Imaging of the carotid artery

Atherosclerosis 220 (2012) 294–309

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

Review

Imaging of the carotid artery Luca Saba a,∗ , Michele Anzidei b , Roberto Sanfilippo c , Roberto Montisci c , Pierleone Lucatelli b , Carlo Catalano b , Roberto Passariello b , Giorgio Mallarini a a b c

Department of Radiology, Azienda Ospedaliero Universitaria (A.O.U.), di Cagliari – Polo di Monserrato, s.s. 554 Monserrato, Cagliari 09045, Italy Departments of Radiological Sciences, University of Rome La Sapienza, Viale Regina Elena 324, 00161 Rome, Italy Department of Vascular Surgery, Azienda Ospedaliero Universitaria (A.O.U.), di Cagliari – Polo di Monserrato, s.s. 554 Monserrato, Cagliari 09045, Italy

a r t i c l e

i n f o

Article history: Received 2 June 2011 Received in revised form 30 August 2011 Accepted 30 August 2011 Available online 17 September 2011 Keywords: Carotid CTA MRA US-ECD

a b s t r a c t In the study of carotid arteries, modern techniques of imaging allow to analyze various alterations beyond simple luminal narrowing, including the morphology of atherosclerotic plaques, the arterial wall and the surrounding structures. By using CTA and MRI it is possible to obtain three-dimensional rendering of anatomic structures with excellent detail for treatment planning. This paper will detail the role of various imaging methods for the assessment of carotid artery pathology with emphasis on the detection, analysis and characterization of carotid atherosclerosis. © 2011 Elsevier Ireland Ltd. All rights reserved.

Contents 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.

15. 16. 17. 18. 19. 20.

General introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Atherosclerosis of carotid artery: from stenosis degree to vulnerable plaque . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Plaque remodeling and location of the plaque . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Quantification of carotid artery stenosis and near occlusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Imaging flow-chart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . US-ECD: introductive notes and stenosis quantification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . US-ECD, plaque morphology (regular, irregular, ulcer) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . US-ECD, plaque type classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . US-ECD, contrast-enhancement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CTA introductive notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CTA, plaque morphology (regular, irregular, ulcer) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CTA, plaque type, volume and CAWT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CTA, notes on radiation and contrast medium risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . MRA: introductive notes and acquisition techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14.1. Non-contrast MRA with Time-of-Flight (ToF) sequences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14.2. Contrast-enhanced MRA with T1-weighted 3D Gradient-Echo sequences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . MRA: stenosis evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . MRA: plaque morphology (regular, irregular, ulcer) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . MRA: plaque type, volume and multicontrast Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Digital subtraction angiography and rotational angiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Future techniques: PET-CT and molecular imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

∗ Corresponding author. Tel.: +39 070 485980; fax: +39 070 485980. E-mail address: [email protected] (L. Saba). 0021-9150/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2011.08.048

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L. Saba et al. / Atherosclerosis 220 (2012) 294–309

1. General introduction Carotid atherosclerosis is one of the most common causes of death and disability in the western countries [1,2]. The microscopic alterations of the initial phase of this disease start during childhood, but usually carotid plaques remain asymptomatic until an advanced pathological stage is reached. In the recent past the degree of carotid artery stenosis was considered the only determinant factor to address patients to treatment [3,4], while at present several other factors are considered potentially important markers for future cerebro-vascular events [5,6], including plaque composition, presence and state of the fibrous cap (FC), intra-plaque hemorrhage, plaque ulceration and plaque location [7–9]. Advanced plaque imaging techniques nowadays allow to analyze plaque morphology and its characteristics, as well as the presence of plaque’s complications such as ulceration, hemorrhage and thrombus. The capability to identify plaques that are more prone to fragment and embolize is now vital for the early diagnosis, prevention, and treatment of stroke and neurological side effects. This paper will detail the role of imaging methods for the assessment of carotid artery pathology with an emphasis on the detection, analysis and characterization of carotid atherosclerosis. 2. Atherosclerosis of carotid artery: from stenosis degree to vulnerable plaque In the past years, the degree of luminal stenosis has been used as a direct measure of atherosclerosis severity. However, in 1988, angiographic studies on coronary arteries [10–13] demonstrated that moderate coronary artery stenosis may lead to acute myocardial infarction and subsequent histopathologic studies showed that plaque erosion and disruption were common morphologic features in symptomatic lesions, indicating that luminal narrowing was not the sole predictor of myocardial infarction. Similar findings were later observed in the carotid arteries [14–16]. Since low grade stenosis were demonstrated capable to produce cerebrovascular events, looking to plaque morphology beyond stenosis degree started to appear appropriate. For these reasons the concept of “vulnerable plaque” was introduced into surgical, histopathological and imaging communities, referring to atheromas containing large necrotic cores covered by a disrupted fibrous cap with a higher tendency to rupture, embolization and thrombosis. 3. Plaque remodeling and location of the plaque The unique geometrical configuration and flow properties of the carotid bifurcation contribute to the formation of atherosclerotic plaques. Usually major atherosclerotic alterations occurs at the outer wall of the proximal segment and sinus of the internal carotid artery, in the region of the lowest wall shear stress. Plaque thickness is the least on the flow divider side at the junction of the internal and external carotid arteries where wall stress is the highest [17]. The concept of remodeling indicates the morphological and ultra-structural variation of a plaque in time: histological analysis of coronary plaques performed within 1 week after miocardial infarction demonstrated features of instability, while tissue evaluations performed within larger time intervals were similar to those in patients with stable angina. These observations demonstrate that atherosclerotic plaques may change in time and it that some determinants of instability may appear transitorily. Recent studies demonstrated that carotid plaque eccentricity can determine the development of a cerebrovascular event. Ohara

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et al. [18] demonstrated that eccentric stenosis was associated with a significantly increased incidence of ipsilateral events if compared with concentric stenosis. In the 2007 Hardie et al. [19] studied the remodeling ratio and eccentricity index of carotid plaques with MDCTA, demonstrating that expansive carotid remodeling is significantly greater in patients with cerebral ischemic symptoms than in asymptomatic patients, and that the extent of remodeling may indicate underling atherosclerotic plaque vulnerability.

4. Quantification of carotid artery stenosis and near occlusion Stenosis degree is currently considered a leading parameter (and in some Institutes “the leading parameter”) for treatment choice. The correlation between the severity of carotid stenosis and the risk of stroke has been widely documented [20–23]. Three large multi-centric randomized studies, NASCET (North American Symptomatic Carotid Endarterectomy Trial), ECST (European Carotid Surgery Trial) and ACAS (Asymptomatic Carotid AtheroSclerosis Group), provided cut-off values stenosis degree indicating possible benefits of carotid endarterectomy (CEA) [20–22]. The most used methods to quantify the degree of carotid artery stenosis are NASCET and ECST, both evaluating the degree of stenosis as the percentage reduction in the linear diameter of the artery. To quantify the degree of the stenosis with NASCET and ECST methods, measurements must be performed on a strictly perpendicular plane to the longitudinal axis of the vessel. It is important to underline that some differences in the evaluation of stenosis degree exist between NASCET and ECST and that the stenosis values derived from these methods on the same vessel are not equal. The NASCET method calculates the ratio between the lumen diameter at the stenosis site and lumen diameter of the distal, healthy internal carotid artery (measured at the level of the II cervical vertebra) (Fig. 1). The ECST method calculates the ratio between the lumen diameter at the stenosis site and the total carotid diameter (including the plaque) (Fig. 1). This measurement technique determines that ECST stenosis degree are larger compared to NASCET values (e.g. a 83% ECST usually is a 70% NASCET [24]). Even if NASCET and ECST measurements can be converted into each other [24], the above mentioned differences cannot be overcome: recently Saba and Mallarini [25] demonstrated that the entity of difference between NASCET and ECST measurements at different degree of stenosis varies markedly and that the entity of variation strongly and inversely depends on the degree of stenosis; moreover, the proportional error tends to zero with the increase of stenosis degree. The methodology of carotid stenosis quantification is widely debated because NASCET and ECTS are indirect ratio-percent methods prone to measurement errors. In both NASCET and ECST trials, stenosis degree was determined by conventional angiography, since CTA and MRA were not available at the time. By using conventional angiography it was necessary to use methods of deriving percent stenosis because standardized stenosis measurement were not consistent with film (in conventional angiography) and because, with the introduction of digital angiography, different degree of magnification were used. However, various studies demonstrated that percentage stenosis measurements are prone to inter-observer variability and errors, mostly due to the incorrect identification of the arterial reference (the distal ICA for NASCET and the ICA lumen for ECST). For these reasons Bartlett et al. [26–28] developed a direct mmmethod for the measurement of carotid stenosis with MDCTA, demonstrating a linear relationship between the residual lumen of the internal carotid artery measured in mm on co-axial sections and NASCET stenosis. In particular a residual carotid diameter of 1.3 mm corresponds to 70% NASCET stenosis and this value was

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Fig. 1. NASCET and ECST criteria. The DSA image, volume rendered post processed CTA image and CE-MRA image (a–c) show the anatomic sites of measurement in the carotid artery for calculating percent stenosis for the NASCET and ECST method. In the NASCET the ratio between the residual luminal surface (inner-to-inner lumen) at the stenosis (e) and the surface of the distal normal lumen (inner-to-inner lumen) where there is no stenosis (d), is calculated. “Inner to inner lumen” measures only the vessel lumen, apart the soft tissue walls. In the ECST the ratio between the residual luminal surface at the stenosis (inner-to-inner lumen) (e) and the total surface (outer-to-outer) (f) is calculated. “Outer to Outer lumen” measures the vessel lumen and the soft tissue walls by comprising the presence of carotid plaque. To quantify stenosis degree radiologists independently elaborated oblique axial images normal to ICA lumen centerline.

proposed by Bartlett as a threshold for severe carotid stenosis with a sensitivity of 88% and a specificity of 92%; these results were also confirmed by other study groups [29]. Last, when using ratio-percent methods for the quantification of the carotid artery stenosis, it is particularly important to introduce the concept of “near occlusion”. Near occlusion stenosis indicates a severe carotid bulb stenosis with homogeneous decrease of the calibre of the ICA distally to the bifurcation, due to relevant flow reduction. In this case, when the distal ICA lumen is partially collapsed (or so called “string sign”), NASCET measurements fail to correctly determine stenosis degree since the distal arterial reference is no more positioned on a healthy segment. Fox et al. [30] reported the following angiographic criteria to define the presence of near occlusion: presence of notable stenosis of the ICA bulb AND distal ICA calibre reduction as compared to:

(A) its expected lumen size, (B) the contra-lateral internal carotid artery lumen, (C) the ipsilateral external carotid artery lumen (if the ratio between the calibres of affected distal ICA and ipsilateral ECA is higher than 1, near occlusion is diagnosed).

Identification of near-occlusion influences treatment planning since it has been demonstrated that this condition determines a lower risk of ipsilateral stroke and that CEA/revascularization are less effective in these patients [31–33].

5. Imaging flow-chart It is well known that symptomatic patients with severe stenosis (>70%) benefit from CEA, and it is therefore vital to image and accurately measure the site of severe narrowing. However, pathological assessment of carotid plaques has also demonstrated that risk of embolism and thrombosis is not only associated with the size of the plaque but also with its composition. The ability to image and identify the “vulnerable plaque” and especially those with hemorrhage will be vital in early diagnosis, prevention, and treatment of stroke and neurological side effects. Nowadays DSA is infrequently necessary and only in cases of severe multiple vessels disease, for which assessment of flow direction and collateral patterns may be important or when the image quality of non-invasive procedure is limited. Recently Jaff et al. [34] proposed that CTA may represent an appropriate first exam for patients with an high likelihood of vascular disease. On the other hand for screening patients with a lower likelihood of neurovascular pathology, Ultra-Sound Echo-ColorDoppler (US-ECD) should be selected. For asymptomatic patients scheduled for surgery as coronary artery bypass graft, abdominal aortic aneurysm and lower limb ischemia, US-ECD represents an accurate and cost-effective non-invasive screening tool [34,35]. If significant steno-obstructive disease of the ICA is detected with USECD, international guidelines suggest that CTA as well as MRA can be used to confirm the diagnosis and to accurately determine the precise degree of stenosis and ensure appropriate treatment planning (i.e., identification of anatomical variation in vessel course, tandem lesions, intracranial atherosclerotic disease, etc.) (Fig. 2).

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Fig. 2. Diagnostic flow-chart.

Whether CTA or MRA should be the second-line examination of choice is still a matter of debate: some studies suggest that a higher agreement rate exists between US-ECD and MRA rather than between US-ECD and CTA [36] and a recently published metaanalysis [37] indicates MRA as the most accurate test for the identification of critical (>70%) stenosis in both symptomatic and asymptomatic subjects. The same studies describe a significantly lower accuracy in the detection of non-critical (50–69%) stenosis for all non-invasive imaging modalities. From our point of view, when ordering a second-line test, physicians should consider that in the large majority of institutions CTA is the most fast, cheap and ready to access technique to confirm US-ECD findings prior to treatment, while state-of-the-art MRA is still far to come in many centers. However, if cutting edge MR scanners and adequate contrast agents are available, MRA can be considered as fast and as reliable as CTA. 6. US-ECD: introductive notes and stenosis quantification US-ECD is globally accepted as the standard imaging modality for first-line diagnosis of atherosclerosis of the carotid artery bifurcation. This high-resolution, non-invasive technique is readily available, rapidly applicable, and can be performed at relatively low cost (Table 1). It has been successfully adopted to identify characteristics of high-risk plaques in patients with atherosclerosis. High frequency linear transducers (>7 MHz) are ideal for the assessment of plaque morphology and quantification of Intima Media Thickness (IMT) whereas lower frequency linear transducers (<7 MHz) are preferred for Doppler examinations. In some particular conditions, like short muscular neck, the use of a linear transducer may be not possible so that a curved-array transducer should be selected. It has been widely demonstrated that US-ECD is a good screening technique even some relevant limitations persist for the quantification

of stenosis degree [38–41], including high operator and center variability, artifacts arising from calcifications, and difficulties in distinguishing subtotal occlusion from total occlusion. Two different approaches may be adopted to quantify the degree of carotid artery stenosis by using US-ECD: 1) morphological and 2) Peak-Systolic-Velocity (PSV) values (Fig. 3). The morphological analysis is based on the ratio-percent methods for the quantification of stenosis degree. On the other hand, PSV evaluates the maximum peak of systolic velocity in the affected vessel. It is widely accepted that average Doppler velocity rises in direct proportion to the degree of stenosis, hence flow velocity is commonly used to evaluate the severity of carotid stenosis and plan the consequent diagnostic and therapeutic approach. The value of PSV that corresponds to a 70% NASCET stenosis degree is still questioned. Saba et al. [49] found that the PSV threshold for a NASCET stenosis ≥70% was 283 cm/s. This value is higher compared with Heijenbrok-Kal et al. [50] where it was indicated a threshold value of 220 cm/s or compared with the study of Grant et al. [51] where the threshold suggested was 230 cm/s. US-ECD can also be used to assess initial, subtle wall alterations in the very early phases of the progression of atherosclerosis: increased thickness of the carotid wall, the intima-media thickness (IMT), was reported to occur early in the pathologic process and several prospective studies have suggested that an increased common carotid artery IMT may represent a significant predictor of coronary and cerebrovascular events [42–44]. High resolution B-mode ultrasound of the carotid arteries allows the identification of the distinct layers in the arterial wall. Typically, longitudinal images of the arterial wall show two parallel echogenic lines separated by a relatively hypoechoic central region referred to as the Intima-Media layer and the distance between these two lines is the IMT. One of the major limitation of this technique is the poor inter-observer and intra-observer variability in the IMT measurement [45–48].

Table 1 Diagnostic performance, strength point, limitations and pitfalls of US-ECD in the evaluation of carotid stenosis, plaque morphology and composition. US-ECD

Stenosis (>70%)

Plaque morphology

Plaque composition

Diagnostic performance

Limitations

Operator dependant

Sensitivity 85% Specificity 84% Detailed view of the plaque with high-resolution probes Calcium induced acoustic shadowing

Moderate correlation with histopathology

Strength points

Sensitivity 89% Specificity 84% Fast and cheap

Pitfalls

Poorly reproducible

Calcium can obscure subtle surface alterations

Faster as compared to CTA and MRA; use of power-Doppler Heavily calcified plaques may hamper detection of other components Amorphous calcifications and hemorrhage are similar

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Fig. 3. Ultrasound analysis of carotid artery stenosis degree. The PSV analysis and morphological analysis are given in panel a and panel b respectively.

7. US-ECD, plaque morphology (regular, irregular, ulcer) In the 2004 Kitamura et al. [44] in a study of 1358 Japanese men without prior history of cardiovascular disease, showed that subjects with irregular carotid plaques identified with US-ECD have an age-adjusted RR of experiencing ischemic stroke of 7.7 (95% CI: 2.0, 30.0), suggesting that plaque surface irregularities represent markers of plaque vulnerability (Fig. 4). These findings were confirmed by Prabhakaran et al. [52] in a large population (1939 patients), demonstrating that plaque surface irregularity is a predictive factor for ischemic stroke with a hazard ratio of 4.0 (95% CI: 1.7, 9.4). It is important to underline, however that in this work the analysis was performed with disregard to laterality (all strokes were taken into consideration, not just those ipsilateral to the analyzed

Fig. 4. Ultrasound examples of regular plaque morphology (a), irregular plaque morphology (b) and ulcerated plaque (c).

carotid plaque). In view of this, plaque irregularities were associated with generalized atherosclerosis, rather than being deemed a direct source of embolic material.

8. US-ECD, plaque type classification Basing on morphological findings derived from US-ECD, evaluation of the various plaque components can be done. In particular, echolucent plaques on B-mode ultrasonography have a higher component of soft tissue, such as lipid or hemorrhage, while echogenic plaques are composed primarily of fibrous tissue [53–55]. The Cardiovascular Health Study [56] showed that asymptomatic elderly patients with a hypo-echoic plaque have a relative risk of ipsilateral ischemic stroke of 2.78 (95% CI, 1.4–5.7), independently from the degree of stenosis and other cardiovascular risk factors. The authors of the Tromsø study group followed up 223 patients with carotid stenosis between 35 and 99% and 215 control subjects for 3 years [57], demonstrating that the RRs of ipsilateral cerebrovascular events in patients with hypo-echoic plaques was 3.52 (95% CI, 1.0–12.4). However, it should be taken in consideration that the Asymptomatic Carotid Surgery Trial did not show any additional influence of plaques echolucency over stenosis degree on the risk of subsequent stroke [58]. The most used ultrasonographic classification for carotid artery plaques are (1) Gray-Weale’s scale modified by Geroulakos [59] and (2) the Bluth [60] classification. In the Weale’s classification modified by Geroulakos it is possible to identify 5 types of carotid artery plaques: type 1 (anechogenic with echogenic fibrous cap), type 2 (predominantly anechogenic but with echogenic areas representing less than 25% of the plaque), type 3 (predominantly hyperechogenic but with anechogenic areas representing less than 25% of the plaque), type 4 (echogenic and homogeneous plaque) and type 5 (unclassified plaques reflecting calcified plaques with areas of acoustic shadowing which hide the deeper part of the arterial layers). In the Bluth et al. [60] classification the plaque are categorized as heterogeneous (Gray-Weale’s classification modified by Geroulakos class 1 and 2) and homogeneous (Gray-Weale’s classification modified by Geroulakos class 3–5) (Fig. 5). One of the major limitation of the US-ECD in the

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Fig. 5. Ultrasound examples of the different types of plaque according to the Bluth’s classification: homogenous type (a) and heterogeneous type (b).

analysis of carotid plaque is the poor reproducibility and this is on the areas of ongoing research. 9. US-ECD, contrast-enhancement Recent studies demonstrated that late onset of plaque enhancement at US after intravenous injection of microbubbles-based contrast agents is greater in symptomatic lesions than in asymptomatic ones [61]. This finding may merely represent the fact that symptomatic plaques have larger intra-plaque neovascularization than asymptomatic plaques and may thus more circulating microbubbles, as demonstrated by Coli et al. [62] in correlation with histological density analysis of microvessels. Furthermore, microbubbles have now been designed so that they can specifically bind to various molecules, therefore, allowing functional and molecular imaging. Recently perfusion imaging using micro-bubbles as contrast agents for US-ECD has been made feasible through developments in the ability to detect harmonics and overtones produced by the bubbles over tissue noise. 10. CTA introductive notes Computed tomography (CT) can provide exquisite, rapid, high resolution imaging of the body and in particular of the vascular system (Table 2). The introduction of multi-detector-row technology gave a tremendous boost to the development of multi-detector CT-angiography (MDCTA) techniques for the evaluation of various arterial regions, while constant advances in spatial and temporal resolution and release of advanced software for image reconstruction have helped to consolidate this technique as a reliable tool for the evaluation of arterial pathology, with particular success in the detection and characterization of carotid atherosclerosis. 11. CTA, plaque morphology (regular, irregular, ulcer) A decade ago, with the introduction of 4 and later of 16 detectorrow scanners investigators started to evaluate the potentialities of MDCTA not only for the detection of carotid stenosis but also for the evaluation of surface irregularities of carotid plaques. In particular De Weert et al. [63] demonstrated that MDCTA can assess plaque morphology with differentiation between smooth, irregular and ulcerated surfaces. By using MDCTA, a smooth surface (Fig. 6a) indicates a regular luminal morphology at the level of the plaque without any sign of ulceration or irregularity, with a plain interface between plaque and lume. Subtle irregularities (Fig. 6b) in

the surface of the plaque are frequently associated with previous stroke/TIA. A criteria proposed to classify plaque morphology as irregular is the presence of pre- or post-stenotic dilatation and/or if the plaque surface morphology shows irregularities without any sign of ulceration. But the most relevant surface alteration that may be detected by MDCTA is ulceration (Figs. 6c and 7). Plaque ulceration has been defined as “an intimal defect” larger than 1000 ␮m in width, exposing the necrotic core of the atheromatous plaque [64]. In the 2007 Saba et al. [65,66] compared MDCTA and USECD in the detection of plaque ulceration by using surgery as gold standard, demonstrating that the diagnostic accuracy of MDCTA is significantly higher (93% versus 37.5%). Ulcerated plaques can be categorized according the classification described by Lovett et al. [67] where type 1 is an ulcer that points out perpendicular to the lumen, type 2 has a narrow neck and points out proximally and distally, type 3 has an ulcer neck proximally and points out distally, type 4 has an ulcer neck distally and points out proximally. Lovett et al. [67] demonstrated that type 1 and type 3 are the most frequent type of ulcers, however without any association with increased risk of adverse cerebrovascular events.

12. CTA, plaque type, volume and CAWT It is possible that even low-grade stenosis in the carotid arteries can lead to the development of cerebrovascular events, for this reason it may be important to look beyond stenosis degree and try to determine plaque characteristics. Schroder et al. [68] differentiated coronary plaques into three categories, including fatty, mixed and calcified lesions (Fig. 8). In this classification fatty (soft plaques) were considered those plaque with a density value <50 HU, mixed plaques those with a density value between 50 and 119 HU and calcified plaque those with a density >120 HU. Other groups [65,66] used this classification in the evaluation of carotid plaques, adopting the use of a 1 mm2 circular or elliptical region of interest cursor (ROI) located in the predominant area of the plaque for the measure of HU attenuation. With this approach, areas showing contamination by contrast medium or calcification non-contributory to the stenosis should be avoided as well as beam hardening in calcified areas. While this method for HU measurement may subjective, some studies demonstrated an optimal inter-observer reproducibility: in particular De Weert et al. [69] reported the following inter-observer coefficients of variation for the absolute measurement of lumen, plaque, calcified, fibrous

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Table 2 Diagnostic performance, strength point, limitations and pitfalls of MDCTA in the evaluation of carotid stenosis, plaque morphology and composition. MDCTA

Stenosis (>70%)

Plaque morphology

Plaque composition

Diagnostic performance

Sensitivity 77% Specificity 95% Higher spatial resolution as compared to MRA May be hampered by wall calcifications, needing longer post-processing Beam hardening artifacts induced by heavily calcified plaques

Sensitivity 100% Specificity 100% Higher spatial resolution as compared to MRA May be hampered by wall calcifications, needing longer post-processing

Moderate correlation with histopathology

Strength points Limitations

Pitfalls

Beam hardening artifacts induced by heavily calcified plaques

tissue, and lipid core: 4%, 19%, 16%, 21%, and 40%, respectively. In the same study the interobserver coefficients of variation for the relative measurement (%) of calcified fibrous tissue and lipid core areas were: 26%, 10%, and 20%, respectively. The intra-observer coefficients of variation for the absolute measurement of lumen, plaque, calcified, fibrous tissue, and lipid core areas were: 3%, 8%, 8%, 11%, and 15%, respectively. It has been demonstrated [65,66] that the HU measured in the center of fibrous-rich regions and lipid core is significantly different and indicated that very hypodense regions (<30 HU) in the center of

Direct visualization of calcium Reduced accuracy in the differentiation of other components as compared to MRI Impossibility to detect hemorrhage

atherosclerotic carotid plaque are associated with the presence of a lipid core (i.e., lipid, hemorrhage, or necrotic debris). It is important to underline that fatty plaques at MDCTA are often associated to the presence of a lipid core, once thought to be an inert deposition of lipid, but now known to be a highly biologically active area. These observations should be adequately taken in consideration by radiologists that should describe the dominant type of the plaque and its characteristics. Probably in the future another important risk facto worth to be added to this classification will be the plaque volume: at this regard, Ouhlous et al. [70] found a moderate

Fig. 6. MDCTA axial (a–c) and Volume Rendered post-processed images (d) examples of different types of luminal plaque morphology: smooth plaque (a), irregular plaque surface (b) and ulcerated carotid plaque (c, d).

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Fig. 7. Post-processed MIP CTA image (a) and DSA (b) indicating an ulcerated plaque (red open arrows). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)

association between the severity of luminal stenosis and plaque volume. Last, recent MDCTA studies [71] demonstrated that MDCTA can easily measure carotid artery wall thickness (CAWT) and found that, by using a 1 mm threshold, there was a significant association between thicker (≥1 mm) CAWT and stroke: (p < 0.0001) [71]:

patients with pathologic CAWT had stroke with an Odds Ratio 8.16, in comparison with patients with normal (<1 mm) CAWT. MDCTA is extremely useful to evaluate the CAWT as compared to US-ECD because the latter suffers from low inter-observer and inter-method agreement [45–48], whereas MDCTA offers optimal reproducibility (Fig. 9) [71].

Fig. 8. Different types of plaque in MDCTA: calcified plaque (a), fatty plaque (b) and mixed plaque (c).

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Fig. 9. IMT and CAWT analysis by using US and CTA respectively. The open white arrow indicates the lumen-intima interface, the white arrow indicates the media-adventitia interface and the red arrow indicates the CAWT. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)

13. CTA, notes on radiation and contrast medium risk The “radiation problem” represents a significant issue in the use of MDCT [72]. Diagnostic radiation exposure and the consequent potential radiation hazards have recently gained consideration in both the scientific and public literature [73]. In biologic material exposed to X-rays the most common scenario is the creation of radicals that can interact with the nearby DNA causing strand breaks or base damage [72]. Although most of the quantitative estimates of the radiation-induced cancer risk are derived from analyses of atomic bomb survivors, there are other supporting studies base on worker in nuclear industry that suggest an increased risk of cancer for those that were exposed to an average dose of approximately 10 mSv. MDCT delivers higher radiation dose as compared to other radiological imaging modalities and it is fundamental to reduce radiation exposure. To obtain a reduction it is necessary to adjust the dose to the patient’s weight and size’s and to optimize mAs and kVs. Ertl-Wagner et al. [74] evaluated the effects of the variable kV values with tube current of 100 mAs. By using a kV of 80, 120 and 140 the mean effective dose estimated were 0.35 mSv, 0.99 mSv and 1.37 mSv respectively. In the following evaluation of quality images the authors did not recommend the use 80 kV because of degradation of quality images, due to an increase in the photoelectric effect and a decrease in Compton scattering. Some CT systems are equipped with an automatic exposure control (AEC) system that continuously modulates the X-ray tube current based on the patient size and tissue density [75]; these systems tailor the X-ray dose to the patient’s size and usually a reduction in radiation dose is possible to obtain. The second important issue in the CTA is the potential intolerance to contrast material [76,77]. Overall iodine is considered safe it increases the sensitivity of the MDCTA exams. An anaphylactic reaction requiring treatment, could be expected in 1 to 500–5000 injections. The risk is increased to 1 to 100–1000 in asthmatics, patients with food and drug allergies and in patients with prior reaction to contrast. The risk of death is 1/50,000–1/500,000. Overall iodine is safe and has been used for many years in million of CT exams. Iodine contrast increases the sensitivity of the MDCTA exams and it is worldwide accepted that the benefits of using iodine contrast typically outweighs the risks. In the use of MDCTA, an important risk is the contrast-induced nephropathy (CIN) that continues to be a common form of hospitalacquired acute renal failure [78]. Although its incidence is low in patients with normal renal function, it can be much higher

in those with severe renal insufficiency at baseline. The risk of dying is greatest in patients who require dialytic support because of the nephropathy. McCullough et al. [79] found that in-hospital mortality rates were 1.1% for patients with no contrast-induced nephropathy compared with 7.1% for those with nephropathy alone, and up to 35.7% for those with nephropathy requiring dialysis. Another potential risk from the use of contrast material is the iodine-induced hyperthyroidism (IIH), or Jod-Basedow phenomenon that indicates a thyrotoxic condition caused by exposure to increased amounts of iodine. This pathology has historically been reported in regions deficient in iodine [80] but with advances in contrast imaging, this hyperthyroidism has more recently been reported in patients following studies that require administration of iodine-containing contrast media [81,82]. 14. MRA: introductive notes and acquisition techniques In the last years MRA has become a fundamental method to evaluate carotid artery pathology (Table 3). With the use different acquisition techniques it is possible to obtain several information that allow to quantify the stenosis degree of carotid artery as well as the plaques composition (Table 4). In order to obtain reliable diagnostic results, physicians and radiologists must be familiar with the different acquisition techniques. 14.1. Non-contrast MRA with Time-of-Flight (ToF) sequences ToF are Gradient-Echo sequences acquired perpendicularly to the longitudinal axis of the vessels with extremely short TR: the resulting difference in spin saturation between the stationary tissues (completely suppressed) and moving protons in blood (un-saturated) creates the so-called “in flow-enhancement” that produces the angiographic effect used for ToF imaging (Fig. 10). TR should be adequately calibrated basing on flow velocity, in order to achieve the maximum possible difference in signal intensity between blood and stationary tissue and to avoid venous enhancement; additional saturation pulses can be adopted to further suppress the intrinsic signal of these structures. ToF sequences can be acquired by using 2D or 3D k-space sampling, the latter also known as MOTSA (multiple overlapping thin slab acquisitions) being more accurate for stenosis detection and grading, for the increased spatial resolution [83]. The main limitation of ToF sequences is represented by the fact that at the site of tighter

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Table 3 Diagnostic performance, strength point, limitations and pitfalls of MRA and CE-MRA in the evaluation of carotid stenosis, plaque morphology and composition. MRA

Stenosis (>70%)

Plaque morphology

Plaque composition

Diagnostic performance (MRA and CE-MRA) Strength points

Sensitivity 88–94% Specificity 84–93% Not hampered by wall calcification, luminographic view Lower spatial resolution as compared to CTA Loss of signal at the site of extremely tight stenoses

Sensitivity 96% Specificity 97% Not hampered by wall calcification, may detect subtle ulcers Lower spatial resolution as compared to CTA Susceptibility artifacts induced by heavily calcified plaques

Significant correlation with histopathology

Limitations Pitfalls

Differentiation between various plaque components Long acquisition, dedicated hardware Partial signal overlap between fibrous core and hemorrhage

Table 4 Signal intensity resume for the analysis of carotid atherosclerotic plaque components at various MRI weightings.

T1-w T2-w PD ToF

Unruptured fibrous cap

Acute hemorrhage

Chronic hemorrhage

Calcium

Uncomplicated lipidic core

Isointense Isointense Isointense Hypointense

Hyperintense Hypointense Hypointense Hyperintense

Hyperintense Hyperintense Hyperintense Hyperintense

Hypointense Hypointense Hypointense Hypointense

Hyperintense Hyperintense Iso-Hyperintense Hypointense

stenosis, blood flow may become turbulent, with slowing moving proton producing dephasation effects with unpredictable signal loss within vessel lumen leading to stenosis overestimation in the critical range for treatment planning [83]. 14.2. Contrast-enhanced MRA with T1-weighted 3D Gradient-Echo sequences CE-MRA is based on the principle of shortening the T1 relaxation time of blood by intravenously injecting Gd-chelate contrast agents. This results in a significant difference in signal intensity between flowing blood and stationary tissue at heavily T1-weighted arterial phase imaging, leading to the high signal intensity of blood on post-Gd T1-weighted sequences (Fig. 10). Vascular enhancement obviously depends on the amount of contrast

agent concentrated within the vascular bed during acquisition; therefore, imaging should be ideally performed at the peak of vascular enhancement, when a maximum difference exists between signal intensity of the target vessel and the surrounding overlapping structures. Unlike ToF imaging, signal of vessels in CE-MRA is less flow sensitive, almost not hampered by flow related artifacts, such as slow-flow phenomena potentially mimicking a significant stenosis or vascular occlusion [84]. A further relevant advantage of CE-MRA is that the usual loss of signal-to-noise ratio (SNR) from faster scanning with most MR pulse sequences can be compensated by injecting the same dose of contrast agent faster over a shorter scan duration. The most relevant limitation of CE-MRA in the imaging of carotid arteries is represented by the fact that the arterial phase acquisition must be limited in duration to avoid the rapid onset of jugular enhancement, thus imposing relevant

Fig. 10. DSA (a), arterial phase CE-MRA (b) and equilibrium phase CE-MRA with Gadofosfevet (c–g) demonstrate a 50% NASCET stenosis degree with an ulceration in the internal carotid artery.

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constrains to spatial resolution [85–87]. This drawback is going to progressively overcome by the wider availability of advanced parallel imaging protocols, dedicated multichannel coils, performing gradients and high-field scanners, with the chance of obtaining CT-like spatial resolution during the arterial phase, almost without any technical limitation. Acquisition parameters change between vendors widely, however there are some concepts that must be kept in mind when setting-up protocols for carotid MRA: - TE, TR and flip-angle values should be kept at minimum in order to maximize the differences in signal intensity between contrast agent and stationary tissues and to minimize T2* effects. - Pre-contrast mask acquisition is mandatory for image subtraction in order to increase intrinsic contrast of angiographic images. - Matrix values should not be lower than 384 × 384, with an effective slice thickness not wider than 1.5 mm. - Acquisition time should not exceed 14–18 s (depending on individual changes in circulation physiology) to avoid venous overlap. - Optimal delay between contrast agent administration and acquisition start should be evaluated with real-time monitoring techniques based on k-space filling evaluation or MR-fluoroscopy; test bolus is also acceptable but is more prone to technical errors and may lead to acquisition mistiming. It should be strictly avoided the use of pre-fixed delay as individual changes in circulation physiology may completely hamper arterial-only acquisitions. Last, the modality of k-space sampling must be adapted for CE-MRA, with centric or elliptic-centric techniques being more convenient to achieve a compromise between the needs for spatial and temporal resolution [88]. 15. MRA: stenosis evaluation Conversely to CTA, MRA does not require any sophisticated postprocessing approach to get rid of calcium-related artifacts, reducing image interpretation time with a simple and fast luminographic display of the arterial anatomy, superimposable to that of DSA. Still this dramatic advantage remains partially unexploited due to inherent technical limitations that keep CTA one step ahead in most clinical settings. In fact, with the use of conventional interstitial contrast agents a relevant conflict persists due to the opposite demands for rapid arterial phase imaging and high spatial resolution and recently published papers reported relatively poor specificities of 75–90.3% in grading vessel stenosis [84–88]. The development of blood-pool contrast agents, such as Gadofosveset (Fig. 10), changed the way of imaging arterial vessels: in addition to the conventional arterial phase imaging, blood-pool CEMRA allows to perform high-resolution acquisitions, which take advantage of the long temporal window during the equilibrium phase of circulation to adjust scan virtually without time limitation using smaller fields of view increased in-plane resolution and extrathin 3D partitions [89]. A similar approach has also been recently reproduced without the need of a dedicated blood-pool agent, by using Gd-BOPTA, a high-relaxivity molecule that has a short and reversible bind to serum albumin with produces a stronger vascular enhancement as compared to other contrast agents, with a slightly prolonged circulation time that allows equilibrium phase imaging in the first minutes after administration [90]. In a clinical setting, when conventional arterial phase (or first-pass imaging) is usually the sole imaging technique available, the time constrains for MRA acquisition may lead to suboptimal spatial resolution, subsequently reducing diagnostic accuracy, finally causing incorrect treatment. It has been demonstrated that equilibrium phase imaging may offer a relevant improvement in the diagnostic performance for stenosis assessment, primarily due to the increase in spatial resolution. Moreover it should be kept in mind that both

the above mentioned contrast agents can be used at lower doses as compared to conventional molecules, reducing the total Gd load required per-examination: this observation is particularly relevant when CE-MRA is going to be performed in renally impaired patients at risk for developing Gd-related NSF. 16. MRA: plaque morphology (regular, irregular, ulcer) In the past, several studies demonstrated that conventional MRA with first-pass imaging may be not sufficiently sensitive for the detection of arterial wall irregularities and ulcers [91]. More recent papers show an increased accuracy in delineation of plaque morphology at reduced voxel size [92–94]. However, with conventional, not state-of-the-art equipment, high-resolution imaging with conventional contrast agents implies an inevitable reduction in SNR and prolongation of acquisition duration with risk of venous overlay that may determine a lack of image quality and accuracy. Extended phase imaging with blood-pool or high-relaxivity molecules overcomes this limitation, as reported in previously published papers [89,90,95], with greater accuracy in the depiction of ulcers or even subtle irregularities of the plaque surface, enabling diagnostic performance similar to those of CTA for the evaluation of plaque morphology [96]. This finding is mostly important if we consider that missed ulcerations or plaque irregularities may lead to mistreatment of patients with only moderate stenoses. Moreover, it seems that high resolution sequences or at least later phases acquisition can demonstrate additional, independent findings related to plaque instability, such as enhancement of vessel wall at the site of the plaque determined by neovascularity of atheroma and proliferation of the vasa vasorum, occurring independently from ulcers in patients with atherosclerosis and arteritis [97–99]. 17. MRA: plaque type, volume and multicontrast Imaging Dedicated MR sequences as well as superficial coils enabling high-resolution, small-FoV, acquisitions with sub-millimetric voxel size have been developed in the last years in order to allow adequate plaque imaging, enabling the identification and differentiation of various plaque components, including calcifications, interstitial hemorrhage, lipid rich necrotic core and fibrous cap [100] (Fig. 11) (Tables 4 and 5). The main rationale of this approach is to go beyond the luminographic approach obtained with CE-MRA (that is limited to the assessment of stenosis and evaluation of the integrity of the plaque/lumen interface), yielding information on the potential thromboembolic activity of atheromas that may be useful in the clinical management of patients with carotid atherosclerosis. From a technical point of view, after localization of the atheroma with a ToF sequence, plaque imaging is performed with a combination of dark-blood T1-weighted, T2-weighted and proton density sequences acquired on a plane that lies co-axial to the plaque [100]. The correct identification of each plaque component is based on signal intensities relative to muscle, with the additional challenge for precise delineation of plaque boundaries. This approach has been demonstrated to be mostly accurate in the detection of calcium and fresh hemorrhage, but some difficulties persist for the differentiation of older thrombus and collagenous tissue, due to partially overlapping signal intensities in the various sequences. Further studies have underlined the potential role of contrast enhancement induced in the atheroma after administration of Gd-chelates to identify active plaques, in excellent agreement with systemic serum markers of inflammation and histopathology [101]. While dedicate plaque imaging represent a significant step toward the recognition of the different biological parameters and histological alterations affecting plaque development and stability, significant technical limitations persist for its wide clinical applicability

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Fig. 11. High resolution MRA (a–c) that indicates the presence of an intra-plaque hemorrhage (white open arrows), confirmed by histological analysis.

beside CE-MRA: in particular, the need for dedicated hardware and sequences and the duration of the examination itself strongly limit its reproducibility on many available scanners. Moreover, in the large majority of institutions, surgical and/or endovascular treatment for carotid atherosclerosis are still performed basing on stenosis degree alone, or at the most on macroscopic signs of plaque instability such as ulcerations or rough irregularities, without taking into account histological considerations. 18. Digital subtraction angiography and rotational angiography Digital subtraction angiography (DSA) remains the putative gold-standard imaging reference for the evaluation of carotid stenosis and plaque morphology. Recently, however, its accuracy

in stenosis grading is becoming controversial [83,102] and its diagnostic role has been widely criticized for the limited number of views, costs and the small but definite risk of complications. Hence, in the vast majority of institution where adequate CT and/or MR technology is available, the diagnostic use of DSA is limited to a small number of cases in which there is no agreement between two or more non-invasive tests. Instead, a large number of DSA procedures is performed when endovascular treatment such as carotid artery stenting (CAS) is needed (Fig. 12). DSA technique is almost identical for both diagnostic and interventional purposes: a selective angiography of the carotid axis can be performed from different arterial access depending on patient’s arterial anatomy, including femoral, axillary, brachial and radial access. The catheterization of the common carotid artery can be done with a direct approach, with a telescopic approach or with a telescopic approach

Table 5 American Heart Association histologic classification for atherosclerotic plaques and modified classification for plaque MRI. AHA classification

Modified AHA classification for MRI

Type I: early lesion with few foam cell infiltration Type II: extensive foam cell infiltration Type III: pre-atheromatous phase with extracellular lipids Type IV: mature atheroma with central lipidic core Type V: fibrous mature atheroma Type VI: unstable plaque, with surface irregularities, hemorrhage and thrombus Type VII: calcified plaque Type VIII: fibrous plaque without lipidic core

Type I–II: normal wall thickness without detectable alterations n/a Type III: concentric/eccentric increase in wall thickness without calcifications Type IV–V: mature atheroma with central lipidic or necrotic core n/a Type VI: unstable plaque, with surface irregularities, hemorrhage and thrombus Type VII: calcified plaque Type VIII: fibrous plaque without lipidic core or with small calcifications

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Fig. 12. DSA (a) demonstrates a severe internal carotid artery stenosis, treated by stent (b). The panel c indicates the MDCTA follow up after 1 month.

with a coaxial technique. When CAS is planned, once the artery has been catheterized pre-dilation is performed when tight stenoses cannot be crossed by the stent delivery system. Pre-dilatation should be carried out using low-profile balloon (2–3.5 mm). Cerebral protection devices must be adopted to reduce the risk for peri-procedural ischemic events [103] and can be divided into three different types on the basis of their technical aspects: filters, distal occlusion balloons and proximal protection systems. Using filter systems, the blood flow is maintained through the ICA and emboli are captured and removed together with the device. Balloon occlusion devices and proximal protection systems completely occlude the flow into the ICA and emboli must be aspirated before balloon deflation or catheter removal. All the patients undergoing a CAS procedure should receive antiplatlet therapy to reduce the risk of myocardial infarction, stroke or vascular death [104]. According to recent protocols, before CAS all patients should be pre-medicated with Aspirin (325 mg/d) starting 72 h before the procedure and with Clopidogrel (75 mg/d) at least 24 h before. During the procedure, immediately after arterial access, 5000 I.U. of Heparin are administered to allow a Activated Clotting Time (ACT) of 275–300 s. Post-procedure medical protocol is based on Lowmolecular-weight Heparin (0.8 mL/d) associated with Clopidogrel (75 mg/d) for 4 weeks. Afterward Aspirin (325 mg/d) or Clopidogrel (75 mg/d) is administered indefinitely. Moreover, recent studies have also shown a role of statins in stabilization of plaque reducing the risk of myocardial infarction and stroke. Due to inherent limits of DSA, in the last ten years threedimensional rotational angiography (3D-RA) has been developed and introduced as diagnostic tool in the neuro-interventional field to plan treatment of intracranial aneurysm, dissections or arteriovenous malformation and thereafter employed also for peripheral applications such as endovascular aortic repair and liver chemoembolization. More recently 3D-RA has been successfully adopted in the assessment of carotid pathology [105]. 3D-RA it is a multiplanar

imaging modality that could overcome the classic limit of the digital subtracted angiography of being two-dimensional, leading to higher sensitivity in detecting and grading arterial pathologies according to other multiplanar imaging modalities [106]. To perform a 3D-RA patient has to be positioned in the isocenter of the scanner, and has to stay motionless for approximate 15 s. Different protocol of contrast media injection has been reported; 20 mL injected at a flow rate of 4 mL/s it is a good compromise to gain a sufficient vessel enhancement during all the acquisition period. The total time needed to perform rotational angiography is 15 s (5 s to obtain the series of rotational mask images, 5 s to reverse the X-ray unit back to its starting position, and 5 s to obtain the series of contrast-enhanced images). The angiographic unit began imaging in the lateral position and then rotated 220◦ around the carotid bifurcation in 5 s to acquire 44 projections. This kind of protocol can substantially lower the radiation dose to the patient by identifying the correct projections that provide maximum information for diagnosis and simultaneously reducing the number of 2D series, which are those that contribute most of the dose to the patient. 19. Future techniques: PET-CT and molecular imaging As mentioned above, knowledge of carotid plaque composition and morphology is critical to determine its vulnerability and the underlying risk of adverse vascular events. While CTA and MRA advances recently led to the possibility to non-invasively acquire in-depth knowledge of plaque composition, including the differentiation of the various components of the atheroma as described at histology, these techniques only produce indirect information about the potential inflammatory components of an atherosclerotic lesion. Recently, a wide variety of studies have been performed with the intent to assess the diagnostic potential of 18F-FDG PET to image and quantify plaque inflammation: basing on the assumption

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that unstable, inflamed plaques are infiltrated by lymphocytes and macrophages, and that this latter cell population can absorb 18F-FDG from the interstitial spaces, 18F-FDG PET can be used to directly detect plaque inflammation in various anatomic locations [107]. These observations are strengthen by the fact that calcium deposition in atherosclerotic lesions, a well known protective factor against plaque fragmentation and instability, is negatively correlated with 18F-FDG uptake. Other studies demonstrated a positive correlation between the grade of 18F-FDG uptake from a discrete lesion and the incidence of adverse vascular events [108]. Moreover, a recently published study [109] has shown that 18FFDG PET imaging is capable of detecting the reduction of vascular inflammation resulting from statin therapy. It should be born in mind that, for a precise anatomic assignment of 18F-FDG uptake to a specific arterial segment, 18F-FDG PET must be mandatory combined with CT images; moreover it should be also considered that only CT can detect and quantify vascular calcifications linked to stable plaques, hence the use of 18F-FDG PET alone in unfit for an accurate topographic evaluation of atherosclerotic lesions. Last, a recently published paper [110] demonstrated that the overall correlations between 18F-FDG PET and morphological and CT/MR plaque imaging findings are weak while correlations between CT and MR findings are moderate to strong. In light of these considerations and of the higher costs of this diagnostic approach as compared to conventional second-line modalities, at present the role of 18F-FDG PET is still marginal to the main diagnostic algorithm of carotid atherosclerosis, while in the future it can be postulated that larger prospective longitudinal studies and the advent of technological advances may fully exploit its potential. The objective of molecular imaging of atherosclerosis is to offer in vivo biology insight as well as new clinically translatable strategy to identify and classify high-risk carotid artery plaques. The development of multimodal, multifunctional nanoparticles to image carotid artery is a growing science in understanding and treating vascular disease. During the development of atherosclerosis, complex interactions take place at the molecular and cellular level, with various atherosclerosis-related biomarkers present at different stages of the disease progression [111]. Currently, a number of molecular markers have been evaluated for molecular imaging of atherosclerosis. These markers are known components of atheroma in animal models with advanced atherosclerosis. Because of the limited imaging contrast from most of these biomarkers, external contrast agents that target certain biomarkers are introduced for different imaging modalities. In molecular imaging techniques, 10–300 nm-sized nanoparticles for vascular endothelium tissue targeting and functionalization (binding with drug, antibodies, peptides, polysaccharides, avidin–biotin cross-linked with polymers) are created. The chemical ligand groups conjugated with nanoparticles and surface ionic properties play significant role in targeting specificity. Authors described the potentialities of liposome vesicles (50–70 nm) in US [112] and MRI [113], perfluorocarbon core emulsions (200–300 nm) for MRI, US, fluorescence, nuclear, CTI [114], HDL, LDL micelles for MRI [115,116]. In nanoparticle, it was described polymer hydroxyl acidic core (PGLA, PLA), dendrimers [polyamidoamine (PAMAM), diaminobutane (DAB)] suitable to make superparamagnetic iron oxide (15–60 nm SPIO) particles to cause dephasing and loss of T2* signal intensity due to susceptibility effects as suitable for passive targeted imaging inflammation of cardiovascular tissue [117,118]. Other gold, carbon nanotube fullerenes (4 nm), quantum dots cadmium selenide spheres (2–10 nm) metal-based agents are in process of standardization and may be useful in fluorescent imaging [119]. Moreover, other investigators have reported possibilities of viral capsid protein cages with gadolinium as potential nanospheres for drug encapsulation and imaging [120,121].

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20. Conclusions The carotid artery pathology is a major cause of death in Western World and non-invasive, in vivo assessment of carotid plaque components represent a fundamental step in the therapy determination. Improvement in imaging techniques allows to study the unstable or vulnerable plaque with precision allowing a correct patient’s risk stratification. MDCTA, MRA and US-ECD represent advanced and reliable methodologies to study carotid plaque characteristics whereas the application of nuclear medicine is still confined in the clinical research.

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