Contrast-Enhanced Ultrasound for Assessing Carotid Atherosclerotic Plaque Lesions

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1 Neuroradiology/Head and Neck Imaging Pictorial Essay Partovi et al. arotid therosclerotic Plaque Lesions Neuroradiology/Head and Neck Imaging Pictorial Essay Downloaded from by on 05/09/18 from IP address opyright RRS. For personal use only; all rights reserved FOUS ON: Sasan Partovi 1 Matthias Loebe 1 Markus schwanden 2 Thomas aldi 2 Kurt. Jäger 2 Steven. Feinstein 3 Daniel Staub 2 Partovi S, Loebe M, schwanden M, et al. Keywords: atherosclerotic disease, carotid lesions, contrast-enhanced ultrasound, intraplaque neovascularization DOI: /JR Received May 30, 2011; accepted after revision ugust 16, D. Staub is supported by research grant PZH from the Swiss National Science Foundation, the Swiss Society of ngiology, and racco Suisse. S.. Feinstein has received speaker honoraria from bbott Laboratories and GE Healthcare and is a consultant for GE Healthcare. 1 Methodist Deakey Heart and Vascular enter, aylor ollege of Medicine, Houston, TX. 2 Department of ngiology, University Hospital asel, Petersgraben 4, 4031 asel, Switzerland. ddress correspondence to D. Staub (staubd@uhbs.ch). 3 Department of Internal Medicine, Section of ardiology, Rush University Medical enter, hicago, IL. WE This is a Web exclusive article. JR 2012; 198:W13 W X/12/1981 W13 merican Roentgen Ray Society ontrast-enhanced Ultrasound for ssessing arotid therosclerotic Plaque Lesions OJETIVE. ontrast-enhanced ultrasound that is used to assess atherosclerotic carotid plaques improves visualization of vessel wall irregularities and provides direct visualization of intraplaque neovascularization. This article illustrates the use of contrast-enhanced ultrasound in the assessment of carotid atherosclerotic lesions. ONLUSION. ontrast-enhanced ultrasound is a new, noninvasive, and safe procedure for imaging carotid atherosclerotic lesions. It is a valuable tool for evaluating the vulnerable plaque at risk for rupture and for evaluating both the development and severity of systemic atherosclerotic disease. P atients with cardiovascular and cerebrovascular disease continue to increase in number, and the complications associated with these conditions remain the leading cause of morbidity and mortality in the United States [1]. urrently, there is an urgent need to develop noninvasive imaging techniques that can provide early detection and classification of atherosclerotic disease [2]. ontrast-enhanced ultrasound is a novel and noninvasive imaging modality that is capable of assessing atherosclerotic carotid lesions at risk for rupture [2, 3]. It can distinguish macrovascular morphology and, with its high temporal and spatial resolution capabilities, is able to detect the microvasculature network including visualization of intraplaque neovascularization [4]. This imaging technique is readily available at the bedside and can be performed with minimal patient discomfort [5]. The contrast agents administered for contrast-enhanced ultrasound are approved by the U.S. Food and Drug dministration (FD) for use in cardiac imaging [2]. The use of contrast-enhanced ultrasound in the carotid artery is still an off-label use in the United States. However, contrast agents may soon receive FD approval for use in the carotid arteries. To this end, radiologists should become familiar with the findings of this imaging technique. This article will illustrate the use of contrast-enhanced ultrasound imaging in the carotid artery, including lesion morphology with a particular focus on intraplaque neovascularization. ontrast gents and Safety The contrast agents administered during a contrast-enhanced ultrasound procedure consist of microbubbles filled with gases (air or high-molecular-weight gas), which serve as true intravascular nondiffusible tracers. The agents are able to detect the microvasculature and give information about the temporal and spatial heterogeneity of tissue perfusion without affecting or interacting with the local environment [3]. urrently, different types of contrast agents are used in the clinical setting: perflutren protein type- microspheres (Optison, GE Healthcare) and perflutren lipid microspheres (Definity, ristol-myers). oth of these agents are approved by the FD. Phospholipid-stabilized microspheres that are composed of sulfur hexafluoride (Sonovue, racco ltana Pharma) are approved for use in Europe [3]. These contrast agents have been shown to have a good safety profile [6]. Undesirable reactions were not serious, transient, and spontaneously resolved without residual effects. The three most common side effects observed in clinical trials were headache (2.3%); injection site pain (1.4%); and injection site bruising, burning, or paresthesia (1.7%) [4]. For contrast-enhanced ultrasound, the perflutren protein type- microspheres and perflutren lipid microspheres are supplied as 3- and 1.5-mL vials, respectively. To attain a total of 10 ml of infusate, dilution is advised with 7.0 and 8.5 ml of 0.9% saline JR:198, January 2012 W13

2 Partovi et al. Downloaded from by on 05/09/18 from IP address opyright RRS. For personal use only; all rights reserved or 5% dextrose, respectively. Thereafter, the contrast agent can be administered via a peripheral vein as a 2-mL bolus followed by an additional 5- to 10-mL saline or dextrose bolus. fter 1 3 minutes, a 2-mL bolus can be repeated for the contralateral carotid artery when required. The maximum dose should not exceed one vial of the contrast agent. ccording to the dosing schedules of the FD for cardiac ultrasound, the safety of bolus sequences has not been investigated. The contraindications are known or suspected cardiac shunts and allergies or hypersensitivity to blood, blood products, albumin, or the ultrasound contrast agent. Intraarterial injection should be avoided. ontrast-enhanced Ultrasound Procedure arotid contrast-enhanced ultrasound imaging usually uses a linear array transducer that transmits frequencies between 3 and 10 MHz and uses a low-level mechanical index between 0.06 and 0.2 [7]. The optimal time window for performing contrast- enhanced ultrasound imaging after administration of the contrast agent is approximately 1 2 minutes [8]. The use of dedicated contrast imaging software with a pulse inversion or harmonic imaging technique is required for increasing the sensitivity to the contrast agent and clarifying the contrast between the vasculature and tissue. The ppearance of the arotid rtery With ontrast-enhanced Ultrasound ontrast-enhanced ultrasound imaging enhances the carotid artery lumen and reveals the appearance of the intima-media complex to be hypoechoic. The adventitia can be visualized directly as a bright echogenic layer (Fig. 1) and, through precise detection of the inner and outer margins of the arterial wall, the carotid lumen can be clearly defined. This allows both the visibility and assessment of carotid lumen irregularities, specifically plaque ulcerations and irregularities of the plaque surface (Figs. 2 4). study showed increased accuracy, sensitivity, and specificity when contrast-enhanced ultrasound was used to assess extracranial carotid disease compared with standard ultrasound [9]. These findings underline the role of contrast-enhanced ultrasound as a valuable tool for better visualizing macrocirculation and associated abnormalities in the carotid artery (Fig. 5). Measurement of arotid Intima- Media Thickness ontrast-enhanced ultrasound is able to detect intimal thickening in the carotid artery. This achievement supports the ability to measure the far- and near-wall intimamedia thickness, which is a surrogate marker of premature atherosclerosis [10]. In contrast to -mode ultrasound, contrast-enhanced ultrasound offers improved resolution of the carotid near wall and thus may be advantageous when determining intima-media thickness [2] (Figs. 6 and 7). The iology and Rationale ehind Intraplaque Neovascularization Studies of histologic specimens have confirmed a network of microvessels within the atherosclerotic carotid lesion. These are known as intraplaque neovascularization and are the result of a process that occurs in the early phases of the atherosclerotic course. Intraplaque neovascularization creates immature leaky microvessels that, in turn, trigger the inflammatory process and may induce intraplaque hemorrhage that eventually leads to instability of the lesion [11]. Intraplaque neovascularization has been found in patients with symptomatic atherosclerosis who suffered a cardiovascular event [7]. These findings show the key role of intraplaque neovascularization in the initiation, progression, and rupture of vulnerable plaque lesions in a carotid artery. ontrast-enhanced Ultrasound Detection of Intraplaque Neovascularization for Risk Stratification of arotid therosclerotic Lesions ontrast-enhanced ultrasound imaging is capable of directly visualizing intraplaque neovascularization in the carotid artery [12 14] (Figs. 8 and 9). Intraplaque neovascularization in the carotid lesions imaged by contrast-enhanced ultrasound were well correlated with histologic specimens obtained after endarterectomy [7, 12, 15, 16]. Furthermore, echolucent plaques on -mode ultrasound have a high lipid content, more hemorrhage, and high macrophage density on histology, whereas echogenic plaques have a higher fibrous content [4]. Patients who have hypoechogenic carotid plaques have an increased risk for ipsilateral ischemic stroke, and, as a result, hypoechogenic plaques are a well-accepted characteristic of high-risk carotid lesions [17]. Our study, as well as that of others, has shown that the more hypoechogenic plaques had a higher degree of intraplaque neovascularization detected by contrast-enhanced ultrasound [12, 14] (Fig. 10). We also showed that more severe lesions (assessed by a higher degree of stenosis and a greater maximum lesion thickness) showed a higher degree of intraplaque neovascularization detected by contrast-enhanced ultrasound [14] (Fig. 10). Xiong et al. [18] showed more ultrasound contrast enhancement in the carotid lesions of symptomatic patients compared with asymptomatic subjects. Our study showed that patients with carotid lesions with a higher degree of intraplaque neovascularization experienced significantly more cardiovascular events, including myocardial infarction, stroke, or transient ischemic attack [13] (Figs ). These studies all show that intraplaque neovascularization detected by contrast-enhanced ultrasound is enhanced in the vulnerable carotid lesions as well as in those lesions associated with symptomatic disease. onclusions ontrast-enhanced ultrasound is a new imaging modality for analyzing atherosclerotic carotid lesion by detecting intraplaque neovascularization and provides valuable information for detecting the vulnerable plaque at risk for rupture. This modality may become a crucial diagnostic tool owing to its contribution to the risk stratification of atherosclerosis as well as to the planning of future therapeutic approaches [19]. However, additional prospective clinical trials are needed to definitively establish contrast-enhanced ultrasound as a significant method for assessing carotid atherosclerotic lesions in the clinical setting and for identifying and precisely defining the subgroup of patients who will most benefit from this imaging modality. References 1. Hossain P, Kawar, El Nahas M. Obesity and diabetes in the developing world: a growing challenge. N Engl J Med 2007; 356: Feinstein S. ontrast ultrasound imaging of the carotid artery vasa vasorum and atherosclerotic plaque neovascularization. J m oll ardiol 2006; 48: Feinstein S, oll, Staub D, et al. ontrast enhanced ultrasound imaging. J Nucl ardiol 2010; 17: Shalhoub J, Owen DR, Gauthier T, Monaco, Leen EL, Davies H. The use of contrast enhanced ultrasound in carotid arterial disease. Eur J Vasc Endovasc Surg 2010; 39: W14 JR:198, January 2012

3 arotid therosclerotic Plaque Lesions Downloaded from by on 05/09/18 from IP address opyright RRS. For personal use only; all rights reserved 5. Wilson SR, Greenbaum LD, Goldberg. ontrast-enhanced ultrasound: what is the evidence and what are the obstacles? JR 2009; 193: Wei K, Mulvagh SL, arson L, et al. The safety of Definity and Optison for ultrasound image enhancement: a retrospective analysis of 78,383 administered contrast doses. J m Soc Echocardiogr 2008; 21: Staub D, Schinkel F, oll, et al. ontrastenhanced ultrasound imaging of the vasa vasorum: from early atherosclerosis to the identification of unstable plaques. J ardiovasc Imaging 2010; 3: Kono Y, Pinnell SP, Sirlin, et al. arotid arteries: contrast-enhanced US angiography preliminary clinical experience. Radiology 2004; 230: Sidhu PS, llan PL, attin F, et al. Diagnostic efficacy of SonoVue, a second generation contrast agent, in the assessment of extracranial carotid or peripheral arteries using colour and spectral Doppler ultrasound: a multicentre study. r J Radiol 2006; 79: Jäger K, Staub D. Did you measure the intima- media thickness? Ultraschall Med 2009; 30: Moreno PR, Purushothaman KR, Sirol M, Levy P, Fuster V. Neovascularization in human atherosclerosis. irculation 2006; 113: oli S, Magnoni M, Sangiorgi G, et al. ontrastenhanced ultrasound imaging of intraplaque neovascularization in carotid arteries: correlation with histology and plaque echogenicity. J m oll ardiol 2008; 52: Staub D, Patel M, Tibrewala, et al. Vasa vasorum and plaque neovascularization on contrastenhanced carotid ultrasound imaging correlates with cardiovascular disease and past cardiovascular events. Stroke 2010; 41: Staub D, Partovi S, Schinkel F, et al. orrelation of carotid artery atherosclerotic lesion echogenicity and severity at standard US with intraplaque neovascularization detected at contrast-enhanced US. Radiology 2011; 258: Hoogi, dam D, Hoffman, Kerner H, Reisner S, Gaitini D. arotid plaque vulnerability: quantification of neovascularization on contrast- enhanced ultrasound with histopathologic correlation. JR 2011; 196: Vicenzini E, Giannoni MF, Puccinelli F, et al. Detection of carotid adventitial vasa vasorum and plaque vascularization with ultrasound cadence contrast pulse sequencing technique and echocontrast agent. Stroke 2007; 38: Grønholdt ML, Nordestgaard G, entzon J, et al. Macrophages are associated with lipid-rich carotid artery plaques, echolucency on -mode imaging, and elevated plasma lipid levels. J Vasc Surg 2002; 35: Xiong L, Deng Y, Zhu Y, Liu YN, i XJ. orrelation of carotid plaque neovascularization detected by using contrast-enhanced US with clinical symptoms. Radiology 2009; 251: Eyding J, Geier, Staub D. urrent strategies and possible perspectives of ultrasonic risk stratification of ischemic stroke in internal carotid artery disease. Ultraschall Med 2011; 32: Fig year-old woman with no cardiovascular disease, no risk factors for cardiovascular disease, and normal carotid ultrasound imaging., -mode carotid ultrasound image using 7-MHz linear array probe reveals no atherosclerotic lesions. = common carotid artery, I = internal carotid artery, E = external carotid artery, IJV = internal jugular vein., olor Doppler ultrasound image that corresponds with., orresponding contrast-enhanced ultrasound imaging using wideband 7L linear-array probe (GE Healthcare), harmonic imaging software, and mechanical index of 0.10 obtained after IV bolus injection of 2 ml of perflutren protein type- microspheres (Optison, GE Healthcare) reveals normal enhancement of carotid artery lumen and vessel wall (arrows). Fig year-old man with recent stroke and ulcerated carotid plaque., -mode carotid ultrasound image using wideband 12L linear array probe (GE Healthcare) reveals atherosclerotic plaque lesion at origin of internal carotid artery., fter IV bolus injection of 2 ml of perflutren protein type- microspheres (Optison, GE Healthcare), corresponding contrast-enhanced ultrasound using wideband 7L linear array probe (GE Healthcare), harmonic imaging software, and mechanical index of 0.10 reveals ulcerated atherosclerotic carotid plaque lesion (arrow). JR:198, January 2012 W15

4 Partovi et al. Downloaded from by on 05/09/18 from IP address opyright RRS. For personal use only; all rights reserved Fig year-old woman with cardiovascular risk factors, such as smoking, arterial hypertension, and high lipids, who has not had cerebrovascular event. Plaque morphology and surface irregularities are seen., -mode ultrasound image using 3-9 MHz linear probe reveals hyperechogenic, inhomogeneous, and partially calcified plaque lesion at origin of internal carotid artery., fter IV bolus injection of 2.5 ml of sulfur hexafluoride (Sonovue, racco ltana Pharma), corresponding contrast-enhanced ultrasound using 3-9 MHz linear probe, contrast imaging software (pulse inversion), and mechanical index of 0.06 improves visualization of lesion surface irregularities (arrows). Fig year-old man with carotid bruit who has coronary artery disease and no cerebrovascular event. Standard ultrasound imaging revealed highgrade carotid stenosis. Plaque morphology is seen., -mode ultrasound image using 3-9 MHz linear probe reveals hypoechogenic and homogeneous plaque at origin of internal carotid artery., fter IV bolus injection of 2.5 ml of sulfur hexafluoride (Sonovue, racco ltana Pharma), corresponding contrast-enhanced ultrasound image using 3-9 MHz linear probe, contrast imaging software (pulse inversion), and mechanical index of 0.06 shows high-grade luminal narrowing of internal carotid artery (arrows) and no plaque surface irregularities. Only few intraplaque neovascularizations at luminal side of plaque (arrowhead) can be visualized. See also Figure S4, cine loop, in supplemental data online. Fig year-old man who developed recurrent episodes of pain over past 2 months that was located at right side of neck (region of carotid bifurcation). Pain was constant, sometimes irradiating to ipsilateral ear, and generally dissolved within few days due to course of nonsteroidal antiinflammatory drug (ibuprofen). Smoking was only cardiovascular risk factor, and patient did not remember any previous trauma of neck. linical course together with findings on standard and contrast-enhanced ultrasound imaging suggest diagnosis of idiopathic carotidynia., -mode ultrasound imaging using 3-9 MHz linear probe revealed hypoechogenic wall thickening at origin of right external carotid artery with only mild lumen narrowing, affecting several wall layers (arrow) and outward extension of vessel (arrowheads)., orresponding contrast-enhanced ultrasound image of carotid lesion after bolus injection of 2.5 ml sulfur hexafluoride (Sonovue, racco ltana Pharma) shows abundant contrast enhancement within vessel wall lesion (arrows), suggesting vascularized and nonspecific inflammatory process usually found in idiopathic carotidynia. See also Figure S5, cine loop, in supplemental data online. W16 JR:198, January 2012

5 arotid therosclerotic Plaque Lesions Downloaded from by on 05/09/18 from IP address opyright RRS. For personal use only; all rights reserved Fig year-old woman with high lipids but no cardiovascular disease., -mode carotid ultrasound using 3-9 MHz linear probe illustrates thickening of intima-media complex., orresponding automated measurement of intima-media complex at far (posterior) wall of distal common carotid artery (box) indicates average intima-media complex of 0.81 mm (lines). Fig year-old woman with known coronary artery disease. fter IV bolus injection of 2 ml of perflutren protein type- microspheres (Optison, GE Healthcare), contrast-enhanced ultrasound using wideband 7L linear array probe (GE Healthcare), harmonic imaging software, and mechanical index of 0.10 shows common carotid artery with near (anterior) and far (posterior) wall carotid intima-media complex that is hypoechogenic (lines). Measurement of carotid intima-media complex at near (anterior) wall of distal common carotid artery reveals maximal carotid intima-media complex thickening of 1.25 mm. RT = right. Fig year-old woman with high lipids but no cardiovascular disease., -mode carotid ultrasound image using 3-9 MHz linear probe reveals hypoechogenic plaque at origin of internal carotid artery., fter IV bolus injection of 2.5 ml of sulfur hexafluoride (Sonovue, racco ltana Pharma), contrastenhanced ultrasound image shows intraplaque neovascularization (arrows) with moving bubbles that reach plaque core. See also Figure S9, cine loop, in supplemental data online. Fig year-old man with cardiovascular risk factors (hypertension, high lipids, smoking history)., -mode carotid ultrasound using 3-9 MHz linear probe reveals mixed hypo- and hyperechogenic plaque at origin of internal carotid artery., fter IV bolus injection of 2.5 ml of sulfur hexafluoride (Sonovue, racco ltana Pharma), contrastenhanced ultrasound shows no intraplaque neovascularization and moving bubbles that are restricted to adventitial vasa vasorum (arrows). See also Figure S8, cine loop, in supplemental data online. JR:198, January 2012 W17

6 Partovi et al. Downloaded from by on 05/09/18 from IP address opyright RRS. For personal use only; all rights reserved Fig year-old man with no cardiovascular disease but several cardiovascular risk factors, including hypertension, high lipids, and moderate smoking., -mode ultrasound image using 5-17 MHz linear probe shows hypoechogenic carotid lesion., Doppler ultrasound image documents high-grade stenosis with peak systolic velocity (PSV) of 233 cm/s and end diastolic velocity (EDV) of 103 cm/s. PW = pulse wave, WF = wall filler, RI = resistive index., fter IV bolus injection of 2.5 ml of sulfur hexafluoride (Sonovue, racco ltana Pharma), contrast-enhanced ultrasound image reveals abundant intraplaque neovascularization and bubbles that reach plaque core (arrows). See also Figure S10D, cine loop, in supplemental data online. Fig year-old woman with right-sided amaurosis fugax and no cardiovascular risk factors., -mode ultrasound image using 5-17 MHz linear probe reveals mixed hypo- and hyperechogenic plaque at origin of right internal carotid artery., fter IV bolus injection of 2.5 ml of sulfur hexafluoride (Sonovue, racco ltana Pharma), contrast-enhanced ultrasound using 3-9 MHz linear probe, contrast imaging software (pulse inversion), and mechanical index of 0.06 reveals abundance of intraplaque neovascularization (arrows) and vasa vasorum (arrowhead) at base of plaque. sterisk indicates arterial branch of external carotid artery. See also Figure S11D, cine loop, in supplemental data online., Zoom image shows intraplaque neovascularization as well as vasa vasorum. See also Figure S10E, cine loop, in supplemental data online. Fig year-old man with several cardiovascular risk factors, including smoking, arterial hypertension, and high lipids. He is asymptomatic and has high-grade stenosis of left internal carotid artery seen on ultrasound imaging. One week after carotid ultrasound was performed, patient had recurrent transient ischemic attacks with short episodes of numbness or tingling of right arm and leg. Subsequently, he underwent urgent left carotid endarterectomy., -mode ultrasound imaging using 3-9 MHz linear probe revealed hypoechogenic left carotid artery lesion., Doppler ultrasound image shows high-grade carotid artery stenosis with peak systolic velocity (PSV) (upper caliper) of 325 cm/s and end diastolic velocity (EDV) (lower caliper) of 160 cm/s. RI = resistive index. (Fig. 12 continues on next page) W18 JR:198, January 2012

7 arotid therosclerotic Plaque Lesions Downloaded from by on 05/09/18 from IP address opyright RRS. For personal use only; all rights reserved Fig. 12 (continued) 61-year-old man with several cardiovascular risk factors, including smoking, arterial hypertension, and high lipids. He is asymptomatic and has high-grade stenosis of left internal carotid artery seen on ultrasound imaging. One week after carotid ultrasound was performed, patient had recurrent transient ischemic attacks with short episodes of numbness or tingling of right arm and leg. Subsequently, he underwent urgent left carotid endarterectomy., ontrast-enhanced ultrasound image shows corresponding carotid lesion after bolus injection of 2.5 ml of sulfur hexafluoride (Sonovue, racco ltana Pharma). D, Zoom image of ultrasound examination of lesion shows abundant intraplaque neovascularizations and bubbles that reach plaque core (arrows). See also Figure S12E, cine loop, in supplemental data online. Fig year-old woman with arterial hypertension and high lipids. She has symptomatic (dysarthria and left-sided central facial palsy) high-grade stenosis of right internal carotid artery seen on ultrasound imaging. She underwent right-sided carotid endarterectomy that revealed plaque with large superimposed thrombus formation., -mode ultrasound image using 3-9 MHz linear probe shows mixed hyper- and hypoechogenic right carotid artery lesion (calipers)., Doppler ultrasound image shows high-grade carotid artery stenosis with peak systolic velocity (PSV) (upper caliper) of 487 cm/s and end diastolic velocity (EDV) (lower caliper) of 194 cm/s. RI = resistive index., ontrast-enhanced ultrasound image of corresponding carotid lesion after bolus injection of 2.5 ml of sulfur hexafluoride (Sonovue, racco ltana Pharma) shows only moderate intraplaque neovascularization at plaque shoulder (arrows) and adventitial vasa vasorum (arrowheads). Most of lesion is not vascularized, which may correspond with intraoperatively revealed superimposed thrombus formation. See also Figure S13D, cine loop, in supplemental data online. FOR YOUR INFORMTION The data supplement accompanying this Web exclusive article can be viewed from the information box in the upper right corner of the article at: D JR:198, January 2012 W19