Acute Atherothrombotic Stroke Research Articles

Особенности анализа ЭЭГ-микросостояний при постинсультной афазии

Knowledge about the specificity of changes in the activity of neural networks associated with realization of thought processes can be used to construct the personalized medical rehabilitation systems. This approach is of particular interest for people with the speech function disturbance due to stroke, since the development of aphasia with the loss of speech leads to severe social maladaptation that worsens the disease outcome. The study was aimed to assess the functional activity of individual neural networks based on the theory of combining the EEG microstate identification technique with the method of determining spatial localization by solving the EEG inverse problem in 27 individuals (15 males and 12 females) with an average age of 52 years, who had speech impairment due to acute atherothrombotic stroke. Mathematical analysis of the scalp bioelectrical activity multichannel recording from the system for EEG microstate model isolation was carried out under changing environmental conditions caused by the auditory-speech load together with the EEG inverse problem solution for each subject. It was found that the speech disorder development depends not only on the fact of damage to brain structures, but also on the deep functional restructuring of both neural streams involved in implementation of brain function and the entire speech connectome. The disease with a predominant motor disorder, that has shown the possibility of transferring functions to the intact hemisphere prefrontal structures, in contrast to sensory disorders representing global changes in the entire speech connectome, can probably be considered the most favorable variant of aphasia.

Endothelial CCRL2 induced by disturbed flow promotes atherosclerosis via chemerin-dependent β2 integrin activation in monocytes.

Chemoattractants and their cognate receptors are essential for leucocyte recruitment during atherogenesis, and atherosclerotic plaques preferentially occur at predilection sites of the arterial wall with disturbed flow (d-flow). In profiling the endothelial expression of atypical chemoattractant receptors (ACKRs), we found that Ackr5 (CCRL2) was up-regulated in an endothelial subpopulation by atherosclerotic stimulation. We therefore investigated the role of CCRL2 and its ligand chemerin in atherosclerosis and the underlying mechanism. By analysing scRNA-seq data of the left carotid artery under d-flow and scRNA-seq datasets GSE131776 of ApoE-/- mice from the Gene Expression Omnibus database, we found that CCRL2 was up-regulated in one subpopulation of endothelial cells in response to d-flow stimulation and atherosclerosis. Using CCRL2-/-ApoE-/- mice, we showed that CCRL2 deficiency protected against plaque formation primarily in the d-flow areas of the aortic arch in ApoE-/- mice fed high-fat diet. Disturbed flow induced the expression of vascular endothelial CCRL2, recruiting chemerin, which caused leucocyte adhesion to the endothelium. Surprisingly, instead of binding to monocytic CMKLR1, chemerin was found to activate β2 integrin, enhancing ERK1/2 phosphorylation and monocyte adhesion. Moreover, chemerin was found to have protein disulfide isomerase-like enzymatic activity, which was responsible for the interaction of chemerin with β2 integrin, as identified by a Di-E-GSSG assay and a proximity ligation assay. For clinical relevance, relatively high serum levels of chemerin were found in patients with acute atherothrombotic stroke compared to healthy individuals. Our findings indicate that d-flow-induced CCRL2 promotes atherosclerotic plaque formation via a novel CCRL2-chemerin-β2 integrin axis, providing potential targets for the prevention or therapeutic intervention of atherosclerosis.

Diffusion-weighted Imaging and Arterial Spin Labeling for Prediction of Cerebral Infarct Volume in Acute Atherothrombotic Stroke.

This study aims to investigate the usefulness of diffusion-weighted imaging (DWI) and arterial spin labeling (ASL) for predicting final infarct volume in patients with acute atherothrombotic subtype cerebral infarction (AT-type stroke). The data of 77 patients with AT-type stroke were retrospectively analyzed. ASL and DWI values of minimum apparent diffusion coefficient (min ADC), mean ADC (mean ADC), minimum cerebral blood flow (min CBF), and mean CBF (mean CBF) of the infarction lesions were measured. Changes in cerebral infarction volume (ΔVolume) were determined by DWI reexamination on the 7th day after onset. Correlations of ADC and CBF with Δ Volume were analyzed. Receiver operating characteristic (ROC) curve analysis was used to determine the usefulness of ADC and CBF values for predicting final infarct volume. There was a significant difference in the distribution of the ΔVolume in AT-type stroke (P<0.0001). The ADC and min CBF values were negatively correlated with the infarct ΔVolume (P<0.05); mean CBF and ΔCBF were not correlated with ΔVolume. When min ADC was ≤0.303 × 10-3 mm2/s, min CBF 1.5 ≤2.415 mL/100 g/min, or min CBF2.5 ≤4.25 mL/100 g/min, ΔVolume was likely to be large. The ROC curve showed the highest predictive value for min ADC and min CBF. Distinctive patterns of quantitative ADC and CBF can be used as a simple and rapid method for predicting change in infarction volume in AT-type stroke.

Порівняльна характеристика факторів атероґенезу в пацієнтів із симптомним і асимптомним перебігом атеросклеротичних каротидних стенозів

To study a comparative assessment of risk factors for atherogenesis in patients with different clinical manifestations of carotid atherosclerotic stenosis. The study included 106 patients (men — 74, women — 32) aged 39 to 79 years (mean age 62.6 ± 0.9), which devided to 3 clinical groups: Group I — 35 patients with acute atherothrombotic stroke with ipsilateral carotid stenosis, group II — 41 patients after acute cerebrovascular events and carotid endarterectomy, group III — 30 patients with asymptomatic atherosclerotic carotid stenosis and the control group, which consisted of 20 relatively healthy individuals. The degree of stenosis of the internal carotid arteries was highest (&gt; 70 %) in the group of patients who underwent carotid endarterectomy. In addition in this group was prevalence younger men, compared with the group of asymptomatic stenosis and women (p = 0.00300), there was an older age of patients and moderate stenosis of 50–69 % (p = 0.00647). In patients with stenotic atherosclerosis of the internal carotid artery, there was a significant increase in the level of Lp-PLA2 compared with the control. This confirms that Lp-PLA2 can be considered as a marker of carotid atherosclerosis and influence the development of ischemic stroke. The highest level of Lp-PLA2 was observed in the clinical group of patients who underwent carotid endarterectomy after ischemic stroke and there was a tendency to a more significant increase in total cholesterol. This suggests a more aggressive course of the atherosclerotic process in patients in this group.

Collagen-Induced Platelet Aggregates, Diabetes, and Aspirin Therapy Predict Clinical Outcomes in Acute Ischemic Stroke

Background: Aggregation of platelets is a trigger for additional development of larger thrombi. This study aimed to identify factors that may affect platelet aggregability and their role in clinical outcomes in acute ischemic stroke. Methods: Consecutive acute ischemic stroke patients (n = 352) who were transferred within 24 hours after its onset were enrolled. Peripheral venous blood was sampled to measure platelet aggregability and other parameters. Results: Mean values of spontaneous small-sized platelet aggregates and collagen- or adenosine diphosphate (ADP)-induced large-sized aggregates were elevated in acute ischemic stroke. In atherothrombotic stroke (n = 178), collagen and ADP-induced large-sized aggregates were positively correlated with HbA1c, respectively. High incidence of the modified Rankin Scales (mRS) 5-6 at discharge was associated with diabetes complication (odds ratio [OR] 8.77, 95% confidence interval [CI] 1.32-57.56). The proportion of patients who were functionally independent (the mRS 0-2) at discharge was lower in the middle tertile of collagen and ADP-induced large-sized aggregates than their low tertile (OR 2.46, 95% CI 1.09-5.58; OR 2.43, 95% CI 1.05-5.59, respectively). Prestroke administration of aspirin recovered the proportion of independence at discharge (OR 0.25, 95% CI 0.06-0.99), and ameliorated incidence of the mRS 5-6. On logistic regression analysis, diabetes, HbA1c, collagen-induced large-sized aggregates, and prestroke administration of aspirin remained independent predictors of clinical outcomes in atherothrombotic stroke. In cardioembolic and lacunar stroke, no relations with clinical outcomes were found. Conclusions: High plasma level of HbA1c is involved in enhanced platelet aggregability in acute atherothrombotic stroke patients, and prestroke administration of aspirin may be beneficial to clinical outcomes.

Serum semaphorin 7A is associated with the risk of acute atherothrombotic stroke.

Semaphorin 7A (Sema7A), a neural guidance cue, was recently identified to regulate atherosclerosis in mice. However, the clinical relevance of Sema7A with atherosclerotic diseases remains unknown. The aim of this study was to investigate the association between serum Sema7A and the risk of acute atherothrombotic stroke (AAS). We measured serum concentrations of Sema7A in 105 newly onset AAS cases and 105 age‐ and sex‐matched controls, showing that median Sema7A level in AAS cases was over three times of that in controls (5.86 vs 1.66 ng/mL). Adjusted for hypertension, body mass index, fasting blood glucose, total cholesterol, triglyceride, high‐density lipoprotein (HDL)‐cholesterol, low‐density lipoprotein (LDL)‐cholesterol, current smoking and alcohol consumption, multivariate logistic regression showed that higher Sema7A was independently associated with the odds of AAS (OR = 6.40, 95% CI: 2.88‐14.25). Each 1‐standard deviation increase in Sema7A was associated with a threefold higher odds of AAS (OR = 3.42, 95% CI: 1.84‐6.35). Importantly, adding Sema7A to a multivariate logistic model containing conventional cardiovascular risk factors improved the area under receiver operating characteristic curves from 0.831 to 0.891 for the association with AAS. In conclusion, elevated serum Sema7A is independently associated with the risk of AAS, suggesting that it may play a potential role in AAS.

Increased Soluble CD137 Levels and CD4+ T-Cell-Associated Expression of CD137 in Acute Atherothrombotic Stroke.

As a proinflammatory cytokine, CD137 (4‐1BB, TNFRSF9) is present in membrane‐bound and soluble forms. Increased expression of CD137 was recently found in T cells in human atherosclerotic plaques. However, the exact role of CD137 in ischemic stroke is not clear. In this study we analyzed the protein levels of soluble CD137 (sCD137) and the expression of CD137 on CD4+ T cells in the peripheral blood of patients with acute atherothrombotic stroke by using the cytometry beads array (CBA) and flow cytometry. Within 24 hours of onset, the stroke patients showed elevated levels of sCD137 (2.7 pg/ml) and CD137 expression on CD4+ T cells (4.9 ± 3.2%) compared with normal controls (1.1 pg/ml, P < 0.01; 1.3 ± 1.0%, P < 0.01). Alterations in CD137 expression may enhance ischemia‐induced inflammatory responses via bidirectional signaling and, consequently, aggravate brain injury in early stages of this disorder.

Recurrent Ischemic Lesions After Acute Atherothrombotic Stroke: Clopidogrel Plus Aspirin Versus Aspirin Alone.

In patients with acute ischemic stroke caused by large artery atherosclerosis, clopidogrel plus aspirin versus aspirin alone might be more effective to prevent recurrent cerebral ischemia. However, there is no clear evidence. In this multicenter, double-blind, placebo-controlled trial, we randomized 358 patients with acute ischemic stroke of presumed large artery atherosclerosis origin within 48 hours of onset to clopidogrel (75 mg/d without loading dose) plus aspirin (300-mg loading followed by 100 mg/d) or to aspirin alone (300-mg loading followed by 100 mg/d) for 30 days. The primary outcome was new symptomatic or asymptomatic ischemic lesion on magnetic resonance imaging within 30 days. Secondary outcomes were 30-day functional disability, clinical stroke recurrence, and composite of major vascular events. Safety outcome was any bleeding. Of 358 patients enrolled, 334 (167 in each group) completed follow-up magnetic resonance imaging. The 30-day new ischemic lesion recurrence rate was comparable between the clopidogrel plus aspirin and the aspirin monotherapy groups (36.5% versus 35.9%; relative risk, 1.02; 95% confidence interval, 0.77-1.35; P=0.91). Of the recurrent ischemic lesions, 94.2% were clinically asymptomatic. There were no differences in secondary outcomes between the 2 groups. Any bleeding were more frequent in the combination group than in the aspirin monotherapy group, but the difference was not significant (16.7% versus 10.7%; P=0.11). One hemorrhagic stroke occurred in the clopidogrel plus aspirin group. Clopidogrel plus aspirin might not be superior to aspirin alone for preventing new ischemic lesion and clinical vascular events in patients with acute ischemic stroke caused by large artery atherosclerosis. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00814268.

Outcomes of Argatroban Treatment in Patients With Atherothrombotic Stroke: Observational Nationwide Study in Japan.

Argatroban, a selective thrombin inhibitor, is recommended for the use in patients with atherothrombotic stroke by the Japanese Guidelines for the Management of Patients with Acute Ischemic Stroke. We performed a nationwide Japanese study to investigate whether argatroban improved early stroke outcomes in patients with acute atherothrombotic stroke. This retrospective observational study, using the Diagnosis Procedure Combination database in Japan, included patients who were hospitalized from July 1, 2010, to March 31, 2012, with a diagnosis of atherothrombotic stroke within 1 day of stroke onset. Patients were divided into 2 groups: those receiving argatroban on admission (argatroban group), and those who did not receive argatroban during hospitalization (control group). To balance the baseline characteristics and concomitant treatments during hospitalization between the 2 groups, one-to-one propensity-score matching analyses were performed. The main outcomes were the modified Rankin Scale score at discharge and the occurrence of hemorrhagic complications during hospitalization. An ordinal logistic regression analysis evaluated the association between argatroban use and modified Rankin Scale at discharge. After propensity-score matching, 2289 pairs of patients were analyzed. There were no significant differences in modified Rankin Scale at discharge between the argatroban and the control groups (adjusted odds ratio, 1.01; 95% confidence interval, 0.88-1.16). The occurrence of hemorrhagic complications did not differ significantly between the argatroban and the control groups (3.5% versus 3.8%; P=0.58). The present study suggested that argatroban was safe, but had no added benefit in early outcomes after acute atherothrombotic stroke.

Abstract T P334: Clopidogrel and Aspirin versus Aspirin Alone for Prevention of Recurrent Ischemic Lesion in Acute Atherothrombotic Stroke: A Randomized, Double-Blind, Placebo-Controlled Trial

Background: Combination treatment with clopidogrel and aspirin is not currently recommended for secondary prevention of stroke, but its superior effect to aspirin alone has been controversial according to stroke subtype and stage. We sought to compare the effect of aspirin and clopidogrel to aspirin alone for recurrent ischemic lesion in acute stage of atherothrombotic stroke. Methods: Combination of clopidogrel and aspirin for prevention of recurrence in acute atherothrombotic stroke study (COMPRESS) was a prospective, randomized, double-blind, placebo-controlled, multicenter trial. We enrolled 358 patients with acute atherothrombotic stroke within 48 hours after symptom onset, and randomly assigned them to receive clopidogrel (75 mg per day) plus aspirin (100 mg per day) or aspirin alone (100 mg per day) for 30 days. The primary endpoint was proportion of patients with a newly developed ischemic lesion within 30 days, as confirmed with brain MRI. Secondary endpoints were modified Rankin Scale scores at 30 days, occurrence of the composite endpoint of non-fatal stroke, myocardial infarction and cardiovascular death, and incidence of all types of stroke. The clinicaltrials.gov registration number for this trial was NCT00814268. Results: Among 358 patients enrolled, 349 patients who received at least one dose of study medication after randomization were included in the efficacy analysis population (clopidogrel plus aspirin, n=174; aspirin alone, n=175).Recurrent ischemic lesions were observed in 61 patients in the combination group (36.5%) and 60 patients in the aspirin alone group (35.9%; p=0.91). The significant difference was not found between the groups in the secondary endpoints. In the safety analysis, any bleeding incidence was non-significantly higher in the combination group (n=29 vs. n=19; p=0.10), and episodes of life-threatening hemorrhage and major hemorrhage were very low in both groups. Conclusion: Combination treatment of clopidogrel and aspirin is not superior to aspirin alone for prevention of recurrent ischemic lesion in acute atherothrombotic stroke patients. Acknowledgement: This study was co-sponsored by Sanofi-Aventis Korea and BMS Korea.

Elevated Plasma Levels but Decreased Platelet-Associated Expression of LIGHT in Patients with Acute Atherothrombotic Stroke

Background: As a member of the tumor necrosis factor superfamily (TNFSF), LIGHT (TNFSF14) is expressed by a variety of immune cells and exists in membrane-bound and soluble forms. Recently, LIGHT was found to be associated with platelets and released upon activation. Activation of endothelia cells by recombinant LIGHT protein results in pro-inflammatory and pro-thrombotic changes. Several studies have reported increased plasma levels of LIGHT in patients with stroke and cardiovascular diseases. However, the form-associated roles of LIGHT in ischemic atherosclerotic stroke remain unclear. Mater?als and Methods: In this study, the platelet LIGHT expression and soluble LIGHT protein were analyzed by flow cytometry and enzyme-linked immunosorbent assay (ELISA) in peripheral blood of patients with acute ischemic atherosclerotic stroke, asymptomatic carotid stenosis (ACS) and normal controls. RESULTS: During the initial 24 h after onset, the stroke patients had decreased LIGHT expression on their platelets (5.9% ± 4.9%) and increased plasma LIGHT levels (36.1 ± 21.0 pg/ml) as compared with normal controls (9.5% ± 3.0%, p p p = 0.0247). Conclus?ons: The dysregulated LIGHT expression reflects a persistent chronic inflammatory response that may have been induced during early stages of ischemic atherosclerotic stroke. Our results strongly suggest distinctive roles of form-associated LIGHT in the disease pathogenesis: platelet-associated LIGHT may contribute to formation and development of carotid atherosclerotic plaque, probably involving plaque destabilization, while soluble LIGHT may predominantly functions as a pro-inflammatory cytokine in the inflammatory process.

Simulation Program to Determine Sample Size and Power for a Multiple Logistic Regression Model with Unspecified Covariate Distributions

Binary logistic regression models are commonly used to assess the association between outcomes and covariates. Many covariates are inherently continuous, and have a variety of distributions, including those that are heavily skewed to the left or right. Existing theoretical formulas, criteria, and simulation programs cannot accurately estimate the sample size and power of non-standard distributions. Therefore, we have developed a simulation program that uses Monte Carlo methods to estimate the exact power of a binary logistic regression model. This power calculation can be used for distributions of any shape and covariates of any type (continuous, ordinal, and nominal), and can account for nonlinear relationships between covariates and outcomes. For illustrative purposes, this simulation program is applied to real data obtained from a study on the influence of smoking on 90-day outcomes after acute atherothrombotic stroke. Our program is applicable to all effect sizes and makes it possible to apply various statistical methods, logistic regression and related simulations such as Bayesian inference with some modifications.

Abstract 18357: Vulnerable Carotid Plaque is Characterized by a Difference in Mobility Between Plaque Core and Cap

Vulnerable carotid plaque can cause an ischemic stroke, but its detection is elusive. The aim was to study the mechanical properties of carotid plaques using ultrasound speckle tracking. Methods: Study population consisted of 61 (aged 53-89, median 68) patients with carotid atherosclerosis: 21 with acute atherothrombotic stroke (7 day after stroke onset) and 40 without symptoms. The stroke subtype was classified according to TOAST criteria. In total, 21 symptomatic and 47 asymptomatic plaques were analyzed. For plaque-free area (PFA) and for each plaque, maximum circumferential and longitudinal strains (S[[Unable to Display Character: с]], Sl) and strain rates (SRc SRl) were measured (with separate measurements for plaque cap, core and base). Plaque characteristics (echogenicity, length, degree of stenosis) were also assessed. Results: plaque and PFA differed in Sl and SRl values, whereas no difference was observed for Sc and SRc (Table 1). Sc and SRc for cap and core of echolucent plaques were higher as compared with hyperechogenic ones (Table 1). For echolucent plaques a significant difference in Sc and SRc was also detected between segments, and the highest values were observed in cap (Table 1). However, for symptomatic plaques, Sc and SRc of plaque core were significantly higher than values for cap (Table 1). Plaque internal motion coefficient Pim=(core SRc - cap SRc)/base SRc was developed to quantify the relative motion of different plaque segments against each other. According to ROC curve analysis, plaques with Pim&gt;0.09 are associated with ischemic event (sensitivity 76%, specificity 65%, AUC=0.76, p&lt;0.001). Logistic regression confirmed that Pim&gt;0,09 is an independent predictor of plaque vulnerability, OR=5.26, 95% CI 1.4-19.3 controlling for age, gender, plaque length, degree of stenosis and echogenicity. Conclusions: Echolucent plaques are more mobile than hyperechogenic ones. In symptomatic plaques, the increased deformation of inner core may be linked with plaque vulnerability.

Effects of smoking on outcomes after acute atherothrombotic stroke in Japanese men

BackgroundThe effects of smoking on clinical outcomes following acute stroke remain controversial. MethodsWe evaluated the influence of smoking on 90-day outcomes after acute atherothrombotic stroke in 292 Japanese men extracted from the database of the Edaravone and Argatroban Stroke Therapy for Acute Ischemic Stroke randomized parallel-group trial that tested the safety and efficacy of edaravone and argatroban therapy in 814 patients in 2004–2008. Smokers were matched with non-smokers of the same age for identical age distribution in the smoker and non-smoker groups. Poor 90-day outcomes (defined as death, Barthel index<60, or modified Rankin score>3) were evaluated using a logistic regression model. Significant variables (P<0.05) in univariate analysis were further evaluated by multivariate logistic regression analysis using a forward-selection method. ResultsBody temperature, age, National Institute of Health Stroke Scale score at admission, systolic blood pressure, and smoking status were selected in the final model. Smokers had significantly increased odds of poor 90-day functional outcomes independent of other statistically significant predictor variables (adjusted odds ratio, 2.28; 95% confidence interval, 1.15–4.55; P=0.019). ConclusionsIn Japanese men, smoking leads to poor functional outcomes at 3months after acute atherothrombotic stroke.

Elevated Plasma Levels and Platelet-Associated Expression of the Pro-Thrombotic and Pro-Inflammatory Protein, LIGHT (TNFSF14), In Sickle Cell Anemia (SCA)

AbstractAbstract 2651 Background:LIGHT (TNFSF14; CD258), a recently-identified member of the TNF superfamily, is found associated with and produced from platelets, amongst other immune cells. Increased circulating levels of this protein have been observed in patients with myocardial infarction and acute atherothrombotic stroke and LIGHT has been proposed as a potential therapeutic target in atherosclerosis, due to its reported pro-thrombotic and pro-inflammatory effects upon human endothelial cells. This study evaluated whether production of LIGHT is altered in patients with sickle cell anemia (SCA), and the participation that the platelets (PLTs) may have in this production, since SCA is characterized by a significant chronic inflammation and endothelial activation that may initiate the vaso-occlusive process. Patients and Methods:Soluble LIGHT (sLIGHT) was determined in PLT-free plasma (obtained by sequential centrifugations and ultrafiltration) from healthy control individuals (CON), SCA patients in steady state (SCA) and SCA patients on hydroxyurea therapy (SCAHU; 20–30 mg/kg/day HU) by ELISA. Expressions of PLT-membrane LIGHT and PLT activation markers were evaluated by flow cytometry using anti-CD258-PE, anti-CD62P-FITC or anti-PAC1-FITC. Subjects had not taken ASA during the previous 14 days. Results:sLIGHT was significantly elevated in the plasma of SCA and SCAHU individuals, compared to CONs (SCA; 35.4 ± 9.4 pg/ml; SCAHU, 37.3 ± 7.5 pg/ml; CON, 9.7 ± 1.5 pg/ml, n=27, 27, 19, resp.; P<0.01 for SCA/SCAHU, compared to CON; Kruskal-Wallis/Dunn's). Plasma sLIGHT in SCA/SCAHU individuals presented no correlation with hematological variables, such as PLT counts (rs=-0.079, P=0.65) and fetal hemoglobin (rs=0.107, P=0.51). In contrast, plasma sLIGHT levels in SCA patients presented an impressive correlation with plasma levels of CD40L, another important PLT-derived inflammatory protein (rs=0.817, P<0.0001 for SCA group and rs=0.651, P<0.0001 for SCA+SCAHU) and correlated with IL-8, an endothelium-derived inflammatory mediator (rs=0.900, P<0.05 for SCA and rs=0.455, P=0.06 for SCA+ SCAHU). Expression of LIGHT protein (CD258) was significantly higher on the membrane of PLTs from SCA and SCAHU individuals, compared to CON PLTs (SCA, 27.1 ± 4.5 %; SCAHU, 33.7 ± 5.8 %; CON, 5.5 ± 1.6 % positive PLTs, n=15, 20, 15, resp.; P<0.001 for SCA/SCAHU comp. CON). Notably, when PLTs were activated by incubation with ADP (20 μM, 30 min), PLTs from SCA/SCAHU individuals still expressed significantly more surface LIGHT than CON PLT (SCA, 41.8 ± 4.5 %; SCAHU, 41.3 ± 5.4 %; CON, 11.1 ± 2.3 % positive PLTs; n=15, 20, 14, resp. P<0.001 for SCA/SCAHU comp. CON); successful activation of PLTs from all groups was confirmed by increased PAC-1 (anti-activated αIIbß3 integrin) binding and increased P-selectin (CD62P, a PLT activation marker) expression (data not shown); furthermore LIGHT expression on ADP-activated cells correlated significantly with both PAC-1 binding (rs=0.483, P=0.03) and P-selectin expression (rs=0.502, P=0.02, n=20) on SCA PLTs. sLIGHT release from SCA PLTs during 90 min (37°C, 5% CO2 in Krebs) was evaluated and demonstrated that PLTs of SCA individuals may be an important source of circulating sLIGHT, releasing 22.2 ± 4.7 pg LIGHT/108 PLTs (n=10); release of sLIGHT from SCA PLT was significantly augmented by incubation with collagen (P<0.01), but not ADP (P>0.05); basal and collagen-stimulated sLIGHT release correlated significantly with CD40L release (rp=0.654; rp=0.764, resp. P<0.05). Conclusion:The pro-inflammatory and atherogenic protein, LIGHT, is found significantly elevated in the plasma of SCA patients. The correlation of plasma LIGHT with IL-8 indicates that LIGHT may participate in, or reflect, endothelial activation, whilst the correlation of circulating LIGHT and PLT release of LIGHT with CD40L indicates that the production of these two proteins may be tightly coupled. LIGHT protein is highly expressed on the PLT surface in SCA and this expression appears to be associated with PLT activation, rather than PLT number. Interestingly, HU therapy was not associated with any significant alteration in circulating LIGHT, nor PLT surface LIGHT. Future investigations will determine the extent of the contribution of LIGHT to endothelial activation, inflammation and vaso-occlusion in SCA and whether this protein holds promise as a potential therapeutic target for the disease. Disclosures:No relevant conflicts of interest to declare.

Enhanced plasma levels of LIGHT in patients with acute atherothrombotic stroke

As a member of the tumor necrosis factor superfamily (TNFSF), LIGHT (TNFSF14) was recently found to be associated with platelets and released upon activation. Increased plasma levels of LIGHT have been reported in patients with myocardial infarction and unstable angina. The aim of the study was to analyze plasma levels of LIGHT in acute ischemic atherosclerotic stroke. The soluble LIGHT protein was analyzed by an enzyme-linked immunosorbent assay in peripheral blood of patients with acute ischemic atherosclerotic stroke (n = 20), asymptomatic carotid stenosis (n = 19) and normal controls (n = 23). During the initial 24 h after onset, the stroke patients had an increased plasma LIGHT levels as compared with normal controls. Moreover, the plasma LIGHT levels of the stroke patients were correlated with blood platelet count (r = 0.6341, P = 0.0027). The elevated LIGHT levels may reflect a persistent chronic inflammatory response that may have been induced during early stages of the disease. We speculate that this derangement of LIGHT may be important for atherogenetic process of ischemic stroke.

Serum osteoprotegerin levels in patients with acute atherothrombotic stroke and lacunar infarct

Background Arterial calcification is associated with increased risk of cardiovascular events. Osteoprotegerin (OPG) is a cytokine involved in the bone metabolism and vascular calcification. Recent data support a relationship between high serum levels of OPG and increased risk for cardiovascular disease in human. The aim of this study was to evaluate the OPG serum levels in acute ischemic stroke. Our study was further designed to detect differences in serum OPG levels between subtypes of ischemic stroke. Materials and methods The study consisted of 51 patients with acute ischemic stroke and 28 control subjects. Stroke subtypes were defined by the TOAST classifications. Serum OPG levels were measured with the ELISA method. Results OPG serum levels were significantly higher in patients with ischemic stroke than in control subjects ( p < 0.001). OPG serum levels were significantly higher in large-vessel disease (LVD) subtype compared with small-vessel disease (SVD) subtype and controls ( p < 0.001, p < 0.001). There was no significant difference in OPG serum levels between SVD group and control subjects. Serum OPG levels were correlated with age ( r = 0.407, p = 0.005) and fasting glucose levels ( r = 0.542, p = 0.001) in ischemic stroke group. Logistic regression analysis showed that plasma OPG levels (OR 2.1, 95% CI, 1.16 to 3.4, p = 0.01) associated with presence of stroke independently of the other risk factors. Conclusions High serum OPG levels were associated with the LVD stroke subtype, suggesting that OPG levels may play role in pathogenesis of atherothrombotic stroke. The precise mechanism for the role of OPG in atherosclerosis needs to be investigated further.

Platelet microparticles and platelet adhesion: Therapeutic implications for the prevention and treatment of stroke

Platelets are believed to play a part in all stages of the pathogenesis of ischemic stroke, from the initial formation of the atherosclerotic plaque, through plaque destabilization to the development of neuronal cell death. A process common to all of these pathogenic changes is the ability of the activated platelet to adhere to the site of disease. In addition, the release of the membrane vesicles from platelets enhances many of these processes. Therefore, an understanding of platelet adhesion and platelet microparticle release can aid the development toward the treatment and prevention of stroke. There has been much research into interventions that can reduce platelet activation in atherosclerosis and stroke. The benefits of nonpharmacologic interventions in stroke, such as diet and lifestyle modification, may in part be mediated by their effects on platelet activation. In addition, the antiplatelet drug aspirin has been shown to be useful in both the treatment of acute stroke and the secondary prevention of atherothrombosis. Other antiplatelet agents, such as the glycoprotein IIb/IIIa inhibitors and triflusal, are currently being evaluated for the treatment of acute atherothrombotic stroke.

Smoke Inhalation

The effects of smoking on clinical outcomes following acute stroke remain controversial.We evaluated the influence of smoking on 90-day outcomes after acute atherothrombotic stroke in 292 Japanese men extracted from the database of the Edaravone and Argatroban Stroke Therapy for Acute Ischemic Stroke randomized parallel-group trial that tested the safety and efficacy of edaravone and argatroban therapy in 814 patients in 2004–2008. Smokers were matched with non-smokers of the same age for identical age distribution in the smoker and non-smoker groups. Poor 90-day outcomes (defined as death, Barthel index < 60, or modified Rankin score > 3) were evaluated using a logistic regression model. Significant variables (P < 0.05) in univariate analysis were further evaluated by multivariate logistic regression analysis using a forward-selection method.Body temperature, age, National Institute of Health Stroke Scale score at admission, systolic blood pressure, and smoking status were selected in the final model. Smokers had significantly increased odds of poor 90-day functional outcomes independent of other statistically significant predictor variables (adjusted odds ratio, 2.28; 95% confidence interval, 1.15–4.55; P = 0.019).In Japanese men, smoking leads to poor functional outcomes at 3 months after acute atherothrombotic stroke.