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Brachial-ankle pulse wave velocity is associated with 3-month functional prognosis after ischemic stroke
Accepted Manuscript Brachial-ankle pulse wave velocity is associated with 3-month functional prognosis after ischemic stroke Kentaro Ishizuka, Takao Hoshino, Satoru Shimizu, Yuka Shirai, Satoko Mizuno, Sono Toi, Kenji Maruyama, Shinichiro Uchiyama, Kazuo Kitagawa PII:
S0021-9150(16)31288-6
DOI:
10.1016/j.atherosclerosis.2016.08.027
Reference:
ATH 14759
To appear in:
Atherosclerosis
Received Date: 22 February 2016 Revised Date:
29 July 2016
Accepted Date: 23 August 2016
Please cite this article as: Ishizuka K, Hoshino T, Shimizu S, Shirai Y, Mizuno S, Toi S, Maruyama K, Uchiyama S, Kitagawa K, Brachial-ankle pulse wave velocity is associated with 3-month functional prognosis after ischemic stroke, Atherosclerosis (2016), doi: 10.1016/j.atherosclerosis.2016.08.027. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Brachial-ankle pulse wave velocity is associated with 3-month functional prognosis after ischemic stroke Kentaro Ishizuka a*, Takao Hoshino a, Satoru Shimizu b, Yuka Shirai a, Satoko Mizuno a, Sono Toi a, Kenji Maruyama a, Shinichiro Uchiyama a, c, d, Kazuo Kitagawa a a
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Department of Neurology, Tokyo Women’s Medical University School of Medicine, Tokyo, Japan b
Medical Research Institute, Tokyo Women’s Medical University School of Medicine, Tokyo, Japan
c
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Clinical Research Center for Medicine, International University of Health and Welfare, Tokyo, Japan
d
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Center for Brain and Cerebral Vessels, Sanno Hospital and Sanno Medical Center, Tokyo, Japan
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*Corresponding author: Department of Neurology, Tokyo Women’s Medical University School of Medicine, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. Tel: +81-3-3353-8111; fax: +81-3-3341-0613. E-mail address: [email protected] (K. Ishizuka)
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ACCEPTED MANUSCRIPT Abstract Background and aims: Brachial-ankle pulse wave velocity (baPWV) is a good measure of arterial stiffness and is associated with risk of future vascular events. The present study aimed
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to examine whether baPWV can also predict 3-month functional outcome after stroke. Methods: This hospital-based study included 327 consecutive patients with acute ischemic stroke and in whom baPWV was measured during hospitalization. We defined good and poor
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functional outcomes as a modified Rankin Scale score of <3 and ≥3 at 3 months, respectively, after initial stroke.
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Results: Patients with poor outcomes were significantly older (73.1 versus 66.3 years, p < 0.001) and more likely to have extracranial carotid arterial stenosis (29.5% versus 13.1%, p < 0.001), atrial fibrillation (21.0% versus 11.3%, p = 0.020), history of coronary artery disease (20.0% versus 11.7%, p = 0.042), and high baPWV value (22.84 versus 19.48 m/s, p < 0.001). Irrespective of patients’ age, sex, baseline risk factors, initial stroke severity, and stroke
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etiology, baPWV was consistently higher in patients with poor outcome than those with good outcome. Multivariate analysis revealed that baPWV >23.11 m/s, calculated from the
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receiver-operating characteristic curve, had an independent predictive value for poor functional outcome (odds ratio, 1.51; 95% confidence interval, 1.08-2.11; p = 0.016).
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Conclusions: BaPWV measured during the acute phase of stroke can independently predict 3-month functional prognosis. We suggest that baPWV should be performed as part of the early stroke work-up to identify patients suffering from severe stroke-related disability.
Key words: arterial stiffness, pulse wave velocity (PWV), ischemic stroke
Running title: arterial stiffness and stroke-related disability
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ACCEPTED MANUSCRIPT 1. Introduction Arterial stiffness increases with age and is a risk factor for atherosclerotic diseases [1-3]. Brachial-ankle pulse wave velocity (baPWV), which can be obtained easily without specialized technical expertise, is a simple and reliable method that can assess arterial
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stiffness [4,5]. In many previous longitudinal studies, high baPWV was reported to be an independent predictor of cardiovascular events and mortality [6-9]. However, few studies have evaluated whether arterial stiffness, assessed by baPWV, can also predict stroke-related
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disability in patients with acute ischemic stroke (AIS). In addition, AIS patients are
heterogeneous in terms of their baseline characteristics and stroke profiles. To date, the
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subpopulation in which baPWV is a useful marker for functional outcome has been poorly studied. The present study aimed to assess the predictive value of baPWV as a 3-month prognostic tool in patients with AIS. We also examined the associations between baPWV and stroke-related functional prognosis, according to patients’ demographics, background risk
2. Patients and methods
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2.1. Study protocol
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factors, initial stroke severity, and stroke etiology.
The ethics committee of our institution approved the study protocol. We conducted a
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hospital-based retrospective study involving 498 consecutive patients with AIS who admitted to our department within 1 week of stroke onset between May 2009 and November 2013 and completed a 3-month follow-up. After excluding 171 patients because of lack of baPWV measurement, 327 were eligible for analysis. We defined AIS as sudden onset of acute neurologic deficits with evidence of acute infarction on brain computed tomography or magnetic resonance imaging. The severity of the event was assessed according to the National Institutes of Health Stroke Scale (NIHSS) score; 3
ACCEPTED MANUSCRIPT NIHSS scores range from 0 to 42, with higher values reflecting more severe neurologic deficits. Etiologic subtypes of stroke were classified on the basis of the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification [10]. Stroke-related functional outcome was assessed using the modified Rankin Scale (mRS) score at 3 months. The mRS defines six
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different grades of disability, from 0 for “no symptoms at all,” to 5 for “severe disability or bedridden, incontinent, and requiring constant nursing care and attention,” to grade 6 for death. We defined good and poor functional outcomes as mRS <3 and ≥3, respectively.
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Follow-up information was obtained in the outpatient clinic by an attending doctor during face-to-face interviews. Patients missing appointments for the visit underwent telephone
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interviews. If the patient could not be contacted, we interviewed their family members, caregivers, or the staff of rehabilitation center or nursing home.
2.2. Risk factors
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Patients were diagnosed with hypertension if they had evidence of systolic blood pressure (BP) ≥140 mmHg or diastolic BP ≥90 mmHg or if they had received any antihypertensive medication. Diabetes mellitus was specified as fasting serum glucose ≥126
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mg/dL, serum glucose ≥200 mg/dL on two random measurements, glycated hemoglobin ≥6.5%, or use of antidiabetic therapy (oral hypoglycemic agents or insulin). Dyslipidemia was
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diagnosed if the patient had low-density lipoprotein cholesterol ≥140 mg/dL or total cholesterol ≥220 mg/dL, or if the patient had been treated with lipid-lowering agents. The estimated glomerular filtration rate was calculated using the modification of diet in renal disease formula with the Japanese coefficient. Chronic kidney disease was defined as an estimated glomerular filtration rate <60 mL·min-1·1.73 m-2. Smoking status was defined as current use. Intracranial arterial stenosis ≥50% on magnetic resonance angiography, 3-dimensional computed tomography angiography, or digital subtraction angiography was 4
ACCEPTED MANUSCRIPT considered a significant finding. Findings of carotid artery ultrasonography were evaluated by trained neurologists, and stenosis ≥50% was defined as significant extracranial arterial stenosis. Patients with either significant intra- or extracranial arterial stenosis were considered
one ECG obtained before or during hospitalization.
2.3. Measurement of baPWV
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to have major arterial lesions. Atrial fibrillation was diagnosed using the findings of at least
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Although carotid-femoral PWV (cfPWV) is the currently gold standard to assess arterial stiffness, baPWV is a more easily obtained index providing similar reliability and
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reproducibility to cfPWV [11,12]. When a patient entered the hospital, baPWV was measured systematically within the first week, by medical technologists certified by Japanese Associations of Medical Technologists, according to a standardized methodology using an automated device (VP-1000; Colin Co. Ltd., Komaki, Japan). This device simultaneously
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measures bilateral brachial and posterior tibial arterial pulse waveforms and arterial BPs using the oscillometric method. The baPWV is automatically calculated as the transmission distance divided by the transmission time. All the technologists involved were fully trained in baPWV
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measurement, and each of them performs more than 250 baPWV examinations per year. We also collected data for mean BP ([systolic BP + 2 × diastolic BP] / 3) in the brachial arteries.
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The higher baPWV value between the right and left sides and ipsilateral BPs were used in the analysis.
2.4. Statistical analysis Statistical significance of intergroup differences was assessed using the χ2 test for categorical variables and Student’s t-test or Mann-Whitney U test for continuous variables. The optimal cutoff value for baPWV was calculated on the basis of the receiver-operating 5
ACCEPTED MANUSCRIPT characteristic curve. To identify predictors of poor functional outcome, we performed multiple logistic regression analysis with adjustments for age, sex, and other variables with p <0.20 in univariate analysis as follows: chronic kidney disease, major artery stenosis, atrial fibrillation, admission NIHSS, baPWV, and mean BP. Odds ratios (ORs) and 95% confidence
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intervals (CIs) were calculated. Furthermore, receiver-operating characteristic curve analysis was performed on the multivariate model to measure the improvement of predictive ability by adding baPWV. We compared the area under the curve between the models with and without
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baPWV. In all analyses, p <0.05 was considered significant.
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3. Results
A total of 327 patients (mean age, 68.5 years; male, 65.6%) were enrolled in this study, and 105 (32.1%) had poor functional outcome at 3 months after stroke. Baseline characteristics are shown in Table 1. Patients in the poor outcome group were significantly
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older (73.1 versus 66.3 years, p < 0.001) and more often presented with atrial fibrillation (21.0% versus 11.3%, p = 0.020), prior coronary artery disease (20.0% versus 11.7%, p = 0.042), and extracranial carotid arterial stenosis (29.5% versus 13.1%, p < 0.001) than those
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in the good outcome group. There was no difference in the prevalence of prior stroke between the groups (12.2% versus 13.3%, p = 0.73). At discharge, 94.8% and 34.9% received any
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antithrombotic therapy and statin, respectively, with no significant differences in the usage rates between the groups (p = 0.63 and 0.69, respectively). The baPWV was significantly higher in the poor than good functional outcome group (22.84 versus 19.48 m/s, p < 0.001). The mean baPWV value tended to be higher in large artery atheroscrelosis than in cardioembolism (21.82 m/s versus 20.52 m/s, p = 0.22) and small vessel disease (21.82 m/s versus 20.47 m/s, p = 0.15). When stratified according to age, sex, comorbid risk factors, initial stroke severity, and stroke subtype, baPWV in the poor outcome group was 6
ACCEPTED MANUSCRIPT consistently higher than those in the good outcome group (Table 2). Specifically, the mean baPWV values in good and poor outcome groups were 20.31 and 23.85 m/s in large artery atherosclerosis (p < 0.001), 19.47 and 22.22 m/s in cardioembolism (p = 0.031), 19.90 and 22.84 m/s in small vessel disease (p = 0.035). The optimal threshold value of baPWV
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calculated using a receiver-operating characteristic curve was 23.11 m/s (sensitivity, 80.6%; specificity, 48.6%). As shown in Fig. 1, patients with baPWV >23.11 m/s more frequently suffered from disabling stroke than those with baPWV ≤23.11 m/s (p < 0.001). Furthermore,
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multivariate analysis demonstrated that baPWV >23.11 m/s was an independent predictor of poor 3-month functional outcome (OR, 1.51; 95% CI, 1.08-2.11; p = 0.016). After additional
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adjustments by the medications (alteplase, antithrombotics, and statin use), baPWV >23.11 m/s was still an independent predictor (OR, 1.53; 95% CI, 1.08-2.15; p = 0.016). According to the receiver-operating characteristic curve analysis, the area under the curve was increased from 0.8568 (95% CI, 0.7971-0.9011) to 0.8621 (95% CI, 0.8034-0.9053) by adding baPWV
4. Discussion
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(p = 0.49).
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The present study demonstrated that arterial stiffness, measured using baPWV, was associated with poor 3-month functional outcome in patients with AIS. The univariate
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analysis showed consistently higher baPWV values in patients with poor prognosis compared to those with good prognosis, when classified into different subpopulations by their demographics, baseline characteristics, initial severity, and stroke etiology. After adjustments for possible confounding factors, baPWV >23.11 m/s contributed to a 1.5-fold increased risk of disabling stroke. According to the sensitivity of 80.6% and the specificity of 48.6%, it may be difficult to predict stroke-related disability precisely by baPWV in isolation. Nevertheless,
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ACCEPTED MANUSCRIPT we believe that baPWV should be still recommended as part of the early stroke work-up to identify patients at high risk of severe sequelae. Arterial stiffness, indicated by aortic PWV between carotid and femoral arteries (i.e., cfPWV), is one of the earliest detectable manifestations of structural and functional changes
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in the arterial wall [1,2]. The European Society for Hypertension/European Society of
Cardiology guideline encourages clinicians to use cfPWV to help determine subclinical
hypertensive organ damage which affects cardiovascular prognosis [13]. According to a
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previous meta-analysis, cfPWV is a strong predictor of future vascular events and mortality, independent of other confounding risk factors [14]. Although cfPWV is the current gold
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standard for detecting aortic stiffness, its measurement requires a high degree of technical expertise and exposure of the patient’s inguinal region, which may somewhat limit its applicability [15]. A novel cuff-based assessment has enabled the measurement of cfPWV without accessing to the inguinal region [16], but this has not been widely used to date. The
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baPWV is primarily used in many Asian countries and more easily obtained without specialized skills (only using pressure cuffs wrapped on the brachium and ankle) [5]; moreover, it is well correlated with cfPWV [11,12]. In addition, similar to cfPWV, the
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associations of baPWV with vascular event risk and mortality were confirmed in a meta-analysis [17]. We applied baPWV because of its convenience and feasibility to maintain
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the consecutive enrollment of patients, thus our aim was to determine the usefulness of baPWV as a prognostic tool for stroke patients. Previous studies have reported the associations of arterial stiffness with early
progression of neurological symptoms [18], 3-month functional outcome [19,20], and mortality [9] in stroke populations. In a report by Gasecki et al using cfPWV, arterial stiffness predicted better functional 3-month outcome (mRS of 0 or 1) in AIS patients [19]. Likewise, Kim et al. reported the usefulness of baPWV as a marker of functional prognosis, irrespective 8
ACCEPTED MANUSCRIPT of the stroke etiology [20]. They found an adjusted OR of 1.88 for mRS ≥3 at 3 months in patients with >22.25 m/s (the highest tertile) of baPWV, which is comparable with our current observations. Furthermore, our study yielded additional knowledge that the prognostic value of baPWV can be valid even when patients were stratified by age, sex, initial stroke severity,
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or presence or absence of known vascular risk factors. On the other hand, they reported the optimal cut-off point of baPWV as >21.33 m/s, which seems substantially lower than that calculated from our cohort (>23.11 m/s). Therefore, despite the agreements in the prognostic
to explain the different cut-off points across the studies.
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value of baPWV for stroke patients, further multi-center, multi-racial evaluations may warrant
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Poor outcome defined by modified Rankin Scale could be a consequence of a composite of different unfavorable events. According to the multivariate analysis, a higher baPWV was associated with poor 3-month functional outcome, independent of initial stroke severity (i.e., admission NIHSS score). Therefore, we can speculate that infarction growth or
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new vascular events were more likely to occur after hospital admission in patients with a higher baPWV. PWV, which integrates alterations of the arterial wall, is associated with the coexistence of extracranial and intracranial large arterial atherosclerosis [21,22]. Furthermore,
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increased pulse pressure with aortic stiffening causes exposure of cerebral small vessels to high pulsatile pressure and flow, which damages cerebral microvasculature [23]. Cerebral
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microcirculation is known to be susceptible to excessive pulsatile stress because of its low impedance [23,24]. High pulse pressure may also lead to plaque rupture in the atherosclerotic lesion due to concentration of circumferential tensile stress [25]. All these factors potentially prompt cerebral ischemia and disturb brain repair, and cause new vascular events as well. In addition, poor recovery after rehabilitation could be another important explanation. Patients with increased arterial stiffness are more likely to have cognitive decline [26] and sarcopenia of the legs [27], both of which might hinder functional recovery after stroke. 9
ACCEPTED MANUSCRIPT The limitations of this study are mainly related to the retrospective analysis, single-center setting, and relatively low power. Patients with mild neurological symptoms, who did not require hospitalization, might have been excluded from the analysis. Furthermore, patients who died acutely or had the most severe stroke might also have been excluded,
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because they could not perform baPWV measurements. Exclusion of 171 patients among 498 patients (almost one-third) possibly led to a selection bias. Although every enrolled patient was treated at the guideline [28] with intense risk factor control, we had no data available on
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the exact change of BP, serum lipid or glucose levels during follow-up, all of which could affect the prognosis. In addition, our results may not be generalizable to other populations
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since the subjects included in this study were all Japanese. The reproducibility of the baPWV value can be another limitation. PWV is directly or indirectly influenced by all factors affecting BP [29], and baPWV may be influenced more than cfPWV [12]. Although we attempted to measure baPWV in a resting condition as possible, stroke patients in the acute
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phase ordinarily tend to be more hypertensive than usual, which might lead to an overestimation of baPWV. To complicate matters further, different size, location, or mechanism of stroke may modulate BP to different degrees [30,31]. Although we conducted
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multivariate adjustments including mean BP at the time of PWV measurement, it was difficult to determine the relative influence of all factors affecting BP. It should also be noted that
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baPWV obtained during the presence of atrial fibrillation might not be accurate [29]. Therefore, caution should be used when interpreting whether baPWV is still valid in predicting the prognosis of patients with AIS with atrial fibrillation. To conclude, arterial stiffness, measured by baPWV during the acute phase of stroke, is independently predictive of poor 3-month functional outcome in patients with AIS. In conjunction with previous reports, our findings suggest that baPWV can be a complementary tool to help identify patients at high risk of poor neurological prognosis. 10
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Conflicts of interest The authors declared they do not have anything to disclose regarding conflict of interest with
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respect to this manuscript.
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ACCEPTED MANUSCRIPT Table 1. Baseline characteristics of patients with good and poor 3-month functional outcomes. Good outcome (n = 222) 66.3 ± 12.8
Poor outcome (n = 105) 73.1 ± 10.0
<0.001
Male
146 (65.8)
69 (65.7)
0.99
Current smoking
33 (14.9)
Comorbidities
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Age, years, mean ± SD
p-value
13 (12.4)
0.55
80 (76.2)
0.20
46 (43.8)
0.47
50 (47.6)
0.69
154 (69.4)
Diabetes mellitus
88 (39.6)
Dyslipidemia
111 (50.0)
Chronic kidney disease
57 (25.7)
37 (35.2)
0.074
Current smoking
33 (14.9)
13 (12.4)
0.55
Atrial fibrillation
25 (11.3)
22 (21.0)
0.020
27 (12.2)
14 (13.3)
0.73
26 (11.7)
21 (20.0)
0.042
3 (2–5)
8 (4.5–10)
<0.001
29 (13.1)
31 (29.5)
<0.001
45 (20.3)
29 (27.6)
0.14
19.48 ± 4.76
22.84 ± 5.41
<0.001
146.3 ± 25.8
151.0 ± 28.0
0.14
83.5 ± 16.7
85.0 ± 18.4
0.45
107.5 ± 17.7
112.9 ± 20.4
0.017
5 (2.3)
3 (2.9)
0.74
211 (95.1)
99 (94.3)
0.63
Antiplatelet
158 (71.2)
69 (65.7)
0.34
Anticoagulant
60 (27.0)
33 (31.4)
0.38
79 (35.6)
35 (33.3)
0.69
History of coronary artery disease
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History of stroke
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Hypertension
Admission NIHSS score, median (IQR) Examinations Extracranial carotid arterial stenosis Intracranial arterial stenosis
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BaPWV, m/s, mean ± SD
BP at the time of baPWV measurement, mmHg, mean ± SD Systolic BP Diastolic BP Alteplase use
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Mean BP
Medications at discharge
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Any antithrombotic agents
Statin
Good and poor outcomes were defined as modified Rankin Scale <3 and ≥3, respectively. Unless otherwise indicated, figures are expressed as n (%). BP, blood pressure; baPWV, brachial-ankle pulse wave velocity; IQR, interquartile range; NIHSS, National Institute of Health Stroke Scale; SD, standard deviation. 17
ACCEPTED MANUSCRIPT Table 2. BaPWV values in patients with good and poor 3-month functional outcome according to demographics, baseline risk factors, initial NIHSS scores, and stroke etiology.
Diabetes mellitus Dyslipidemia Chronic kidney disease
p-value
< 70 y
156
17.69 ± 4.02
21.14 ± 5.64
<0.001
≥ 70 y
171
21.67 ± 4.70
23.65 ± 5.14
0.010
Male
215
19.52 ± 4.52
23.12 ± 5.59
<0.001
Female
112
19.41 ± 5.21
22.27 ± 5.08
0.007
Yes
234
20.22 ± 0.38
23.76 ± 0.53
<0.001
No
93
19.89 ± 5.93
17.82 ± 4.77
0.085
Yes
134
20.33 ± 4.74
23.29 ± 5.33
0.001
No
193
18.92 ± 4.71
22.48 ± 5.50
<0.001
Yes
161
19.79 ± 4.18
23.44 ± 5.51
<0.001
No
166
19.18 ± 5.28
22.29 ± 5.31
<0.001
94
19.56 ± 4.72
20.99 ± 4.59
0.15
253
19.46 ± 4.79
23.84 ± 5.59
<0.001
258
19.56 ± 4.83
23.00 ± 4.69
<0.001
69
18.65 ± 3.90
22.65 ± 6.15
0.011
103
20.31 ± 4.37
23.85 ± 4.86
<0.001
Cardioembolism
73
19.47 ± 4.62
22.22 ± 5.99
0.031
SVD
87
19.90 ± 4.78
22.84 ± 6.22
0.035
Yes No
Initial NIHSS
<8 ≥8 LAA
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Stroke subtype by TOAST
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Hypertension
Poor outcome
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Sex
Good outcome
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Age
n
Good and poor outcomes were defined as modified Rankin Scale <3 and ≥3, respectively.
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Figures are expressed as mean ± standard deviation.
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baPWV, brachial-ankle pulse wave velocity; LAA, large artery atherosclerosis; NIHSS, National Institute of Health Stroke Scale; SVD, small vessel disease.
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ACCEPTED MANUSCRIPT Fig. 1. Distribution of modified Rankin Scale scores at 3 months after stroke onset in patients with baPWV ≤ 23.11 and > 23.11 m/s. Patients with brachial-ankle pulse wave velocity (baPWV) >23.11 m/s showed significantly poorer functional outcome than those
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with baPWV ≤23.11 m/s (p < 0.001).
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ACCEPTED MANUSCRIPT Highlights Arterial stiffness was associated with poor 3-month functional outcome after stroke. Brachial-ankle pulse wave velocity (BaPWV) >23.11 m/s contributed to a 1.5-fold increased risk of disabling stroke.
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BaPWV may be recommended as part of early stroke work-up for predicting prognosis.
S0021-9150(16)31288-6
DOI:
10.1016/j.atherosclerosis.2016.08.027
Reference:
ATH 14759
To appear in:
Atherosclerosis
Received Date: 22 February 2016 Revised Date:
29 July 2016
Accepted Date: 23 August 2016
Please cite this article as: Ishizuka K, Hoshino T, Shimizu S, Shirai Y, Mizuno S, Toi S, Maruyama K, Uchiyama S, Kitagawa K, Brachial-ankle pulse wave velocity is associated with 3-month functional prognosis after ischemic stroke, Atherosclerosis (2016), doi: 10.1016/j.atherosclerosis.2016.08.027. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Brachial-ankle pulse wave velocity is associated with 3-month functional prognosis after ischemic stroke Kentaro Ishizuka a*, Takao Hoshino a, Satoru Shimizu b, Yuka Shirai a, Satoko Mizuno a, Sono Toi a, Kenji Maruyama a, Shinichiro Uchiyama a, c, d, Kazuo Kitagawa a a
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Department of Neurology, Tokyo Women’s Medical University School of Medicine, Tokyo, Japan b
Medical Research Institute, Tokyo Women’s Medical University School of Medicine, Tokyo, Japan
c
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Clinical Research Center for Medicine, International University of Health and Welfare, Tokyo, Japan
d
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Center for Brain and Cerebral Vessels, Sanno Hospital and Sanno Medical Center, Tokyo, Japan
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*Corresponding author: Department of Neurology, Tokyo Women’s Medical University School of Medicine, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. Tel: +81-3-3353-8111; fax: +81-3-3341-0613. E-mail address: [email protected] (K. Ishizuka)
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ACCEPTED MANUSCRIPT Abstract Background and aims: Brachial-ankle pulse wave velocity (baPWV) is a good measure of arterial stiffness and is associated with risk of future vascular events. The present study aimed
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to examine whether baPWV can also predict 3-month functional outcome after stroke. Methods: This hospital-based study included 327 consecutive patients with acute ischemic stroke and in whom baPWV was measured during hospitalization. We defined good and poor
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functional outcomes as a modified Rankin Scale score of <3 and ≥3 at 3 months, respectively, after initial stroke.
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Results: Patients with poor outcomes were significantly older (73.1 versus 66.3 years, p < 0.001) and more likely to have extracranial carotid arterial stenosis (29.5% versus 13.1%, p < 0.001), atrial fibrillation (21.0% versus 11.3%, p = 0.020), history of coronary artery disease (20.0% versus 11.7%, p = 0.042), and high baPWV value (22.84 versus 19.48 m/s, p < 0.001). Irrespective of patients’ age, sex, baseline risk factors, initial stroke severity, and stroke
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etiology, baPWV was consistently higher in patients with poor outcome than those with good outcome. Multivariate analysis revealed that baPWV >23.11 m/s, calculated from the
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receiver-operating characteristic curve, had an independent predictive value for poor functional outcome (odds ratio, 1.51; 95% confidence interval, 1.08-2.11; p = 0.016).
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Conclusions: BaPWV measured during the acute phase of stroke can independently predict 3-month functional prognosis. We suggest that baPWV should be performed as part of the early stroke work-up to identify patients suffering from severe stroke-related disability.
Key words: arterial stiffness, pulse wave velocity (PWV), ischemic stroke
Running title: arterial stiffness and stroke-related disability
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ACCEPTED MANUSCRIPT 1. Introduction Arterial stiffness increases with age and is a risk factor for atherosclerotic diseases [1-3]. Brachial-ankle pulse wave velocity (baPWV), which can be obtained easily without specialized technical expertise, is a simple and reliable method that can assess arterial
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stiffness [4,5]. In many previous longitudinal studies, high baPWV was reported to be an independent predictor of cardiovascular events and mortality [6-9]. However, few studies have evaluated whether arterial stiffness, assessed by baPWV, can also predict stroke-related
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disability in patients with acute ischemic stroke (AIS). In addition, AIS patients are
heterogeneous in terms of their baseline characteristics and stroke profiles. To date, the
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subpopulation in which baPWV is a useful marker for functional outcome has been poorly studied. The present study aimed to assess the predictive value of baPWV as a 3-month prognostic tool in patients with AIS. We also examined the associations between baPWV and stroke-related functional prognosis, according to patients’ demographics, background risk
2. Patients and methods
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2.1. Study protocol
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factors, initial stroke severity, and stroke etiology.
The ethics committee of our institution approved the study protocol. We conducted a
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hospital-based retrospective study involving 498 consecutive patients with AIS who admitted to our department within 1 week of stroke onset between May 2009 and November 2013 and completed a 3-month follow-up. After excluding 171 patients because of lack of baPWV measurement, 327 were eligible for analysis. We defined AIS as sudden onset of acute neurologic deficits with evidence of acute infarction on brain computed tomography or magnetic resonance imaging. The severity of the event was assessed according to the National Institutes of Health Stroke Scale (NIHSS) score; 3
ACCEPTED MANUSCRIPT NIHSS scores range from 0 to 42, with higher values reflecting more severe neurologic deficits. Etiologic subtypes of stroke were classified on the basis of the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification [10]. Stroke-related functional outcome was assessed using the modified Rankin Scale (mRS) score at 3 months. The mRS defines six
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different grades of disability, from 0 for “no symptoms at all,” to 5 for “severe disability or bedridden, incontinent, and requiring constant nursing care and attention,” to grade 6 for death. We defined good and poor functional outcomes as mRS <3 and ≥3, respectively.
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Follow-up information was obtained in the outpatient clinic by an attending doctor during face-to-face interviews. Patients missing appointments for the visit underwent telephone
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interviews. If the patient could not be contacted, we interviewed their family members, caregivers, or the staff of rehabilitation center or nursing home.
2.2. Risk factors
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Patients were diagnosed with hypertension if they had evidence of systolic blood pressure (BP) ≥140 mmHg or diastolic BP ≥90 mmHg or if they had received any antihypertensive medication. Diabetes mellitus was specified as fasting serum glucose ≥126
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mg/dL, serum glucose ≥200 mg/dL on two random measurements, glycated hemoglobin ≥6.5%, or use of antidiabetic therapy (oral hypoglycemic agents or insulin). Dyslipidemia was
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diagnosed if the patient had low-density lipoprotein cholesterol ≥140 mg/dL or total cholesterol ≥220 mg/dL, or if the patient had been treated with lipid-lowering agents. The estimated glomerular filtration rate was calculated using the modification of diet in renal disease formula with the Japanese coefficient. Chronic kidney disease was defined as an estimated glomerular filtration rate <60 mL·min-1·1.73 m-2. Smoking status was defined as current use. Intracranial arterial stenosis ≥50% on magnetic resonance angiography, 3-dimensional computed tomography angiography, or digital subtraction angiography was 4
ACCEPTED MANUSCRIPT considered a significant finding. Findings of carotid artery ultrasonography were evaluated by trained neurologists, and stenosis ≥50% was defined as significant extracranial arterial stenosis. Patients with either significant intra- or extracranial arterial stenosis were considered
one ECG obtained before or during hospitalization.
2.3. Measurement of baPWV
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to have major arterial lesions. Atrial fibrillation was diagnosed using the findings of at least
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Although carotid-femoral PWV (cfPWV) is the currently gold standard to assess arterial stiffness, baPWV is a more easily obtained index providing similar reliability and
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reproducibility to cfPWV [11,12]. When a patient entered the hospital, baPWV was measured systematically within the first week, by medical technologists certified by Japanese Associations of Medical Technologists, according to a standardized methodology using an automated device (VP-1000; Colin Co. Ltd., Komaki, Japan). This device simultaneously
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measures bilateral brachial and posterior tibial arterial pulse waveforms and arterial BPs using the oscillometric method. The baPWV is automatically calculated as the transmission distance divided by the transmission time. All the technologists involved were fully trained in baPWV
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measurement, and each of them performs more than 250 baPWV examinations per year. We also collected data for mean BP ([systolic BP + 2 × diastolic BP] / 3) in the brachial arteries.
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The higher baPWV value between the right and left sides and ipsilateral BPs were used in the analysis.
2.4. Statistical analysis Statistical significance of intergroup differences was assessed using the χ2 test for categorical variables and Student’s t-test or Mann-Whitney U test for continuous variables. The optimal cutoff value for baPWV was calculated on the basis of the receiver-operating 5
ACCEPTED MANUSCRIPT characteristic curve. To identify predictors of poor functional outcome, we performed multiple logistic regression analysis with adjustments for age, sex, and other variables with p <0.20 in univariate analysis as follows: chronic kidney disease, major artery stenosis, atrial fibrillation, admission NIHSS, baPWV, and mean BP. Odds ratios (ORs) and 95% confidence
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intervals (CIs) were calculated. Furthermore, receiver-operating characteristic curve analysis was performed on the multivariate model to measure the improvement of predictive ability by adding baPWV. We compared the area under the curve between the models with and without
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baPWV. In all analyses, p <0.05 was considered significant.
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3. Results
A total of 327 patients (mean age, 68.5 years; male, 65.6%) were enrolled in this study, and 105 (32.1%) had poor functional outcome at 3 months after stroke. Baseline characteristics are shown in Table 1. Patients in the poor outcome group were significantly
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older (73.1 versus 66.3 years, p < 0.001) and more often presented with atrial fibrillation (21.0% versus 11.3%, p = 0.020), prior coronary artery disease (20.0% versus 11.7%, p = 0.042), and extracranial carotid arterial stenosis (29.5% versus 13.1%, p < 0.001) than those
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in the good outcome group. There was no difference in the prevalence of prior stroke between the groups (12.2% versus 13.3%, p = 0.73). At discharge, 94.8% and 34.9% received any
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antithrombotic therapy and statin, respectively, with no significant differences in the usage rates between the groups (p = 0.63 and 0.69, respectively). The baPWV was significantly higher in the poor than good functional outcome group (22.84 versus 19.48 m/s, p < 0.001). The mean baPWV value tended to be higher in large artery atheroscrelosis than in cardioembolism (21.82 m/s versus 20.52 m/s, p = 0.22) and small vessel disease (21.82 m/s versus 20.47 m/s, p = 0.15). When stratified according to age, sex, comorbid risk factors, initial stroke severity, and stroke subtype, baPWV in the poor outcome group was 6
ACCEPTED MANUSCRIPT consistently higher than those in the good outcome group (Table 2). Specifically, the mean baPWV values in good and poor outcome groups were 20.31 and 23.85 m/s in large artery atherosclerosis (p < 0.001), 19.47 and 22.22 m/s in cardioembolism (p = 0.031), 19.90 and 22.84 m/s in small vessel disease (p = 0.035). The optimal threshold value of baPWV
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calculated using a receiver-operating characteristic curve was 23.11 m/s (sensitivity, 80.6%; specificity, 48.6%). As shown in Fig. 1, patients with baPWV >23.11 m/s more frequently suffered from disabling stroke than those with baPWV ≤23.11 m/s (p < 0.001). Furthermore,
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multivariate analysis demonstrated that baPWV >23.11 m/s was an independent predictor of poor 3-month functional outcome (OR, 1.51; 95% CI, 1.08-2.11; p = 0.016). After additional
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adjustments by the medications (alteplase, antithrombotics, and statin use), baPWV >23.11 m/s was still an independent predictor (OR, 1.53; 95% CI, 1.08-2.15; p = 0.016). According to the receiver-operating characteristic curve analysis, the area under the curve was increased from 0.8568 (95% CI, 0.7971-0.9011) to 0.8621 (95% CI, 0.8034-0.9053) by adding baPWV
4. Discussion
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(p = 0.49).
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The present study demonstrated that arterial stiffness, measured using baPWV, was associated with poor 3-month functional outcome in patients with AIS. The univariate
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analysis showed consistently higher baPWV values in patients with poor prognosis compared to those with good prognosis, when classified into different subpopulations by their demographics, baseline characteristics, initial severity, and stroke etiology. After adjustments for possible confounding factors, baPWV >23.11 m/s contributed to a 1.5-fold increased risk of disabling stroke. According to the sensitivity of 80.6% and the specificity of 48.6%, it may be difficult to predict stroke-related disability precisely by baPWV in isolation. Nevertheless,
7
ACCEPTED MANUSCRIPT we believe that baPWV should be still recommended as part of the early stroke work-up to identify patients at high risk of severe sequelae. Arterial stiffness, indicated by aortic PWV between carotid and femoral arteries (i.e., cfPWV), is one of the earliest detectable manifestations of structural and functional changes
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in the arterial wall [1,2]. The European Society for Hypertension/European Society of
Cardiology guideline encourages clinicians to use cfPWV to help determine subclinical
hypertensive organ damage which affects cardiovascular prognosis [13]. According to a
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previous meta-analysis, cfPWV is a strong predictor of future vascular events and mortality, independent of other confounding risk factors [14]. Although cfPWV is the current gold
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standard for detecting aortic stiffness, its measurement requires a high degree of technical expertise and exposure of the patient’s inguinal region, which may somewhat limit its applicability [15]. A novel cuff-based assessment has enabled the measurement of cfPWV without accessing to the inguinal region [16], but this has not been widely used to date. The
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baPWV is primarily used in many Asian countries and more easily obtained without specialized skills (only using pressure cuffs wrapped on the brachium and ankle) [5]; moreover, it is well correlated with cfPWV [11,12]. In addition, similar to cfPWV, the
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associations of baPWV with vascular event risk and mortality were confirmed in a meta-analysis [17]. We applied baPWV because of its convenience and feasibility to maintain
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the consecutive enrollment of patients, thus our aim was to determine the usefulness of baPWV as a prognostic tool for stroke patients. Previous studies have reported the associations of arterial stiffness with early
progression of neurological symptoms [18], 3-month functional outcome [19,20], and mortality [9] in stroke populations. In a report by Gasecki et al using cfPWV, arterial stiffness predicted better functional 3-month outcome (mRS of 0 or 1) in AIS patients [19]. Likewise, Kim et al. reported the usefulness of baPWV as a marker of functional prognosis, irrespective 8
ACCEPTED MANUSCRIPT of the stroke etiology [20]. They found an adjusted OR of 1.88 for mRS ≥3 at 3 months in patients with >22.25 m/s (the highest tertile) of baPWV, which is comparable with our current observations. Furthermore, our study yielded additional knowledge that the prognostic value of baPWV can be valid even when patients were stratified by age, sex, initial stroke severity,
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or presence or absence of known vascular risk factors. On the other hand, they reported the optimal cut-off point of baPWV as >21.33 m/s, which seems substantially lower than that calculated from our cohort (>23.11 m/s). Therefore, despite the agreements in the prognostic
to explain the different cut-off points across the studies.
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value of baPWV for stroke patients, further multi-center, multi-racial evaluations may warrant
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Poor outcome defined by modified Rankin Scale could be a consequence of a composite of different unfavorable events. According to the multivariate analysis, a higher baPWV was associated with poor 3-month functional outcome, independent of initial stroke severity (i.e., admission NIHSS score). Therefore, we can speculate that infarction growth or
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new vascular events were more likely to occur after hospital admission in patients with a higher baPWV. PWV, which integrates alterations of the arterial wall, is associated with the coexistence of extracranial and intracranial large arterial atherosclerosis [21,22]. Furthermore,
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increased pulse pressure with aortic stiffening causes exposure of cerebral small vessels to high pulsatile pressure and flow, which damages cerebral microvasculature [23]. Cerebral
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microcirculation is known to be susceptible to excessive pulsatile stress because of its low impedance [23,24]. High pulse pressure may also lead to plaque rupture in the atherosclerotic lesion due to concentration of circumferential tensile stress [25]. All these factors potentially prompt cerebral ischemia and disturb brain repair, and cause new vascular events as well. In addition, poor recovery after rehabilitation could be another important explanation. Patients with increased arterial stiffness are more likely to have cognitive decline [26] and sarcopenia of the legs [27], both of which might hinder functional recovery after stroke. 9
ACCEPTED MANUSCRIPT The limitations of this study are mainly related to the retrospective analysis, single-center setting, and relatively low power. Patients with mild neurological symptoms, who did not require hospitalization, might have been excluded from the analysis. Furthermore, patients who died acutely or had the most severe stroke might also have been excluded,
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because they could not perform baPWV measurements. Exclusion of 171 patients among 498 patients (almost one-third) possibly led to a selection bias. Although every enrolled patient was treated at the guideline [28] with intense risk factor control, we had no data available on
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the exact change of BP, serum lipid or glucose levels during follow-up, all of which could affect the prognosis. In addition, our results may not be generalizable to other populations
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since the subjects included in this study were all Japanese. The reproducibility of the baPWV value can be another limitation. PWV is directly or indirectly influenced by all factors affecting BP [29], and baPWV may be influenced more than cfPWV [12]. Although we attempted to measure baPWV in a resting condition as possible, stroke patients in the acute
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phase ordinarily tend to be more hypertensive than usual, which might lead to an overestimation of baPWV. To complicate matters further, different size, location, or mechanism of stroke may modulate BP to different degrees [30,31]. Although we conducted
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multivariate adjustments including mean BP at the time of PWV measurement, it was difficult to determine the relative influence of all factors affecting BP. It should also be noted that
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baPWV obtained during the presence of atrial fibrillation might not be accurate [29]. Therefore, caution should be used when interpreting whether baPWV is still valid in predicting the prognosis of patients with AIS with atrial fibrillation. To conclude, arterial stiffness, measured by baPWV during the acute phase of stroke, is independently predictive of poor 3-month functional outcome in patients with AIS. In conjunction with previous reports, our findings suggest that baPWV can be a complementary tool to help identify patients at high risk of poor neurological prognosis. 10
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Conflicts of interest The authors declared they do not have anything to disclose regarding conflict of interest with
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respect to this manuscript.
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ACCEPTED MANUSCRIPT Table 1. Baseline characteristics of patients with good and poor 3-month functional outcomes. Good outcome (n = 222) 66.3 ± 12.8
Poor outcome (n = 105) 73.1 ± 10.0
<0.001
Male
146 (65.8)
69 (65.7)
0.99
Current smoking
33 (14.9)
Comorbidities
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Age, years, mean ± SD
p-value
13 (12.4)
0.55
80 (76.2)
0.20
46 (43.8)
0.47
50 (47.6)
0.69
154 (69.4)
Diabetes mellitus
88 (39.6)
Dyslipidemia
111 (50.0)
Chronic kidney disease
57 (25.7)
37 (35.2)
0.074
Current smoking
33 (14.9)
13 (12.4)
0.55
Atrial fibrillation
25 (11.3)
22 (21.0)
0.020
27 (12.2)
14 (13.3)
0.73
26 (11.7)
21 (20.0)
0.042
3 (2–5)
8 (4.5–10)
<0.001
29 (13.1)
31 (29.5)
<0.001
45 (20.3)
29 (27.6)
0.14
19.48 ± 4.76
22.84 ± 5.41
<0.001
146.3 ± 25.8
151.0 ± 28.0
0.14
83.5 ± 16.7
85.0 ± 18.4
0.45
107.5 ± 17.7
112.9 ± 20.4
0.017
5 (2.3)
3 (2.9)
0.74
211 (95.1)
99 (94.3)
0.63
Antiplatelet
158 (71.2)
69 (65.7)
0.34
Anticoagulant
60 (27.0)
33 (31.4)
0.38
79 (35.6)
35 (33.3)
0.69
History of coronary artery disease
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History of stroke
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Admission NIHSS score, median (IQR) Examinations Extracranial carotid arterial stenosis Intracranial arterial stenosis
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BaPWV, m/s, mean ± SD
BP at the time of baPWV measurement, mmHg, mean ± SD Systolic BP Diastolic BP Alteplase use
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Mean BP
Medications at discharge
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Any antithrombotic agents
Statin
Good and poor outcomes were defined as modified Rankin Scale <3 and ≥3, respectively. Unless otherwise indicated, figures are expressed as n (%). BP, blood pressure; baPWV, brachial-ankle pulse wave velocity; IQR, interquartile range; NIHSS, National Institute of Health Stroke Scale; SD, standard deviation. 17
ACCEPTED MANUSCRIPT Table 2. BaPWV values in patients with good and poor 3-month functional outcome according to demographics, baseline risk factors, initial NIHSS scores, and stroke etiology.
Diabetes mellitus Dyslipidemia Chronic kidney disease
p-value
< 70 y
156
17.69 ± 4.02
21.14 ± 5.64
<0.001
≥ 70 y
171
21.67 ± 4.70
23.65 ± 5.14
0.010
Male
215
19.52 ± 4.52
23.12 ± 5.59
<0.001
Female
112
19.41 ± 5.21
22.27 ± 5.08
0.007
Yes
234
20.22 ± 0.38
23.76 ± 0.53
<0.001
No
93
19.89 ± 5.93
17.82 ± 4.77
0.085
Yes
134
20.33 ± 4.74
23.29 ± 5.33
0.001
No
193
18.92 ± 4.71
22.48 ± 5.50
<0.001
Yes
161
19.79 ± 4.18
23.44 ± 5.51
<0.001
No
166
19.18 ± 5.28
22.29 ± 5.31
<0.001
94
19.56 ± 4.72
20.99 ± 4.59
0.15
253
19.46 ± 4.79
23.84 ± 5.59
<0.001
258
19.56 ± 4.83
23.00 ± 4.69
<0.001
69
18.65 ± 3.90
22.65 ± 6.15
0.011
103
20.31 ± 4.37
23.85 ± 4.86
<0.001
Cardioembolism
73
19.47 ± 4.62
22.22 ± 5.99
0.031
SVD
87
19.90 ± 4.78
22.84 ± 6.22
0.035
Yes No
Initial NIHSS
<8 ≥8 LAA
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Stroke subtype by TOAST
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Hypertension
Poor outcome
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Sex
Good outcome
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Age
n
Good and poor outcomes were defined as modified Rankin Scale <3 and ≥3, respectively.
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Figures are expressed as mean ± standard deviation.
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baPWV, brachial-ankle pulse wave velocity; LAA, large artery atherosclerosis; NIHSS, National Institute of Health Stroke Scale; SVD, small vessel disease.
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ACCEPTED MANUSCRIPT Fig. 1. Distribution of modified Rankin Scale scores at 3 months after stroke onset in patients with baPWV ≤ 23.11 and > 23.11 m/s. Patients with brachial-ankle pulse wave velocity (baPWV) >23.11 m/s showed significantly poorer functional outcome than those
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with baPWV ≤23.11 m/s (p < 0.001).
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ACCEPTED MANUSCRIPT Highlights Arterial stiffness was associated with poor 3-month functional outcome after stroke. Brachial-ankle pulse wave velocity (BaPWV) >23.11 m/s contributed to a 1.5-fold increased risk of disabling stroke.
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BaPWV may be recommended as part of early stroke work-up for predicting prognosis.