Markers of thrombin generation are associated with myocardial necrosis and left ventricular impairment in patients with ST-elevation myocardial infarction.

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.

Effect of Revascularization on Exercise-Induced Changes in Cardiac and Prothrombotic Biomarkers in Patients with Coronary Artery Disease.

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.

Echocardiographic evaluation of aged male cross country skiers.

The aim of this echocardiographic study was to evaluate the effects of long-term endurance training on cardiac structure and function in three different age groups of 48 healthy middle-aged and old former or still active male cross country skiers (23 in age group I: age 58.6 ± 2.2 years; 21 in age group II: age 74.9 ± 2.2 years; four in age group III: age 89.5 ± 1.9 years). The two oldest age groups were combined and compared with age group I. No significant differences in left atrial or ventricular dimensions between these two age groups were found. A high proportion of enlarged left atrial dimensions were found among all subjects with 80% exceeding the upper reference limit of 40 mm in diameter (LADs) and 94% exceeding the upper reference limit of 20 cm(2) in area (LAAs). Mean values for LADs (mm) and LAAs (cm(2) ) were: group I: 41.9 ± 4.7 and 24.7 ± 3.3; group II: 43.5 ± 4.8 and 25.2 ± 3.7; group III: 44.5 ± 4.7 and 25.8 ± 3.7. Left ventricular diastolic diameter exceeded the upper reference limits of >54 mm in 20 subjects among all. The groups had preserved systolic and age-related diastolic function.

Mortality and cardiovascular morbidity among long-term endurance male cross country skiers followed for 28-30 years.

Longevity and reduced mortality and cardiovascular disease (CVD) mortality and morbidity compared with the general population are described among former athletes in a few studies only. The aim of the study was to assess the outcomes of mortality and CVD morbidity after 30 years follow-up in long-term cross country skiers. The study was based on three different age groups of 122 long-term long-endurance cross country skiers participating in studies in 1976 and 1981. A total of 78/85 skiers completed the 28-30 year follow-up, while 37 were dead. Causes of deaths through 2006 were ascertained using the National Death Register. Morbidity or mortality data were available in 115 subjects. Total deaths were 31% compared with 40% in the general male population (P=0.04). Exercise electrocardiographic ST-depression in 1981 was associated with the later appearance of coronary heart disease (HR 2.90; P=0.033). Body mass index and average systolic blood pressure from 1976 to 1981 were predictors of later appearance of CVD (HR 1.23; P=0.034 and HR 1.03; P=0.048, respectively). Long-term aerobic exercise appears to be associated with reduced all-cause mortality.

Adipose tissue pro-inflammatory gene expression is associated with cardiovascular disease.

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.

Studies on very long chain marine n-3 fatty acids in patients with atherosclerotic heart disease with special focus on mechanisms, dosage and formulas of supplementation.

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.

Changes in cardiorespiratory function in different groups of former and still active male cross-country skiers: a 28-30-year follow-up study.

The aim of the study was to assess longitudinal changes in cardiorespiratory function in different groups of current or former endurance trained male cross-country skiers. Three different age groups (n=122) took part in a similar study in 1976. Of 86 men still alive 78 responded (90.7%). Thirty-two from group I (age 58.7+/-2.3) and 36 from group II (age 74.5+/-2.5) participated in a maximum exercise test. We found significant difference in decline in VO2max between age groups (%/decade: 6.7+/-3.6 vs 13.9+/-3.2; P=0.0001 and in L/min/decade: 0.32+/-0.18 vs 0.53+/-0.14; P=0.0001). Men in group I (but only a tendency in group II) who were still competing and reported unchanged training patterns had a significant attenuated decline in VO2max (%/decade: 4.1+/-3.7 vs 8.1+/-2.8; P=0.003 and L/min: 0.19+/-0.0.17 vs 0.39+/-0.15; P=0.004). This study shows that lifelong endurance training does not stop the decline in VO2max with ageing, but vigorous training is important to attenuate the decline.

γδ T cells compose a developmentally regulated intrauterine population and protect against vaginal candidiasis.

This most comprehensive analysis to date of γδ T cells in the murine uterus reveals them to compose a unique local T-cell compartment. Consistent with earlier reports, most cells expressed a canonical Vγ6Vδ1 TCR, and produced interleukin (IL)-17A upon stimulation. Nonetheless, contrasting with earlier reports, uterine γδ T cells were not obviously intraepithelial, being more akin to sub-epithelial Vγ6Vδ1+ T cells at several other anatomical sites. By contrast to other tissues however, the uterine compartment also included non-Vγ6+, IFN-γ-producing cells; was strikingly enriched in young mice; expressed genes hitherto associated with the uterus, including the progesterone receptor; and did not require microbes for development and/or maintenance. This notwithstanding, γδ T-cell deficiency severely impaired resistance to reproductive tract infection by Candida albicans, associated with decreased responses of IL-17-dependent neutrophils. These findings emphasise tissue-specific complexities of different mucosal γδ cell compartments, and their evident importance in lymphoid stress-surveillance against barrier infection.

Endogenous thrombin potential (ETP) in plasma from patients with AMI during antithrombotic treatment.

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.

Cigarette smoking represses expression of cytokine IL-12 and its regulator miR-21-An observational study in patients with coronary artery disease.

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.

Galectin-3, a marker of cardiac remodeling, is inversely related to serum levels of marine omega-3 fatty acids. A cross-sectional study.

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.

Follow-up of diet and cardiovascular risk factors 20 years after cessation of intervention in the Oslo Diet and Antismoking Study.

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.

N-3 fatty acids do not prevent restenosis after coronary angioplasty: results from the CART study. Coronary Angioplasty Restenosis Trial.

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.

Effects of long-term anticoagulant therapy in subgroups after acute myocardial infarction.

This post hoc analysis of the Warfarin Re-Infarction Study evaluates the effect of long-term anticoagulant therapy in different subgroups after acute myocardial infarction (MI). The study population comprised 1214 patients. The mean duration of treatment was 37 months. The overall significance of prespecified prognostic factors was assessed by univariate survival analyses. Those risk factors that yielded a statistically significant result were evaluated with regard to response to treatment in a stratified manner. After stratification, heterogeneity across the strata was found to pertain to the effect of treatment with warfarin in subjects with prior MI and diabetes mellitus. Hence, mortality was not found to be influenced favorably by warfarin therapy in patients with previous MI. Likewise, recurrent MI was not significantly reduced by warfarin therapy in patients with prior MI or diabetes mellitus. Although not statistically significant, increasing age was associated with less benefit from therapy. The findings persisted also after controlling for possible confounders in a Cox regression model. Thus, our data suggest a lack of a beneficial effect by warfarin therapy in subjects with prior MI or diabetes mellitus, when the therapy is given for the sole purpose of secondary prophylaxis of MI. Furthermore, a trend toward an attenuated effect of therapy was found among the oldest patients.

A brief review on high on-aspirin residual platelet reactivity.

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.

Genes expressed in coronary thrombi are associated with ischemic time in patients with acute myocardial infarction.

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.

Effect of angiotensin II receptor blockade on fibrinolysis during acute hyperinsulinemia in patients with essential hypertension.

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.

Long-term metabolic effects of n-3 polyunsaturated fatty acids in patients with coronary artery disease.

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.

Increased levels of soluble tissue factor during long-term treatment with warfarin in patients after an acute myocardial infarction.

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.

Sustained prothrombotic profile after hip replacement surgery: the influence of prolonged prophylaxis with dalteparin.

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.