NATURE|Vol 451|21 February 2008|doi:10.1038/nature06803                                                                   ...
INSIGHT PROGRESS                                                                                                          ...
NATURE|Vol 451|21 February 2008                                                                                           ...
INSIGHT PROGRESS                                                                                                          ...
NATURE|Vol 451|21 February 2008                                                                                           ...
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  1. 1. NATURE|Vol 451|21 February 2008|doi:10.1038/nature06803 INSIGHT PROGRESSImaging of atheroscleroticcardiovascular diseaseJavier Sanz1 & Zahi A. Fayad1,2Atherosclerosis 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 diagnosisbefore 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 theresults 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 beenvascular 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 being 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, metabolicand undertreatment of individuals with risk factors for atherosclerosis. status, the presence of regions lacking sufficient blood flow (ischaemicAtherosclerosis is characterized by the thickening of the arterial wall regions), and coronary artery stenosis3. At present, MRI is considered toto form an atherosclerotic plaque, a process in which cholesterol depo- be the most accurate modality for assessing the volume, mass and ejectionsition, inflammation, extracellular-matrix formation and thrombosis fraction of both the left ventricle and the right ventricle, parameters withhave important roles1 (Fig. 1) (see pages 904 and 914). Symptoms occur important prognostic implications. MRI can also detect changes in thelate in the course of disease and are usually caused by the narrowing magnetic properties of the tissue that are associated with increased waterof the lumen of the artery, which can happen gradually (as a result of content; this allows imaging of myocardial oedema, which occurs in acuteprogressive 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 myocardialcan affect almost any organ, although coronary heart disease and stroke scarring and/or necrosis within a few minutes of administration (referredare 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 showingadvanced 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 occurstenosis 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 myocardiumated abnormalities in the arteries (including the coronary arteries) to showing delayed enhancement in patients without known myocardialbe observed, down to the cellular and molecular level in some cases. infarction was identified as the best predictor of future adverse cardiacSome 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 doesresearch. Here, we discuss recent advances in imaging cardiovascular not involve ionizing radiation, it can be used serially in animal or humanatherosclerotic disease, including revealing both the primary changes, studies to test the effects of therapeutic interventions on the myocardiumin the blood vessel wall, and the secondary changes, in the structure in vivo; such testing therefore requires fewer individuals than for otherand 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 bediscuss the growing field of molecular imaging. important for assessing the potential benefits of myocardial regenerative therapy (see page 937).The heartCardiac function, perfusion and contractility can be assessed non-inva- The coronary arteriessively by using various techniques: ultrasound, single-photon-emission The narrowing of non-cardiac arteries has traditionally been detectedCT (SPECT), positron-emission tomography (PET) and, more recently, non-invasively by using techniques such as ultrasound, CT or MRI. CTMRI. These imaging techniques all provide information with diagnostic is well suited to studying all vascular regions, although it requires the use1 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, OneGustave L. Levy Place, New York, New York 10029, USA. 953
  2. 2. INSIGHT PROGRESS NATURE|Vol 451|21 February 2008of potentially nephrotoxic contrast agents and ionizing radiation. These The arterial wallslimitations can now be largely overcome by using whole-body magnetic Atherosclerosis is a disease of the blood vessel wall, so the ability toresonance angiography, which can be carried out in less than 90 s. This identify plaques before luminal stenosis develops is the cornerstone oftechnique 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 techniquesdecade, 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, mostto multidetector CT (MDCT) scanners that can simultaneously acquire extensively, intravascular ultrasound11. These modalities are suitable for256 ‘slices’ in less than 250 ms, providing a complete coronary angiogram evaluating the coronary arteries and — because of the proximity of thein less than 15 s. In selected patients with stable disease and a normal imaging probe to the vessel wall — provide high spatial resolution (forcardiac rhythm, MDCT has a sensitivity of 96% and a specificity of 74% example, < 15 μm with optical coherence tomography). However, thefor detecting significant coronary stenoses (defined as more than 50% requirement for catheterization is a definite limitation. Ultrasound cannarrowing of the diameter of the artery) compared with the traditional, also be used non-invasively to measure the intima-media thickness of theinvasive technique, catheterization, which is the gold standard8. From a carotid arteries, because these arteries are located superficially. Increasedclinical perspective, the most important advantage of MDCT is its high carotid intima-media thickness provides some additive information tonegative predictive value: that is, a normal result on an MDCT exam can conventional risk factors in determining the risk of future myocardialconvincingly 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 nowto be of adequate quality, but this might be overcome by using the newest be imaged non-invasively (as described earlier). CT has, however, longgeneration of CT equipment, in which two X-ray sources and detectors are been used for the non-invasive detection of coronary calcium depositspresent in a single scanner (known as dual-source CT), thereby improving (yielding a ‘calcium score’), a specific indicator of atherosclerosis thatthe temporal resolution of images10. 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 stageFigure 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. 25.954
  3. 3. NATURE|Vol 451|21 February 2008 INSIGHT PROGRESS 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- 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 canincreases 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 importantin combination with the carotid intima-media thickness, could be used goals of imaging. The probability of plaque rupture and the subsequentfor initial stratification of cardiovascular risk in the general population14. clinical complications differ substantially between plaque types. FeaturesNonetheless, this approach is not without controversy, largely because of higher rupture risk include the following: active inflammation, a thinof 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 diameterall coronary lesions are non-calcified plaques. Such plaques can now by more than 90%, superficial calcified nodules, intraplaque haemorrhagebe detected with modern CT scanners after contrast agents have been and outward remodelling20. By combining images acquired with differentadministered to patients. Moreover, in patients with chest pain, it was parameters, MRI can reliably detect and quantify plaque components suchrecently shown that the extent of non-calcified atherosclerosis in a coro- as lipids, fibro-cellular tissue, calcium and intraplaque haemorrhage, andnary CT angiogram is correlated with increasing mortality16. CT can can detect and characterize a superimposed thrombus21,22. The clinicalalso provide reasonably accurate quantification of plaque size and crude implications of these capabilities were highlighted in a recent study ofcharacterization of plaque composition, on the basis of lipid-rich tissue asymptomatic patients with moderate carotid stenosis (50–79% luminalattenuating 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 notexposing the patient to ionizing radiation. ‘Black-blood’ techniques (an Molecular imagingimaging 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) improvedsubmillimetre resolution and high reproducibility, providing new indi- markedly in the past decade, but it has also become increasinglyces of atherosclerotic burden that can be applied to large populations18. possible to detect biological processes at the cellular or even molecularUsing this technique, with serial testing of an individual, it is possible to level. Molecular imaging relies on the use of contrast agents that targettrack changes in arterial disease and to test the effects of therapies for specific cells or molecular pathways of relevance to disease. In additionatherosclerosis in a completely non-invasive manner19. Although prelimi- to the various imaging techniques being developed, contrast agents fornary data show that it is feasible to use MRI to evaluate the coronary artery tracking potentially important components of atherosclerotic disease 955
  4. 4. INSIGHT PROGRESS NATURE|Vol 451|21 February 2008 a The choice of target for imaging is also clearly important. Because b c 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- d rophage scavenger receptor30. Similarly, in rabbits, specific uptake of an 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)Figure 2 | Multimodal imaging of inflammation and atherosclerosis.a, Molecular imaging of macrophages by using CT, with the iodinated — for the sensitive and reproducible detection of vascular inflammation33.contrast agent N1177. After in vitro incubation of mouse macrophages This combination approach allows the most appropriate technique(s) forwith N1177, light microscopy in a phase-contrast mode shows the presence a particular patient, vascular region and/or disease stage to be chosen andof multiple cytoplasmic granules (red arrow), confirming uptake of the takes advantage of the particular strengths of each modality.contrast agent by macrophages. b, Three-dimensional reconstruction Thrombi are another attractive target for imaging, because acuteof a rabbit’s abdominal aorta at 2 h after intravenous administration of clinical events often occur as a result of thrombosis triggered by plaqueN1177. A false-colour image of N1177 staining is shown overlaid on an rupture (Fig. 1). In animal models, thrombi of different ages and in dif-angiogram. Intense red spots indicate areas of N1177 accumulation in ferent vascular regions have been detected with MRI34, and this approachaortic plaques, which are rich in macrophages (white arrows). Organs with is now being investigated in humans26. At the other end of the timelinehigh macrophage density are also visible, including the spleen (top right). of atherosclerotic-plaque progression (Fig. 1), cell-adhesion moleculesc, A combined PET and CT image of a human neck (axial view).Atherosclerotic pathology is present at the bifurcation of the right participate in the early development of lesions by facilitating the recruit-common carotid artery (red arrows), as determined by the presence of ment of leukocytes into the vessel wall. In an animal model, increasedheavy calcification and large amounts of [18F]fluorodeoxyglucose, which amounts of vascular cell-adhesion molecule 1 (VCAM1) were found inis indicative of inflammatory activity. d, Black-blood MRI of the same aortic plaques by using a dual contrast agent detectable by both MRI andartery. Carotid arterial wall thickening is evident, as are two areas of signal optical imaging35. A similar approach, which used ultrasound detectiondrop (red arrows), which correspond to calcified regions. (Panels a and b of microbubbles, found increased expression of endothelial selectins inreproduced, with permission, from ref. 31. Panels c and d reproduced, with the heart of rats that had been subjected to transient myocardial ischaemiapermission, from ref. 26.) followed by reperfusion36. Development of such probes for clinical use could allow the identification of atherosclerosis at early stages and theare at various stages of development22,24–28 (Fig. 1 and Table 1). Most of detection of plaque rupture (which, even when clinically silent, indicatesthe available probes are in experimental testing, although some have disease instability).already advanced to clinical evaluation. Imaging probes typically include Another possibility is to use probes that emit a detectable signal onlya moiety (such as an antibody or specific ligand) with high affinity for after they have been activated by the target. For example, in a recent studythe desired target molecule. Alternatively, the probe can be modified of an experimental model of atherosclerosis, a fluorescent probe activatedto facilitate uptake by specific cells. In addition, probes are designed to by enzymatic degradation was used to reveal intraplaque protease activitybe detected by various modalities, including ultrasound (which detects with near-infrared fluorescence37.microbubbles), SPECT and PET (radioactive isotopes), MRI (paramag- In addition to being diagnostic and prognostic indicators, probesnetic and superparamagnetic compounds), CT (iodinated compounds) could also be used for therapeutic purposes, to deliver drugs in a targetedor optical imaging (fluorochromes). Many of the targets of interest are manner. An example of this is a study in which rabbits were adminis-located in deep organs and are present at very low (nanomolar) concen- tered paramagnetic nanoparticles loaded with an antiangiogenic drug,trations; imaging modalities therefore need to be highly sensitive, as well resulting in a reduction in the extent of blood vessels in atheroscleroticas safe and economically viable. plaques, as observed by non-invasive tracking with MRI38. In addition, Ultrasound is widely available, safe and inexpensive, but it has insuf- haematopoietic or cardiac stem cells for use in cell-based therapy couldficient penetration for the non-invasive imaging of deep vessels (including be tagged with appropriate imaging probes, providing insights into thethe coronary arteries) with high spatial resolution or sensitivity. SPECT role and fate of these cells after their administration39.and PET have a high sensitivity, but they also have limited spatial resolu-tion and the additional disadvantage of requiring the use of radioactive Future directionsagents. By contrast, MRI has a somewhat lower sensitivity than SPECT Rapid technological progress is transforming the imaging of atheroscle-and PET and requires prolonged imaging times, but it is safe and provides rotic cardiovascular disease from a method of diagnosis in symptom-excellent resolution (~10 μm with high-field magnets). CT, conversely, atic patients to a tool for the non-invasive detection of early subclinicaloffers the advantages of fast scanning times and superior performance for abnormalities. In addition, a new generation of hybrid technology iscoronary angiography, at the expense of limited sensitivity and the use of now becoming available; this technology combines multiple imagingnephrotoxic agents and ionizing radiation. Optical imaging techniques — modalities in a single platform, using one machine for more than onefor example, near-infrared fluorescence reflectance or fluorescence molec- type of imaging (Fig. 2c). And new probes designed to be detected byular tomography — have excellent sensitivity and temporal resolution and several modalities can take advantage of the strengths of each.allow the tissue distribution of the probe to be precisely determined with The availability of more powerful imaging techniques has the potentialex vivo fluorescence microscopy. So far, however, such techniques can to improve our understanding of the biology of atherosclerosis. Much ofbe used non-invasively only to monitor superficial structures because of the current knowledge has been inferred from static histopathologicalthe limited ability of light to penetrate tissue. Optical imaging techniques observations of animal models or human tissue samples studied at dif-and some SPECT and MRI techniques have the advantage of being able ferent disease stages or after various therapeutic interventions. By usingto detect more than one molecular signature at a time. molecular imaging, it is now becoming increasingly possible to obtain956
  5. 5. NATURE|Vol 451|21 February 2008 INSIGHT PROGRESSnon-invasively — from living experimental animals and, even, humans Committee to Update the 2000 Expert Consensus Document on Electron Beam— the type of information that was previously available only through Computed Tomography). Circulation 115, 402–426 (2007). 14. Naghavi, M. et al. From vulnerable plaque to vulnerable patient — part III: executiveimmunohistochemistry. summary of the Screening for Heart Attack Prevention and Education (SHAPE) Task Force Improved imaging technologies also hold promise for aiding drug report. Am. J. Cardiol. 98, 2H–15H (2006).development. Rather than relying on the plasma concentrations of a 15. Clouse, M. E. et al. How useful is computed tomography for screening for coronary artery disease? Circulation 113, 125–146 (2006).specific therapeutic agent to infer that it has been delivered to the target 16. Min, J. K. et al. Prognostic value of multidetector coronary computed tomographicorgan, imaging might be able to provide a direct read-out of the agent’s angiography for prediction of all-cause mortality. J. Am. Coll. Cardiol. 50, 1161–1170 (2007).local concentration and activity. Such information could be enormously 17. Cordeiro, M. A. & Lima, J. A. Atherosclerotic plaque characterization by multidetector row computed tomography angiography. J. Am. Coll. Cardiol. 47, C40–C47 (2006).helpful for deciding which therapies are the best candidates for proceed- 18. Khera, A. et al. Relationship between C-reactive protein and subclinical atherosclerosis: theing to clinical trials26. Dallas Heart Study. Circulation 113, 38–43 (2006). Prospective studies that will provide information about the signifi- 19. Corti, R. et al. Effects of aggressive versus conventional lipid-lowering therapy by simvastatin on human atherosclerotic lesions: a prospective, randomized, double-blindcance of currently available imaging data, considered either alone or in trial with high-resolution magnetic resonance imaging. J. Am. Coll. Cardiol. 46, 106–112the context of conventional risk factors and emerging serum and genetic (2005).biomarkers (see page 949), are in progress. Examples are the Multi- 20. Naghavi, M. et al. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: part I. Circulation 108, 1664–1672 (2003).Ethnic Study of Atherosclerosis (MESA; 21. Saam, T. et al. The vulnerable, or high-risk, atherosclerotic plaque: noninvasive MR imagingand the High-Risk Plaque (HRP) Initiative (http://www.hrpinitiative. for characterization and assessment. Radiology 244, 64–77 (2007).com), both studies of asymptomatic individuals of various ethnic back- 22. Briley-Saebo, K. C. et al. Magnetic resonance imaging of vulnerable atheroscleroticgrounds. Another example is a subset of the FREEDOM trial (Future plaques: current imaging strategies and molecular imaging probes. J. Magn. Reson. Imaging 26, 460–479 (2007).Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal 23. Takaya, N. et al. Association between carotid plaque characteristics and subsequentManagement of Multivessel Disease trial), which involves diabetic individ- ischemic cerebrovascular events: a prospective assessment with MRI — initial results.uals with proven coronary heart disease. With data from such investiga- Stroke 37, 818–823 (2006). 24. Choudhury, R. P., Fuster, V. & Fayad, Z. A. Molecular, cellular and functional imaging oftions, it might be possible to distinguish which patients would benefit from atherothrombosis. Nature Rev. Drug Discov. 3, 913–925 (2004).therapeutic intervention. 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ACCF/AHA 2007 clinical expert consensus document on coronary 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 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. ( 957