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Brachial-ankle pulse wave velocity for predicting functional outcomes in patients with cryptogenic stroke
Journal of Clinical Neuroscience xxx (xxxx) xxx
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Clinical study
Brachial-ankle pulse wave velocity for predicting functional outcomes in patients with cryptogenic stroke Minho Han a, Young Dae Kim a, Hyung Jong Park a,b, In Gun Hwang a, Junghye Choi a, Jimin Ha a,c, Ji Hoe Heo a, Hyo Suk Nam a,⇑ a b c
Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea Department of Neurology, Keimyung University School of Medicine, Daegu, South Korea Brain Korea 21 Plus Project for Medical Science, Yonsei University, Seoul, South Korea
a r t i c l e
i n f o
Article history: Received 5 May 2019 Accepted 8 July 2019 Available online xxxx Keywords: Brachial-ankle pulse wave velocity Cryptogenic stroke Prognosis Stroke
a b s t r a c t Even after extensive standard evaluation, the probable cause of stroke in some patients remains unclear; this condition is defined as cryptogenic stroke (CS). The prognosis of patients with CS is largely undetermined. We investigated whether higher brachial-ankle pulse wave velocities (baPWVs) can predict poor functional outcomes at 3 months after stroke onset in these patients. We investigated patients with CS with first-ever acute cerebral infarction who underwent baPWV measurements. The stroke subtypes were classified using the Trial of ORG 10172 in Acute Stroke Treatment classification. Poor functional outcomes were defined as modified Rankin Scale scores of >2 at 3 months after stroke onset. In total, 595 patients with CS were included; among them, 360 were men (60.5%). Their mean age was 65.0 ± 12.4 years. One-hundred-eleven patients (18.7%) had poor functional outcomes. In the multivariable logistic regression analysis, the cutoff baPWV value based on the receiver-operating characteristic curve was >1968 cm/s, which was determined as a strong independent predictor (OR 3.159, 95% CI 1.487–6.715, p = 0.003). The OR of the cutoff value was higher in the patients with CS with initial National Institutes of Health Stroke Scale (NIHSS) scores of 5 (OR 4.252, 95% CI 1.596–11.324, p = 0.004); that in the patients with initial NIHSS scores of <5 was not significant (OR 1.671, 95% CI 0.620–4.505, p = 0.310). baPWV measurement during the acute stroke phase might be useful in identifying patients with CS at high risks of having a poor neurological prognosis. Ó 2019 Elsevier Ltd. All rights reserved.
1. Introduction A number of patients with stroke have no detectable cause despite extensive standard evaluation, including brain imaging and angiographic studies, echocardiography, inpatient cardiac telemetry, or 24-h Holter monitoring. This condition is defined as cryptogenic stroke (CS) according to the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification [1]. CS is more frequent in younger patients than in older ones and is mostly caused by embolisms from proximal arterial sources, paroxysmal atrial fibrillation, or upstream veins via a patent foramen ovale [2]. However, the factors associated with the prognosis of patients with CS remain controversial. The brachial-ankle pulse wave velocity (baPWV) is a simple, non-invasive indicator of arterial stiffness. The baPWV is associ-
ated with higher risk and mortality with respect to cardiovascular events, such as coronary heart disease and stroke [3]. Previous studies have shown that arterial stiffness in relation to the PWV was associated with both the short- and long-term functional outcomes in acute ischemic stroke [4,5]; however, the outcomes were different according to the stroke subtype [6]. Limited knowledge is known regarding the prognosis of patients with CS with greater arterial stiffness. To the best of our knowledge, no study has investigated the association of the baPWV with the prognosis of patients with CS. In this regard, we hypothesized that a higher baPWV can predict poor functional outcomes at 3 months after stroke onset in these patients. 2. Materials and methods 2.1. Patients and evaluation
⇑ Corresponding author at: Department of Neurology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemoon-gu, Seoul 03722, South Korea. E-mail address: [email protected] (H.S. Nam).
The study subjects were drawn from 3738 consecutive patients with acute ischemic stroke who had been registered in the
https://doi.org/10.1016/j.jocn.2019.07.050 0967-5868/Ó 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: M. Han, Y. D. Kim, H. J. Park et al., Brachial-ankle pulse wave velocity for predicting functional outcomes in patients with cryptogenic stroke, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.07.050
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M. Han et al. / Journal of Clinical Neuroscience xxx (xxxx) xxx
prospective stroke registry from January 2007 to June 2013. During admission, all patients with cerebral infarction or transient ischemic attack within 7 days after symptom onset were thoroughly evaluated for medical history, clinical manifestations, and vascular risk factors. Each patient was evaluated via 12-lead electrocardiography, chest X-ray, lipid profile tests, and standard blood tests. All registered patients underwent brain imaging studies, including brain computed tomography (CT) and/or magnetic resonance imaging. Angiographic studies via CT angiography, magnetic resonance angiography, or digital subtraction angiography were performed. Additional blood tests for coagulopathy or prothrombotic conditions were conducted in the patients younger than 45 years. Transesophageal echocardiography was included in the standard evaluation, except in the patients with decreased consciousness, impending brain herniation, poor systemic condition, or inability to tolerate the use of an esophageal transducer owing to swallowing difficulty or tracheal intubation and those who did not provide informed consent [7]. Transthoracic echocardiography, heart CT, and Holter monitoring were also performed in selected patients [8]. Most patients were admitted to the stroke unit and underwent continuous electrocardiographic monitoring during their stay. 2.2. Stroke subtype classification The stroke classifications were determined during weekly conferences based on a consensus of stroke neurologists. The stroke subtypes were identified according to the TOAST classification [1]. We defined CS as stroke of an undetermined etiology attributable to negative evaluation findings, despite extensive work-up. Data, including clinical information; risk factors; and imaging study, laboratory analysis, and other special evaluation findings, were collected. Along with these data, the patients’ prognosis during hospitalization and long-term outcomes were also determined. The data were prospectively entered into a web-based registry. 2.3. baPWV The baPWV was measured in the supine position once at <7 days from admission using an automatic device (VP-1000; Colin Co., Ltd., Komaki, Japan), which has been validated previously [5]. This device measures bilateral brachial and posterior tibial arterial pulse waveforms using the oscillometric method. The transmission distance between the brachium and the ankle for the baPWV is calculated based on the height of the patients. The baPWV is automatically calculated as the transmission distance divided by the transmission time between the two arterial points, expressed in centimeters per second. There are four baPWV parameters: right, left, maximum, and mean baPWVs. The mean baPWV is calculated as (right baPWV + left baPWV)/2. The maximum baPWV is the higher baPWV between the right and left sides, which was finally used in the multivariable analysis.
had low-density lipoprotein cholesterol levels of 4.1 mmol/L or total cholesterol levels of 6.2 mmol/L. Current smoking was defined as having smoked a cigarette within 1 year prior to admission [9]. 2.5. Follow-up and outcome measures Stroke-related functional outcomes were assessed using the modified Rankin Scale (mRS) score via a direct interview performed by a physician or through a telephone interview conducted by a well-trained research nurse after 3 months from stroke onset. The mRS consists of six different grades of disability, from 0 indicating ‘‘no symptoms at all” to 5 indicating ‘‘severe disability or bedridden, incontinent, and requiring constant nursing care and attention” or 6 indicating ‘‘death.” A poor functional outcome was defined as an mRS score of 3 at 3 months after stroke onset [10]. 2.6. Statistical analysis SPSS for Windows (version 23, SPSS, Chicago, IL, USA) was used for the statistical analysis. The patients were divided into two groups according to the mRS score at 3 months after stroke onset. The statistical significance of intergroup differences was assessed using the v2 or Fisher’s exact test for categorical variables and independent two-sample t-test or Mann-Whitney U test for continuous variables. Data were expressed as means ± standard deviations or medians (interquartile ranges) for continuous variables and numbers (%) for categorical variables. A receiver-operating characteristic (ROC) curve analysis was performed to identify the optimal cutoff value of the baPWV with the highest Youden index (sensitivity + specificity – 1). We also performed multivariable logistic regression analyses with adjustments for confounding factors to investigate the association of the baPWV with the shortterm functional outcomes of the patients with CS. All p values were 2-tailed, and differences were considered significant at p < 0.05. 3. Results 3.1. Patient enrollment During the study period, 3738 consecutive patients with acute ischemic stroke were registered. The exclusion criteria were stroke subtypes other than CS, including transient ischemic attack (n = 52), small vessel occlusion (n = 329), large artery atherosclerosis (n = 762), cardioembolism (n = 1007), stroke of other determined causes (n = 89), and stroke of two or more causes (n = 682); incomplete evaluation (n = 11); follow-up loss (n = 34); and not performed baPWV measurement (n = 177) (Fig. 1). After exclusion, a total of 595 patients with CS were finally enrolled in this study.
2.4. Demographic characteristics and risk factors 3.2. Univariable analysis We collected data on the baseline characteristics, including sex, age, and neurological deficit (National Institutes of Health Stroke Scale [NIHSS] score) at admission, presence of risk factors, and premorbid use of medications. Hypertension was diagnosed in cases in which a patient was on antihypertensive medications or had systolic arterial pressures of 140 mmHg or diastolic arterial pressures of 90 mmHg on repeated measurements during admission. Diabetes mellitus was diagnosed in cases when a patient had taken an oral hypoglycemic agent or insulin or had fasting plasma glucose levels of 7.0 mmol/L. Hypercholesterolemia was diagnosed in cases in which a patient had taken lipid-lowering agents or
The mean patient age was 65.0 ± 12.4 years; among the 595 patients with CS, 360 were men (60.5%). One hundred eleven patients (18.7%) had poor functional outcomes. The univariable analysis revealed that poor functional outcomes at 3 months were associated with old age, female sex, initial stroke severity, no current smoking, low levels of hemoglobin and triglyceride, high levels of high-sensitivity C-reactive protein and D-dimer, and increased baPWV. The patients with CS with poor outcomes had higher baPWVs, including the right, left, maximum, and mean baPWVs (all p < 0.001). The duration from admission to baPWV
Please cite this article as: M. Han, Y. D. Kim, H. J. Park et al., Brachial-ankle pulse wave velocity for predicting functional outcomes in patients with cryptogenic stroke, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.07.050
M. Han et al. / Journal of Clinical Neuroscience xxx (xxxx) xxx
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Fig. 1. Flow chart of inclusion and exclusion criteria. mRS = modified Rankin Scale; baPWV = brachial-ankle pulse wave velocity.
measurement was longer in the patients with poor outcomes (p < 0.001) (Table 1). 3.3. Multivariable analysis We performed a multivariable analysis after adjusting for sex, age, and variables that exhibited a p-value of <0.05 in the univariable analyses (Table 2). The maximum baPWV constituted the independent predictors of poor outcomes (odds ratio [OR] 1.018, 95% confidence interval [CI] 1.006–1.029, p = 0.003). The cutoff value of the maximum baPWV based on the ROC curve was >1968 cm/s, which was determined to be a strong independent predictor of poor outcomes (OR 3.159, 95% CI 1.487–6.715, p = 0.003). The 592 CS patients with NIHSS score at admission were divided into the minor stroke (n = 438, patients with NIHSS scores of <5 at admission) and major stroke groups (n = 154, patients with NIHSS scores of 5 at admission). Using this grouping, the multivariable analysis was performed to determine the prognostic factor in the patients with CS according to the initial stroke severity. In the major stroke group, the cutoff value of the maximum baPWV was >1990 cm/s, and in the minor stroke group, the cutoff value was >2382 cm/s. The OR of the cutoff values was higher in the major stroke group (OR 4.252, 95% CI 1.596–11.324, p = 0.004; supplementary material (1). In contrast, the OR was not significant in the minor stroke group (OR 1.671, 95% CI 0.620–4.505, p = 0.310; supplementary material (2). Another subgroup analysis was performed according to age; we divided the patients into the older age group (n = 309, >65 years) and younger age group (n = 286, 65 years). In the older age group, the cutoff value of the maximum baPWV was > 2054 cm/s, and in the younger age group, the cutoff value was >1977 cm/s. The cutoff value of the baPWV was significant in both the older age group (OR 2.592, 95% CI 1.125– 5.971, p = 0.025; supplementary material (3) and younger age group (OR 9.407, 95% CI 1.693–52.26, p = 0.310; supplementary material (4).
4. Discussion We demonstrated that arterial stiffness indicated by the baPWV was independently associated with poor functional outcomes at 3 months in the patients with CS; the association was more robust in the patients with a higher initial stroke severity. Arterial stiffness often precedes cardiovascular diseases and is associated with the development of hypertension, macro/ microvascular damage, functional impairment, and brain structural injury [11–13]. Increased arterial stiffness is responsible for the inadequate increase in the systolic arterial pressure and relative decrease in the diastolic pressure, which transmits higher pulse pressures to the small vessels of the distal organs, including the brain [13]. The brain has continuous and passive perfusion at high-volume flows throughout systole and diastole, and it is particularly susceptible to the excessive pulsatile stress because of low cerebral vascular resistance [11]. Consequently, high pulsatile stress results in stretch, necrosis, hypertrophy, fibrosis, calcification, remodeling, and atherosclerosis of the vessel wall [14]. PWV measurement is one of the most representative and noninvasive techniques for assessing the stiffness of the central artery [15]. Carotid-femoral PWV (cfPWV) measurement is the gold standard method for PWV measurement; the cfPWV is an independent predictor of cardiovascular disease. However, a substantial degree of cooperation and a longer procedural time is required in adequately determining the cfPWV. Conversely, the baPWV has been used as an alternative indicator owing to its simplicity, short sampling time, and its prediction power being similar to that of cfPWV in estimating arterial stiffness [10,15]. In addition to arterial stiffness, an increased baPWV is more closely associated with intracranial atherosclerosis than with extracranial atherosclerosis, and it worsens when intracranial atherosclerosis is severe, or atherosclerosis is present both intracranially and extracranially [16]. Thus, the baPWV is increased in ischemic stroke, especially in small-vessel disease because arte-
Please cite this article as: M. Han, Y. D. Kim, H. J. Park et al., Brachial-ankle pulse wave velocity for predicting functional outcomes in patients with cryptogenic stroke, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.07.050
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Table 1 Demographic characteristics and comparisons between patients with good and poor outcomes. Total (n = 595)
Good outcomes (mRS score of 0–2; n = 484)
Poor outcomes (mRS score of 3–6; n = 111)
p value
Age, y Men NIHSS score at admission Systolic arterial pressure, mmHg Diastolic arterial pressure, mmHg Thrombolysis therapy
65.0 ± 12.4 360 (60.5) 2.0 [1.0, 5.0] 158.5 ± 29.7 87.3 ± 16.0 32 (5.4)
63.6 ± 12.3 310 (64.0) 2.0 [1.0, 4.0] 158.9 ± 29.2 87.7 ± 16.0 23 (4.8)
71.2 ± 11.1 50 (45.0) 8.0 [4.0, 12.3] 156.7 ± 31.6 85.8 ± 15.9 9 (8.1)
<0.001 <0.001 <0.001 0.469 0.260 0.157
Risk factors Hypertension Diabetes mellitus Hypercholesterolemia Current smoking Coronary artery disease
449 188 102 162 109
(75.5) (31.6) (17.1) (27.2) (18.3)
370 (76.4) 152 (31.4) 77 (15.9) 143 (29.5) 92 (19.0)
79 36 25 19 17
(71.2) (32.4) (22.5) (17.1) (15.3)
0.244 0.834 0.095 0.008 0.364
Premorbid medication Antiplatelet Anticoagulant Statin Antihypertensive
168 (28.2) 6 (1.0) 87 (14.6) 152 (25.5)
140 (28.9) 6 (1.2) 74 (15.3) 122 (25.2)
28 (25.2) 0 (0.0) 13 (11.7) 30 (27.0)
0.435 0.600 0.336 0.692
Laboratory findings Hemoglobin level, g/dL hs-CRP level, mg/L Cholesterol level, mg/dL Triglyceride level, mg/dL Glucose level, mg/dL D-dimer level, mg/L
14.0 [12.7, 15.1] 1.5 [0.8, 5.2] 179.0 [152.0, 206.0] 107.0 [79.0, 150.5] 122.0 [105.0, 155.0] 173.5 [84.0, 337.5]
14.2 [12.9, 15.3] 1.3 [0.7, 3.5] 180.0 [152.0, 205.0] 111.0 [80.0, 155.3] 121.5 [105.0, 152.0] 146.0 [78.0, 277.0]
13.1 [11.5, 14.1] 5.4 [1.8, 14.2] 178.0 [153.0, 212.0] 92.0 [73.0, 124.0] 122.0 [102.0, 164.0] 339.0 [188.5, 1495.5]
<0.001 <0.001 0.907 0.002 0.920 <0.001
baPWV measurement Right baPWV, cm/s Left baPWV, cm/s Maximum baPWV, cm/s Mean baPWV, cm/s Time of baPWV measurement after admission, d
2015.4 ± 534.3 1980.7 ± 528.5 2058.7 ± 561.3 1998.3 ± 521.4 3.0 [2.0, 4.0]
1968.8 ± 513.3 1933.3 ± 496.5 2005.2 ± 527.9 1951.3 ± 497.1 3.0 [2.0, 4.0]
2218.8 ± 577.5 2187.3 ± 610.8 2292.0 ± 640.3 2203.3 ± 575.4 4.0 [3.0, 6.0]
<0.001 <0.001 <0.001 <0.001 <0.001
Data are expressed as means ± standard deviations, medians [interquartile ranges], or numbers (%). baPWV = brachial-ankle pulse wave velocity; hs-CRP = high-sensitivity C-reactive protein; mRS = modified Rankin Scale; NIHSS = National Institutes of Health Stroke Scale.
Table 2 Predictors of poor functional outcomes at 3 months. Univariable OR (95% CI)
p value
Multivariablea OR (95% CI)
p value
Men Age, y NIHSS score at admission Current smoking Hemoglobin level, g/dL hs-CRP level, mg/L Triglyceride level, mg/dL D-dimer level, mg/L Time of baPWV measurement after admission, d
0.460 (0.303–0.698) 1.060 (1.038–1.081) 1.277 (1.214–1.343) 0.492 (0.290–0.838) 0.755 (0.683–0.835) 1.018 (1.009–1.028) 1.000 (0.995–1.005) 1.000 (1.000–1.000) 1.228 (1.114–1.355)
<0.001 <0.001 <0.001 0.009 <0.001 <0.001 0.969 0.005 <0.001
0.732 (0.347–1.544) 1.030 (0.995–1.066) 1.293 (1.200–1.392) 1.407 (0.583–3.399) 0.822 (0.687–0.982) 1.009 (1.001–1.018) 0.995 (0.989–1.002) 1.000 (1.000–1.000) 1.076 (0.973–1.189)
0.413 0.097 <0.001 0.447 0.031 0.037 0.134 0.753 0.155
baPWV measurement Cutoff value of the maximum baPWV, >1968 cm/s
2.914 (1.862–4.560)
<0.001
3.159 (1.487–6.715)
0.003
Data were derived from the logistic regression analysis. baPWV = brachial-ankle pulse wave velocity; hs-CRP = high-sensitivity C-reactive protein; NIHSS = National Institutes of Health Stroke Scale; OR = odds ratio; CI = confidence interval. a adjusted for sex, age, NIHSS score at admission, current smoking, hemoglobin level, hs-CRP level, triglyceride level, D-dimer level, and time of baPWV measurement after admission.
rial stiffness can reduce the buffering function of the aorta and then increase the transmission of higher pulse pressures into the cerebral arterioles [17]. However, the association of the baPWV with stroke outcomes is controversial because it may be different depending on the stroke subtypes, including CS [6]. CS accounts for 10% to 40% of all ischemic strokes. Approximately 20% of patients with CS experience recurrent stroke [18], and 23% to 35% have poor short-term outcomes [19]. Despite the concealed accompanying burdens of less than 50% of atherosclerosis, cardioembolic sources, such as paroxysmal atrial fibrillation, or accompanying small-artery diseases, including white matter
hyper-intensity, constitute possible prognostic factors; however, the factors related to the poor outcomes in patients with CS are still unclear [18]. In this study, increased arterial stiffness was a strong prognostic factor of outcomes after stroke, and measuring the baPWV can be useful to predict poor outcomes in patients with CS. The reason for the association between higher baPWVs and poor outcomes in patients with CS is not entirely clear but may be related to macrovascular and microvascular injuries. First, complex atherosclerotic plaques in the thoracic aorta are known as a potential source of cerebral emboli and can cause CS [20]. Recent research indicates that the substantial diastolic retrograde flow
Please cite this article as: M. Han, Y. D. Kim, H. J. Park et al., Brachial-ankle pulse wave velocity for predicting functional outcomes in patients with cryptogenic stroke, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.07.050
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originating from complex plaques in the descending aorta causes embolic stroke in patients with CS. The retrograde flow becomes more pronounced as the degree of aortic artery stiffness increases. Pronounced retrograde flows increase the early diastolic blood flow into the carotid artery and cerebral blood vessels. Thus, enhanced retrograde flows resulting from increased arterial stiffness may increase the risk of ischemic stroke by introducing an embolus from the complex plaque in the descending aorta into the carotid and vertebral arteries [21]. Beyond the occurrence of CS in patients who had aortic atherosclerosis, advanced aortic atherosclerosis is frequently found in older patients. Arterial stiffness is also associated with increasing age [22]. Because age is a strong prognostic factor of stroke outcomes, the association may be incidental. We conducted further analyses by grouping the patients according to age. Our supporting data showed that the baPWV predicted a poor prognosis in both the older and younger patients with CS (supplementary material 3 and 4). The OR of the baPWV was higher in the younger patients than in the older patients, suggesting that the baPWV itself is a prognostic indicator of CS. Second, patients with abnormal arterial stiffness have blunted microvascular reactivity to ischemic stress [23]. Structural injury or functional impairment in the cerebral artery, associated with arterial stiffness, may inhibit the formation of the collateral blood flow during the acute phase of CS [24]. In addition, arterial stiffness is increased in patients with endothelial dysfunction, oxidative stress, and inflammatory conditions [25]. These factors could increase the occurrence of ischemic cerebral injury after stroke onset. Third, the initial stroke severity has been known as a strong predictor of long-term outcomes in patients with ischemic stroke [5]. In this study, the prognostic value of the baPWV was significant in the patients with CS with a higher initial stroke severity; the association was not apparent in the patients with minor CS. These features suggest that an abnormal baPWV is associated with the initial stroke severity. However, further investigation of the association between arterial stiffness and CS is required because the causes of these findings are not yet clearly known. This study had several limitations. First, this was an observational study; this study design limits the conclusion on the casual relationship between the baPWV and functional outcomes after acute stroke. Second, this study was performed at a single center and included a population with a single ethnicity. In addition, 177 patients who did not undergo baPWV measurement were excluded from the study, which may have caused a selection bias. Third, even if we collected data on and adjusted for multiple risk factors, there was a possibility of a residual confounding effect. In conclusion, we demonstrated that arterial stiffness, measured by the baPWV during the acute phase of stroke, was an independent predictor of poor 3-month functional outcomes in patients with CS. Our findings suggest that the baPWV can be a complementary indicator to help identify patients with CS at a high risk of having a poor neurological prognosis. Statement of ethics This study was approved by the Institutional Review Board of Severance Hospital, Yonsei University Health System. Informed consent was waived owing to the retrospective nature of the study (IRB 4-2016-1151). Disclosure statement The authors declare that they have no conflicts of interest to disclose.
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Funding sources This work was supported by a National Research Foundation of Korea grant funded by the Korean government (MSIP) (2016R1C1B2016028) and a faculty research grant of Yonsei University College of Medicine (6-2019-0065). Author contributions M.H.: acquisition of data, analysis and interpretation of data, drafting of manuscript and statistical analysis; H.S.N.: study concept and design, analysis and interpretation of data, drafting of manuscript, critical revision, and study supervision; Y.D.K., H.J.P., I.G.H., J.C., J.H., and J.H.H.: critical revision of manuscript. Appendix A. Supplementary material Supplementary data to this article can be found online at https://doi.org/10.1016/j.jocn.2019.07.050. References [1] Adams Jr HP, Bendixen BH, Kappelle LJ, Biller J, Love BB, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. Toast. Trial of org 10172 in acute stroke treatment. Stroke 1993;24:35–41. [2] Fonseca AC, Ferro JM. Cryptogenic stroke. Eur J Neurol 2015;22:618–23. [3] Boutouyrie P, Tropeano AI, Asmar R, Gautier I, Benetos A, Lacolley P, et al. Aortic stiffness is an independent predictor of primary coronary events in hypertensive patients: a longitudinal study. Hypertension 2002;39:10–5. [4] Ishizuka K, Hoshino T, Shimizu S, Shirai Y, Mizuno S, Toi S, et al. Brachial-ankle pulse wave velocity is associated with 3-month functional prognosis after ischemic stroke. Atherosclerosis 2016;255:1–5. [5] Kim J, Song TJ, Song D, Lee KJ, Kim EH, Lee HS, et al. Brachial-ankle pulse wave velocity is a strong predictor for mortality in patients with acute stroke. Hypertension 2014;64:240–6. [6] Tuttolomondo A, Casuccio A, Della Corte V, Maida C, Pecoraro R, Di Raimondo D, et al. Endothelial function and arterial stiffness indexes in subjects with acute ischemic stroke: relationship with toast subtype. Atherosclerosis 2017;256:94–9. [7] Cho HJ, Choi HY, Kim YD, Nam HS, Han SW, Ha JW, et al. Transoesophageal echocardiography in patients with acute stroke with sinus rhythm and no cardiac disease history. J Neurol Neurosurg Psychiatry 2010;81:412–5. [8] Yoo J, Yang JH, Choi BW, Kim YD, Nam HS, Choi HY, et al. The frequency and risk of preclinical coronary artery disease detected using multichannel cardiac computed tomography in patients with ischemic stroke. Cerebrovasc Dis 2012;33:286–94. [9] Han M, Kim YD, Park HJ, Hwang IG, Choi J, Ha J, et al. Prediction of functional outcome using the novel asymmetric middle cerebral artery index in cryptogenic stroke patients. PLoS One 2019;14:e0208918. [10] Kim J, Song TJ, Kim EH, Lee KJ, Lee HS, Nam CM, et al. Brachial-ankle pulse wave velocity for predicting functional outcome in acute stroke. Stroke 2014;45:2305–10. [11] Mitchell GF, van Buchem MA, Sigurdsson S, Gotal JD, Jonsdottir MK, Kjartansson O, et al. Arterial stiffness, pressure and flow pulsatility and brain structure and function: the age, gene/environment susceptibility–reykjavik study. Brain 2011;134:3398–407. [12] Webb AJ, Simoni M, Mazzucco S, Kuker W, Schulz U, Rothwell PM. Increased cerebral arterial pulsatility in patients with leukoaraiosis: arterial stiffness enhances transmission of aortic pulsatility. Stroke 2012;43:2631–6. [13] Zeki Al Hazzouri A, Newman AB, Simonsick E, Sink KM, Sutton Tyrrell K, Watson N, et al. Pulse wave velocity and cognitive decline in elders: the health, aging, and body composition study. Stroke 2013;44:388–93. [14] Laurent S, Briet M, Boutouyrie P. Large and small artery cross-talk and recent morbidity-mortality trials in hypertension. Hypertension 2009;54:388–92. [15] Tanaka H, Munakata M, Kawano Y, Ohishi M, Shoji T, Sugawara J, et al. Comparison between carotid-femoral and brachial-ankle pulse wave velocity as measures of arterial stiffness. J Hypertens 2009;27:2022–7. [16] Kim J, Cha MJ, Lee DH, Lee HS, Nam CM, Nam HS, et al. The association between cerebral atherosclerosis and arterial stiffness in acute ischemic stroke. Atherosclerosis 2011;219:887–91. [17] Wohlfahrt P, Krajcoviechova A, Jozifova M, Mayer O, Vanek J, Filipovsky J, et al. Large artery stiffness and carotid flow pulsatility in stroke survivors. J Hypertens. 2014;32:1097–103. [18] Li L, Yiin GS, Geraghty OC, Schulz UG, Kuker W, Mehta Z, et al. Incidence, outcome, risk factors, and long-term prognosis of cryptogenic transient ischaemic attack and ischaemic stroke: a population-based study. Lancet Neurol 2015;14:903–13.
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Please cite this article as: M. Han, Y. D. Kim, H. J. Park et al., Brachial-ankle pulse wave velocity for predicting functional outcomes in patients with cryptogenic stroke, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.07.050
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Clinical study
Brachial-ankle pulse wave velocity for predicting functional outcomes in patients with cryptogenic stroke Minho Han a, Young Dae Kim a, Hyung Jong Park a,b, In Gun Hwang a, Junghye Choi a, Jimin Ha a,c, Ji Hoe Heo a, Hyo Suk Nam a,⇑ a b c
Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea Department of Neurology, Keimyung University School of Medicine, Daegu, South Korea Brain Korea 21 Plus Project for Medical Science, Yonsei University, Seoul, South Korea
a r t i c l e
i n f o
Article history: Received 5 May 2019 Accepted 8 July 2019 Available online xxxx Keywords: Brachial-ankle pulse wave velocity Cryptogenic stroke Prognosis Stroke
a b s t r a c t Even after extensive standard evaluation, the probable cause of stroke in some patients remains unclear; this condition is defined as cryptogenic stroke (CS). The prognosis of patients with CS is largely undetermined. We investigated whether higher brachial-ankle pulse wave velocities (baPWVs) can predict poor functional outcomes at 3 months after stroke onset in these patients. We investigated patients with CS with first-ever acute cerebral infarction who underwent baPWV measurements. The stroke subtypes were classified using the Trial of ORG 10172 in Acute Stroke Treatment classification. Poor functional outcomes were defined as modified Rankin Scale scores of >2 at 3 months after stroke onset. In total, 595 patients with CS were included; among them, 360 were men (60.5%). Their mean age was 65.0 ± 12.4 years. One-hundred-eleven patients (18.7%) had poor functional outcomes. In the multivariable logistic regression analysis, the cutoff baPWV value based on the receiver-operating characteristic curve was >1968 cm/s, which was determined as a strong independent predictor (OR 3.159, 95% CI 1.487–6.715, p = 0.003). The OR of the cutoff value was higher in the patients with CS with initial National Institutes of Health Stroke Scale (NIHSS) scores of 5 (OR 4.252, 95% CI 1.596–11.324, p = 0.004); that in the patients with initial NIHSS scores of <5 was not significant (OR 1.671, 95% CI 0.620–4.505, p = 0.310). baPWV measurement during the acute stroke phase might be useful in identifying patients with CS at high risks of having a poor neurological prognosis. Ó 2019 Elsevier Ltd. All rights reserved.
1. Introduction A number of patients with stroke have no detectable cause despite extensive standard evaluation, including brain imaging and angiographic studies, echocardiography, inpatient cardiac telemetry, or 24-h Holter monitoring. This condition is defined as cryptogenic stroke (CS) according to the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification [1]. CS is more frequent in younger patients than in older ones and is mostly caused by embolisms from proximal arterial sources, paroxysmal atrial fibrillation, or upstream veins via a patent foramen ovale [2]. However, the factors associated with the prognosis of patients with CS remain controversial. The brachial-ankle pulse wave velocity (baPWV) is a simple, non-invasive indicator of arterial stiffness. The baPWV is associ-
ated with higher risk and mortality with respect to cardiovascular events, such as coronary heart disease and stroke [3]. Previous studies have shown that arterial stiffness in relation to the PWV was associated with both the short- and long-term functional outcomes in acute ischemic stroke [4,5]; however, the outcomes were different according to the stroke subtype [6]. Limited knowledge is known regarding the prognosis of patients with CS with greater arterial stiffness. To the best of our knowledge, no study has investigated the association of the baPWV with the prognosis of patients with CS. In this regard, we hypothesized that a higher baPWV can predict poor functional outcomes at 3 months after stroke onset in these patients. 2. Materials and methods 2.1. Patients and evaluation
⇑ Corresponding author at: Department of Neurology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemoon-gu, Seoul 03722, South Korea. E-mail address: [email protected] (H.S. Nam).
The study subjects were drawn from 3738 consecutive patients with acute ischemic stroke who had been registered in the
https://doi.org/10.1016/j.jocn.2019.07.050 0967-5868/Ó 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: M. Han, Y. D. Kim, H. J. Park et al., Brachial-ankle pulse wave velocity for predicting functional outcomes in patients with cryptogenic stroke, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.07.050
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prospective stroke registry from January 2007 to June 2013. During admission, all patients with cerebral infarction or transient ischemic attack within 7 days after symptom onset were thoroughly evaluated for medical history, clinical manifestations, and vascular risk factors. Each patient was evaluated via 12-lead electrocardiography, chest X-ray, lipid profile tests, and standard blood tests. All registered patients underwent brain imaging studies, including brain computed tomography (CT) and/or magnetic resonance imaging. Angiographic studies via CT angiography, magnetic resonance angiography, or digital subtraction angiography were performed. Additional blood tests for coagulopathy or prothrombotic conditions were conducted in the patients younger than 45 years. Transesophageal echocardiography was included in the standard evaluation, except in the patients with decreased consciousness, impending brain herniation, poor systemic condition, or inability to tolerate the use of an esophageal transducer owing to swallowing difficulty or tracheal intubation and those who did not provide informed consent [7]. Transthoracic echocardiography, heart CT, and Holter monitoring were also performed in selected patients [8]. Most patients were admitted to the stroke unit and underwent continuous electrocardiographic monitoring during their stay. 2.2. Stroke subtype classification The stroke classifications were determined during weekly conferences based on a consensus of stroke neurologists. The stroke subtypes were identified according to the TOAST classification [1]. We defined CS as stroke of an undetermined etiology attributable to negative evaluation findings, despite extensive work-up. Data, including clinical information; risk factors; and imaging study, laboratory analysis, and other special evaluation findings, were collected. Along with these data, the patients’ prognosis during hospitalization and long-term outcomes were also determined. The data were prospectively entered into a web-based registry. 2.3. baPWV The baPWV was measured in the supine position once at <7 days from admission using an automatic device (VP-1000; Colin Co., Ltd., Komaki, Japan), which has been validated previously [5]. This device measures bilateral brachial and posterior tibial arterial pulse waveforms using the oscillometric method. The transmission distance between the brachium and the ankle for the baPWV is calculated based on the height of the patients. The baPWV is automatically calculated as the transmission distance divided by the transmission time between the two arterial points, expressed in centimeters per second. There are four baPWV parameters: right, left, maximum, and mean baPWVs. The mean baPWV is calculated as (right baPWV + left baPWV)/2. The maximum baPWV is the higher baPWV between the right and left sides, which was finally used in the multivariable analysis.
had low-density lipoprotein cholesterol levels of 4.1 mmol/L or total cholesterol levels of 6.2 mmol/L. Current smoking was defined as having smoked a cigarette within 1 year prior to admission [9]. 2.5. Follow-up and outcome measures Stroke-related functional outcomes were assessed using the modified Rankin Scale (mRS) score via a direct interview performed by a physician or through a telephone interview conducted by a well-trained research nurse after 3 months from stroke onset. The mRS consists of six different grades of disability, from 0 indicating ‘‘no symptoms at all” to 5 indicating ‘‘severe disability or bedridden, incontinent, and requiring constant nursing care and attention” or 6 indicating ‘‘death.” A poor functional outcome was defined as an mRS score of 3 at 3 months after stroke onset [10]. 2.6. Statistical analysis SPSS for Windows (version 23, SPSS, Chicago, IL, USA) was used for the statistical analysis. The patients were divided into two groups according to the mRS score at 3 months after stroke onset. The statistical significance of intergroup differences was assessed using the v2 or Fisher’s exact test for categorical variables and independent two-sample t-test or Mann-Whitney U test for continuous variables. Data were expressed as means ± standard deviations or medians (interquartile ranges) for continuous variables and numbers (%) for categorical variables. A receiver-operating characteristic (ROC) curve analysis was performed to identify the optimal cutoff value of the baPWV with the highest Youden index (sensitivity + specificity – 1). We also performed multivariable logistic regression analyses with adjustments for confounding factors to investigate the association of the baPWV with the shortterm functional outcomes of the patients with CS. All p values were 2-tailed, and differences were considered significant at p < 0.05. 3. Results 3.1. Patient enrollment During the study period, 3738 consecutive patients with acute ischemic stroke were registered. The exclusion criteria were stroke subtypes other than CS, including transient ischemic attack (n = 52), small vessel occlusion (n = 329), large artery atherosclerosis (n = 762), cardioembolism (n = 1007), stroke of other determined causes (n = 89), and stroke of two or more causes (n = 682); incomplete evaluation (n = 11); follow-up loss (n = 34); and not performed baPWV measurement (n = 177) (Fig. 1). After exclusion, a total of 595 patients with CS were finally enrolled in this study.
2.4. Demographic characteristics and risk factors 3.2. Univariable analysis We collected data on the baseline characteristics, including sex, age, and neurological deficit (National Institutes of Health Stroke Scale [NIHSS] score) at admission, presence of risk factors, and premorbid use of medications. Hypertension was diagnosed in cases in which a patient was on antihypertensive medications or had systolic arterial pressures of 140 mmHg or diastolic arterial pressures of 90 mmHg on repeated measurements during admission. Diabetes mellitus was diagnosed in cases when a patient had taken an oral hypoglycemic agent or insulin or had fasting plasma glucose levels of 7.0 mmol/L. Hypercholesterolemia was diagnosed in cases in which a patient had taken lipid-lowering agents or
The mean patient age was 65.0 ± 12.4 years; among the 595 patients with CS, 360 were men (60.5%). One hundred eleven patients (18.7%) had poor functional outcomes. The univariable analysis revealed that poor functional outcomes at 3 months were associated with old age, female sex, initial stroke severity, no current smoking, low levels of hemoglobin and triglyceride, high levels of high-sensitivity C-reactive protein and D-dimer, and increased baPWV. The patients with CS with poor outcomes had higher baPWVs, including the right, left, maximum, and mean baPWVs (all p < 0.001). The duration from admission to baPWV
Please cite this article as: M. Han, Y. D. Kim, H. J. Park et al., Brachial-ankle pulse wave velocity for predicting functional outcomes in patients with cryptogenic stroke, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.07.050
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Fig. 1. Flow chart of inclusion and exclusion criteria. mRS = modified Rankin Scale; baPWV = brachial-ankle pulse wave velocity.
measurement was longer in the patients with poor outcomes (p < 0.001) (Table 1). 3.3. Multivariable analysis We performed a multivariable analysis after adjusting for sex, age, and variables that exhibited a p-value of <0.05 in the univariable analyses (Table 2). The maximum baPWV constituted the independent predictors of poor outcomes (odds ratio [OR] 1.018, 95% confidence interval [CI] 1.006–1.029, p = 0.003). The cutoff value of the maximum baPWV based on the ROC curve was >1968 cm/s, which was determined to be a strong independent predictor of poor outcomes (OR 3.159, 95% CI 1.487–6.715, p = 0.003). The 592 CS patients with NIHSS score at admission were divided into the minor stroke (n = 438, patients with NIHSS scores of <5 at admission) and major stroke groups (n = 154, patients with NIHSS scores of 5 at admission). Using this grouping, the multivariable analysis was performed to determine the prognostic factor in the patients with CS according to the initial stroke severity. In the major stroke group, the cutoff value of the maximum baPWV was >1990 cm/s, and in the minor stroke group, the cutoff value was >2382 cm/s. The OR of the cutoff values was higher in the major stroke group (OR 4.252, 95% CI 1.596–11.324, p = 0.004; supplementary material (1). In contrast, the OR was not significant in the minor stroke group (OR 1.671, 95% CI 0.620–4.505, p = 0.310; supplementary material (2). Another subgroup analysis was performed according to age; we divided the patients into the older age group (n = 309, >65 years) and younger age group (n = 286, 65 years). In the older age group, the cutoff value of the maximum baPWV was > 2054 cm/s, and in the younger age group, the cutoff value was >1977 cm/s. The cutoff value of the baPWV was significant in both the older age group (OR 2.592, 95% CI 1.125– 5.971, p = 0.025; supplementary material (3) and younger age group (OR 9.407, 95% CI 1.693–52.26, p = 0.310; supplementary material (4).
4. Discussion We demonstrated that arterial stiffness indicated by the baPWV was independently associated with poor functional outcomes at 3 months in the patients with CS; the association was more robust in the patients with a higher initial stroke severity. Arterial stiffness often precedes cardiovascular diseases and is associated with the development of hypertension, macro/ microvascular damage, functional impairment, and brain structural injury [11–13]. Increased arterial stiffness is responsible for the inadequate increase in the systolic arterial pressure and relative decrease in the diastolic pressure, which transmits higher pulse pressures to the small vessels of the distal organs, including the brain [13]. The brain has continuous and passive perfusion at high-volume flows throughout systole and diastole, and it is particularly susceptible to the excessive pulsatile stress because of low cerebral vascular resistance [11]. Consequently, high pulsatile stress results in stretch, necrosis, hypertrophy, fibrosis, calcification, remodeling, and atherosclerosis of the vessel wall [14]. PWV measurement is one of the most representative and noninvasive techniques for assessing the stiffness of the central artery [15]. Carotid-femoral PWV (cfPWV) measurement is the gold standard method for PWV measurement; the cfPWV is an independent predictor of cardiovascular disease. However, a substantial degree of cooperation and a longer procedural time is required in adequately determining the cfPWV. Conversely, the baPWV has been used as an alternative indicator owing to its simplicity, short sampling time, and its prediction power being similar to that of cfPWV in estimating arterial stiffness [10,15]. In addition to arterial stiffness, an increased baPWV is more closely associated with intracranial atherosclerosis than with extracranial atherosclerosis, and it worsens when intracranial atherosclerosis is severe, or atherosclerosis is present both intracranially and extracranially [16]. Thus, the baPWV is increased in ischemic stroke, especially in small-vessel disease because arte-
Please cite this article as: M. Han, Y. D. Kim, H. J. Park et al., Brachial-ankle pulse wave velocity for predicting functional outcomes in patients with cryptogenic stroke, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.07.050
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Table 1 Demographic characteristics and comparisons between patients with good and poor outcomes. Total (n = 595)
Good outcomes (mRS score of 0–2; n = 484)
Poor outcomes (mRS score of 3–6; n = 111)
p value
Age, y Men NIHSS score at admission Systolic arterial pressure, mmHg Diastolic arterial pressure, mmHg Thrombolysis therapy
65.0 ± 12.4 360 (60.5) 2.0 [1.0, 5.0] 158.5 ± 29.7 87.3 ± 16.0 32 (5.4)
63.6 ± 12.3 310 (64.0) 2.0 [1.0, 4.0] 158.9 ± 29.2 87.7 ± 16.0 23 (4.8)
71.2 ± 11.1 50 (45.0) 8.0 [4.0, 12.3] 156.7 ± 31.6 85.8 ± 15.9 9 (8.1)
<0.001 <0.001 <0.001 0.469 0.260 0.157
Risk factors Hypertension Diabetes mellitus Hypercholesterolemia Current smoking Coronary artery disease
449 188 102 162 109
(75.5) (31.6) (17.1) (27.2) (18.3)
370 (76.4) 152 (31.4) 77 (15.9) 143 (29.5) 92 (19.0)
79 36 25 19 17
(71.2) (32.4) (22.5) (17.1) (15.3)
0.244 0.834 0.095 0.008 0.364
Premorbid medication Antiplatelet Anticoagulant Statin Antihypertensive
168 (28.2) 6 (1.0) 87 (14.6) 152 (25.5)
140 (28.9) 6 (1.2) 74 (15.3) 122 (25.2)
28 (25.2) 0 (0.0) 13 (11.7) 30 (27.0)
0.435 0.600 0.336 0.692
Laboratory findings Hemoglobin level, g/dL hs-CRP level, mg/L Cholesterol level, mg/dL Triglyceride level, mg/dL Glucose level, mg/dL D-dimer level, mg/L
14.0 [12.7, 15.1] 1.5 [0.8, 5.2] 179.0 [152.0, 206.0] 107.0 [79.0, 150.5] 122.0 [105.0, 155.0] 173.5 [84.0, 337.5]
14.2 [12.9, 15.3] 1.3 [0.7, 3.5] 180.0 [152.0, 205.0] 111.0 [80.0, 155.3] 121.5 [105.0, 152.0] 146.0 [78.0, 277.0]
13.1 [11.5, 14.1] 5.4 [1.8, 14.2] 178.0 [153.0, 212.0] 92.0 [73.0, 124.0] 122.0 [102.0, 164.0] 339.0 [188.5, 1495.5]
<0.001 <0.001 0.907 0.002 0.920 <0.001
baPWV measurement Right baPWV, cm/s Left baPWV, cm/s Maximum baPWV, cm/s Mean baPWV, cm/s Time of baPWV measurement after admission, d
2015.4 ± 534.3 1980.7 ± 528.5 2058.7 ± 561.3 1998.3 ± 521.4 3.0 [2.0, 4.0]
1968.8 ± 513.3 1933.3 ± 496.5 2005.2 ± 527.9 1951.3 ± 497.1 3.0 [2.0, 4.0]
2218.8 ± 577.5 2187.3 ± 610.8 2292.0 ± 640.3 2203.3 ± 575.4 4.0 [3.0, 6.0]
<0.001 <0.001 <0.001 <0.001 <0.001
Data are expressed as means ± standard deviations, medians [interquartile ranges], or numbers (%). baPWV = brachial-ankle pulse wave velocity; hs-CRP = high-sensitivity C-reactive protein; mRS = modified Rankin Scale; NIHSS = National Institutes of Health Stroke Scale.
Table 2 Predictors of poor functional outcomes at 3 months. Univariable OR (95% CI)
p value
Multivariablea OR (95% CI)
p value
Men Age, y NIHSS score at admission Current smoking Hemoglobin level, g/dL hs-CRP level, mg/L Triglyceride level, mg/dL D-dimer level, mg/L Time of baPWV measurement after admission, d
0.460 (0.303–0.698) 1.060 (1.038–1.081) 1.277 (1.214–1.343) 0.492 (0.290–0.838) 0.755 (0.683–0.835) 1.018 (1.009–1.028) 1.000 (0.995–1.005) 1.000 (1.000–1.000) 1.228 (1.114–1.355)
<0.001 <0.001 <0.001 0.009 <0.001 <0.001 0.969 0.005 <0.001
0.732 (0.347–1.544) 1.030 (0.995–1.066) 1.293 (1.200–1.392) 1.407 (0.583–3.399) 0.822 (0.687–0.982) 1.009 (1.001–1.018) 0.995 (0.989–1.002) 1.000 (1.000–1.000) 1.076 (0.973–1.189)
0.413 0.097 <0.001 0.447 0.031 0.037 0.134 0.753 0.155
baPWV measurement Cutoff value of the maximum baPWV, >1968 cm/s
2.914 (1.862–4.560)
<0.001
3.159 (1.487–6.715)
0.003
Data were derived from the logistic regression analysis. baPWV = brachial-ankle pulse wave velocity; hs-CRP = high-sensitivity C-reactive protein; NIHSS = National Institutes of Health Stroke Scale; OR = odds ratio; CI = confidence interval. a adjusted for sex, age, NIHSS score at admission, current smoking, hemoglobin level, hs-CRP level, triglyceride level, D-dimer level, and time of baPWV measurement after admission.
rial stiffness can reduce the buffering function of the aorta and then increase the transmission of higher pulse pressures into the cerebral arterioles [17]. However, the association of the baPWV with stroke outcomes is controversial because it may be different depending on the stroke subtypes, including CS [6]. CS accounts for 10% to 40% of all ischemic strokes. Approximately 20% of patients with CS experience recurrent stroke [18], and 23% to 35% have poor short-term outcomes [19]. Despite the concealed accompanying burdens of less than 50% of atherosclerosis, cardioembolic sources, such as paroxysmal atrial fibrillation, or accompanying small-artery diseases, including white matter
hyper-intensity, constitute possible prognostic factors; however, the factors related to the poor outcomes in patients with CS are still unclear [18]. In this study, increased arterial stiffness was a strong prognostic factor of outcomes after stroke, and measuring the baPWV can be useful to predict poor outcomes in patients with CS. The reason for the association between higher baPWVs and poor outcomes in patients with CS is not entirely clear but may be related to macrovascular and microvascular injuries. First, complex atherosclerotic plaques in the thoracic aorta are known as a potential source of cerebral emboli and can cause CS [20]. Recent research indicates that the substantial diastolic retrograde flow
Please cite this article as: M. Han, Y. D. Kim, H. J. Park et al., Brachial-ankle pulse wave velocity for predicting functional outcomes in patients with cryptogenic stroke, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.07.050
M. Han et al. / Journal of Clinical Neuroscience xxx (xxxx) xxx
originating from complex plaques in the descending aorta causes embolic stroke in patients with CS. The retrograde flow becomes more pronounced as the degree of aortic artery stiffness increases. Pronounced retrograde flows increase the early diastolic blood flow into the carotid artery and cerebral blood vessels. Thus, enhanced retrograde flows resulting from increased arterial stiffness may increase the risk of ischemic stroke by introducing an embolus from the complex plaque in the descending aorta into the carotid and vertebral arteries [21]. Beyond the occurrence of CS in patients who had aortic atherosclerosis, advanced aortic atherosclerosis is frequently found in older patients. Arterial stiffness is also associated with increasing age [22]. Because age is a strong prognostic factor of stroke outcomes, the association may be incidental. We conducted further analyses by grouping the patients according to age. Our supporting data showed that the baPWV predicted a poor prognosis in both the older and younger patients with CS (supplementary material 3 and 4). The OR of the baPWV was higher in the younger patients than in the older patients, suggesting that the baPWV itself is a prognostic indicator of CS. Second, patients with abnormal arterial stiffness have blunted microvascular reactivity to ischemic stress [23]. Structural injury or functional impairment in the cerebral artery, associated with arterial stiffness, may inhibit the formation of the collateral blood flow during the acute phase of CS [24]. In addition, arterial stiffness is increased in patients with endothelial dysfunction, oxidative stress, and inflammatory conditions [25]. These factors could increase the occurrence of ischemic cerebral injury after stroke onset. Third, the initial stroke severity has been known as a strong predictor of long-term outcomes in patients with ischemic stroke [5]. In this study, the prognostic value of the baPWV was significant in the patients with CS with a higher initial stroke severity; the association was not apparent in the patients with minor CS. These features suggest that an abnormal baPWV is associated with the initial stroke severity. However, further investigation of the association between arterial stiffness and CS is required because the causes of these findings are not yet clearly known. This study had several limitations. First, this was an observational study; this study design limits the conclusion on the casual relationship between the baPWV and functional outcomes after acute stroke. Second, this study was performed at a single center and included a population with a single ethnicity. In addition, 177 patients who did not undergo baPWV measurement were excluded from the study, which may have caused a selection bias. Third, even if we collected data on and adjusted for multiple risk factors, there was a possibility of a residual confounding effect. In conclusion, we demonstrated that arterial stiffness, measured by the baPWV during the acute phase of stroke, was an independent predictor of poor 3-month functional outcomes in patients with CS. Our findings suggest that the baPWV can be a complementary indicator to help identify patients with CS at a high risk of having a poor neurological prognosis. Statement of ethics This study was approved by the Institutional Review Board of Severance Hospital, Yonsei University Health System. Informed consent was waived owing to the retrospective nature of the study (IRB 4-2016-1151). Disclosure statement The authors declare that they have no conflicts of interest to disclose.
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Funding sources This work was supported by a National Research Foundation of Korea grant funded by the Korean government (MSIP) (2016R1C1B2016028) and a faculty research grant of Yonsei University College of Medicine (6-2019-0065). Author contributions M.H.: acquisition of data, analysis and interpretation of data, drafting of manuscript and statistical analysis; H.S.N.: study concept and design, analysis and interpretation of data, drafting of manuscript, critical revision, and study supervision; Y.D.K., H.J.P., I.G.H., J.C., J.H., and J.H.H.: critical revision of manuscript. Appendix A. Supplementary material Supplementary data to this article can be found online at https://doi.org/10.1016/j.jocn.2019.07.050. References [1] Adams Jr HP, Bendixen BH, Kappelle LJ, Biller J, Love BB, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. Toast. Trial of org 10172 in acute stroke treatment. Stroke 1993;24:35–41. [2] Fonseca AC, Ferro JM. Cryptogenic stroke. Eur J Neurol 2015;22:618–23. [3] Boutouyrie P, Tropeano AI, Asmar R, Gautier I, Benetos A, Lacolley P, et al. Aortic stiffness is an independent predictor of primary coronary events in hypertensive patients: a longitudinal study. Hypertension 2002;39:10–5. [4] Ishizuka K, Hoshino T, Shimizu S, Shirai Y, Mizuno S, Toi S, et al. Brachial-ankle pulse wave velocity is associated with 3-month functional prognosis after ischemic stroke. Atherosclerosis 2016;255:1–5. [5] Kim J, Song TJ, Song D, Lee KJ, Kim EH, Lee HS, et al. Brachial-ankle pulse wave velocity is a strong predictor for mortality in patients with acute stroke. Hypertension 2014;64:240–6. [6] Tuttolomondo A, Casuccio A, Della Corte V, Maida C, Pecoraro R, Di Raimondo D, et al. Endothelial function and arterial stiffness indexes in subjects with acute ischemic stroke: relationship with toast subtype. Atherosclerosis 2017;256:94–9. [7] Cho HJ, Choi HY, Kim YD, Nam HS, Han SW, Ha JW, et al. Transoesophageal echocardiography in patients with acute stroke with sinus rhythm and no cardiac disease history. J Neurol Neurosurg Psychiatry 2010;81:412–5. [8] Yoo J, Yang JH, Choi BW, Kim YD, Nam HS, Choi HY, et al. The frequency and risk of preclinical coronary artery disease detected using multichannel cardiac computed tomography in patients with ischemic stroke. Cerebrovasc Dis 2012;33:286–94. [9] Han M, Kim YD, Park HJ, Hwang IG, Choi J, Ha J, et al. Prediction of functional outcome using the novel asymmetric middle cerebral artery index in cryptogenic stroke patients. PLoS One 2019;14:e0208918. [10] Kim J, Song TJ, Kim EH, Lee KJ, Lee HS, Nam CM, et al. Brachial-ankle pulse wave velocity for predicting functional outcome in acute stroke. Stroke 2014;45:2305–10. [11] Mitchell GF, van Buchem MA, Sigurdsson S, Gotal JD, Jonsdottir MK, Kjartansson O, et al. Arterial stiffness, pressure and flow pulsatility and brain structure and function: the age, gene/environment susceptibility–reykjavik study. Brain 2011;134:3398–407. [12] Webb AJ, Simoni M, Mazzucco S, Kuker W, Schulz U, Rothwell PM. Increased cerebral arterial pulsatility in patients with leukoaraiosis: arterial stiffness enhances transmission of aortic pulsatility. Stroke 2012;43:2631–6. [13] Zeki Al Hazzouri A, Newman AB, Simonsick E, Sink KM, Sutton Tyrrell K, Watson N, et al. Pulse wave velocity and cognitive decline in elders: the health, aging, and body composition study. Stroke 2013;44:388–93. [14] Laurent S, Briet M, Boutouyrie P. Large and small artery cross-talk and recent morbidity-mortality trials in hypertension. Hypertension 2009;54:388–92. [15] Tanaka H, Munakata M, Kawano Y, Ohishi M, Shoji T, Sugawara J, et al. Comparison between carotid-femoral and brachial-ankle pulse wave velocity as measures of arterial stiffness. J Hypertens 2009;27:2022–7. [16] Kim J, Cha MJ, Lee DH, Lee HS, Nam CM, Nam HS, et al. The association between cerebral atherosclerosis and arterial stiffness in acute ischemic stroke. Atherosclerosis 2011;219:887–91. [17] Wohlfahrt P, Krajcoviechova A, Jozifova M, Mayer O, Vanek J, Filipovsky J, et al. Large artery stiffness and carotid flow pulsatility in stroke survivors. J Hypertens. 2014;32:1097–103. [18] Li L, Yiin GS, Geraghty OC, Schulz UG, Kuker W, Mehta Z, et al. Incidence, outcome, risk factors, and long-term prognosis of cryptogenic transient ischaemic attack and ischaemic stroke: a population-based study. Lancet Neurol 2015;14:903–13.
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Please cite this article as: M. Han, Y. D. Kim, H. J. Park et al., Brachial-ankle pulse wave velocity for predicting functional outcomes in patients with cryptogenic stroke, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.07.050