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INTRODUCTION: Platelet activation, thrombin generation and fibrin formation play important roles in intracoronary thrombus formation, which may lead to acute myocardial infarction. We investigated whether the prothrombotic markers D-dimer, pro-thrombin fragment 1 + 2 (F1 + 2) and endogenous thrombin potential (ETP) are associated with myocardial necrosis assessed by Troponin T (TnT), and left ventricular impairment assessed by left ventricular ejection fraction (LVEF) and N-terminal pro b-type natriuretic peptide (NT-proBNP). MATERIALS/METHODS: Patients (n = 987) with ST-elevation mycardial infarction (STEMI) were included. Blood samples were drawn at a median time of 24 h after onset of symptoms. RESULTS: Statistically significant correlations were found between both peak TnT and D-dimer (p < 0.001) and F1 + 2 (p < 0.001), and between NT-proBNP and D-dimer (p = 0.001) and F1 + 2 (p < 0.001). When dividing TnT and NT-proBNP levels into quartiles there were significant trends for increased levels of both markers across quartiles (all p < 0.001) D-dimer remained significantly associated with NT-proBNP after adjustments for covariates (p = 0.001) whereas the association between NTproBNP and F1 + 2 was no longer statistically significant (p = 0.324). A significant inverse correlation was found between LVEF and D-dimer (p < 0.001) and F1 + 2 (p = 0.013). When dichotomizing LVEF levels at 40 %, we observed significantly higher levels of both D-dimer (p < 0.001) and F1 + 2 (p = 0.016) in the group with low EF (n = 147). SUMMARY/CONCLUSION: In our cohort of STEMI patients we demonstrated that levels of D-dimer and F1 + 2 were significantly associated with myocardial necrosis as assessed by peak TnT. High levels of these coagulation markers in patients with low LVEF and high NTproBNP may indicate a hypercoagulable state in patients with impaired myocardial function.
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BACKGROUND: Surgery induces inflammation and pro-inflammatory cytokines are associated with post-operative complications. In cardiac surgery, it has been shown that volatile anaesthetics have cardioprotective properties. We explored whether sevoflurane affects the pro-inflammatory response favourably compared with total intravenous anaesthesia (TIVA) after surgery. METHODS: We measured monocyte chemotactic protein 1 (MCP-1), matrix metalloproteinase 9 (MMP-9), C-reactive protein (CRP), vascular cell adhesion molecule 1 (VCAM-1), interleukin (IL)-6 and IL-8 perioperatively and evaluated if the anaesthetic regimen affected these mediators. Our hypothesis was that sevoflurane-based anaesthesia is associated with a reduced release of biomarkers of inflammation compared with TIVA with propofol/remifentanil. RESULTS: In the total population, MCP-1, MMP-9, IL-6 and IL-8 increased 30 min after arrival intensive care unit, compared with before surgery (P < 0.001), whereas CRP and VCAM-1 transiently declined (P < 0.001). From 30 min after arrival intensive care unit to 1st post-operative day, MCP-1 and IL-6 levels declined (P < 0.001), CRP and VCAM-1 increased (P < 0.001), whereas MMP-9 and IL-8 were not significantly altered. Pre-operatively there were no significant differences in any variables between the two anaesthetic groups. Lower levels of MCP-1 and IL-8 (P < 0.001) and higher levels of IL-6 and MMP-9 (P = 0.003) were found in the sevoflurane group, compared with the TIVA group 30 min post-operatively. CRP and VCAM-1 levels did not differ. There were no significant differences between the two anaesthetic groups before surgery or at 1st post-operative day. CONCLUSION: We found an inflammatory response during the observation period, which was modified by the anaesthetic regimen in the early phase. This short-lasting difference is probably too short to support a cardioprotective effect of sevoflurane compared with TIVA in open abdominal aortic surgery.
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Citocinas/sangue , Inflamação/sangue , Éteres Metílicos/sangue , Éteres Metílicos/farmacologia , Complicações Pós-Operatórias/sangue , Procedimentos Cirúrgicos Vasculares , Idoso , Anestesia Intravenosa , Anestésicos Inalatórios/sangue , Anestésicos Inalatórios/farmacologia , Anestésicos Intravenosos/sangue , Anestésicos Intravenosos/farmacologia , Biomarcadores/sangue , Proteína C-Reativa , Cardiotônicos/sangue , Quimiocina CCL2/sangue , Citocinas/efeitos dos fármacos , Feminino , Humanos , Interleucina-6/sangue , Interleucina-8/sangue , Masculino , Metaloproteinase 9 da Matriz/sangue , Estudos Prospectivos , Sevoflurano , Molécula 1 de Adesão de Célula Vascular/sangueRESUMO
We examined whether resting levels and exercise-induced changes during exercise ECG stress test (EST) of cardiac Troponin T (cTnT), NT-proBNP and prothrombotic markers were affected by revascularization in patients with coronary artery disease (CAD).EST1 was performed before coronary angiography and revascularization, and patients (n = 20) with confirmed CAD, performed another EST (EST2) 9 weeks later. Blood samples were drawn at rest and within five min after termination of ESTs.cTnT and NT-proBNP increased during exercise at both ESTs (p < 0.001, all). Resting cTnT levels at EST2 versus EST1 were significantly higher (p = 0.02) whereas NT-proBNP did not differ. At both visits, increased D-dimer (p = 0.008 and <0.001), pro-thrombin fragment 1 + 2 (p = 0.009 and 0.001) and tissue factor pathway inhibitor (TFPI) (p < 0.001 and 0.001) during exercise were demonstrated. Resting levels of endogenous thrombin potential (ETP) and TFPI were reduced at EST2 versus EST1 (p < 0.01).Revascularization did not affect exercise-induced release of cardiac and prothrombotic biomarkers and did not reduce resting levels of cTnT or NT-proBNP, suggesting revascularization per se not to prevent secretion of biomarkers. The lower resting levels of ETP and TFPI after revascularization may however, be indicative of reduced thrombin generation and endothelial activation.Clinicaltrials.gov, CADENCE, NCT01495091 https://clinicaltrials.gov/ct2/show/NCT01495091?term = 01495091&draw = 2&rank = 1.
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Doença da Artéria Coronariana , Biomarcadores , Angiografia Coronária , Doença da Artéria Coronariana/cirurgia , Humanos , Peptídeo Natriurético Encefálico , Fragmentos de Peptídeos , Trombina , Troponina TRESUMO
BACKGROUND: Obese patients are at high risk of developing cardiovascular disease. Several studies suggest obesity as an independent risk factor. Adipose tissue is now accepted as an endocrine organ that produces and secretes a variety of cytokines, hormones and other metabolic players involved in the pathogenesis of atherosclerosis. Among this versatile group of mediators and effectors of inflammation and atherothrombosis, we have studied the expression of matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1), plasminogen activator inhibitor-1 (PAI-1), interleukin-18 (IL-18) and interleukin-6 (IL-6). All these markers, in their circulatory form, have been associated with cardiovascular disease. However, there is no much data available on their expression in adipose tissue in human subjects with and without cardiovascular disease. MATERIAL AND METHODS: We successfully isolated RNA from subcutaneous fat biopsies of 61 patients with or without cardiovascular disease. We then measured the RNA expression of MMP-9, TIMP-1, PAI-1, IL-18 and IL-6 with Real-Time PCR, using relative quantification. RESULTS: Albeit not statistically significant, all inflammatory mediators - except IL-18 - were highly expressed in patients with cardiovascular disease (n = 16) compared with those without (n = 45). Pooling the gene expression data, trying to capture the overall inflammatory activity in adipose tissue in a score system, we observed a highly significant association with CVD. CONCLUSIONS: Trying to capture the overall inflammatory activity, in addition to the mass of adipose tissue, could provide useful hints towards a pathogenetic link between obesity and presence of cardiovascular disease.
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Tecido Adiposo/metabolismo , Biomarcadores/metabolismo , Doenças Cardiovasculares/diagnóstico , Obesidade/complicações , Idoso , Doenças Cardiovasculares/patologia , Estudos Transversais , Humanos , Interleucina-18/metabolismo , Interleucina-6/metabolismo , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Obesidade/metabolismo , Inibidor 1 de Ativador de Plasminogênio/metabolismo , RNA Mensageiro/metabolismo , Fatores de Risco , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Túnica Média/patologiaRESUMO
Based on experience from randomised trials with n-3 PUFA we intend to answer some relevant questions in patients with coronary heart disease. In the SHOT study supplementation with 3.4 g/day of highly concentrated n-3 PUFA for 1 year significantly reduced the occlusion rate of venous aortocoronary bypass grafts, and this effect correlated significantly to the change in serum levels of n-3 fatty acids. In the CART study 5.1 g/day of highly concentrated n-3 PUFA did not reduce the incidence of restenosis after 6 months. If anything, a negative effect was observed. The background for this was probably a pro-oxidative and proinflammatory mechanism as elucidated in substudies. In the OVITES trial the addition of vitamin E did not counteract the proinflammatory effect of high amounts of n-3 PUFA supplementation as observed in CART, although circulating oxidative substances were unaffected. In the "Fiord-to-table" study replacement of fish oils by vegetable oils in the feed of farmed Atlantic salmon was mirrored in the fatty acid profile of the salmon fillets as well as in that of serum from patients after ingesting about 700 g/week for six weeks. A parallel reduction of the proinflammatory profile was observed only in patients who ingested salmon fed on fish oil.
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Doença da Artéria Coronariana/tratamento farmacológico , Ácidos Graxos Ômega-3/uso terapêutico , Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácidos Docosa-Hexaenoicos/farmacologia , Ácidos Docosa-Hexaenoicos/uso terapêutico , Composição de Medicamentos , Ácido Eicosapentaenoico/administração & dosagem , Ácido Eicosapentaenoico/farmacologia , Ácido Eicosapentaenoico/uso terapêutico , Ácidos Graxos Monoinsaturados , Ácidos Graxos Ômega-3/administração & dosagem , Ácidos Graxos Ômega-3/farmacologia , Óleos de Peixe/farmacologia , Humanos , Óleos de Plantas/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Óleo de Brassica napus , Vitamina E/farmacologiaRESUMO
BACKGROUND: The beneficial impact of warfarin in preventing new events after AMI is well established. Decrease in thrombin generation seems to be the key element in anticoagulant treatment. OBJECTIVES: The aims were to investigate the effect of warfarin and platelet inhibition on thrombin generation, assessed by the endogenous thrombin potential (ETP), and study the relation between coagulation parameters and ETP in patients with AMI. PATIENTS/METHODS: In the present sub-study of the WARIS II trial, patients with AMI were randomly assigned to treatment with aspirin 160 mg/d (n=57), aspirin 75 mg/d and warfarin (INR 2.0-2.5) (n=68) or warfarin (INR 2.8-4.2) (n=61). Fasting blood samples were collected from patients at discharge from hospital and after 6 weeks treatment. RESULTS: Correlation analyses showed that both ETP and peak thrombin levels were significantly correlated with Factor VII Ag (r=0.38 and 0.36 respectively, p<0.01 for both) and with F1+2 (r=0.26 and 0.23 respectively, p=0.01 for both) at baseline. Antithrombotic treatment for 6 weeks caused a highly significant inhibition of ETP in patients treated with warfarin (-28%+/-5%, p<0.001), and patients treated with aspirin/warfarin (-24%+/-8%, p=0.04). Similarly, peak thrombin levels were reduced in patients treated with warfarin (-18%+/-7%, p=0.049) and aspirin/warfarin (-19%+/-5%, p=0.029), whereas an increase (12%+/-4%, p=0.029) occurred during aspirin treatment alone. F1+2 levels decreased by 64% and 58% in the warfarin and aspirin/warfarin groups, respectively (p=0.001 for both). CONCLUSIONS: In patients with AMI, warfarin significantly reduced the endogenous thrombin generation and the potential to generate thrombin in plasma ex vivo, whereas aspirin alone had no effect on thrombin generation in vivo or ex vivo, assessed by ETP.
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Anticoagulantes/uso terapêutico , Aspirina/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Inibidores da Agregação Plaquetária/uso terapêutico , Trombina/metabolismo , Varfarina/uso terapêutico , Testes de Coagulação Sanguínea , Quimioterapia Combinada , Humanos , Coeficiente Internacional Normatizado , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/sangueRESUMO
RATIONALE: The heterodimer IL-12 is an inducer of Th1 responses and stimulates INFÆ´ production. Micro-RNA-21 (miR-21) is described as a key regulator of the pro-inflammatory response and has IL-12p35 mRNA as one of its main targets. The IL-12p40 1188A/C genetic variant located in 3'untranslated region (UTR), thus environmentally exposed, has further been reported to modify IL-12 levels. We have previously reported on the lowering effect of cigarette smoke on circulating IL-12 in patients with coronary artery disease (CAD). OBJECTIVES: To explore if cigarette smoking affects IL-12p35, IL-12p40, INFÆ´ and miR-21 gene-expression and further modulates any effect of the IL-12p40 polymorphism on circulating IL-12 levels. METHODS AND RESULTS: The IL-12p40 1188A/C polymorphism was analyzed in 1001 stable CAD patients, of which 330 subjects were included for IL-12p35, IL-12p40 and INFÆ´ gene-expression analyses in circulating leukocytes and 200 were further selected for plasma miR-21 analysis. Smoking associated with lower expression of miR-21 and its target IL-12p35 mRNA (adjusted p<0.05, both) whereas the influence on INFÆ´ expression tended to be high-dose reliant (p = 0.057). The IL-12p40 CC genotype associated with elevated circulating IL-12 levels, however, when stratified according to smoking, only in the non-smoking group (adjusted p < 0.05). Although the markers were mainly downregulated in current smokers, their inter-correlations were potentiated. CONCLUSION: Smoking associated with reduced miR-21 gene-repression and the results can therefore not explain the previously observed reduction in circulating IL-12. Smoking attenuated the IL-12 pro-inflammatory axis in which the investigated IL-12p40 genetic variant may have different clinical impact in smokers vs non-smokers.
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Fumar Cigarros , Doença da Artéria Coronariana/etiologia , Regulação da Expressão Gênica , Interleucina-12/genética , MicroRNAs/genética , Adulto , Idoso , Biomarcadores , Fumar Cigarros/efeitos adversos , Doença da Artéria Coronariana/metabolismo , Citocinas/genética , Citocinas/metabolismo , Feminino , Genótipo , Humanos , Interleucina-12/metabolismo , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Polimorfismo GenéticoRESUMO
OBJECTIVE: Marine polyunsaturated n-3 fatty acids (n-3 PUFA) may have cardioprotective effects and beneficial influence on the fibrotic process. We evaluated the associations between serum marine n-3 PUFA and selected biomarkers of fibrosis and cardiac remodeling in elderly patients with acute myocardial infarction. SETTING: From the ongoing OMega-3 fatty acids in Elderly patients with Myocardial Infarction (OMEMI) trial, 299 patients were investigated. Soluble ST2 (sST2), Galectin-3 (Gal-3) and the serum content of major marine n-3 and n-6 PUFA were analyzed 2-8 weeks after the index acute myocardial infarction. RESULTS: Gal-3 was inversely correlated to eicosapentaenoic acid (r = -.120, p = .039) and docosahexaenoic acid (r = -.125, p = .031) and positively correlated to the n-6/n-3 ratio (r = .131, p = .023). Gal-3 levels were significantly higher in diabetics vs non-diabetics (12.00 vs 9.61 ng/mL, p = .007) and in patients with NYHA class ≥III for dyspnea at inclusion (11.33 vs 9.75 ng/mL, p = .006). CONCLUSIONS: The associations between the marine n-3 PUFA and levels of Gal-3 indicate beneficial effects of n-3 PUFA on cardiac remodeling in an elderly population with acute myocardial infarction.
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OBJECTIVE: The Oslo Diet and Antismoking study was a 5-year randomised trial initiated in 1972-1973, which studied the effect of dietary change and smoking cessation for the prevention of coronary heart disease among high-risk middle-aged men. To test the long-term maintenance of lifestyle change, we examined diet and cardiovascular risk factors in subjects initially randomised to the control and intervention groups 20 years after cessation of the intervention. SUBJECTS AND DESIGN: Of the original cohort that included 1232 participants, 910 survivors were identified in 1997 and cardiovascular risk factors were measured in 563 (62%) in 1997-1999. Of these, 558 (99%) also completed questionnaires about their food intake and attitudes to health and diet. RESULTS: Cigarette smoking was nearly halved between baseline and 20-year follow-up in each of the intervention and control groups (P<0.001 within groups), but did not differ between the intervention group (39%) versus the control group (34%); P=0.07. Body mass index increased by 1.4+/-2.6 and 1.6+/-2.6 kg/m(2) between baseline and 20-year follow-up in the intervention and control groups, respectively (P<0.001 within groups; NS between groups). Serum total cholesterol and triglyceride concentrations decreased substantially in subjects treated or untreated with statins (P<0.001 within the intervention and control groups) but did not differ between the groups (total cholesterol change of -1.4+/-1.3 and -1.3+/-1.2 mmol/l, respectively, and triglyceride change of -0.5+/-1.0 mmol/l in both groups). Men in the intervention group reported a less atherogenic fat quality score and lower intakes of fat, saturated fat and cholesterol, higher intakes of long chain polyunsaturated fatty acids, protein and beta-carotene and greater attention to lifestyle and change of diet than the control group (all P<0.05). The fatty acid concentrations did not differ, however, between the intervention and control groups (P>0.05). CONCLUSIONS: No long-term differences in smoking rates or lipid concentrations between the intervention and control groups were observed in the surviving attendees two decades after the end of the trial. Lifestyle intervention still influenced the dietary intake, though modestly.
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Doenças Cardiovasculares/prevenção & controle , Dieta , Gorduras na Dieta/administração & dosagem , Estilo de Vida , Abandono do Hábito de Fumar , Idoso , Índice de Massa Corporal , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Colesterol/sangue , Estudos de Coortes , Comportamento Alimentar/fisiologia , Seguimentos , Humanos , Masculino , Noruega , Educação de Pacientes como Assunto , Fatores de Risco , Triglicerídeos/sangueRESUMO
OBJECTIVES: The aim of the study was to investigate whether omega-3 fatty acids (n-3 FA) reduce the occurrence of restenosis after percutaneous transluminal coronary angioplasty. BACKGROUND: Meta-analyses have shown significant reduction of restenosis after coronary angioplasty upon supplementation with n-3 FA. METHODS: In a prospective, placebo-controlled, double-blind study, 500 patients were randomly allocated to treatment with n-3 FA (Omacor, Pronova AS, Oslo, Norway) 5.1 g/day or corn oil (placebo) starting at least two weeks prior to elective coronary angioplasty. The treatment was continued until restenosis evaluation by quantitative coronary angiography after six months. Stenosis was defined as a minimal luminal diameter (MLD) < 40% of the reference diameter. Successful coronary angioplasty was defined as > or = 20% acute gain in MLD and a residual stenosis < 50%. Restenosis was defined as > or = 20% late loss of diameter and stenosis > 50% or an increase in stenosis of > or = 0.7 mm. Three-hundred ninety-two patients fulfilled the criteria for initial stenosis and successful coronary angioplasty, and, except four patients who died, none were lost for follow-up. RESULTS: Restenosis occurred in 108/266 (40.6%) of the treated stenoses in the Omacor group and in 93/263 (35.4%) in the placebo group (odds ratio [OR] 1.25, 95% confidence interval [CI] [0.87-1.80] p = 0.21). In the Omacor group one or more restenoses occurred in 90/196 (45.9%) patients as compared with 86/192 (44.8%) in the placebo group (OR 1.05, 95% CI [0.69-1.59] p = 0.82). CONCLUSIONS: Supplementation with 5.1 g n-3 FA/day for six months, initiated at least two weeks prior to coronary angioplasty did not reduce the incidence of restenosis.
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Angioplastia Coronária com Balão , Doença das Coronárias/terapia , Ácidos Graxos Ômega-3/administração & dosagem , Idoso , Animais , Óleo de Milho/administração & dosagem , Angiografia Coronária , Doença das Coronárias/diagnóstico por imagem , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pré-Medicação , Estudos Prospectivos , Recidiva , Falha de TratamentoRESUMO
Although aspirin is effective in secondary prevention in coronary heart disease, new thromboembolic events in patients on aspirin are frequently seen. In trials on aspirin-treated patients, platelet function tests have revealed large variability in platelet aggregation. This phenomenon has been named aspirin resistance, aspirin non-responsiveness or high-on-aspirin residual platelet reactivity. The mechanism of aspirin antiplatelet effect is due to the inhibition of cyclooxygenase-1 enzyme in platelets. In some trials, almost all patients on aspirin have a very low level of serum thromboxane B2, indicating that the measured platelet reactivity in aspirin-treated patients might be due to platelet activation via other pathways, such as ADP or thrombin. The prevalence of real aspirin resistance seems to be very low, and probably the term "high-on-aspirin residual platelet reactivity" should be preferred to describe this phenomenon.
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Aspirina/farmacologia , Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Animais , Aspirina/efeitos adversos , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/prevenção & controle , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Humanos , Ativação Plaquetária/fisiologia , Agregação Plaquetária/fisiologia , Inibidores da Agregação Plaquetária/efeitos adversos , Testes de Função Plaquetária/métodosRESUMO
INTRODUCTION: Reports on the content of aspirated coronary thrombi have until now mainly focused on cellular components. We investigated the genetic expression of selected mediators and proteases actively involved in the pathophysiological process of acute myocardial infarction in aspirated coronary thrombi. MATERIALS AND METHODS: In this cross-sectional study, RNA from coronary thrombi in 67 subjects with acute myocardial infarction was isolated. Gene expression arrays of selected markers were performed by RT-PCR with relative quantification. RESULTS: Twenty of 22 markers were expressed in >50% of the samples. The relative quantification of P-selectin correlated negatively to total ischemic time (p=0.01), while genes related to fibrinolysis (t-PA, u-PA, PAI-1), inflammation (PTX3, CXCL9, MCP-1, IL18, TNFα) and plaque instability (MMP-2 and TIMP-1) correlated positively to total ischemic time (all<0.05). Long ischemic time (>4.0 hours) associated with a relative reduction in the expression of P-selectin and a relative increase in the expression of t-PA, u-PA, PAI-1, PTX3, CXCL9, MCP-1, IL-18, TNFα, MMP-2 and TIMP-1. The presence of type 2 diabetes associated with 3.2-fold increased PAI-1 expression (adjusted p=0.033), while the presence of hypertension associated with about 50% reduction of IL-8 and TIMP-1. Smoking and overweight did not affect any markers. CONCLUSIONS: The gene expression profile from coronary thrombi differed according to ischemic time, shown by reduced content of platelet markers and increased content of fibrinolytic, inflammatory and plaque instability mediators over time. Patients with type 2 diabetes showed increased expression of PAI-1, indicative of reduced fibrinolysis.
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Trombose Coronária/genética , Infarto do Miocárdio/genética , Doença Aguda , Estudos de Coortes , Trombose Coronária/complicações , Estudos Transversais , Feminino , Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/fisiopatologiaRESUMO
We performed the present study to investigate indirectly the in vivo effects of angiotensin II on fibrinolysis and catecholamines by treatment with losartan, a selective angiotensin II type 1 receptor antagonist. The effects were evaluated in basal conditions as well as in two different models of acute hyperinsulinemia physiologically induced by oral glucose ingestion and by a euglycemic glucose clamp technique. Twenty subjects with moderate hypertension were included in a randomized, double-blind, placebo-controlled crossover study of 4-week treatment periods. Plasma levels of catecholamines, tissue plasminogen activator activity and antigen, and plasminogen activator inhibitor type 1 activity and antigen were unchanged in the basal state after 4 weeks of treatment. During both models of hyperinsulinemia, plasminogen activator inhibitor activity and antigen decreased significantly (both P<.001), and tissue plasminogen activator activity increased significantly (P<.Ol). Norepinephrine did not change during any of the procedures, whereas epinephrine increased significantly after 3 hours of the oral glucose tolerance test. Changes from baseline did not differ between the treatment and placebo regimens during the hyperinsulinemic procedures with regard to either of the fibrinolytic variables or the catecholamines. In conclusion, we could not demonstrate any effects of 4 weeks of treatment with losartan on plasma levels of fibrinolytic variables or catecholamines either in basal conditions or during acute hyperinsulinemia. However, the present findings do not preclude more direct effects of angiotensin II or involvement of other receptor subtypes on fibrinolysis.
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Antagonistas de Receptores de Angiotensina , Anti-Hipertensivos/farmacologia , Compostos de Bifenilo/farmacologia , Catecolaminas/sangue , Fibrinólise/efeitos dos fármacos , Hiperinsulinismo/sangue , Hipertensão/sangue , Imidazóis/farmacologia , Tetrazóis/farmacologia , Adulto , Idoso , Glicemia , Estudos Cross-Over , Método Duplo-Cego , Feminino , Teste de Tolerância a Glucose , Humanos , Hiperinsulinismo/complicações , Hipertensão/complicações , Losartan , Masculino , Pessoa de Meia-Idade , Ativador de Plasminogênio Tecidual/sangueRESUMO
The long-term metabolic effects of n-3 fatty acids were studied in patients with coronary artery disease. They were investigated before and 9 mo after bypass surgery. After postoperative randomization, 260 patients received 4 g fish-oil concentrate/d (approximately 3.4 g eicosapentaenoic and docosahexaenoic acids/d), whereas 251 patients comprised the control group. No group differences in the intake of energy and nutrients, apart from n-3 fatty acids, were discerned from dietary records. Compliance was affirmed by analyses of serum phospholipid fatty acids. Serum triglyceride concentrations were lowered by 19.1% in the fish-oil group, but no influence on the concentrations of cholesterol or apolipoproteins A-I and B-100 was seen. The concentrations of plasma glucose and serum insulin and C-peptide were not influenced by fish oil. The activity of liver enzymes increased slightly, but significantly, in the fish-oil group, whereas no group difference in the serum concentrations of thiobarbituric acid-reactive substances was observed. Thus, no adverse metabolic effects of long-term fish-oil supplementation assumed to be of clinical importance were seen.
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Doença das Coronárias/metabolismo , Ácidos Graxos Ômega-3/farmacologia , Idoso , Alanina Transaminase/sangue , Apolipoproteína A-I/sangue , Apolipoproteína B-100 , Apolipoproteínas B/sangue , Aspartato Aminotransferases/sangue , Glicemia/análise , Peptídeo C/sangue , Colesterol/sangue , Doença das Coronárias/prevenção & controle , Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Ômega-3/uso terapêutico , Feminino , Óleos de Peixe/metabolismo , Óleos de Peixe/farmacologia , Óleos de Peixe/uso terapêutico , Humanos , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Fosfolipídeos/sangue , Estudos Prospectivos , Substâncias Reativas com Ácido Tiobarbitúrico/análise , Fatores de Tempo , Triglicerídeos/sangue , gama-Glutamiltransferase/sangueRESUMO
Antithrombotic treatment with warfarin and/or aspirin is widely used in preventing recurrence of thrombotic events after an acute myocardial infarction (AMI). The objective of this study was to evaluate the long-term influence of warfarin at different INR levels and/or aspirin on some hemostatic variables in patients after an AMI. A subpopulation of the WARIS-II trial in which patients after an acute MI were randomly assigned to treatment with aspirin 160 mg d(-1), aspirin 75 mg d(-1) and warfarin (target INR 2.0-2.5) or warfarin (target INR 2.8-4.2) was studied. Fasting blood samples were collected before randomization 5-7 days after the AMI, after 6 weeks and 4 years for determinations of prothrombin fragment 1 + 2 (F1 + 2), soluble tissue factor (sTF), D-dimer and fibrinogen. In the warfarin-alone group as compared with the aspirin-alone group significantly lower levels of F1 + 2 and D-dimer (P < 0.001 for both), but significantly higher levels of sTF (P = 0.007) were found after 6 weeks. The same pattern was found after 4 years. When comparing the combined group with the aspirin alone group, similar profiles were seen. The levels of F1 + 2 in the combined group were, however, significantly higher than in the warfarin alone group after 6 weeks and 4 years (both P < 0.01). During long-term treatment with warfarin in patients after an AMI increased levels of sTF were found. However, significantly reduced levels of the coagulation products were obtained, indicating reduced thrombin generation. The increased levels of sTF during warfarin therapy are suggested to appear on the basis of reduced consumption.
Assuntos
Infarto do Miocárdio/sangue , Infarto do Miocárdio/tratamento farmacológico , Tromboplastina/efeitos dos fármacos , Varfarina/farmacologia , Adulto , Idoso , Aspirina/farmacologia , Aspirina/uso terapêutico , Biomarcadores/sangue , Fatores de Coagulação Sanguínea/análise , Quimioterapia Combinada , Feminino , Hemostasia/efeitos dos fármacos , Humanos , Coeficiente Internacional Normatizado , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Solubilidade , Tromboplastina/análise , Fatores de Tempo , Varfarina/uso terapêuticoRESUMO
In a randomized trial on the effect of dalteparin for 5 weeks after HRS we evaluated hemostatic variables in plasma sampled before and 1, 6 and 35 days postoperatively. In 218 patients we found that prothrombin fragment 1 + 2 (F1 + 2), thrombin-antithrombin complexes (TAT), d-dimer and fibrinogen were significantly higher on day 35 as compared with baseline values in the placebo group (P < 0.001 for all). The same pattern was found in the dalteparin group, but with significantly lower values for F1 + 2, TAT and d-dimer. In patients in the placebo group with venographically proven deep vein thrombosis (DVT) on day 35 (33%), significantly higher values were found for F1 + 2, TAT and d-dimer than in patients without DVT. Patients in the highest quartile of d-dimer (>2850 ng mL-1) had an odds ratio for the presence of DVT of 24.0 when compared with patients in the lowest quartile (<1625 ng mL-1). It is concluded that a substantial hypercoagulability is sustained until day 35 after HRS, significantly reduced with prolonged administration of dalteparin.
Assuntos
Artroplastia de Quadril/efeitos adversos , Trombofilia/tratamento farmacológico , Trombose/prevenção & controle , Idoso , Anticoagulantes/farmacologia , Anticoagulantes/uso terapêutico , Fatores de Coagulação Sanguínea/análise , Fatores de Coagulação Sanguínea/efeitos dos fármacos , Dalteparina/farmacologia , Dalteparina/uso terapêutico , Feminino , Humanos , Masculino , Flebografia , Complicações Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/prevenção & controle , Trombofilia/etiologia , Trombofilia/prevenção & controle , Trombose/tratamento farmacológico , Trombose/etiologia , Trombose Venosa/diagnóstico , Trombose Venosa/prevenção & controleRESUMO
The effects of dietary trans fatty acids on fasting and diurnal variation in hemostatic variables are not known. This study compares the effects of three diets with three different margarines, one based on palm oil (PALM-diet), one based on partially hydrogenated soybean oil (PHSO, TRANS-diet) and one with a high content of polyunsaturated fatty acids (PUFA-diet) on diurnal postprandial hemostatic variables. A strictly controlled dietary Latin square study was performed and nine young female participants consumed each of the diets for 17 days in a random order. The sum of the cholesterol-increasing fatty acids (C12:0, C14:0, C16:0) was 36.3% of total fatty acids in the PALM-diet, the same as the sum of saturated-(C12:0, C14:0, C16:0) (12.5%) and trans fatty acids (23.1%) in the TRANS-diet. The sum of C12:0, C14:0 and C16:0 was 20.7% in the PUFA-diet. The amount of fat made up 30-31% of energy in all diets. Nine participants completed the study. The diurnal postprandial state level of tissue plasminogen activator (t-PA) activity was significantly decreased on the TRANS-diet compared with the PALM-diet. t-PA activity was also decreased on the PUFA-diet compared with PALM-diet but the difference was below statistical significance (P=0.07, Bonferonni adjusted). There were no significant differences in either fasting levels or in circadian variation of t-PA antigen, PAI-1 activity, PAI-antigen, factor VII coagulant activity or fibrinogen between the three diets. Our results indicate that dietary trans fatty acids from PHSO has an unfavourable effect on postprandial t-PA activity and thus possibly on the fibrinolytic system compared with palm oil.
Assuntos
Gorduras Insaturadas na Dieta/farmacologia , Margarina/análise , Óleos de Plantas/farmacologia , Óleo de Soja/farmacologia , Ativador de Plasminogênio Tecidual/sangue , Adulto , Ingestão de Alimentos , Ácidos Graxos Insaturados/farmacologia , Comportamento Alimentar , Feminino , Fibrinólise/efeitos dos fármacos , Humanos , Hidrogenação , Óleo de Palmeira , Distribuição AleatóriaRESUMO
BACKGROUND: cellular adhesion molecules (CAMs) expressed on the endothelial surface play a key role in the inflammatory process of atherosclerosis, and increased expression of CAMs has been shown in hypercholesterolemic individuals. The expression of CAMs is mediated by several cytokines including tumor necrosis factor alpha (TNF alpha) and interleukin 6 (IL-6). The aim of the present study was to assess the influence of pravastatin 40 mg per day on selected soluble CAMs; intercellular adhesion molecule 1 (ICAM-1), vascular cellular adhesion molecule 1 (VCAM-1), E-selectin, P-selectin and some circulating markers of inflammation; C-reactive protein (CRP) and the cytokines TNF alpha and IL-6. 40 non-diabetic men, age below 70 years, with serum total cholesterol 6--10 mmol/l combined with HDL-cholesterol < or =1.2 mmol/l were included. The study was randomized, double blinded, placebo controlled, cross over designed with 8 weeks intervention periods. Fasting blood samples were drawn after 8 and 16 weeks. RESULTS (MEDIAN VALUES): significant reduction of total cholesterol was achieved after treatment with pravastatin (7.8 on placebo vs. 5.7 mmol/l on pravastatin). TNF alpha was significantly reduced after treatment with pravastatin (1.33 on placebo vs. 1.10 pg/ml on pravastatin, P=0.032), whereas no differences in the levels of the measured sCAMs, CRP and IL-6 were found. Subgroup analysis among smokers versus non-smokers showed a significant reduction in the level of TNF alpha only among the smokers. CONCLUSION: hypercholesterolemic individuals treated with pravastatin 40 mg per day for 8 weeks showed a statistically significant reduction in the levels of TNF alpha as compared with placebo.
Assuntos
Anticolesterolemiantes/uso terapêutico , Hipercolesterolemia/sangue , Hipercolesterolemia/tratamento farmacológico , Pravastatina/uso terapêutico , Fator de Necrose Tumoral alfa/metabolismo , Biomarcadores/sangue , Método Duplo-Cego , Humanos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Fatores de TempoRESUMO
Infectious agents are possible stimulators of inflammation in atherogenesis. The aim of this study was to investigate if Chlamydia pneumoniae and Helicobacter pylori were associated with elevated levels of tumor necrosis factor alpha (TNFalpha) and interleukin-6 in coronary heart disease (CHD) patients (n=193) and age- and sex-matched controls (n=193) as markers of increased inflammatory activity. C reactive protein (CRP) and fibrinogen were also included. Serologic status towards the two bacteria was measured and levels of the inflammatory markers were compared between seropositives and seronegatives, each study group being evaluated separately. In CHD patients Chlamydia lipopolysaccharide (LPS) IgA seropositivity predicted elevated TNFalpha levels (P=0.009), still statistically significant after adjustment for traditional cardiovascular risk factors (P=0.005). Chlamydia LPS IgG seropositivity independently predicted fibrinogen levels in CHD patients (P=0.028), while no association between serology and inflammatory markers were observed among controls. H. pylori seropositivity alone was not associated with any increase in the inflammatory markers in any of the two groups. However, in CHD patients seropositivity to both agents predicted higher levels of TNFalpha (P=0.041), CRP (P=0.037) and fibrinogen (P=0.001) compared to double seronegativity. We conclude that C. pneumoniae LPS seropositivity may contribute to increased vascular inflammation in CHD patients, possibly even more pronounced when present in combination with H. pylori seropositivity.
Assuntos
Infecções por Chlamydia/sangue , Doença das Coronárias/microbiologia , Infecções por Helicobacter/sangue , Fator de Necrose Tumoral alfa/metabolismo , Adulto , Idoso , Anticorpos Antibacterianos/sangue , Proteína C-Reativa/metabolismo , Chlamydophila pneumoniae/imunologia , Chlamydophila pneumoniae/isolamento & purificação , Doença das Coronárias/sangue , Feminino , Helicobacter pylori/imunologia , Helicobacter pylori/isolamento & purificação , Humanos , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
OBJECTIVE: To investigate the metabolic effects of losartan (Cozaar) in patients with essential hypertension. METHODS: Twenty patients with mild hypertension (office blood pressure > 140/95 mmHg and home diastolic blood pressure > 90 mmHg) were examined in a double-blind, placebo-controlled cross-over study of 4 weeks of treatment with 50-100 mg losartan. The effects on glucose metabolism were assessed by euglycaemic glucose clamp examinations [glucose disposal rate (GDR, mg/kg per min)] and oral glucose-tolerance tests (OGTT). RESULTS: Supine blood pressure was reduced from 146 +/- 3/90 +/- 3 mmHg on placebo to 134 +/- 4/83 +/- 3 mmHg on losartan and the difference was maintained during 120 min of insulin infusion and glucose clamping. GDR was 6.2 +/- 0.5 mg/kg per min on placebo and 6.4 +/- 0.5 mg/kg per min on losartan. The glucose and insulin responses (the area under the curve) during OGTT were similar with placebo and losartan (0.86 +/- 0.3 versus 0.88 +/- 0.4 and 341 +/- 60 versus 356 +/- 60, respectively; arbitary units). Serum cholesterol was 5.3 +/- 0.2 mmol/l on placebo and 5.1 +/- 0.2 mmol/l losartan treatment. High-density lipoprotein cholesterol and triglycerides were, respectively, 1.1 +/- 0.1 and 1.5 +/- 0.2 mmol/l with placebo, and 1.1 +/- 0.1 and 1.4 +/- 0.1 mmol/l with losartan treatment. CONCLUSION: In mildly hypertensive patients, selective angiotensin II receptor antagonism with losartan for 4 weeks lowers blood pressure at rest and during 120 min of glucose clamping, and has neutral effects on insulin sensitivity, glucose metabolism and serum lipids.