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Archives of Gerontology and Geriatrics 61 (2015) 7275

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Archives of Gerontology and Geriatrics


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Association between red blood cell distribution width (RDW)


and carotid artery atherosclerosis (CAS) in patients
with primary ischemic stroke
He Jia a,*, Huimian Li a, Yan Zhang b, Che Li c, Yingyun Hu d, Chunfang Xia e
a
Department of Geriatrics, the Second Afliated Hospital of ZhengZhou University, Zhengzhou, Henan Province 474500, China
b
Department of Pathology, the Second Afliated Hospital of Zhengzhou University, Zhengzhou, Henan Province 474500, China
c
Department of Epidemiology and Health Statistics, School of Public Health, Zhengzhou University, Zhengzhou, Henan Province 450001, China
d
Hunan Provincial Tumor Hospital, Changsha, Hunan Province 410013, China
e
Department of Oncology, The Second Xiangya Hospital of Central South University, Changsha, Hunan Province 410011, China

A R T I C L E I N F O A B S T R A C T

Article history: Background: The present study aimed to explore the association between RDW and CAS in patients with
Received 17 February 2015 ischemic stroke, expecting to nd a new and signicant diagnosis index for clinical practice.
Received in revised form 9 April 2015 Methods: This cross-sectional study involves 432 consecutive patients with primary ischemic stroke
Accepted 10 April 2015
(within 72 h). All subjects were conrmed by magnetic resonance imaging, and underwent physical
Available online 20 April 2015
examination, laboratory tests and carotid ultrasonography check. Finally, 392 patients were included
according to the exclusion criteria. The odds ratios of independent variables were calculated using
Keywords:
stepwise multiple logistic regression.
Red cell blood distribution width
Carotid artery atherosclerosis
Results: Carotid intimal-medial thickness (IMT) and RDW are both signicantly different between CAS
Ischemic stroke group and control group. Univariate analyses show that high-sensitive C-reactive protein (Hs-CRP) and
RDW (r = 0.436) are both in signicantly positive association with IMT. Stepwise multiple logistic
regression shows that RDW is an independent protective factor of CAS in patients with ischemic stroke.
Compared with the lowest quartile, the second to fourth quartiles are 1.13 (95% CI: 1.133.05), 2.02 (95%
CI: 1.664.67), and 3.10 (95% CI: 2.467.65), respectively.
Conclusion: The present study suggested that RDW level were higher than non-CAS in patients with
primary ischemic stroke. Our results facilitated a bridge to connect RDW with ischemic stroke and
further conrmed the role of RDW in the progression of the ischemic stroke.
2015 Elsevier Ireland Ltd. All rights reserved.

1. Introduction association with inammatory status (Lappe et al., 2011), growing


attention has been paid to RDW in various elds.
RDW is an index of blood routine examination. It is usually used Ultrasound examination of carotid IMT and carotid plaque is
for the diagnosis of different types of anemia. RDW is recently widely used in quantication of atherosclerosis, evaluation of
suggested as an important factor of adverse events in the general future risk of stroke, and as surrogate endpoints for clinical
population (Perlstein, Weuve, Pfeffer & Beckamn, 2009; Patel, diseases. Carotid plaque and IMT are associated with subclinical
Ferrucci, Ershler, Longo & Guralnik, 2009). RDW is also associated atherosclerosis, a risk factor of cerebral infarction or ischemic
with many clinical outcomes of cardiovascular events, such as stroke (Everson-Rose et al., 2014; Savoiu et al., 2009). CAS is
early-stage renal function damage and CAS in hypertensive signicantly related with inammatory response of the vascular
patients (Li, Chen, Yuan, Zhou & Kuang, 2014; Wen, 2010), acute endothelial injury, while RDW is also involved in the process of
myocardial infarction (Sangoi et al., 2014; Sun et al., 2014) and inammation (Almer et al., 2013). Therefore, RDW might be
heart failure (Shao, Li, Li & Liu, 2015). Since the conrmation of its associated with CAS, which has never been studied in patients with
ischemic stroke. Identication of early risk factors is greatly
important for diseases such as stroke, which is featured with high
rates of mortality and stroke-induced disability. The present study
* Corresponding author. Tel.: +86 0371 63620507; fax: +86 0371 63620507.
E-mail address: jiahezz1975@126.com (H. Jia). aims to explore the relationship between RDW and CAS in patients

http://dx.doi.org/10.1016/j.archger.2015.04.005
0167-4943/ 2015 Elsevier Ireland Ltd. All rights reserved.
H. Jia et al. / Archives of Gerontology and Geriatrics 61 (2015) 7275 73

with ischemic stroke, expecting to nd a new signicant diagnosis Distributional normality of each continuous variable was assessed by
index for clinical practice. the KolmogorovSmirnov test. Between-group differences were
tested by Students t-test or Chi-square test, as appropriate.
2. Methods Correlation coefcients between IMT and other variables were
calculated with Pearsons or Spearmans test, as appropriate. Odds
2.1. Study population ratios (ORs) were computed with multiple logistic regressions.
Collinearity diagnostics within variables was applied before the
In this cross-sectional study, totally 432 consecutive patients regression model was built. Statistical analyses were performed on
with primary ischemic stroke were recruited from the Second SPSS 18.0 (SPSS Inc., Chicago, IL, USA), with the signicance level at
Afliated Hospital of Zhengzhou University from November 2013 P < 0.05.
and October 2014. All subjects were conrmed by magnetic
resonance imaging (MRI), and underwent physical examination,
laboratory tests and carotid ultrasonography check. The exclusion 3. Results
criteria are as follows: (1) history of ischemic stroke; (2)
hemorrhagic stroke, mixed stroke or adenomas apoplexy; (3) 3.1. Baseline characteristics of subjects
second stroke due to other factors (e.g. surgery); (4) severe renal
function impairment, gout, diabetic ketoacidosis, coronary bypass The baseline characteristics are shown in Table 1. Totally 180
surgery or angioplasty; and (5) incapability of communication due CAS patients and 212 non-CAS patients were nally included. The
to severe stroke. According to the above criteria, 40 patients were patients were aged from 60 to 70 years old. The sex ratios were
excluded and 392 patients were included. The study protocol was comparable between groups. IMTs and RDWs are both signicantly
approved by the Ethics Committee at Southern Medical School of different between groups (both P < 0.001). Compared with the
Zhengzhou University. control group, the CAS group tended to be smokers, hypertensive
and higher levels in BMI, waist circumference, SBP, DBP,
2.2. Physical and laboratory examinations triglyceride, total cholesterol, 2hPG, serum creatinine, uric acid,
blood urea nitrogen, Hs-CRP, WBC and hemoglobin (P < 0.05).
The patients demographic characteristics including age, sex, There is no difference in other variables between groups (P > 0.05).
height, weight, waist circumference, alcohol use and smoking The results were shown in Table 1.
status were acquired through a standardized questionnaire.
Smoking was dened as at least one cigarette daily for 1 year 3.2. Univariate analyses
and drinking was dened as at least 50 g of alcohol daily for 1 year.
Body mass index (BMI) was calculated as weight (kg) divided by In the whole study population, HDL-cholesterol is negatively
height squared (m2). associated with IMT. IMT is positively and signicantly associated
Hypertension was dened as systolic blood pressure (SBP)  with BMI, smoking status, SBP, triglyceride, serum creatinine, uric
140 mmHg and (or) diastolic blood pressure (DBP)  90 mmHg
(Chobanian et al., 2003). Diabetes was determined through self-
Table 1
reporting with a validated history or through new diagnosis by an oral Clinical characteristics of ischemic stroke patients with and without CAS.
glucose tolerance test (WHO: fasting plasma glucose  7.0 mmol/L, or
Parameters Carotid artery atherosclerosis P
2-h postprandial glucose  11.1 mmol/L (Kuzuya et al., 2002).
Coronary artery disease was diagnosed from history of myocardial No (n = 212) Yes (n = 180)
infarction or more than 75% narrowing of coronary artery. Age (year) 65.9  10.2 64.8  9.8 0.279
Blood routine indices including red blood cell (RBC) count, Sex (male) 107 (50.5%) 94 (52.2%) 0.729
white blood cell (WBC) count, platelet count, hemoglobin count, Smoking (yes) 47 (22.2%) 61 (33.9%) 0.009
Drinking history (yes) 21 (9.9%) 27 (15.0%) 0.125
RDW and mean corpuscular volume were tested using an
Hypertension (yes) 84 (39.6%) 94 (52.2%) 0.013
automated biochemical analyzer. Serum creatinine level, plasma Coronary artery disease (yes) 25 (11.6%) 19 (10.6%) 0.699
glucose level, serum lipid status (total cholesterol, low- and high- Diabetes mellitus (yes) 28 (13.2%) 26 (14.4%) 0.723
density lipoprotein and triglyceride) and inammatory factors (e.g. Body mass index (kg/m2) 25.8  2.8 26.6  2.5 0.003
high-sensitive C-reactive protein, Hs-CRP) were also determined. Waist circumference (cm) 88.3  8.0 91.4  8.2 <0.001
Systolic blood pressure 138.8  9.3 141.8  10.5 0.003
(mmHg)
2.3. Carotid ultrasonography Diastolic blood pressure 78.5  10.6 80.8  11.2 0.037
(mmHg)
Carotid ultrasonography on each subject was performed by a Triglyceride (mmol/dL) 1.4  0.5 1.7  0.5 <0.001
HDL-cholesterol (mmol/dL) 1.1  0.2 1.0  0.2 <0.001
single sonographer with a commercial machine (ALOCA Prosound
LDL-cholesterol (mmol/dL) 3.2  1.0 3.3  0.9 0.302
a5) with a linear probe at frequency of 7.510.0 Hz. The distal Total cholesterol (mmol/dL) 5.2  0.9 5.4  0.9 0.029
walls from the anterior, lateral and posterior longitudinal walls Fasting plasma glucose 5.6  2.1 5.9  2.3 0.178
were recorded for carotid IMT. Both the left and right common (mmol/dL)
carotid arteries were examined. IMT was calculated as mean of the 2 h postprandial glucose 9.9  3.6 10.6  2.8 0.035
(mmol/dL)
bulb and common carotid segment measurements. Carotid plaque HbA1c (%) 5.9  1.2 6.2  1.8 0.050
was dened as plaque encroaching into the arterial lumen by at Serum creatinine (mmol/dL) 68.3  9.0 74.1  10.5 <0.001
least 0.5 mm or 50% of the surrounding IMT and IMT  1.5 mm Serum uric acid (mmol/L) 353.9  126.3 396.2  125.8 0.001
(Touboul et al., 2012). Blood urea nitrogen (mmol/L) 4.7  1.2 4.9  1.1 0.011
Hs-CRP (mg/dL) 2.3  0.7 2.6  0.9 <0.001
Red blood cell (1012/L) 4.4  0.4 4.6  0.4 <0.001
2.4. Statistical analysis White blood cell (109/L) 5.8  2.4 6.4  2.5 0.016
Red cell distribution width (%) 13.4  0.2 14.2  0.4 <0.001
The patients were divided into a CAS group and a non-CAS Blood platelet (109/L) 210.6  64 205.4  54 0.390
group. Data were reported as mean  standard deviation for Hemoglobin (g/L) 155.6  13.4 149.2  14.8 <0.001
IMT (mm) 0.84  0.19 0.98  0.13 <0.001
qualitative variables and as percentages for quantitative variables.
74 H. Jia et al. / Archives of Gerontology and Geriatrics 61 (2015) 7275

Table 2 inammation or lipid prole (Vaya et al., 2014). A national


Partial correlation analysis between IMT and other variables in patients with
representative study from American adults suggests that higher
ischemic stroke.
RDW level (fourth vs. rst quartile) among stroke patients
Variables Correlation coefcient P value independently predicted subsequent cardiovascular death
Age (years) 0.037 0.430 (HR = 2.38 and 95% CI: 1.414.01) and all-cause death (HR = 2.0,
Body mass index (kg/m2) 0.084 0.019 95% CI: 1.253.20) (Ani & Ovbiagele, 2009). This study suggests
Waist circumference (cm) 0.097 0.421 that elevated RDW level may be associated with occurrence of
Systolic blood pressure (mmHg) 0.117 0.020
stroke as well as cardiovascular and all-cause deaths in stroke
Diastolic blood pressure (mmHg) 0.076 0.218
Serum creatinine (mmol/L) 0.402 0.004 patients (Ani & Ovbiagele, 2009). The above studies have one
Serum uric acid (mmol/L) 0.378 0.015 commonness: the biological mechanisms are still not illustrated.
Blood urea nitrogen (mmol/L) 0.267 0.032 Increased carotid IMT is treated as the early progression of CAS
Total cholesterol (mmol/L) 0.034 0.612
(Ekart, Hojs, Hojs-Fabjan & Balon, 2005; Hojs, 2000) and also
Triglyceride (mmol/L) 0.234 0.012
HDL-cholesterol (mmol) 0.189 0.023
suggested to be associated with cardiovascular events including
LDL-cholesterol (mmol) 0.031 0.508 ischemic stroke (Guaricci, Brunetti, Di Biase & Pontone, 2015). Our
Fasting plasma glucose (mmol/L) 0.030 0.745 results facilitate a bridge to connect RDW with ischemic stroke.
2hPG (mmol/dL) 0.048 0.684 Recent evidence suggests that early progression of CAS is
HbA1c (%) 0.067 0.438
associated with inammatory status. The number of elevated
Hs-CRP (mg/dL) 0.105 0.012
RDW 0.436 0.001 inammatory markers is positively and signicantly associated
with baseline CCA-IMT (Willeit et al., 2014). RDW is also involved
in inammatory responses. As reported, elevated inammation
level is related with higher erythropoietin concentration in non-
acid, blood urea nitrogen, Hs-CRP and RDW (r = 0.436, P = 0.001), anemic adults, while an inverse relationship was found in anemic
but not signicantly with other variables (Table 2). patients (Ferrucci et al., 2005). This result suggests that elevation of
erythropoietin under an inammatory status is a protective
3.3. Multiple logistic regression compensation reaction to keep the hemoglobin level within the
normal range. Anemia would occur upon the breakage of
The stepwise multiple logistic regression model involves CAS protective function. Many inammatory markers such as Hs-CRP
status as the dependent variable and other variables as covariates. are involved in the progression of CAS. The Hs-CRP is a downstream
The results show that RDW is an independent predictive factor of inammatory marker and participated in immune cell chemotaxis,
CAS in patients with ischemic stroke. Compared with the lowest macrophage phagocytosis, platelet activation and complement
quartile, the second to fourth quartiles are 1.13 (95% CI: 1.133.05), activation (Kim et al., 2013). The Hs-CRP produced by tissue
2.02 (95% CI: 1.664.67) and 3.10 (95% CI: 2.467.65), respectively. macrophages and vascular smooth muscle cells could appear in the
Other factors include smoking status (OR = 3.14, 95% CI: 1.66 CAS plaque (Piechota & Piechota, 2005). As reported, Hs-CRP is
7.00), hypertension (OR = 4.65, 95% CI: 2.837.64), TG (OR = 1.57, independently associated with RDW level (Lippi et al., 2009). Our
95% CI: 1.312.01), serum uric acid (OR = 1.14, 95% CI: 1.082.34) results also show CAS patients have higher Hs-CRP level than non-
and blood urea nitrogen (OR = 1.30, 95% CI: 1.011.67) (Table 3). CAS patients and further conrm the important role of RDW in
increasing inammation load. Another important factor is oxida-
4. Discussion tive stress. The imbalance between the antioxygen and oxygen free
radical production systems causes peroxidative damage and lipid
The main nding is that we identied an independent graded peroxidative injury, which are involved in the procession of
relationship between RDW and CAS in patients with primary cardiovascular events in these patients (Karamouzis et al., 2008).
ischemic stroke. The results are similar to a previous study Moreover, elevated oxidative stress could also damage macro-
involving patients with cardiovascular diseases (Tonelli et al., molecules, membranes, DNA and enzymes involved in cellular
2008). As reported, RDW is signicantly associated with IMT, and a functions (Suematsu et al., 2003). As reported, serum selenium is
higher RDW level was observed in CAS patients. Unlike the present associated with RDW level among 786 women above age 65 within
study, Yangs smaller-size study involved patients with essential 24 months of follow-up (Kohler et al., 2009). Another population-
hypertension (Wen, 2010). A casecontrol study suggests that based study shows that RDW level is also independently related
RDW is also related with ischemic stroke, and higher RDW with weaker pulmonary function (Grant et al., 2003).
increased the risk of ischemic stroke (Ramirez-Moreno et al., Our study has several limitations. The major limitation is the
2013). Another case-control study shows that RDW > 14% nature of cross-sectional design, and it still remains unclear
increased the risk of CS by 2.5-fold, irrespective of anemia, whether RDW is just a marker or mediator of CAS. Second, some

Table 3
Multiple logistic regression for CAS in patients with ischemic stroke.

Variables B S.E. Wald P value Odds ratio 95% CI

Smoking 0.933 0.243 9.086 0.003 2.08 1.293.38


Hypertension 1.537 0.253 33.018 <0.001 4.65 2.837.64
Triglyceride 0.458 0.321 4.011 0.025 1.57 1.312.01
Serum uric acid 0.132 0.401 5.981 0.023 1.14 1.082.34
RDW
The lowest quartile Reference
The second quartile 0.472 0.278 4.234 0.040 1.60 1.133.05
The third quartile 0.601 0.461 7.264 0.004 2.02 1.664.67
The fourth quartile 1.13 0.684 6.656 0.010 3.10 2.467.65
Blood urea nitrogen 0.259 0.129 4.066 0.044 1.30 1.011.67
Constant 10.92 4.121 7.481 0.012
H. Jia et al. / Archives of Gerontology and Geriatrics 61 (2015) 7275 75

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