Extracranial Atherosclerosis Research Articles

Reduced endothelial progenitor cells in extracranial arterial stenosis but not intracranial arterial stenosis

Endothelial progenitor cells (EPCs) are novel markers of endothelial dysfunction and are related to cardiovascular disease. However, their relationship with cerebral atherosclerosis (CA) has not been investigated extensively. We aim to study the relationship between CA severity and EPC subpopulations levels. We enrolled 197 patients in this study. EPCs were measured by flow cytometry. Digital subtraction angiography was used to assess CA. Arterial lesion severity was evaluated among cerebral arteries which showed steno-occlusion change and the extent of that condition. There was a significant inverse correlation between EPCs level and CA prevalence after adjusting for confounders (CD45(-/dim)CD34(+)CD309(+) cells: odds ratio [OR], 0.110; 95% confidence interval [CI], 0.026-0.475; P = .00; CD45(-/dim)CD133(+)CD309(+) cells: OR, 0.134; 95% CI, 0.030-0.599; P = .01; CD45(-/dim) CD34(+)CD133(+)CD309(+) cells: OR, 0.010; 95% CI, 0.001-0 .541, P = .02). Multivariate logistic regression analysis showed that only the EPCs level was significantly inversely associated with extracranial atherosclerosis rather than intracranial atherosclerosis (P > .05). Our data indicated that EPCs subpopulations were independent predictors for CA severity, even after controlling for traditional risk factors.

Intracranial versus Extracranial Symptomatic Carotid Atherosclerosis in Chinese Patients: Risk Factors, Stroke Mechanisms, and Long-Term Prognosis

This study aims to investigate the clinical-radiological features and stroke mechanisms of symptomatic intracranial internal carotid artery (IICA) atherosclerosis and prognoses of patients with IICA atherosclosis, and compare these data with those from patients with symptomatic extranial carotid artery (EICA) atherosclerosis. We prospectively recruited 155 patients with symptomatic IICA or EICA atherosclerosis (stenosis ≥50% or occlusion) from 1968 Chinese patients with a first-ever ischemic stroke or transient ischemic attack. The patients were followed up for stroke recurrence, cardiovascular events, and death. There were 80 and 75 patients in the IICA and EICA groups, respectively. Multivariate logistic regression analyses showed that the patients in the IICA group were associated with hypertension (odds ratio [OR], 5.980; 95% confidence interval [CI], 1.790-19.976) and asymptomatic intracranial atherosclerosis (OR, 2.564; 95% CI, 1.222-5.377), while the patients in the EICA group were associated with smoking (OR, 2.397; 95% CI, 1.150-4.998) and contralateral EICA disease (OR, 4.742; 95% CI, 1.455-15.455). Hemodynamic stroke alone was more common in the IICA group; artery-to-artery embolism was identified more often in the EICA group (P <.05). The cumulative incidences of ipsilateral stroke recurrence, stroke recurrence and cardiovascular events, and death at 5 years were 43.5%, 52.4%, and 27.3%, respectively, in the patients of the IICA group, which did not differ from those of the EICA group. IICA atherosclerosis as well as EICA atherosclerosis is an important cause of stroke in Chinese patients. Patients with symptomatic IICA atherosclerosis had unique clinical-radiological features and stroke mechanisms compared with those with symptomatic EICA atherosclerosis; their long-term prognosis was poor.

Characterization of intracranial atherosclerotic stenosis using high-resolution MRI study--rationale and design.

Intracranial atherosclerosis is a leading cause of stroke, but little is known about the composition of the intracranial atherosclerotic lesion and how intracranial plaque morphology is related to the risk of stroke. High-resolution magnetic resonance imaging (HR MRI) has been used in patients with extracranial carotid atherosclerosis as an invivo tool to identify, with high-interrater agreement, histologically defined plaque components (i.e., intraplaque hemorrhage, fibrous cap, and lipid core), which have been shown to be predictors of recurrent stroke. With careful imaging the components ofatherosclerotic plaque can be visualized in the intracranial arteries using HRMRI, but there are no reports of reproducibility or interrater reliability. The Characterization of intracranial atherosclerotic stenosis using high-resolution MRI (CHIASM) study is a single-center NIH-funded prospective observational study, to (1) demonstrate high -interrater agreement for identifying intracranial plaque components on HR MRI, (2) determine the frequency of these components in symptomatic versus asymptomatic plaques, and (3) estimate the 1-year rate of stroke in the territory of high-risk plaque components. CHIASM will recruit 90 patients with 50-99% intracranial atherosclerosis to undergo HRMRI of the intracranial artery plaque at enrollment and 1-year follow-up. Both symptomatic and asymptomatic subjects will be recruited. Determination of good interrater reliability is an important first step in the development of HR MRI as a tool to predict risk in patients with intracranial atherosclerosis. This study will inform the design of future multicenter studies to determine the prevalence and prognosis of intracranial atherosclerotic plaque components. Such studies could lead to new understanding of the pathophysiological mechanisms of cerebral ischemia in patients with atherosclerotic intracranial stenosis, improvements in risk stratification, and potentially to new treatments of this common and serious disease.

Advantage in Bright-blood and Black-blood Magnetic Resonance Imaging with High-resolution for Analysis of Carotid Atherosclerotic Plaques.

Background:About 50% of the cerebral ischemia events are induced by intracranial and extracranial atherosclerosis. This study aimed to evaluate the feasibility and accuracy for displaying atherosclerotic plaques in carotid arteries and analyzing their ingredients by using high-resolution new magnetic resonance imaging (MRI) techniques.Methods:Totally, 49 patients suspected of extracranial carotid artery stenosis were subjected to cranial MRI scan and magnetic resonance angiography (MRA) examination on carotid arteries, and high-resolution bright-blood and black-blood MRI analysis was carried out within 1 week. Digital subtraction angiography (DSA) examination was carried out for 16 patients within 1 month.Results:Totally, 103 plaques were detected in the 49 patients, which were characterized by localized or diffusive thickening of the vessel wall, with the intrusion of crescent-shaped abnormal signal into lumens. Fibrous cap was displayed as isointensity in T1-weighted image (T1WI) and hyperintensities in proton density weighted image (PDWI) and T2-weighted image (T2WI), lipid core was displayed as isointensity or slight hyperintensities in T1WI, isointensity, hyperintensities or hypointensity in PDWI, and hypointensity in T2WI. Calcification in plaques was detected in 11 patients. Eight patients were detected with irregular plaque surface or ulcerative plaques, which were characterized by irregular intravascular space surface in the black-blood sequences, black hypointensity band was not detected in three-dimensional time-of-flight, or the hypointensity band was not continuous, and intrusion of hyperintensities into plaques can be detected. Bright-blood and black-blood techniques were highly correlated with the diagnosis of contrast-enhanced MRA in angiostenosis degree, Rs = 0.97, P < 0.001. In comparison to DSA, the sensitivity, specificity, and accuracy of MRI diagnosis of stenosis for ≥50% were 88.9%, 100%, and 97.9%, respectively.Conclusions:High-resolution bright-blood and black-blood sequential MRI analysis can accurately analyze ingredients in atherosclerotic plaques. Determined by DSA, MRI diagnosis of stenosis can correctly evaluate the serious degree of arteriostenosis.

Epicardial fat volume is related to atherosclerotic calcification in multiple vessel beds

To investigate relationships between epicardial fat volume and atherosclerosis in multiple major vessel beds. From the population-based Rotterdam Study, 2298 participants underwent computed tomography examinations to quantify epicardial fat volume and atherosclerotic calcification volume in the coronary arteries, aortic arch, and extracranial and intracranial internal carotid arteries. Using linear regression modelling, we investigated relationships of epicardial fat volume with atherosclerotic calcification volume in each vessel bed, adjusting for conventional cardiovascular risk factors (waist circumference, systolic and diastolic blood pressure, total and high-density lipoprotein cholesterol, smoking, diabetes, and usage of blood pressure-lowering and lipid-lowering medication). To test whether associations of epicardial fat with calcification per vessel bed were independent of calcification elsewhere, we created a model in which all vessel beds were entered together. We found that a larger epicardial fat volume was associated with larger calcification volumes in the coronary arteries, aortic arch, and extracranial carotid arteries in both sexes. After adjustment for cardiovascular risk factors, larger epicardial fat volume was related to coronary and extracranial carotid artery calcification volume in males only [difference in calcification volume per SD increase in epicardial fat volume: 0.12 (95% confidence interval, CI: 0.04; 0.19) and 0.14 (95% CI: 0.06; 0.22)]. These associations remained unchanged after entering all vessel beds into one model. Larger volumes of epicardial fat are associated with larger amounts of coronary and extracranial carotid artery atherosclerosis in males, independent of cardiovascular risk factors. This could imply that epicardial fat also exerts a systemic effect on atherosclerosis development. Future longitudinal research is warranted to further disentangle these relationships with a specific focus on sex differences.

Evaluation of intracranial and extracranial atherosclerosis

Ischemic stroke brings heavy social and family burden because of its high morbidity, mortality, disability rate and recurrence rate. Intracranial and extracranial atherosclerosis is an important cause of ischemic stroke throughout the world and is associated with a high risk of recurrent stroke. The comprehensive evaluation of atherosclerosis plays an important role in risk stratification and clinical decision making. This paper makes a brief review on the main evaluation indexes and common assessments of intracranial and extracranial atherosclerosis. DOI: 10.3969/j.issn.1672-6731.2015.03.005

Compensatory intracranial arterial dilatation in extracranial carotid atherosclerosis: the Northern Manhattan study.

There is a scarcity of data supporting the association between atherosclerosis and dolichoectasia in unbiased samples. To test the hypothesis that the association between dolichoectasia and extracranial carotid atherosclerosis depends on the degree of collateral circulation. The Northern Manhattan Study magnetic resonance imaging substudy consists of 1290 participants who remained stroke-free at the time of magnetic resonance imaging. Arterial diameters were collected in all participants with available magnetic resonance angiography. Dolichoectasia was defined as a head-size adjusted diameter >2 standard deviation for each artery. Carotid Doppler was used to evaluate for carotid atherosclerosis (carotid plaque, maximum plaque thickness and carotid intima media thickness). We included 994 participants with available Doppler and magnetic resonance angiography data (mean age 63 years, 60% female). Any dolichoectasia was reported in 16% of participants, 54% had at least one carotid plaque and the mean carotid intima media thickness was 0·92 ± 0·09 mm. After adjusting for demographic and clinical characteristics, there was no association between markers of carotid atherosclerosis and dolichoectasia. However, stratifying by collaterals, it was observed that dolichoectasia was more likely in the anterior and posterior circulations when collaterals were available among participants with carotid atherosclerosis. These associations were confirmed by noting an increment in arterial diameters in the corresponding arteries ipsilateral and contralateral to each carotid as well as in the posterior circulation. We did not find an association of extracranial carotid atherosclerosis with dolichoectasia. However, we found that dolichoectasia is more frequent when intracranial collaterals are available suggesting a compensatory process that needs further investigation.

Abstract T MP57: Coexisting Cerebrovascular Disease and Risk of Occult Atrial Fibrillation in Patients With Embolic Stroke of Undetermined Source

Background and objective: Secondary prevention after embolic stroke of undetermined source (ESUS) remains a clinical problem. Presence of asymptomatic cerebral large-artery atherosclerosis or small vessel disease could be aprioristically taken as an indicator of a lower risk for an occult cardiac source of emboli, thus influencing our secondary prevention strategy. We aimed to study the relationship between presence and degree of coexisting cerebrovascular disease and the risk of occult paroxysmal atrial fibrillation (OPAF) in ESUS patients. Methods: Longitudinal prospective study in patients fulfilling ESUS criteria after complete neurovascular and cardiac diagnostic workup, who were implanted with a subcutaneous REVEAL-XT loop-recorder to detect OPAF and followed-up for≥ 6 months. At baseline, cerebral large-artery atherosclerosis was assessed with cervical and transcranial ultrasound. Brain magnetic resonance imaging was used to evaluate small vessel disease. Periventricular (PV) and subcortical (SC) white matter hiperintensities (WMH) were categorized using the Fazekas score. Results: We studied 136 ESUS patients from October 2010 to December 2013 (71 men, mean age 67), who were followed-up for a mean time of 594 days. OPAF was detected in 56 (41%) of them. No relationship was found between extracranial or intracranial atherosclerosis and OPAF. Kaplan-Meier curves and crude Cox-regression analyses found associations between OPAF risk and age, smoking, CHA2DS2VASC score, presence of lacunar infarctions, and presence and degree of PVWMH &amp; SCWMH. A multivariable-adjusted Cox regression model identified grade 2-3 PVWMH (HR 3.6, [2.0-6.5], p&lt;0.001) and age as independent predictors of OPAF. Conclusion: Coexisting small vessel disease, specifically in the form of periventricular WMH, is a predictor of OPAF in ESUS patients. Presence of large-artery atherosclerosis does not lower the risk for OPAF. Therefore, OPAF should be actively pursued in ESUS patients regardless the coexistence of asymptomatic cerebrovascular disease.

Association of Apolipoprotein A1, B with Stenosis of Intracranial and Extracranial Arteries in Patients with Cerebral Infarction.

To investigate the distribution of stenosis of intracranial and extracranial arteries of Han population patients suffering from cerebral infarction in the city of Quanzhou in Fujian and to determine the correlation of apolipoprotein A1 and apolipoprotein B with intracranial and extracranial atherosclerosis stenosis. For this study, we enrolled patients with cerebral infarction between December 2009 and October 2012 at the Neurology Department of The Second Affiliated Hospital of Fujian Medical University. All patients were examined by computed tomography angiography (CTA). Past medical history, demographic data, and biochemical markers were collected. Multiple logistic regression analysis was used to study the association between apo A1, apo B, and cerebral atherosclerosis stenosis. A total of 412 patients were included in this study. 137 cases (33.3%) were classified as the intracranial atherosclerosis stenosis (ICAS) group, 74 cases (18.0%) as the combined intracranial and extracranial atherosclerosis stenosis (COAS) group, 44 cases (0.7%) as the extracranial atherosclerosis stenosis (ECAS) group, and 157 cases (38.1%) as the non-cerebral atherosclerosis stenosis (NCAS) group. Middle cerebral arteries (43.8%) were the most common lesions of intracranial arterial atherosclerosis stenosis. Extracranial carotid stenosis (30.7%) were more likely to be stenoses in the extracranial internal carotid arteries. Compared with the NCAS group, apo B was significantly higher (p < 0.001), apo A1 was significantly lower in the ICAS group and COAS group (p = 0.02 and p = 0.030). Compared with the mild atherosclerosis stenosis group, apo B was higher in the severe extracranial atherosclerosis stenosis group (p = 0.03), apo A1 was lower in the severe intracranial atherosclerosis stenosis group (p < 0.001). The multiple logistic regression analyses showed that when apo A1 > 1.28 g/L, it was an independent protective factor of intracranial stenosis (OR, 0.39), apo B was an independent risk factor of the cerebral atherosclerosis stenosis group, and when apo B > 1.16, it is significantly associated with the cerebral atherosclerosis stenosis group (ICAS: OR, 6.41) (ECAS: OR, 5.15). 1. The occurrence of atherosclerosis stenosis in intracranial arteries is more frequent than that in extracranial arteries in population with cerebral infarction; 2. Apo B is an independent risk factor of intracranial and extracranial arterial stenosis, apo A1 is associated with the degree of intracranial stenosis and an independent protector of intracranial stenosis.

Embolic strokes of undetermined source in the Athens stroke registry: a descriptive analysis.

A new clinical construct termed embolic stroke of undetermined source (ESUS) was recently introduced, but no such population has been described yet. Our aim is to provide a detailed descriptive analysis of an ESUS population derived from a large prospective ischemic stroke registry using the proposed diagnostic criteria. The criteria proposed by the Cryptogenic Stroke/ESUS International Working Group were applied to the Athens Stroke Registry to identify all ESUS patients. ESUS was defined as a radiologically confirmed nonlacunar brain infarct in the absence of (a) extracranial or intracranial atherosclerosis causing ≥50% luminal stenosis in arteries supplying the ischemic area, (b) major-risk cardioembolic source, and (c) any other specific cause of stroke. Among 2735 patients admitted between 1992 and 2011, 275 (10.0%) were classified as ESUS. In the majority of ESUS (74.2%), symptoms were maximal at onset. ESUS were of moderate severity (median National Institute Health Stroke Scale score, 5). The most prevalent risk factor was arterial hypertension (64.7%), and 50.9% of patients were dyslipidemic. Among potential causes of the ESUS, covert atrial fibrillation (AF) was the most prevalent: in 30 (10.9%) patients, AF was diagnosed during hospitalization for stroke recurrence, whereas in 50 (18.2%) patients AF was detected after repeated ECG monitoring during follow-up. Also, covert AF was strongly suggested in 38 patients (13.8%) but never recorded. About 10% of patients with first-ever ischemic stroke met criteria for ESUS; covert paroxysmal AF seems to be a frequent cause of ESUS.

Effects of neck radiation therapy on extra-cranial carotid arteries atherosclerosis disease prevalence: systematic review and a meta-analysis.

IntroductionRadiation arteritis following neck irradiation as a treatment for head and neck malignancy has been well documented. The long-term sequelae of radiation exposure of the carotid arteries may take years to manifest clinically, and extra-cranial carotid artery (ECCA) stenosis is a well-recognised vascular complication. These carotid lesions should not be regarded as benign and should be treated in the same manner as standard carotid stenosis. Previous studies have noted increased cerebrovascular events such as stroke in this cohort of patients because of high-grade symptomatic carotid stenosis resulting in emboli.AimTo evaluate the effect of radiation therapy on ECCA atherosclerosis progression.MethodsOnline search for case-control studies and randomised clinical trials that reported on stenosis in extra-cranial carotid arteries in patients with neck malignancies who received radiation therapy (RT) comparing them to patients with neck malignancies who did not receive RT.ResultsEight studies were included in the final analysis with total of 1070 patients – 596 received RT compared to 474 in the control group. There was statistically significant difference in overall stenosis rate (Pooled risk ratio = 4.38 [2.98, 6.45], P = 0.00001) and severe stenosis (Pooled risk ratio = 7.51 [2.78, 20.32], P <0.0001), both being higher in the RT group. Pooled analysis of the five studies that reported on mild stenosis also showed significant difference (Pooled risk ratio = 2.74 [1.75, 4.30], 95% CI, P = 0.0001).ConclusionThe incidence of severe ECCA stenosis is higher among patients who received RT for neck malignancies. Those patients should be closely monitored and screening programs should be considered in all patients who receive neck RT.

Progression of intracranial major artery stenosis is associated with baseline carotid and intracranial atherosclerosis.

Intracranial atherosclerotic major artery stenosis (IMAS) is associated with a high risk of ischemic stroke. Carotid ultrasound (US) has been widely used to evaluate an individual's atherosclerotic burden, but no information is available on whether the carotid US findings are associated with IMAS progression. The aim of the present study was to identify the associations among traditional risk factors, the duplex carotid US findings and IMAS progression in patients with varying degrees of carotid atherosclerosis. All patients who underwent a set of imaging studies (MRI, MRA and carotid US) in our outpatient clinic were screened. A total of 101 patients with a mean age of 75.0±10.6 years, who received the same imaging studies with a mean interval of two years, were studied. In each patient, the extent of stenosis of three arteries (both middle cerebral arteries [MCAs] and the basilar artery [BA]) was classified into five grades. The total score of the three arteries was calculated as the global stenosis score (GSS). The progression of IMAS was defined as worsening of stenosis by ≥1 grade on final MRA. The maximum IMT (maxIMT), plaque findings and carotid stenosis were measured by carotid US. A multivariate stepwise logistic regression analysis was used to identify independent predictors of IMAS progression. Follow-up MRA revealed IMAS progression in 12 patients (11.9%). The logistic regression analysis demonstrated that the baseline GSS (p=0.008) and carotid stenosis ≥70% on the baseline carotid US (p=0.023) were significantly associated with IMAS progression. The baseline severity of intracranial and extracranial atherosclerosis was significantly associated with the progression of IMAS.

High Frequency of Intracranial Arterial Stenosis and Cannabis Use in Ischaemic Stroke in the Young

Background: Leading aetiologies of ischaemic stroke in young adults are cervico-cerebral arterial dissections and cardio-embolism, but the causes remain undetermined in a considerable proportion of cases. In a few reports, intracranial arterial stenosis has been suggested to be a potential cause of ischaemic stroke in young adults. The aim of our work was to evaluate the frequency, characteristics and risk factors of intracranial arterial stenosis in a prospective series of young ischaemic stroke patients. Methods: The study was based on a prospective consecutive hospital-based series of 159 patients aged 18-45 years who were admitted to our unit for an acute ischaemic stroke from October 2005 to December 2010. A structured questionnaire was used in order to assess common vascular risk factors such as hypertension, diabetes, hypercholesterolemia, use of tobacco, alcohol and illicit drugs, migraine, and, in women, oral contraceptive use. A systematic screening was performed, including the following: brain magnetic resonance imaging or, if not feasible, brain computed tomography scan, carotid and vertebral Duplex scanning and trans-cranial Doppler sonography, 3D time-of-flight magnetic resonance cerebral angiography or cerebral computed tomography angiography. Long-duration electrocardiography, trans-thoracic and trans-oesophageal echocardiography were performed and laboratory blood investigations were extensive. Urine samples were screened for cannabinoids, cocaine, amphetamine and methylene-dioxy-methamphetamine. When this initial work-up was inconclusive, trans-femoral intra-arterial selective digital subtraction angiography with reconstructed 3D images was performed. Results: In this series, 49 patients (31%) had intracranial arterial stenosis. Other defined causes were found in 91 patients (57%), including cardio-embolism in 32 (20%), cervical dissection in 23 (14%), extracranial atherosclerosis in 7 (4%), haematological disorders in 7 (4%), small vessel disease in 1, and isolated patent foramen ovale in 21 (13%); in 19 patients (12%), ischaemic stroke was related to an undetermined aetiology. Comparing risk factors between patients with intracranial arterial stenosis and those with other definite causes showed that there were only two significant differences: a lower age and a higher frequency of vasoactive substances (especially cannabis) in patients with intracranial arterial stenosis. All intracranial arterial stenosis in patients who used vasoactive substances were located in several intracranial vessels. Conclusions: Intracranial arterial stenosis may be an important mechanism of stroke in young patients and it should be systematically investigated using vascular imaging. Strong questioning about illicit drug consumption (including cannabis) or vasoactive medication use should also be performed. It should be emphasized for health prevention in young adults that cannabis use might be associated with critical consequences such as stroke.

Abstract T P129: Association of Increased Serum Alkaline Phosphatase with Intracranial Atherosclerosis

Background: Vascular calcification is strongly associated with cardiovascular morbidity and mortality by reducing arterial elastance. Recently alkaline phosphatase (ALP) is identified as the critical factor for vascular calcification, but no clinical studies investigating relevance of ALP and cerebral atherosclerosis have been reported. In this study, we assessed the hypothesis that increased levels of serum ALP may be associated with severity of cerebral atherosclerosis. Methods: From October 2010 to March 2012, we prospectively included total 518 patients (313 men/205 women) aged 25-96 years with acute ischemic stroke. Cardioembolic stroke patients were excluded because of the interference by acute arterial embolic occlusion. The patients were divided by baseline measurements into quantiles of ALP levels (&lt;58, 58-69, 70-89, &gt;90 IU/L). Bilateral middle cerebral arteries, distal internal carotid arteries and basilar artery were selected for the evaluation of intracranial atherosclerosis, bilateral proximal internal carotid arteries and common carotid arteries for the extracranial atherosclerosis. We defined significant arterial stenosis as moderate or more stenosis (50-100%) evaluated by at least one angiographic study using MR angiography, CT angiography or digital subtraction angiography. Statistical analyses were performed using the multivariate logistic regression analysis adjusted for age, gender, hypertension, diabetes, dyslipidemia, smoking, presence of secondary prevention, serum calcium levels. Results: In the multivariate logistic regression analysis, compared with the first ALP quantile, adjusted odds ratio of the third and fourth quantiles for significant intracranial atherosclerosis were 2.30 (95% confidence interval 1.06-5.01) and 3.84 (1.78-8.30). There was no significant correlation between ALP levels and significant extracranial atherosclerosis. Conclusions: In conclusion, our study demonstrated that increased serum levels of ALP are an independent risk factor for significant intracranial atherosclerosis.

Serum calcium and phosphate concentrations and intracranial atherosclerosis

ObjectiveSerum calcium and phosphate concentrations are independent risk factors for stroke and positively associated with extracranial carotid atherosclerosis. We evaluated whether higher serum calcium and phosphate concentrations would be associated with intracranial atherosclerosis in a stroke-free Korean population. MethodsWe retrospectively analyzed the records of 361 stroke-free subjects who consecutively visited a general health promotion center. Included subjects had serum calcium, phosphate, and albumin drawn and underwent brain magnetic resonance angiography. The basilar, middle cerebral, intracranial internal carotid, and intracranial vertebral arteries were evaluated. Serum calcium concentration was corrected for serum albumin concentration. ResultsMean ± SD values were 52 ± 10 years for age, 2.35 ± 0.09 mmol/l for uncorrected serum calcium concentration, 2.24 ± 0.08 mmol/l for corrected serum calcium concentration, and 1.19 ± 0.18 mmol/l for serum phosphate concentration. Seventy-four subjects (21%) had intracranial atherosclerosis. Subjects in the upper three quartiles of corrected serum calcium concentration had a significantly greater risk for intracranial atherosclerosis compared with the lowest quartile with the odds ratios of 3.50 (95% confidence interval 1.50–8.15), 3.11 (95% confidence interval 1.26–7.69), and 3.77 (95% confidence interval 1.58–9.03), respectively. However, serum phosphate and uncorrected serum calcium concentrations were not associated with intracranial atherosclerosis. ConclusionCorrected serum calcium concentrations are positively associated with the presence of intracranial atherosclerosis.

Comparacoes preliminares entre a histologia virtual ultrassonografica in vivo e os achados histopatologicos da placa carotidea produto de endarterectomia

CONTEXTO: A doença aterosclerótica da carótida extracraniana é uma das principais causas evitáveis de acidente vascular cerebral isquêmico (AVCi), sendo este a segunda causa mais comum de morte nos países desenvolvidos. Nos grandes estudos sobre a cirurgia carotídea, a indicação estava embasada fundamentalmente no grau de estenose arterial. Analisar somente o grau de estenose, entretanto, não revela todas as características da placa, na medida em que a morfologia e a composição da placa complementam a avaliação da doença carotídea avançada e são fundamentais para a análise e o acompanhamento da maioria das placas carotídeas tratadas clinicamente. OBJETIVO: Correlacionar a caracterização dos componentes da placa de ateroma pela histologia virtual ultrassonográfica (HVUS) com a histologia. MÉTODOS: As imagens pré-operatórias obtidas por ultrassonografia transcutânea de 12 placas de ateroma de bifurcação carotídea foram submetidas a um programa de computador, o qual correlacionou os níveis de cinza com os prováveis componentes da placa da bifurcação carotídea (HVUS). Estes achados foram correlacionados com o exame anatomopatológico das placas coletadas pela cirurgia de endarterectomia. RESULTADOS: O coeficiente de correlação de Pearson para os conteúdos de lipídeos e músculo/tecido fibroso foram, respectivamente, R=0,83 para gordura e R=0,91 para músculo/tecido fibroso. Quanto ao cálcio e ao sangue, foram R=0,05 e R=0,19, respectivamente. CONCLUSÕES: O presente trabalho corrobora a literatura demonstrando que a histologia virtual computadorizada baseada em ultrassonografia transcutânea apresenta boa correlação com os achados da histologia quanto ao conteúdo da placa. Maiores estudos para a padronização da técnica e o aperfeiçoamento do programa de análise permitirão maior uso clínico deste método.

Genetic Variant RNF213 c.14576G&gt;A in Various Phenotypes of Intracranial Major Artery Stenosis/Occlusion

Recently, we reported a common genetic variant, ring finger protein 213 (RNF213) c.14576G>A variant, a susceptibility gene for moyamoya disease (MMD), among patients with intracranial major artery stenosis/occlusion (ICASO) in a selected Japanese population. The aim of this 2-center-based case-control study was to confirm our previous finding in a larger population. Study participants were recruited from The University of Tokyo Hospital and Kanto Neurosurgical Hospital. The occurrence rate of c.14576G>A variant was investigated in 323 patients, 22 with definite MMD, 8 with unilateral MMD, 84 with ICASO in the absence of MMD (non-MMD ICASO), 34 with extracranial carotid atherosclerosis, 44 with cerebral aneurysm, 21 with intracerebral hemorrhage, and 110 control subjects. RNF213 c.14576G>A variant was found in 1.8% (2/110) of the normal control group and had significant associations with definite MMD (P<0.0001; odds ratio, 144.0; 95% confidence interval, 26.7-775.9), unilateral MMD (P=0.0001; odds ratio, 54.0; 95% confidence interval, 7.5-386.8), and non-MMD ICASO (P<0.0001; odds ratio, 16.8; 95% confidence interval, 3.81-74.5). There was no significant association with extracranial carotid atherosclerosis, cerebral aneurysm, or intracerebral hemorrhage. This result replicated our previous findings. A particular subset of patients with various phenotypes of ICASO has a common genetic variant, RNF213 c.14576G>A, indicating that RNF213 c.14576G>A variant is a high-risk allele for ICASO.

Prevalence of intracranial large artery stenosis and occlusion in patients with acute ischaemic stroke or TIA

Intracranial large artery stenosis and occlusion disease has been considered to be the cause of 8–10 % of ischaemic strokes in North America, and 30–50 % of strokes and more than 50 % of transient ischaemic attacks in Chinese population. So far we do not know the real prevalence of intracranial disease (ID) and the distribution of its risk factors in European population. We aimed to determine the prevalence and risk factors of ID in a European stroke population with computed tomography angiography (CTA). A retrospective study of consecutive ischaemic patients at the Stroke Unit of Utrecht, The Netherlands, from September 2006 to August 2008 was conducted. We assessed the presence of occlusion and/or stenosis of intracranial Internal Carotid Artery (ICA) and Middle Cerebral Artery on post-contrast 30-mm reconstruction axial CTA images. We analyzed the proportion of patients with ID, and the association of ID with risk factors and stroke subtype. In 220 patients (187 with stroke, 33 with TIA; mean age was 65 years, 57.3 % were male), intracranial stenosis was found in 6.4 % (95 % CI 3.9–10.4), intracranial occlusion in 34.5 % (95 % CI 28.6–41.0), and both occlusion and stenosis in 2.3 % (95 % CI 1.0–5.2). Multivariate analysis showed that the variables independently associated with ID were: extracranial ICA atherosclerosis (OR, 24.64; 95 % CI 6.30–96.38) and stroke subtypes TACS–PACS (OR, 7.61; 95 % CI 3.31–17.49). In conclusion, prevalence of intracranial stenosis in our study may well be consistent with previous observations in European and non-European population. ID may have been an underestimated condition in ischaemic Caucasian population.

Nilotinib treatment‐associated cerebrovascular disease and stroke

Treatment of chronic myelogenous leukemia (CML) with nilotinib has been associated with progressive peripheral arterial disease (PAD), but there has been no report of cerebrovascular involvement 1, 2. We describe rapid progression of intra- and extra-cranial atherosclerosis leading to stroke in a previously reported patient with nilotinib-associated PAD 2. A 70-year-old woman presented with acute onset of left-sided weakness and dysarthria. Her past medical history of CML and treatment has been well described 2. Before her CML diagnosis in 1996, she had no history of vascular disease. Her prior treatment regimen included interferon-alpha and low-dose cytarabine followed by imatinib in 2000. After dendritic cell vaccine therapy was unsuccessful, tipifarnib was added in 2004. Due to lack of response and progressive disease, she was switched to nilotinib in 2004 with complete cytogenetic remission. The patient developed symptoms attributable to PAD in 2007 and underwent multiple angioplasty and stenting procedures with recurrent in-stent thromboses. With recurrent claudication symptoms in 2010, she had a superficial femoral to below-knee popliteal artery bypass. Coronary artery disease was diagnosed in 2008, and she underwent percutaneous transluminal coronary angioplasty and stenting followed by four-vessel coronary artery bypass grafting. She has renal artery and mesenteric artery stenosis on angiography. During her course on nilotinib, the patient was diagnosed with hypertension, hyperlipidemia, and prediabetes, which were all controlled on medications. Her medication regimen included aspirin, clopidogrel, and warfarin. In 2008, there was a strong suspicion that her progressive atheromatous disease was attributable to nilotinib with the decision made to continue in the context of imatinib-refractory CML. In 2011, the patient had two episodes of confusion. Magnetic resonance angiography (MRA) showed multifocal narrowing involving both middle cerebral arteries (MCA) and posterior cerebral artery (Fig. 1, top row). There was 50–60% narrowing of the right internal carotid artery (ICA). The episodes were of unclear relationship to the vessel findings. In November 2012, in the setting of postprandial hypotension, she developed acute onset of left-sided weakness with cortical sensory loss of her left upper extremity. An MRI showed a right MCA distribution ischemic stroke. MRA showed diffuse intracranial atherosclerosis (Fig. 1, bottom row) and high-grade stenosis of the extracranial R ICA. A conventional angiogram revealed similar changes and near occlusion (>95%) of the right ICA. The risk of surgical or endovascular carotid intervention was deemed high due to diffuse intracranial disease, and she was maintained on dual antiplatelet therapy and anticoagulation with permissive blood pressure parameters. Nilotinib was shown superior to imatinib for the treatment of CML; however, follow-up was limited to 24 months 3. Further reports have identified rapidly progressive PAD as a significant side effect of nilotinib therapy 1, 2. Our patient had no vascular disease risk factors prior to treatment with nilotinib and developed progressive PAD followed by accelerated atheromatous cerebrovascular disease. Cerebrovascular involvement and stroke have not been previously reported in patients on nilotinib therapy; however, clinicians should be aware of the risk of cerebrovascular events with nilotinib and educate patients on the symptoms of stroke. Elizabeth A. Coon1* Nicholas L. Zalewski2 Ernest Matthew Hoffman1 Ayalew Tefferi3 Kelly D. Flemming4 1Department of Neurology, Mayo Clinic, Rochester, Minnesota 2University of Nebraska Medical Center, Omaha, Nebraska 3Department of Hematology, Mayo Clinic, Rochester, Minnesota

Is there a consistent association between coronary heart disease and ischemic stroke caused by intracranial atherosclerosis?

Coronary heart disease and ischemic stroke are frequent coexistent conditions that share risk factors and pose major burdens to global health. Even though a clear relation has been established between extracranial internal carotid artery atherosclerosis and symptomatic or asymptomatic coronary heart disease, there is a gap in knowledge about the association between intracranial atherosclerosis and coronary heart disease. Intracranial atherosclerosis is associated with high risks of stroke recurrence and vascular death. More research and clinical trials are needed to answer whether early diagnosis of asymptomatic coronary heart disease and aggressive treatment can decrease the risk of vascular death in patients with ischemic stroke caused by intracranial atherosclerosis.