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- and prognostic value, and their strengths and limitations have been
vascular disease is the leading cause of death worldwide. This is mainly reviewed recently2.
a result of the increasing prevalence of atherosclerosis, owing to the age- MRI, in particular, has emerged as a versatile technique that can be
ing population, the improved survival of patients with atherosclerotic used to assess multiple cardiac parameters non-invasively in a single ses-
cardiovascular disease and, above all, the widespread under-recognition sion. These parameters include cardiac structure and function, metabolic
and undertreatment of individuals with risk factors for atherosclerosis. status, the presence of regions lacking sufficient blood flow (ischaemic
Atherosclerosis is characterized by the thickening of the arterial wall regions), and coronary artery stenosis3. At present, MRI is considered to
to form an atherosclerotic plaque, a process in which cholesterol depo- be the most accurate modality for assessing the volume, mass and ejection
sition, inflammation, extracellular-matrix formation and thrombosis fraction of both the left ventricle and the right ventricle, parameters with
have important roles1 (Fig. 1) (see pages 904 and 914). Symptoms occur important prognostic implications. MRI can also detect changes in the
late in the course of disease and are usually caused by the narrowing magnetic properties of the tissue that are associated with increased water
of the lumen of the artery, which can happen gradually (as a result of content; this allows imaging of myocardial oedema, which occurs in acute
progressive plaque growth) or suddenly (as a result of plaque rupture ischaemic injury. In addition, MRI can capture the accumulation of gado-
and, subsequently, thrombosis). The resultant decrease in blood supply linium ion (Gd3+)-based contrast agents that occurs in areas of myocardial
can affect almost any organ, although coronary heart disease and stroke scarring and/or necrosis within a few minutes of administration (referred
are the most common consequences. to as delayed enhancement), allowing myocardial infarction to be imaged
Traditionally, diagnosis of atherosclerosis was possible only at with unsurpassed resolution. The proportion of the myocardium showing
advanced stages of disease, either by directly revealing the narrowing delayed enhancement inversely correlates with the likelihood of dysfunc-
of the arterial lumen (stenosis) or by evaluating the effect of arterial tional myocardial segments recovering contractility. Recovery can occur
stenosis on organ perfusion. However, new imaging approaches allow spontaneously or through revascularization, processes that are indica-
the assessment not only of the morphology of blood vessels but also tive of heart injury known as ‘stunning’ and ‘hibernation’, respectively4.
of the composition of the vessel walls, enabling atherosclerosis-associ- In a recent study, the detection of even small amounts of myocardium
ated abnormalities in the arteries (including the coronary arteries) to showing delayed enhancement in patients without known myocardial
be observed, down to the cellular and molecular level in some cases. infarction was identified as the best predictor of future adverse cardiac
Some of these approaches are now in clinical use or are being tested in events and death, in comparison with other commonly used clinical indi-
clinical trials, whereas others are better suited to basic and translational ces5. Moreover, because MRI provides highly reproducible results and does
research. Here, we discuss recent advances in imaging cardiovascular not involve ionizing radiation, it can be used serially in animal or human
atherosclerotic disease, including revealing both the primary changes, studies to test the effects of therapeutic interventions on the myocardium
in the blood vessel wall, and the secondary changes, in the structure in vivo; such testing therefore requires fewer individuals than for other
and function of the heart. We focus first on advances in computed imaging techniques6. On the basis of these capabilities, MRI of the heart,
tomography (CT) and magnetic resonance imaging (MRI) and then either alone or in combination with other imaging modalities, could be
discuss the growing field of molecular imaging. important for assessing the potential benefits of myocardial regenerative
therapy (see page 937).
The heart
Cardiac function, perfusion and contractility can be assessed non-inva- The coronary arteries
sively by using various techniques: ultrasound, single-photon-emission The narrowing of non-cardiac arteries has traditionally been detected
CT (SPECT), positron-emission tomography (PET) and, more recently, non-invasively by using techniques such as ultrasound, CT or MRI. CT
MRI. These imaging techniques all provide information with diagnostic 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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INSIGHT PROGRESS NATURE|Vol 451|21 February 2008
of potentially nephrotoxic contrast agents and ionizing radiation. These The arterial walls
limitations can now be largely overcome by using whole-body magnetic Atherosclerosis is a disease of the blood vessel wall, so the ability to
resonance angiography, which can be carried out in less than 90 s. This identify plaques before luminal stenosis develops is the cornerstone of
technique allows stenoses to be detected in the entire arterial system early disease detection. However, the thinness of the normal vessel wall
— except the coronary circulation — in a single examination7. (< 1 mm for most arteries) presents a huge challenge for imaging. Several
Until recently, imaging of coronary stenoses required the insertion of invasive (catheter-based) techniques have been used to evaluate the mor-
a catheter into the coronary artery during X-ray angiography. In the past phology of plaques and other features of the vessel wall. These techniques
decade, however, it has become possible to image the coronary arter- include angioscopy (direct visualization of the inner surface of the ves-
ies non-invasively, by using contrast-enhanced CT. CT technology has sel wall by using fibre-optic technology), optical coherence tomography,
evolved from machines that needed about 300 s to obtain a single image thermography, near-infrared spectroscopy, intravascular MRI and, most
to multidetector CT (MDCT) scanners that can simultaneously acquire extensively, intravascular ultrasound11. These modalities are suitable for
256 ‘slices’ in less than 250 ms, providing a complete coronary angiogram evaluating the coronary arteries and — because of the proximity of the
in less than 15 s. In selected patients with stable disease and a normal imaging probe to the vessel wall — provide high spatial resolution (for
cardiac rhythm, MDCT has a sensitivity of 96% and a specificity of 74% example, < 15 μm with optical coherence tomography). However, the
for detecting significant coronary stenoses (defined as more than 50% requirement for catheterization is a definite limitation. Ultrasound can
narrowing of the diameter of the artery) compared with the traditional, also be used non-invasively to measure the intima-media thickness of the
invasive technique, catheterization, which is the gold standard8. From a carotid arteries, because these arteries are located superficially. Increased
clinical perspective, the most important advantage of MDCT is its high carotid intima-media thickness provides some additive information to
negative predictive value: that is, a normal result on an MDCT exam can conventional risk factors in determining the risk of future myocardial
convincingly rule out the possibility that significant coronary disease is infarction or stroke12.
present9. One limitation is that the heart rate must be slow for the image With recently developed CT technology, the coronary arteries can now
to be of adequate quality, but this might be overcome by using the newest be imaged non-invasively (as described earlier). CT has, however, long
generation of CT equipment, in which two X-ray sources and detectors are been used for the non-invasive detection of coronary calcium deposits
present in a single scanner (known as dual-source CT), thereby improving (yielding a ‘calcium score’), a specific indicator of atherosclerosis that
the temporal resolution of images10. has prognostic value in asymptomatic individuals. Depending on the
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
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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NATURE|Vol 451|21 February 2008 INSIGHT PROGRESS
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- wall, this remains challenging because of the small diameter, the tortuos-
cular disease, and so on) and the thresholds used, the risk of subsequent ity (twistedness) and the continuous movement of the coronary arteries.
death or myocardial infarction associated with a high calcium score Therefore, MRI is mainly used to study extra-cardiac vessels. MRI can
increases up to 12-fold after adjusting for conventional risk factors13. As also be used to provide insight into the composition and biological activ-
a result, it has been proposed that the coronary calcium score, alone or ity of different types of atherosclerotic lesion, one of the most important
in combination with the carotid intima-media thickness, could be used goals of imaging. The probability of plaque rupture and the subsequent
for initial stratification of cardiovascular risk in the general population14. clinical complications differ substantially between plaque types. Features
Nonetheless, this approach is not without controversy, largely because of higher rupture risk include the following: active inflammation, a thin
of the required X-ray exposure and the financial cost15. Although coro- fibrous cap with a large lipid core, erosion or fissure of the plaque surface,
nary calcifications are easily detected by CT, about three-quarters of a superimposed thrombus, a stenosis that narrows the luminal diameter
all coronary lesions are non-calcified plaques. Such plaques can now by more than 90%, superficial calcified nodules, intraplaque haemorrhage
be detected with modern CT scanners after contrast agents have been and outward remodelling20. By combining images acquired with different
administered to patients. Moreover, in patients with chest pain, it was parameters, MRI can reliably detect and quantify plaque components such
recently shown that the extent of non-calcified atherosclerosis in a coro- as lipids, fibro-cellular tissue, calcium and intraplaque haemorrhage, and
nary CT angiogram is correlated with increasing mortality16. CT can can detect and characterize a superimposed thrombus21,22. The clinical
also provide reasonably accurate quantification of plaque size and crude implications of these capabilities were highlighted in a recent study of
characterization of plaque composition, on the basis of lipid-rich tissue asymptomatic patients with moderate carotid stenosis (50–79% luminal
attenuating X-rays to a smaller extent than fibrous tissue17. narrowing) in which several high-risk features of the plaques observed by
MRI has also developed into an excellent modality for non-invasively using MRI predicted subsequent cerebrovascular events23.
evaluating the blood vessel wall, and it has the advantage over CT of not
exposing the patient to ionizing radiation. ‘Black-blood’ techniques (an Molecular imaging
imaging approach in which the blood appears black and the arterial wall Not only has the ability to image cardiovascular anatomy and physi-
can be seen) accurately depict plaque presence, size and morphology with ology on a macroscopic scale (as has been discussed so far) improved
submillimetre resolution and high reproducibility, providing new indi- markedly in the past decade, but it has also become increasingly
ces of atherosclerotic burden that can be applied to large populations18. possible to detect biological processes at the cellular or even molecular
Using this technique, with serial testing of an individual, it is possible to level. Molecular imaging relies on the use of contrast agents that target
track changes in arterial disease and to test the effects of therapies for specific cells or molecular pathways of relevance to disease. In addition
atherosclerosis in a completely non-invasive manner19. Although prelimi- to the various imaging techniques being developed, contrast agents for
nary data show that it is feasible to use MRI to evaluate the coronary artery tracking potentially important components of atherosclerotic disease
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INSIGHT PROGRESS NATURE|Vol 451|21 February 2008
non-invasively — from living experimental animals and, even, humans Committee to Update the 2000 Expert Consensus Document on Electron Beam
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artery calcium scoring by computed tomography in global cardiovascular risk assessment Author Information Reprints and permissions information is available at
and in evaluation of patients with chest pain: a report of the American College of npg.nature.com/reprints. The authors declare no competing financial interests.
Cardiology Foundation Clinical Expert Consensus Task Force (ACCF/AHA Writing Correspondence should be addressed to Z.A.F. (zahi.fayad@mssm.edu).
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