Journal of Clinical Laboratory Analysis 00: 16 (2016)

Atrial Fibrillation is Strongly Associated With the Neutrophil to

Lymphocyte Ratio in Acute Ischemic Stroke Patients: A
Retrospective Study
Kyungdong Min,1 Seungwon Kwon,1* Seung-Yeon Cho,1 Woo Jun Choi,2
Seong-Uk Park,1 Woo-Sang Jung,1 Sang-Kwan Moon,1 Jung-Mi Park,1
Chang-Nam Ko,1 and Ki-Ho Cho1
1
Department of Cardiology and Neurology, College of Korean Medicine, Kyung Hee
University, Seoul, Korea
2
Department of Korean Medicine Cardiology and Neurology, Graduate School, Kyung Hee
University, Seoul, Korea

Background: No study has investigated brillation, other heart diseases, CE and

the relationship between hospital-admis-
sion neutrophil and lymphocyte ratio
(NLR) and various stroke risk factors. We
sought to determine which stroke risk fac-
tor could be the most appropriate predictor
of NLR in acute ischemic stroke. Meth-
ods: We collected data on various stroke
risk factors and National Institutes of
Health Stroke Scale (NIHSS) score in
1,053 acute ischemic stroke patients. The
regression analysis was adjusted for con-
founding factors such as stroke risk fac-
tors. Results: There was a trend of
increased NLR with a rise in alcohol con-
sumption, the prevalence of hypertension,
cardioembolism (CE) etiology, the NIHSS
scores in men and the prevalence of atrial
Key words: acute ischemic stroke; atrial brillation; diabetes mellitus; neutrophil to
lymphocyte ratio; stroke prognosis
small vessel occlusion etiology and the
NIHSS scores in women. Multiple linear
regression analyses, adjusted for con-
founding factors, showed that the atrial b-
rillation and NIHSS scores in men and
atrial brillation, diabetes mellitus as well
as NIHSS scores in women had a signi-
cant positive association with NLR. How-
ever, a negative association was showed
for body mass index (BMI). Conclusion:
We conrmed that the atrial brillation can
be a predictor of high NLR in acute stroke
patients, and diabetes mellitus as well
as low BMI could be a predictor of high
NLR in female acute ischemic stroke
patients. J. Clin. Lab. Anal. 00:16,
2016. 2016 Wiley Periodicals, Inc.

inexpensive and simple, NLR could be a suitable mar-

INTRODUCTION
The neutrophil to lymphocyte ratio (NLR) is an
important measure of systemic inflammation that has
been used as a marker of subclinical inflammation.
Recently, NLR has been used to predict the prognosis
of cerebrovascular disease, including ischemic stroke
and transient ischemic attack (TIA; 16). Previous
studies have suggested that a higher NLR in acute
ischemic stroke patients is associated with increased
short-term mortality (2), poor prognosis (1, 35), and
a poor 90-day outcome after endovascular stroke ther-
apy (6). In a clinical setting, most hospitals conduct a
complete blood cell count (CBC) and differential
blood count test. Furthermore, as this test is
ker for detecting the prognosis of acute ischemic
stroke.
However, to the best of our knowledge, no study
has previously investigated the relationship between
hospital-admission NLR and various stroke risk fac-
tors. We hypothesized that some of the ischemic stroke
*Correspondence to: Seungwon Kwon, Department of Cardiology
and Neurology, College of Korean Medicine, Kyung Hee University,
1 Hoegi-dong, Dongdaemun-gu, Seoul 02447, Korea. E-mail:
kkokkottung@hanmail.net
Received 10 April 2016; Accepted 9 July 2016
DOI 10.1002/jcla.22041
Published online in Wiley Online Library (wileyonlinelibrary.com).

2016 Wiley Periodicals, Inc.

2 Min et al.
risk factors could play a role in elevating NLR in
acute ischemic stroke patients. Furthermore, it could
be another predictor for the prognosis of acute
ischemic stroke. Therefore, in this study, we sought to
determine which stroke risk factor could be the most
appropriate predictor of NLR in acute ischemic
stroke.
METHODS
Subjects and Data Collection
In the present study, we collected patient informa-
tion from January 2010 to September 2015 at Kyung
Hee University Korean Medicine Hospital. We
selected 1,053 subjects (576 men and 477 women) who
met the following inclusion criteria: (1) acute ischemic
stroke patients who were admitted to the hospital
within 7 days from onset, (2) patients who received a
CBC and differential 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), current smoking, alcohol consumption
and National Institutes of Health Stroke Scale
(NIHSS) score. We also investigated the prevalence of
ischemic stroke risk factors, such as hypertension, dia-
betes mellitus, dyslipidemia, atrial fibrillation, other
heart diseases (including coronary heart disease, cardiac
valve disease, and heart failure, etc.), previous stroke
(frequency), family history of stroke, carotid artery
stenosis, and cerebral artery stenosis based on medical
records. Etiologies of ischemic stroke based on the Trial
of Org 10172 in Acute Stroke Treatment classification
of the stroke (7, 8) were investigated. We calculated the
NLR based on the CBC results at admission.
We evaluated alcohol consumption by asking
patients about their consumption amount per drinking
event and weekly frequency of drinking during the pre-
vious year. Through these answers, we categorized
alcohol consumption state as follows: no drink, mod-
erate, heavy, and binge drinker based on the Drinking
Levels of the National Institute on Alcohol Abuse and
Alcoholism. Subjects were also questioned regarding
smoking status and asked to provide information on
the number of packs per day and the smoking dura-
tion (pack-year (pack-yr)).
The prevalence of hypertension, dyslipidemia, and
diabetes mellitus were defined by the presence of med-
ication for each diseases or a medical doctors diag-
nosis. The prevalence of atrial fibrillation was defined
via the presence of atrial fibrillation in 12-lead elec-
trocardiography, 24-hr holter electrocardiography, or
J. Clin. Lab. Anal.
echocardiography. Other heart diseases were defined
through the presence of medication related to those
diseases and abnormal findings in the 12-lead electro-
cardiography, 24-hr holter electrocardiography, or
echocardiography. Carotid artery and cerebral artery
stenosis were defined by relevant findings (more than
50% stenosis) in magnetic resonance angiography,
computed tomography angiography, transfemoral
cerebral angiography, carotid duplex ultrasonography
or transcranial Doppler sonography.
Physical Measurements
BMI was calculated by dividing the body weight
(kg) by the height squared (m2).
Complete Blood Count Measurements
CBC and differential counts were measured using an
ADVIA2120i (Siemens, Munich, Germany). The
NLR was calculated by the following equation:
NLR Neutrophil counts/Lymphocyte counts:
Statistical Analysis
All analyses were performed independently for each
sex. We also divided subjects into two groups accord-
ing to their NLR values: the low NLR group
(NLR 2.5538, which was the median value of NLR
in this study) and the high NLR group
(NLR > 2.5538). Baseline characteristics (age, BMI,
NIHSS score, NLR date from onset in days), current
smoking, alcohol consumption, and prevalence of risk
factors) were compared between men and women.
Paired t-tests were performed for continuous values
and chi-square tests were performed for categorical
values. In the regression analysis, NLR was the depen-
dent variable. We remove the variables without statis-
tical significance in a stepwise fashion until the
adjusted R2 reached the highest value. The analysis
was adjusted for the following confounding factors:
NIHSS score, current smoking history, alcohol con-
sumption, and a medical history of atrial fibrillation,
dyslipidemia, or other heart diseases in men; NIHSS
score, age, BMI, and a medical history of atrial fibril-
lation, diabetes mellitus, or carotid artery stenosis in
women.
All statistical analyses were performed using SPSS
version 10.0 (SPSS Inc., Chicago, IL, USA), and sig-
nificance was defined as a P-value < 0.05. The study
protocol conforms to the ethical guidelines of the 1975
Declaration of Helsinki.
 Association of NLR and Atrial Fibrillation 3

RESULTS NLR, smoking status, alcohol consumption, hyperten-

Baseline Characteristics
Subject were a mean age of 65.69  11.86
(mean  SD) and 70.08  10.66 years old for men
and women, respectively. The mean BMI was
23.89  2.90 kg/m2 for men and 23.64  3.45 kg/m2
for women. The mean NLR was 3.49  3.60 for men
and 3.09  2.40 for women. The most frequent etiol-
ogy of ischemic stroke was small vessel occlusion
(SVO) in both sexes. The mean amount of smoking
was 17.29  23.25 pack-yr for men and 1.72  8.54
pack-yr for women. The alcohol consumption was as
follows: 21.9% moderate, 32.8% heavy, 4.3% binge
for men and 12.2% moderate, 4.4% heavy, 0.0% binge
for women. There were significant differences in age,
sion, dyslipidemia, and other heart diseases prevalence
between men and women. Taken together, this sug-
gests that male and female study participants have dra-
matic lifestyle differences that greatly influence the
occurrence of ischemic stroke (Table 1).
Comparison of Baseline Characteristics Between
the Low NLR Group and High NLR Group
We divided the subjects into two groups according
to the median NLR value (2.5538). There were statisti-
cally significant differences between the two groups in
the amount of alcohol consumption, prevalence of
hypertension, etiology of cardioembolism (CE) and
NIHSS scores for men and in BMI, prevalence of

TABLE 1. Baseline Characteristics

Men Women

N Mean  SD N Mean  SD P-value

Age (years) 576 65.69  11.86 477 70.08  10.66 <0.001

BMI (kg/m2) 576 23.89  2.90 477 23.64  3.45 0.186
NIHSS 576 4.52  2.71 477 4.61  2.82 0.602
NLR 576 3.49  3.60 477 3.09  2.40 0.040
NLR date from on set (days) 576 1.94  11.68 477 2.40  2.13 0.394
Smoking (pack-yr) 576 17.29  23.25 477 1.72  8.54 <0.001

N % N %

Ischemic stroke type (TOAST)

LAA 142 24.7 93 19.5 0.053
SVO 366 63.5 336 70.4 0.018
CE 32 5.6 21 4.4 0.479
SOE 2 0.3 3 0.6 0.663
SUE 33 5.7 23 4.8 0.582
Hypertension 373 64.8 362 75.9 <0.001
Dyslipidemia 241 41.8 247 51.8 0.001
Diabetes 184 31.9 161 33.8 0.553
Atrial fibrillation 41 7.1 40 8.4 0.486
Other heart diseases 22 3.8 36 7.5 0.010
Previous stroke 0.348
No 416 72.2 355 74.4
One time 151 26.2 118 23.3
Two times 6 1.0 8 1.7
Three times 1 0.2 3 0.6
Family history of stroke 142 24.7 105 22.0 0.342
Carotid artery stenosis 301 52.3 244 51.2 0.710
Cerebral artery stenosis 262 45.5 227 47.6 0.535
Alcohol consumption <0.001
No 236 41.0 398 83.4
Moderate 126 21.9 58 12.2
Heavy 189 32.8 21 4.4
Binge 25 4.3 0 0.0

P-values were evaluated using the paired t-test (for continuous values) and the chi-square test (for categorical values).
Bold values mean the significance of P-value (<0.05).
BMI, body mass index; NIHSS, National Institutes of Health Stroke Scale; NLR, neutrophil to lymphocyte ratio; TOAST: Trial of Org
10172 in Acute Stroke Treatment; LAA, large artery atherosclerosis; CE, cardioembolism; SVO, small vessel occlusion; SOE, stroke of other
determined etiology; SUE, stroke of undetermined etiology; pack-yr, pack-year.

J. Clin. Lab. Anal.

4 Min et al.

TABLE 2. Comparison Between the Low NLR Group and High NLR Group
(A) Men Low NLR group (n = 273) High NLR group (n = 303) P-value

Age 65.14  11.16 66.18  12.46 0.288

BMI (kg/m2) 23.89  2.89 23.90  2.91 0.937
Neutrophil/lymphocyte ratio 1.87  0.45 4.95  4.47 <0.001
Smoking (pack-yr) 18.61  24.35 16.08  22.16 0.199
Current smoking (yes/no) 107 (39.2%) 95 (31.4%) 0.054
Alcohol consumption (yes/no) 177 (64.84%) 166 (54.79%) 0.017
Previous stroke 0.449
One time 66 (24.26%) 85 (28.15%)
Two times 2 (0.74%) 4 (1.32%)
Three times 0 (0%) 1 (0.33%)
Prevalence of risk factor
Hypertension 161 (58.97%) 212 (66.97%) 0.007
Dyslipidemia 124 (45.42%) 117 (38.61%) 0.108
Diabetes mellitus 86 (31.50%) 98 (32.34%) 0.858
Atrial fibrillation 15 (5.49%) 26 (8.58%) 0.194
Carotid artery stenosis 149 (54.58%) 152 (50.33%) 0.317
Cerebral artery stenosis 116 (42.49%) 146 (49.17%) 0.181
Other heart diseases 6 (2.20%) 16 (5.28%) 0.080
Stroke family history 75 (27.47%) 67 (22.11%) 0.147
Ischemic stroke type (TOAST)
LAA 65 (23.8%) 77 (25.%4) 0.699
SVO 182 (66.7%) 184 (60.7%) 0.142
CE 8 (2.9%) 24 (7.9%) 0.010
SOE 8 (2.9%) 24 (7.9%) 0.224
SUE 15 (5.5%) 18 (5.9%) 0.859
NIHSS 4.15  2.31 4.86  2.98 0.002

(B) Women Low NLR group (n = 253) High NLR group (n = 224) P-value

Age 69.20  10.07 71.08  11.24 0.054

BMI (kg/m2) 23.95  3.15 23.28  3.74 0.036
Neutrophil/lymphocyte ratio 1.72  0.47 4.64  2.75 <0.001
Smoking (pack-yr) 1.65  8.24 1.80  8.89 0.853
Current smoking (yes/no) 19 (7.51%) 12 (5.36%) 0.359
Alcohol consumption (yes/no) 42 (16.60%) 38 (16.96%) 1.000
Previous stroke 0.751
One time 57 (22.53%) 54 (24.11%)
Two times 3 (1.19%) 5 (2.23%)
Three times 2 (0.79%) 1 (0.45%)
Prevalence of risk factor
Hypertension 192 (75.89%) 170 (75.89%) 0.642
Dyslipidemia 134 (53.17%) 113 (50.45%) 0.582
Diabetes mellitus 83 (32.81%) 78 (34.82%) 0.698
Atrial fibrillation 10 (3.95%) 30 (13.39%) <0.001
Carotid artery stenosis 127 (50.20%) 117 (52.23%) 0.714
Cerebral artery stenosis 115 (45.45%) 112 (50.00%) 0.358
Other heart diseases 13 (5.14%) 23 (10.27%) 0.038
Stroke family history 59 (23.32%) 46 (20.54%) 0.507
Ischemic stroke type (TOAST)
LAA 45 (17.8%) 48 (21.4%) 0.355
SVO 191 (75.5%) 145 (64.7%) 0.012
CE 6 (2.4%) 15 (6.7%) 0.025
SOE 0 (0%) 3 (1.3%) 0.103
SUE 11 (4.3%) 12 (5.4%) 0.671
NIHSS 4.15  2.55 5.14  3.02 <0.001

Low NLR group: NLR 2.5538 which is a median value of NLR, high NLR group: NLR > 2.5538. P-values were obtained via the paired
t-test (continuous values) or chi-square test (categorical values).
Low NLR group, low neutrophil to lymphocyte ratio group; high IMT group, high neutrophil to lymphocyte ratio group; BMI, body mass index;
TOAST, Trial of Org 10172 in Acute Stroke Treatment; LAA, large artery atherosclerosis; CE, cardioembolism; SVO, small vessel occlusion; SOE,
stroke of other determined etiology; SUE, stroke of undetermined etiology; NIHSS, National Institutes of Health Stroke Scale; pack-yr, pack-year.

J. Clin. Lab. Anal.

 Association of NLR and Atrial Fibrillation 5

atrial fibrillation, other heart diseases, etiology of CE
and SVO and NIHSS scores for women. Alcohol con-
sumption, prevalence of hypertension, NIHSS scores
in men and prevalence of atrial fibrillation, other heart
diseases, NIHSS scores in women tended to increase
with the NLR. In contrast, BMI in women tended to
decrease with the NLR (Table 2).
Multiple Linear Regression Model of the NLR in Men
Table 3 shows the results of the multiple linear
regression analyses of NLR and the baseline character-
istics (prevalence of risk factors of stroke, age, NIHSS,
etc.). In men, after adjusting for the confounding fac-
tors, such as smoking, alcohol consumption, atrial fib-
rillation, dyslipidemia, other heart diseases, and
NIHSS, a significant positive association was observed
for atrial fibrillation (P = 0.008) and NIHSS scores
(P = 0.018) (adjusted R2 = 0.031, root mean squared
error [MSE] = 7016.13).
Multiple Linear Regression Model of the NLR in
Women
In women, multiple linear regression analyses for the
confounding factors, such as age, BMI, atrial fibrillation,
diabetes mellitus, carotid artery stenosis, and NIHSS,
showed a significant positive association for atrial fibril-
lation (P = 0.002), diabetes mellitus (P = 0.037), and
NIHSS scores (P = 0.002) (Table 4). At the same time, a
negative association was found for BMI (P = 0.049)
(adjusted R2 = 0.031, root MSE = 7016.13).
DISCUSSION
NLR is currently used as a predictor of prognosis
for cardiovascular disease (9), cancer (10, 11), and
stroke and TIA (16). As a result of its simplicity and
inexpensive costs, previous studies have suggested that
NLR could be an effective prognostic marker for acute
ischemic stroke, cardiovascular disease, and cancer.
Furthermore, NLR has been proven as a useful mar-
ker for the severity of carotid artery stenosis (12, 13)
in acute stroke patients and the risk of stroke in
patients with atrial fibrillation (14, 15). However, no
previous study has focused on the relationship between
NLR and various stroke risk factors, which are found
in acute stroke patients. Therefore, the present study
aimed to assess the relationship between NLR and
ischemic stroke risk factors.
This study evaluated the association between NLR
and the prevalence of stroke risk factors as well as
NIHSS, in order to examine the relationship between
subclinical inflammation and the various characteris-
tics of acute ischemic stroke patients. Through this
study, we sought to identify which risk factors could
be the most appropriate predictor of NLR and the
prognosis of acute ischemic stroke. Our findings show

TABLE 3. Results of Multiple Linear Regression for NLR in

Men Acute Ischemic Stroke Patients TABLE 4. Results of Multiple Linear Regression for NLR in
Women Acute Ischemic Stroke Patients
Men
Men
Adjusted Root
Estimate SE P-value R2 MSE Adjusted Root
Estimate SE P-value R2 MSE
0.031 7,016.13
Current smoking 0.326 0.327 0.319 0.066 2525.629
Alcohol 0.444 0.321 0.168 Age 0.016 0.010 0.120
consumption BMI 0.63 0.032 0.049
(yes/no) Prevalence of risk factor
Prevalence of risk factor Atrial 1.251 0.396 0.002
Atrial 1.611 0.602 0.008 fibrillation
fibrillation Diabetes 0.475 0.230 0.037
Dyslipidemia 0.384 0.312 0.219 mellitus
Other heart 0.774 0.803 0.335 Carotid 0.183 0.220 0.407
diseases stenosis
NIHSS 0.137 0.057 0.018 NIHSS 0.123 0.039 0.002

Atrial fibrillation, dyslipidemia, and other heart diseases refer to having
a medical history of each disease. P-values were evaluated using the mul-
tiple linear regression test (NIHSS was treated as continuous values and
current smoking, alcohol consumption, atrial fibrillation, dyslipidemia,
and other heart diseases were treated as categorical values).
NLR, neutrophil to lymphocyte ratio; NIHSS, National Institutes of
Health Stroke Scale; R2, root-square; root MSE, root mean squared
error.
Atrial fibrillation, diabetes mellitus, and carotid stenosis refer to hav-
ing a medical history of each disease. P-values were evaluated using
the multiple linear regression test (age, BMI, and NIHSS were trea-
ted as continuous values and atrial fibrillation, diabetes mellitus, and
carotid stenosis were treated as categorical values).
NLR, neutrophil to lymphocyte ratio; BMI, body mass index;
NIHSS, National Institutes of Health Stroke Scale; R2, root-square;
root MSE, root mean squared error.

J. Clin. Lab. Anal.

6 Min et al.
that NLR was significantly and positively associated
with the prevalence of atrial fibrillation and severity of
neurological symptoms (NIHSS scores) in men. Fur-
thermore, NLR was significantly and positively associ-
ated with the prevalence of atrial fibrillation, diabetes
mellitus, and severity of neurological symptoms
(NIHSS scores) in women. On the other hand, in
women, NLR was significantly and negatively associ-
ated with BMI. Furthermore, in this study, we con-
firmed that atrial fibrillation can be a predictor of a
high NLR value in acute stroke patients, and that the
prevalence of diabetes mellitus as well as a low BMI
could be a predictor of high NLR value in female
acute ischemic stroke patients.
We also found that the prevalence of atrial fibrilla-
tion has a significant and positive association with
NLR in both sexes. In previous studies, atrial fibrilla-
tion has been shown to have a strong relationship with
systematic inflammation and inflammation has been
further suggested to play a vital role in the pathogene-
sis of atrial fibrillation. For example, the inflammatory
response after cardiac surgery has been a proven pre-
dictor of postoperative atrial fibrillation (16). Increased
levels of plasma neopterin, which is synthesized by
human macrophages upon stimulation with the cyto-
kine interferon-gamma, is indicative of a pro-inflam-
matory immune status observed in patients with
persistent atrial fibrillation (17). Monocyte toll-like
receptor-4 expression was also an independent predic-
tor of atrial fibrillation recurrence (18). Moreover,
another study suggests that increased M1 macrophage
infiltration is associated with thrombogenesis in rheu-
matic mitral stenosis patients with atrial fibrillation
(19). We believe that these previous findings are in
agreement with the results of the present study. Fur-
thermore, we assumed that a persistent subclinical
inflammatory state among patients with atrial fibrilla-
tion would affect the severity of the inflammatory
response in acute ischemic stroke and negatively affect
the prognosis of acute ischemic stroke.
The limitations of this study are as follows. First, as
this was a retrospective study using data from a single
hospital, we cannot make a concrete conclusion in sup-
port of our hypothesis. Second, the number of subjects
was relatively small. Thus, further evaluation in an addi-
tional future large-scale prospective study is required.
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