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CEUS carotid artery imaging and identification of risk of heart attack or stroke

Contrast enhanced ultrasound (CEUS) imaging of carotid arteries is a unique and reliable diagnostic tool that can help physicians directly identify patients with systemic atherosclerosis who are at high risk for a heart attack or stroke. This safe, non-invasive imaging option also permits physicians to monitor the effectiveness of anti-atherosclerosis therapy on an ongoing basis.

CEUS uses ultrasound contrast agents (UCAs), also known as ultrasound enhancement agents, to improve the clarity and reliability of conventional ultrasound scans. UCAs are comprised of liquid suspensions of biodegradable gas-filled microspheres (sometimes called “microbubbles”). When they are injected into a patient’s arm vein during an ultrasound exam, they flow through the body’s microcirculation without impediment, and are metabolized and expelled from the body within minutes.

When used in ultrasound imaging of the carotid arteries, UCAs improve visualization of carotid vessel wall irregularities and “vulnerable plaque” (carotid intraplaque neovascularization) at risk for rupture. Vulnerable carotid plaque correlates with transient ischemic attack and stroke.

The availability of CEUS to identify vulnerable plaque and stratify risk is clinically significant because not all carotid plaque is prone to rupture and, accordingly, traditional parameters for identifying carotid risk (degree of stenosis, systolic peak velocity) do not sufficiently predict actual risk of plaque embolism. However, carotid plaque neovascularization, evaluated with CEUS, strongly correlates with all expressions of plaque instability — intraplaque neovascularization, hemorrhage, surface ulceration and low echogenicity. CEUS thus provides a more reliable method of evaluating atherosclerotic lesions at high risk of rupture.

In using CEUS to evaluate carotid plaque, it may be noted that plaque with low echogenicity, surface ulceration and intraplaque hemorrhage (shown histopathologically) have greater CEUS enhancement than calcific or fibrous plaques. Further, plaques with higher CEUS enhancement have significant plaque vascularization, and irregular ulcerated plaque surfaces, a lipid necrotic core, a thin fibrous cap, an anechoic-hypoechoic appearance and intraplaque neovessels characterize potentially unstable atherosclerotic lesions at high risk of rupture and thrombosis.

Thus, the combined applications of CEUS for diagnosis and monitoring of therapy provide unique opportunities for clinicians to identify and stratify risk, and more effectively direct therapy for “at risk” individuals presenting with a predisposed phenotype.

Additional background – carotid “vasa vasorum”

CEUS is currently the only non-invasive imaging tool that identifies the presence of “vasa vasorum” microvessels within the carotid artery wall and atherosclerotic plaque. “Vasa vasorum” are, literally translated, the “vessels supplying blood to vessels.” These microvascular networks are critical to the development and subsequent progression of plaque vulnerability.

Vasa vasorum are routinely present along the arterial walls (adventitial surfaces), providing a normal mechanism to supply nutrients to the arterial wall. They also may be present within carotid plaque. In disease states driven by excessive local inflammation and hypoxia, these microvessels (vasa vasorum) proliferate rapidly to supply oxygen to hypoxic tissues.

The adventitial vasa vasorum are believed to be integrally involved in the development of atherosclerosis, and the development and destabilization of atheromatous plaques may be linked to intra-plaque hemorrhage and/or inflammation. Further, the initial hyperplasia of the adventitial vasa vasorum is believed to occur in the early phases of the development of inflammation and atherosclerosis, with vasa vasorum generated due to local metabolic needs within the carotid media, intima and plaques. The rapid growth of these microvessels constitute ectopic neovascularization and are associated with rupture and untoward clinical events. Plaque neovascularization is believed to discriminate between vulnerable and non-vulnerable plaques in symptomatic versus asymptomatic patients.

Select references:

Feinstein, S.B., The powerful microbubble: from bench to bedside, from intravascular indicator to therapeutic delivery system, and beyond. Am J Physiol Heart Circ Physiol, 2004. 287(2): p. H450-7.

Feinstein, S.B., Contrast ultrasound imaging of the carotid artery vasa vasorum and atherosclerotic plaque neovascularization. J Am Coll Cardiol, 2006. 48(2): p. 236-43.

Staub, D., et al., Contrast-enhanced ultrasound imaging of the vasa vasorum: from early atherosclerosis to the identification of unstable plaques. JACC Cardiovasc Imaging, 2010. 3(7): p. 761-71.

Barger, A.C., et al., Hypothesis: vasa vasorum and neovascularization of human coronary arteries. A possible role in the pathophysiology of atherosclerosis. N Engl J Med, 1984. 310(3): p. 175-7.

Wilson, S.H., et al., Simvastatin preserves the structure of coronary adventitial vasa vasorum in experimental hypercholesterolemia independent of lipid lowering. Circulation, 2002. 105(4): p. 415-8.

Schinkel, A.F., et al., Contrast-enhanced ultrasound for imaging vasa vasorum: comparison with histopathology in a swine model of atherosclerosis. Eur J Echocardiogr, 2010. 11(8): p. 659-64.

Hellings, W.E., et al., Composition of carotid atherosclerotic plaque is associated with cardiovascular outcome: a prognostic study. Circulation, 2010. 121(17): p. 1941-50.

Staub, D., et al., Vasa vasorum and plaque neovascularization on contrast-enhanced carotid ultrasound imaging correlates with cardiovascular disease and past cardiovascular events. Stroke, 2010. 41(1): p. 41-7.

Varetto, G, et al., Use of Contrast-Enhanced Ultrasound in Carotid Atherosclerotic Disease: Limits and Perspectives, Biomed Res Int. 2015; 2015: 293163.

On completion of the non-contrast enhanced portion of the examination, ultrasound, commercial ultrasound contrast agents are then injected. The ultrasound machine settings should include a linear array vascular probe equipped with harmonic software. When operating in the contrast-enhanced mode, a low mechanical index ranging from 0.06 to 0.18MI is required. The overall gain, time-gain compensation and compression once optimized are considered pre-sets.

Select a commercial ultrasound contrast agents and using normal saline, dilute the contents in a syringe to 10mL. The mixed contrast agents are to be injected via a peripheral vein as a bolus of 2 mL followed by a saline bolus of 2-3 mL. Additional injections may be repeated if the carotid artery lumen is not fully opacified. The images are to be recorded and stored digitally for offline analysis (qualitative and quantitative).

Assessment of microvascular flow (vasa vasorum):

Based on standard B-mode ultrasound images, the presence of atherosclerotic plaques is defined using the criteria outlined in the 2007 Mannheim consensus (see reference 64 below).

Following the injection of the ultrasound contrast agent, the lumen of carotid artery is enhanced within 10 to 30 seconds. Using the low mechanical index settings and the contrast-enhanced harmonic software, carotid plaques and the intima-media complex appear as hypoechoic with the bright adventitial layer. The presence of microvascular (vasa vasorum) blood flow “activity” within the adventitial layer or the within the plaque is identified based on the dynamic movement of the echogenic reflectors (microspheres). This indicates increased the presence of microvessels within the adventitial vasa vasorum and plaque. Whereas, fixed echogenic reflectors are considered as strong acoustic reflections based on tissue characteristics and do not represent active microvascular flow.

Qualitative analyses:

Currently, adventitial vasa vasorum activity are graded based on the presence of visible microspheres confined to the adventitial layer or the adjacent 5 mm of the periadventitial tissue located along the walls of the common carotid artery or bifurcation: Grade 1 is defined as no microspheres noted in the adventitial layer and adjacent periadventital tissue; grade 2: clear visible microspheres within the adventitial layer or adjacent periadventitial tissue.

Intraplaque neovascularization is defined as grade 1: no appearance of microbubbles within the plaque or microbubbles confined to plaque adventitial side. Grade 2 reveals a clear visible appearance of microbubbles within the plaque moving from the adventitial side or shoulder reaching plaque core. And grade 3, the highest grade of intraplaque neovascularization (right or left side) corresponds to marked increases in microbubbles activity within the body of the plaque.

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Contrast-enhanced ultrasound image of the carotid lumen.
Contrast-enhanced ultrasound image of the carotid lumen.
Intraplaque neovascularization (vasa vasorum)
  1. Spence, J.D., Approaching Automated 3-Dimensional Measurement of Atherosclerotic Plaque Volume. J Am Coll Cardiol, 2017. 70(3): p. 314-317.
  2. Spence, J.D., 3D Ultrasound for Imaging and Quantifying Carotid Ulcers. AJNR Am J Neuroradiol, 2017. 38(5): p. E34-E36.
  3. Sillesen, H., et al., Carotid plaque thickness and carotid plaque burden predict future cardiovascular events in asymptomatic adult Americans. Eur Heart J Cardiovasc Imaging, 2017.
  4. Sidhu, P.S., et al., The EFSUMB Guidelines and Recommendations for the Clinical Practice of Contrast-Enhanced Ultrasound (CEUS) in Non-Hepatic Applications: Update 2017 (Short Version).Ultraschall Med, 2017. 39(2): p. 154-180.
  5. Sandholt, B.V., et al., Inter-Scan Reproducibility of Carotid Plaque Volume Measurements by 3-D Ultrasound. Ultrasound Med Biol, 2017. 44(3): p. 670-676.
  6. Sack, M.N., et al., Basic Biology of Oxidative Stress and the Cardiovascular System: Part 1 of a 3-Part Series. J Am Coll Cardiol, 2017. 70(2): p. 196-211.
  7. Lopez-Melgar, B., et al., Subclinical Atherosclerosis Burden by 3D Ultrasound in Mid-Life: The PESA Study. J Am Coll Cardiol, 2017. 70(3): p. 301-313.
  8. Alagna G, C.V., ASSESSMENT OF A NEW 3D-ARTERIAL ANALYSIS SOFTWARE IN THE EVALUATION OF CAROTID ATHEROSCLEROTIC PLAQUE’S STENOSIS AND VULNERABILITY, AS COMPARED WITH CEUS, CTA AND HISTOLOGIC EXAMINATION. RSNA, 2017.
  9. Yoon, J.H., et al., The Value of Elastic Modulus Index as a Novel Surrogate Marker for Cardiovascular Risk Stratification by Dimensional Speckle-Tracking Carotid Ultrasonography. J Cardiovasc Ultrasound, 2016. 24(3): p. 215-222.
  10. Tremblay, S., et al., Non-invasive brain stimulation as a tool to study cerebellar-M1 interactions in humans. Cerebellum Ataxias, 2016. 3: p. 19.
  11. Saha, S.A., V. Gourineni, and S.B. Feinstein, The Use of Contrast-enhanced Ultrasonography for Imaging of Carotid Atherosclerotic Plaques: Current Evidence, Future Directions. Neuroimaging Clin N Am, 2016. 26(1): p. 81-96.
  12. Lopez-Melgar, B., et al., Accurate quantification of atherosclerotic plaque volume by 3D vascular ultrasound using the volumetric linear array method. Atherosclerosis, 2016. 248: p. 230-7.
  13. Huang, R., et al., Detection of Carotid Atherosclerotic Plaque Neovascularization Using Contrast Enhanced Ultrasound: A Systematic Review and Meta-Analysis of Diagnostic Accuracy Studies. J Am Soc Echocardiogr, 2016. 29(6): p. 491-502.
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