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New Advances in Noninvasive Imaging of the Carotid Artery:

CIMT, Contrast-Enhanced Ultrasound, and Vasa Vasorum

Blai Coll, Vijay Nambi, and Steven B. Feinstein

Corresponding author:

Steven B. Feinstein

Professor of Medicine/Cardiology,

1015 Jelke,

1750 West Congress Parkway,

Rush University Medical Center,

Chicago, IL 60612, USA

e-mail: sfeinste@rush.edu

Abstract

Carotid ultrasound measurement of carotid intima-media thickness (C-IMT) and

detection of plaques is an useful method to better assess cardiovascular disease

risk status, especially in those at intermediate risk. We discuss the use C-IMT

and other emerging techniques such as contrast-enhanced carotid ultrasound

imaging in the evaluation of the carotid artery and its value in cardiovascular

disease.

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Keywords: Carotid intima-media thickness (CIMT); Contrast-enhanced

ultrasound (CEUS); Vasa vasorum; Atherosclerosis

Introduction

With the pan-epidemic of obesity, metabolic syndrome (MetSyn), and diabetes,

the worldwide cardiovascular risks of suffering a premature cardiovascular event

have increased significantly [1]. Current estimates state that in the United States

alone, there are approximately 44 million Americans diagnosed with MetSyn with

150 million worldwide. Based on a recent meta-analysis of the consequences of

MetSyn, it is notable that women have a one-third increase in death rates over

that of men [2]. And based on a review by Cowie et al. in 2006 [3], approximately

73 million Americans have diabetes or exhibit impaired fasting glucose. Clearly,

the MetSyn and diabetes significantly increase the risk for premature

cardiovascular morbidity and mortality.

Based on these data, it is imperative that we develop noninvasive imaging

systems capable of detecting and monitoring premature atherosclerosis in

populations. Therefore, it is reasonable to assume that the development of

advanced noninvasive technologies to detect surrogate markers of

atherosclerosis is a laudable public health initiative.

First, is a noninvasive, ultrasound-based system capable of detecting

systemic atherosclerosis an appropriate surrogate marker of disease? Arguably,

based on 24 years of clinical data, the widespread use of CIMT as a surrogate

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marker for detecting and monitoring atherosclerosis has stood the test of time

and clearly serves as a reliable surrogate marker in prospective population

studies [4].

Second, the discussion will focus on the added clinical value of contrast-

enhanced ultrasound (CEUS) for the following: 1) visualization of the entire

carotid artery vasculature, 2) enhancement of the near wall CIMT, and 3)

identification of the adventitial and intraplaque vasa vasorum. Importantly,

noninvasive detection of neovascularization within the vessel wall is associated

with premature atherosclerosis, a precursor to overt atheroslcerosis. The value of

using CEUS to detect and quantify preclinical disease is legion.

Third, the future of CEUS and three-dimensional (3D) volumetric,

ultrasound-based imaging will be discussed. It is anticipated that a 3D/four-

dimensional (4D) system can be devised to provide individualized assessment of

premature atherosclerosis versus assessment of relative risk in large population

studies. It is believed that a volumetric analysis approach is required because the

atherosclerosis process is eccentric and focal within the vasculature.

Therefore, the overall goal is to provide widely available, simple,

noninvasive, cost-effective technology to screen populations considered at risk

for coronary artery disease or described as “vulnerable” patients [5, 6].

Noninvasive, Ultrasound-Based Assessment of Cardiovascular Disease

Cardiovascular prevention is, in part, based on the identification of risk factors,

which includes serum cholesterol and blood pressure leading to an estimation of

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cardiovascular risk scores based on traditional scoring systems (ie, Framingham,

risk score, etc.). This process represents a uniform, validated and robust method

to classify high-risk and very low risk individuals. However, cardiovascular scores

do not clearly differentiate those individuals who are classified at intermediate

risk, and those subjects who will suffer a cardiovascular event in the future. The

need to further classify at-risk individuals is especially important because nearly

62% of patients who suffer from a coronary heart event present with no or a

single conventional risk factor [7]. Carotid ultrasound—measuring carotid intima-

media thickness (CIMT)—and the diagnoses of carotid plaques may provide

additional power to further identify those at-risk individuals. The measurement of

CIMT remains a well-established and accepted surrogate marker of

cardiovascular disease (CVD) [8]. It has been extensively studied in numerous

clinical trials [9] beginning with the initial description by Pignoli and Longo [10] in

1986 and currently accounts for the most extensive literature in the field of

atherosclerosis imaging.

The CIMT measurement directly correlates with pathology [11, 12] and is

indicative of the thickness of the arterial wall, and is precisely imaged using

ultrasound technology. In clinical studies, the CIMT measurement parallels the

significance of traditional cardiovascular risk factors, thus highlighting the utility

and consistency of using noninvasive measurements to assess risk factors

based on vessel wall biology. Over the years, clinical trials have provided

outcomes that support the role of CIMT measurements for predicting

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cardiovascular events (ie, the thicker the CIMT, the higher the rate of myocardial

infarction or stroke) [13].

The application of CIMT has become an accepted, reliable surrogate

marker for determination of atherosclerosis and is endorsed by the US Food and

Drug Administration (FDA) and by the European Agency for the Evaluation of

Medicinal Products. Today, CIMT measurements represent the preferred

technique for noninvasively assessing atherosclerosis in most clinical trial

studies, and clinical guidelines and scientific societies recommend the use of

carotid ultrasound to further assess cardiovascular status in selected populations

[14].

In low-to-intermediate cardiovascular risk groups, the presence of carotid

atherosclerosis has been studied. In a recently performed research study

(Unpublished data; Coll B. et al) the Spanish Society of Cardiology examined the

reclassification rate of low- to intermediate-risk individuals based on carotid

ultrasound imaging compared with the SCORE (Systemic Coronary Risk

Estimation) risk. In their study, 3778 volunteers were selected based on the

following criteria: no previous CVD, no diabetes mellitus, and SCORE risk low to

intermediate (< 5% probability to suffer from a fatal CVD in the following 10

years). From this group, 2354 healthy individuals were identified, and CIMT and

carotid plaques were identified along with clinical and laboratory data. The result

was that 37.4% of subjects revealed carotid atherosclerosis.

Using multivariate analyses, the variables that significantly related to the

presence of carotid atherosclerosis were age, male, and high blood pressure.

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Conversely, SCORE risk was not significantly related with carotid

atherosclerosis.

These results are consistent with the data published from earlier authors.

For example, Postley et al. [15] included 715 low-to-intermediate Framingham

risk subjects and reported a prevalence of carotid plaque at 32.8%. Age, male

gender, and dyslipidemia were among the significant related variables. Similarly,

in the Northern Manhattan Study, 1445 subjects were examined and the

prevalence of carotid plaques was 58%, although 459 (21%) of the participants

had previously suffered from a cardiovascular event [16].

Overall, there exists a significant dissociation between traditional risk

assessment and the observed presence of atherosclerosis as detected by

ultrasonography. Traditional risk assessment models (eg, Framingham, SCORE,

etc.) are designed to prospectively identify subjects who are at risk for suffering

from a premature cardiovascular event; these models were not based on the use

of surrogate markers of systemic atherosclerosis. However, subjects who are

identified with atherosclerosis based on noninvasive imaging techniques are at

an increased cardiovascular risk. Population-based studies have consistently

shown that the presence of carotid atherosclerosis served as an independent

variable in the prediction of cardiovascular events, coronary heart disease, and

stroke. Davidsson et al. [17] recently reported that the odds ratio of

cardiovascular events in subjects with a carotid plaque was 2.09 (CI, 1.05–4.16;

P = 0.03) in a multivariate analyses of 391 males from Sweden. Further, the

presence of carotid plaque was associated with a 2.9-fold (CI, 1.22–7.07)

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increased risk of cardiovascular events as noted in an observational study of 767

healthy Mediterranean subjects [18].

With regard to the categorical increments in IMT, a measured CIMT

difference of 0.1 mm, corrected for age and gender, yielded a 10% to 15%

increase in future cardiovascular events and an increased stroke risk of 13% to

18% [4]. Further, sensitivity, specificity, and receiver operating characteristic

curves are consistently enhanced after carotid ultrasound results are

incorporated into the equation [19].

Recently, a major new finding was reported by Nambi et al. [20•], in which

the authors correlated cardiovascular events to CIMT and carotid plaque from the

ARIC (Atherosclerosis Risk i Communities) database. The authors commented

on the predictive role of carotid ultrasound (CIMT and plaque) from a serial

analysis of 13,145 healthy subjects. In this study, there were 1812 cardiovascular

events reported over a mean follow-up of 15 years. Area under the curve

significantly increased following the addition of CIMT and plaque when added to

the conventional risk factors. Moreover, the authors cited a significant

improvement in the net reclassification index when using carotid ultrasound

(21.7% of participants in the intermediate-risk group were correctly reclassified).

CEUS Imaging, CIMT, and Intraplaque/Adventitial Vasa Vasorum

Ultrasound contrast agents (UCAs) are intravascular indicators that serve as

near perfect acoustic reflectors. As a class, UCAs are micron-sized, air-filled

spheres composed of a thin shell (generally lipid or protein) and a relatively

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nondiffusible gas; Albunex (Mallinckrodt Medical, St. Louis, MO), the first

commercial UCA, was approved by the FDA in 1994. Currently, UCAs are

clinically indicated in a variety of ultrasound applications for cardiac imaging in

the United States and for body imaging globally.

CEUS imaging, when used for vascular applications, enhances the vessel

lumen and, consequently, provides complete visualization of the carotid artery

vasculature, luminal surfaces, near and far IMT, and adventital and intraplaque

angiogenesis (vasa vasorum).

CEUS: near wall CIMT

Initially described in 2004, CEUS provided a reliable and precise measurement of

the near wall CIMT compared with CIMT measurements performed without the

use of UCAs [21].

The historic focus on the quantification of IMT from the far wall of the

common carotid artery was deliberate and based on utilitarian issues surrounding

technique and acoustics [22, 23]. Although the far wall measurement of the

common carotid remains the most reliable measurement, systemic

atherosclerosis is not uniquely confined to a specific domain. Despite the higher

prevalence of atherosclerosis on the near and distal carotid walls, there are

inherent acoustic and technical explanations for the difficulties encountered in

acoustically defining the near wall of the common carotid artery. In fact, in the

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2004 report by Macioch et al. [21], the near wall of the common carotid artery

wall measured 20% thicker than that of the far wall; these findings are consistent

with the histology report by Wong et al. in 1993 [11].

CEUS: vasa vasorum

The first clinical description of the carotid artery vasa vasorum using CEUS was

reported in 2004 [24]. These initial dramatic images were subsequently validated

using histology specimens [25•]. The CEUS method for detecting carotid artery

angiogenesis was subsequently corroborated by independent groups [26–28].

These reports provided evidence that the use of CEUS is a practical,

noninvasive, cost-effective method to identify the neovascularization in patients

who are considered “at risk.”

In support of measuring neovascularization with CEUS methods, Fleiner

et al. [29] published an important article in which they described

neovascularization (vasa vasorum) noting that these changes were harbingers of

systemic atherosclerosis, which appear to predate incremental changes in CIMT.

From their work: “… findings indicate that there is an association among

intraplaque hemorrhage, an increase in the size of the necrotic core, and lesion

instability in coronary plaques.” And “…a hyperplastic network of vasa vasorum

constitutes an early sign of symptomatic atherosclerosis; importantly, these

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changes were observed to precede the development of increased intima-media-

thickness.”

Fleiner et al. [29] examined carotid, renal, and iliac arteries from autopsies

of 49 subjects, of which approximately half died of CVDs while the “control” group

died of unrelated causes. In the cardiovascular subgroup, two distinct findings

were observed: 1) presence of ectopic intraplaque neovascularization, and 2)

hyperplasia of adventitial vasa vasorum. The authors noted that ectopic

neovascularization reflected an adaptive response of the arterial wall to an

increased nutritional demand and occurs in the course of intima thickening. The

authors concluded that the presence of a hyperplastic network of vasa vasorum

differentiated symptomatic and asymptomatic patients.

In addition to the work of Fleiner et al. [29], Moreno and Fuster [30] and

Dunmore et al. [31] noted that adventitial vasa vasorum (neovascularization)

discriminates between active versus nonactive (vulnerable) plaques in

symptomatic versus asymptomatic subjects. The presence of these angiogenic

vessels was observed in all systemic arteries, which included the aorta,

coronaries, carotids, and the femoral arteries. Moreno and Fuster [30] concluded

that “… pathologic neovascularization of the vessel wall is a consistent feature of

atherosclerotic plaque development and progression of the disease.”

Dunmore et al. [31] a vascular surgeon, commented: “…Symptomatic

carotid plaques contain abnormal, immature microvessels similar to those found

in tumors and healing wounds. Such vessels could contribute to plaque instability

by acting as sites of vascular leakage by inflammatory cell recruitment....”.

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Jeziorska and Woolley [32] noted the presence of initial, diffuse

neovascularization at each stage of atherosclerotic plaque formation. Their

conclusions were based on an examination of 191 carotid endarterectomy

specimens. The tissue specimens were divided into six categories, types I

through VI, based on degree of atherosclerotic progression, with type I lesions

being the earliest and type VI lesions being the most advanced. Noting that

conventional staining procedures typically underestimated the extent of

neovascularization, they employed staining of monoclonal antibodies to CD31,

CD34, and von Willebrand factor to provide “… an ultra-sensitive technique with

which to visualize blood vessels in early atherosclerotic lesions…”. The authors

concluded that “...new microvessels are a prominent feature of even the early

developmental stages of atherosclerosis.”

And most recently, there appears to be a paradigm change in thinking of

plaque “vulnerability” as reflected in the comments by Shalhoub et al. [33] in their

review article. The authors stated the following: “…2D CEUS presents the

possibility of imaging plaque microvasculature, a proven hallmark of

vulnerability.”

Historically, pathologists, physiologists, and surgeons have long

recognized the association of angiogenesis and plaque. In a seminal paper from

1984, Barger et al. [34] noted that in 1938 Winternitz described “…presence of

rich vascular channels surrounding and penetrating sclerotic lesions.”

Subsequently, Barger et al. [34] published a manuscript in which they

noted that if the coronary arteries were free of atherosclerosis the adventitial

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vasa vasorum vessels were minimally present, whereas in areas with

atherosclerosis the pattern of vasa vasorum was “strikingly different” and was

associated with the presence of “a dense plexus of microvessels … suggesting

marked neovascularization.”.

Kumamoto M. et al [35] concluded that the regions of coronary

atherosclerotic injury are especially rich in vasa vasorum and thus that

neovascularization may play “a fundamental role in the pathogenesis of the

atherosclerotic process and its sequelae”

Further, Barger et al. [34] noted that minimal neovascularization showed in

cases of little or no evidence of atherosclerosis, whereas specimens with a

greater proportion of neovascularization “invariably showed atherosclerotic

changes.” Barger et al. observed that the most striking feature of the heavily

neovascularized areas “was the involvement of the inner media or intima/plaque

locations by microvessels.”

Experimental animal models of atherosclerosis reflect the concept that

angiogenesis is intimately involved in the pathophysiology of atherosclerosis and

present as “outside-to-inside” genesis of atherosclerosis. Heistad and Armstrong

[36] described a five- to sixfold increase in blood flow via vasa vasorum in the

coronary intima and media in diet-induced atherosclerotic monkeys compared

with nonhypercholesterolemic monkeys. And Moulten [37] and Wilson et al. [38]

reported on the development of experimental animal models designed to test the

hypothesis that angiogenesis is associated with the atherosclerosis process.

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Recently, Schinkel et al. [39•] reported on the experimentally induced femoral

wall angiogenesis in the Rapacz familial hypercholesterolemic swine model.

The initial CEUS report that described neovascularization within the

carotid plaque provided an opportunity to define intraplaque perfusion in an in

vivo setting using real-time ultrasound systems coupled with unparalleled spatial

and temporal image resolution and without ionizing radiation. Uniquely, CEUS

imaging can be performed at the bedside, using current commercial equipment,

without incurring ionizing radiation and remains cost-effective for screening at-

risk populations. The ability to provide bedside documentation of a vessel wall

neovascularization permits initiation of treatment for an inflamed vessel wall,

which represents a “vulnerable” plaque.

Conclusions

Although there is substantial clinical validation of the use of carotid artery (CIMT)

as a surrogate marker for systemic atherosclerosis in populations, there is a

need to provide a volumetric analysis of the entire vascular bed to provide a total

“plaque burden” for populations and, specifically, for an individual subject.

Total plaque burden within the carotid artery would constitute an

improvement in accuracy for detecting and monitoring systemic atherosclerosis

[40]. The basis for applying a volumetric approach to plaque detection and

angiogenesis is supported by several recent articles in which the authors

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described measurement of the carotid plaque area as superior compared with

the CIMT for detecting significant disease based on a clinical outcome study [41].

Therefore, based on the development of newer, real-time 3D/4D

ultrasound technologies, it is possible to provide a total volumetric analysis of

both the CIMT as well as the angiogenesis associated with the vessel wall.

It is anticipated that with the continued ultrasound technology

developments of miniaturization and image automation, quantification of

preclinical atherosclerosis in at-risk populations will prove to provide life-saving

events while maintaining cost-effectiveness for a wide cross-section of the

community.

Disclosure

Dr. Steven B. Feinstein has been a speaker for Abbott, Takeda, and General

Electric. Blai Coll received speaker honorarium from Novartis, Astra and Abbott.

Vijay Nambi received research support collaboration with General Electric and

speaker honorarium from the American Heart Association.

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• Of importance

•• Of major importance

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In this recent publication, the authors provided a new experimental model for the

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