Risk Factors and Clinical Outcomes Associated with Intracranial and Extracranial Atherosclerotic Stenosis Acute Ischemic Stroke Chunyan Lei, MD,* Bo Wu, MD, PhD,*† Ming Liu, MD, PhD,*† and Yanchao Chen, MD*

Background: The aim of this study was to investigate differences in risk factors, lipid profiles, mortality, and poor functional outcome in the long term in patients who had stroke associated with intracranial and/or extracranial atherosclerotic stenosis. Methods: We consecutively and prospectively enrolled patients admitted to our hospital with acute ischemic stroke. Included patients were classified into 4 groups based on stroke subtype: noncerebral artery stenosis (NCAS), intracranial stenosis (IS), extracranial stenosis (ES), and combined intracranial and extracranial stenosis (IES). Risk factors, lipid profiles, mortality, and poor functional outcome in the long term were compared among the stenosis subtypes. Results: In total, 1196 patients were included in the analysis. Independent IS markers were found to be diabetes mellitus (odds ratio [OR] 1.41, 95% confidence interval [CI] 1.08-1.80, P 5 .01) and low-density lipoprotein (LDL) of 2.6 mmol/L or more at admission (OR 3.48, 95% CI 2.69-4.50, P , .01). Factors that increased risk for ES and IES were male gender (ES, OR 2.26, 95% CI 1.29-3.98, P , .01; IES, OR 1.65, 95% CI 1.08-2.53, P 5 .02), older age (ES, OR 1.03, 95% CI 1.01-1.05, P 5 .02; IES, OR 1.03, 95% CI 1.01-1.04, P , .01), and LDL of 2.6 mmol/L or more (ES, OR 1.74, 95% CI 1.052.88, P 5 .03; IES, OR 2.08, 95% CI 1.36-3.18, P , .01). Poor functional outcome and mortality were significantly more frequent in the IS and IES groups than in the NCAS group at 3 months and 1 year after discharge. Conclusions: Patients with IS and IES were at higher risk of poor functional outcome and mortality than were patients with NCAS. Risk factors and lipid profiles differed among the stenosis subtypes. Thus, targeted strategies may need to take these differences into account to prevent or manage poor functional outcomes and mortality. Key Words: Atherosclerosis—risk factors—lipid profiles—poor functional outcome—mortality. Ó 2014 by National Stroke Association

Introduction Intracranial and extracranial atherosclerotic stenoses have emerged as the most common stroke subtypes worldwide, especially in Asians.1-2 However, studies have focused mainly on intracranial atherosclerotic

From the *Stroke Clinical Research Unit, Department of Neurology, West China Hospital, Sichuan University, Sichuan Province; and †State Key Laboratory of Human Disease Biotherapy and Ministry of Education, West China Hospital, Sichuan University, Sichuan Province, People’s Republic of China. Received August 12, 2013; revision received September 23, 2013; accepted September 25, 2013. Grant support: This research was supported by the Science and Technology Support Program of the Department of Science and Technology of Sichuan Province (2012FZ0006) and the National Key

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stenosis, showing that patients with this subtype are at higher risk of future vascular events.3 Thus, it is important to identify those stroke patients with intracranial and/or extracranial atherosclerosis at high risk of mortality in the long term. Several studies have suggested that

Technology R&D Program for the 12th 5-Year Plan of People’s Republic of China (2011BAI08B05). Conflict of interest: None. Address correspondence to Bo Wu, MD, PhD, Stroke Clinical Research Unit, Department of Neurology, West China Hospital, Sichuan University, No. 37 Guo Xue Xiang, Chengdu 610041, Sichuan Province, People’s Republic of China. E-mail: dragonwbtxf@ hotmail.com; [email protected]. 1052-3057/$ - see front matter Ó 2014 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2013.09.024

Journal of Stroke and Cerebrovascular Diseases, Vol. 23, No. 5 (May-June), 2014: pp 1112-1117

CEREBRAL ATHEROSCLEROTIC STENOSIS STROKE

certain risk factors, such as hypertension and diabetes, are significant predictors of cerebral artery atherosclerotic stenosis.3-7 However, it remains unclear which of these factors confers higher risk of atherosclerosis, in particular vascular locations.8 This highlights the need for large, prospective studies of the risk factors associated with intracranial and extracranial stenosis (IES). Identifying these risk factors may lead to targeted strategies that can decrease poor functional outcome and mortality after stroke. One possible risk factor for intracranial and extracranial atherosclerosis is the lipid profile, which refers to the absolute and relative amounts of low-density lipoprotein (LDL), high-density lipoprotein (HDL), cholesterol, and triglycerides. High lipid levels have been identified as an independent risk factor for atherosclerotic disease.4,9 Elevated lipid levels contribute to the initiation, progression, and subsequent rupture of atherosclerotic plaques; they inhibit the thrombolytic activity of tissue plasminogen; and they are associated with endothelial dysfunction and inflammation. Despite the clear links between high lipid levels and atherosclerosis, whether particular lipid profiles are associated with risk of intracranial and/or extracranial atherosclerosis, especially multiple intracranial and extracranial atherosclerosis, has never been systematically investigated. If lipid profiles can be used as a biological marker of intracranial and/or extracranial atherosclerosis, they may help physicians identify patients at higher risk of future ischemic events. The present study aimed to take advantage of a largescale, long-term prospective database of patients with acute ischemic stroke in China to identify risk factors of IES and examine the influence of IES on long-term recovery from ischemic stroke.

Materials and Methods

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All patients underwent neuroimaging and vascular imaging. Most patients underwent brain magnetic resonance angiography and cervical computerized tomography angiography; patients who were noncompliant or who had contraindications to magnetic resonance were analyzed instead by digital subtraction angiography. The intracranial artery was evaluated in the intracranial segment of the internal carotid and vertebral arteries, the basilar artery, the proximal segment of the middle cerebral artery (M1), the anterior cerebral artery (A1), and the posterior cerebral artery (P1). Two analysts blinded to patient clinical data independently interpreted the angiography results, and interanalyst agreement on the presence of stenosis was acceptable (k 5 0.84). When there was disagreement, a third neurologist was consulted and a consensus decision was reached. Patients with stenosis lesions were further examined to rule out cardioembolic or other obvious causes of the lesions. Only patients whose stenosis lesions were true atherosclerotic lesions were retained in the analysis.

Classification of Cerebral Atherosclerotic Stenosis Significant stenosis was defined as a more than 50% atherosclerotic stenosis or occlusion of the large intracranial and extracranial carotid arteries. Patients were classified into the following groups based on the presence and location of cerebral atherosclerotic stenosis: noncerebral artery stenosis (NCAS) group, who lacked significant atherosclerotic stenosis in the intracranial and extracranial arteries; intracranial stenosis (IS) group, who had significant atherosclerotic stenosis in the intracranial arteries but not in the extracranial ones; extracranial stenosis (ES) group, who had significant atherosclerotic stenosis in the extracranial arteries but not in the intracranial ones; and IES group, who had significant stenosis in both the intracranial and extracranial arteries.

Patients and Evaluation This study was conducted using prospective data from the Chengdu Stroke Registry Project. Details of the Chengdu Stroke Registry have been described previously.10 This registry project was approved by the Scientific Research Department of West China Hospital, and it was designed in accordance with local ethics criteria for human research. Informed consent was obtained from subjects or their guardians. In the present study, we included patients admitted between January 1, 2009 and May 31, 2012, within 7 days of ischemic stroke onset. Patients were excluded if their lipid profiles were not measured within 24 hours of hospital admission, they had any medical condition or were taking medication that might influence serum lipid levels, their neuroimaging and vascular imaging workups were incomplete, their stenosis had nonatherosclerotic causes, or they had chronic hepatic or renal failure.

Data Collection On admission, baseline information was collected on age, gender, initial stroke severity assessed by the National Institutes of Health Stroke Scale, and risk factors (hypertension, diabetes mellitus, current smokers, and current drinkers). Hypertension was defined as current use of antihypertensive medications or systolic blood pressure of 140 mm Hg or more and/or diastolic blood pressure of 90 mm Hg or more. Diabetes mellitus was defined as the use of antidiabetic medication or a fasting serum glucose level of 7.0 mmol/L or more. Patients who had smoked 1 cigarette/d or more for at least 1 year were classified as current smokers. Patients who had consumed 50 mL or more of alcohol/d for more than 1 year were defined as current drinkers. Poor functional outcome was defined as a modified Rankin Scale score above 2.

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Statistical Analysis All statistical analyses were performed using SPSS version 16 (IBM, Chicago, IL). The c2 or Fisher exact tests were used to compare group outcomes for categorical variables. Student t test, the Mann–Whitney U test, and 1-way analysis of variance were used to compare group outcomes for continuous variables when appropriate. Two-sided values of P less than .05 were considered statistically significant. Variables that were identified as significant in the univariate analysis (P # .05) were used in forward stepwise multivariate regression to examine their independent contributions to the distribution of patients among the 4 groups.

Results Baseline Characteristics The final group of patients comprised 748 men (62.5%) and 448 women (37.5%) with a mean age of 66.40 6 13.04 years. Patients were assigned to groups based on their stenosis subtype: NCAS, 501 (42.1%); IS, 492 (40.8%); ES, 79 (6.7%); and IES, 124 (10.4%). Baseline characteristics of each group are presented in Table 1. The arterial stenosis was located most frequently in the middle cerebral artery (n 5 365), followed by the internal carotid artery (proximal, 135; distal, 198), posterior cerebral artery (238), anterior cerebral artery (179), vertebral artery (proximal, 76; distal, 62), common carotid artery (74), and basilar artery (55; Fig 1).

post hoc analysis, the IS, ES, and IES groups were found to be significantly older and to have significantly higher rates of elevated cholesterol and LDL than the NCAS group. The IS and ES groups also had significantly higher rates of elevated triglyceride level than did the NCAS group. The IS group had significantly higher rates of hypertension and diabetes mellitus than did the NCAS group and higher diastolic blood pressure. Logistic regression identified the following independent markers of IS: diabetes mellitus (odds ratio [OR] 1.41, 95% confidence interval [CI] 1.08-1.80, P 5 .01) and LDL of 2.6 mmol/L or more (OR 3.48, 95% CI 2.69-4.50, P , .01; Table 2). It identified the following independent markers of ES and IES: male gender (ES, OR 2.26, 95% CI 1.29-3.98, P , .01; IES, OR 1.65, 95%CI 1.08-2.53, P 5 .02), older age (ES, OR 1.03, 95% CI 1.01-1.05, P 5 .02; IES, OR 1.03, 95%CI 1.01-1.04, P , .01), and LDL of 2.6 mmol/L or more (ES, OR 1.74, 95% CI 1.052.88, P 5 .03; IES, OR 2.08, 95% CI 1.36-3.18, P , .01; Table 2). Of the 492 patients in the IS group, 261 (67.44%) experienced multiple IS, whereas 38 of the 79 patients in the ES group (48.10%) experienced multiple ES. Regression modeling identified older age, cholesterol of 5.7 mmol/ L or more, HDL of .9 mmol/L or less, and LDL of 2.6 mmol/L or more as significantly predictive of multiple IS (Table 3). In contrast, older age, male gender, and LDL of 2.6 mmol/L or more were predictive of multiple ES (Table 3).

Mortality and Poor Functional Outcome at 3 Months and 1 Year

Risk Factors for Arterial Atherosclerotic Stenosis Patients in the IS, ES, and IES groups were more likely than those in the NCAS group to be men and older with hypertension, diabetes mellitus, and high lipid levels. In

The stenosis groups differed significantly in the proportions of patients showing poor functional outcome on the modified Rankin Scale at 3 months and 1 year after

Table 1. Risk factors associated with stroke because of intracranial and/or extracranial atherosclerotic stenosis

Variable

NACS group (n 5 501)

IS group (n 5 492)

ES group (n 5 79)

IES group (n 5 124)

Overall P

Female, n (%) Age Hypertension, n (%) Current drinker, n (%) Current smoker, n (%) Systolic BP (mm Hg) Diastolic BP (mm Hg) Diabetes mellitus Cholesterol $ 5.7 mmol/L, n (%) TG $ 1.7 mmol/L, n (%) HDL # .9 mmol/L, n (%) LDL $ 2.6 mmol/L, n (%)

198 (39.5) 62.05 6 13.72 240 (48.0) 103 (20.6) 162 (32.4) 140.94 6 23.32 82.41 6 14.34 123 (24.6%) 5 (1.0%) 126 (25.1%) 90 (18.0%) 131 (26.1%)

196 (39.9) 63.44 6 12.56* 279 (57.3)* 162 (33.4) 162 (33.4) 145.97 6 22.74 85.20 6 14.56* 166 (33.7%)* 56 (11.4%)* 186 (37.8%)* 100 (20.3%) 339 (68.9%)*

18 (22.8)* 65.74 6 12.47* 48 (59.3) 33 (40.7) 33 (40.7) 159.75 6 165.72* 81.53 6 12.47 22 (27.8%) 9 (11.4%)* 28 (35.4%)* 17 (21.5%) 51 (64.6%)*

35 (28.2)* 67.07 6 11.61* 75 (59.1) 34 (26.8) 52 (41.3) 146.75 6 21.91 83.06 6 14.23 29 (23.4%) 18 (14.6%)* 36 (29.0%) 17 (13.7%) 85 (68.5%)*

.002 ,.001 .009 .208 .166 .010 .010 .018 ,.001 .002 .480 ,.001

Abbreviations: BP, blood pressure; ES, extracranial stenosis; HDL, high-density lipoprotein; IES, intracranial and extracranial stenosis; IS, intracranial stenosis; LDL, low-density lipoprotein; NACS, noncerebral artery stenosis; TG, triglycerides. *Significantly different from the NACS group (P , .05).

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lowest in patients with NCAS (11.9%). Post hoc analysis showed mortality rates to be significantly lower in the NCAS group than in the IS group (P 5 .04) or IES group (P , .01). In contrast, the mortality rate was similar for the NCAS and ES groups (P 5 .73). Kaplan–Meier survival analysis confirmed that fewer patients died during follow-up in the NCAS group than in the IS group (P 5 .048) or IES group (P , .01).

Discussion

Figure 1. Location of atherosclerotic stenosis in the study population. Abbreviations: ACA, anterior cerebral artery; BA, basilar artery; CAA, common carotid artery; DVA, distal vertebral artery; DICA, distal internal carotid artery; MCA, middle cerebral artery; PCA, posterior cerebral artery; PICA, proximal internal carotid artery; PVA, proximal vertebral artery.

discharge (P , .01). In post hoc analysis, the proportion of patients with poor functional outcome was significantly lower in the NCAS group (3 months, 22.4%; 1 year, 17.3%) than in the IS group (37.3%, P , .01; 30.2%, P , .01) or IES group (42.7%, P , .01; 37.4%, P , .01). However, the proportions in the NCAS group were similar to those in the ES group (25.9%, P 5 .69; 22.9%, P 5 .22). These results indicate that the IS and IES groups were at greater risk of poor functional outcome at both 3 months and 1 year (Table 4). In fact, this elevated risk remained significant even after adjusting the data for age, gender, hypertension, diabetes mellitus, and National Institutes of Health Stroke Scale score on admission (Table 4). During follow-up, 182 patients (15.2%) died. Mortality rates were highest among patients with IES (23.7%), followed by patients with IS (16.5%) or ES (13.3%), and

This large prospective study in China investigated the location of cerebral atherosclerotic lesions in patients with first-ever ischemic stroke because of atherosclerotic stenosis. We found intracranial atherosclerotic lesions to be approximately 3.6-fold more frequent than extracranial atherosclerotic lesions. Atherosclerosis in the middle cerebral artery was the most frequent cause of strokes associated with atherosclerotic stenosis, followed by atherosclerosis in the internal carotid artery. Our results also showed that patients with IS and IES were at higher risk of poor functional outcome and mortality at 3 months and 1 year after discharge than were patients with NCAS, confirming and extending previous reports that patients with intracranial atherosclerosis are at greatest risk of death. Thus, early and aggressive therapy may be necessary in the high-risk group of stroke patients with intracranial and/or extracranial atherosclerosis. Our finding that different risk factors are associated with different stenosis subtypes may help clinicians individualize treatment to minimize the risk of adverse outcomes. Among our patients with diabetes mellitus, intracranial atherosclerotic lesions were more frequent than intracranial lesions, especially in patients with multiple stenosis. This is consistent with reports that diabetes mellitus is a more significant risk factor for IS than for ES.5,11,12 How diabetes contributes to intracranial large-artery occlusive disease remains unclear. It may exacerbate atherosclerotic stenosis by an unknown mechanism and decrease fibrinolytic activity by inducing insulin resistance.6,11,12 Future research should explore this apparent association

Table 2. Multivariate model to identify factors that predict location of arterial atherosclerotic stenosis Variable

IS group OR (95% CI)

P

ES group OR (95% CI)

P

IES group OR (95% CI)

P

Male gender Age increase (per 1 yr) Hypertension Diabetes mellitus Cholesterol $ 5.7 mmol/L TG $ 1.7 mmol/L HDL # .9 mmol/L LDL $ 2.6 mmol/L

.82 (.63-1.06) 1.00 (.99-1.01) 1.17 (.91-1.52) 1.41 (1.08-1.8) 1.41 (.87-12.29) 1.14 (.92-1.43) 1.12 (.88-1.43) 3.48 (2.69-4.50)

.13 .53 .22 .01 .17 .24 .36 ,.01

2.26 (1.29-3.98) 1.03 (1.01-1.05) 1.123 (.76-2.00) 1.02 (.60.-1.73) 1.08 (.46-2.53) 1.07 (.70-1.61) 1.16 (.73-1.87) 1.74 (1.05-2.88)

,.01 .02 .40 .95 .86 .77 .52 .03

1.65 (1.08-2.53) 1.03 (1.01-1.04) 1.11 (.75-1.66) .76 (.49-1.20) 2.05 (1.12-3.72) .91 (.59-1.40) .69 (.39-1.22) 2.08 (1.36-3.18)

.02 ,.01 .58 .24 .02 .67 .20 ,.01

Abbreviations: ES, extracranial stenosis; IES, intracranial and extracranial stenosis; IS, intracranial stenosis; TG, triglycerides.

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Table 3. Multivariate model to identify factors that predict multiple extracranial or intracranial atherosclerotic stenosis Multiple IS

Multiple ES

Variable

OR (95% CI)

P

OR (95% CI)

P

Male gender Age increase (per 1 yr) Hypertension Diabetes mellitus Cholesterol $ 5.7 mmol/L TG $ 1.7 mmol/L HDL # .9 mmol/L LDL $ 2.6 mmol/L

.94 (.72-1.22) 1.01 (1.00-1.02) 1.24 (.82-1.45) 1.09 (.82-1.45) 1.68 (1.05-2.71) 1.01 (.79-1.29) 2.15 (1.89-3.47) 3.21 (2.45-4.23)

.63 .01 .11 .53 .03 .94 .02 ,.01

3.80 (1.55-9.32) 1.05 (1.02-1.08) 1.47 (.73-3.00) 1.03 (.92-1.17) 1.14 (.38-3.46) 1.27 (.79-2.05) .68 (.25-1.84) 2.17 (1.04-4.55)

,.01 ,.01 .28 .59 .82 .33 .45 .04

Abbreviations: CI, confidence interval; ES, extracranial stenosis; HDL, high-density lipoprotein; IS, intracranial stenosis; LDL, low-density lipoprotein; OR, odds ratio; TG, triglycerides.

between diabetes mellitus and intracranial atherosclerotic lesions in greater depth. We found lipid profiles to differ significantly between patients with IS or ES, supporting and extending previous findings that high lipid levels are an independent risk factor for atherosclerosis in patients with ischemic stroke or coronary heart disease in various ethnic groups.4,6,7-9 Specifically, our results suggest that a high LDL level and low HDL level are independent markers of IS, particularly of multiple IS. These findings are consistent with a recent study showing that treatments aimed at simultaneously raising HDL and lowering LDL in patients with artery atherosclerotic disease are more effective than treatments that only lower LDL.13 The observed role of elevated LDL as a biomarker of atherosclerotic stenosis in stroke may reflect its potential ability to contribute to the pathogenesis of atherosclerosis through several mechanisms. High levels of LDL, especially of the oxidized form of LDL, promote endothelial dysfunction, an initial step in atheroma formation. They also promote the growth and migration of smooth muscle cells, monocytes/macrophages, and fibroblasts; they upregulate endothelial expression of adhesion molecules; and they impair endothelium-dependent vasomotor function. All these processes play important roles in atherosclerosis.14,15 Although elevated LDL has been identified as a risk factor of atherosclerotic stenosis stroke, HDL has been

identified as a strong, independent protective factor. HDL slows or prevents the formation of atherosclerotic lesions by removing excess cholesterol from cells and preventing endothelial dysfunction.16 HDL also shows antioxidative, anti-inflammatory, and antiapoptopic activity. Moreover, HDL can retard the oxidation of LDL and limit its atherogenicity.17 Our results, together with these previous studies, strengthen the case for designing treatments that not only reduce LDL but also increase HDL in patients with atherosclerotic stenosis stroke. Our results suggest that male gender and older age are independent markers of ES, consistent with previous studies.4,18 Older age is not directly associated with extracranial atherosclerosis but rather indirectly as an index of exposure to cerebrovascular risk factors. Our results further implicate elevated serum lipids as a risk factor for ES, consistent with several other studies.3,7,19 Our study has some limitations. First, its design was cross-sectional, so we could not directly assess the prognostic impact of different lipid profiles and cerebrovascular risk factors in patients with symptomatic intracranial and/or extracranial atherosclerosis. Second, our study population was hospital based, so it may not accurately reflect what happens in the general population. Despite its limitations, our study is one of the largest prospective investigations so far of patients with acute ischemic stroke caused by intracranial and/or extracranial atherosclerosis. Patients presented different lipid

Table 4. OR and 95% CI for poor functional outcome because of ischemic stroke caused by IS or combined IES Unadjusted OR (95% CI)

IS IES

Adjusted OR (95% CI)*

3 mo

1y

3 mo

1y

1.69 (1.32-2.17) 1.81 (1.25-2.62)

1.56 (1.20-2.03) 1.92 (1.31-2.81)

1.45 (1.09-1.98) 1.48 (1.11-2.30)

1.37 (1.01-1.85) 1.55 (1.13-2.42)

Abbreviations: CI, confidence interval; ES, extracranial stenosis; IES, intracranial and extracranial stenosis; IS, intracranial stenosis; OR, odds ratio. *Data were adjusted for age, gender, hypertension, diabetes mellitus, and National Institutes of Health Stroke Scale score on admission.

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profiles and cerebrovascular risk factors and different rates of mortality and poor functional outcome in the long term, depending on whether their atherosclerosis was intracranial and/or extracranial. These differences may help clinicians individualize treatment to prevent recurrent vascular events and decrease mortality.

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1117 9. Kim DE, Kim JY, Jeong SW, et al. Association between changes in lipid profiles and progression of symptomatic intracranial atherosclerotic stenosis: a prospective multicenter study. Stroke 2012;43:1824-1830. 10. Wu B, Lin S, Hao Z, et al. Proportion, risk factors and outcome of lacunar infarction: a hospital-based study in a Chinese population. Cerebrovasc Dis 2010;29: 181-187. 11. Chaturvedi S, Turan TN, Lynn MJ, et al. Risk factor status and vascular events in patients with symptomatic intracranial stenosis. Neurology 2007;69:2063-2068. 12. Turan TN, Makki AA, Tsappidi S, et al. Risk factors associated with severity and location of intracranial arterial stenosis. Stroke 2010;41:1636-1640. 13. Muntner P, Lee F, Astor BC. Association of high-density lipoprotein cholesterol with coronary heart disease risk across categories of low-density lipoprotein cholesterol: the atherosclerosis risk in communities study. Am J Med Sci 2011;341:173-180. 14. Mitra S, Deshmukh A, Sachdeva R, et al. Oxidized lowdensity lipoprotein and atherosclerosis implications in antioxidant therapy. Am J Med Sci 2011;342:135-142. 15. Paoletti R, Gotto AM Jr, Hajjar DP. Inflammation in atherosclerosis and implications for therapy. Circulation 2004;109:III20-III26. 16. Savel J, Lafitte M, Pucheu Y, et al. Very low level of HDL cholesterol and atherosclerosis, a variable relationship—a review of LCAT deficiency. Vasc Health Risk Manag 2012; 8:357-361. 17. Mackness B, Mackness M. The antioxidant properties of high-density lipoproteins in atherosclerosis. Panminerva Med 2012;54:83-90. 18. de Weerd M, Greving JP, de Jong AW, et al. Prevalence of asymptomatic carotid artery stenosis according to age and sex systematic review and metaregression analysis. Stroke 2009;40:1105-1113. 19. den Hartog AG, Achterberg S, Moll FL, et al. Asymptomatic carotid artery stenosis and the risk of ischemic stroke according to subtype in patients with clinical manifest arterial disease. Stroke 2013;44:1002-1007.

Risk factors and clinical outcomes associated with intracranial and extracranial atherosclerotic stenosis acute ischemic stroke.

The aim of this study was to investigate differences in risk factors, lipid profiles, mortality, and poor functional outcome in the long term in patie...
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