Atherothrombotic Stroke Research Articles

Mechanisms of ischemic stroke in HIV-infected patients

To evaluate the types and mechanisms of stroke in a large population of HIV-infected patients. We reviewed records of consecutive HIV-infected patients with acute stroke admitted to a large metropolitan hospital between 1996 and 2004. Stroke mechanism was defined by consensus between two cerebrovascular neurologists using TOAST classification. A total of 82 patients were included, 77 with ischemic stroke and 5 with intracerebral hemorrhage. Mean age was 42 years and 89% were African American. Previous diagnosis of HIV infection was documented in 91% and AIDS diagnosis in 80%. Mean CD4 count was 113 cells/mm(3) and 85% had CD4 count <200 cells/mm(3). A total of 61% of patients had received combination antiretroviral treatment (CART). The mechanism of ischemic stroke was large artery atherosclerosis in 12%, cardiac embolism in 18%, small vessel occlusion in 18%, other determined etiology in 23%, and undetermined in 29% (including 19% with incomplete evaluation). Vasculitis was deemed responsible for the stroke in 10 patients (13%) and hypercoagulability in 7 (9%). Protein S deficiency was noted in 10/22 (45%) and anticardiolipin antibodies in 9/31 (29%) tested patients. When comparing patients with large or small vessel disease (atherothrombotic strokes) vs the rest of the population, there were no differences in exposure to CART or CD4 count, but patients with non-atherothrombotic strokes were younger (p = 0.04). Recent cocaine exposure was less common among patients with atherothrombotic strokes (p = 0.02). Strokes were fatal or severely disabling in 35% of cases. Stroke mechanisms are variable in HIV-infected patients, with a relatively high incidence of vasculitis and hypercoagulability. In our population of severely immunodepressed patients, exposure to combination antiretroviral treatment did not significantly influence the mechanism of stroke.

Reactive oxygen species plasmatic levels in ischemic stroke

Oxidative stress is probably one of the mechanisms involved in neuronal damage induced by ischemia-reperfusion, and the antioxidant activity of plasma may be an important factor providing protection from neurological damage caused by stroke-associated oxidative stress. The aim of this study was to investigate the status of oxidative stress, NO and ONOO(-) levels in patients with atherothrombotic and lacunar acute ischemic stroke and iNOS, eNOS and nitrotyrosine expression in the same patients. Plasma ONOO(-) levels were significantly higher in patients than in controls while NO decreases in patients in respect to controls. Densitometric analysis of bands indicated that iNOS and N-Tyr protein levels were significantly higher in patients in respect to controls. This study has highlighted a significant NO decrease in our patients compared with controls and this is most probably due to the increased expression of inducible NO synthase by the effect of thrombotic attack. In fact, the constitutive NO isoforms, which produce small amounts of NO, are beneficial, while activation of the inducible isoform of NO, which produces much more NO, causes injury, being its toxicity greatly enhanced by generation of peroxynitrite. The significant ONOO(-) increase observed in our patients, compared to controls, is most probably due to reaction of NO with O(2)(*-) . These findings suggest that free radical production and oxidative stress in ischemic stroke might have a major role in the pathogenesis of ischemic brain injury. Peroxynitrite might be the main marker of brain damage and neurological impairment in acute ischemic stroke.

Burden of carotid atherosclerosis in patients with stroke: relationships with circulating endothelial progenitor cells and hypertension

Recent studies suggest that reductions in circulating endothelial progenitor cells (EPCs) may contribute to the development of atherosclerosis. However, whether reduced circulating EPCs contribute to cerebrovascular disease remains undefined. We tested the hypothesis that reduced circulating EPCs was associated with an increased burden of carotid atherosclerosis. The level of circulating CD34+/KDR+ EPCs and the extent of carotid atherosclerosis were determined in 30 patients with a history of atherothrombotic ischaemic stroke and 30 age- and sex-matched controls (mean age: 63+/-2 years; 63% men). Stroke patients, compared with controls, had significantly higher carotid mean maximum intima-media thickness (mmIMT) (1.08+/-0.05 versus 0.90+/-0.02 mm, P=0.002), prevalence of carotid plaque (60.0 versus 23.3%, P=0.004) and a lower number of circulating CD34+/KDR+ EPCs (235.7+/-45.5 versus 400.4+/-56.8 cells/mul, P=0.027). The circulating CD34+/KDR+ EPC count correlated negatively with carotid mmIMT (r=-0.50, P<0.001), and was an independent risk factor for increased carotid mmIMT>1 mm (odds ratio (OR): 7.71; 95% confidence interval (CI): 1.62-36.74, P=0.010) and the presence of carotid plaque (OR: 7.04; 95% CI: 1.95-25.43, P=0.003). Furthermore, stroke patients with low (<25th percentile of controls) as compared to those with normal CD34+/KDR+ EPC count had a significantly greater carotid mmIMT (1.21+/-0.07 versus 0.93+/-0.05 mm, P=0.005) and a significantly higher prevalence of carotid plaque (87.5% versus 28.6%; P=0.001). Our observations suggested that reduced circulating EPC may contribute to the progression of carotid atherosclerosis. Circulating EPC count may provide a novel marker for the burden of carotid atherosclerosis.

動脈硬化性病変に起因する脳梗塞の「原因」に関する一考察

We recruited 229 consecutive patients (145 men) aged 29-96 years (mean 70 years). All gave informed consent in this study. Patients were classified into “cardiogenic embolism (cardiogenic),” “atherothrombotic stroke (atheroma),” “lacuna stroke (lacuna)” and “others.” In “atheroma” and “lacuna” groups, significant arterial stenosis as the source was disclosed in 55.6%. The stenotic lesions considerably existed in the extra-cranial region, such as cervical internal carotid artery, foraminal segment of the vertebral artery, or vertebral artery origin. In half of the patients with previous attacks, significant arterial lesions were identified as the source. The symptoms caused by these arterial lesions tended to be slight. Therefore, the source may be overlooked, resulting in relapse. Determining the source is important as careful neurological assessment may enable a favorable clinical outcome.

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.

Apolipoprotein E and First-ever Ischaemic Stroke in Greek Hospitalized Patients

The association between apolipoprotein E (ApoE) polymorphism and stroke is still controversial. This study investigated the potential association between ApoE genotypes and stroke subtypes, and risk factors for ischaemic stroke in Greek patients hospitalized with their first-ever ischaemic stroke. One hundred patients (70 men and 30 women; mean age +/- SD 60.7 +/-9.8 years) were included in the study. The control group comprised 96 age- and sex-matched healthy volunteers. Cerebral infarction was classified as atherothrombotic, cardioembolic or lacunar small-vessel stroke. The three common ApoE alleles (E2, E3 and E4) were determined using the semi-nested polymerase chain reaction. No significant difference in the ApoE alleles was found between patients and controls. Similarly, there was no significant association between ApoE alleles and stroke subtypes, common risk factors for ischaemic stroke and neck vessel stenosis. Although the sample size was small, these results do not support a role for ApoE polymorphism in the pathogenesis of ischaemic stroke.

Silent Coronaropathy: Usefulness of Dobutamine Stress Echocardiography in Ischemic Stroke

Background: Several testing options are available to detect asymptomatic coronary artery disease (CAD). Dobutamine stress echocardiography (DSE) has been reported to increase the sensitivity and specificity of stress testing to detect CAD. Most studies concerned patients with known or suspected CAD who have a high pretest probability of disease. We aimed to perform a preliminary evaluation of DSE in atherothrombotic stroke. Methods: Patients with transient ischemic attack or nondisabling ischemic stroke attributable to an atherothrombotic source were prospectively recruited. Patients with a history of angina pectoris or electrocardiographic signs of previous myocardial infarction were excluded. DSE was considered positive when regional reduction or deterioration of myocardial thickening developed in 1 segment. Coronary angiography was performed in patients with positive DSE. Results: Sixty-four patients were recruited. Analysis of DSE was possible in 60 patients. Overall the test provided clinically useful information in 60/64 patients studied (>90%). DSE was positive in 9 patients (15%). Coronary angiography was performed in 8 patients, high-grade focal lesions were found in 3 patients, and 5 patients showed diffuse atheroma. Univariate logistic regression analysis showed that the main factor predictive of a positive DSE was the presence of an aortic arch atheroma (p = 0.003). Multivariate logistic regression analysis showed that two factors had an independent predictive value of positive DSE: aortic arch atheroma (p = 0.007) and dyslipidemia (p = 0.09). Conclusion: DSE may improve prevention of further vascular events in patients with an atherothrombotic source of ischemic stroke. This screening may be of particular benefit to patients with an aortic arch atheroma.

IL6 -174 G/C and Fibrinogen-β-455 G/A Polymorphisms in Ischemic Cerebrovascular Disease (ICD).

Ischemic cerebrovascular disease (ICD) is a multi-factorial entity whose anatomopathologic substrate is atherosclerosis. The inflammatory cells migrate to vascular endothelium and release chemokines such as interleukin 6 (IL6), resulting in the atheroma plaque development. The IL6 production induces acute phase proteins synthesis such as fibrinogen.Objective. The purpose of this case-control study is to analyze the ICD risk associated to the polymorphisms IL6-174 G/C and beta chain of fibrinogen-455 G/A (fibri-β-455). The association of these polymorphisms, classic vascular risks factors and ICD subtypes according to TOAST classification has also been explored.Methods and patients. A total of 159 ICD diagnosed patients (82 female and 77 male; mean age 67.7±15) were analysed. They were matched for age (±5 years) and sex with a control group (65.6±14) without thrombotic history. AHT, DM, dyslipidaemia and smoking habit data were collected for each group. Polymorphisms were analysed by PCR-RFLP. Serum IL6 was measured by ELISA and fibrinogen by Clauss method. Statistic analysis was made with the SAS v9 software.Results. Genotype analysis showed a significant higher prevalence of the genotypes G/G and G/C IL6 -174 in the patients (OR: 1.49, IC 95%: 0.95–2.34, p: 0.049). By contrast, the fibri-β-455 genotypes were not different in patients and controls (p= 0.230). When the stroke subtypes were analysed, we found that IL6-174 G/C genotype was more frequent in cardioembolic (60.0%) and atherothrombotic ICD subtypes (58.3%). In relation to fibri-β-455 G/A, the A allele showed a increased prevalence in atherothrombotic stroke (43.2%) (p= 0.049).We observed an association between the dyslipidaemia and IL6-174 G/C polymorphism (p= 0.034) and smoking habit with fibri-β-455G/A (p= 0.072). No synergic relation were found between IL6-174 G/C and fibri-β-455 G/A. The G allele IL6-174 G/C carriers group presented higher serum IL6 levels than C allele carriers, 5.85 pg/ml (2.9–34.5) vs. 4.94pg/ml (2.5–11.4). Also, allele A fibri-β-455 G/A was associated with a higher fibrinogen levels than G allele, 329 mg/dl (210–686) versus 280 mg/dl (107–783).Conclusion. There is an association between-174 IL6 G/C polymorphism and ischemic stroke. By contrast, we did not find any association between fibri-β-455 G/A, and ICD. Besides, the analysis performed by ICD subtypes showed an association of this polymorphism and atherothrombotic subtype. These results suggest a relation between smoking habit and fibri-β-455 G/A, and dislypidaemia and-174 IL6 G/C polymorphism.

Platelet glycoprotein polymorphisms: Risk, in vivo expression and severity of atherothrombotic stroke in Chinese

Background Polymorphisms in platelet glycoprotein (GP) receptors Ia, Ib and IIIa may be heritable risk factors for platelet-dependent thrombosis leading to death. The precipitation of stroke by occlusive thrombi has led to the investigation of the platelet surface GP receptors, that are involved in critical steps in the activation of platelets. Three polymorphisms in the GP Iba gene and one in each of GPIIIa, GP Ia were selected based on the evidence of functional effects on structure or expression as candidates for risk. We also determined whether these polymorphisms were associated with in vivo expression levels of platelet GP receptors and the severity of the neurological deficit. Methods A Chinese hospital-based case-control study was conducted with 119 cases of atherothrombotic stroke and 166 age and sex matched controls. Genotyping was performed on lymphocyte DNA by standard methods and platelet GP expression levels were measured by flow-cytometry. Results Allele and genotype frequencies of the GP receptor polymorphisms differ considerably between ethnic populations. We found the D allele of the GP Iba VNTR polymorphism was significantly associated with atherothrombotic stroke in our Chinese cohort, however we did not find a relationship among these polymorphisms, the expression levels of GP receptors and severity of the neurological deficit. Conclusions In our Chinese cohort the D allele of the GP Iba VNTR polymorphism is associated with atherothrombotic stroke. The number of VNTR repeats alters the length of amino acid sequence, which might affect the structure and function of this receptor.

Prognostic significance of plasma resistin levels in patients with atherothrombotic ischemic stroke

Background Resistin (RSN) is an adipocytokine involved in insulin resistance, obesity and atherosclerosis. This study aimed to investigate the association between plasma RSN and outcome after ischemic stroke. Methods RSN measured within 24 h after the event was related to functional outcome and 5-year survival in 211 subjects with first-ever atherothrombotic ischemic stroke. Prognosis was assessed by the Kaplan Meier and the Cox techniques. Results The probabilities of death were 80.4%, 46.2% and 15.7% ( p < 0.001) for patients stratified according to tertiles of RSN (> 30 ng/mL, 20–30 ng/mL and < 20 ng/mL, respectively). The proportion of dependency (modified Rankin Scale score ≥ 3) was greater in 5-year survivors with RSN in the upper tertile (6/11 [54.5%]) compared to the middle (20/56 [35.7%]) and the lowest tertile (8/43 [18.6%]; p < 0.01). C-reactive protein levels (hazard ratio [HR] 3.96 [95% CI 2.06, 8.91]; p < 0.001), coronary heart disease (2.69 [1.62, 6.23]; p < 0.001), RSN levels (2.12 [1.31, 5.08] p < 0.001), National Institute of Health Stroke Scale score (2.02 [1.23, 4.49]; p < 0.01) and age (1.84 [1.19, 3.93]; p < 0.01) were independent predictors of death. Conclusions High plasma RSN appears to be associated with increased risk of 5-year mortality or disability after atherothrombotic ischemic stroke, independently of other adverse predictors.

Effect of routine therapy and selective plasmapheresis on electrical properties of cryoglobulins during ischemic stroke

The charge properties of cryoglobulins were examined during the first 21 days of ischemic stroke (atherothrombotic and cardioembolic). Routine drug therapy produced no effect on the charge of cryoglobulins. Plasmapheresis significantly modified the electrokinetic parameters of cryoglobulins during atherothrombotic stroke and produced less pronounced effect on these proteins during cardioembolic stroke.

Polymorphism of SG13S114T/A in the ALOX5AP Gene and the Risk for Stroke in a Large Chinese Cohort

The 5-lipoxygenase activating protein, an important regulator in the biosynthesis of proinflammatory leukotrienes, has been reported to confer risks for cardiovascular diseases and stroke. The purpose of this study is to assess whether genetic variants in the ALOX5AP encoding the 5-lipoxygenase activating protein will influence the risk for stroke in the Chinese population. A total of 1 773 patients with stroke and 1 713 controls were recruited from seven clinical centers. Polymorphisms of SG13S114T/A and SG13S89G/A in the ALOX5AP were genotyped by the polymerase chain reaction and the restriction enzyme analysis. The multivariate logistic regression model was used to exclude the influence of the conventional vascular risk factors on stroke. The frequency of SG13S114A allele in the ALOX5AP was significantly higher in male patients with thrombotic stroke (33.6%) than in controls (29.2%; P=0.014). The SG13S114AA genotype was significantly associated with a 1.62-fold risk for thrombotic stroke in men (95% confidence interval, 1.11 to 2.35; P=0.012). The SG13S89G/A variant was not associated with stroke or its subtypes. Haplotype analysis showed no significant differences between stroke patients and controls. The present study suggested that a common genetic variant SG13S114T/A in the ALOX5AP gene is associated with an increased risk for atherothrombotic stroke in Chinese males, and racial differences in allele and genotype frequencies may account partially for the different association findings between populations.

Blood Lipids in Brain Infarction Subtypes

Background: Little is known about the relationship between hypercholesterolaemia and specific aetiological subtypes of brain infarction (BI). Methods: In a cross-sectional study of 492 pairs of patients with a BI proven by MRI and matched hospital controls, we determined the blood levels of triglycerides, total, HDL and LDL cholesterol, and apolipoprotein A₁ and B, in the same centralized laboratory. We performed aetiological BI subtype classification. Results: Except for triglycerides, the risk of BI increased continuously with the lipid levels, without any heterogeneity between the main BI subtypes or the group on lipid-lowering therapy. The adjusted odds ratio per standard deviation in LDL cholesterol (0.93 mmol/l) was 1.74 (95% confidence interval, 1.02–2.98) in atherothrombotic strokes (n = 109) and 2.71 (95% confidence interval, 1.60–4.55) in lacunar strokes (n = 105). Eighty percent of patients were above the ATP-III guideline threshold LDL cholesterol of 2.59 mmol/l (100 mg/dl), with a major contribution of both atherothrombotic and lacunar stroke subtypes to this group. Conclusions: These findings suggest that blood lipids, particularly total and LDL cholesterol levels, are associated with all subtypes of BI, and that LDL above 2.59 mmol/l is highly prevalent.

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.

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Increased Serum Malondialdehyde Levels in Chronic Stage of Ischemic Stroke

Serum lipoperoxidation products such as malondialdehyde (MDA) reflect oxidative stress. There are contradictory results addressing the levels of lipoperoxidation products in chronic phase of ischemic stroke. In the present study, we aimed to determine the serum MDA levels in stroke patients 6 months after the cerebrovascular accident. We also compared serum MDA levels in two major groups of patients with ischemic stroke resulting from small vessel and large vessel diseases, respectively. Serum MDA levels of thirty-eight patients who had ischemic stroke (19 with atherothrombotic ischemic stroke and 19 with lacunar infarction) and 30 healthy volunteers were measured. While there was no significant difference in serum MDA levels between the chronic ischemic stroke subgroups (p = 0.795), the serum MDA levels of patients with atherothrombotic ischemic stroke (p < 0.001) or with lacunar infarction (p < 0.001) were significantly higher compared to the control group. We also demonstrated that serum MDA levels of the patients with and those without hypertension (p = 0.846), diabetes mellitus (p = 0.891), or dyslipidemia (p = 0.38) were not significantly different. In conclusion, serum MDA levels were elevated in chronic stroke patients with small or large vessel diseases. To the best of our knowledge, this is the first report showing that serum MDA levels of these two groups are not significantly different. Furthermore, serum MDA levels do not differ solely by the existence or nonexistence of hypertension, diabetes mellitus or hyperlipidemia.

How and When Do We Alter Inflammatory Mechanisms in Stroke? Will It Help?

The emerging recognition of atherosclerosis as primarily a chronic inflammatory process opens new possibilities to the treatment options that can reduce the risk of atherothrombotic stroke. The question is, "How do we alter the inflammatory mechanisms in atherosclerosis and will it reduce the risk of stroke?" Investigation into the fundamental pathophysiological mechanisms involved in the initiation, formation, and activation of atherosclerotic plaques is critical if we are to successfully employ pharmacotherapeutic strategies to reduce stroke risk. This article will review the key inflammatory elements associated with atherosclerosis and atherothrombotic stroke, identify potential inflammatory markers associated with the increased risk of stroke, review the effects of currently available medications that may have a beneficial impact on atherosclerosis and stroke, and briefly explore potential future strategies for reducing inflammation.

Detection and Management of Associated Atherothrombotic Locations in Patients with a Recent Atherothrombotic Ischemic Stroke: Results of the DETECT Survey

Background: Cerebral infarction (CI), myocardial infarction, peripheral artery disease (PAD) and aortic atheroma are the main clinical manifestations of atherothrombosis. Long-term prevention after CI of atherothrombotic origin may require preventive measures at other sites, such as specific drug therapies, surgery, or angioplasty. Therefore the detection of other locations is potentially important. Objectives: The primary objective was to describe the other locations of atherothrombosis in patients hospitalized for a recent cerebral infarct of atherothrombotic origin. Secondary objectives were to describe their vascular risk factor profiles, and their management before and after the cerebral event. Method: This prospective, observational, multicenter survey was conducted in France between September 2003 and July 2004, mainly in neurological departments and stroke units. Results: 753 patients were included (74% men; mean age 69.3 years). Previous coronary events had occurred in 119 (16%). Previous stroke or transient ischemic attacks had occurred in 233 (31%). PAD was already known in 109 (15%). A search for other atherothrombotic locations was positive in 216 patients (29%). The minimum prevalence for any associated atherothrombotic location (either present before or identified during hospitalization) was 47.5% for any location, 33.7% for coronary artery disease, 16.6% for aortic atheroma, and 22.7% for PAD. Conclusion: Fifty percent of the patients with recent atherothrombotic CI have other locations of atherothrombosis. For this reason, a systematic search for these other locations is recommended because of the possible therapeutic consequences. However, the question of the most appropriate period for this search after the cerebral event remains unsettled.

頸動脈可動性病変を認め急性期に内膜剥離術を行った脳梗塞の１例

頸動脈可動性病変を認め急性期に内膜剥離術を行った脳梗塞の１例

The Vulnerable Carotid Artery Plaque

Atherosclerosis is a diffuse, chronic inflammatory disorder that involves the vascular, metabolic, and immune systems and leads to plaque vulnerability. The traditional risk assessment relies on clinical, biological, and conventional imaging tools. However, these tools fall short in predicting near-future events in patients with vulnerable carotid artery plaque. In current clinical practice, anatomic imaging modalities, such as B-mode ultrasound, spiral computed tomography angiography, and high-resolution MRI, can identify several morphological features characteristic of the vulnerable plaque but give little or no information regarding molecular and cellular mechanisms. This review is dedicated to factors involved in carotid artery plaque vulnerability and to new imaging methods that target this condition. Our aim is to describe the following: (1) conventional pathologic and imaging markers predictive of plaque vulnerability; (2) the role of relevant biological, genetic, and mechanical factors; (3) the potential of new imaging methods; and (4) current and emerging treatments. A multimodal assessment of plaque vulnerability involving the combination of systemic markers, new imaging methods that target inflammatory and thrombotic components, and the potential of emerging therapies may lead to a new stratification system for atherothrombotic risk and to a better prevention of atherothrombotic stroke.