ATVB in Focus

Vascular Calcification: Basic Mechanisms to Clinical Perspectives

Series Editors: Ann Marie Schmidt and Renu Virmani

Is Carotid Intima-Media Thickness as Predictive

as Other Noninvasive Techniques for the Detection
of Coronary Artery Disease?
Yiyi Zhang, Eliseo Guallar, Ye Qiao, Bruce A. Wasserman
AbstractCarotid intima-media thickness (CIMT) measured by B-mode ultrasound is the most widely used noninvasive
imaging method to assess atherosclerosis and cardiovascular risk. CIMT has been consistently associated with coronary
artery disease and stroke; however, recent meta-analyses and systematic reviews suggest that its clinical usefulness may
be limited because the addition of CIMT to traditional risk factors has not improved the risk prediction of cardiovascular
events in the general population. Characterizing the carotid wall by MRI may have greater clinical utility compared with
CIMT measurements by ultrasound. Unlike CIMT, MRI measurements of wall thickness include the adventitia and may
be sensitive to adventitial thickening that results from vasa vasorum proliferation as a sign of early plaque development.
MRI also has the ability to image the entire circumference of the carotid wall, including the outer wall of the carotid
bulb where plaque forms in its earliest stage, and identify plaque components such as the lipid core, fibrous cap, and
intraplaque hemorrhage that are closely related to plaque vulnerability and cardiovascular risk. Additional research is
needed to assess the added prognostic value of MRI measurements of wall and plaque features in risk prediction beyond
traditional risk factors.(Arterioscler Thromb Vasc Biol. 2014;34:1341-1345.)
Key Words: atherosclerosis carotid intima-media thickness coronary disease magnetic resonance imaging
ultrasonography

therosclerosis is a systemic, chronic inflammatory disorder usually involving multiple vascular territories in the
same patient, with carotid and coronary artery plaque known
to be closely related.1,2 Both cross-sectional and longitudinal
imaging studies have linked atherosclerotic plaque features
between carotid and coronary arteries.310 Cross-sectional
studies have shown associations between carotid intimamedia thickness (CIMT) and the severity and extent of coronary atherosclerosis based on angiography.58 Furthermore,
calcification and lipid-rich necrotic core identified in carotid
plaque by MRI have been associated with stenosis and calcification on coronary angiography, and carotid intraplaque hemorrhage on MRI has been associated with partially calcified
coronary plaques on agniography.3,4,9 In addition, CIMT and
the presence of carotid artery plaque significantly predicted
incident coronary artery calcium as well as the progression of
coronary artery calcium in a prospective cohort study of 5445
participants from the Multi-Ethnic Study of Atherosclerosis
(MESA).10

The superficial location, large size, and relative immobility

of the carotid arteries make them especially amenable to noninvasive imaging, and thus characterization of atherosclerosis in the carotid arteries might offer valuable insight into the
atherosclerosis status in other vascular beds. This is particularly important for assessing coronary artery atherosclerosis
because coronary arteries are difficult to image in noninvasive
studies. As a consequence, ultrasound imaging of the carotid
arteries became a popular clinical measurement, with carotid
CIMT measured by B-mode ultrasound being the most widely
used noninvasive imaging method to assess cardiovascular
risk in primary prevention settings.11
This review summarizes the available epidemiological data
examining the clinical usefulness of CIMT for risk prediction
of coronary artery disease (CAD) and compares CIMT with
other noninvasive modalities measuring carotid wall thickness and plaque such as MRI, 3-dimensional (3D) ultrasound,
computed tomography (CT), and fluorodeoxyglucose positron
emission tomography (FDG-PET).

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CIMT has been consistently associated with CAD and stroke,12,13

but its clinical usefulness in adding predictive risk discrimination

CIMT by B-Mode Ultrasound and CAD

Received on: December 25, 2013; final version accepted on: April 1, 2014.
From the Departments of Epidemiology and Medicine, and Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University
Bloomberg School of Public Health, Baltimore, MD (Y.Z., E.G.); and Russell H. Morgan Department of Radiology and Radiological Sciences, Johns
Hopkins Hospital, Baltimore, MD (Y.Q., B.A.W.).
Correspondence to Bruce A. Wasserman, MD, Johns Hopkins Hospital, 367 E Park Bldg, 600 N Wolfe St, Baltimore, MD 21287. E-mail bwasser@jhmi.edu
2014 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.org

DOI: 10.1161/ATVBAHA.113.302075

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by guest on March 6, 2016
1341

1342 Arterioscler Thromb Vasc Biol July 2014

Nonstandard Abbreviations and Acronyms

CAD
CIMT
CT
FDG-PET

coronary artery disease

carotid intima-media thickness
computed tomography
fluorodeoxyglucose positron emission tomography

beyond traditional risk factors identified by the Framingham Risk

Score has been questioned in recent systematic reviews and metaanalyses.1214 A meta-analysis using individual data from 14 population-based cohorts (45828 participants) reported that for every
0.1-mm increase in the common CIMT, the hazard ratio of firsttime myocardial infarction or stroke was 1.09 (1.071.12),13 with
minor improvement in prediction when added to the Framingham
Risk Score (0.002 increase in the C-statistic; net reclassification improvement, 0.8%).13 These results suggest that current
evidence does not support routine use of CIMT in the general
population to screen for cardiovascular disease because the added
value is too small to result in health benefits. Of note, several
recent studies have also explored other CIMT metrics (including
CIMT progression, average of the maximal CIMT measured in
different segments, and maximal CIMT of the internal carotid
artery) and found significant associations with cardiovascular
events.1518 However, the clinical utility of these CIMT measurements beyond traditional risk factors is yet to be determined.12,13,19

Limitations of CIMT Measurements by

B-Mode Ultrasound
Several limitations of the CIMT measurements by B-mode
ultrasound may explain its lack of added prognostic value to
the Framingham Risk Score. CIMT is usually measured in the
common carotid artery because of its easier accessibility and
perpendicular location to the ultrasound beam, whereas carotid
atherosclerosis predominantly occurs earliest downstream in the
bulb (and often only in the bulb), which may not be as easily visible with B-mode ultrasound.20 Indeed, the presence of carotid
plaque may be a stronger predictor of CAD than CIMT. A metaanalysis found that the presence of carotid plaque had a significantly higher diagnostic accuracy for the prediction of future
myocardial infarction compared with CIMT.21 In this meta-analysis, CIMT measurement including plaque thickness in the bulb
was a stronger predictor of cardiovascular events compared with
CIMT in the common carotid artery, where it was less likely
to develop plaque, whereas the presence of carotid plaque was
more predictive than either CIMT phenotype.21
In addition, B-mode ultrasound measurements of CIMT
are usually based on far wall views of the carotid artery and
are limited in measuring the entire circumference of the wall.
Plaque formation in the carotid bifurcation, however, typically
begins along the outer wall of the bulb because of predisposing hemodynamic factors and then progresses to involve the
circumference of the bulb.22,23 Because of the typical orientation of the carotid bifurcation in the neck relative to the ultrasound transducer at the skin surface, the outer wall of the bulb
may lie tangential to the ultrasound beam and, therefore, is not
sensitively measured by B-mode ultrasound.
Finally, CIMT is a relatively simplistic measure of the
carotid wall that fails to capture the complexity of plaque

features.20 Components of carotid plaque, especially lipid-rich

necrotic core, intraplaque hemorrhage, and thin fibrous cap,
are closely related to plaque vulnerability and cardiovascular
risk.24 However, B-mode ultrasound is restricted in its ability
to define those plaque components.

MRI Versus CIMT

Recently, MRI has emerged as a superior noninvasive modality to characterize plaque features and image the arterial
wall.25 Wall thickness measurements by MRI may have greater
clinical utility compared with CIMT measurements by ultrasound. CIMT measurements include the sum of the intima
and media, whereas MRI measurements can also include the
adventitia.26,27 The adventitia is important for defining vascular inflammation because it is the source of vasa vasorum
that proliferate into the arterial wall with intimal thickening
and might be useful for detecting early plaque.28 Adventitial
vasa vasorum may also provide insight into the progression
of atherosclerosis to symptomatic disease. In a postmortem
study of iliac, carotid, and renal arteries, patients with a history of cardiovascular events had a denser network of vasa
vasorum in the adventitial layer compared with those without
events, and adventitial thickening was present in arteries with
negligible intimal thickening and normal arterial wall dimensions, suggesting that adventitial thickening can be an early
sign of atherosclerosis.29 Another study of patients undergoing MRI for carotid plaque evaluation found that prominence
of the adventitia seen on the MRI was associated with recent
cerebrovascular ischemic events.30 Because wall thickness
measurements by MRI include the adventitia, they may be
sensitive to adventitial thickening that results from vasa vasorum proliferation as a sign of either early plaque development
or later plaque instability.
In contrast to CIMT measurements by ultrasound, MRI
has the ability to image the entire circumference of the wall
and hence is able to detect early wall thickening that occurs
along the outer wall of the carotid bulb where plaque forms
in its earliest stage.22,23,31 In addition, MRI has the ability to
accurately identify plaque components such as lipid core,
fibrous cap, and intraplaque hemorrhage that are closely
related to plaque vulnerability and cardiovascular risk
(Figure).30,3236 Carotid plaque burden and composition measured by MRI have been significantly associated with CAD
in several small cross-sectional studies.3,4,9 We continue to
await validation from population-based studies, but early
findings from the Atherosclerosis Risk in Communities
(ARIC) study and the MESA study showed that MRI measures of carotid artery remodeling, plaque burden, and
plaque characteristics were independently associated with
incident cardiovascular events.37,38
Overall, there is good correlation between wall area, wall
thickness, and plaque index measured by MRI and CIMT
measurements obtained by ultrasound,39,40 but carotid MRI
has higher reproducibility compared with ultrasound.4042
Reader variability, rather than scan acquisition variability,
seems to be the primary factor affecting the reliability of
MRI measurements of carotid plaque characteristics, and
reader error is mostly influenced by the size of the structure being measured relative to the spatial resolution of the

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Zhang et al CIMT for Detection of Coronary Artery Disease 1343

Figure. MR images of a carotid artery plaque that had progressed to cause critical stenosis in a 74-year-old man who went on to endarterectomy with corresponding histology shown. A high-resolution MR image (A) using a technique that suppresses luminal signal (*)
highlights the eccentric plaque (orange arrows). Marked hyperintense signal within the plaque (green arrows) is indicative of hemorrhage
within its core. After gadolinium-based contrast administration, a repeat high-resolution MR image (B) shows a triangular region of avid
enhancement (orange arrow) compatible with inflammatory tissue. Adventitial enhancement (yellow arrows) is also indicative of plaque
inflammation. Hemorrhage generally shows a relative lack of enhancement (green arrows). Histological section stained with Movat pentochrome (C) shows intraplaque hemorrhage (red tissue) and inflammation with neovascularity (tissue in and around box surrounded by
hemorrhage) within the necrotic core confirming the components identified on the corresponding MR image. High-power view of the box
shown in C (D) demonstrates inflammatory tissue with endothelial cells (arrows), indicative of neovessels, surrounded by lymphocytes.

scanner.43 With recent increases in field strength of MRI

scanners used in clinical practice, one can achieve higher
resolutions and expect further improvement in reliability
estimates, as well as in our ability to detect early disease
with small structural changes.44,45

Limitations of MRI
The clinical applicability of carotid MRI must be considered in
light of several potential limitations of this imaging technique.
Compared with carotid ultrasound, MRI is more expensive
with a cost that can be >10 that of an ultrasound examination.46 Moreover, because of its high construction cost, MRI
scanners tend to be less accessible compared with ultrasound
systems. The high cost and limited availability of MRI may
restrict its use as a first-line screening tool for asymptomatic
atherosclerosis.47,48 Other relative limitations of carotid MRI
include longer scan times and sensitivity to motion. Safety
concerns also must be considered with MRI scanners that
are not relevant to ultrasound, especially contraindications to
exposure to the magnetic field. These include metallic foreign
bodies in the orbit or near vital structures, cochlear implants,
and pacemakers. Local heating with skin burns can occur from
certain medicine patches, tattoos, or permanent cosmetics.
More commonly, claustrophobia poses a relative contraindication although most patients are able to tolerate the examination
with sedation or using an open or wide-bore system.

Other Noninvasive Imaging Modalities

Recent advances in ultrasound technology have led to 3D
techniques that have the ability to directly measure total
plaque volume and vessel wall volume and are more sensitive
to plaque changes compared with CIMT.49,50 Together with
morphological B-mode ultrasound, 3D ultrasound may be a
more cost-effective plaque measurement and cardiovascular
risk screening tool compared with MRI. Compared with MRI,
however, 3D ultrasound is limited in its ability for soft tissue
characterization and cannot distinguish lipid-rich necrotic core

from intraplaque hemorrhage.51 Calcification is another major

barrier for 3D ultrasound because large calcified plaques can
cause acoustic shadowing and obscure the structure behind the
surface of calcification.51,52
CT is not a preferred modality for measuring carotid wall or
plaque because of limitations associated with dense calcification, poor contrast between lipid and fibrotic components, and
exposure to radiation.47 Nevertheless, 1 study reported that
there was good agreement between carotid artery wall thickness measurements by multidetector-row CT angiography and
CIMT measurements by ultrasound.53 Another study showed
that carotid wall enhancement on CT angiography, indicating vasa vasorum neovascularization, was associated with
previous stroke or transient ischemic attack.54 Because of its
imaging limitations and risk related to radiation, carotid CT
imaging is unlikely to play a major role as a screening tool for
cardiovascular disease.
18
F-FDG-PET is another noninvasive imaging modality for
assessing plaque vulnerability, particularly plaque inflammation. FDG is taken up by macrophages and can be imaged
with PET to identify areas of inflammation and vulnerability
to rupture.55 Some key limitations of FDG-PET include the
low specificity of FDG uptake and its poor resolution compared with MRI or CT.47 To compensate for this, PET has been
coupled with MRI or CT in PET/MRI or PET/CT scanners,
which combine both modalities and can tie together detailed
anatomic information of MRI or CT scanning along with the
functional information of PET scanning. The clinical role of
FDG-PET in predicting cardiovascular disease is still under
active investigation. A study of 40 patients undergoing carotid
FDG-PET imaging found higher FDG uptake in those with
a history of CAD.56 In 101 patients with stable cancer who
underwent whole-body 18F-FDG-PET/CT scans, high arterial
wall FDG uptake was associated with recent cardiovascular
events occurring <6 months before or after PET.57 Another
study of 932 patients with cancer showed that increased arterial wall FDG uptake was predictive of incident vascular
event (defined as ischemic stroke, myocardial infarction, or

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1344 Arterioscler Thromb Vasc Biol July 2014

revascularization).58 Functional imaging of atherosclerotic
plaque to identify vulnerable features is an evolving field and
can also be done by other techniques. For example, molecular imaging agents have been designed for MRI, including
functionalized nanoparticles that bind to fibrin59 and receptormediated agents that target neovascularity.60 The description
of these techniques is beyond the scope of this review.

Economic Considerations
It has been estimated that 30 million Americans 50 years of
age may need screening for asymptomatic atherosclerosis.46
Compared with ultrasound, the high cost of MRI and other
nonultrasound-based imaging techniques limits their use as
first-line screening tools for asymptomatic atherosclerosis.
These more advanced imaging techniques may better serve
as a second step in multimodality screening, in which patients
are first screened with a low-cost imaging technique such as
ultrasound, and those with abnormal findings will receive an
additional scan using advanced imaging techniques to provide more specific characterization of plaque features and
improved risk stratification.47 However, to our knowledge,
there are no data evaluating the economic impact of the use
of advanced imaging modalities for atherosclerosis screening
thus far.47 Additional research is necessary to determine the
cost-effectiveness of alternative imaging strategies, especially
for asymptomatic individuals.

Conclusions
In summary, there is a modest association between CIMT
assessed by B-mode ultrasound and CAD, but the addition of
CIMT to traditional risk factors does not improve risk prediction in the general population. MRI may be a superior noninvasive modality to measure carotid wall thickness and to
characterize plaque composition for this purpose. Additional
research in population-based studies is needed to better assess
the added prognostic value of MRI measurements of wall and
plaque features in risk prediction beyond traditional risk factors.

Sources of Funding
This research was supported by contract R01HL105930 from the
National Heart, Lung, and Blood Institute (to B.A. Wasserman).

Disclosures
None.

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Is Carotid Intima-Media Thickness as Predictive as Other Noninvasive Techniques for the

Detection of Coronary Artery Disease?
Yiyi Zhang, Eliseo Guallar, Ye Qiao and Bruce A. Wasserman
Arterioscler Thromb Vasc Biol. 2014;34:1341-1345; originally published online April 24, 2014;
doi: 10.1161/ATVBAHA.113.302075
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