Inter-arm Blood Pressure Difference is Associated with Recurrent Stroke in Non-cardioembolic Stroke Patients

Recurrent stroke increases mortality and aggravates the disability of stroke patients. We hypothesized that increased inter-arm systolic blood pressure difference and inter-arm diastolic blood pressure difference would be related to recurrent stroke in non-cardioembolic stroke patients. A total of 1226 consecutive non-cardioembolic first-ever ischemic stroke patients, in whom bilateral brachial blood pressures were measured by an automated ankle-brachial index measuring device, were included in our study. Recurrent stroke was defined as newly developed neurologic symptoms with relevant lesions on brain CT and/or MRI after 7 days or hospital discharge. Inter-arm systolic and diastolic blood pressure differences ≥10 mmHg were noted in 9.7% (120/1226) and 5.0% (62/1226) of patients, respectively. During a median 24 months of follow-up, 105 (8.5%) patients experienced recurrent stroke. Patients who had inter-arm systolic blood pressure difference ≥10 mmHg showed increased risk of recurrent stroke (hazard ratio:1.77, 95% confidence interval: 1.04–3.00, p = 0.033). Moreover, inter-arm diastolic blood pressure difference ≥10 mmHg was also independently associated with increased risk of recurrent stroke (hazard ratio:2.92, 95% confidence interval: 1.59–5.34, p = 0.001). In conclusion, inter-arm blood pressure difference ≥10 mmHg may be associated with increased risk recurrent stroke in non-cardioembolic stroke patients.

The systolic (IASBD) and diastolic (IADBD) blood pressure difference ≥10 mmHg was noted in 9.7% (120/1226) and 5.0% (62/1226), respectively. The patients with IASBD ≥10 mmHg had more frequent history of hypertension, coronary artery disease (CAD), metabolic syndrome, regular alcohol intake, left ventricular hypertrophy, large artery atherosclerosis stroke subtype, cerebral atherosclerosis, and high-grade white matter hyperintensities. Moreover, body mass index, pulse rate, systolic blood pressure, diastolic blood pressure, and baPWV were higher in patients with IASBD ≥10 mmHg compared to those with IASBD <10 mmHg (Table 1). Patients with IADBD ≥10 mmHg had more frequent history of CAD, regular alcohol intake, left ventricular hypertrophy, cerebral atherosclerosis, and high-grade white matter hyperintensities. In addition, body mass index, National Institutes of Health Stroke Scale (NIHSS) score, pulse rate, systolic blood pressure, and diastolic blood pressure were higher in patients with IADBD ≥10 mmHg compared to those with IADBD <10 mmHg (Table 1).

Discussion
Our study showed that IASBD and/or IADBD ≥10 mmHg was associated with recurrent stroke after adjustment for stroke severity (NIHSS), cerebral atherosclerosis, baPWV, and high-grade white matter hyperintensities, which were closely related factors for stroke. Thus, our study suggests that IASBD or IADBD, which can be easily measured in a clinical field, may be an independent factor for associating or predicting recurrent stroke in non-cardioembolic stroke patients.
Our study demonstrated that IASBD and/or IADBD ≥10 mmHg was associated with recurrent stroke after non-cardioembolic stroke. Previous studies reported that IABD is related with vascular death and all-cause mortality 12 , and these results were consistently noted in populations without known cardiovascular disease 13 and in chronic kidney disease patients 14 . In elderly patients with hypertension, IASBD ≥10 mmHg was an independent risk factor for increasing the risk of cardiovascular disease and mortality 15 . In contrast, the Framingham Heart Study reported no significant relationship with IABD and mortality 16 . However, up to now, preceding studies regarding IABD and recurrent stroke are rare. In a previous study of patients with acute ischemic stroke, IASBD and/or IADBD ≥10 mmHg was associated with long-term mortality 11 . In patients with non-cardioembolic stroke, cerebral artery stenosis, which is a major predictor for poor prognosis after stroke, was diversely associated with IABD 4 . Another study showed low ABI was associated with recurrent stroke in patients with acute cerebral infarction 17 . Our study supports these findings and may give additive information for the associations of IABD and stroke recurrence. Moreover, bi-brachial blood pressure measurements might play a role as a screening tool for stroke patients to estimate the possibility of recurrent stroke in non-cardioembolic stroke patients.
Our study demonstrated that large artery atherosclerosis stroke subtype was more frequently noted in the IASBD ≥10 mmHg group than in the IASBD <10 mmHg group for the stroke subtype of recurrent stroke. These results are consistent with previous findings that IABD is associated with cerebral atherosclerosis 4 , which is an important risk factor for ischemic stroke occurrence or recurrence. Another study also revealed association of arterial stiffness index and large artery atherosclerosis stroke subtype 18 , and the results of previous studies in which large artery atherosclerosis was associated with asymptomatic lacunar infarction 19 . Meanwhile, hemorrhagic stroke subtype was less frequently noted in the IASBD ≥10 mmHg group than in those with IASBD <10 mmHg. In contrast to our results, previous studies have revealed large artery atherosclerosis, such as aortic atheroma, was significantly associated with cerebral microbleeds that act as imaging biomarkers for future (2019) 9:12758 | https://doi.org/10.1038/s41598-019-49294-8 www.nature.com/scientificreports www.nature.com/scientificreports/ cerebral haemorrhage 19,20 . These results suggest that a large IABD causes cerebral hypoperfusion in the brain, resulting in an ischemic prone state rather than a hemorrhagic prone state, but further research is needed.
Several hypotheses may explain the relationship of IABD with recurrent stroke. IABD is related with advanced atherosclerotic disease in the aorta and its large branches 9 , which may cause an insufficient cerebral blood www.nature.com/scientificreports www.nature.com/scientificreports/ flow 21 . The hemodynamic dysfunction may be a part of the cause of recurrent stroke or poor clinical outcome 22 . Furthermore, larger atherosclerotic burden is correlated with early poor clinical outcome in stroke population 10 . In addition, previous study discovered that IABD resulting from one-arm ischemia in hypertensive or normotensive patients was related with flow-mediated dilatation 23 , which represents endothelial dysfunction. Increased arterial stiffness may be a link for our study. Arterial stiffness is associated with worse outcome in patients with acute cerebral infarction [24][25][26] . A population-based study showed large IABD was related with arterial stiffness, which is in line with our study 27 .
There are some limitations in our research. First, although consecutive patients were included in this study, the possibility of selection bias exists because of the retrospective study design. Second, it is difficult to generalize our findings to another population or cohort considering that our study population is limited to a single comprehensive center. Third, multiple, automatic, and simultaneous assessments are recommended for accurate IABD measurements rather than a single, manual, and sequential evaluation methods. We used an automatic and simultaneous measurement device; however, IABD was investigated only once during the ABI assessment and additional follow up data was lacking.
In conclusion, our results demonstrated that IASBD ≥10 mmHg and/or IADBD ≥10 mmHg is associated with recurrent stroke. An IABD ≥10 mmHg could be a useful indicator of risk of recurrent stroke in non-cardioembolic stroke patients.

Methods
Study population. Patients admitted to our stroke center between January 2010 and August 2016, with firstever transient ischemic attack or acute ischemic stroke within 24 hours after symptom onset were enrolled 28 . For total 1782 patients, medical history, demographics, previous history of cardiovascular risk factors, neuroimaging findings and neurologic examination data were collected. All admitted stroke patients underwent chest x-ray,  Table 2. Subtypes and location of stroke recurrence according to IASBD and IADBD ≥10 mmHg. Data are shown as n (%) or mean ± standard deviation. The p values are derived by Chi's square test. IASBD: inter-arm systolic blood pressure difference, IADBD: inter-arm diastolic blood pressure difference. www.nature.com/scientificreports www.nature.com/scientificreports/ routine blood tests, and electrocardiography. Brain computed tomography (CT) and/or magnetic resonance imaging (MRI) and vascular imaging with MRI or CT were performed. In our department, ABI examination was investigated as one of the routine procedures to evaluate peripheral arterial occlusive lesions, performed at subacute stage (3-7 days after admission) 29 . Our study was approved by Ewha Womans University Mokdong hospital Institutional Review Board (IRB number 2017-04-017), and the requirement of obtaining patients' informed consent was waived because of the retrospective, cross-sectional, and observational nature of the study. All research was performed in accordance with relevant guidelines and regulations.
Among the 1782 patients, those with potential cardiac source of embolism (PCSE; n = 261, which including persistent atrial fibrillation (AF)/flutter (n = 190), paroxysmal AF (n = 45), sick sinus syndrome (n = 8), and other PCSE (n = 18)), stroke subtype of other determined (rare causes)(n = 23), stroke subtype of undetermined incomplete evaluation (n = 12) and transient ischemic attack (n = 141) were not included. Patients with PCSE were not included because AF can cause inaccurate measurements of brachial-ankle pulse wave velocity (baPWV) and blood pressures (systolic and diastolic) 4,30 . Patients who did not perform brain MRI (n = 22) or with poor image quality (n = 6) or with missing ABI data (n = 43) were excluded from this study. Patients having abnormal ABI (less than 0.9, n = 48) were also excluded because baPWV results could be checked inaccurately 31 . The final number of subjects were 1,226 ( Supplementary Fig. 1). Definitions for vascular risk factors are described in the supplemental methods and in a prior study 4,32 . Stroke was classified with the Trial of Org 10172 in Acute Stroke Treatment classification system 33 . Neurological severity was investigated using the NIHSS score. Antihypertensive treatment before ABI was defined as in case of treatment with intravenous or oral antihypertensive agents were performed before ABI examination was undertaken.
Measuring blood pressure in both arms and inter-arm blood pressure differences. Details for measurement of ABI were described in previous study 34 . In brief, The ABI test was performed by a well-trained examiner with more than 5 years of experience. Before taking the exam, patients had at least 5 minutes rest in a quiet room. The bilateral brachial systolic and diastolic blood pressures were measured automatically and simultaneously with an automated device for ABI test (VP-1000; Colin Co. Ltd, Komaki, Japan) in supine position after discharge of the bowels/bladder in the morning. Pressure cuffs were wrapped on both the brachial and posterior tibial arteries to measure the arterial blood pressure using the oscillometric method 34 . The ABI test was performed after the patients became neurologically stable. A large systolic (IASBD) or diastolic IABD (IADBD) was defined as an absolute inter-arm blood pressure difference ≥10 mmHg, which is frequently used and validated for major cardiovascular outcome as a cut-off value 3,35 . Cerebral atherosclerosis and high-grade white matter hyperintensities. The degree of intracranial and extracranial cerebral atherosclerosis (ICAS and ECAS) stenosis was measured using brain CT angiography, MR angiography and/or digital subtraction angiography 19 . The existence of arterial stenosis was defined as more than 50% reduction in luminal diameters 36,37 . The Fazekas score of ≥2 in the deep or periventricular white matter on T2-weighted image or fluid-attenuated inversion recovery were defined as high-grade white matter hyperintensities 38 . Outcome measures. The follow up schedule for the patients was three months, one year, and every year after discharge. In each follow up, vital signs, newly developed vascular risk factors, and recurrence of stroke were  Table 3. Frequency of developing clinical events and results of uni and multivariate analysis for recurrent stroke according to IABD. Cox proportional hazards regression were used for uni-and multivariate analysis. Data are shown as percent (number of case/numbers of total patients for each group) or hazard ratio (95% confidence interval). *p < 0.05. HR: hazard ratio, CI: confidence interval, IABD: inter-arm blood pressure difference, IASBD: inter-arm systolic blood pressure difference, IADBD: inter-arm diastolic blood pressure difference, N/A: not applicable. a: adjusted for sex, age, hypertension, diabetes mellitus, smoking, coronary artery disease, metabolic syndrome, National Institutes of Health Stroke Scale, stroke subtype, cerebral atherosclerosis, brachial-ankle pulse wave velocity, and high-grade white matter hyperintensities.