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Atherosclerotic plaque
8.1
Introduction
Atherosclerosis is a chronic inflammatory disease [ ]. Although great strides have been made in the diagnosis and management of atherosclerotic cardiovascular disease (CVD), overall mortality due to underlying atherosclerosis remains a leading cause of death in industrialized countries [ , ]. For example, more than one-third of all deaths in the United States are attributed to CVD, including atherosclerotic coronary disease and stroke [ ]. By 2030, it is projected that more than 148 million of the US population would have heart disease. Given the gravity of this situation, it is of paramount importance to improve cardiac risk assessment in order to identify at-risk individuals. Significant advances have been made over the past decade in noninvasive cardiac imaging, permitting earlier detection of vascular atherosclerotic disease beyond conventional risk calculator assessments. The ability to directly visualize atherosclerotic plaque has spawned further efforts to refine imaging-based detection of plaque with ultrasound (US), computed tomography (CT), magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT), and positron emission tomography (PET). This chapter will focus on the utility and applications of noninvasive imaging modalities—US, CT, MRI, SPECT, and PET—and their individual, yet complementary roles in the detection and characterization of atherosclerotic plaque.
It is well documented that atherosclerotic plaque rupture is the underlying pathophysiologic mechanism governing the majority of CVD complications, including myocardial infarction (MI), stroke, and sudden cardiac death [ ]. Despite contemporary guideline-based management for at-risk and established CAD patients, cardiovascular events persist at an alarming rate. This risk is thought to be due to unabated systemic inflammation [ ]. Inflammation is at the crossroads of atherosclerotic plaque initiation, progression, and complications from atherothrombosis [ ]. There are many notable steps in the inflammatory cascade that lends to atherogenesis: endothelial cell damage, up-regulation of endothelium adhesion molecules, accumulation of oxidized lipoproteins, monocyte recruitment and subsequent foam cell formation, angiogenesis, microcalcifications, and apoptosis. Unperturbed, these highly coordinated molecular and cellular events result in plaque destabilization. This end event is mediated by activated inflammatory cells, notably macrophages, which release degradative enzymes and confer an increased risk for plaque rupture. In addition to inflammation, other plaque properties such as presence of thin-cap fibroatheroma and lipid-rich necrotic core define an inflamed or high-risk plaque, which are the culprit lesions responsible for vascular atherothrombosis and adverse CV events [ ].
Accordingly, early detection of both atherosclerotic disease and high-risk plaques is crucial to abating the total burden of CVD and its potential clinical complications [ , ]. In this regard, the use of noninvasive imaging techniques offer substantial advantage over standard CV risk calculators or invasive modalities, by affording the assessment of both anatomical and functional atherosclerosis parameters before the onset of clinical manifestations.
8.2
Non-invasive imaging of atherosclerosis
8.2.1
Carotid artery ultrasound
Carotid ultrasound allows visualization of the carotid arteries with an axial and lateral resolution of 0.044 and 0.25 mm, respectively. Intima-media thickness (IMT) is represented by the measured longitudinal distance between: (1) lumen-to-intima, and (2) media-to-adventitia boundaries [ ]. The identification of a carotid atherosclerotic plaque is defined as focal IMT thickness of 50% or > 0.5 mm relative to the adjacent arterial wall, or alternatively, an absolute IMT > 1.5 mm [ ]. Carotid IMT (CIMT) using ultrasound, with standardized protocols and excellent sonographers and readers, lends to highly reproducible IMT measurements [ ].
Another form of carotid ultrasound involves the use of injected contrast, intravascular microbubbles, which permit the visualization of micro- and macro-vasculature, and notably, intraplaque neovascularization [ ], as validated by histopathologic exam. Neovascularization occurs early in atherogenesis, whereby the formation of leaky micro-vessels within plaque pose an increased risk for hemorrhage and potentiation of inflammation, leading to plaque instability [ ] ( Figure 8.1 ). As such, detection of neovascularization by contrast-enhanced ultrasound (CEUS) is a potential marker of high-risk atheromatous lesions. The diagnostic yield of CEUS has been explored in a few studies. In one such study, CEUS with perflubutane was used in 50 patients prior to carotid endarterectomy. We measured enhanced intensity and assessed the correlation between contrast effect and histopathology, comparing symptomatic and asymptomatic plaques. In both symptomatic and asymptomatic plaques, the correlation between CEUS based intensity in the plaque shoulder was associated with neovessel density ( P < 0.01; ρ = 0.43). Furthermore, CEUS intensity of the plaque shoulder was greater in ruptured plaques than those without ( P < 0.05), and in symptomatic versus asymptomatic plaques ( P < 0.01). These compelling results warrant larger longitudinal studies to explore the potential prognostic utility of CEUS.
Another advance in ultrasound plaque imaging involves the use of 3-dimensional (3D) ultrasound imaging, which builds upon many of the core principles of ultrasound imaging. This ultrasound technique enables not only visualization of carotid plaque, but more accurately quantifies plaque size and vessel volume. Plaque volume, as assessed with 3D ultrasound, has been shown to be a more robust metric than CIMT alone; hence, a highly sensitive means to detect plaque progression, by over two orders of magnitude more than IMT [ ]. Since atherosclerotic plaque increases in size faster longitudinally than it thickens, employing 3D ultrasound allows for smaller sample sizes in the serial assessment of an intervention on plaque progression [ ]. Thus, the role of 3D ultrasound plaque imaging in drug trials may prove to be cost-effective and lead to more testing of novel pharmacotherapeutics. Moreover, 3D ultrasound holds predictive and incremental value to coronary artery calcium scoring (CACS) [ ], a well-accepted biomarker of CAD that carries prognostic value. The ability of 3D-CIMT to predict subsequent CVD events is actively being studied in the BioImage study (clinicaltrials.gov NCT00738725) and the ability to detect high-risk plaque features in the Canadian Atherosclerosis Imaging Network (NCT01456403).
8.2.1.1
CIMT and cardiovascular risk
The value of CIMT measures is buttressed by a strong association between increased CIMT and major traditional cardiac risk factors [ , ]. Furthermore, epidemiological studies have demonstrated substantial predictive value of CIMT for future CVD events, independent of well-recognized traditional cardiovascular risk factors [ ]. The net reclassification index (NRI) is significant with the addition of maximum CIMT of the internal carotid artery ( P < 0.001). Additional IMT indices have also been investigated. For example, in the Atherosclerosis Risk in Communities (ARIC) study, the presence of plaque in addition to increased CIMT improved the NRI by 9.9% [ ]. Notably, the presence of hypoechoic plaques (indicative of lipid-rich content), has been shown to be an independent predictor of CV death [ , ].
8.2.1.2
CIMT and clinical trials
CIMT is used to quantify the degree of early atherosclerosis and to monitor the extent of modulation in response to novel therapies, in particular those that target lipids and blood pressure. In one study, a significant reduction in CIMT progression during statin therapy [ ] was demonstrated. Although there was no regression of plaque in a separate study, a greater reduction of IMT progression was observed in response to intensification of statin therapy [ ]. The results of these CIMT based trials are concordant with the results of clinical outcomes in clinical studies [ , ]. Despite these promising results with anti-lipid therapy, these results have not been replicated with anti-hypertensives or non-statin agents [ ]. Additional studies using plaque-imaging ultrasound techniques are necessary to determine the overall utility and prognostic vale of this technology among the landscape of other imaging modalities, to be discussed in this chapter.
Advantages of ultrasound technology, in comparison to CT, MRI, and nuclear imaging, rest in its broader availability and lower cost profile. Importantly, ultrasound-based plaque imaging affords a reproducible measurement that does not involve any radiation exposure. It has demonstrable value in predicting future CV risk, independent of traditional CV risk factors. For all these reasons, plaque imaging by ultrasound (i.e., CIMT, 3D ultrasound, CEUS) is an attractive modality to employ in the risk assessment of early atherosclerosis in patients.
8.3
Computed tomography
8.3.1
Coronary artery calcium scoring
CACS can be performed by noncontrast-enhanced computed tomography [ ]. CACS is a relatively simple technique associated with a low radiation dose in the range of ~ 1 mSv [ ]. The conventional Agatston score is calculated by measuring areas with a CT attenuation value above 130HU (Hounsfield units), multiplying each calcified lesion by a factor related to the maximum attenuation value, and then adding up the per-slice scores to acquire a total calcium score. Alternative measures of coronary calcium, the calcium volume, the calcium mass, or calcium density may be more reproducible or provide incremental prognostic value [ ]. Nevertheless, because of its long existence and familiarity, the Agatston score remains the most frequently reported coronary calcium measure, and correlates well with overall atherosclerotic burden. In the general population, the calcium score increases with age, is higher in men than women, and appears to vary by race.
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