ARTICLE IN PRESS

Can the Neutrophil-to-Lymphocyte Ratio Appropriately

Predict Carotid Artery Stenosis in Patients with Ischemic
Stroke?A Retrospective Study

Sangho Hyun, MD, Seungwon Kwon, MD, SeungYeon Cho, MD, PhD,
SeongUk Park, MD, PhD, WooSang Jung, MD, PhD, SangKwan Moon, MD, PhD,
JungMi Park, MD, PhD, ChangNam Ko, MD, PhD, and KiHo Cho, MD, PhD

Background: Carotid stenosis is a risk factor in ischemic stroke. Although C-reactive

protein, interleukin-6, and tumor necrosis factor-alpha are known to predict carotid
atherosclerosis, they are difficult to obtain in clinical practice. By studying the as-
sociation between neutrophil-to-lymphocyte ratio (NLR) and carotid artery intima
media thickening (IMT) in patients with ischemic stroke, we determined that the
NLR can predict carotid stenosis. Methods: We selected 252 patients with acute to
subacute ischemic stroke who underwent carotid ultrasonography and complete
and differential blood cell count tests. We collected data on sex, age, body mass
index (BMI), alcohol consumption, smoking, hypertension, diabetes mellitus,
dyslipidemia, and heart disease. Male and female patients were analyzed sepa-
rately. We divided the subjects into 2 groups according to carotid IMT, and compared
baseline characteristics and NLR between the 2 groups. The regression analysis
was adjusted for confounding factors such as age, BMI, NLR, smoking, alcohol
consumption, and a medical history of hypertension, diabetes mellitus, dyslipidemia,
or heart disease. Results: Carotid IMT tended to significantly increase with NLR
and age in men and with age in women. In men, multiple linear regression anal-
yses adjusted for confounding factors showed that NLR (P < 0.001) and age
(P = 0.001) had a significant positive association with carotid IMT (adjusted R2 = 0.185,
root mean squared error [MSE] = 0.152). However, no parameters showed
significant positive associations in women. Conclusion: NLR can be a clinically
significant predictor of the degree of carotid stenosis in male patients
with ischemic stroke. However, additional studies are required to obtain more con-
crete results. Key Words: Neutrophil-to-lymphocyte ratioCarotid artery
stenosisAtherosclerosisIschemic strokeAtherosclerosis predictor.
2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.

From the Department of Cardiology and Neurology, College of
Korean Medicine, Kyung Hee University, Seoul, Republic of Korea.
Received June 28, 2015; revision received July 22, 2015; accepted
July 29, 2015.
Grant support: No financial support was received during the study.
All authors declare that they have no conflicts of interest.
Address correspondence to Seungwon Kwon, Department of
Cardiology and Neurology, College of Korean Medicine, Kyung Hee
University, 1 Hoegi-dong, Dongdaemun-gu, Seoul 130-702, Korea.
E-mail: kkokkottung@hanmail.net.
1052-3057/$ - see front matter
2015 National Stroke Association. Published by Elsevier Inc. All
rights reserved.
http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2015.07.024
Introduction
Carotid stenosis is accompanied by the narrowing or
constriction of the lumen of the carotid artery. It is usually
caused by atherosclerosis and is known to be a risk factor
for ischemic stroke. Asymptomatic carotid stenosis is
present in 50%-99% of ischemic stroke cases, and the annual
incidence of stroke is approximately 1%-3.4%.1 As carotid
stenosis is considered a causal factor of ischemic stroke,
it is actively studied worldwide. At present, carotid artery
endarterectomy and percutaneous angioplasty of the carotid
artery are considered as secondary prevention for high-
risk patients with ischemic stroke.2-5

Journal of Stroke and Cerebrovascular Diseases, Vol. , No. (), 2015: pp 1

 ARTICLE IN PRESS
2 S. HYUN ET AL.
It has been shown recently that circulating biomarkers
related to the systemic immune system, including C-reactive
protein, interleukin (IL)-6, and tumor necrosis factor-
alpha (TNF-), reliably predict atherosclerosis in carotid
intimamedia thickening (IMT).6 This shows that athero-
sclerosis is the focal expression of a systemic disease
affecting medium- and large-sized arteries. In this manner,
immune factors play a key role in the progression of ath-
erosclerosis. However, immune-related biomarkers such
as IL-6 and TNF- are difficult to obtain in common clin-
ical practice. Therefore, simpler and more convenient
markers are needed.
We considered that the neutrophil-to-lymphocyte ratio
(NLR) can serve as an alternative marker for predicting
carotid stenosis. NLR has already been used to predict
subclinical inflammation in patients with cancer7,8 or vas-
cular disease (including coronary artery disease and
stroke).9-13 Thus, NLR has been known as a prognostic
predictor of acute stroke,10-13 coronary artery disease,9 and
cancer.7,8 However, to the best of our knowledge, no study
has investigated the potential of NLR to predict carotid
stenosis in patients with stroke.
In the present study, we determined that the NLR can
serve as a predictive index for carotid stenosis by study-
ing the association between NLR and carotid artery IMT
in Korean patients with ischemic stroke.
Methods
Subjects and Data Collection
In the present study, we collected patient information
for the period from August 2008 to December 2014 at
Kyung Hee University Hospital and Kyung Hee Uni-
versity Korean Medicine Hospital. We selected 252 subjects
(133 men and 119 women) who met the following in-
clusion criteria: (1) patients with acute to subacute ischemic
stroke, (2) patients who underwent carotid ultrasonog-
raphy within 1 month of stroke onset, and (3) patients
who received a complete blood count (CBC) and differ-
ential blood count test at admission. Subjects with missing
data were excluded.
We retrospectively collected data from subjects medical
records including sex, age, and body mass index (BMI).
We also investigated the prevalence of hypertension, di-
abetes mellitus, dyslipidemia, and heart disease (including
coronary heart disease, cardiac valve disease, heart failure,
and arrhythmias) based on medical records. We ob-
tained the maximum IMT of both internal carotid arteries
from the carotid ultrasonography results and calculated
the NLR based on the CBC results.
We evaluated alcohol consumption by asking pa-
tients their consumption amount per drinking event and
weekly frequency of drinking during the previous 1-year
period. Subjects were asked on smoking status, includ-
ing how many packs of cigarettes they consume per day
and how long they have been smoking (pack-year).
Physical Measurements
BMI was calculated by dividing the body weight (kg)
by the height squared (m2).
CBC Measurements
CBC and differential counts were measured using an
ADVIA 2120i (Siemens, Munich, Germany). The NLR was
calculated by the following equation:
NLR = Neutrophil counts Lymphocyte counts
Internal Carotid Artery IMT Measurements
The IMT of both internal carotid arteries was mea-
sured. We measured the minimum and maximum IMT
in each internal carotid artery. Among the 4 IMT
values (minimum and maximum in each artery), we se-
lected the thickest as the maximum IMT of the carotid
artery.
Statistical Analysis
Data were analyzed by sex. We divided the
subjects into 2 groups according to the maximum IMT
values: the low IMT group (maximum IMT 1 mm) and
the high IMT group (maximum IMT > 1 mm). Baseline
characteristics (age, BMI, NLR, alcohol consumption, prev-
alence of risk factors) were compared between men and
women. Paired t-tests were performed for continuous
values and chi-square tests were performed for categor-
ical values. In the regression analysis, the dependent
variable was IMT. The analysis was adjusted for the
following confounding factors: age, BMI, NLR, smoking
history, alcohol consumption, and a medical history of
hypertension, diabetes mellitus, dyslipidemia, or heart
disease.
All statistical analyses were performed using SPSS
version 10.0 (SPSS Inc., Chicago, IL), and significance was
defined as a P value less than 0.05. The study protocol
conforms to the ethical guidelines of the 1975 Declara-
tion of Helsinki.
Results
Baseline Characteristics
The mean ages of the subjects were 65.91 11.00
(mean standard deviation) and 70.45 10.23 years for
men and women, respectively. The mean BMI was
23.98 2.93 kg/m2 for men and 22.95 3.20 kg/m2 for
women. The mean maximum IMT was 1.12 .43 mm for
men and 1.14 .52 mm for women. The mean NLR was
3.27 2.02 for men and 3.52 3.60 for women. The mean
smoking amount was 24.73 25.34 pack-years for men
and 1.25 5.86 pack-years for women. The mean alcohol
consumption was 2.57 3.95 for men and 0.13 0.62 for
women. The prevalences of hypertension, dyslipidemia,
 ARTICLE IN PRESS
ASSOCIATION OF NLR AND CAROTID STENOSIS 3
Table 1. Baseline characteristics

Men Women

Mean standard Mean standard

N deviation N deviation P value

Age (years) 133 65.91 11.00 119 70.45 10.23 .001

BMI (kg/m2) 133 23.98 2.93 119 22.95 3.20 .008
IMT (mm) 133 1.12 .43 119 1.14 .52 .736
Neutrophil-to-lymphocyte ratio 133 3.27 2.02 119 3.52 3.60 .489
Smoking (pack-year) 133 24.73 25.34 119 1.25 5.86 <.001
Alcohol consumption 133 2.57 3.95 119 .13 .62 <.001

N % N %

Hypertension .026
No 46 34.59 26 21.85
Yes 87 65.41 93 78.15
Dyslipidemia .392
No 38 28.57 28 23.53
Yes 95 71.43 91 76.47
Diabetes .896
No 85 63.91 75 63.03
Yes 48 36.09 44 36.97
Heart disease .287
No 108 81.20 90 75.63
Yes 25 18.80 29 24.37

Abbreviations: BMI, body mass index; IMT, intimamedia thickening.

P values were evaluated using the paired t-test (for continuous values) and the chi-square test (for categorical values). Bold means statis-
tically significant.
Alcohol consumption was calculated as: consumption amount of alcohol (Korean beverage SOJU 1 bottle) per event frequency of events
per week.

diabetes, and heart disease were 65.41%, 71.43%, 36.09%,
and 18.80% for men and 78.15%, 76.47%, 36.97%, and 24.37%
for women, respectively. There were significant differ-
ences in age, BMI, smoking status, alcohol consumption,
and hypertension prevalence between men and women.
This suggests that male and female study participants
had lifestyle differences that greatly influence atheroscle-
rosis including carotid artery atherosclerosis (Table 1).
Comparison of Baseline Characteristics between the
Low IMT Group and the High IMT Group
We divided the subjects into 2 groups according to the
maximum IMT values. There were statistically signifi-
cant differences between the 2 groups in age and NLR
for men and in age for women. In both male and female
patients, age and NLR values tended to increase with the
maximum IMT values (Table 2).
Multiple Linear Regression Model of the Maximum
IMT of the Carotid Artery in Men
Table 3 shows the results of multiple linear regres-
sion analyses of the associations between NLR and the
maximum IMT of the internal carotid artery. In men, after
adjusting for the confounding factors age, BMI, NLR,
smoking, alcohol consumption, hypertension, diabetes,
dyslipidemia, and heart disease, a significant positive as-
sociation was observed for age (P = 0.001) and NLR
(P < 0.001) (adjusted R2 = 0.185, root mean squared error
[MSE] = 0.152).
Multiple Linear Regression Model of the Maximum
IMT of the Carotid Artery in Women
In women, multiple linear regression analyses ad-
justed for the confounding factors age, BMI, NLR, smoking,
alcohol consumption, hypertension, diabetes, dyslipidemia,
and heart disease showed no significant positive asso-
ciations (adjusted R2 = 0.088, root MSE = 0.256).
Discussion
This study evaluated the associations between the NLR
and the maximum carotid IMT of both left and right carotid
arteries to examine the relationship between subclinical
inflammation and carotid artery stenosis in patients with
acute ischemic stroke. Our findings showed that the NLR
was significantly and positively associated with the
 ARTICLE IN PRESS
4 S. HYUN ET AL.
Table 2. Comparison between the low IMT group and the high IMT group

(A) Men Low IMT group (n = 67) High IMT group (n = 66) P value

Age 63.09 11.76 68.77 9.43 .003

BMI (kg/m2) 24.12 2.64 23.83 3.22 .572
Neutrophil-to-lymphocyte ratio 2.65 1.49 3.90 2.29 <.001
Smoking (pack-year) 24.10 23.73 25.36 27.05 .775
Alcohol consumption 3.10 4.59 2.04 3.11 .123
Prevalence of risk factor
Hypertension 42 (62.69%) 45 (68.18%) .585
Dyslipidemia 45 (67.16%) 50 (75.76%) .338
Diabetes mellitus 24 (32.82%) 24 (36.36%) 1.000
Heart disease 13 (19.40%) 12 (18.18%) 1.000

(B) Women Low IMT group (n = 58) High IMT group (n = 61) P value

Age 68.09 11.31 72.69 8.58 .013

BMI (kg/m2) 22.61 2.39 23.27 3.81 .262
Neutrophil-to-lymphocyte ratio 3.46 4.46 3.58 2.58 .854
Smoking (pack-year) .91 4.84 1.57 6.71 .536
Alcohol consumption .14 .57 .12 .67 .908
Prevalence of risk factor
Hypertension 43 (74.14%) 50 (81.97%) .376
Dyslipidemia 17 (29.31%) 27 (44.26%) .128
Diabetes mellitus 41 (70.69%) 50 (81.97%) .195
Heart disease 15 (25.86%) 14 (22.95%) .831

Abbreviations: BMI, body mass index; low IMT group, low intimamedia thickening group; high IMT group, high intimamedia thick-
ening group.
Low IMT group: IMT equal to or less than 1 mm calculated by carotid Doppler; high IMT group: IMT greater than 1 mm calculated by
carotid Doppler.
Alcohol consumption was calculated as: consumption amount of alcohol (Korean beverage SOJU 1 bottle) per event frequency of events
per week.
P values were obtained via paired t-test (continuous values) or chi-square test (categorical values). Bold means statistically significant.

maximum carotid IMT value in men. On the other hand,
the NLR was not significantly associated with the
maximum carotid IMT value in women.
NLR is a marker of subclinical inflammation. Cur-
rently, it is used as a predictor of cardiovascular disease,9
cancer,7,8 and cerebrovascular disease. Previous studies have
suggested NLR as a simple and useful predictor of short-
term prognosis in patients with acute stroke or transient
ischemic attack .10-13 For example, when 151 patients with
a first acute ischemic stroke were monitored over the 30
days following their stroke, both the NLR and infarct
volume of the nonsurviving group were significantly higher
than the corresponding values in the surviving group.13
Another study compared NLR, white blood cell count,
C-reactive protein, gamma-glutamyltransferase, homo-
cysteine, and mean platelet volume values between 70
patients with first-ever atherothrombotic acute ischemic
stroke and 70 healthy subjects. The results showed sig-
nificantly higher white blood cell count, C-reactive protein,
homocysteine, and NLR values in patients than in con-
trols. Moreover, the white blood cell count and NLR values
were significantly higher in dead patients. On the basis
of these results, this previous study suggests NLR as a
simple, inexpensive, and readily available prognostic marker
for acute ischemic stroke.12 However, no previous studies
focused on the relationship between NLR and carotid ath-
erosclerosis in patients with stroke.
To assess the potential of NLR as a predictor of carotid
atherosclerosis in patients with ischemic stroke, we focused
on differences in carotid IMT progression between men
and women. A previous genome-wide interaction study
suggested that multiple loci may modulate sex differ-
ences in carotid IMT. In addition, genetic variants of the
LEKR1 and GALNT10 genes have been associated with
the control of adiposity and weight.14 Another previous
study suggested that there are age and sex differences
in the effect of parental stroke on the progression of carotid
IMT. In that study, parental stroke was associated with
carotid artery IMT progression, and this was more obvious
in the young, especially among women.15 Furthermore,
a previous study suggested that sex hormones (estra-
diol and dehydroepiandrosterone) are significantly
associated with adiposity and that the association of an-
drogens differs qualitatively by sex.16 As a result, women
and men have significantly different lipid, apoprotein, and
lipoprotein values,17 and women have higher apolipoprotein
 ARTICLE IN PRESS
ASSOCIATION OF NLR AND CAROTID STENOSIS 5
Table 3. Results of multiple linear regression for IMT of the carotid artery

Men Women

Standard Adjusted Root Standard Adjusted Root

Estimate error P value R2 MSE Estimate error P value R2 MSE

.185 .152 .088 .256

Age .012 .003 .001 .014 .005 .005
BMI .009 .013 .063 .008 .015 .586
Neutrophil-to-lymphocyte .071 .018 <.001 .005 .013 .691
ratio
Smoking (pack-year) .002 .001 .221 .004 .010 .702
Alcohol consumption .008 .009 .362 .002 .094 .983
Prevalence of risk factor
Hypertension .045 .076 .559 .010 .117 .934
Dyslipidemia .077 .077 .319 .152 .114 .184
Diabetes mellitus .047 .072 .513 .200 .101 .050
Heart disease .148 .093 .116 .067 .110 .542

Abbreviations: BMI, body mass index; IMT, intimamedia thickening; R2, root-square; MSE, mean squared error.
Alcohol consumption was calculated as follows: consumption amount of alcohol (Korean beverage SOJU 1 bottle) per event frequency
of events per week.
Hypertension, dyslipidemia, diabetes mellitus, and heart disease refer to having a medical history of each disease.
P values were evaluated using the multiple linear regression test (age, BMI, neutrophil-to-lymphocyte ratio, smoking, and alcohol con-
sumption were treated as continuous values and hypertension, dyslipidemia, diabetes mellitus, and heart disease were treated as categorical
values). Bold means statistically significant.

A-I production rates than men.18 Although there was no
statistical difference in the baseline data of men and women
in this study, we decided to analyze each sex separately
to reflect the above phenomenon.
The present study has the following strengths. In this
study, we confirmed that NLR can be a predictor of the
degree of carotid artery atherosclerosis in male patients
with stroke, which has not been previously reported. A
previous review study noted the following circulating in-
flammatory biomarkers as having a relationship with
carotid artery stenosis due to atherosclerosis: fibrino-
gen, TNF-, IL 1, IL-6, IL-10, anticytomegalovirus IgG
antibody titer, high-sensitivity C-reactive protein (hs-
CRP), serum levels of vascular cell adhesion molecule-1
(sVCAM-1), S100A8, S100A9, S100A12, the apolipoprotein
B/A1 ratio, oxidized low-density lipoprotein (OxLDL),
homeostatic model assessment (HOMA) insulin resis-
tance, baseline conjugated dienes-low density lipoprotein
(BCD-LDL), L-selectin, E-selectin, neopterin, matrix
metalloproteinase-1 (MMP-1), MMP-2, MMP-3, MMP-7,
MMP-8, MMP-9, tissue inhibitor of metalloproteinase-1
(TIMP-1), TIMP-2, CD19 + CD40 + and CD19 + CD86 + B
cell counts, etc.6 Although many biomarkers are associ-
ated with carotid atherosclerosis, their assessment is both
costly and complicated. However, assessing NLR is easier
than assessing other inflammatory biomarkers. Further-
more, the NLR equation is simple. Therefore, we consider
NLR to be a potentially useful marker for predicting the
degree of carotid atherosclerosis in male patients with
stroke.
The limitations of this study are as follows. First, as
this was a retrospective study using data from one hos-
pital, we cannot make a concrete conclusion to support
our hypothesis. Second, there was a relatively small number
of subjects. Thus, association of NLR and carotid IMT
will require further evaluation in an additional future large-
scale prospective study.
Conclusions
We suggest that NLR can serve as a clinically signif-
icant predictor of the degree of carotid stenosis in male
patients with ischemic stroke. However, additional large-
scale studies will be required to evaluate the optimal cut-
off values of NLR for determining the degree of carotid
atherosclerosis.
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