ORIGINAL ARTICLE

Arterial pre-hypertension and hypertension in intracranial versus extracranial cerebrovascular stenosis

a Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing; bChina National Clinical Research Center for Neurological Diseases, Beijing; cCenter of Stroke, Beijing Institute for Brain Disorders, Beijing; dBeijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China; eDepartment of Epidemiology and Biostatistics, School of Population Health, University of Queensland, Brisbane, QLD, Australia; fDepartment of Emergency Medicine, Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessels, Beijing, China; gChanning Laboratory, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA; hDepartment of Nutrition, Harvard University School of Public Health, Boston, MA, USA; iDepartment of Cardiology, Kailuan Hospital, Tangshan; jBeijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing; kKey Laboratory of Ophthalmology and Visual Science, Beijing Tongren Hospital, Capital Medical University, Beijing, China; and lDepartment of Ophthalmology, Medical Faculty Mannheim of the Ruprecht- Karls-University, Heidelberg, Germany

Keywords:

blood pressure, extracranial artery stenosis, hypertension, intracranial artery stenosis, pre-hypertension Received 3 September 2014 Accepted 7 October 2014 European Journal of Neurology 2015, 22: 533–539 doi:10.1111/ene.12611

Background and purpose: Since it has remained unclear whether arterial prehypertension is a risk factor for cerebrovascular diseases, potential associations between arterial pre-hypertension and intracranial arterial stenosis (ICAS) and extracranial arterial stenosis (ECAS) were assessed. Methods: The population-based Asymptomatic Polyvascular Abnormalities in Community Study was a sub-study of employees and retirees of the coal mining industry in China. Our study examined asymptomatic polyvascular abnormalities in a general population and with an age of 40+ years without history of stroke, transient ischaemic attacks and coronary heart disease. ICAS was diagnosed by transcranial Doppler sonography and was defined by peak flow velocity criteria; ECAS was diagnosed by carotid duplex sonography and was defined by the diameter of the common carotid artery or internal carotid artery. Results: Out of 4422 study participants, 711 (16.1%) subjects showed an asymptomatic ICAS and 292 (6.6%) showed an asymptomatic ECAS. After adjusting for relevant risk factors, higher prevalence of ICAS was significantly associated with higher prevalence of pre-hypertension [odds ratio (OR) 1.55; 95% confidence interval (CI) 1.11, 2.16; P = 0.010] and hypertension (OR 1.80; 95% CI 1.53, 2.11; P < 0.001). Stratified by gender, the association was stronger for men than for women. Asymptomatic ECAS was not significantly associated with the prevalence of pre-hypertension (OR 0.78; 95% CI 0.55, 1.10) or of hypertension (OR 1.06; 95% CI 0.91, 1.24). Conclusions: The results suggest that arterial pre-hypertension in addition to hypertension is associated with a higher prevalence of asymptomatic ICAS, more in men.

Introduction Correspondence: Xingquan Zhao, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, 6 Tiantan Xili, Dongcheng District, Beijing 100050, China (tel.: 86 10 67098471; fax: 86 10 67013383; e-mail: [email protected]). Shouling Wu, Department of Cardiology, Kailuan Hospital, Hebei United University, Tangshan 063000, China (tel.: 86 315 3025655; fax: 86 315 3025655; e-mail: [email protected]). Dandan Wang and Yong Zhou contributed equally to this work and share the first authorship.

© 2014 EAN

Arterial hypertension has been recognized as one of the globally most important risk factors for the development of major causes of disability and mortality [1– 3]. This holds true in particular for cardiovascular and cerebrovascular diseases [1–5]. Arterial pre-hypertension has been defined as systolic blood pressure

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EUROPEAN JOURNAL OF NEUROLOGY

D. Wanga,b,c,d, Y. Zhoua,b,c,d, Y. Guoe, C. Wanga,b,c,d, A. Wanga,b,c,d, Z. Jinf, X. Gaog,h, S. Wui, X. Zhaoa,b,c,d and J. B. Jonasj,k,l

D. WANG ET AL.

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between 120 and 139 mmHg or a diastolic blood pressure between 80 and 89 mmHg [6]. Compared with arterial normotension, arterial pre-hypertension is associated with a higher risk of developing arterial hypertension [7]. Whilst the association between prehypertension and cardiovascular events has been shown in large-scale studies, it has remained unclear whether arterial pre-hypertension is a risk factor also for cerebrovascular diseases [8–17]. Since common pre-stages of cerebrovascular events are intracranial stenoses (ICAS) and extracranial stenoses (ECAS), this study was conducted to examine whether the prevalence of arterial pre-hypertension is associated with the presence of ICAS and ECAS and whether the ICAS and ECAS differ in their relationships with arterial pre-hypertension and hypertension.

Materials and methods The Asymptomatic Polyvascular Abnormalities in Community Study is a community-based observational study to investigate the epidemiology of asymptomatic polyvascular abnormalities in Chinese adults older than 40 years, who were without a history of stroke, transient ischaemic attack and coronary disease at baseline [18–20]. The study was performed according to the guidelines from the Helsinki Declaration and was approved by the Ethics Committees of the Kailuan General Hospital and the Beijing Tiantan Hospital. Written informed consent was obtained from all participants. Subjects were also informed of abnormal findings and recommended treatment. Subjects with incomplete data on blood pressure and vascular examination results and subjects without a good temporal window were excluded from our study. Finally, a total of 4422 participants were eligible and included in the study. Structured interviews with a standardized questionnaire were performed by trained investigators. Age

was analyzed as covariates including a cut-off value of 60 years for older age. Smoking was defined as at least one cigarette per day for more than a year. Alcohol consumption was defined as an intake of at least 80 g of liquor a day for more than 1 year. Smoking or drinking cessation was considered only if it lasted for at least 1 year. For measurement of blood pressure, the participant sat quietly for 5 min before blood pressure was measured with a mercury manometer. Three measures, taken 30 s apart, were recorded. The average of the three measurements was used for the statistical analysis. According to the recommendations of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, normal blood pressure was defined as systolic pressure 120 cm/s for the anterior cerebral artery, >100 cm/s for the posterior cerebral artery and vertebra-basilar artery, and >120 cm/s for the terminal and siphon internal carotid artery (Fig. 1). The neurologists were masked to the blood pressure measurements and other laboratory results.

400 365

347

350

300 260 250

236

200

150

93

100

68

61

50

0

48.8%

51.3%

ICA terminal

MCA

33.2%

36.6%

ICA siphon

ACA

13.1%

BA

9.6%

VA

8.6%

PCA

3 OA

0.4%

Figure 1 Prevalence of intracranial arterial stenosis stratified by the intracerebral location. ICA, internal carotid artery; MCA, middle cerebral artery; ACA, anterior cerebral artery; BA, basilar artery; VA, vertebral artery; PCA, posterior cerebral artery; OA, ophthalmic artery.

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ARTERIAL PRE-HYPERTENSION AND CEREBROVASCULAR STENOSIS

For the assessment of an ECAS, each participant underwent bilateral carotid duplex sonography. A carotid stenosis (≥50%) was graded based on the recommendations from the Society of Radiologists in Ultrasound Consensus Conference [23]. If carotid artery diameter measurements were not available, ECAS was defined by a peak systolic blood flow velocity ≥125 cm/s and a vertical artery peak systolic blood flow velocity of ≥170 cm/s in the common carotid artery or internal carotid artery. Blood samples were collected from the antecubital vein in the morning after an overnight fasting and transfused into vacuum tubes containing ethylenediaminetetraacetic acid. The blood samples underwent a biochemical analysis for measurement of the blood concentrations of glucose, uric acid, C-reactive protein, homocysteine and blood lipids. Statistical tests were carried out with a commercially available software program (SPSS software, version 21.0, IBM-SPSS, Chicago, IL, USA). Depending on the distribution of the parameters, their means were compared using Student’s t test or the non-parametric Wilcoxon test and Mann Whitney test. The chi-squared test was used for comparison of categorical variables. Binary logistic regression models were applied to assess associations between the presence of ICAS or ECAS and other parameters such as age and

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sex. Odds ratios (ORs) were calculated and their 95% confidence intervals (CIs) are presented. The null hypothesis was rejected for P < 0.05.

Results Out of the study population of 4422 persons, 711 (16.1%) subjects showed an ICAS and 292 (6.6%) subjects showed an ECAS (Table 1). The frequency of artery stenosis was highest in the internal carotid artery and lowest in the posterior cerebral artery and the ophthalmic artery (Fig. 1). In univariate analysis, pre-hypertension (OR = 1.60; P = 0.003) and hypertension (OR = 2.12; P < 0.001), in addition to a multitude of other parameters, were significantly associated with the presence of asymptomatic ICAS (Tables 1 and 2). The multivariate analysis included the presence of ICAS as dependent variable and as independent variables all those parameters (age, sex, body mass index, smoking, alcohol consumption, history of diabetes, dyslipidemia, and blood concentration of uric acid, C-reactive protein and homocysteine) (Table 1) which were significantly associated with ICAS in the univariate analysis. It revealed that the presence of ICAS remained significantly associated with pre-hypertension (OR = 1.55; P = 0.01) and hypertension (OR = 1.80; P < 0.001)

Table 1 Baseline characteristics (median, 25% interquartile range, 75% interquartile range) of patients with intracranial artery stenosis or extracranial artery stenosis in the Asymptomatic Polyvascular Abnormalities in Community Study Intracranial artery stenosis

Male (%) Age (years) Body mass index (kg/m2) Smoking (%) Alcohol consumption (%) Diabetes mellitus (%) Dyslipidemia (%) Glucose (mmol/l) Triglyceride (mmol/l) Cholesterol (mmol/l) Low-density lipoprotein (mmol/l) High-density lipoprotein (mmol/l) C-reactive protein (mg/l) Homocysteine (lmol/l) Uric acid (lmol/l) Blood pressure category Normal Pre-hypertension Arterial hypertension Use of antihypertensive drugs

© 2014 EAN

Extracranial artery stenosis

All (n = 4422)

No (n = 3711)

Yes (n = 711)

P value

No (n = 4130)

Yes (n = 292)

P value

2717 51.0 24.7 1491 667 492 2099 5.2 1.3 4.9 2.6

2268 49.7 24.7 1267 585 337 1709 5.2 1.3 4.9 2.6

449 59.2 24.8 224 82 155 390 5.4 1.3 5.2 2.7

0.31