Vulnerable Plaque Imaging

Neuroimag Clin N Am 15 (2005) 609 – 621

Vulnerable Plaque Imaging John W. Chen, MD, PhDa,T, Bruce A. Wasserman, MDb a

Division of Neuroradiology, Department of Radiology, Massachusetts General Hospital, Boston, MA, USA b Neuroradiology Division, Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions, Baltimore, MD, USA

More than 16 million people die worldwide from cardiovascular diseases (CVD) each year, despite recent advances treatment [1]. Coronary heart disease and stroke are the two leading subsets of CVD that cause significant morbidity and mortality. The common pathway leading to these diseases is atherosclerosis. Atherosclerosis is the process in which deposits of fatty substances, cholesterol, cellular waste products, calcium, and other substances accumulate in the wall of an artery to form plaque, typically affecting medium- and large-sized arteries. In postmortem, histopathologic studies, patients who have fatal coronary events have severely stenotic coronary artery lesions, with more than 90% cross-sectional diameter narrowing [2 – 5]. Similarly, the North American Symptomatic Carotid Endarectomy Trial [6] and the European Carotid Surgery Trial [7] show that patients who have symptomatic carotid stenosis above 70% benefit more from surgical than medical treatment with regard to stroke risk. These studies form the basis for reliance on measurements of vascular lumenal narrowing to predict future CVD events. With regard to coronary arteries specifically, however, some researchers believe that there is compensatory enlargement of the arterial lumen in response to plaque formation, potentially limiting the use of the angiographic stenosis as a criterion to assess CVD risk [8,9]. Moreover, retrospective studies in patients who have acute myocardial infarction or unstable angina show that 78% to 97% of the culprit lesions

T Corresponding author. E-mail address: [email protected] (J.W. Chen).

are less than 50% stenotic on the initial arteriogram before an acute event [10 – 12]—although the culprit lesions causing fatal coronary events have greater than 90% stenosis. This implies that—at least in the cardiac model—there is a sudden change in the degree of stenosis before a fatal event and that the narrowing caused by plaque does not portend the risk for ischemic events fully. Rather, the risk or vulnerability of a plaque suddenly to become critically stenotic (ie, become a culprit lesion) is the most important factor. Contributing to a plaque’s stroke risk are its composition and structure, independent of its hemodynamic effect on the lumen. The features that create a plaque’s instability and its potential to disrupt are the basis for the concept of plaque vulnerability [13]. Various terms are used in the literature and by clinicians to refer to vulnerable plaques, including highrisk plaques, hot plaques, unstable plaques, soft plaques, and noncalcified plaques.

Plaque vulnerability Falk [13] divides plaques into two types, a hard collagen-rich plaque, with barely detectable lipid, and a soft plaque, with a prominent pool of extracellular lipid separated by a fibrous cap, and reports that soft plaque is more vulnerable, because the thin fibrous cap may rupture to expose underlying thrombogenic material to the flowing blood. Davies and colleagues [14] show that plaques that have undergone ulceration and thrombosis (ie, vulnerable plaques) contain a large lipid core (> 40% of the cross-sectional area) and a fibrous cap that con-

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tains a larger volume of monocytes/macrophages than plaques that do not undergo rupture and thrombosis. Burke and colleagues [15] define a vulnerable coronary plaque further as a plaque with a fibrous cap less than 65 mm thick and an infiltrate of macrophages, with or without plaque rupture; plaques that ruptured had an average thickness of 23 ± 19 mm, with 95% of the caps measuring less than 64 mm. Symptomatic carotid plaques are shown to behave similarly by Carr and coworkers [16], who report fibrous cap thinning in 95% of symptomatic plaques compared with 48% of asymptomatic plaques, with symptomatic plaques more prone to rupture. In addition, they found that foam cell infiltration of the fibrous cap was significantly more common in symptomatic plaques (84% versus 44%), but no significant differences were found between plaque hemorrhage, necrotic core, luminal thrombus, shape, plaque type, and smooth muscle cell infiltration [16]. Inflammatory cells (activated macrophages and T lymphocytes) also play an important role in atherosclerosis [17,18], and adhesion molecules (such as vascular cell adhesion molecule [VCAM]-1) that recruit these cells are elevated in plaques [19]. These inflammatory cells secrete cytokines that can oxidize low-density lipoprotein (LDL) [17] and high-density lipoprotein (HDL) [20] and cause thinning and disruption of the fibrous cap through activation of matrix metalloproteinases that remodel the extracellular matrix [18,21 – 24]. In addition, serum inflammatory markers, such as C-reactive protein (CRP) [25,26] and myeloperoxidase (MPO) [27,28], are elevated in patients at higher risk for CVD events. Therefore, it is evident that plaque disruption occurs most often where the fibrous cap is the thinnest and most heavily infiltrated by inflammatory/foam cells [29]. Although it is understood that rupture-prone vulnerable plaques often have a large lipid pool, a thin cap, and macrophage-dense inflammation on or beneath its surface [29], the actual site of rupture typically is in an area of increased mechanical stress. Lee and colleagues took in vitro plaque specimens and measured stress at different points in the plaque, and found that the stress is highest at the shoulder region of the plaque, regardless of size [30 – 32]. When Lee and colleagues replaced the lipid core with calcium, the plaque became more stable. In addition, according to Laplace law, if all else is equal, the tension created in fibrous caps of mildly stenotic lesions is greater than that created in caps of severely stenotic lesions, because of the smaller lumen size [29]. This may explain why retrospective angiographic studies of culprit coronary lesions show only moderate narrowing, because plaques that are

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only mild or moderately stenotic may be more prone to rupture than severely stenotic plaques. Histologic examination of thrombosed atherosclerotic arteries show that in advanced plaques, microscopic fissures in the collagen cap exposes thrombogenic material to blood in the lumen, causing small, probably silent, thrombi to form [33]. Although the thin-cap atheroma is a well-accepted model and the most common type of vulnerable plaque, plaque composition is heterogeneous, and multiple factors predispose to thrombus formation in addition to cap thickness. Virmani and colleagues describe a classification of plaques based on analysis of coronary arteries implicated as the cause for sudden cardiac death [34]. In this classification, plaques with thin caps were most likely to rupture [35]. Besides this type of vulnerable plaque, in 25% to 30%, an erosive plaque was identified, for which serial sectioning of a thrombosed arterial segment fails to reveal fibrous cap rupture [34]. In these erosive plaques, the endothelium is absent at the erosion site, with variable macrophage and T-lymphocyte infiltration. Erosive plaques contain high concentrations of proteoglycans, which—when exposed in denuded endothelium—is extremely thrombogenic [34,36]. The most rare type of vulnerable plaque is a calcified nodule and refers to a lesion with fibrous cap disruption and thrombi associated with an eruptive, dense, calcific nodule. This is different from a fibrocalcific lesion, which contains a thick fibrous cap overlying extensive accumulation of calcium in the intima and which usually is stable and less vulnerable to rupture. Intraplaque hemorrhage, although not a type of vulnerable plaque, may represent plaque fissuring and be a precursor of plaque rupture [37]. Neovascularization is found in ruptured plaque specimens in the human aorta [38]. Neovascularity is believed to be reflective of inflammation within a plaque, associated with increased accumulation of macrophages and T lymphocytes and, hence, contributes to plaque vulnerability [39]. Fleiner and coworkers show that, in patients who suffered a cardiovascular event, the carotid, iliac, and renal arteries had a denser network of vasa vasorum [40]. In carotid artery lesions, plaque rupture and hemorrhage were associated with neovascularity within the plaque and fibrous cap [41]. Naghavi and coworkers devised a consensus statement defining major and minor criteria for vulnerable plaque (Box 1) [42,43]. Fig. 1 shows a schematic representation of a vulnerable plaque using the major criteria. It should be emphasized that these criteria are based on retrospective studies that await validation by

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Box 1. Criteria for vulnerable plaque Major
Active inflammation
Thin cap with large lipid core
Endothelial denudation with superficial platelet aggregation
Fissured plaques Minor
Superficial calcified nodule
Glistening yellow
Intraplaque hemorrhage
Endothelial dysfunction
Outward remodeling Modified from Naghavi M, Libby P, Falk E, et al. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: part I. Circulation 2003;108:1664 – 72; with permission.

prospective studies. Imaging will play an important role to facilitate these prospective studies, because it can allow noninvasive characterization of the plaque, with identification of vulnerable features. This is insightful particularly for plaques that otherwise are not amenable to pathologic analysis, such as carotid plaque causing low-grade stenosis. Based on these criteria, anatomic and functional imaging modalities will play significant and complementary roles, with the goals of identifying vulnerable plaques before they become culprit lesions and of improved diagnosis and assessment of a patient’s risk for future cardiovascular events, so that early prevention and treatment can be instituted.

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High-resolution MR imaging There is a large body of experience in using MR imaging to distinguish the components of atherosclerotic plaque [44 – 51]. T2-weighted imaging was believed to offer the best contrast to discriminate plaque components, as demonstrated by Martin and colleagues [52]. Toussaint and coworkers [44] performed T1- and T2-weighted imaging of dissected human arteries, and found, on T2-weighted images, a higher contrast-to-noise ratio (CNR) for the lipid core compared with the more collagenous fibrous cap. Calcification was identified better on T1-weighted images. They also found that this relationship holds regardless of the magnetic field strength used, from 1.5 T to 9.4 T. This was verified in vivo, demonstrating that in addition to distinguishing between the lipid core, fibrous cap, and calcifications, intraplaque hemorrhage also can be identified [53]. T2-weighted imaging alone, however, was insufficient to characterize and classify plaques fully [54]. Shinnar and colleagues [45] show that, using a multisequence approach with T1-, T2-, proton density-, and diffusion-weighted images, high sensitivity and specificity can be achieved for identifying different plaque components, albeit at 9.4 T. Similarly, Yuan and colleagues [55] show that multisequence MR imaging can be sensitive to different types of lipid composition, including triglycerides, unesterified and esterified cholesterol, and phospholipids. Since these initial studies, many investigators have found that MR imaging can detect the gamut of plaque composition, including the detection of a thin fibrous cap and cap rupture [46,47,51], intraplaque hemorrhage [48,50], and necrotic/lipid core [44,45, 48,51]. The clinical usefulness of these measures is reported by Yuan and coworkers [47], who show that a thin or ruptured fibrous cap detected by in-vivo MR imaging of the carotid artery is associated with an

Noninvasive imaging modalities MR imaging MR imaging has the ability to characterize the soft tissue components of plaques based on inherent differences in signal. The ability of MR imaging to resolve small structures, such as the components of plaque, depends on the signal achievable for that structure. With improved surface coil technology and MR imaging scanners using higher field strengths MR imaging has become a powerful tool for this purpose.

Fig. 1. Schematic representation of a vulnerable plaque. The goal of vulnerable plaque imaging is to identify lesions with these components before significant thrombosis occurs.

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odds ratio of 23 for having had a recent transient ischemic attach or stroke. MR imaging also can be used to image the thrombus associated with plaque rupture. Murphy and coworkers [56] used a T1-weighted fat saturated black blood technique to detect methemoglobin, an intermediate (subacute) breakdown product of blood. They applied this technique to image the carotid arteries of 120 patients who had suspected severe carotid artery stenosis and previous acute cerebral ischemia, and found that high signal, reflecting the presence of methemoglobin, was detected in 60% of the symptomatic patients’ ipsilateral carotid arteries versus 36% of their contralateral arteries. For acute thrombus detection, Viereck and colleagues [57] realized that—unlike hematomas and venous thrombi, which are rich in red blood cells and hemoglobin and, hence, have vastly different MR signal characteristics, depending on the age of the clot—the initial thrombus formed from plaque rupture is more platelet rich. Platelet-rich thrombus may be difficult to distinguish from the vessel wall using standard MR imaging protocols. They demonstrated, in ex-vivo rabbit plaques, that diffusion-weighted images gave the best contrast for distinguishing these platelet-rich thrombi from the vessel wall and can be helpful in identifying the culprit lesion after a vulnerable plaque has caused thrombosis [57]. In this study, however, the field strength used was 11.7 T, which is not clinically practical. At lower field strengths (1.5 T), the investigators were unable to separate the thrombus from the vessel wall [58].

Gadolinium-enhanced MR imaging Gadolinium is an extracellular contrast agent with uptake mediated by passive diffusion. It is well tolerated and has broad applications because of

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its ability to detect pathology, including neoplastic processes and inflammation. Its application for plaque characterization is reported by Wasserman and coworkers [49]. In that study, nine subjects who had carotid atherosclerosis were evaluated with double oblique, contrast-enhanced, double inversionrecovery, fast spin-echo MR imaging. Fibrocellular tissue within atheroma selectively enhanced 29% after administration of gadolinium-based contrast. This enhancement helped discriminate fibrous cap from lipid core with a CNR as good as or better than that with T2-weighted MR imaging. In addition, compared with T2-weighted images, there was approximately twice the signal-to-noise ratio, allowing for improved delineation versus the adjacent lipid core. Another study reveals that peak discrimination between the cap and the lipid core is maintained over 30 minutes after gadolinium administration [59]. Fig. 2 demonstrates the enhancing cap after gadolinium administration. Gadolinium also is known to localize in areas of increased vascularity, a feature that can be exploited when searching for neovascularity within plaque. Kerwin and colleagues show that, in carotid plaque, dynamic imaging with gadolinium correlates well (correlation coefficient 0.80, P< 0.001) with histologic sections staining for Ulex and CD-31, which reflect angiogenesis [60].

Specific MR imaging contrast agents There are many ongoing efforts to discover more specific contrast agents, some with well-defined mechanisms of uptake other than diffusion, which can target different components of the vulnerable plaque. This discussion is not meant to be exhaustive, rather, representative of the breadth and promise of contrast agents to increase diagnostic sensitivity in

Fig. 2. Postcontrast, high-resolution, T1-weighted, black blood MR imaging demonstrating that there is increased enhancement of the cap after the administration of intravenous gadolinium. (A) Precontrast. (B) Postcontrast.

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identifying vulnerable plaque. Most of these agents are experimental and have limited validation to date in small groups of animals or patients. Fibrin-binding agents. Fibrin is a predominant component of thrombus, and detection of fibrin can help identify sites of microfissures that may go on to frank disruption, leading to a clinical event. Furthermore, a significant minority of vulnerable plaques do not rupture, rather, are erosive, exposing the underlying matrix proteins and proteoglycans to the blood, causing thrombi to form [34]. Fibrin detection would help to identify these lesions. Yu and coworkers [61] and Flacke and colleagues [62] developed gadoliniumbased nanoparticles that accumulate selectively in thrombi. They demonstrate that large CNRs can be achieved in thrombi created in dogs, although a large payload of contrast agent was required. Botnar and colleagues [63] describe the usefulness of a gadoliniumbased peptide agent that binds to fibrin, EP-1873. Enhancement with this agent was demonstrated in sites of plaque rupture induced in nine rabbits, with histologic confirmation of uptake of the agent to areas of fibrin. Specificity was not determined, however. Neovascularization agents. Winter and coworkers report the use of avb3-integrin – targeted gadolinium nanoparticles to detect sites of neovascularization. They demonstrate enhancement in areas of neovascularity by 47% in a rabbit model injected intravenously with this agent [64]. The tolerance of this agent in humans and its application for identifying vulnerable plaque remain to be tested. Inflammation agents. The role of inflammation is well established in plaque vulnerability [18,21,25]. Although gadolinium is capable of detecting areas of inflammation, agents that are more specific may

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provide more useful information regarding the possible role of anti-inflammatory medication for plaque regression [65,66] and more sensitive detection of the inflammatory process that precedes plaque rupture. A variety of potential cellular and molecular targets exists for molecular imaging to detect inflammation. Ultrasmall paramagnetic iron oxide nanoparticles (USPIO) are taken up by the reticuloendothelial cells, such as macrophages, and can be used to image sites of macrophage accumulation that could reflect significant inflammation within a plaque. Trivedi and coworkers [67] demonstrate USPIO uptake in endarterectomy specimens of seven patients injected with the agent preoperatively, with detectable signal reduction peaking at 24 to 36 hours after injection relative to baseline scans. The USPIO colocalized with activated macrophages on specimen analysis. The source of activated macrophages, however, remains to be determined; these could be derived from migrated blood-borne monocytes, activated macrophages from smooth muscle cells, or foam cells corresponding to macrophages at a later stage [68]. It is a promising agent, although quantification by MR imaging remains to be shown. Fig. 3 demonstrates the use of cross-linked iron oxide nanoparticles in the detection of macrophages in plaques of the aortic root. Aside from cellular targets of inflammation, another potential molecular target is MPO, an enzyme secreted by activated neutrophils and macrophages in response to inflammation and injury, which has been found in vulnerable plaques [18,69]. MPO usually colocalizes with oxidized LDLs [70]. MPO activity also is linked to the activation of matrix metalloproteinase-7 proenzyme (matrilysin), suggesting that MPO oxidation products may regulate the activity of matrilysin in vivo [23], potentially inducing plaque rupture. MPO also is found to modify

Fig. 3. Cross-linked iron oxide nanoparticles taken up by activated macrophages in plaques cause loss of T2 signal in the atherosclerotic aortic root (arrows) in an apoE-knockout mouse, but not in an apoE-knockout mouse injected with saline, at 9.4 T. (A) Infected with iron oxide. (B) Injected with saline. (Courtesy of Matthias Nahrendorf, MD, and Farouc Jaffer, MD, Charlestown, MA.)

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HDL, thereby altering its interaction with scavenger receptors, reversing its protective role [20,71]. A recent study in more than 600 patients established that a single MPO measurement in plasma could predict the risk of major adverse cardiac events within the subsequent 6 months [72]. Another study demonstrates that plasma levels of MPO are elevated in stroke patients [73]. To image MPO activity, Chen and coworkers [74] developed a gadolinium-based agent targeting MPO. In the presence of MPO, the agent is oligomerized. The resulting increased molecular size generates increased T1 signal by a factor of two relative to nonactivated agents not exposed to MPO (Fig. 4). Lipophilic agents. As discussed previously, Wasserman and coworkers show that the use of contrast agents can improve the differentiation between the lipid core and fibrous cap by relatively greater enhancement of the cap [49]. Alternative, gadofluorine, originally developed for magnetic resonance lymphography [75,76], seems to target the lipid core [77,78]. Gadofluorine is a macrocyclic gadoliniumbased lipophilic agent that forms micelles and may be able bind lipid-rich regions. In one study, Sirol and coworkers [77] demonstrate that there is increased enhancement in the more lipid-rich regions of the plaque. Frias and coworkers developed a recombinant HDL-like nanoparticle with a gadolinium payload to

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target plaques [79]. They show, in an apoE-knockout mouse model, that there is 35% increased enhancement of the wall compared with precontrast images. The nanoparticles seemed to be taken up by macrophages within the plaques. CT Electron beam CT and multidetector CT are highly sensitive to calcification and are used as a screening tool for coronary screening asymptomatic individuals [80,81]. The presence and extent of coronary calcium seem to correlate with overall plaque burden [82 – 85]. The calcium scores generated from CT studies have high negative predictive values, and a high calcium score is associated with increased risk for adverse events. In 31 patients, calcified plaque of the extracranial carotid artery is 21 times less likely to be symptomatic than is noncalcified plaque [86]. A recent study evaluating the diagnostic accuracy of 16-slice CT scanners in the determination of plaque morphology and composition, using popliteal arteries from amputations, finds 16-slice CT to be reliable in assessing plaque morphology, especially in distinguishing between calcified and noncalcified lesions [87]. CT, however, had low diagnostic accuracy in further classifying plaques as lipid rich or fibrotic. Comparing MR imaging with 16-slice CT, Viles-Gonzalez and coworkers [88] find that CT offers the advantage of very short image acquisition time, which potentially allows it to be more useful for coronary artery imaging. MR imaging, however, provides better tissue characterization. Ultrasound

Fig. 4. MPO-sensitive gadolinium-based agent demonstrating nearly twofold increased CNR when activated by MPO. MPO is embedded in a basement membrane extract in the right thigh to simulate a lesion rich in MPO, such as a vulnerable plaque (arrow). The contralateral side has no MPO embedded, simulating a lesion such as a stable plaque. (Courtesy of John Chen, MD, PhD, Charlestown, MA.)

For routine clinical evaluation of carotid disease, ultrasound is an important modality to assess the degree of stenosis through B-mode imaging and Doppler velocity measurements. Furthermore, the echogenicity of a plaque is related to its composition. On B-mode imaging, hypoechoic plaques are associated with increased lipid content, macrophage density [89], and intraplaque hemorrhage [90] and are more prone to rupture [91]. A prospective study of 4886 individuals finds that hypoechoic plaques and stenosis greater than 50% are associated with increased risk for future stroke [92], especially in asymptomatic individuals [91]. Although echolucency is associated with increased risk for stroke, because lipid and hemorrhage appear similar and hypoechoic, the major limitations of ultrasound, insofar as vul-

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nerable plaque imaging is concerned, is its insensitivity to characterize vulnerable plaques to stratify risk further. Furthermore, heavy calcification can produce prominent shadowing that can interfere with plaque characterization. Radionuclide imaging Like MR imaging, radionuclide imaging relies on innovative radiotracers targeting plaque components to detect vulnerability. Unlike MR imaging, nuclear imaging is highly sensitive, and only a small amount of tracer is needed to detect pathology. Most such agents, however, are in development and remain experimental. Many of these have show initial promise in animal models but have yet to be validated in humans. A few examples are described later. Single photon emission CT imaging A variety of radiolabeled substances has been developed to target atherosclerotic lesions. Radiolabeled LDL and oxidized LDL re used to visualize atheroma better, but the presence of LDL does not necessarily indicate a vulnerable plaque [93 – 98]. Similarly, the apo-B portion of the LDL is radiolabeled and used successfully in rabbits to image atherosclerosis [99]. Antibody-based tracers to proliferating smooth muscle cells also have been developed but with limited success for vulnerable plaque detection [100,101], showing positive uptake in 50% of controls [101]. There also is much effort in designing tracers that can target thrombosis. For example, radiolabeled fibrinogen was developed but did not show much promise because of low sensitivity for arterial thrombus [102]. Fibrin fragments labeled with iodine-123 (123I) and technetium-99m (99mTc) were used to detect deep venous thrombus in animal models [103], but application to vulnerable plaque detection has yet to be demonstrated. Radiolabeled peptides, mainly targeting GPIIb/IIIa receptors in activated platelets, also have been produced. An example of such an agent is DMP-444-99mTc, which can identify platelet-rich thrombus in canine coronary arteries and may become useful for detecting culprit lesions and thrombogenic plaques [104]. Annexin V, a small protein that binds to activated platelets and apoptotic vascular smooth muscle cells in the fibrous cap [105 – 107], is shown to image left atrial thrombus in a porcine model [108]. Blankenberg and coworkers [109] conjected 99mTc-Annexin V, 125I-MCP-1 (a monomeric polypeptide with high affinity to chemokine receptor expressed on the surface of human monocytes), and fluorodeoxyglucose (FDG) (see

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discussion later of positron emission tomographic [PET] imaging) into apoE-knockout mice and found that each tracer localized to varying degrees within an atherosclerotic lesion, with distinctly different patterns of plaque localization. These investigators are working on histologic correlation to determine the cellular targets for each tracer to explain the observed differences. Positron emission tomographic imaging PET imaging offers improved resolution over single photon emission CT (SPECT), although the short half-lives of these agents make them less practical. Florine-18 – FDG is taken up by macrophages [110] and can be used as a measure of inflammation within the plaque [18]. Rudd and coworkers [111] show that FDG is taken up in human carotid atherosclerotic lesions using PET coregistered with CT, with a 27% increased accumulation rate in symptomatic lesions. Ogawa and colleagues [112] show further, in a rabbit model, that the accumulation indeed colocalized to macrophages and not to other cells, such as smooth muscle. Fig. 5 illustrates that FDG/PET imaging can be used in human to localize vascular inflammation. Although FDG seems a promising agent, challenges include the lack of resolution to localize lesions fully. To this end, the emergence and availability of PET/CT scanners may allow better locali-

Fig. 5. Increased FDG uptake in an aortic graft infection, demonstrating that PET-FDG can be used to image vascular inflammation. (Courtesy of Alan Fischman, MD, PhD, Boston, MA.)

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zation of vulnerable plaques. Comparing FDG uptake with calcium detection in thoracic aorta in 85 consecutive cancer patients, Tatsumi and colleagues [113] find that the site of calcification mostly was distinct from that of FDG uptake and that uptake was increased in women, patients who have hyperlipidemia, and patients who have history of CVD. Despite the potential demonstrated for atherosclerosis imaging by FDG/PET in the aorta and carotid arteries, it may not be possible to image vulnerable plaque in coronary arteries with FDG because of the avid uptake of this agent in myocardium.

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cannot penetrate deeper into the plaque to determine composition. In addition, a major drawback of both of these modalities is that they require the inflation of a proximal balloon to obstruct blood flow, which can cause ischemia and vessel injury. Thermography

The inability for conventional angiography to characterize the vulnerable features of plaque has driven the development of invasive modalities to be used to assess the risk of a lesion and, in some cases, provide an opportunity to intervene based on these results.

Inflammation is an important contributor to plaque disruption, and the goal of thermography is to detect temperature changes associated with this process. Thermography uses a specially designed catheter to measure temperature changes in the wall of the vessel [116]. Ex-vivo studies in human carotid atherosclerotic plaques show that temperature differences within the plaque are related to the cell density of macrophages [117]. In-vivo studies also demonstrate that macrophage mass determines temperature of a plaque [118], and there is a more elevated temperature in patients who have acute coronary syndrome [119]. There is a reduced temperature difference between normal coronary artery walls and plaques treated with statin therapy [120].

Intravascular ultrasound

Intravascular MR imaging

Of the invasive modalities, intravascular ultrasound (IVUS) is the best established. It is a catheterbased technique that can provide high-resolution images of the vessel wall and plaque, because its proximity to the tissue imaged enables the use of high ultrasound frequencies. A miniaturized ultrasound transducer is attached to a catheter and typically operates at 30 to 40 MHz, allowing for a spatial resolution of approximately 150 to 200 mm. IVUS allows the visualization of the full circumference of the vessel wall through tomography. As with conventional ultrasound, IVUS can detect lipid-laden lesions as hypoechoic structures. IVUS is capable of revealing the true plaque size and accounting for vascular remodeling during plaque development [114]. As with conventional ultrasound, however, the echogenicity and texture of different tissue components may exhibit comparable acoustic properties, thus limiting IVUS in the assessment of plaque vulnerability [115].

A potential limitation of noninvasive MR imaging is that of low signal because of the small size of the arteries of interest, for example, the coronary arteries. This may be overcome by placing the coil in near proximity to the plaque (ie, intravascularly via a catheter). Rogers and colleagues [121] show ex-vivo carotid specimens, in which intravascular MR imaging at 0.5 T can be used to detect plaque components, including fibrous cap, lipid core, and calcium. Using hyperlipidemic rabbits, intravascular MR imaging can achieve a resolution of 117  156 mm, compared with 234  468 mm using a surface coil [122].

Invasive imaging modalities

Optical coherence tomography and angioscopy Optical coherence tomography uses near-infrared waves and interferometry. It has higher resolution than IVUS, at approximately 10 to 20 mm. Angioscopy uses a camera attached to a catheter, analogous to endoscopy, and can detect fissuring or thrombus. It is able to examine only the luminal surface and

The vulnerable patient Recently, a new concept has emerged: the concept of the vulnerable patient. Patients do not have just one vulnerable plaque but often multiple plaques with similar characteristics in different vascular territories [42,43,123 – 126]. In addition, there is elevation of inflammatory markers in patients who have acute coronary syndrome, such as CRP and MPO [25,27,127]. Imaging combined with serum markers, such as MPO [27] and CRP [26], may be used to identify a vulnerable patient. Any one of the vulnerable plaques in a patient may become the culprit lesion and cause significant morbidity and mortality.

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Systemic inflammation, along with significant vulnerable plaque burden, may trigger sudden rupture of vulnerable plaques that cause subsequent catastrophic CVD [124]. The emphasis, therefore, is shifting from the evaluation of an individual plaque to global assessment of the cardiovascular state.

Summary The concept of vulnerable plaque is well established, owing to increasing evidence from clinical and basic research. With this has come a paradigm shift from focusing on the hemodynamic effect of plaque to its structure and composition. Increasingly, it is evident that methods must be developed to detect and characterize vulnerable plaque. Although MR imaging, CT, and ultrasound provide data regarding the vulnerability of a single lesion, future studies may rely more heavily on nuclear medicine techniques that offer a functional assessment of the entire cardiovascular system.

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