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The individual susceptibility to risk factors and atherosclerosis varies greatly, explaining the well-known limitations of risk factors as prognostic tools.8,9,10,11 However, an alternative and potentially much more rewarding approach to finding those at highest risk for atherothrombotic events is at hand. It is not based only on risk factors for getting atherosclerosis, but it also incorporates direct and indirect evidence for already having diseased arteries without knowing it (subclinical atherosclerosis), capturing the overall impact of all risk and susceptibility factors combined, known as well as unknown.86 Subclinical atherosclerosis can be detected by imaging, and its severity and extent (burden), progression rate (activity), and thrombosis-risk (vulnerability) can be assessed.15,16,17,45,86
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Burden of Atherosclerosis
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The number and severity of stenoses determined by coronary angiography are signs of atherosclerosis with diagnostic, therapeutic, and prognostic implications.87,88,89 However, most acute coronary events originate from angiographically nonobstructive plaques, probably because they are much more numerous.25,45,90,91,92,93 An irregular lumen and/or filling defects indicating plaque disruption and/or thrombosis are associated with worse outcomes.94 In contrast to coronary luminography, CAC detected by computed tomography (CT) imaging reveals the diseased arterial wall directly and correlates strongly with plaque burden.71,95 The total amount of CAC (usually expressed as the Agatston score) is a strong predictor of coronary events and provides prognostic information beyond that provided by traditional risk factor scoring.96
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Contrast-enhanced CT angiography not only visualizes the lumen but also the arterial wall. Because the strong relationship between the CAC score and coronary events is mediated predominantly by coexisting noncalcified or less calcified vulnerable plaques, total or noncalcified plaque burden detected by CT angiography may prove to be an even better marker of risk than the CAC score.58,97
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Intravascular ultrasound (IVUS) can detect and localize plaque as well as quantitate plaque burden, but it requires selective catheterization and motorized pullback in the arteries of interest. Serial examinations of well-defined coronary segments have been used to monitor the speed of plaque progression (or regression) over time in patients with established CHD.98
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Imaging inflammation in atherosclerosis serves two different purposes: detecting vulnerable patients (systemic activity) or vulnerable plaques of the rupture-prone type (focal activity). Because atherosclerosis is an innate inflammatory disease, inflammatory activity is not confined to just a few atherosclerotic lesions but is present, more or less, in all such lesions throughout the body.18,19 In contrast, vulnerable plaques are relatively rare,49 and inflammation plays a causal role in plaque rupture only if the microstructure of the plaque is permissive for rupture (TCFA) (see Fig. 32–5), as described in Plaque Vulnerability.
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With its high sensitivity, positron emission tomography (PET) imaging using fluorine-18-fluorodeoxyglucose (FDG) has evolved as a promising method for the detection of arterial inflammation when combined with higher-resolution CT or magnetic resonance imaging to help localize the signal to the arterial wall.99,100,101 With adequate suppression of myocardial FDG uptake using a low-carbohydrate, high-fat diet rather than a fasting protocol, coronary FDG uptake was recently identified in a large proportion of cancer patients undergoing invasive coronary angiography because of suspected or manifest ischemic heart disease.102
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In carotid atherosclerosis, proof-of-concept studies, focusing on symptomatic or stenotic carotid plaques, have documented a positive correlation between FDG uptake and macrophage density.103,104 Other studies have revealed widespread FDG uptake in asymptomatic plaques and arterial segments unlikely to harbor vulnerable plaques, and FDG uptakes among different arteries in the same person correlate strongly.99,100 In asymptomatic persons undergoing ultrasound screening for carotid artery disease, as many as 30% of ultrasound-defined atherosclerotic arteries and 10% of normal arteries accumulated FDG,105 supporting the current understanding that FDG-defined inflammation may be used to assess systemic disease activity unrelated to plaque vulnerability. Arterial inflammation defined by FDG-PET imaging appears to be dynamic and modifiable by a healthier lifestyle and short-term statin treatment.106,107,108 In a population of stable cancer patients, extensive arterial FDG accumulation was associated with recent and/or near-term cardiovascular events,109 supporting the “vulnerable patient” concept.110 Contrast-enhanced magnetic resonance imaging is also able to detect plaque inflammation, but its sensitivity is much lower than that of nuclear imaging.111
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Inflammation is not common in plaque erosion and not enough to make a vulnerable plaque of the most common type, the TCFA, where the microstructure of the plaque needs to be permissive for plaque rupture (see Figs. 32–3, 32–4, 32–5).25,45 No distinct morphologic feature characterizes the erosion-prone type of vulnerable plaque (see Fig. 32–6).4 Consequently, useful targets for imaging of erosion-prone plaques remain elusive. In contrast, the TCFA has a distinct microstructure, including a large necrotic core covered by a thin and inflamed fibrous cap, and other characteristic plaque features are common, such as a big-size, expansive remodeling, neovascularization (angiogenesis), and a spotty pattern of calcification (see Fig. 32–7).25,45
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Although inflammation most likely plays a causal role in plaque rupture, it does not necessarily imply that inflammation also is a useful target for the detection of plaques assumed to be rupture-prone, such as TCFA. A unique feature of TCFA is the location of inflammation within the plaque rather than the overall severity of plaque inflammation. In coronary TCFA, the macrophage density within the thin and disrupted fibrous cap is high (~14%),56 but the whole-plaque macrophage density is only 2.0% ± 1.9% (mean ± SD) versus 1.1% ± 1.5% in “stable” fibroatheromas.27 These low values and the substantial overlap, indicated by the large SDs, probably preclude the use of plaque inflammation as a useful standalone marker of vulnerability (see Fig. 32–5).
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Coronary CT angiography may not only visualize the lumen and detect obstructive and nonobstructive plaques, it may also quantify calcified and noncalcified plaque burden. Furthermore, coronary CT angiography may also provide additional prognostic information by detection of higher-risk plaques characterized by large plaque volume, low CT attenuation, napkin-ring sign, expansive remodeling, and spotty calcification.112,113
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Many catheter-based technologies have been developed, or are under development, for the assessment of coronary atherosclerosis and vulnerable plaques, including conventional grayscale IVUS, virtual histology IVUS and other ultrasound-based tissue characterization modalities, optical coherence tomography, angioscopy, near-infrared spectroscopy, intracoronary magnetic resonance imaging, thermography, and vascular profiling.114,115,116,117 Because vulnerable coronary plaques of the rupture-prone type (TCFA) are relatively large, not numerous, and often cluster proximally in the major coronary arteries, their detection in patients undergoing percutaneous coronary interventions might be feasible.49