NATURE|Vol 451|21 February 2008|doi:10.

1038/nature06803 INSIGHT PROGRESS

Imaging of atherosclerotic
cardiovascular disease
Javier Sanz1 & Zahi A. Fayad1,2

Atherosclerosis is characterized by thickening of the walls of the arteries, a process that occurs slowly and
‘silently’ over decades. This prolonged course of disease provides a window of opportunity for diagnosis
before symptoms occur. But, until recently, only advanced atherosclerotic disease could be observed. Now,
developments in imaging technology offer many enticing prospects, including detecting atherosclerosis early,
grouping individuals by the probability that they will develop symptoms of atherosclerosis, assessing the
results of treatment and improving the current understanding of the biology of atherosclerosis.

Despite considerable therapeutic advances over the past 50 years, cardio-
vascular disease is the leading cause of death worldwide. This is mainly
a result of the increasing prevalence of atherosclerosis, owing to the age-
ing population, the improved survival of patients with atherosclerotic
cardiovascular disease and, above all, the widespread under-recognition
and undertreatment of individuals with risk factors for atherosclerosis.
Atherosclerosis is characterized by the thickening of the arterial wall
to form an atherosclerotic plaque, a process in which cholesterol depo-
sition, inflammation, extracellular-matrix formation and thrombosis
have important roles1 (Fig. 1) (see pages 904 and 914). Symptoms occur
late in the course of disease and are usually caused by the narrowing
of the lumen of the artery, which can happen gradually (as a result of
progressive plaque growth) or suddenly (as a result of plaque rupture
and, subsequently, thrombosis). The resultant decrease in blood supply
can affect almost any organ, although coronary heart disease and stroke
are the most common consequences.
Traditionally, diagnosis of atherosclerosis was possible only at
advanced stages of disease, either by directly revealing the narrowing
of the arterial lumen (stenosis) or by evaluating the effect of arterial
stenosis on organ perfusion. However, new imaging approaches allow
the assessment not only of the morphology of blood vessels but also
of the composition of the vessel walls, enabling atherosclerosis-associ-
ated abnormalities in the arteries (including the coronary arteries) to
be observed, down to the cellular and molecular level in some cases.
Some of these approaches are now in clinical use or are being tested in
clinical trials, whereas others are better suited to basic and translational
research. Here, we discuss recent advances in imaging cardiovascular
atherosclerotic disease, including revealing both the primary changes,
in the blood vessel wall, and the secondary changes, in the structure
and function of the heart. We focus first on advances in computed
tomography (CT) and magnetic resonance imaging (MRI) and then
discuss the growing field of molecular imaging.
The heart
Cardiac function, perfusion and contractility can be assessed non-inva-
sively by using various techniques: ultrasound, single-photon-emission
CT (SPECT), positron-emission tomography (PET) and, more recently,
MRI. These imaging techniques all provide information with diagnostic
and prognostic value, and their strengths and limitations have been
reviewed recently2.
MRI, in particular, has emerged as a versatile technique that can be
used to assess multiple cardiac parameters non-invasively in a single ses-
sion. These parameters include cardiac structure and function, metabolic
status, the presence of regions lacking sufficient blood flow (ischaemic
regions), and coronary artery stenosis3. At present, MRI is considered to
be the most accurate modality for assessing the volume, mass and ejection
fraction of both the left ventricle and the right ventricle, parameters with
important prognostic implications. MRI can also detect changes in the
magnetic properties of the tissue that are associated with increased water
content; this allows imaging of myocardial oedema, which occurs in acute
ischaemic injury. In addition, MRI can capture the accumulation of gado-
linium ion (Gd3+)-based contrast agents that occurs in areas of myocardial
scarring and/or necrosis within a few minutes of administration (referred
to as delayed enhancement), allowing myocardial infarction to be imaged
with unsurpassed resolution. The proportion of the myocardium showing
delayed enhancement inversely correlates with the likelihood of dysfunc-
tional myocardial segments recovering contractility. Recovery can occur
spontaneously or through revascularization, processes that are indica-
tive of heart injury known as ‘stunning’ and ‘hibernation’, respectively4.
In a recent study, the detection of even small amounts of myocardium
showing delayed enhancement in patients without known myocardial
infarction was identified as the best predictor of future adverse cardiac
events and death, in comparison with other commonly used clinical indi-
ces5. Moreover, because MRI provides highly reproducible results and does
not involve ionizing radiation, it can be used serially in animal or human
studies to test the effects of therapeutic interventions on the myocardium
in vivo; such testing therefore requires fewer individuals than for other
imaging techniques6. On the basis of these capabilities, MRI of the heart,
either alone or in combination with other imaging modalities, could be
important for assessing the potential benefits of myocardial regenerative
therapy (see page 937).
The coronary arteries
The narrowing of non-cardiac arteries has traditionally been detected
non-invasively by using techniques such as ultrasound, CT or MRI. CT
is well suited to studying all vascular regions, although it requires the use

1
The Zena and Michael A. Wiener Cardiovascular Institute and Marie-Josee and Henry R. Kravis Center for Cardiovascular Health, Mount Sinai School of Medicine, One Gustave L. Levy Place,
New York, New York 10029, USA. 2Translational and Molecular Imaging Institute, Imaging Science Laboratories, Departments of Radiology and Medicine, Mount Sinai School of Medicine, One
Gustave L. Levy Place, New York, New York 10029, USA.

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of potentially nephrotoxic contrast agents and ionizing radiation. These
limitations can now be largely overcome by using whole-body magnetic
resonance angiography, which can be carried out in less than 90 s. This
technique allows stenoses to be detected in the entire arterial system
— except the coronary circulation — in a single examination7.
Until recently, imaging of coronary stenoses required the insertion of
a catheter into the coronary artery during X-ray angiography. In the past
decade, however, it has become possible to image the coronary arter-
ies non-invasively, by using contrast-enhanced CT. CT technology has
evolved from machines that needed about 300 s to obtain a single image
to multidetector CT (MDCT) scanners that can simultaneously acquire
256 ‘slices’ in less than 250 ms, providing a complete coronary angiogram
in less than 15 s. In selected patients with stable disease and a normal
cardiac rhythm, MDCT has a sensitivity of 96% and a specificity of 74%
for detecting significant coronary stenoses (defined as more than 50%
narrowing of the diameter of the artery) compared with the traditional,
invasive technique, catheterization, which is the gold standard8. From a
clinical perspective, the most important advantage of MDCT is its high
negative predictive value: that is, a normal result on an MDCT exam can
convincingly rule out the possibility that significant coronary disease is
present9. One limitation is that the heart rate must be slow for the image
to be of adequate quality, but this might be overcome by using the newest
generation of CT equipment, in which two X-ray sources and detectors are
present in a single scanner (known as dual-source CT), thereby improving
the temporal resolution of images10.
The arterial walls
Atherosclerosis is a disease of the blood vessel wall, so the ability to
identify plaques before luminal stenosis develops is the cornerstone of
early disease detection. However, the thinness of the normal vessel wall
(< 1 mm for most arteries) presents a huge challenge for imaging. Several
invasive (catheter-based) techniques have been used to evaluate the mor-
phology of plaques and other features of the vessel wall. These techniques
include angioscopy (direct visualization of the inner surface of the ves-
sel wall by using fibre-optic technology), optical coherence tomography,
thermography, near-infrared spectroscopy, intravascular MRI and, most
extensively, intravascular ultrasound11. These modalities are suitable for
evaluating the coronary arteries and — because of the proximity of the
imaging probe to the vessel wall — provide high spatial resolution (for
example, < 15 μm with optical coherence tomography). However, the
requirement for catheterization is a definite limitation. Ultrasound can
also be used non-invasively to measure the intima-media thickness of the
carotid arteries, because these arteries are located superficially. Increased
carotid intima-media thickness provides some additive information to
conventional risk factors in determining the risk of future myocardial
infarction or stroke12.
With recently developed CT technology, the coronary arteries can now
be imaged non-invasively (as described earlier). CT has, however, long
been used for the non-invasive detection of coronary calcium deposits
(yielding a ‘calcium score’), a specific indicator of atherosclerosis that
has prognostic value in asymptomatic individuals. Depending on the

Process Endothelial- Endothelial- Inflammation Proteolysis Lipid-core Angiogenesis Thrombosis

cell dysfunction cell activation Apoptosis and fibrous-
cap formation

Target Flow-mediated Adhesion Macrophages MMPs Lipid core αvβ3-Integrin Fibrin

vasodilation molecules Cathepsins Fibrous cap Platelets (αIIbβ3-integrin)
Tissue factor

Fibrin
Fibrous cap
Platelet Thrombus
Monocyte
Blood
recruitment
VCAM1, ICAM1
and selectins
Endothelial cell
Smooth
muscle
cell
↓Nitric-oxide Apoptotic cell
production
Tissue factor

LDL Cholesterol
MMP Lipid-rich
Collagen fibril necrotic core
T cell

Foam cell

Tissue
Internal elastic lamina
αvβ3-Integrin

New blood vessel

Approximate I II III IV V VI
AHA lesion
stage
Figure 1 | The development of an atherosclerotic lesion. The progression of at each stage are also listed. AHA, American Heart Association; ICAM1,
an atherosclerotic lesion is shown in a simplified form, developing from a intercellular adhesion molecule 1; LDL, low-density lipoprotein; MMP,
normal blood vessel (far left) to a vessel with an atherosclerotic plaque and matrix metalloproteinase; VCAM1, vascular cell-adhesion molecule 1.
superimposed thrombus (far right). Potential targets for molecular imaging Figure adapted, with permission, from ref. 25.
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Table 1 | Targets and contrast agents for molecular imaging of atherosclerosis

Target Biological roles Contrast agent* Rationale for use Modality
Inflammatory Crucial in early plaque development, lipid Ultrasmall superparamagnetic Phagocytosed by macrophages MRI
cells modification, smooth muscle cell proliferation, iron-oxide particles29
(including extracellular-matrix formation, angiogenesis, [18F]Fluorodeoxyglucose32,33 Taken up by metabolically active cells PET
macrophages) plaque rupture and thrombosis
N1177 (iodinated particle)31 Accumulates in macrophages CT
CD204-specific-antibody- Target the macrophage scavenger receptor MRI
carrying, Gd3+-loaded (CD204)
micelles30
99m
Tc-labelled interleukin-2 Binds to activated T cells SPECT
99m
Apoptotic cells Release pro-coagulant and pro-oxidative stimuli Tc-labelled annexin V High affinity for phosphatidylserine, a molecule SPECT
that contribute to plaque destabilization and Annexin-V-crosslinked iron present at the surface of apoptotic cells MRI and
myocardial injury oxide–Cy5.5 NIRF
Proteases Participate in plaque remodelling and rupture, as Gelatinase probe Fluorescent substrate for MMP2 and MMP9 NIRF
well as in infarct remodelling and healing Prosense37 Fluorescent substrate for cathepsins NIRF
P947 Contains an MMP-inhibitory peptide MRI
Vascular Mediate the adhesion of inflammatory cells to VINP-28 (ref. 35) Contains a peptide with high affinity for VCAM1 MRI and
cell-adhesion the endothelium and the recruitment of these NIRF
molecules cells into atherosclerotic lesions and injured Microbubbles containing sialyl- Bind to selectins Ultrasound
myocardium LewisX (ref. 36)

Extracellular An important component of plaques, particularly Gadofluorine Binds to extracellular-matrix components MRI
matrix abundant in advanced lesions (such as tenascin, proteoglycans and collagen)
99m
Lipoproteins Involved in the trafficking of cholesterol between Tc-labelled MDA2 Binds to oxidized LDL, a potent intraplaque SPECT
the blood and atherosclerotic plaques pro-inflammatory stimulus
HDL-like nanoparticles HDL removes cholesterol from plaques MRI
(known as reverse cholesterol transport)
New blood Contribute to intraplaque haemorrhage, plaque Paramagnetic nanoparticles38 Target αVβ3-integrin, a key mediator of MRI
vessels growth and destabilization, and myocardial healing 99mTc-labelled NC100692 angiogenesis SPECT
and remodelling
Thrombi A hallmark of acute vascular syndromes, and EP-2104R (ref. 34) Contains a peptide with a high affinity for fibrin MRI
promote plaque growth 99m
Tc-labelled apcitide Contains a peptide with a high affinity for the SPECT
platelet cell-surface molecule αIIbβ3-integrin
IR-786-labelled platelets40 Incorporated into thrombi NIRF
*For agents for which no reference is given, and for discussion of other potential targets, see refs 22, 24–28. HDL, high-density lipoprotein; LDL, low-density lipoprotein; MDA2, monoclonal antibody specific for
malondialdehyde; MMP, matrix metalloproteinase; NIRF, near-infrared fluorescence; Tc, technetium; VCAM1, vascular cell-adhesion molecule 1.

individual studied (in terms of age, ethnicity, baseline risk of cardiovas-
cular disease, and so on) and the thresholds used, the risk of subsequent
death or myocardial infarction associated with a high calcium score
increases up to 12-fold after adjusting for conventional risk factors13. As
a result, it has been proposed that the coronary calcium score, alone or
in combination with the carotid intima-media thickness, could be used
for initial stratification of cardiovascular risk in the general population14.
Nonetheless, this approach is not without controversy, largely because
of the required X-ray exposure and the financial cost15. Although coro-
nary calcifications are easily detected by CT, about three-quarters of
all coronary lesions are non-calcified plaques. Such plaques can now
be detected with modern CT scanners after contrast agents have been
administered to patients. Moreover, in patients with chest pain, it was
recently shown that the extent of non-calcified atherosclerosis in a coro-
nary CT angiogram is correlated with increasing mortality16. CT can
also provide reasonably accurate quantification of plaque size and crude
characterization of plaque composition, on the basis of lipid-rich tissue
attenuating X-rays to a smaller extent than fibrous tissue17.
MRI has also developed into an excellent modality for non-invasively
evaluating the blood vessel wall, and it has the advantage over CT of not
exposing the patient to ionizing radiation. ‘Black-blood’ techniques (an
imaging approach in which the blood appears black and the arterial wall
can be seen) accurately depict plaque presence, size and morphology with
submillimetre resolution and high reproducibility, providing new indi-
ces of atherosclerotic burden that can be applied to large populations18.
Using this technique, with serial testing of an individual, it is possible to
track changes in arterial disease and to test the effects of therapies for
atherosclerosis in a completely non-invasive manner19. Although prelimi-
nary data show that it is feasible to use MRI to evaluate the coronary artery
wall, this remains challenging because of the small diameter, the tortuos-
ity (twistedness) and the continuous movement of the coronary arteries.
Therefore, MRI is mainly used to study extra-cardiac vessels. MRI can
also be used to provide insight into the composition and biological activ-
ity of different types of atherosclerotic lesion, one of the most important
goals of imaging. The probability of plaque rupture and the subsequent
clinical complications differ substantially between plaque types. Features
of higher rupture risk include the following: active inflammation, a thin
fibrous cap with a large lipid core, erosion or fissure of the plaque surface,
a superimposed thrombus, a stenosis that narrows the luminal diameter
by more than 90%, superficial calcified nodules, intraplaque haemorrhage
and outward remodelling20. By combining images acquired with different
parameters, MRI can reliably detect and quantify plaque components such
as lipids, fibro-cellular tissue, calcium and intraplaque haemorrhage, and
can detect and characterize a superimposed thrombus21,22. The clinical
implications of these capabilities were highlighted in a recent study of
asymptomatic patients with moderate carotid stenosis (50–79% luminal
narrowing) in which several high-risk features of the plaques observed by
using MRI predicted subsequent cerebrovascular events23.
Molecular imaging
Not only has the ability to image cardiovascular anatomy and physi-
ology on a macroscopic scale (as has been discussed so far) improved
markedly in the past decade, but it has also become increasingly
possible to detect biological processes at the cellular or even molecular
level. Molecular imaging relies on the use of contrast agents that target
specific cells or molecular pathways of relevance to disease. In addition
to the various imaging techniques being developed, contrast agents for
tracking potentially important components of atherosclerotic disease
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a The choice of target for imaging is also clearly important. Because
b c
d rophage scavenger receptor30. Similarly, in rabbits, specific uptake of an
Figure 2 | Multimodal imaging of inflammation and atherosclerosis.
a, Molecular imaging of macrophages by using CT, with the iodinated
contrast agent N1177. After in vitro incubation of mouse macrophages
with N1177, light microscopy in a phase-contrast mode shows the presence
of multiple cytoplasmic granules (red arrow), confirming uptake of the
contrast agent by macrophages. b, Three-dimensional reconstruction
of a rabbit’s abdominal aorta at 2 h after intravenous administration of
N1177. A false-colour image of N1177 staining is shown overlaid on an
angiogram. Intense red spots indicate areas of N1177 accumulation in
aortic plaques, which are rich in macrophages (white arrows). Organs with
high macrophage density are also visible, including the spleen (top right).
c, A combined PET and CT image of a human neck (axial view).
Atherosclerotic pathology is present at the bifurcation of the right
common carotid artery (red arrows), as determined by the presence of
heavy calcification and large amounts of [18F]fluorodeoxyglucose, which
is indicative of inflammatory activity. d, Black-blood MRI of the same
artery. Carotid arterial wall thickening is evident, as are two areas of signal
drop (red arrows), which correspond to calcified regions. (Panels a and b
reproduced, with permission, from ref. 31. Panels c and d reproduced, with
permission, from ref. 26.)
are at various stages of development22,24–28 (Fig. 1 and Table 1). Most of
the available probes are in experimental testing, although some have
already advanced to clinical evaluation. Imaging probes typically include
a moiety (such as an antibody or specific ligand) with high affinity for
the desired target molecule. Alternatively, the probe can be modified
to facilitate uptake by specific cells. In addition, probes are designed to
be detected by various modalities, including ultrasound (which detects
microbubbles), SPECT and PET (radioactive isotopes), MRI (paramag-
netic and superparamagnetic compounds), CT (iodinated compounds)
or optical imaging (fluorochromes). Many of the targets of interest are
located in deep organs and are present at very low (nanomolar) concen-
trations; imaging modalities therefore need to be highly sensitive, as well
as safe and economically viable.
Ultrasound is widely available, safe and inexpensive, but it has insuf-
ficient penetration for the non-invasive imaging of deep vessels (including
the coronary arteries) with high spatial resolution or sensitivity. SPECT
and PET have a high sensitivity, but they also have limited spatial resolu-
tion and the additional disadvantage of requiring the use of radioactive
agents. By contrast, MRI has a somewhat lower sensitivity than SPECT
and PET and requires prolonged imaging times, but it is safe and provides
excellent resolution (~10 μm with high-field magnets). CT, conversely,
offers the advantages of fast scanning times and superior performance for
coronary angiography, at the expense of limited sensitivity and the use of
nephrotoxic agents and ionizing radiation. Optical imaging techniques —
for example, near-infrared fluorescence reflectance or fluorescence molec-
ular tomography — have excellent sensitivity and temporal resolution and
allow the tissue distribution of the probe to be precisely determined with
ex vivo fluorescence microscopy. So far, however, such techniques can
be used non-invasively only to monitor superficial structures because of
the limited ability of light to penetrate tissue. Optical imaging techniques
and some SPECT and MRI techniques have the advantage of being able
to detect more than one molecular signature at a time.
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NATURE|Vol 451|21 February 2008
inflammation has a crucial role at all stages of atherosclerosis (Fig. 1),
macrophages are currently one of the most appealing targets. Ultrasmall
paramagnetic iron-oxide particles are engulfed by macrophages in vivo,
and this causes a detectable decrease in the MRI signal in proportion to the
degree of atherosclerotic plaque inflammation, as shown in human stud-
ies29. A strong correlation between macrophage density and MRI signal
was also found recently in a mouse model of atherosclerosis, by using a
contrast agent consisting of Gd3+-loaded micelles targeted to the mac-
iodine-containing contrast agent by macrophages allows atherosclerotic
lesions to be detected by using CT31 (Fig. 2a, b). Also, with PET, the sig-
nal from [18F]fluorodeoxyglucose correlates with the concentration of
macrophages in human atherosclerotic plaques32. Moreover, by using
specialized equipment, several imaging techniques can be used concur-
rently — for example, PET together with CT or, recently, MRI (Fig. 2c, d)
— for the sensitive and reproducible detection of vascular inflammation33.
This combination approach allows the most appropriate technique(s) for
a particular patient, vascular region and/or disease stage to be chosen and
takes advantage of the particular strengths of each modality.
Thrombi are another attractive target for imaging, because acute
clinical events often occur as a result of thrombosis triggered by plaque
rupture (Fig. 1). In animal models, thrombi of different ages and in dif-
ferent vascular regions have been detected with MRI34, and this approach
is now being investigated in humans26. At the other end of the timeline
of atherosclerotic-plaque progression (Fig. 1), cell-adhesion molecules
participate in the early development of lesions by facilitating the recruit-
ment of leukocytes into the vessel wall. In an animal model, increased
amounts of vascular cell-adhesion molecule 1 (VCAM1) were found in
aortic plaques by using a dual contrast agent detectable by both MRI and
optical imaging35. A similar approach, which used ultrasound detection
of microbubbles, found increased expression of endothelial selectins in
the heart of rats that had been subjected to transient myocardial ischaemia
followed by reperfusion36. Development of such probes for clinical use
could allow the identification of atherosclerosis at early stages and the
detection of plaque rupture (which, even when clinically silent, indicates
disease instability).
Another possibility is to use probes that emit a detectable signal only
after they have been activated by the target. For example, in a recent study
of an experimental model of atherosclerosis, a fluorescent probe activated
by enzymatic degradation was used to reveal intraplaque protease activity
with near-infrared fluorescence37.
In addition to being diagnostic and prognostic indicators, probes
could also be used for therapeutic purposes, to deliver drugs in a targeted
manner. An example of this is a study in which rabbits were adminis-
tered paramagnetic nanoparticles loaded with an antiangiogenic drug,
resulting in a reduction in the extent of blood vessels in atherosclerotic
plaques, as observed by non-invasive tracking with MRI38. In addition,
haematopoietic or cardiac stem cells for use in cell-based therapy could
be tagged with appropriate imaging probes, providing insights into the
role and fate of these cells after their administration39.
Future directions
Rapid technological progress is transforming the imaging of atheroscle-
rotic cardiovascular disease from a method of diagnosis in symptom-
atic patients to a tool for the non-invasive detection of early subclinical
abnormalities. In addition, a new generation of hybrid technology is
now becoming available; this technology combines multiple imaging
modalities in a single platform, using one machine for more than one
type of imaging (Fig. 2c). And new probes designed to be detected by
several modalities can take advantage of the strengths of each.
The availability of more powerful imaging techniques has the potential
to improve our understanding of the biology of atherosclerosis. Much of
the current knowledge has been inferred from static histopathological
observations of animal models or human tissue samples studied at dif-
ferent disease stages or after various therapeutic interventions. By using
molecular imaging, it is now becoming increasingly possible to obtain
NATURE|Vol 451|21 February 2008
non-invasively — from living experimental animals and, even, humans
— the type of information that was previously available only through
immunohistochemistry.
Improved imaging technologies also hold promise for aiding drug
development. Rather than relying on the plasma concentrations of a
specific therapeutic agent to infer that it has been delivered to the target
organ, imaging might be able to provide a direct read-out of the agent’s
local concentration and activity. Such information could be enormously
helpful for deciding which therapies are the best candidates for proceed-
ing to clinical trials26.
Prospective studies that will provide information about the signifi-
cance of currently available imaging data, considered either alone or in
the context of conventional risk factors and emerging serum and genetic
biomarkers (see page 949), are in progress. Examples are the Multi-
Ethnic Study of Atherosclerosis (MESA; http://www.mesa-nhlbi.org/)
and the High-Risk Plaque (HRP) Initiative (http://www.hrpinitiative.
com), both studies of asymptomatic individuals of various ethnic back-
grounds. Another example is a subset of the FREEDOM trial (Future
Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal
Management of Multivessel Disease trial), which involves diabetic individ-
uals with proven coronary heart disease. With data from such investiga-
tions, it might be possible to distinguish which patients would benefit from
therapeutic intervention. Preventing atherothrombotic events through
early detection would have enormous medical impact, and imaging is
set to have a prominent role in making this a reality. In this regard, it will
be imperative to evaluate emerging imaging technologies rigorously to
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Acknowledgements This work was partly funded by the National Institutes of
Health and the National Heart, Lung, and Blood Institute.
Author Information Reprints and permissions information is available at
npg.nature.com/reprints. The authors declare no competing financial interests.
Correspondence should be addressed to Z.A.F. (zahi.fayad@mssm.edu).
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