Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular events commonly recur in stroke patients on aspirin, and may reflect incomplete inhibition of platelet function with aspirin therapy. The platelet function analyser (PFA-100) activates platelets by aspirating a blood sample at a moderately high shear rate through a capillary to a biologically active membrane with a central aperture. The membrane is coated with collagen, and either ADP (C-ADP) or epinephrine (C-EPI). The time taken for activated platelets to adhere, aggregate, and occlude the aperture is called the closure time. Previous studies have shown that aspirin prolongs the C-EPI closure time, without prolongation of the C-ADP closure time, in the majority of control subjects. We hypothesised that the PFA-100 would provide a sensitive assay for the detection of early and convalescent phase cerebrovascular disease (CVD) patients who had incomplete inhibition of platelet function with aspirin. We investigated potential cyclooxygenase-dependent and -independent mechanisms that might influence the responsiveness to aspirin using the PFA-100. Patients were studied during the early (< or = 4 weeks, n=57) and convalescent phases ((< or = 3 months, n=46) after ischaemic stroke or TIA. To investigate potential mechanisms that could contribute to aspirin responsiveness on the PFA-100, we measured von Willebrand factor antigen levels, and carried out platelet aggregometry experiments in platelet-rich plasma in response to sodium arachidonate (1 mM) and ADP (5 microM). Sixty percent of patients in the early phase and 43% of patients in the convalescent phase did not have prolonged C-EPI closure times on 75-300 mg of aspirin daily, and were defined as aspirin non-responders. Median C-ADP closure times were significantly shorter in aspirin non-responders than aspirin-responders in both the early and convalescent phases after symptom onset (P=0.008), suggesting platelet hyper-reactivity to collagen or ADP in the aspirin non-responder subgroup. There was a significant inverse relationship between plasma von Willebrand factor antigen levels and C-EPI closure times in both early and convalescent phase CVD patients (P=0.008). Mean von Willebrand factor antigen levels were significantly higher in aspirin non-responders than aspirin responsive patients in the early (P=0.001), but not convalescent phase (P=0.2) after stroke and TIA. None of the patients studied were defined as being aspirin-resistant using sodium arachidonate- or ADP-induced platelet aggregometry. A large proportion of ischaemic CVD patients have incomplete inhibition of platelet function with low to medium dose aspirin using the PFA-100. The results suggest that cyclooxygenase-independent mechanisms, including elevated von Willebrand factor antigen levels, play an important role in mediating aspirin non-responsiveness on the PFA-100.
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PMID:Assessment of the antiplatelet effects of low to medium dose aspirin in the early and late phases after ischaemic stroke and TIA. 1601 77

There is current interest in the associations of circulating inflammatory markers (C-reactive protein, fibrinogen, white cell count, albumin, erythrocyte sedimentation rate, the factor VIII:von Willebrand factor complex, the tissue plasminogen activator:plasminogen activator inhibitor type 1 complex, fibrin D-dimer) not only with prognosis in acute coronary syndromes and acute stroke, but also in prediction of cardiovascular events in the general population. Recent meta-analyses of long-term prospective studies have established their associations with coronary heart disease (CHD) events, which may be cause, consequence or coincidence. These markers are also associated in epidemiologic studies of general populations with many cardiovascular risk factors (which may confound their associations with CHD risk), and also with asymptomatic arterial disease (of which they be consequences: 'reverse causality'). The causality of their associations with cardiovascular events is questioned by their lack of specificity for risk of cardiovascular events; and by the lack of association of their functional genotypes with CHD in 'Mendelian randomized trials'. Hence, proof of causality awaits testing in randomized-controlled trials of long-term selective reduction by future agents. Markers are of little additional predictive value to current cardiovascular risk scores, and it is premature to advocate their use in screening for cardiovascular risk prior to careful evaluation of costs, risks, and benefits.
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PMID:Circulating inflammatory markers and risks of cardiovascular and non-cardiovascular disease. 1610 27

The effects of statins on gene expression of cerebral endothelial cells (ECs) in vivo have not been investigated after stroke. We developed a rapid double immunofluorescent staining protocol with antibodies against von Willebrand factor (a marker for endothelium) and glial fibrillary acidic protein (a marker for astrocytes) for laser capture microdissection to isolate single ECs in brain tissue of the rat. Using this protocol in combination with real-time PCR, we found that stroke significantly increased mRNA levels of protease-activated receptor 1 (PAR-1) and tissue factor (TF) in ECs isolated from ischemic cerebral microvessels compared with nonischemic vessels. Treatment of embolic stroke with recombinant human tissue plasminogen activator (rht-PA) 4 h after stroke further elevated PAR-1 mRNA levels nearly 1000-fold in the core and 500-fold in the boundary above the nonstroke group 30 h after stroke, while TF mRNA levels were elevated approximately 10 fold above the nonstroke group. Furthermore, stroke significantly increased matrix metalloproteinase (MMP) 2 and 9 mRNA levels in the ischemic core and boundary regions 6 and 30 h after stroke. Treatment with rht-PA-upregulated MMP2 expression in the ischemic boundary and core. Atorvastatin completely blocked rht-PA upregulation of the above genes, when atorvastatin in combination with rht-PA was administered 4 h after stroke. Monotherapy of atorvastatin 4 h after stroke did not significantly reduce expression of genes examined in the present study. These data provide evidence that atorvastatin reduces exogenous tPA-aggravated cerebral endothelial genes that mediate thrombosis and blood-brain barrier permeability, which could contribute to the beneficial effects of statins on thrombolytic treatment of acute stroke.
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PMID:Atorvastatin downregulates tissue plasminogen activator-aggravated genes mediating coagulation and vascular permeability in single cerebral endothelial cells captured by laser microdissection. 1617 9

Early diagnosing and modification or elimination of atherosclerosis risk factors with the descendants of the ill with past ischemic stroke (IS) might reduce risk of subsequent stroke incidence in the family, or myocardial infarction or other disease being atherosclerosis - derivative. This subject seems to be essential because it concerns young people. The purpose of the present study is identification and assessment of metabolic atherosclerosis risk factors with adult progeny of the ill with past IS at young age. There were examined 43 adult children of the parents who fell ill at young age (between 39 and 55 years in case of men and 60 years in case of women) with IS. The test group included 21 men and 22 women aged from 19 to 39 years (average age - 26.3 years). The reference group consisted of 40 persons, including 18 men and 22 women aged from 22 to 39 years (average age - 26.8 years). The persons from reference group were corresponding (in respect of structural aspects, such as age and sex) to the test group, their parents had negative history towards atherosclerosis - derivative illnesses. None of the patients under examination was a cigarette smoker. Examination of both groups consisted in conducting anamnesis, measurement of body weighing and height, blood pressure as well as evaluation of biochemical atherosclerosis risk factors. Blood testing (blood serum or plasma) consisted of blood cell count and ESR as well as blood glucose level, creatinine, urea, transaminase and bilirubin levels as well as total cholesterol, LDL cholesterol and HDL cholesterol fractions, apolipoprotein B, apolipoprotein AI, lipoprotein (a), triglycerides, homocysteine, folate, fibrinogen, von Willebrand factor and C-reactive protein level. Among persons whose parents were affected, at young age, with IS higher average level of BMI (24.2 +/- 3.8 kg/m2) was detected as compared with that in the reference group (22.4 +/- 2.5 kg/m2), LDL cholesterol fraction (2.7 +/- 0.8 mmol/l vs 2.4 +/- 0.6 mmol/l) and triglycerides (1.1 +/- 0.4 mmol/l vs 0.8 +/- 0.4 mmol/l) as well as lower level of apolipoprotein Al (1.5 +/- 0.2 g/l vs 1.6 +/- 0.2 g/l). Average values of other factors in the blood serum were not significantly different in both with compared groups. In case of women, whose parents were affected with IS, higher levels of the following indicators were detected: BMI (24.3 +/- 3.9 kg/mz vs 21.5 +/- 2.3 kg/m2), total cholesterol (5.1 +/- 0.7 mmol/l vs 4.4 +/- 0.5 mmol/l, LDL cholesterol (2.7 +/- 0.6 mmol/l vs 2.1 +/- 0.4 mmol/l), apolipoprotein B (1.0 +/- 0.1 g/l vs 0.8 +/- 0.1 g/l), lipoprotein (a) (0.3 +/- 0.2 g/l vs 0.2 +/- 0.1 g/l) and triglycerides (1.0 +/- 0.4 mmol/l vs 0.7 +/- 0.2 mmol/l). In group of men whose parents were affected with IS lower levels of apolipoprotein Al (1.3 +/- 0.2 g/l vs 1.5 +/- 0.2 g/l) and of von Willebrand factor (71.4 +/- 23.9% vs 87.1% +/- 16,8%) were detected. Descendents of the ill with past IS should be treated as higher risk group especially when supranormative values of metabolic atherosclerosis risk factors are detected with them. In case of persons with positive family history of IS, having higher values of metabolic atherosclerosis risk factors, it is necessary to apply intensive actions towards change of their life styles, and if necessary - also to include pharmacological treatment.
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PMID:[Assessment of metabolic atherosclerosis risk factors in progeny of patients with past ischemic stroke]. 1620 32

Increasing blood levels of hemostatic variables may increase the risk of thrombosis, while increasing levels of rheological variables which reduce blood flow may increase the risk of ischemic events. Systematic reviews of prospective cohort studies of hemostatic and rheological variables suggest that increasing blood levels of fibrinogen, von Willebrand factor, tissue plasminogen activator antigen, fibrin D-dimer, hematocrit, viscosity, and erythrocyte sedimentation rate may be predictors of risk of coronary heart disease (CHD), but their causal relevance is unknown. At present, data for the associations of other hemostatic variables with CHD, and for the associations of hemostatic variables with stroke, venous thromboembolism, and mortality, is relatively sparse and inconclusive. More detailed syntheses of existing prospective data (such as the Fibrinogen Studies Collaboration), observational studies of CHD and the genetic determinants of these plasma components, as well as large-scale randomized trials should help to determine whether or not these associations are (1) useful in prediction of cardiovascular risk and/or (2) of causal significance.
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PMID:Hemostatic and rheological variables and risk of cardiovascular disease. 1622 32

Platelet glycoprotein (GP)Ib-IX-V and GPVI are unique platelet receptors that bind von Willebrand factor or collagen, respectively, and control the initial interaction of circulating platelets with the blood vessel wall in physiology (hemostasis) or pathology (heart attack or stroke). Engagement of GPIbalpha (the major ligand-binding subunit of GPIb-IX-V) by von Willebrand factor or GPVI by collagen, leads to mobilization of cytosolic Ca2+, secretion of platelet agonists such as ADP, cytoskeletal changes, and activation of the platelet integrin alphaIIbbeta3 that mediates von Willebrand factor- or fibrinogen-dependent platelet aggregation. Recent evidence suggests the cytosolic regulatory protein, calmodulin, plays a central role in regulating GPVI or GPIb-IX-V: first, calmodulin directly binds to conserved, juxtamembrane motifs within cytoplasmic domains of both GPVI and GPIb-IX-V (GPIbbeta and GPV subunits) on resting platelets, interactions that dissociate upon platelet activation; second, an intact calmodulin-binding site within GPVI in transfected cells is required for CaCa2+ signaling, but not for GPVI-dependent pathways involving Src family kinases or co-associated FcRgamma-chain; and third, calmodulin regulates metalloproteinase-dependent ectodomain shedding of GPVI and GPV from human platelets. Other vascular cell adhesion receptors, i.e. leukocyte L-selectin, or PECAM-1 (platelet-endothelial cell adhesion molecule-1), also bind calmodulin within the juxtamembrane region of their cytoplasmic tails, an interaction involved in their proteolytic regulation. Further studies should define the precise functional role of calmodulin in thrombus formation initiated by GPIb-IX-V or GPVI.
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PMID:Role of calmodulin in platelet receptor function. 1625 Aug 59

Normal adults have very few circulating endothelial cells (CECs) in their blood, but increased levels have been shown in association with conditions associated with endothelial damage such as myocardial infarction and stroke. As atrial fibrillation (AF) is associated with a hypercoagulable state and abnormalities of plasma indices of endothelial damage/dysfunction, we hypothesised that CECs would also be raised in this condition, and would correlate with these plasma markers. We measured CECs (by immunofluoresence) as an indicator of frank endothelial damage, alongside 3 plasma indices of endothelial perturbation: von Willebrand factor (vWf), soluble E-selectin and soluble thrombomodulin (sTM) (all ELISA) in 28 patients with chronic 'stable' AF, 63 patients with AF plus an acute cardiovascular or cerebrovascular event as positive controls, and 20 healthy subjects in sinus rhythm as negative controls. Chronic 'stable' AF patients had significantly higher levels of plasma vWf (p<0.001 ), but comparable numbers of CECs (p=0.1638) in comparison to healthy controls. In patients with AF associated with an acute cardiovascular or cerebrovascular event, levels of CECs (p<0.0001) and sTM (p=0.004), but not vWf or sEsel, were significantly increased in comparison to chronic 'stable' AF patients. Patients with uncomplicated AF have abnormal systemic endothelial damage/dysfunction, as evident by increased plasma vWf levels, but normal numbers of CECs, compared to subjects in sinus rhythm. However, following clinical complications, such as stroke or significant haemodynamic compromise, further endothelial disturbance (as indicated by high levels of sTM and CECs) suggests additional endothelial damage.
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PMID:Circulating endothelial cells in atrial fibrillation with and without acute cardiovascular disease. 1627 Jun 20

Increased numbers of CD146-bearing circulating endothelial cells (CECs) in the peripheral blood probably represent the most direct evidence of endothelial cell damage. As acute ischaemic strokes are associated with endothelial abnormalities, we hypothesised that these CECs are raised in acute stroke, and that they would correlate with the other indices of endothelial perturbation, i.e. plasma von Willebrand factor (vWf) and soluble E-selectin. We studied 29 hypertensive patients (19 male; mean age 63 years) who presented with an acute stroke and compared them with 30 high risk hypertensive patients (21 male; mean age 62 years) and 30 normotensive controls (16 male; mean age 58 years). CECs were estimated by CD146 immunobead capture, vWf and soluble E-selectin by ELISA. Patients with an acute ischaemic stroke had significantly higher numbers of CECs/ml of blood (p<0.001) plasma vWf (p=0.008) soluble E-selectin (p=0.002) and higher systolic blood pressure (SBP) as compared to the other groups. The number of CECs significantly correlated with soluble E-selectin (r=0.432, p<0.001) and vWf (r=0.349, p=0.001) but not with SBP (r=0.198, p=0.069). However, in multivariate analysis, only disease group (i.e. health, hypertension or stroke) was associated with increased CECs. Acute ischaemic stroke is associated with increased numbers of CECs. The latter correlate well with established plasma markers of endothelial dysfunction or damage, thus unequivocally confirming severe vasculopathy in this condition. However, the greatest influence on CECs numbers was clinical group.
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PMID:Circulating endothelial cells in acute ischaemic stroke. 1627 Jun 21

Although the mechanisms of action by which aspirin, clopidogrel and dipyridamole inhibit platelets are well characterised, their effects on soluble modulators of thrombosis, inflammation, and endothelial function have yet to assessed systematically. In this investigation aspirin (A), clopidogrel (C), and dipyridamole (D) were administered singly and in combination (A, C, D, AC, AD, CD, ACD) in random order for 2 weeks (without washout) to 11 healthy subjects and 11 patients with previous ischaemic stroke. At the end of each treatment period plasma cyclic guanosine monophosphate (cGMP), monocyte chemoattractant pertide-1 (MCP-1), nitric oxide metabolites (NO(x)), plasminogen activator inhibitor-1 (PAI-1) and von Willebrand factor (vWf); and serum C-reactive protein (CRP) and platelet derived growth factor (PDGF); were measured blinded to treatment. Dipyridamole reduced plasma vWf levels (%) in both volunteers, -10.0 (4.95), and patients, -10.11 (4.34) (p < 0.05). Dipyridamole also lowered CRP (mg/l) in patients, -0.96 (0.47), but not volunteers. Clopidogrel reduced PAI-1 (ng/ml) in volunteers, -5.30 (2.20) (p < 0.05), and patients, -3.61 (2.75) (non-significant trend). Aspirin lowered PDGF (ng/ml) in volunteers, -3.46 (1.55), but not patients. Triple antiplatelet therapy was superior to dual and mono therapy in reducing vWf levels. In conclusion, antiplatelet agents have non-platelet-related effects on soluble modulators of thrombosis, inflammation, and endothelial function. In particular, dipyridamole reduces plasma vWf and clopidogrel lowers plasma PAI-1 levels. These effects may explain, in part, their roles in preventing atherothrombogenesis.
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PMID:Effect of aspirin, clopidogrel and dipyridamole on soluble markers of vascular function in normal volunteers and patients with prior ischaemic stroke. 1642 Oct 11

Congestive heart failure (CHF) is associated with marked endothelial dysfunction. We hypothesized that acute and chronic CHF may manifest different degrees of endothelial damage/dysfunction and activation, as reflected by different plasma endothelial markers, such as von Willebrand factor (vWF) and soluble thrombomodulin (both are indexes of endothelial damage/dysfunction) and soluble E-selectin (an index of endothelial activation). Second, we hypothesized a relation between endothelial markers and B-type natriuretic peptide (BNP, an index of cardiac function) in acute and chronic CHF that could be linked to prognosis. To test this hypothesis, we studied 35 patients with acute CHF, 40 patients with chronic CHF, and 32 healthy controls. The patients with CHF were followed up for the combined outcomes of cardiovascular death, nonfatal myocardial infarction, stroke, thromboembolism, and recurrent admissions to the hospital. vWF (p = 0.001), soluble thrombomodulin, E-selectin, and BNP (all p <0.0001) were higher in patients with acute and chronic CHF compared with controls. When the 2 CHF groups were compared, no significant differences were found in vWF or E-selectin (p = NS), but soluble thrombomodulin was significantly elevated in acute CHF (Tukey's post hoc test, p <0.05). Only high vWF was associated with a poorer outcome (log-rank test, p = 0.0188). None of the endothelial indexes correlated with plasma BNP. After a median follow-up of 18 months, only high (median or higher) vWF levels were predictive of adverse outcomes in the patients with CHF (log-rank statistic = 5.52, degree of freedom 1, p = 0.0188). In conclusion, despite similar ejection fractions, patients with acute and chronic CHF have different degrees of endothelial damage/dysfunction and activation, which may be related to differences in pathophysiology. High levels of vWF were associated with a worse short-term outcome. These endothelial markers were unrelated to plasma BNP levels and may imply a different release mechanism.
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PMID:Endothelial activation, dysfunction, and damage in congestive heart failure and the relation to brain natriuretic peptide and outcomes. 1649 Apr 35


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