Underhill HR, Yuan C, Yarnykh VL, Chu B, Oikawa M, Polissar NL, Schwartz SM, Jarvik GP, and
Hatsukami TS. Arterial remodeling in the subclinical carotid artery disease. JACC Cardiovasc Imaging 2: 13811389, 2009.
195.
van Bochove GS, Sanders HMHF, de Smet M, Keizer HM, Mulder WJM, Krams R, Strijkers GJ,
and Nicolay K. Molecular MR Imaging of Collagen in Mouse Atherosclerosis by Using Paramagnetic CNA35
Micelles. European Journal of Inorganic Chemistry 2012: 2115-2125, 2012.
196.
van Tilborg GA, Vucic E, Strijkers GJ, Cormode DP, Mani V, Skajaa T, Reutelingsperger CP,
Fayad ZA, Mulder WJ, and Nicolay K. Annexin A5-functionalized bimodal nanoparticles for MRI and
fluorescence imaging of atherosclerotic plaques. Bioconjugate chemistry 21: 1794-1803, 2010.
197.
Vasilyev N, Williams T, Brennan ML, Unzek S, Zhou X, Heinecke JW, Spitz DR, Topol EJ, Hazen
SL, and Penn MS. Myeloperoxidase-generated oxidants modulate left ventricular remodeling but not infarct size
after myocardial infarction. Circulation 112: 2812-2820, 2005.
198.
Verhaert D, Thavendiranathan P, Giri S, Mihai G, Rajagopalan S, Simonetti OP, and Raman SV.
Direct T2 quantification of myocardial edema in acute ischemic injury. JACC Cardiovasc Imaging 4: 269-278,
2011.
199.
Vidmar J, Blinc A, and Sersa I. A comparison of the ADC and T2 mapping in an assessment of bloodclot lysability. NMR in biomedicine 23: 34-40, 2010.
200.
Viereck J, Ruberg FL, Qiao Y, Perez AS, Detwiller K, Johnstone M, and Hamilton JA. MRI of
atherothrombosis associated with plaque rupture. Arterioscler Thromb Vasc Biol 25: 240-245, 2005.
201.
Virmani R, Kolodgie FD, Burke AP, Finn AV, Gold HK, Tulenko TN, Wrenn SP, and Narula J.
Atherosclerotic plaque progression and vulnerability to rupture: angiogenesis as a source of intraplaque
hemorrhage. Arterioscler Thromb Vasc Biol 25: 2054-2061, 2005.
202.
von Bary C, Makowski M, Preissel A, Keithahn A, Warley A, Spuentrup E, Buecker A, Lazewatsky
J, Cesati R, Onthank D, Schickl N, Schachoff S, Hausleiter J, Schomig A, Schwaiger M, Robinson S, and
Botnar R. MRI of coronary wall remodeling in a swine model of coronary injury using an elastin-binding contrast
agent. Circ Cardiovasc Imaging 4: 147-155.
͵ͳ
ͳͳ͸͵
ͳͳ͸Ͷ
ͳͳ͸ͷ
ͳͳ͸͸
ͳͳ͸͹
ͳͳ͸ͺ
ͳͳ͸ͻ
ͳͳ͹Ͳ
ͳͳ͹ͳ
ͳͳ͹ʹ
ͳͳ͹͵
ͳͳ͹Ͷ
ͳͳ͹ͷ
ͳͳ͹͸
ͳͳ͹͹
ͳͳ͹ͺ
ͳͳ͹ͻ
ͳͳͺͲ
ͳͳͺͳ
ͳͳͺʹ
ͳͳͺ͵
ͳͳͺͶ
ͳͳͺͷ
ͳͳͺ͸
ͳͳͺ͹
ͳͳͺͺ
ͳͳͺͻ
ͳͳͻͲ
ͳͳͻͳ
ͳͳͻʹ
ͳͳͻ͵
ͳͳͻͶ
ͳͳͻͷ
ͳͳͻ͸
ͳͳͻ͹
ͳͳͻͺ
ͳͳͻͻ
ͳʹͲͲ
ͳʹͲͳ
ͳʹͲʹ
ͳʹͲ͵
ͳʹͲͶ
ͳʹͲͷ
ͳʹͲ͸
ͳʹͲ͹
ͳʹͲͺ
ͳʹͲͻ
ͳʹͳͲ
203.
von Elverfeldt D, Meissner M, Peter K, Paul D, Meixner F, Neudorfer I, Merkle A, Harloff A, Zirlik
A, Schollhorn J, Markl M, Hennig J, Bode C, and von zur Muhlen C. An approach towards molecular
imaging of activated platelets allows imaging of symptomatic human carotid plaques in a new model of a tissue
flow chamber. Contrast Media Mol Imaging 7: 204-213, 2012.
204.
von zur Muhlen C, von Elverfeldt D, Moeller JA, Choudhury RP, Paul D, Hagemeyer CE,
Olschewski M, Becker A, Neudorfer I, Bassler N, Schwarz M, Bode C, and Peter K. Magnetic resonance
imaging contrast agent targeted toward activated platelets allows in vivo detection of thrombosis and monitoring
of thrombolysis. Circulation 118: 258-267, 2008.
205.
Wagner A, Mahrholdt H, Holly TA, Elliott MD, Regenfus M, Parker M, Klocke FJ, Bonow RO, Kim
RJ, and Judd RM. Contrast-enhanced MRI and routine single photon emission computed tomography (SPECT)
perfusion imaging for detection of subendocardial myocardial infarcts: an imaging study. Lancet 361: 374-379,
2003.
206.
Weissleder R, Tung CH, Mahmood U, and Bogdanov A, Jr. In vivo imaging of tumors with proteaseactivated near-infrared fluorescent probes. Nature biotechnology 17: 375-378, 1999.
207.
Werns SW, Walton JA, Hsia HH, Nabel EG, Sanz ML, and Pitt B. Evidence of endothelial dysfunction
in angiographically normal coronary arteries of patients with coronary artery disease. Circulation 79: 287-291,
1989.
208.
White HD and Chew DP. Acute myocardial infarction. Lancet 372: 570-584, 2008.
209.
Wildgruber M, Settles M, Rickmer R, Ntziachristos V, Rummeny E, Botnar RM, and Huber A.
Magnetic Resonance Imaging of Murine Myocardial Infarction with an Elastin-binding Contrast Agent.
Proceedings of Radiological Society of North America 2010.
210.
Winter PM, Cai K, Chen J, Adair CR, Kiefer GE, Athey PS, Gaffney PJ, Buff CE, Robertson JD,
Caruthers SD, Wickline SA, and Lanza GM. Targeted PARACEST nanoparticle contrast agent for the
detection of fibrin. Magn Reson Med 56: 1384-1388, 2006.
211.
Winter PM, Morawski AM, Caruthers SD, Fuhrhop RW, Zhang H, Williams TA, Allen JS, Lacy EK,
Robertson JD, Lanza GM, and Wickline SA. Molecular imaging of angiogenesis in early-stage atherosclerosis
with alpha(v)beta3-integrin-targeted nanoparticles. Circulation 108: 2270-2274, 2003.
212.
Winter PM, Neubauer AM, Caruthers SD, Harris TD, Robertson JD, Williams TA, Schmieder AH,
Hu G, Allen JS, Lacy EK, Zhang H, Wickline SA, and Lanza GM. Endothelial alpha(v)beta3 integrin-targeted
fumagillin nanoparticles inhibit angiogenesis in atherosclerosis. Arterioscler Thromb Vasc Biol 26: 2103-2109,
2006.
213.
Yamakoshi Y, Qiao H, Lowell AN, Woods M, Paulose B, Nakao Y, Zhang H, Liu T, Lund-Katz S,
and Zhou R. LDL-based nanoparticles for contrast enhanced MRI of atheroplaques in mouse models. Chem
Commun (Camb) 47: 8835-8837.
214.
Yancy AD, Olzinski AR, Hu TC, Lenhard SC, Aravindhan K, Gruver SM, Jacobs PM, Willette RN,
and Jucker BM. Differential uptake of ferumoxtran-10 and ferumoxytol, ultrasmall superparamagnetic iron oxide
contrast agents in rabbit: critical determinants of atherosclerotic plaque labeling. Journal of magnetic resonance
imaging : JMRI 21: 432-442, 2005.
215.
Yang F, Liu YH, Yang XP, Xu J, Kapke A, and Carretero OA. Myocardial infarction and cardiac
remodelling in mice. Exp Physiol 87: 547-555, 2002.
216.
Yang Y, Yanasak N, Schumacher A, and Hu TC. Temporal and noninvasive monitoring of
inflammatory-cell infiltration to myocardial infarction sites using micrometer-sized iron oxide particles. Magn
Reson Med 63: 33-40, 2010.
217.
Yuan C, Zhang SX, Polissar NL, Echelard D, Ortiz G, Davis JW, Ellington E, Ferguson MS, and
Hatsukami TS. Identification of fibrous cap rupture with magnetic resonance imaging is highly associated with
recent transient ischemic attack or stroke. Circulation 105: 181-185, 2002.
ͳʹͳͳ
ͳʹͳʹ
ͳʹͳ͵
ͳʹͳͶ
ͳʹͳͷ
ͳʹͳ͸
͵ʹ
1, P-s
electi
n)
(Micr
o
iron o particles
xide
– MP of
IIO)
Pre
T2*
Ad
(VCAM hesion
8. THROMBUS
(Gadofosv
Fib
Fibrin
Trichrome staining
pa VS
rti OP
cl
es
Fibrous cap
monocyte
VCAM1
2. INFLAMMATION
(macrophages)
Sc
a
7. Extracellular
Matrix
ELASTIN
Gd-peptide
(CP1052)
3. LIPIDS
(cholesteryl esters,
cholesterol crystals)
MPO(Gd]
M
MPO IHC
A)
DWI
DWI
Lipids
d
24h Post
Pre
Post
v
3)
MPO (Gd)
Post
A-O
d)
MyeloAnnexinA5 (Gd-micelles)
peroxidase
se
O3
(G
te
Ex vivo DWI
4. ENZYMES
LD
L
dD
DL
(
5. APOPTOSIS
(G
rH
gr
in
s
6. Neovascularization
v
(G
d-i rec eng
mm ep
e
un to r
om r
ice
lle
s)
24h Post
tra iza
ns tio
fer n
Post
CO
LL
AG
Ma
gn
EN
et
SGM
1. ENDOTHELIUM
In
Magnetization transfer
ility
tide
Gd-peptide
04)
(EP 2104)
T1W Direct
thrombus
mbus
imaging
ging
eset)
C
Permeab
B
48h Post
SPECT/CT day 3
11
1
(tra In-DO
nsg TA
-F
l
SP utam XIII
ina
EC
T/C
s
T e)
Collagen CE-IR
Co
en
llag
T2W
7. EXTRACELLULAR
MATRIX
(Days - weeks)
1. EDEMA
(Hours)
H 2O
n
ulatio
accum
M
IR LGE
MRI
(EP3533)
64Cu-DOTA-
Increased
Ly-6hii
2. NECROSIS
extracellular
(Hours)
Ly-6
Ly
6loo Gd
space
6. NEOVASCULARIZATION
( 2 weeks)
VEGF121 (PET)
3. APOPTOSIS
(Hours)
5. ENZYMATIC
ACTIVITY
(Days - weeks)
MMP
4. INFLAMMATION
(Days)
MPO
18F-4V
PET/CT
19
FM
RI
DG
18 F
VSOP
T2*W
MRI
Day 14 post MI
Fused 18FDG-PET & MRI
2 days post VSOP
ET
MPO-Gd
T1w MRI
-P
Activatable
able
cence
fluorescence
sensor
AnxCLIOCy5.5
VC
AM
-1
Mac
r
pha oge
TAF
)
-R
c
)T
D grin
9m
(9
RG inte
T
3 EC
v
( SP
MRI
IR LGE
MRI
(Gd-DTPA)
T2*W MR
I