Carotid plaque rather than intima-media thickness as a predictor of recurrent vascular events in patients with acute ischemic stroke
Yoon et al. Cardiovascular Ultrasound
Carotid plaque rather than intima-media thickness as a predictor of recurrent vascular events in patients with acute ischemic stroke
Hyun Ju Yoon 0 1
Kye Hun Kim 0 1
Hyukjin Park 1
Jae Yeong Cho 0 1
Young Joon Hong 1
Hyung Wook Park 1
Ju Han Kim 1
Youngkeun Ahn 1
Myung Ho Jeong 1
Jeong Gwan Cho 0 1
Jong Chun Park 0 1
0 Translational Research Center on Aging, Chonnam National University Hospital , 42 Jaebong-ro, Donggu, Gwangju 501-757 , South Korea
1 Department of Cardiovascular Medicine, Chonnam National University Hospital , 42 Jaebong-ro, Donggu, Gwangju 501-757 , South Korea
Background: To investigate the impacts of carotid plaque and intima-media thickness (IMT) on future vascular events (VEs) in the patients with acute ischemic stroke. Methods: A total of 479 consecutive Korean patients with acute ischemic stroke were divided into 2 groups according to development of VEs; VE group (65.4 ± 10.9 years) vs no VE group (62.8 ± 13.2 years). VEs were defined as the development of recurrent stroke, coronary events, peripheral arterial disease, and death. Clinical, laboratory, and imaging findings were compared between the groups. Results: During 105.5 ± 29.0 months of follow up, VEs were developed in 142 patients (29.6%). In univariate analysis, VEs were significantly associated with age, gender, diabetes, renal function, lipid levels, left ventricular function, carotid plaque or IMT. In multivariate analysis, the presence of carotid plaque, diabetes, renal function and male gender were independent predictors of future VEs in the patients with ischemic stroke, but carotid IMT was not a predictor of future VEs. Event free survival was significantly lower in patients with carotid plaque than without carotid plaque on Kaplan-Meier analysis (log rank p < 0.001). Conclusion: The present study demonstrated that diabetes, impaired renal function, male gender, and the presence of carotid plaque rather than IMT were independent predictors of future VEs in Korean patients with acute ischemic stroke. Active medical management and careful monitoring for the development of recurrent VEs are strongly recommended in patients with acute ischemic stroke and carotid plaque.
Carotid artery; Plaque; Intima-media thickness; Stroke
Atherosclerotic cardiovascular disease (CVD) is a major
cause of mortality and morbidity in worldwide. Carotid
atherosclerosis is not only a marker of systemic
atherosclerosis but also a predictor of ischemic cerebrovascular
]. Carotid ultrasound is an efficient, relatively
inexpensive, highly reproducible method to evaluate
atherosclerotic change of the carotid artery by measuring
the presence of plaques or intima-media thickness
(IMT) of the carotid artery. The increased carotid IMT
and the presence of carotid plaques are well established
predictors of CVD and ischemic stroke [
intima-media thickening or plaques of the carotid artery
may reflect different biological aspects of atherosclerotic
process, the significance of carotid plaque or IMT in the
prediction of atherosclerotic CVD or ischemic stroke may
be different. According to the results of a recent
metaanalysis, the measurement of carotid plaque seems to be a
superior method than carotid IMT in predicting the
development of CVD [
]. In contrary to carotid plaque,
furthermore, the association between carotid IMT and
CVD has been questioned in some studies [
After a first attack of stroke, secondary prevention for
future vascular events (VEs) including recurrent stroke
is very important. Major hemispheric stroke, ischemic
stroke, and atrial fibrillation have been suggested as
clinical predictors of recurrent stroke after an index stroke
]. Recent studies have also suggested that carotid
IMT or plaque can be a useful imaging marker for
stroke recurrence [
]. However, the comparison
between carotid IMT and plaque on future VEs including
stroke recurrence after an index stroke has been poorly
studied. We hypothesized that the significance of carotid
IMT and plaque on future VEs would be different after a
first attack of stroke of ischemic etiology. Therefore, the
aim of this study was to investigate the impacts of
carotid IMT and plaque on future VEs in the patients with
acute ischemic stroke.
Study design and population
The present study is a single center, retrospective
observational study, and the study protocol was approved
by the Institutional Review Board of our institution
(No = 2010–05-092).
From 2007 to 2008, a total of 2607 Korean patients
were diagnosed as acute stroke. After excluding 2128
patients, a total of 479 patients with ischemic stroke who
had baseline echocardiography and carotid ultrasound at
admission were finally enrolled and divided into 2
groups according to the development of VE: VE group
(n = 142, 65.42 ± 10.9 years, 99 males) vs no VE group
(n = 337, 62.77 ± 13.2 years, 166 males). The reasons of
exclusion were as follows; 1) no baseline
echocardiography or carotid ultrasound study (n = 837), 2) previous
history of stroke (n = 361), 3) cardio-embolic stroke
including atrial fibrillation, mechanical valve, or mitral
stenosis (n = 276), 4) transient ischemic attack (n = 269), 5)
hemorrhagic stroke (n = 260), 6) cryptogenic stroke with
confirmed patent foramen ovale (n = 125). After discharge
from an index stroke, the study subjects underwent
clinical follow up at out-patient clinic for 105.5 ± 29.0 months,
and follow up information including VEs were obtained
from medical records.
Definition of stroke and VEs
According to the updated definition of stroke of the
current guideline, ischemic stroke was diagnosed by the
combination of symptoms and/or signs of typical
neurological dysfunction and imaging evidence of central
nervous system infarction. Therefore, ischemic stroke was
defined as an episode of neurological dysfunction caused
by focal cerebral, spinal, or retinal infarction on imaging
VEs were defined as the development of recurrent
stroke, coronary events, peripheral arterial disease,
and cardiovascular death during the study period in
the present study. Recurrent stroke was defined as the
development of a new focal neurologic deficit or new
deterioration of a previous deficit accompanied by a
de novo imaging evidence of brain infarction, but the
development of transient ischemic attack or hemorrhagic
transformation of the previous infarct lesion was excluded
in the present study. Coronary event was defined as the
development of obstructive atherosclerotic coronary artery
disease (% diameter stenosis >70%) or myocardial
infarction demonstrated by conventional coronary or cardiac
CT angiography. Peripheral arterial disease was defined as
the development of a narrowing of the arteries other than
those that supply the heart or the brain with an ankle
brachial index <0.9.
Routine laboratory study was performed as soon as
possible after admission, and blood samples to assess the
serum lipid profile and glucose were obtained in the
next morning after fasting more than 9 h. C-reactive
protein (CRP) was measured by the
immunoturbidimetric CRP-Latex (II) assay using an Olympus 5431 auto
analyzer (Olympus America Inc., Melville, NY, USA).
Carotid ultrasound examination
Carotid ultrasound examination was performed on both
common carotid arteries (CCA) and internal carotid
arteries (ICA) using a 10 MHz linear probe (Vivid 7, GE
Vingmed Ultrasound, Horten, Norway) according to the
current guideline [
]. With the subject in the supine
position and with slight hyperextension of the neck, the
CCA and carotid bulb were identified.
Carotid arteries were examined bilaterally in the
transversal and longitudinal planes. Following short-axis
2D image acquisition of the CCA, long-axis B-mode
ultrasound images were acquired for the subsequent
measurements. After placing a region of interest in the far wall of
the CCA, the mean IMT was estimated in a region free of
atherosclerotic plaques by using semi-automated
vesselwall detection software, AutoIMT® by GE Healthcare [
Averaged IMT values of the left and right CCAs were
subsequently used in all analyses. Carotid IMT is defined as a
double-line pattern visualized by echo 2D on both walls of
the CCA in a longitudinal view. Two parallel lines (leading
edges of two anatomical boundaries) form it. Mean
IMT was computed from 80 to 120 measurements over
a 10 mm span ending 5 mm proximal to the transition
between the CCA and bulb regions. Intra- and
interoperator coefficients of variation were 2.8% and 3.0%,
respectively, and intra- and inter-operator intra-class
correlations were both 0.97. Plaque was defined as a
protrusion of the vessel wall into the arterial lumen of
at least 0.5 mm, with an IMT 50% that of the
surrounding sites or an IMT > 1.5 mm as measured from the
media-adventitia interface to the intima lumen
interface. Regardless of locations, the presence of any plaque
in CCA or bulb or ICA was considered as the presence
of carotid plaque in the present study. First of all, the
presence or absence of carotid plaques were evaluated
and then texture were classified into soft, mixed, and
calcified based on echogenicity. In the case of multiple
plaques, we measured maximal protruding diameter
from carotid wall. On a longitudinal two-dimensional
ultrasound image of the carotid artery, the anterior
(near) and posterior (far) walls of the carotid artery
appear as two bright white lines separated by a
hypoechogenic space. End-diastolic images were frozen, and the
far wall IMT was identified as the region between the
lumen-intima interface and the media-adventitia
interface using semiautomatic method. It contained CCA,
bulb and proximal ICA plaques. Peak systolic and end
diastolic carotid flow velocity was measured by pulse
wave Doppler on the CCA and the ICA [
Echocardiographic images from various echocardiographic
windows were obtained by using a digital ultrasonographic
equipment system (Vivid 7, GE Vingmed Ultrasound,
Horten, Norway). Digital cine loops were obtained for
subsequent offline analysis. All of the data were analyzed
by using the computerized offline software package
(EchoPAC PC 6.0.0, GE Vingmed Ultrasound, Horten, Norway).
Routine echocardiographic examinations were performed
in accordance with the recommendation of the current
]. Ejection fraction were measured by using
Simpson’s biplane method. The intra-observer and
interobserver variabilities of Simpson’s method were 4% ± 5%
and 5% ± 4% (absolute difference divided by the mean
measurement value). The early (E) and late diastolic
velocities (A) of the mitral inflow were measured by using
pulsed wave Doppler from the apical 4-chamber view,
with the sample volume positioned at the tip of the mitral
leaflets. The early (e′), late diastolic (a′), and systolic
velocities of the mitral septal annulus were measured by
using tissue Doppler imaging in the apical four chamber
The statistical Package for Social Sciences (SPSS) for
Windows, version 18.0 (Chicago, Illinois, USA) was used
for statistical analysis. Data are presented as percents or
mean ± standard deviation. The differences of the
categorical variables were evaluated by Chi-square test,
and the continuous variables were compared using
independent t test. The event-free survival rate was
evaluated by using the Kaplan-Meier analysis, and the
event rates were compared using the log-rank test. To
identify the independent predictor of long term
vascular events, multivariate logistic regression analysis was
applied to the significant variables in univariate analysis.
A p-value less than 0.05 was considered as statistically
Baseline characteristics are summarized in the Table 1.
Age was older and male gender was more prevalent in
VE group than in no VE group. Diabetes mellitus and
prior history of cerebrovascular accident were more
frequent in VE group than in no VE group. Other baseline
characteristics were not different between the groups.
Laboratory findings and discharge medication
Laboratory findings are summarized in the Table 2. The
levels of serum glucose, hemoglobin A1c, and creatinine
were significantly higher, whereas the levels of total and
low density lipoprotein cholesterol were significantly
lower in VE group than in no VE group. There was no
significant difference in discharge medication between
groups (Table 3).
Echocardiographic findings are summarized in the Table 4.
Left ventricular end-systolic dimension was larger, whereas
ejection fraction was decreased in VE group than in no VE
group. Other echocardiographic findings were not different
between the groups.
BMI body mass index, CVA cerebrovascular accident, SBP systolic blood pressure,
DBP diastolic blood pressure
Carotid ultrasound findings
Carotid ultrasound findings are summarized in the Table
5. Carotid plaques were found in 181 cases (37.8%) out
of 479 patients with stroke. Regardless of location, the
presence of CCA, bulb, or ICA plaque was significantly
frequent in VE group than in no VE group. Significant
ICA stenosis (>50%) was not different between the
groups. Carotid revascularization was performed only in
2 patients of VE group and 2 patients of no VE group.
IMT of the left CCA and mean IMT of the both CCA
were thicker in VE group than in no VE group, but IMT
of the right CCA was not different between the groups.
The size and types of carotid plaque and blood flow
variables of the CCA were not different between the groups.
VEs and predictors of VEs during clinical follow up
During 105.5 ± 29 months of clinical follow up, VEs
were developed in 142 patients (29.6%); recurrent stroke
in 73 patients (15.2%), coronary events in 57 patients
(11.9%), peripheral arterial disease in 16 patients (3.3%),
and death in 9 patients (1.9%).
Multivariate analyses to identify independent predictors
of VEs were performed, and the results are summarized in
the Table 6. Diabetes, renal function, male gender, and the
presence of carotid plaque in any site were independent
predictors of future VEs in patients with acute ischemic
stroke on multivariate analysis. However, carotid IMT was
not an independent predictor of future VEs. The risk of
future VEs was greatest in acute ischemic stroke patients
with both carotid plaque and diabetes. In subgroup
analysis, carotid IMT was not an independent predictor
of future VEs in stroke patients without carotid plaque.
Carotid plaque and VEs
The presence of carotid plaque was significantly
associated with recurrent stroke and total VEs, but it was not
a predictor of coronary events, peripheral arterial disease
and deaths (Fig. 1). On Kaplan-Meier analysis, event
free survival for recurrent stroke and total VEs was
significantly lower in acute ischemic stroke patients with
carotid plaque than in without carotid plaque (log rank
p < 0.001) (Fig. 2).
In the present study, the authors want to compare the
significance between carotid IMT and plaque on future
VEs including stroke recurrence after an index stroke,
and the results of the present study demonstrated several
clinically important findings. First, recurrent VEs are not
infrequent in Korean patients with ischemic stroke after
an index event, and non-cerebral VEs including coronary
and peripheral artery disease comprise about a half of
VEs. Second, carotid plaque rather than carotid IMT is a
useful prognostic marker for the development of future
VEs in Korean patients with ischemic stroke. Therefore,
careful search for non-cerebral vascular diseases and
active medical management for preventing recurrent stroke
are strongly recommended in acute ischemic stroke
patients with carotid plaque. Thirdly, the presence of carotid
plaque at any sites, as a whole, was an independent
predictor of future VEs, whereas the presence of plaque at
CCA or bulb or ICA showed marginal significance for
predicting VEs. Therefore, the present study suggested
that a thorough evaluation for the presence of plaques in
whole carotid arterial trees including CCA, bulb, and ICA
should be performed for risk stratification in patients with
acute ischemic stroke.
The risk for the development of future stroke is
significantly higher in survivors of first-ever stroke than in
general population [
], the risk of stroke recurrence is
known to be greatest during the first week after index
]. According to a current meta-analysis, the
cumulative risk of stroke recurrence is gradually
increased as time goes by and is 3.1% at 30 days, 11.1% at
1 year, 26.4% at 5 years, and 39.2% at 10 years after
initial stroke [
]. In the present study, recurrent stroke
was developed in 15.2% during 8.7 years of clinical
follow up, and the rate of stroke recurrence seems to be
lower than that of a current meta-analysis [
]. The rate
of stroke recurrence was 18.4% at 5 years in the
retrospective cohort study of Sun et al. [
] and 19.8% at
years in the study of Lee et al. [
], and the recurrence
rate of these studies were similar to that of our study.
The differences of stroke recurrence might be explained
by the differences in study population among the studies.
In contrary to a current meta-analysis [
], the present
study cannot reflect true incidence of stroke recurrence,
because the present study only included stroke patients of
ischemic etiology with carotid ultrasound and
Stroke recurrence is known to be associated with poor
long-term clinical outcomes and quality of life [
After a first attack of stroke, therefore, early identification
of high risk group and secondary prevention for future
vascular events (VEs) including recurrent stroke would be
very important. Despite of high prevalence of classic risk
factors such as hypertension and dyslipidemia in patients
with recurrent stroke as in the study of Leoo et al.,
hypertension and dyslipidemia were not predictors of stroke
recurrence in the present study . Rather, among classic
risk factors for CVD, diabetes was the only significant
predictor of stroke recurrence in the present study. In
addition to classic risk factors, therefore, it is suggested
that other risk factors or predictors for stroke recurrence
should be identified to improve clinical outcomes. The
previous studies have suggested several clinical predictors
for stroke recurrence, and these include major
hemispheric stroke, ischemic stroke, male gender, diabetes,
advanced age, and atrial fibrillation [
]. In the
present study, diabetes, renal function, and male gender
were significant clinical predictors of future VEs. History
of coronary artery disease, severe stenosis or occlusion of
large cerebral artery, and multiple acute cerebral infarcts
suggested as independent predictors of recurrent ischemic
stroke or TIA within one year . Several studies have
suggested that carotid plaque or IMT can be used as
imaging marker not only in the prediction of development of
first-ever stroke [
] but also in the prediction of stroke
], even though the significance of
carotid IMT or plaque may differ [
]. Our previous study
also demonstrated that the significance of carotid IMT is
different from carotid plaque on ischemic stroke .
Despite of these differences, the comparison between carotid
IMT and plaque on future VEs after an index stroke has
been poorly studied previously. And the results of the
present study demonstrated that carotid plaque than
carotid IMT is a significant imaging marker for stroke
recurrence. The present study also suggested that a thorough
evaluation for the presence of plaques in whole carotid
arterial trees including CCA, bulb, and ICA should be
performed for risk stratification in patients with acute
ischemic stroke. In the present study, the presence of
both carotid plaque and diabetes was more strongly
associated with stroke recurrence, and thus this subgroup
of ischemic stroke patients should be more carefully
monitored and actively managed for preventing VEs.
As a whole, the prevalence of carotid plaque was
37.8% in the present study population with ischemic
stroke (8.1% in CCA, 29.4% in carotid bulb, 11.3% in
ICA, respectively), and carotid bulb was also the most
common site for plaque formation in this study as in
previous studies [
]. In the previous studies involving
Korean population, the prevalence of carotid plaque was
5.7% in general population [
] and 24.6 ~ 42.1% in
patients with atherosclerotic CVD such as coronary artery
], and the result of the present study also
showed quite similar to those of the previous studies.
In addition to the presence of carotid plaque, the
characteristics of plaques are also important for predicting
stroke recurrence. The previous studies have shown that
echolucent or large or mobile plaques are associated
with stroke recurrence [
13, 32, 33
], but the echogenicity,
size or mobility of carotid plaque was not associated
with stroke recurrence in the present study. The reason
why the characteristics of plaque were not associated
with VEs in the present study is unclear, and selection
bias from the retrospective nature of this study or ethnic
differences might be possible explanations.
In population with ischemic stroke, future coronary or
peripheral artery disease events and need for
revascularization are not infrequent and the result of the present study
was also demonstrated the association between stroke and
systemic atherosclerotic vascular events [
development or identification of coronary or peripheral artery
disease was also not infrequent in the present study and
developed in 57 patients (11.9%) and in 16 patients (3.3%),
respectively. Therefore, careful evaluation for coronary or
peripheral artery disease should be performed by
noninvasive coronary imaging or ankle-brachial index in
patients with ischemic stroke. Although the presence of
carotid plaque was a significant predictor of recurrent
stroke, it was not an independent predictor of future
coronary or peripheral vascular events in the present
study. No association between carotid plaque and systemic
vascular events might be explained by multi-factorial
pathogenic mechanism of coronary or peripheral artery
disease or small number of study population of the
present study. Increased value of CCA IMT is known to
be associated with a higher long-term risk of extracranial
vascular events such as coronary or peripheral artery
disease in a cohort study of Purroy et al. , it was not s
predictor of future VEs in the present study.
The present study has several potential limitations. First,
the present study has all limitations of a retrospective
analysis including selection bias. As discussed already,
the present study only included stroke patients of
ischemic etiology with carotid ultrasound and
echocardiography studies. Many of the patients with ischemic stroke
were excluded because of the absence of ultrasound
studies, and thus the result of the present study cannot
be generalized. Second, the present study did not consider
the impacts of interventional therapy or medications, and
these also might influence on future VEs. Third, the
incidence of coronary or peripheral vascular events might be
underestimated because non-cerebral systemic vascular
events were not evaluated routinely and usually evaluated
in symptomatic patients.
In conclusion, despite these potential limitations, the
results of the present study demonstrated that diabetes,
impaired renal function, male gender, and the presence
of carotid plaque rather than IMT were independent
predictors of future VEs in Korean patients with acute
ischemic stroke. Active medical management and careful
monitoring for the development of recurrent VEs are
strongly recommended in patients with acute ischemic
stroke and carotid plaque.
This research was supported by a grant (CRI 13904–21) of Chonnam National
University Hospital Biomedical Research Institute.
Availability of data and materials
The datasets used and/or analysed during the current study available from
the corresponding author on reasonable request.
HJY, KHK, HP, JYC, YJH, HWP and JHK made substantial contributions to
patient inclusion, HJY and KHK to data analysis and YA, MHJ, JGC and JCP to
data interpretation. All authors have contributed in writing and correcting
the manuscript and approved the submission of the manuscript.
Ethics approval and consent to participate
The study was approved by the Institutional Review Board of Chonnam
National University Hospital (No = 2010–05-092), Gwangju, Republic of Korea.
Consent for publication
The authors declare that they have no competing interests.
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