Coronary and carotid atherosclerosis: How useful is the imaging?

Atherosclerosis 231 (2013) 323e333

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Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis

Review

Coronary and carotid atherosclerosis: How useful is the imaging? Pranvera Ibrahimi, Fisnik Jashari, Rachel Nicoll, Gani Bajraktari, Per Wester, Michael Y. Henein* Heart Centre and Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden

a r t i c l e i n f o

a b s t r a c t

Article history: Received 23 July 2013 Received in revised form 13 September 2013 Accepted 30 September 2013 Available online 11 October 2013

The recent advancement of imaging modalities has made possible visualization of atherosclerosis disease in all phases of its development. Markers of subclinical atherosclerosis or even the most advanced plaque features are acquired by invasive (IVUS, OCT) and non-invasive imaging modalities (US, MRI, CTA). Determining plaques prone to rupture (vulnerable plaques) might help to identify patients at risk for myocardial infarction or stroke. The most accepted features of plaque vulnerability include: thin cap fibroatheroma, large lipid core, intimal spotty calcification, positive remodeling and intraplaque neovascularizations. Today, research is focusing on finding imaging techniques that are less invasive, less radiation and can detect most of the vulnerable plaque features. While, carotid atherosclerosis can be visualized using noninvasive imaging, such as US, MRI and CT, imaging plaque feature in coronary arteries needs invasive imaging modalities. However, atherosclerosis is a systemic disease with plaque development simultaneously in different arteries and data acquisition in carotid arteries can add useful information for prediction of coronary events. Ó 2013 Elsevier Ireland Ltd. All rights reserved.

Keywords: Atherosclerosis imaging Arterial calcification Dupplex ultrasound Intravascular ultrasound OCT

Contents 1. 2.

3. 4.

5. 6. 7.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323 Imaging subclinical atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324 2.1. Carotid intima media thickness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324 2.2. Carotid total plaque area (volume) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325 2.3. Coronary artery calcium score (CACS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325 Vulnerable plaque and the vulnerable patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325 Imaging vulnerable atherosclerotic plaque . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326 4.1. Positive wall remodeling and large plaque lipid core . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326 4.2. Plaque morphology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326 4.3. Thin cap fibroatheroma (TCFA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326 4.4. Plaque composition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327 4.5. Neovascularization and intraplaque hemorrhage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327 4.6. Plaque inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329 Plaque calcification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329 Imaging atherosclerosis in multiple sites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330

1. Introduction

* Corresponding author. E-mail address: [email protected] (M.Y. Henein). 0021-9150/$ e see front matter Ó 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.atherosclerosis.2013.09.035

Atherosclerosis can lead to life-threatening cardiovascular (CV) events such as myocardial infarction (MI) or ischemic stroke (IS). The majority of events derive from the rupture or erosion of atherosclerotic plaque, with a superimposed thrombus. This may

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completely occlude the lumen (the commonest pathomechanism in MI) or may embolize to occlude a distal branch (as in IS) [1]. The risk of atherosclerotic plaque rupture does not necessarily correlate with stenosis severity, a dissociation revealed in many studies [2,3] and clinical trials, which have shown that statins markedly reduce acute ischemic events [4] with only modest reduction in the degree of stenosis [5]. Imaging atherosclerotic plaque using conventional arteriography has major limitations as it is unable to detect positively remodeled lesions, which do not significantly impinge on the lumen [6]. More recent technology, such as intravascular ultrasound (IVUS) and optical coherence tomography (OCT), can overcome this limitation and even provide information on the plaque type and thickness of the cap and highlight features affecting vulnerability: inflammation, neovascularization, ulceration and calcification (Fig. 1). Determination of the type of plaque prone to rupture might, therefore, help to identify patients at risk for MI [7,8], although these techniques are invasive and not practical for routine daily use. Another feature of plaque instability is low echogenicity and neovascularization [9]. On the other hand, noninvasive computerized tomography (CT) enables not only determination of the severity of luminal narrowing, but also visualization of plaque calcification and positive wall remodeling [10] (Fig. 1). Positron emission tomography (PET) and magnetic resonance imaging (MRI) provide similar information about the carotid circulation. They also assist in demonstrating the extent of disease spread [11], increased c-IMT and unstable plaques, which are at increased risk of causing acute events [12]. These imaging techniques have been validated against histological findings, thus strengthening their potential regular clinical application [13]. This

review focuses on imaging modalities that visualize atherosclerosis, assess its features and its predictive value as well as its response to medical therapy. 2. Imaging subclinical atherosclerosis It has been proposed that indicators of subclinical atherosclerosis, such as c-IMT, carotid total plaque area and coronary artery calcium score (CACS), might usefully predict vascular events. 2.1. Carotid intima media thickness C-IMT is defined as the distance between the lumeneintima interface and the mediaeadventitia interface, a measurement that can easily and reproducibly be obtained using Duplex ultrasound [14] (Fig. 1). It has been shown to be closely associated with the risk of developing future ischemic heart disease and stroke. The ARIC (Atherosclerosis Risk in Communities) study indicated that in middle-aged patients for every 1.9 mm increment of c-IMT, the risk for MI or sudden cardiac death increases by 36% [15]. C-IMT measurements also improved traditional risk factors for prediction of CV events. In particular, among intermediate-risk patients, the addition of c-IMT and plaque information led to clinical net reclassification improvement of approximately 9.9% [16]. Likewise, statins trials have consistently shown that a regression in c-IMT is associated with a reduction in CV events [17,18], particularly in patients with intensive therapy [19]. However, these findings have been contradicted by the recent evidence which found no association between c-IMT progression and CV risk in the general

Fig. 1. The usefulness of the imaging modalities in detection of plaque features and its stability. CTCAeCT coronary angiography.

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population [20,21]. Even, adding c-IMT to the Framingham risk score did not improve risk prediction in diabetic patients [22]. 2.2. Carotid total plaque area (volume) Carotid plaques usually enlarge in all directions, with the rate of longitudinal growth being twice as fast as transverse growth, which makes measurement of plaque area much more accurate for assessing disease progression and predicting future events. Spence et al. [23] demonstrated that baseline carotid plaque area is a strong predictor of the combined outcome of MI, IS and vascular death. The combined 5-year risk increased by quartile of plaque area: 5.6%, 10.7%, 13.9%, and 19.5% (P < 0.001 for all) after adjusting for baseline patient characteristics [23]. While c-IMT predicts IS more strongly than MI [24,25], carotid plaque area predicts both events; an area of 0.46e1.18 cm2 has a 5 year risk of 12.3% for both events and a 3.9% risk for IS alone [23]. Plaque area has also been used for accurate assessment of the effect of therapy [23] (Fig. 2). Furthermore, total plaque volume (TPV), particularly its rate of progression, has recently been shown as a better predictor for TIA, stroke, MI or death compared to IMT and plaque area [26]. 2.3. Coronary artery calcium score (CACS) Calcium formation in the arterial wall is an active process, involving osteoblast-like cells. Studies have shown that CAC provides incremental information beyond traditional risk factors for predicting coronary events [27,28], hence improving an individual’s risk stratification [29] (Fig. 2). Although the CACS correlates with cIMT [30], the former has higher predictive accuracy for CV events [31]. After adjustment for each other as well as age, race and gender, the hazard ratio for CVD increased 2.1-fold (95%CI, 1.8e2.5) for each 1-standard deviation increment of log-transformed CACS, vs. 1.3fold (95% CI, 1.1e1.4) for each 1-SD increment of the maximum cIMT. Determination of the CACS is easy, rapid, reproducible, relatively cheap and requires only low-dose radiation (<1 mSv) [32]. The Multi-Ethnic Study of Atherosclerosis (MESA) showed that in patients with a CACS>300 the likelihood of coronary events was almost 10 times that of patients with zero calcification [28]. In the Heinz Nixdorf Recall Study, the CACS accurately reclassified patients at intermediate cardiac risk according to Framingham Risk Score, with a net reclassification index (NRI) of 21.7% as low risk (CACS <100) and 30.6% as high risk (CACS
400) [33]. However, some studies have indicated that the absence of CAC does not completely eliminate the possibility of CAD [34,35]. A recent analysis from the MESA study showed that 16% of the coronary arteries with significant stenosis had no CAC at baseline [36]. In

Fig. 2. Increased IMT (white arrow) and atherosclerotic plaque (red arrow) in the common carotid artery. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 3. Carotid CTA showing plaque calcification (red arrows). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

addition, approximately 20% of asymptomatic patients with cardiac risk factors but no detectable CAC have significant stenosis, with evidence of ischemia in one third of them [37]. 3. Vulnerable plaque and the vulnerable patient Several studies have described plaques that are at increased risk of rupture with potential for causing acute events, as vulnerable. The most accepted features of vulnerability include: thin cap fibroatheroma (<64 nm), large lipid core (>40% of plaque volume), spotty calcification (as opposed to a calcified plaque cap), positive remodeling and intraplaque neovascularizations [1]. Despite that, in ACS patients IVUS and OCT have found ruptured plaques in arterial beds other than the one containing the culprit lesion, suggesting a significant role for systemic inflammation, as measured by C-reactive protein (CRP) [38]. Moreover, fibrous caps may show evidence of multiple ruptures and subsequent healing, despite a lack of symptoms [39]. These findings support the recent appreciation of atherosclerosis as a dynamic pathology, with silent and stable plaques suddenly acquiring vulnerable characteristics followed by rupture. However, the factors provoking plaque destabilization and the speed of effect remain to be determined. Furthermore, conventional atherosclerotic plaques are often formed at the bifurcations of the coronary and carotid arteries, but ruptured plaques causing subsequent events in patients with aggressive inflammatory response do not always follow this pattern. To better understand this unstable atherosclerotic pathophysiology, accurate longitudinal non-invasive arterial imaging able to detect vulnerable plaques and assess their response to various medications is of immense importance. It should also be remembered that atherosclerosis typically affects more than one vessel in the same arterial bed, with different plaque forms,

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consistency and degree of stability [1]. Finally, carotid neovascularization has been reported as a sign of diffuse disease and vulnerability [40], while carotid calcification has been found to predict future ACS [41] it has a protective role in the carotid artery [42]. 4. Imaging vulnerable atherosclerotic plaque Since low-grade stenosis does not exclude the future occurrence of acute events in coronary and carotid arteries, determination of plaque features beyond the degree of stenosis is important. 4.1. Positive wall remodeling and large plaque lipid core Positive vascular remodeling is defined as outward prominence of the arterial wall, which may take place in the early stages of atherosclerosis [6]. The nature of such arterial wall changes limits the optimum use of cross sectional imaging techniques and makes MRI and CT angiography (CTA) (Figs. 3 and 4) the best modalities for longitudinal follow-up studies. The latter has been revalidated against IVUS and has proved highly reproducible [43,44]. Remodeling of target lesions is determined by the remodeling index (RI),

calculated as external elastic membrane area divided by the respective proximal and distal segment reference area. Positive remodeling is defined as an RI
1.05 and negative remodeling as an RI <1.05. Compared to lesions with negative remodeling, positive remodeling may include a large lipid core of >40% plaque area [45]. Coronary and carotid artery positive remodeling and a large lipid core characterize plaque vulnerability [46], and can easily be imaged using MRI [47] and CTA [48]. Kitagawa et al. [49] showed that positive wall remodeling was the only factor that correlated with culprit lesions causing acute coronary syndrome (ACS). Similar findings have been reproduced by IVUS studies [50]. In addition, positive remodeling is presumed to be associated with inflammation and increased propensity for rupture. A study by Kroner et al. using IVUS demonstrated that thin-capped fibroatheromas were associated with 43% of positively remodeled plaques by CT as compared with 4.8% of negatively remodeled lesions [51]. In the PROSPECT trial the highest risk plaques (with a likelihood of 17.2% to cause acute ischemic events within three years) were those defined by a minimum lumen area of <4 mm2 and a large plaque burden (
70%) [52]. Finally, extensive carotid remodeling is significantly greater in patients with cerebral ischemic symptoms compared to asymptomatic patients [53]. Regression of plaque volume with statin therapy has been proved in the Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden (ASTEROID) [54]. Likewise, the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial, which found that 18 months’ treatment with 80 mg Atorvastatin lowered LDLcholesterol level to 78 mg/dL and stopped progression of plaque volume [55]. This encouraged Von Brigelen et al. [56] in an observation study to suggest that an LDL-cholesterol of 75 mg/dL could be the threshold below which no increase of atherosclerotic dimensions may occur. Recently, Lee et al. used IVUS to compare the effects of 20 mg/day atorvastatin and 10 mg/day rosuvastatin on mild coronary atherosclerotic plaques (20%e50% luminal narrowing and lesion length >10 mm) and reported significant regression of coronary atherosclerosis, particularly with the former [57]. Similar results have been produced by serial CT scanning [58] and high-resolution MRI, testing simvastatin on carotid lesions [2]. 4.2. Plaque morphology Several studies have suggested that irregular coronary and carotid plaques, identified by conventional angiography, Multi Detector CTA (MDCTA) or ultrasound (US) (Fig. 5), represent markers of plaque instability. Lesion eccentricity, with irregularities on coronary angiography, is associated with ruptured plaques and thrombosis based on postmortem and clinical angiographic studies [59]. Kitamura et al. showed that subjects with irregular carotid plaques have an age-adjusted RR of experiencing IS of 7.7 (95% CI: 2.0, 30) [60]. The relevance of plaque irregularities as a predictive factor for IS was also confirmed in a large population (1939 patients) [61]. MDCTA and US can assess plaque morphology and accurately differentiate between smooth, irregular and ulcerated surfaces. Saba et al. demonstrated that diagnostic accuracy of plaque ulceration by MDCTA is significantly higher than by US (93% vs. 37.5%) [62]. Contrast-enhanced US used to assess atherosclerotic carotid plaques improves visualization of vessel wall irregularities and ulceration [63]. 4.3. Thin cap fibroatheroma (TCFA)

Fig. 4. MRI angiography showing a lesion in the internal carotid artery (arrow).

The fibrous cap represents the portion of the plaque that faces the vascular lumen and maintains the integrity of the plaque. Thinning of the fibrous cap is considered an independent risk for

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Fig. 5. US Doppler of an atherosclerotic plaque located in the carotid bifurcation; left: showing heterogeneity; right: irregular plaque.

acute ischemic events and leads to plaque rupture [64]. The critical thickness of a fibrous cap prone to rupture is nearly three times greater for carotid than for coronary plaques (72  15 vs. 23  17 microns) [65], suggesting a possibility for early detection by MRI scanning [66]. It has been suggested that the fibrous cap is thinned by autolysis via the action of metalloproteinase released by macrophages [67]. In coronary arteries, OCT enables identification of TCFA [68] (Fig. 6). IVUS-derived TCFA is defined as plaque burden of
40% with a confluent necrotic core >10% in direct contact with the lumen. In contrast, MRI with delayed gadolinium (Gd) clearance has been shown to accurately detect TCFA [69]. Direct comparison of endarterectomy studies showed that Gd retention, due to inflammation, primarily occurred in regions with TCFA <60 mm. Sano et al. [70] used IVUS to investigate 160 non-significant coronary lesions in 140 patients with angina, who were followed up for 30 months. Of the 12 plaques which ruptured, generating ACS, all proved to have baseline thin TCFA, significantly greater RI and higher percentage of lipid pool area. Similar results have been reproduced by Takaya et al. [66] in the carotid circulation, which showed an increased occurrence of subsequent neurological complications over a mean follow up period of 38 months.

4.4. Plaque composition Plaque composition is similar in coronary and carotid arteries, irrespective of its age, and this will largely determine relative stability. Plaques may histologically be described as fibrosed, fibrofatty, fatty, hemorrhagic, necrotic or calcified, with plaques that are necrotic or calcified being generally stable [71]. Although coronary IVUS (Fig. 7) and carotid US imaging have demonstrated that echolucent plaques may reflect lipid deposits, hemorrhage, necrotic debris [72], or inflammation [73] associated with an unstable clinical presentation [74], these imaging modalities have shown only modest accuracy [75]. Recent technical advances with radiofrequency signal analysis using VH-IVUS [76] (Fig. 7) enable radiographers to critically distinguish between the four different plaque components: fibrotic, fibro-fatty, necrotic, and dense calcium [77] (Tables 1 and 2). These are represented as green, light green, red, and white, respectively. This technique could be ideal for assessing the response of plaque composition to pharmacological intervention [78], as well as providing endpoints for drug development [79]. Other imaging modalities, such as OCT, IV-MRI, MDCT and MRI, can provide equal information on plaque characterization (Tables 1 and 2). Using CTA, Schroder et al. [80] differentiated coronary plaques into three categories comprising fatty, mixed and calcified lesions as <50 (Hounsfield Units) HU, 50-119HU and >120HU respectively. Recently Saba et al. [81] suggested that the HU values of plaque may change significantly according to the selected kiloelectron volt; therefore, the HU-based plaque type should be classified according to the energy level applied. Plaque composition may also play an important role in the occurrence and extent of distal embolization after vascular intervention. Observational studies show a clear relationship between the amount of necrotic core as visualized by VH-IVUS and distal embolization [82]. The gray scale median (GSM) measurement combined with color mapping of the carotid plaques adequately correlates with the different histopathological components and allows relatively accurate identification of determinants of plaque instability [73]. Low GSM is associated with ischemic events and increased brain microembolisations [83], but it tends to increase with statins [84]. Furthermore, carotid plaque echolucency measured as GSM is important in planning the procedure to use for the treatment, carotid plaque echolucency with a GSM value of <25 increase the risk of stroke in carotid artery stenting [85]. 4.5. Neovascularization and intraplaque hemorrhage

Fig. 6. Coronary OCT show an atherosclerotic plaque with irregular luminal surface, suggested plaque rupture (red arrow), and a calcium spot (white arrow). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Neovascularization and intraplaque hemorrhage have been linked to vulnerable plaque. Neovascularization: The vasa vasorum consists of small blood vessels that supply the arterial wall with nutrients and oxygen. They are predominantly located in the adventitial layer, but factors

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Fig. 7. Coronary plaques in the culprit vessel of a patient presenting with unstable angina pectoris: (A) Multi-slice computed tomography (MSCT) multiplanar reconstruction of the right coronary artery showing obstructive non-calcified and mixed plaques. (B) to (E) Gray-scale intravascular ultrasound (IVUS) images and the corresponding VH (virtual histology) IVUS images. In (B), small amount of plaque in the proximal right coronary artery is seen, which appears normal on MSCT. TCFA (thin cap fibroatheroma) with a large amount of necrotic core is detected in proximally and distally located non-calcified plaques of the right coronary artery (C) and (E). A corresponding cross-section of a mixed plaque in the mid-right coronary artery shows plaque with calcium on VH IVUS (D). Multiple obstructive stenoses in the right coronary artery were confirmed on invasive coronary angiography (F) and (G). VH IVUS plaque components: dark green indicates fibrotic tissue; light green, fibro-fatty tissue; red, necrotic core; white, dense calcium. Reprinted, with permission, from Pundziute et al. [150]. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

such as hypoxia and inflammation may stimulate the extent and distribution of the vascular network within the arterial wall [86]. Histological studies have confirmed a network of microvessels within atherosclerotic lesions, known as intraplaque neovascularization (IPN), which originate from the adventitia and extend to the media and intima [87]. IPN creates immature microvessels responsible for the trafficking of macrophages and T cells and for the extravasation of erythrocytes [88]. Plaque neovascularization in coronary arteries can be evaluated using the recently developed contrast-enhanced IVUS [89] or OCT [90]. Likewise, cardiac MRI with Gd contrast can show enhanced atherosclerotic plaques, which are associated with microvessel density on histopathological examination [91]. Furthermore, imaging and histological studies have shown that neovascularization is associated with characteristics of vulnerability and symptomatic disease [92]. Patients with a higher degree of IPN carotid lesions experienced significantly more CV events [92,93]. Contrast enhanced ultrasound (CEUS) is a novel technique that has the potential to visualize neovascularization in carotid plaques [94]. US contrast agents consist of microbubbles that allow assessment of the amount of blood in the microvasculature within a

vascular region [95]. Significant acoustic plaque enhancement has been correlated with histopathology [96] and clinical presentation [97]. Intra-plaque hemorrhage (IPH) is defined as the extravasation of red blood cells (RBCs) mixed with fibrin and platelet matrix within the plaque. The RBC membrane contains 40% more cholesterol than any other cell in the body and is thus considered as the major source of lipid core expansion [40]. IPH has been shown to predict future ischemic events [98] by contributing to the deposition of free cholesterol, enhancing macrophage infiltration and increasing the necrotic core, thus promoting plaque vulnerability. In addition, IPH increases critical intra-plaque stress, which in turn leads to plaque rupture and thrombosis [99]. Approximately 40% of high-risk plaques in the carotid artery have IPH [98]. Despite the available vascular imaging technology, highresolution, multicontrast MRI is the only technique capable of detecting the presence and age of carotid IPH [100]. In vivo findings have been revalidated histologically [101] and the ability of MRI to detect IPH as the cause of cerebrovascular events has been confirmed [66]. Furthermore, carotid IPH has been shown to predict recurrence of strokes and TIAs [102] as well as spontaneous

Table 1 Plaque composition as evaluated by invasive and non-invasive imaging modalities. Imaging modalities Invasive IVUS

Reference

Histological/Ivus validation (Accuracy)

Histological differentiation

Limitations

Nair et al. [146] Nasu et al. [77]

Acc: 80e96%

Fibrous, fibro-fatty, necrotic and calcified tissue

OCT Yabushita et al. [147] IV-MRI Larose et al. [148] Non-invasive MDCT de Wert et al. [149]

Se: 71e96%; Sp: 90e98% Se: 73e100%; Sp:81e94%

Fibrous, fibro-calcific, fatty tissue, fibrose cap Fibrous, fatty, calcified tissue

Invasiveness, limited spatial resolution, limited to identify extent of plaque behind calcium Invasiveness, limited tissue penetration Invasiveness, balloon occlusion is needed

Se: 90%; Acc: 73%

MRI

Se: 78e92%, Sp: 68e98%

Plaque components derived from HU: fibrous, fatty, calcified tissue Lipid rich necrotic core, intra-plaque hemorrhage, intact fibrous cap

Radiation, overlap in the attenuation spectrum of fatty and fibrous tissue Contrast agent, cardiac motion artifact, limited spatial resolution

Cai et al. [101]

P. Ibrahimi et al. / Atherosclerosis 231 (2013) 323e333 Table 2 Different imaging modalities for detection of plaque features. Plaque feature

Coronary

Carotid

TCFA Positive remodeling Large lipid core Plaque composition Neovascularization Intraplaque hemorrhage Inflammation Calcification

IVUS, OCT IVUS, MRI, CTA MDCT, MRI, IVUS VH-IVUS Contrast enhanced-IVUS, OCT N/A Dual gating PET105 (ongoing) CT, IVUS

IVUS, OCT, MRI MRI, CTA, IVUS US-GSM/JBA, MDCT US-GSM, MDCT CEUS MRI FDG-PET US, CT

micro-embolic activity in trans-cranial Doppler (TCD) imaging [103]. A potential explanation for IPH as the source of cerebrovascular events has been thought to be due to expansion of sharptipped cholesterol crystals within the necrotic core, cutting through the vasa vasorum [88,104]. Despite the above facts, accurate detection of the exact cause of cerebrovascular events may be difficult. 4.6. Plaque inflammation Macrophages are the key inflammatory cells in atherosclerotic plaque, which have higher glucose metabolism than other cells (Fig. 1) [67]. 18Fluorine-labeled 2-deoxy-D-glucose (FDG) is a glucose analog that competes with glucose to facilitate intracellular transport, currently is in widespread use for imaging cancer [105]. After accumulation in the cells, FDG can be imaged and quantified by PET, which may be used to assess the response to medications (Table 3) [104]. In patients with recent stroke or TIA, levels of FDG in the culprit plaques have been shown to be higher than in the contralateral vessel [106] and to correlate with raised inflammatory markers including CRP, matrix metalloproteinases (MMPs) [107]. FDG uptake has been reported to correlate with the number of macrophages [108], to be associated with markers of plaque instability [109] and to correlate with microembolic signals on transcranial Doppler ultrasound [110]. However, not all studies have substantiated this association [111,112]. Recently, Folco et al. showed that pro-atherogenic inflammatory stimuli do not increase the rate of glucose uptake in human macrophages but hypoxia. This suggests that FDG uptake signals in atheroma may reflect hypoxia-

Table 3 Improvement of vulnerable plaque visualization using modified imaging techniques. Imaging modality

Vulnerable plaque features

Vulnerable plaque features assessed using modified imaging techniques

MDCT

Positive wall remodeling Plaque area Lower plaque density (<30HU) Plaque composition Intraplaque hemorrhage

Inflammation

MRI

US IVUS

OCT

Plaque area Plaque echolucency Positive wall remodeling Plaque area Spotty calcifications

TCFA Plaque composition

(N1177-specific contrast agent)

Neovascularization (Gadoflourine M or gadolinium) Inflammation (Iron oxide nanoparticle) Plaque composition (GSM) Neovascularisation (microbubbles) Plaque composition (RF-IVUS) Neovascularisation (microbubbles) TCFA Extent of plaque behind calcium nodule (RF-IVUS) Inflammation Neovascularization (OCT-Doppler)

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stimulated macrophages rather than mere inflammatory burden [113]. Late phase CEUS has been recently trialed to provide similar information, promising a tissue-specific marker of inflammation with a potential role in the risk stratification of atherosclerotic carotid stenosis [114]. Imaging inflammation in coronary arteries presents a particular challenge. Even though coronary plaques are more heavily inflamed compared to those in the carotids [115], coronary arteries are too small to be adequately assessed by PET scanning and imaging is likely to be hindered by respiratory and cardiac motion. Furthermore, FDG is also taken up by the myocardium, which preferentially metabolizes glucose over free fatty acids [116]. These issues have led researchers to focus on modifying imaging techniques and searching for more specific tracers, such as C-PK11195 [117], and Ga-DOTATATE [118]. Work with dual gating PET data for both respiratory and cardiac motion to improve definition of individual plaques is ongoing [119]. Furthermore, attempts to switch myocardial metabolism to free fatty acids by using a low carbohydrate and high fat preparation before imaging seems to be promising [120]. Finally, FDG PET/CT has recently been used to assess the early plaque response to statin therapy. After three months of treatment, inflammation was significantly reduced with atorvastatin 80 mg but not atorvastatin 10 mg [121]. 5. Plaque calcification Calcium formation may be found in any arterial bed as well as in the microvessels, where it is known as calciphylaxis or calcific uraemic arteriolopathy. It may be present in the lumen as a calcified plaque cap and may also invade the intima or media, the latter being common in chronic kidney disease or type II diabetes. There are marked similarities between intimal and medial calcification, with both producing inflammatory markers and cytokines (e.g. TNF-alpha, CRP, MCP-1, CD40-CD154, and IL-6) [122,123]. Nevertheless, osteogenic differentiation with metaplastic bone formation is only rarely seen in intimal calcification, whereas it is often seen in medial calcification [124]. Plaque calcification can be assessed by a number of imaging modalities including CT, MRI, IVUS and OCT (Figs. 6e8), although it has been shown that characterization of overall plaque echogenicity by standard B-mode US scan may not adequately reflect the degree of carotid plaque calcification [125]. Medial calcification causes arterial stiffness and increased pulse pressure but the consequences of intimal or plaque calcification is less clear, whereas micro-calcifications in the intima (spotty calcification) have been shown to destabilize the plaques [42]. Unfortunately, currently available CT imaging cannot distinguish between intimal and medial calcification [126], while only invasive OCT can distinguish between the two [68]. Haimovici et al. [127] in 1991 stated that patterns of atherosclerosis are strongly influenced by intrinsic differences in the cells composing the vascular system at different locations. Although some distinct differences between the coronary and carotid artery exist with regard to the pattern of ulceration, hemorrhage or calcified nodule in the plaque [128], there is a significant overlap between them. Calcified atherosclerotic plaques in the coronary and carotid arteries generally share common risk factors [129]. Furthermore, significant correlation was found between the presence and extent of calcification in coronary and carotid vessel beds [128]. The CACS was independently associated with the degree of internal carotid artery stenosis and with irregular carotid plaque surface, regardless of race or ethnicity [130]. However, although CAC has been correlated with significant vessel stenosis and plaque burden [131e133], the association between severe calcification in the carotid artery and the degree of carotid stenosis is not well

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Fig. 8. Coronary CT scan (left) showing extensive right coronary calcification, not delineated on conventional angiography (right).

determined [134]. Similarly, whereas CAC has been established as a strong and independent risk factor for CHD events [135,136] and stroke [137], conflicting data exists with regards to the role of carotid artery calcification in stroke prediction [138,139], in contrast to CHD [140]. The degree of plaque calcification found in carotid endarterectomy (CAE) specimens has been shown to be more severe in patients with prior ACS and in those who had developed ACS during follow-up after CEA, compared with patients who did not develop ACS [141]. On the other hand, a recent study showed that CAC correlates with characteristics of advanced carotid plaque [130]. This correlation indicates that calcification in each vascular bed is a sign of more extensive atherosclerotic burden in the other bed (Table 4). In support of this, the presence of calcification in atherosclerotic plaques is associated with high levels of inflammatory markers, such as CRP, IL-6 and adipokines [127,142].

6. Imaging atherosclerosis in multiple sites Some individuals with atherosclerotic disease are particularly prone to instability and rupture of plaques, and hence clinical complications. This instability could be influenced by systemic factors, such as infection, autoimmunity or genetics. Unstable plaques could often be present at multiple sites or even in different arterial systems, constituting a higher risk for recurrent symptoms and complications. At three years follow up, the rates of MI, stroke or vascular death was 25% for patients with symptomatic disease in one vascular system and >40% in multiple sites of atherosclerosis [1]. Indeed, patients with detectable disease in the coronary and peripheral arteries carry twice the level of risk as those presenting with CAD alone [143]. Interestingly, the presence of bilateral carotid

Table 4 Calcification in coronary and carotid artery, association with acute events and degree of stenosis. Events/Features

Coronary calcification

Carotid calcification

Future MI Future Stroke Degree of stenosis in corresponding artery All cause mortality

Predicted Predicted Correlated

Predicted Conflict data! Conflict data!

Associated

Associated

disease proved a better predictor of CAD than the extent or severity of disease in either bifurcation [144]. Furthermore, the presence of triple vessel coronary disease is an independent predictor of severe or total internal carotid occlusion [145].

7. Conclusion We have described the currently available techniques for imaging atherosclerotic plaques and their progression from subclinical to more advanced disease. In addition, we have discussed the potential ability of those imaging modalities for detecting vulnerable plaques which might cause ACS or stroke. While CAC scoring remains a valid method for prediction of coronary artery disease, the role of c-IMT is not supported by recent studies. There is no single technique that could identify lesions with the potential to cause ACS or stroke, with their properties of thin cap, large lipid core, spotty calcification, positive remodeling, intraplaque neovascularization, and inflammation. Nevertheless, while identification of a thin fibrous cap in the coronary artery requires an invasive approach, similar carotid artery pathology can be detected by MRI. Moreover, the degree of inflammation in carotid artery disease can be quantified by nuclear scanning techniques (PET/ FDG) but their application in coronary motion artifacts, particularly of small vessels is not feasible. On the other hand, calcification of the coronary arteries can easily be quantified by MDCT, despite its inability to distinguish accurately the layers involved, a limitation that can be overcome by OCT. Although calcification has often been seen as a predictor of CV events, it could have a stabilizing effect on vulnerable plaques, although the full extent and features of this property need to be further investigated in detail. Thus, it seems that the optimum imaging strategy for accurate identification of plaque type is integration of various imaging modalities with their unique individual advantages. Moreover, a widespread disease in different arterial systems is consistent with a vulnerable patient who may need aggressive risk factor control and prophylactic antithrombotic therapy.

References [1] Jashari F, Ibrahimi P, Nicoll R, Bajraktari G, Wester P, Henein MY. Coronary and carotid atherosclerosis: similarities and differences. Atherosclerosis 2013 Apr;227(2):193e200.

P. Ibrahimi et al. / Atherosclerosis 231 (2013) 323e333 [2] Hellings WE, Peeters W, Moll FL, Pasterkamp G. From vulnerable plaque to vulnerable patient: the search for biomarkers of plaque destabilization. Trends Cardiovasc Med 2007 Jul;17(5):162e71. [3] Hackett D, Davies G, Maseri A. Pre-existing coronary stenoses in patients with first myocardial infarction are not necessarily severe. Eur Heart J 1988 Dec;9(12):1317e23. [4] Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994 Nov 19;344(8934):1383e9. [5] Corti R, Fayad ZA, Fuster V, et al. Effects of lipid-lowering by simvastatin on human atherosclerotic lesions: a longitudinal study by high-resolution, noninvasive magnetic resonance imaging. Circulation 2001 Jul 17;104(3): 249e52. [6] Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, Kolettis GJ. Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med 1987 May 28;316(22):1371e5. [7] Nissen SE, Gurley JC, Grines CL, et al. Intravascular ultrasound assessment of lumen size and wall morphology in normal subjects and patients with coronary artery disease. Circulation 1991 Sep;84(3):1087e99. [8] Kubo T, Imanishi T, Takarada S, et al. Assessment of culprit lesion morphology in acute myocardial infarction: ability of optical coherence tomography compared with intravascular ultrasound and coronary angioscopy. J Am Coll Cardiol 2007 Sep 4;50(10):933e9. [9] Honda O, Sugiyama S, Kugiyama K, et al. Echolucent carotid plaques predict future coronary events in patients with coronary artery disease. J Am Coll Cardiol 2004 Apr 7;43(7):1177e84. [10] Rothwell PM, Villagra R, Gibson R, Donders RC, Warlow CP. Evidence of a chronic systemic cause of instability of atherosclerotic plaques. Lancet 2000 Jan 1;355(9197):19e24. [11] Chen WQ, Zhang M, Ji XP, et al. Usefulness of high-frequency vascular ultrasound imaging and serum inflammatory markers to predict plaque rupture in patients with stable and unstable angina pectoris. Am J Cardiol 2007 Nov 1;100(9):1341e6. [12] O’Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson Jr SK. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. Engl J Med 1999 Jan 7;340(1):14e22. [13] Vancraeynest D, Pasquet A, Roelants V, Gerber BL, Vanoverschelde JL. Imaging the vulnerable plaque. J Am Coll Cardiol 2011 May 17;57(20): 1961e79. [14] Wikstrand J. Methodological considerations of ultrasound measurement of carotid artery intima-media thickness and lumen diameter. Clin Physiol Funct Imaging 2007 Nov;27(6):341e5. [15] Chambless LE, Heiss G, Folsom AR, et al. Association of coronary heart disease incidence with carotid arterial wall thickness and major risk factors: the Atherosclerosis Risk in Communities (ARIC) Study, 1987-1993. Am J Epidemiol 1997 Sep 15;146(6):483e94. [16] Nambi V, Chambless L, Folsom AR, et al. Carotid intima-media thickness and presence or absence of plaque improves prediction of coronary heart disease risk: the ARIC (Atherosclerosis Risk in Communities) study. J Am Coll Cardiol 2010 Apr 13;55(15):1600e7. [17] Crouse 3rd JR, Raichlen JS, Riley WA, et al. METEOR Study Group. Effect of rosuvastatin on progression of carotid intima-media thickness in low-risk individuals with subclinical atherosclerosis: the METEOR Trial. JAMA 2007 Mar 28;297(12):1344e53. [18] Amarenco P, Labreuche J, Lavallée P, Touboul PJ. Statins in stroke prevention and carotid atherosclerosis: systematic review and up-to-date meta-analysis. Stroke 2004 Dec;35(12):2902e9. [19] Smilde TJ, van Wissen S, Wollersheim H, Trip MD, Kastelein JJ, Stalenhoef AF. Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective, randomised, double-blind trial. Lancet 2001 Feb 24;357(9256):577e81. [20] Lorenz MW, Polak JF, Kavousi M, et al. Carotid intima-media thickness progression to predict cardiovascular events in the general population (the PROG-IMT collaborative project): a meta-analysis of individual participant data. Lancet 2012 Jun 2;379(9831):2053e62. [21] Rundek T, Blanton SH, Bartels S, et al. Traditional risk factors are not major contributors to the variance in carotid intima-media thickness. Stroke 2013 Aug;44(8):2101e8. [22] den Ruijter HM, Peters SA, Groenewegen KA, et al. Common carotid intima-media thickness does not add to Framingham risk score in individuals with diabetes mellitus: the USE-IMT initiative. Diabetologia 2013 Jul;56(7):1494e502. [23] Spence JD, Eliasziw M, DiCicco M, Hackam DG, Galil R, Lohmann T. Carotid plaque area: a tool for targeting and evaluating vascular preventive therapy. Stroke 2002 Dec;33(12):2916e22. [24] Ebrahim S, Papacosta O, Whincup P, et al. Carotid plaque, intima media thickness, cardiovascular risk factors, and prevalent cardiovascular disease in men and women: the British Regional Heart Study. Stroke 1999 Apr;30(4): 841e50. [25] Bots ML, Hoes AW, Koudstaal PJ, Hofman A, Grobbee DE. Common carotid intima-media thickness and risk of stroke and myocardial infarction: the Rotterdam Study. Circulation 1997 Sep 2;96(5):1432e7. [26] Wannarong T, Parraga G, Buchanan D, et al. Progression of carotid plaque volume predicts cardiovascular events. Stroke 2013 Jul;44(7):1859e65.

331

[27] McEvoy JW, Nasir K, Blumenthal RS. Calcium score reclassification: how should baseline risk be measured? J Am Coll Cardiol 2011 Jun 14;57(24): 2456e7. [28] Budoff MJ, Young R, Lopez VA, et al. Progression of coronary calcium and incident coronary heart disease events: MESA (Multi-Ethnic Study of Atherosclerosis). J Am Coll Cardiol 2013 Mar 26;61(12):1231e9. [29] Polonsky TS, McClelland RL, Jorgensen NW, et al. Coronary artery calcium score and risk classification for coronary heart disease prediction. JAMA 2010 Apr 28;303(16):1610e6. [30] Taylor AJ, Bindeman J, Le TP, et al. Progression of calcified coronary atherosclerosis: relationship to coronary risk factors and carotid intimamediathickness. Atherosclerosis 2008 Mar;197(1):339e45. [31] Folsom AR, Kronmal RA, Detrano RC, et al. Coronary artery calcification compared with carotid intima-media thickness in the prediction of cardiovascular disease incidence: the Multi-Ethnic Study of Atherosclerosis (MESA). Arch Intern Med 2008 Jun 23;168(12):1333e9. [32] Gallino A, Stuber M, Crea F, et al. “In vivo” imaging of atherosclerosis. Atherosclerosis 2012 Sep;224(1):25e36. [33] Erbel R, Möhlenkamp S, Moebus S., Heinz Nixdorf Recall Study Investigative Group. Coronary risk stratification, discrimination, and reclassification improvement based on quantification of subclinical coronary atherosclerosis: the Heinz Nixdorf Recall study. J Am Coll Cardiol 2010 Oct 19;56(17): 1397e406. [34] Schenker MP, Dorbala S, Hong EC, et al. Interrelation of coronary calcification, myocardial ischemia, and outcomes in patients with intermediate likelihood of coronary artery disease: a combined positron emission tomography/computed tomography study. Circulation 2008 Apr 1;117(13): 1693e700. [35] Henneman MM, Schuijf JD, Pundziute G, et al. Noninvasive evaluation with multislice computed tomography in suspected acute coronary syndrome: plaque morphology on multislice computed tomography versus coronary calcium score. J Am Coll Cardiol 2008 Jul 15;52(3):216e22. [36] Rosen BD, Fernandes V, McClelland RL, et al. Relationship between baseline coronary calcium score and demonstration of coronary artery stenoses during follow-up MESA (Multi-Ethnic Study of Atherosclerosis). JACC Cardiovasc Imaging 2009 Oct;2(10):1175e83. [37] Iwasaki K, Matsumoto T, Aono H, Furukawa H, Samukawa M. Prevalence of subclinical atherosclerosis in asymptomatic patients with low-tointermediate risk by 64-slice computed tomography. Coron Artery Dis 2011 Jan;22(1):18e25. [38] Nakanishi K, Fukuda S, Shimada K, et al. Non-obstructive low attenuation coronary plaque predicts three-year acute coronary syndrome events in patients with hypertension: multidetector computed tomographic study. J Cardiol 2012 Mar;59(2):167e75. [39] Teng Z, Degnan AJ, Sadat U, et al. Characterization of healing following atherosclerotic carotid plaque rupture in acutely symptomatic patients: an exploratory study using in vivo cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2011 Oct 27;13:64. [40] Koole D, Heyligers J, Moll FL, Pasterkamp G. Intraplaque neovascularization and hemorrhage: markers for cardiovascular risk stratification and therapeutic monitoring. J Cardiovasc Med (Hagerstown) 2012 Oct;13(10):635e9. [41] Hellings WE, Peeters W, Moll FL, et al. Composition of carotid atherosclerotic plaque is associated with cardiovascular outcome: a prognostic study. Circulation 2010 May 4;121(17):1941e50. [42] Nicoll R, Henein MY. Arterial calcification: friend or foe? Int J Cardiol 2013 Jul 31;167(2):322e7. [43] Rinehart S, Vazquez G, Qian Z, Murrieta L, Christian K, Voros S. Quantitative measurements of coronary arterial stenosis, plaque geometry, and composition are highly reproducible with a standardized coronary arterial computed tomographic approach in high-quality CT datasets. J Cardiovasc Comput Tomogr 2011 Jan-Feb;5(1):35e43. [44] Achenbach S, Ropers D, Hoffmann U, et al. Assessment of coronary remodeling in stenotic and nonstenotic coronary atherosclerotic lesions by multidetector spiral computed tomography. J Am Coll Cardiol 2004 Mar 3;43(5): 842e7. [45] Matsuo Y, Takumi T, Mathew V, et al. Plaque characteristics and arterial remodeling in coronary and peripheral arterial systems. Atherosclerosis 2012 Aug;223(2):365e71. [46] Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2000 May;20(5): 1262e75. [47] Hayashi K, Mani V, Nemade A, et al. Variations in atherosclerosis and remodeling patterns in aorta and carotids. J Cardiovasc Magn Reson 2010 Mar 5;12:10. [48] Motoyama S, Sarai M, Inoue K, et al. Morphologic and functional assessment of coronary artery diseaseepotential application of computed tomography angiography and myocardial perfusion imaging. Circ J 2013;77(2):411e7. [49] Kitagawa T, Yamamoto H, Horiguchi J, et al. Characterization of noncalcified coronary plaques and identification of culprit lesions in patients with acute coronary syndrome by 64-slice computed tomography. JACC Cardiovasc Imaging 2009 Feb;2(2):153e60. [50] Takeuchi H, Morino Y, Matsukage T, et al. Impact of vascular remodeling on the coronary plaque compositions: an investigation with in vivo tissue

332

[51]

[52]

[53]

[54]

[55]

[56]

[57]

[58]

[59]

[60]

[61]

[62]

[63]

[64]

[65]

[66]

[67] [68]

[69]

[70]

[71] [72]

[73]

[74]

[75]

P. Ibrahimi et al. / Atherosclerosis 231 (2013) 323e333 characterization using integrated backscatter-intravascular ultrasound. Atherosclerosis 2009 Feb;202(2):476e82. Kröner ES, van Velzen JE, Boogers MJ, et al. Positive remodeling on coronary computed tomography as a marker for plaque vulnerability on virtual histology intravascular ultrasound. Am J Cardiol 2011 Jun 15;107(12):1725e9. Stone GW, Maehara A, Lansky AJ, et al., PROSPECT Investigators. A prospective natural-history study of coronary atherosclerosis. N Engl J Med 2011 Jan 20;364(3):226e35. Hardie AD, Kramer CM, Raghavan P, Baskurt E, Nandalur KR. The impact of expansive arterial remodeling on clinical presentation in carotid artery disease: a multidetector CT angiography study. AJNR Am J Neuroradiol 2007 Jun-Jul;28(6):1067e70. Ballantyne CM, Raichlen JS, Nicholls SJ, et al., ASTEROID Investigators. Effect of rosuvastatin therapy on coronary artery stenoses assessed by quantitative coronary angiography: a study to evaluate the effect of rosuvastatin on intravascular ultrasound-derived coronary atheroma burden. Circulation 2008 May 13;117(19):2458e66. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 2004;291:1071e80. von Birgelen C, Hartmann M, Mintz GS, Baumgart D, Schmermund A, Erbel R. Relation between progression and regression of atherosclerotic left main coronary artery disease and serum cholesterol levels as assessed with serial long-term (> or ¼12 months) follow-up intravascular ultrasound. Circulation 2003 Dec 2;108(22):2757e62. Lee CW, Kang SJ, Ahn JM, et al. Comparison of effects of atorvastatin (20 mg) versus rosuvastatin (10 mg) therapy on mild coronary atherosclerotic plaques (from the ARTMAP trial). Am J Cardiol 2012 Jun 15;109(12):1700e4. Inoue K, Motoyama S, Sarai M, et al. Serial coronary CT angiography-verified changes in plaque characteristics as an end point: evaluation of effect of statin intervention. JACC Cardiovasc Imaging 2010 Jul;3(7):691e8. Waxman S, Mittleman MA, Zarich SW, et al. Plaque disruption and thrombus in Ambrose’s angiographic coronary lesion types. Am J Cardiol 2003 Jul 1;92(1):16e20. Kitamura A, Iso H, Imano H, et al. Carotid intima-media thickness and plaque characteristics as a risk factor for stroke in Japanese elderly men. Stroke 2004;35:2788e94. Prabhakaran S, Rundek T, Ramas R, et al. Carotid plaque surface irregularity predicts ischemic stroke: the northern Manhattan study. Stroke 2006 Nov;37(11):2696e701. Saba L, Caddeo G, Sanfilippo R, Montisci R, Mallarini G. CT and ultrasound in the study of ulcerated carotid plaque compared with surgical results: potentialities and advantages of multidetector row CT angiography. AJNR Am J Neuroradiol 2007 Jun-Jul;28(6):1061e6. Ten Kate GL, van Dijk AC, van den Oord SC, et al. Usefulness of contrastenhanced ultrasound for detection of carotid plaque ulceration in patients with symptomatic carotid atherosclerosis. Am J Cardiol 2013 Jul 15;112(2): 292e8. Redgrave JN, Lovett JK, Gallagher PJ, Rothwell PM. Histological assessment of 526 symptomatic carotid plaques in relation to the nature and timing of ischemic symptoms: the Oxford plaque study. Circulation 2006 May 16;113(19):2320e8. Li ZY, Howarth SP, Tang T, Gillard JH. How critical is fibrous cap thickness to carotid plaque stability? A flow-plaque interaction model. Stroke 2006 May;37(5):1195e9. Takaya N, Yuan C, Chu B, et al. Association between carotid plaque characteristics and subsequent ischemic cerebrovascular events: a prospective assessment with MRIeinitial results. Stroke 2006 Mar;37(3):818e23. Libby P. Inflammation in atherosclerosis. Nature 2002 Dec 19-26;420(6917): 868e74. Cassar A, Matsuo Y, Herrmann J. Coronary atherosclerosis with vulnerable plaque and complicated lesions in transplant recipients: new insight into cardiac allograft vasculopathy by optical coherence tomography. Eur Heart J 2013 Sep;34(33):2610e7. Larose E, Kinlay S, Selwyn AP, et al. Improved characterization of atherosclerotic plaques by gadolinium contrast during intravascular magnetic resonance imaging of human arteries. Atherosclerosis 2008 Feb;196(2): 919e25. Sano K, Kawasaki M, Ishihara Y, et al. Assessment of vulnerable plaques causing acute coronary syndrome using integrated backscatter intravascular ultrasound. J Am Coll Cardiol 2006 Feb 21;47(4):734e41. Virmani R, Burke AP, Farb A, Kolodgie FD. Pathology of the vulnerable plaque. J Am Coll Cardiol 2006 Apr 18;47(Suppl. 8):C13e8. AbuRahma AF, Kyer 3rd PD, Robinson PA, Hannay RS. The correlation of ultrasonic carotid plaque morphology and carotid plaque hemorrhage: clinical implications. Surgery 1998 Oct;124(4):721e6 discussion 726e8. Tegos TJ, Sohail M, Sabetai MM, et al. Echomorphologic and histopathologic characteristics of unstable carotid plaques. AJNR Am J Neuroradiol 2000 NovDec;21(10):1937e44. Grønholdt ML, Wiebe BM, Laursen H, Nielsen TG, Schroeder TV, Sillesen H. Lipid-rich carotid artery plaques appear echolucent on ultrasound B-mode images and may be associated with intraplaque haemorrhage. Eur J Vasc Endovasc Surg 1997 Dec;14(6):439e45. Palmer ND, Northridge D, Lessells A, McDicken WN, Fox KA. In vitro analysis of coronary atheromatous lesions by intravascular ultrasound;

[76]

[77]

[78]

[79]

[80]

[81]

[82]

[83]

[84]

[85]

[86]

[87]

[88]

[89]

[90]

[91]

[92]

[93]

[94]

[95]

[96]

[97]

[98]

[99]

reproducibility and histological correlation of lesion morphology. Eur Heart J 1999 Dec;20(23):1701e6. König A, Margolis MP, Virmani R, Holmes D, Klauss V. Technology insight: in vivo coronary plaque classification by intravascular ultrasonography radiofrequency analysis. Nat Clin Pract Cardiovasc Med 2008 Apr;5(4): 219e29. Nasu K, Tsuchikane E, Katoh O, et al. Accuracy of in vivo coronary plaque morphology assessment: a validation study of in vivo virtual histology compared with in vitro histopathology. J Am Coll Cardiol 2006 Jun 20;47(12): 2405e12. Kawasaki M, Sano K, Okubo M, et al. Volumetric quantitative analysis of tissue characteristics of coronary plaques after statin therapy using threedimensional integrated backscatter intravascular ultrasound. J Am Coll Cardiol 2005 Jun 21;45(12):1946e53. Serruys PW, García-García HM, Buszman P, et al. Effects of the direct lipoprotein-associated phospholipase A(2) inhibitor darapladib on human coronary atherosclerotic plaque. Circulation 2008 Sep 9;118(11):1172e82. Schroeder S, Kopp AF, Baumbach A, et al. Noninvasive detection and evaluation of the atherosclerotic plaque with multislice computed tomography. J Am Coll Cardiol 2001;37:1430e5. Saba L, Argiolas GM, Siotto P, Piga M. Carotid artery plaque characterization using CT multienergy imaging. AJNR Am J Neuroradiol 2013 Apr;34(4): 855e9. Claessen BE, Maehara A, Fahy M, Xu K, Stone GW, Mintz GS. Plaque composition by intravascular ultrasound and distal embolization after percutaneous coronary intervention. JACC Cardiovasc Imaging 2012 Mar;5(Suppl. 3):S111e8. Sztajzel R, Momjian-Mayor I, Comelli M, Momjian S. Correlation of cerebrovascular symptoms and microembolic signals with the stratified grayscale median analysis and color mapping of the carotid plaque. Stroke 2006 Mar;37(3):824e9. Della-Morte D, Moussa I, Elkind MS, et al. The short-term effect of atorvastatin on carotid plaque morphology assessed by computer-assisted grayscale densitometry: a pilot study. Neurol Res 2011 Nov;33(9):991e4. Biasi GM, Froio A, Diethrich EB, et al. Carotid plaque echolucency increases the risk of stroke in carotid stenting: the Imaging in Carotid Angioplasty and Risk of Stroke (ICAROS) study. Circulation 2004 Aug 10;110(6):756e62. Epub 2004 Jul 26. Sluimer JC, Gasc JM, van Wanroij JL, et al. Hypoxia, hypoxia-inducible transcription factor, and macrophages in human atherosclerotic plaques are correlated with intraplaque angiogenesis. J Am Coll Cardiol 2008 Apr 1;51(13):1258e65. Virmani R, Kolodgie FD, Burke AP, et al. Atherosclerotic plaque progression and vulnerability to rupture: angiogenesis as a source of intraplaque hemorrhage. Arterioscler Thromb Vasc Biol 2005 Oct;25(10):2054e61. Mughal MM, Khan MK, DeMarco JK, Majid A, Shamoun F, Abela GS. Symptomatic and asymptomatic carotid artery plaque. Expert Rev Cardiovasc Ther 2011 Oct;9(10):1315e30. Vavuranakis M, Kakadiaris IA, O’Malley SM, et al. A new method for assessment of plaque vulnerability based on vasa vasorum imaging, by using contrast-enhanced intravascular ultrasound and differential image analysis. Int J Cardiol 2008 Oct 30;130(1):23e9. Kato K, Yonetsu T, Kim SJ, et al. Nonculprit plaques in patients with acute coronary syndromes have more vulnerable features compared with those with non-acute coronary syndromes: a 3-vessel optical coherence tomography study. Circ Cardiovasc Imaging 2012 Jul;5(4):433e40. Sirol M, Moreno PR, Purushothaman KR, et al. Increased neovascularization in advanced lipid-rich atherosclerotic lesions detected by gadofluorine-Menhanced MRI: implications for plaque vulnerability. Circ Cardiovasc Imaging 2009 Sep;2(5):391e6. Fleiner M, Kummer M, Mirlacher M, et al. Arterial neovascularization and inflammation in vulnerable patients: early and late signs of symptomaticatherosclerosis. Circulation 2004 Nov 2;110(18):2843e50. Staub D, Schinkel AF, Coll B, et al. Contrast-enhanced ultrasound imaging of the vasa vasorum: from early atherosclerosis to the identification of unstable plaques. JACC Cardiovasc Imaging 2010 Jul;3(7):761e71. Coli S, Magnoni M, Sangiorgi G, et al. Contrast-enhanced ultrasound imaging of intraplaque neovascularization in carotid arteries: correlation with histology and plaque echogenicity. J Am Coll Cardiol 2008 Jul 15;52(3):223e30. Yang H, Xiong X, Zhang L, Wu C, Liu Y. Adhesion of bio-functionalized ultrasound microbubbles to endothelial cells by targeting to vascular cell adhesion molecule-1 under shear flow. Int J Nanomedicine 2011;6:2043e51. Ten Kate GL, van den Oord SC, Sijbrands EJ, et al. Current status and future developments of contrast-enhanced ultrasound of carotid atherosclerosis. J Vasc Surg 2013 Feb;57(2):539e46. Xiong L, Deng YB, Zhu Y, Liu YN, Bi XJ. Correlation of carotid plaque neovascularization detected by using contrast-enhanced US with clinical symptoms. Radiology 2009 May;251(2):583e9. Kockx MM, Cromheeke KM, Knaapen MW, et al. Phagocytosis and macrophage activation associated with hemorrhagic microvessels in human atherosclerosis. Arterioscler Thromb Vasc Biol 2003 Mar 1;23(3):440e6. Huang X, Teng Z, Canton G, Ferguson M, Yuan C, Tang D. Intraplaque hemorrhage is associated with higher structural stresses in human atherosclerotic plaques: an in vivo MRI-based 3D fluid-structure interaction study. Biomed Eng Online 2010 Dec 31;9:86.

P. Ibrahimi et al. / Atherosclerosis 231 (2013) 323e333 [100] Takaya N, Yuan C, Chu B, et al. Presence of intraplaque hemorrhage stimulates progression of carotid atherosclerotic plaques: a high-resolution magnetic resonance imaging study. Circulation 2005 May 31;111(21): 2768e75. [101] Cai J, Hatsukami TS, Ferguson MS, et al. In vivo quantitative measurement of intact fibrous cap and lipid-rich necrotic core size in atherosclerotic carotid plaque: comparison of high-resolution, contrast-enhanced magnetic resonance imaging and histology. Circulation 2005 Nov 29;112(22):3437e44. [102] Kurosaki Y, Yoshida K, Endo H, Chin M, Yamagata S. Association between carotid atherosclerosis plaque with high signal intensity on T1-weighted imaging and subsequent ipsilateral ischemic events. Neurosurgery 2011 Jan;68(1):62e7 discussion 67. [103] Altaf N, Goode SD, Beech A, et al. Plaque hemorrhage is a marker of thromboembolic activity in patients with symptomatic carotid disease. Radiology 2011 Feb;258(2):538e45. [104] Sheikine Y, Akram K. FDG-PET imaging of atherosclerosis: do we know what we see? Atherosclerosis 2010 Aug;211(2):371e80. [105] Kelloff GJ, Hoffman JM, Johnson B, et al. Progress and promise of FDG-PET imaging for cancer patient management and oncologic drug development. Clin Cancer Res 2005 Apr 15;11(8):2785e808. [106] Rudd JH, Warburton EA, Fryer TD. Imaging atherosclerotic plaque inflammation with [18F]-fluorodeoxyglucose positron emission tomography. Circulation 2002 Jun 11;105(23):2708e11. [107] Pedersen SF, Graebe M, Fisker Hag AM, Højgaard L, Sillesen H, Kjaer A. Gene expression and 18FDG uptake in atherosclerotic carotid plaques. Nucl Med Commun 2010 May;31(5):423e9. [108] Ogawa M, Ishino S, Mukai T, et al. (18)F-FDG accumulation in atherosclerotic plaques: immunohistochemical and PET imaging study. J Nucl Med 2004 Jul;45(7):1245e50. [109] Silvera SS, Aidi HE, Rudd JH, et al. Multimodality imaging of atherosclerotic plaque activity and composition using FDG-PET/CT and MRI in carotid and femoral arteries. Atherosclerosis 2009 Nov;207(1):139e43. [110] Moustafa RR, Izquierdo-Garcia D, Fryer TD, et al. Carotid plaque inflammation is associated with cerebral microembolism in patients with recent transient ischemic attack or stroke: a pilot study. Circ Cardiovasc Imaging 2010 Sep;3(5):536e41. [111] Lederman RJ, Raylman RR, Fisher SJ, et al. Detection of atherosclerosis using a novel positron-sensitive probe and 18-fluorodeoxyglucose (FDG). Nucl Med Commun 2001 Jul;22(7):747e53. [112] Matter CM, Wyss MT, Meier P, et al. 18F-choline images murine atherosclerotic plaques ex vivo. Arterioscler Thromb Vasc Biol 2006 Mar;26(3): 584e9. [113] Folco EJ, Sheikine Y, Rocha VZ, et al. Hypoxia but not inflammation augments glucose uptake in human macrophages: implications for imaging atherosclerosis with 18fluorine-labeled 2-deoxy-D-glucose positron emission tomography. J Am Coll Cardiol 2011 Aug 2;58(6):603e14. [114] Owen DR, Shalhoub J, Miller S, et al. Inflammation within carotid atherosclerotic plaque: assessment with late-phase contrast-enhanced US. Radiology 2010 May;255(2):638e44. [115] Verhoeven BA, Moll FL, Koekkoek JA, et al. Statin treatment is not associated with consistent alterations in inflammatory status of carotid atherosclerotic plaques: a retrospective study in 378 patients undergoing carotid endarterectomy. Stroke 2006 Aug;37(8):2054e60. [116] Joshi FR, Lindsay AC, Obaid DR, Falk E, Rudd JH. Non-invasive imaging of atherosclerosis. Eur Heart J Cardiovasc Imaging 2012 Mar;13(3):205e18. [117] Gaemperli O, Shalhoub J, Owen DR, et al. Imaging intraplaque inflammation in carotid atherosclerosis with 11C-PK11195 positron emission tomography/ computed tomography. Eur Heart J 2012 Aug;33(15):1902e10. [118] Rominger A, Saam T, Vogl E, et al. In vivo imaging of macrophage activity in the coronary arteries using 68Ga-DOTATATE PET/CT: correlation with coronary calcium burden and risk factors. J Nucl Med 2010 Feb;51(2): 193e7. [119] Teräs M, Kokki T, Durand-Schaefer N, et al. Dual-gated cardiac PET-clinical feasibility study. Eur J Nucl Med Mol Imaging 2010 Mar;37(3):505e16. [120] Wykrzykowska J, Lehman S, Williams G, et al. Imaging of inflamed and vulnerable plaque in coronary arteries with 18F-FDG PET/CT in patients with suppression of myocardial uptake using a low-carbohydrate, high-fat preparation. J Nucl Med 2009 Apr;50(4):563e8. [121] Tawakol A, Fayad ZA, Mogg R, et al. Intensification of statin therapy results in a rapid reduction in atherosclerotic inflammation: results of a multicenter fluorodeoxyglucose-positron emission tomography/computed tomography feasibility study. J Am Coll Cardiol 2013 Sep 3;62(10):909e17. [122] Saremi A, Anderson RJ, Luo P, et al. Association between IL-6 and the extent of coronary atherosclerosis in the veterans affairs diabetes trial (VADT). Atherosclerosis 2009 Apr;203(2):610e4. [123] Moe SM, Chen NX. Inflammation and vascular calcification. Blood Purif 2005;23(1):64e71. [124] Doherty TM, Asotra K, Fitzpatrick LA. Calcification in atherosclerosis: bone biology and chronic inflammation at the arterial crossroads. Proc Natl Acad Sci U S A 2003 Sep 30;100(20):11201e6. [125] Denzel C, Lell M, Maak M. Carotid artery calcium: accuracy of a calcium score by computed tomography-an in vitro study with comparison to sonography and histology. Eur J Vasc Endovasc Surg 2004 Aug;28(2):214e20.

333

[126] van der Giessen AG, Gijsen FJ. Small coronary calcifications are not detectable by 64-slice contrast enhanced computed tomography. Int J Cardiovasc Imaging 2011 Jan;27(1):143e52. [127] Haimovici H. The role of arterial tissue susceptibility in atherogenesis. Tex Heart Inst J 1991;18:81e3. [128] Virmani R, Ladich ER, Burke AP, Kolodgie FD. Histopathology of carotid atherosclerotic disease. Neurosurgery 2006 Nov;59(5 Suppl. 3):S219e27 discussion S3e13. [129] Wagenknecht LE, Langefeld CD, Freedman BI, Carr JJ, Bowden DW. A comparison of risk factors for calcified atherosclerotic plaque in the coronary, carotid, and abdominal aortic arteries: the diabetes heart study. Am J Epidemiol 2007 Aug 1;166(3):340e7. [130] Lee KB, Budoff MJ, Zavodni A, et al. Coronary artery calcium is associated with degree of stenosis and surface irregularity of carotid artery. Atherosclerosis 2012 Jul;223(1):160e5. [131] Knez A, Becker A, Leber A. Relation of coronary calcium scores by electron beam tomography to obstructive disease in 2,115 symptomatic patients. Am J Cardiol 2004 May 1;93(9):1150e2. [132] Greenland P, Bonow RO, Brundage BH, et al. ACCF/AHA 2007 clinical expert consensus document on coronary artery calcium scoring by computed tomography in global cardiovascular risk assessment and in evaluation of patients with chest pain: a report of the American College of Cardiology Foundation Clinical Expert Consensus Task Force (ACCF/AHA Writing Committee to Update the 2000 Expert Consensus Document on Electron Beam Computed Tomography) developed in collaboration with the Society of Atherosclerosis Imaging and Prevention and the Society of Cardiovascular Computed Tomography. J Am Coll Cardiol 2007 Jan 23;49(3):378e402. [133] Bajraktari G, Nicoll R, Ibrahimi P, Jashari F, Schmermund A, Henein MY. Coronary calcium score correlates with estimate of total plaque burden. Int J Cardiol 2012 Nov 21 pii: S0167eS5273 (12)01457-X. [134] Marquering HA, Majoie CB, Smagge L. The relation of carotid calcium volume with carotid artery stenosis in symptomatic patients. AJNR Am J Neuroradiol 2011 Aug;32(7):1182e7. [135] Arad Y, Goodman KJ, Roth M, Newstein D, Guerci AD. Coronary calcification, coronary disease risk factors, C-reactive protein, and atherosclerotic cardiovascular disease events: the St. Francis Heart Study. J Am Coll Cardiol 2005 Jul 5;46(1):158e65. [136] Detrano R, Guerci AD, Carr JJ. Coronary calcium as a predictor of coronary events in four racial or ethnic groups. N Engl J Med 2008 Mar 27;358(13):1336e45. [137] Hermann DM, Gronewold J, Lehmann N, et al. Coronary artery calcification is an independent stroke predictor in the general population. Stroke 2013 Apr;44(4):1008e13. [138] de Weert TT, Cakir H, Rozie S. Intracranial internal carotid artery calcifications: association with vascular risk factors and ischemic cerebrovascular disease. AJNR Am J Neuroradiol 2009 Jan;30(1):177e84. [139] Prabhakaran S, Singh R, Zhou X, Ramas R, Sacco RL, Rundek T. Presence of calcified carotid plaque predicts vascular events: the Northern Manhattan Study. Atherosclerosis 2007 Nov;195(1):e197e201. [140] Elias-Smale SE, Wieberdink RG, Odink AE, et al. Burden of atherosclerosis improves the prediction of coronary heart disease but not cerebrovascular events: the Rotterdam Study. Eur Heart J 2011 Aug;32(16):2050e8. [141] Ciccone MM, Marzullo A, Mizio D, et al. Can carotid plaque histology selectively predict the risk of an acute coronary syndrome? Int Heart J 2011;52(2):72e7. [142] Abedin M, Tintut Y, Demer LL. Vascular calcification: mechanisms and clinical ramifications. Arterioscler Thromb Vasc Biol 2004 Jul;24(7):1161e70. [143] Alberts MJ, Bhatt DL, Mas JL, et al., Reduction of Atherothrombosis for Continued Health Registry Investigators. Three-year follow-up and event rates in the international REduction of Atherothrombosis for Continued Health Registry. Eur Heart J 2009;30:2318e26. [144] Touzé E, Varenne O, Calvet D, Mas JL. Coronary risk stratification in patientswith ischemic stroke or transient ischemic stroke attack. Int J Stroke 2007 Aug;2(3):177e83. [145] Steinvil A, Sadeh B, Arbel Y, et al. Prevalence and predictors of concomitant carotid and coronary artery atherosclerotic disease. J Am Coll Cardiol 2011 Feb15;57(7):779e83. [146] Nair A, Kuban BD, Tuzcu EM, Schoenhagen P, Nissen SE, Vince DG. Coronary plaque classification with intravascular ultrasound radiofrequency data analysis. Circulation 2002 Oct 22;106(17):2200e6. [147] Yabushita H, Bouma BE, Houser SL, et al. Characterization of human atherosclerosis by optical coherence tomography. Circulation 2002 Sep 24;106(13):1640e5. [148] Larose E, Yeghiazarians Y, Libby P, et al. Characterization of human atherosclerotic plaques by intravascular magnetic resonance imaging. Circulation 2005 Oct 11;112(15):2324e31. [149] de Weert TT, Ouhlous M, Meijering E, et al. In vivo characterization and quantification of atherosclerotic carotid plaque components with multidetector computed tomography and histopathological correlation. Arterioscler Thromb Vasc Biol 2006 Oct;26(10):2366e72. [150] Pundziute G, Schuijf JD, Jukema JW, et al. Evaluation of plaque characteristics in acute coronary syndromes: non invasive assessment with multislicecomputed tomography and invasive evaluation with intravascular ultrasound radiofrequency data analysis. Eur Heart J 2008 Oct;29(19):2373e81.