Role of the RNF213 Variant in Vascular Outcomes in Patients With Intracranial Atherosclerosis.

Background The RNF213 (ring finger protein 213 gene) variant R4810K is a susceptibility allele not only for Moyamoya disease (MMD) but also for intracranial atherosclerosis (ICAS) in East Asian populations. We hypothesized that this variant would affect the distribution of ICAS and recurrence of cerebrovascular events. Methods and Results We conducted a prospective study of patients with ICAS and MMD using high-resolution magnetic resonance imaging and RNF213 R4810K genotyping. Patients were included in the ICAS group when relevant plaques existed on high-resolution magnetic resonance imagingand in the MMD group when they carried the variant and high-resolution magnetic resonance imaging showed no plaques but characteristic features of MMD. We compared clinical and neuroimaging features of patients with ICAS-RNF213+ with patients with ICAS-RNF213- and of patients with MMD. Of 477 patients, 238 patients were in the ICAS group and 239 were in the MMD group. Among patients with ICAS, 79 patients (33.2%) were in the ICAS-RNF213+ group and 159 (66.8%) in the ICAS-RNF213- group. Tandem lesions were significantly more common in the ICAS-RNF213+ group than in the ICAS-RNF213- group (40.3% versus 72.2%, P<0.001), and their distributions were similar between the ICAS-RNF213+ and MMD groups. The presence of the R4810K variant (hazard ratio [HR], 3.203; 95% CI, 1.149-9.459; P=0.026) and tandem lesions (≥3) (HR, 8.315; 95% CI, 1.930-39.607; P=0.005) were independently associated with recurrent cerebrovascular events. Conclusions Patients with ICAS carrying the RNF213 R4810K variant showed clinical and imaging features distinct from patients with ICAS without the variant, suggesting that the R4810K variant plays a role in intracranial atherosclerosis in East Asian patients.

SNP rs2043211 (p.C10X) in CARD8 Is Associated with Large-Artery Atherosclerosis Stroke in a Chinese Population.

SNP rs2043211 in CARD8 was found to have significant association with ischemic stroke. This study aimed to explore the possible association between rs2043211 and large-artery atherosclerosis stroke in Chinese and explain the possible mechanism. In total, 716 large-artery atherosclerosis stroke patients and 1088 controls were included in the study. Co-dominant, dominant, and recessive genetic models were constructed to evaluate the relationship between rs2043211 and large-artery atherosclerosis stroke risk by odds ratios with 95% confidence intervals. Stratified and interaction analyses were also done. We selected another 111 large-artery atherosclerosis stroke patients and measured the CARD8 levels in their plasma samples by enzyme-linked immunosorbent assay. Participants who carry T/T genotype have a higher risk of large-artery atherosclerosis stroke compared with those carry A/T or A/A genotypes (odds ratio = 1.35, 95% confidence intervals 1.03-1.77, P = 0.029). The higher risk for the T/T genotype is still notable in female, people with hypertension, and people without diabetes. In the interaction analysis, compared to the non-hypertensive participants with the wild homozygote type A/A, the hypertensive participants with the A/T+T/T homozygote had 3.27-fold increased risk (odds ratio = 3.27, 95% confidence intervals 2.33-4.60). The A/A group had lower CARD8 levels in plasma than the A/T and T/T group (P < 0.001). Further bioinformatics prediction indicated that the rs2043211 could significantly influence the mRNA secondary structure and protein expression of CARD8 (eQTL P = 9.8 × 10-198). The rs2043211 is probably a novel biomarker for large-artery atherosclerosis stroke in Chinese.

MMP9 rs17576 Is Simultaneously Correlated with Symptomatic Intracranial Atherosclerotic Stenosis and White Matter Hyperintensities in Chinese Population.

PURPOSE: The aim of this study was screening for single nucleotide polymorphisms (SNPs) associated with white matter hyperintensities (WMHs) in symptomatic intracranial atherosclerotic stenosis (sICAS) patients and exploring a possible connection in the genetic background between macrovascular disease and small vessel disease. METHODS: There were 400 sICAS patients enrolled in the study. Fazekas scores were applied to WMH classification. Healthy controls were referred to 1,000 Genome Project and GeneSky company who provided 1,007 Chinese healthy controls. Fast target sequencing technology was used to select the SNPs of 102 genes related to the pathogenesis of sICAS in the sICAS patients. RESULTS: The allele frequencies of 88 SNPs were significantly different between the sICAS group and the healthy controls (p < 0.05). The allele frequencies of 53 SNPs were significantly different between the sICAS patients with and without WMHs (p < 0.05). Further analysis found that matrix metalloproteinase 9 (MMP9) rs17576 was simultaneously related to sICAS and WMHs. The frequency of the rs17576 A allele was significantly lower in sICAS patients when compared to the normal controls (p = 0.03, OR [95% CI] = 0.75 [0.625-0.91]). Also, the frequency of the rs17576 genotypes was significantly different under codominant (p = 0.009), dominant (p = 0.014), and recessive (p= 0.023) models. The frequency of the rs17576 A allele was significantly higher in sICAS with WMH patients, compared to those without WMHs (p = 0.022, OR [95% CI] = 1.54 [1.06-2.22]); the frequency of the rs17576 genotypes was significantly different under codominant (p = 0.019) and recessive (p = 0.032) models. Logistic regression analysis showed that age, hypertension, and MMP9 rs17576 AA genotype were independent risk factors for sICAS with WMHs. CONCLUSION: MMP9 rs17576 may be simultaneously associated with the risk of sICAS and WMHs.

Prevalence and Correlates of Intracranial Atherosclerotic Disease Among Community-Dwelling Older Adults of Amerindian Ancestry. The Three Villages Study.

BACKGROUND: Knowledge on the prevalence and correlates of intracranial atherosclerotic disease (ICAD) is limited. We aimed to assess prevalence, clinical and neuroimaging correlates of ICAD in a cohort of older adults of Amerindian ancestry. METHODS: The study included 581 community-dwellers aged ≥60 years (mean age 71 ± 8.4 years; 57% women) living in rural Ecuadorian villages. ICAD was identified by means of CT determinations of carotid siphon calcifications (CSC) or MRA findings of significant stenosis of intracranial arteries. Fully-adjusted logistic regression models were fitted with biomarkers of ICAD as the dependent variables. RESULTS: A total of 205 (35%) of 581 participants had ICAD, including 185 with high calcium content in the carotid siphons and 40 with significant stenosis of at least one intracranial artery (20 subjects had both biomarkers). Increasing age, high fasting blood glucose, >10 enlarged basal ganglia-perivascular spaces and non-lacunar strokes were associated with high calcium content in the carotid siphons. In contrast, male gender, moderate-to-severe white matter hyperintensities, lacunar and non-lacunar strokes were associated with significant stenosis of intracranial arteries. Stroke was more common among subjects with any biomarker of ICAD than in those with no biomarkers (29% versus 9%, p < 0.001). Significant stenosis of intracranial arteries was more often associated with stroke than high calcium content in the carotid siphons, suggesting that CSC are more likely an ICAD biomarker than causally related to stroke. CONCLUSIONS: ICAD prevalence in Amerindians is high, and is significantly associated with stroke. CSC and significant stenosis of intracranial arteries may represent different phenotypes of ICAD.

A Preliminary Study of the Association between Apolipoprotein E Promoter Methylation and Atherosclerotic Cerebral Infarction.

AIM: To investigate association of Apolipoprotein E (ApoE) gene promoter methylation with atherosclerotic cerebral infarction (ACI) in the Han Chinese population. METHODS: Twenty-six ACI patients (the case group) and 26 healthy (the control group) were recruited randomly from Henan Han nationality population, from April 2016 to August 2016. Bisulfite pyrosequencing technology was used to examine the role of the aberrant gene promoter methylation in ACI in Han Chinese population. Especially, we used the odds ratio and 95% confidence interval (95% CI) method to elevate the correlation between ApoE Promoter Methylation and ACI. RESULTS: The case group was significantly more likely to have hypertension and carotid atherosclerotic plaques (Table 1). The case group had significantly lower levels of high-density lipoprotein cholesterol (HDL-C), folate, and higher levels of homocysteine (Table 2). We observed that ACI patients (n = 26) had significantly higher methylation levels at cytosine-phosphate-guanine (CpG) 14 and CpG16 compared with controls (n = 26) (Table 3). Importantly, our results indicated a significant association between ApoE promoter methylation and ACI (OR = 16.146; 95% CI, 1.154-225.832; P* < .05; P*: adjusted for age, gender, carotid atherosclerotic plaque, hypertension, HDL-C, homocysteine, and folate) (Table 4). CONCLUSIONS: Our study indicates that ApoE promoter methylation may be associated with ACI in Han Chinese people.

Intracranial artery stenosis magnetic resonance imaging aetiology and progression study: Rationale and design.

BACKGROUND: It has been shown that intracranial artery stenosis (ICAS) plays a key role in Chinese ischemic stroke or transient ischemic attack (TIA) patients. Many vascular diseases can lead to ICAS, such as atherosclerosis, dissection, vasculitis, moyamoya disease, and reversible cerebral vasoconstriction syndrome (RCVS). In addition, progression of intracranial atherosclerotic disease (ICAD) will increase the risk of ischemic cerebrovascular events. The ICASMAP study primarily aims to determine the etiology and disease distribution of ICAS using noninvasive magnetic resonance (MR) imaging and evaluate the rate for progression of ICAD in symptomatic population. METHODS: The ICASMAP study is a prospective, observational, and multicenter study by recruiting 300 subjects (18-80 years old) with recent stroke or TIA (within 2 weeks after onset of symptoms) in China. All the subjects will undergo MR imaging examination including brain and intracranial artery MR imaging at baseline. In addition, the clinical risk factors will be collected and blood biomarkers will be tested. A subgroup of more than 200 subjects who were diagnosed with ICAD according to baseline MR imaging will be followed up for 2 years. During the follow-up study, MR imaging examination will be performed at 12 and 24 months. The primary end point is presence of progression of intracranial artery atherosclerotic plaques. CONCLUSIONS: The ICASMAP study investigates the etiology of ICAS and progression of ICAD in Chinese stroke patients and may help to improve the precise diagnosis and intervention of ICAS and stroke prevention.

Distribution of Cervicocephalic Atherosclerotic Lesions and Their Correlation with Cardiovascular Risk Factors in a Population of Amerindians. The Atahualpa Project.

BACKGROUND: No information is available on the distribution of cervicocephalic atherosclerosis in Amerindians. We aimed to assess the distribution of these lesions and their correlation with cardiovascular risk factors in Amerindians living in rural Ecuador. METHODS: Atahualpa residents aged ≥40years underwent head CT for assessment of carotid siphon calcifications (CSC) and sonographic examination for measurement of the carotid intima media thickness (cIMT). CSC were used as a surrogate of intracranial atherosclerosis and the cIMT as a surrogate of extracranial atherosclerosis. Linear regression and multinomial logistic regression models were fitted to assess the association between cIMT and CSC, and to evaluate differences in risk factors across individuals with atherosclerosis involving both arterial beds when compared with those with extra- or intracranial atherosclerosis alone, or no atherosclerosis. RESULTS: Of 590 participants, 145 had high calcium content in the carotid siphons and 87 had a cIMT >1mm (25% versus 15%, P < .001). Thirty-eight (7%) individuals had atherosclerosis at both vascular beds, 107 (18%) had intracranial atherosclerosis, and 49 (8%) had extracranial atherosclerosis alone. The cIMT and CSC were independently associated (P = .008). When compared with participants without atherosclerosis, those with atherosclerosis at both vascular beds were older, more often male, hypertensive and diabetic. Subjects with intracranial atherosclerosis alone were older, and those with extracranial atherosclerosis alone reported less physical activity than those without atherosclerosis. CONCLUSION: Intracranial atherosclerosis is more common than extracranial atherosclerosis in Amerindians. Traditional risk factors only explain a minority of cases of cervicocephalic atherosclerosis in this population.

Distribution and Temporal Trends From 1993 to 2015 of Ischemic Stroke Subtypes: A Systematic Review and Meta-Analysis.

BACKGROUND AND PURPOSE: Preventive strategies, together with demographic and socioeconomic changes, might have modified the worldwide distribution of ischemic stroke (IS) subtypes. We investigated those changes by means of a systematic review and meta-analysis. METHODS: We evaluated all population- and hospital-based studies reporting the distribution of IS etiologic subtypes according to the TOAST criteria (Trial of ORG 10172 in Acute Stroke Treatment). Studies were identified by searching articles indexed on PubMed and Scopus from January 1, 1993, to June 30, 2017. Two independent investigators extracted data and checked them for accuracy. Proportions of each etiologic subtype were pooled according to a random effect meta-analytic model weighted by study size; temporal trends were assessed using a mixed-effect meta-regression model. RESULTS: Sixty-five studies including patients from 1993 to 2015 were finally included. Overall, ISs were attributed to cardioembolism (22%; 95% confidence interval [CI], 20-23); large artery atherosclerosis (23%; 95% CI, 21-25); small artery occlusion (22%; 95% CI, 21-24); other determined cause (3%; 95% CI, 3-3); and undetermined cause (26%; 95% CI, 24-28). Cardioembolism was the leading IS etiologic subtype in whites (28%; 95% CI, 26-29) and large artery atherosclerosis in Asians (33%; 95% CI, 31-36). Meta-regression showed an increasing temporal trend for cardioembolism in whites (2.4% annually, P=0.008) and large artery atherosclerosis in Asians (5.7% annually, P<0.001), and a decrease for small artery occlusion in whites (-4.7% annually, P=0.001); there was considerable heterogeneity across all the analyses. CONCLUSIONS: According to our systematic review and meta-analysis, cardioembolism in whites and large artery atherosclerosis in Asians are the leading causes of IS. The heterogeneous distribution of etiologic subtypes of IS may depend on the demographic and socioeconomic characteristics of the different populations. More extensive protocols should be adopted to reduce the persistently relevant proportion of undetermined cause IS.

Racial Differences in Prevalence and Risk for Intracranial Atherosclerosis in a US Community-Based Population.

Importance: Intracranial atherosclerotic disease (ICAD) is an important cause of stroke; however, little is known about racial differences in ICAD prevalence and its risk factors. Objective: To determine racial differences in ICAD prevalence and the risk factors (both midlife and concurrent) associated with its development in a large, US community-based cohort. Design, Setting, and Participants: Analysis of 1752 black and white participants recruited from the Atherosclerosis Risk in Communities (ARIC) cohort study who underwent 3-dimensional intracranial vessel wall magnetic resonance imaging from October 18, 2011 to December 30, 2013; data analysis was performed from October 18, 2011 to May 13, 2015. Exposures: Midlife and concurrent cardiovascular risk factors. Main Outcomes and Measures: Intracranial plaque presence, size (maximum normalized wall index) and number were assessed by vessel wall magnetic resonance imaging. Midlife and concurrent vascular risk factor associations were determined by Poisson regression (plaque presence), negative binominal regression (plaque number), and linear regression (plaque size), and compared between races. Results: Of the 1752 study participants (mean [SD] age, 77.6 [5.3] years; range, 67-90 years), 1023 (58.4%) were women and 518 (29.6%) were black. Black men had the highest prevalence (50.9% vs 35.9% for black women, 35.5% for white men, and 30.2% for white women; P < .001) and the highest frequency (22.4% vs 12.1% for black women, 10.7% for white men, and 8.7% for white women; P < .01) of multiple plaques. Prevalence increased with age, reaching 50% before ages 68, 84, and 88 years in black men, white men, and white women, respectively (ICAD prevalence remained <50% in black women). Midlife hypertension and hyperlipidemia were associated with 29% (prevalence ratio [PR], 1.29; 95% CI, 1.08-1.55) and 18% (PR, 1.18; 95% CI, 0.98-1.42), respectively, increased ICAD prevalence with no significant differences between races. Midlife hypertension was also associated with larger plaques (1.11 higher mean maximum normalized wall index; 95% CI, 0.21-2.01). Midlife smoking and diabetes were associated with increased risk of ICAD in black individuals (102% [PR, 2.02; 95% CI, 1.12-3.63] and 57% [PR, 1.57; 95% CI, 1.13- 2.19], respectively), but not in white participants (P < .05 interaction by race). Conclusions and Relevance: The prevalence of ICAD was highest in black men. Midlife smoking and diabetes were strongly associated with late-life ICAD in blacks only, whereas midlife hypertension and hyperlipidemia were associated with late-life ICAD in both races. These associations may help to explain racial differences in US stroke rates and offer insight into preventive risk-factor management strategies.

Correlation of Plasma Vascular Endothelial Growth Factor and Endostatin Levels with Symptomatic Intra- and Extracranial Atherosclerotic Stenosis in a Chinese Han Population.

BACKGROUND: Symptomatic intracranial atherosclerotic stenosis (ICAS) and extracranial atherosclerotic stenosis (ECAS) are different in many aspects. Here, we explored the association between the location or severity of atherosclerotic stenosis and pro- or antiangiogenic factors, specifically vascular endothelial growth factor (VEGF) and endostatin (ES). METHODS: We evaluated 198 consecutive patients with acute ischemia stroke: 132 with large-artery atherosclerosis (LAA) and 66 with small-artery occlusion (small-vessel occlusion). The LAA group was subclassified into 102 patients with ICAS and 30 with ECAS. Independent associations of VEGF, ES levels, and VEGF/ES ratio with the location of cerebral stenosis and the severity or short-term prognosis (14th day modified Rankin Scale) of ICAS were evaluated. RESULTS: Plasma concentrations of VEGF and ES were lower (P < .05) in ICAS (38.07, 32.76-46.28 pg/mL and 58.95, 55.04-59.77 ng/mL) than those in ECAS (45.00, 34.30-83.34 pg/mL and 140.74, 85.63-231.21 ng/mL). Logistic regression analysis showed that VEGF concentrations and dyslipidemia were independently associated with ICAS, with odds ratios of .987 [95% CI = (.976, .998)] and .265 [95% CI = (.103, .792)], respectively. Moreover, plasmatic VEGF levels increased gradually along with the severity of ICAS (P = .003), and lower levels of ES (P = .040) or a higher VEGF/ES ratio (P = .048) were related to unfavorable short-term prognosis of ICAS. CONCLUSION: Lower VEGF levels are associated with the presence of symptomatic ICAS, but not with ECAS. Furthermore, the severity of ICAS is positively correlated with the levels of VEGF, and lower ES levels or a predominance of VEGF over ES are predictors of poor short-term prognosis of ICAS.

Adiponectin Gene Polymorphism and Ischemic Stroke Subtypes in a Chinese Population.

As an adipose tissue-specific protein, adiponectin has been suggested as a protective factor for stroke, acting through anti-inflammatory and antiatherogenic effects. Therefore, we aimed to investigate whether 3 polymorphisms (rs1501299, rs2241767, and rs3774261) in the adiponectin (ADIPOQ) gene and their haplotypes were associated with ischemic stroke (IS) and its subtypes in a Chinese population. ADIPOQ gene rs1501299, rs2241767, and rs3774261 polymorphisms were analyzed in 385 IS patients, including 182 patients with large-artery atherosclerosis (LAA), 203 patients with small-vessel occlusion (SVO), and 418 matched controls. The subjects were genotyped by using polymerase chain reaction-restriction fragment length polymorphism analysis. In univariate logistic analysis, the A allele frequency of rs2241767 was moderately higher in IS and LAA patients than that in controls (P = .028 and P = .017, respectively). Compared with the wide-type AA homozygote, both the genotype GG and the dominant model (GG+AG) of rs2241767 moderately increased the risk of LAA (P = .040 and P = .034, respectively). In multivariate logistic regression analysis, the genotype GG of rs2241767 was independently related to IS and LAA patients (adjusted, odds ratio [OR] = 1.822, 95% confidence interval [CI]: 1.037-3.202, P = .037 and OR = 2.051, 95% CI: 1.041-4.041, P = .038, respectively) rather than SVO. In contrast, no relationship was observed between the polymorphism of rs1501299 and rs3774261 and either subtype of IS using both univariate and multivariate logistic regression analyses. In addition, the Trs1501299-Grs2241767-Ars3774261 haplotype showed a moderately increased risk of IS and LAA (OR = 1.595, 95% CI: 1.058-2.406, P = .025 and OR = 1.709, 95% CI: 1.047-2.789, P = .031, respectively) but not of SVO. In conclusion, this study tentatively demonstrated that the polymorphism of rs2241767 and the Trs1501299-Grs2241767-Ars3774261 haplotype were associated with susceptibility to IS and LAA in a Chinese population.

Smoking and white matter hyperintensity progression: the ARIC-MRI Study.

OBJECTIVE: Our objective was to examine the link between smoking and smoking history, including smoking intensity and cessation, overall and by race, in a biracial prospective cohort study. METHODS: A subset of Atherosclerosis Risk in Communities Study participants (n = 972, 49% black) completed brain MRI scans twice (1993-1995 and 2004-2006). We defined white matter hyperintensity (WMH) progression as an increase of ≥2 points on the 9-point Cardiovascular Health Study scale across scans. Participants reported information on smoking behavior at the baseline MRI and at 2 prior study visits, approximately 3 and 6 years before baseline. We used adjusted logistic regression to evaluate the association between smoking variables and WMH progression in the total sample and separately by race (black and white). RESULTS: We found WMH progression in 23% of participants (30% of black participants, 17% of white participants). Overall, being a current smoker 6 years before baseline was associated with WMH progression. In race-stratified analyses, we found adverse associations with smoking status at multiple time points and persistent smoking in white but not in black participants. However, we found no statistical support for effect modification by race for most of these analyses. Increasing pack-years of smoking was associated with greater risk of WMH progression, while time since quitting and age at smoking initiation were not associated with WMH progression, with little indication of differences in these associations by race. CONCLUSIONS: Our findings concur with previous studies suggesting a relationship between smoking and WMH progression, and further demonstrate a dose-dependent association.

Intracranial carotid artery atherosclerosis and the risk of stroke in whites: the Rotterdam Study.

IMPORTANCE: Intracranial atherosclerosis represents a relatively unexplored, but potentially important, cause of stroke in a white population. OBJECTIVE: To investigate the relationship between intracranial carotid artery calcification (ICAC) as a marker of intracranial atherosclerosis and the risk of stroke in whites. DESIGN, SETTING, AND PARTICIPANTS: A population-based cohort study in the general community with 6 years of follow-up was conducted (the Rotterdam Study). Between 2003 and 2006, a random sample of 2323 stroke-free persons (mean age, 69.5 years) underwent computed tomography scanning to quantify ICAC volume. All participants were continuously monitored for the occurrence of stroke until January 1, 2012. EXPOSURE: Atherosclerotic calcification in the intracranial internal carotid arteries. MAIN OUTCOME AND MEASURE: Incident stroke. RESULTS: During 14,055 person-years of follow-up, 91 participants had a stroke, of which 74 were ischemic. Larger ICAC volume was related to a higher risk of stroke, independent of cardiovascular risk factors, ultrasound carotid plaque score, and calcification in other vessels (fully adjusted hazard ratio per an increase of 1 SD in ICAC volume, 1.43 [95% CI, 1.04-1.96]). Intracranial carotid artery calcification contributed to 75% of all strokes; for aortic arch and extracranial carotid artery calcification this incidence was only 45% and 25%, respectively. CONCLUSIONS AND RELEVANCE: Our findings establish intracranial atherosclerosis as a major risk factor for stroke in the general white population and suggest that its contribution to the proportion of all strokes may be greater than that of large-artery atherosclerosis in more proximally located vessel beds.

Synergistic effect of ALOX5AP polymorphisms and cigarette smoking on the risk of atherosclerotic cerebral infarction in a Northern Han Chinese population.

The effect of activating 5-lipoxygenase (ALOX5AP) gene polymorphisms on stroke risk may be influenced by the coexistence of modifiable predisposing conditions. We explored the interactions of ALOX5AP polymorphisms and cigarette smoking in a case-control study of patients with atherosclerotic cerebral infarction (ACI). Three polymorphisms of the ALOX5AP gene (rs10507391, rs4769874, and rs9551963) were analyzed in 420 ACI patients and 488 unrelated healthy controls matched for age and sex from a Northern Han Chinese population. Among the three single nucleotide polymorphisms, only rs10507391 genotype TT/TA was observed to be associated with an increased risk of ACI on multivariate analysis (odds ratio [OR]=1.82, 95% confidence interval [CI]=1.14-2.92, p=0.012) compared with the AA genotype. However, after stratifying by smoking status, multivariate logistic regression analysis revealed that rs10507391 genotype TT/TA and rs9551963 genotype CC/CA had a 5.63-fold (OR=5.63, 95%CI=2.00-15.84, p=0.001) and a 2.71-fold (OR=2.71, 95%CI=1.28-5.73, p=0.009) increased risk for ACI patients who smoked compared with the AA genotype, respectively. Additionally, according to the haplotype analysis, the risk of haplotype TGC (OR=3.12, 95%CI=2.00-4.88, p<0.001, corrected p [pc]<0.001) increased for ACI patients who smoked compared to the data (OR=1.60, 95%CI=1.28-1.98, p<0.001, pc<0.001) in total samples. These results suggest that ALOX5AP polymorphisms are associated with ACI, and cigarette smoking along with ALOX5AP could increase the risk of ACI.

Prevalence of symptomatic intracranial atherosclerosis in Caucasians: a prospective, multicenter, transcranial Doppler study.

BACKGROUND: There are limited data available regarding symptomatic intracranial atherosclerosis (SIA) prevalence in Caucasians. We sought to investigate SIA prevalence among Caucasian patients hospitalized with acute cerebral ischemia (ACI) in a prospective, multicenter Transcranial Doppler sonography (TCD) study. METHODS: Consecutive patients with ACI were prospectively evaluated with TCD over a 24-month-period. The previously validated criteria of SONIA trial were used for detection of >50% intracranial stenosis with TCD. Brain angiography was performed to confirm the diagnosis in cases with abnormal TCD findings. SIA was diagnosed when there was evidence of a cerebral infarction in the territory of the stenotic artery (identified by TCD and confirmed by Magnetic resonance angiography [MRA]/Computed tomography angiography [CTA]). RESULTS: A total of 467 consecutive patients with ACI (60.4% men, mean age 58 ± 14 years) were evaluated. SIA was documented in 43 patients (9.2%; 95%CI: 6.9%-12.2%). The most common SIA location was M1MCA (34.9%) followed by TICA (18.8%). Diabetes mellitus (OR: 4.25, 95%CI: 2.18-8.26; P < .001) and hypertension (OR: 2.41, 95%CI: 1.02-5.67; P = .045) were independently associated with SIA on multivariate models adjusting for potential confounders. CONCLUSIONS: SIA was identified in almost 10% of patients admitted with symptoms of ACI. These preliminary findings support further collaborative initiatives among stroke physicians to increase the yield of SIA detection in Caucasian patients with ACI.

Geographic and sex difference in the distribution of intracranial atherosclerosis in China.

BACKGROUND AND PURPOSE: Geographic variation and sex difference in the distribution of intracranial atherosclerosis (ICAS) have not been fully discussed before in Chinese patients with cerebral ischemia. We performed this study with the aim to investigate geographic and sex difference in the distribution of ICAS in China. METHODS: In this prospective multicenter study, we evaluated 2864 consecutive patients who experienced an acute cerebral ischemia within 7 days of symptom onset in 22 hospitals in China. All the inclusive patients underwent 3-dimensional time-of-flight MR angiography and duplex color Doppler ultrasound or contrast-enhanced MR angiography to document the presence of intracranial or extracranial stenosis. Intracranial large-artery atherosclerosis was defined as ≥50% diameter reduction on MR angiography. RESULTS: The proportion of patients with ICAS was significantly higher in north China than in south China (50.22% versus 41.88%; P<0.0001). Patients in the north were likely to consume more alcohol and smoke more cigarettes and had significantly higher proportion of diabetes mellitus, family history of stroke, history of cerebral ischemia, heart disease, and higher body mass index. In patients aged >63 years, the percentage of ICAS in women was notably higher than in men (51.51% versus 45.40%; P=0.028). In elderly patients, women had higher proportion of diabetes mellitus, hypertension, hyperlipidemia, and heart disease than men. CONCLUSIONS: There exists geographic and sex difference in the distribution of symptomatic ICAS in China. Public health measures should strengthen improving social determinants of health and risk factor prevention/control in high-risk populations for decreasing stroke risk.

Stroke radiology and distinguishing characteristics of intracranial atherosclerotic disease in native South Asian Pakistanis.

BACKGROUND: There are no descriptions of stroke mechanisms from intracranial atherosclerotic disease in native South Asian Pakistanis. METHODS: Men and women aged ≥ 18 years with acute stroke presenting to four tertiary care hospitals in Karachi, Pakistan were screened using magnetic resonance angiography/transcranial Doppler scans. Trial of ORG 10172 in Acute Stroke Treatment criteria were applied to identify strokes from intracranial atherosclerotic disease. RESULTS: We studied 245 patients with acute stroke due to intracranial atherosclerotic disease. Two hundred thirty scans were reviewed. Also, 206/230 (89.0%) showed acute ischaemia. The most frequent presentation was with cortically based strokes in 42.2% (87/206) followed by border-zone infarcts (52/206, 25.2%). Increasing degrees of stenosis correlated with the development of both cortical and border-zone strokes (P = 0.002). Important associated findings were frequent atrophy (166/230, 72.2%), silent brain infarcts (66/230, 28%) and a marked lack of severe leukoaraiosis identified in only 68/230 (29.6%). A total of 1870 arteries were studied individually. Middle cerebral artery was the symptomatic stroke vessel in half, presenting with complete occlusion in 66%. Evidence of biological disease, symptomatic or asymptomatic was identified in 753 (40.2%) vessels of which 543 (72%) were significantly (>50%) stenosed at presentation. CONCLUSION: Intracranial atherosclerotic disease is a diffuse process in Pakistani south Asians, with involvement of multiple vessels in addition to the symptomatic vessel. The middle cerebral artery is the most frequent symptomatic vessel presenting with cortical embolic infarcts. There is a relative lack of leukoaraiosis. Concomitant atrophy, silent brain infarcts and recent ischaemia in the symptomatic territory are all frequently associated findings.

The Barcelona-Asymptomatic Intracranial Atherosclerosis (AsIA) study: prevalence and risk factors.

BACKGROUND AND PURPOSE: The ongoing population-based Barcelona-Asymptomatic Intracranial Atherosclerosis (Barcelona-AsIA) study is a prospective study that plans to investigate the natural history of asymptomatic intracranial atherosclerosis (AsIA) in a Caucasian-Mediterranean population, which remains unknown until now. The present study aims to determine the prevalence of AsIA and associated risk factors in the final study cohort. METHODS: Crossover, population-based study of a representative sample (randomly selected from our reference population) older than 50 with a moderate-high vascular risk assessed by the vascular equation REGICOR and prior history of neither stroke nor ischemic heart disease. Anthropometric, demographic, clinical data and blood samples were collected at baseline. All individuals underwent a complete extracranial and transcranial color-coded duplex (TCCD) examination. TCCD criteria were used to identify and classify the degree of intracranial stenoses. RESULTS: A total of 933 subjects (64% men, mean age 66.3 years) were included in the study. One or more intracranial stenoses were detected at baseline in 80 subjects (8.6%) of whom 31 (3.3%) had moderate-severe lesions. The higher the REGICOR scores the greater the prevalence of AsIA (6.6%, 10.2% and 25% for REGICOR scores 5-9, 10-14 and ≥15, p<0.001). Diabetes (OR 2.95; 95% CI (1.68-5.18); p<0.001), age (OR 1.05; 95% CI (1.02-1.08); p=0.001) and hypertension (OR 1.78; 95% CI (1.02-3.13); p=0.04) were independently associated with any degree of AsIA, while diabetes (OR 2.85; 95% CI (1.16-6.96); p=0.02) and age kept independently associated with moderate-severe AsIA. CONCLUSION: The prevalence of AsIA and moderate-severe AsIA in stroke-free Caucasians with a moderate-high vascular risk were 8.6% and 3.3% respectively. Diabetes and age were independently associated with moderate-severe AsIA.

Coexistent extra- and intracranial stenosis, cervical atherosclerosis, and abnormal ankle brachial index in acute ischemic stroke.

BACKGROUND: There are limited data regarding abnormal ankle brachial index (ABI) with coexistent extracranial carotid stenosis (ECS), intracranial stenosis (ICS), and nonstenotic cervical atherosclerosis (CAS) in stroke, especially in Asia. METHODS: We studied the prevalence of ECS, ICS, CAS, and combined ECS and ICS in 756 Thai patients with acute ischemic stroke and correlated sites of atherosclerosis with stroke risk factors and abnormal ABI. RESULTS: The prevalence of ECS was 8.8%, ICS 52.6%, CAS 36.0%, abnormal ABI 18.8%, combined ECS and ICS 4.6%, combined ECS and abnormal ABI 2.8%, combined ICS and abnormal ABI 10.6%, and combined ECS, ICS, and abnormal ABI 1.6%. The prevalence of ECS, CAS, and combined ECS and ICS was higher in abnormal ABI compared to normal ABI (14.8% v 7.5% [P = .006]; 46.5% v 33.5% [P = .004], and 8.4% v 3.7% [P = .016], respectively). ECS was significantly correlated with history of coronary artery disease (CAD) and abnormal ABI; ICS with male gender, no alcohol use, and no atrial fibrillation; CAS with age ≥ 60 years, history of CAD and abnormal ABI; and combined ECS and ICS with history of CAD. CONCLUSIONS: The frequency of atherosclerosis, especially ICS, was high. Cervicocerebral atherosclerosis was higher in abnormal ABI. This suggests that ischemic stroke patients should be screened for ECS, CAS, ICS, and abnormal ABI, especially in specific subsets (age ≥ 60 years, male gender, and history of CAD). The improved identification of vascular lesions could allow for a more optimal choice of antithrombotics, neurointervention, and more aggressive control of risk factors, potentially improving prevention of disease progression and a decrease in recurrent vascular events.