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  • Ernofsson, Mats, et al. (författare)
  • Monocyte tissue factor expression, cell activation and thrombin formation during cardiopulmonary bypass : a clinical study
  • 1997
  • Ingår i: Journal of Thoracic and Cardiovascular Surgery. - 0022-5223 .- 1097-685X. ; 113:3, s. 576-584
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVES: Cardiopulmonary bypass is associated with extensive thrombin generation and cell activation. Our main hypothesis in this study was that the expression of tissue factor on circulating monocytes contributes to the formation of thrombin. METHODS: Markers of activation of the coagulation cascade and cell activation were measured in 26 patients undergoing elective heart operations randomized to the use of heparin-coated (Duraflo II, n = 13) or standard cardiopulmonary bypass circuits (n = 13). RESULTS: Thrombin generation, measured as the thrombin-antithrombin complex, increased considerably during cardiopulmonary bypass with peak levels 3 hours afterward and with remaining elevation 20 hours later. Despite increased monocyte and granulocyte activation and increased levels of monocyte chemotactic protein-1, which upregulates monocyte tissue factor expression in vitro, monocyte tissue factor expression was not increased at the end of cardiopulmonary bypass. Furthermore, at this time the monocytes were less sensitive to in vitro stimulation by endotoxin. These results might be explained by simultaneous enhanced levels of interleukin-10, which effectively downregulates monocyte tissue factor expression in vitro. Twenty hours after cardiopulmonary bypass was discontinued, the tissue factor expression on freshly isolated monocytes and on monocytes stimulated by endotoxin was significantly increased compared with preoperative levels. At this time increased activation markers of granulocytes, monocytes, and lymphocytes were also recorded. None of the measured parameters was found to be different between the groups. CONCLUSIONS: The tissue factor expression on circulating monocytes is upregulated the day after heart operations. The clinical relevance and the regulatory mechanism behind the enhanced expression, however, are not fully elucidated.
  • Ernofsson, Mats, et al. (författare)
  • Platelet-derived growth factor-BB and monocyte chemotactic protein-1 induce human peripheral blood monocytes to express tissue factor
  • 1996
  • Ingår i: Thrombosis Research. - : Elsevier BV. - 0049-3848 .- 1879-2472. ; 83:4, s. 307-320
  • Tidskriftsartikel (refereegranskat)abstract
    • Monocytes induced to express tissue factor (TF), the initiator of the clotting cascade, might play an important role in the pathogenesis of atherosclerosis. We have investigated the TF-inducing capacity of two factors thought to be involved in atherogenesis, i.e. the platelet derived growth factor-BB (PDGF-BB) and monocyte chemotactic protein-1 (MCP-1), a member of the chemokine superfamily. PDGF-BB and MCP-1 are potent chemotactic and activating factors for human blood monocytes. alpha-thrombin which is known to induce TF in endothelial cells and that recently has been shown to induce secretion of MCP-1 from endothelial cells and monocytes was also studied. PDGF-BB induced a dose-dependent expression of TF-antigen in monocytes with maximal response at 20-50 ng/mL. At higher concentrations the expression was reduced. No synergistic effect between PDGF-BB and LPS was seen. MCP-1 also induced a dose-dependent TF-expression with maximal response at 50 ng/mL. In contrast to these results thrombin did not. MCP-1 had a slight, but not significant, priming effect on LPS-induced TF expression. These data show that PDGF-BB and MCP-1 are potent inducers of TF in human peripheral blood monocytes. We suggest that this TF-induction might be an important link between hemostasis and inflammation.
  • Ernofsson, Mats, et al. (författare)
  • Thrombin generation during cardiopulmonary bypass using heparin-coated circuits or standard circuits
  • 1995
  • Ingår i: Scandinavian journal of thoracic and cardiovascular surgery. - 0036-5580. ; 29:4, s. 157-165
  • Recension (övrigt vetenskapligt/konstnärligt)abstract
    • For quantitative comparison of thrombin generation during cardiopulmonary bypass (CPB) with heparin-coated vs conventional CPB circuits, thrombin-antithrombin III complex (TAT) and prothrombin fragment 1 + 2 (F1 + 2) were analyzed in 20 patients undergoing combined heart valve surgery and coronary artery bypass grafting (CABG), in ten cases with heparin-coated circuits (COMB-HC) and in ten with standard circuits (COMB-C). Extensive thrombin generation was found in both groups, with maximal TAT and F1 + 2 levels at the end of CPB. Of 15 operations with only CABG, seven were performed with heparin-coated circuits and heparin dose 40% of normal (CABG-HC), and eight with standard circuits and normal heparin doses (CABG-C). TAT was maximal at the end of CPB and F1 + 2 peaked 3 hours after protamine injection. At the end of CPB both levels were significantly higher in the CABG-HC than in the CABG-C group, though thrombin generation was less than in the COMB groups. The abundant thrombin generation during CPB thus was much more pronounced during complex operations. Use of heparin-coated circuits did not reduce thrombin generation, which was increased by 60% reduction of the systemic heparin dose. The clinical implications are still unknown, as no complications were observed.
  • Folkersen, Lasse, et al. (författare)
  • Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.
  • 2020
  • Ingår i: Nature metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 2:10, s. 1135-1148
  • Tidskriftsartikel (refereegranskat)abstract
    • Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.
  • Frostfeldt, Gunnar, et al. (författare)
  • Low molecular weight heparin (Dalteparin) as adjuvant treatment to thrombolysis in acute myocardial infarction-a pilot study : BIOchemical markers in acute coronary syndromes (BIOMACS II)
  • 1999
  • Ingår i: Journal of the American College of Cardiology. - 0735-1097 .- 1558-3597. ; 33:3, s. 627-633
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVES: This randomized, double blind, placebo-controlled pilot trial evaluated the effect of dalteparin as an adjuvant to thrombolysis in patients with acute myocardial infarction regarding early reperfusion, recurrent ischemia and patency at 24 h. BACKGROUND: Low-molecular-weight heparin, given subcutaneously twice daily without monitoring, might be an attractive alternative to conventional intravenous heparin in the treatment of acute myocardial infarction. METHODS: In 101 patients dalteparin/placebo 100 IU/kg was given just before streptokinase and a second injection 120 IU/kg after 12 h. Monitoring with continuous vector-ECG was done to obtain signs of early reperfusion and later ischemic episodes. Blood samples for myoglobin were obtained at start and after 90 min to evaluate signs of reperfusion. Coronary angiography was performed after 20-28 h to evaluate TIMI-flow in the infarct-related artery. RESULTS: Dalteparin added to streptokinase tended to provide a higher rate of TIMI grade 3 flow in infarct-related artery compared to placebo, 68% versus 51% (p = 0.10). Dalteparin had no effects on noninvasive signs of early reperfusion. In patients with signs of early reperfusion, there seemed to be a higher rate of TIMI grade 3 flow, 74% versus 46% (myoglobin) (p = 0.04) and 73% versus 52% (vector-ECG) (p = 0.11). Ischemic episodes 6-24 h. after start of treatment were fewer in the dalteparin group, 16% versus 38% (p = 0.04). CONCLUSIONS: When dalteparin was added as an adjuvant to streptokinase and aspirin, there were tendencies for less ECG monitoring evidence of recurrent ischemia and better patency at 24 h, warranting further study.
  • Ganna, Andrea, et al. (författare)
  • Large-scale Metabolomic Profiling Identifies Novel Biomarkers for Incident Coronary Heart Disease
  • 2014
  • Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 10:12, s. e1004801-
  • Tidskriftsartikel (refereegranskat)abstract
    • Analyses of circulating metabolites in large prospective epidemiological studies could lead to improved prediction and better biological understanding of coronary heart disease (CHD). We performed a mass spectrometry-based non-targeted metabolomics study for association with incident CHD events in 1,028 individuals (131 events; 10 y. median follow-up) with validation in 1,670 individuals (282 events; 3.9 y. median follow-up). Four metabolites were replicated and independent of main cardiovascular risk factors [lysophosphatidylcholine 18∶1 (hazard ratio [HR] per standard deviation [SD] increment = 0.77, P-value<0.001), lysophosphatidylcholine 18∶2 (HR = 0.81, P-value<0.001), monoglyceride 18∶2 (MG 18∶2; HR = 1.18, P-value = 0.011) and sphingomyelin 28∶1 (HR = 0.85, P-value = 0.015)]. Together they contributed to moderate improvements in discrimination and re-classification in addition to traditional risk factors (C-statistic: 0.76 vs. 0.75; NRI: 9.2%). MG 18∶2 was associated with CHD independently of triglycerides. Lysophosphatidylcholines were negatively associated with body mass index, C-reactive protein and with less evidence of subclinical cardiovascular disease in additional 970 participants; a reverse pattern was observed for MG 18∶2. MG 18∶2 showed an enrichment (P-value = 0.002) of significant associations with CHD-associated SNPs (P-value = 1.2×10-7 for association with rs964184 in the ZNF259/APOA5 region) and a weak, but positive causal effect (odds ratio = 1.05 per SD increment in MG 18∶2, P-value = 0.05) on CHD, as suggested by Mendelian randomization analysis. In conclusion, we identified four lipid-related metabolites with evidence for clinical utility, as well as a causal role in CHD development.
  • Giannitsis, Evangelos, et al. (författare)
  • How to use D-dimer in acute cardiovascular care
  • 2017
  • Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 2048-8726 .- 2048-8734. ; 6:1, s. 69-80
  • Tidskriftsartikel (refereegranskat)abstract
    • D-dimer testing is important to aid in the exclusion of venous thromboembolic events (VTEs), including deep venous thrombosis and pulmonary embolism, and it may be used to evaluate suspected aortic dissection. D-dimer is produced upon activation of the coagulation system with the generation and subsequent degradation of cross-linked fibrin by plasmin. Many different assays for D-dimer testing are currently used in routine care. However, these tests are neither standardized nor harmonized. Consequently, only clinically validated assays and assay specific decision limits should be used for routine testing. For the exclusion of pulmonary embolism/deep vein thrombosis, age-adjusted cut-offs are recommend. Clinicians must be aware of the validated use of their hospital's D-dimer assay to avoid inappropriate use of this biomarker in routine care.
  • Giannitsis, Evangelos, et al. (författare)
  • Outcomes after planned invasive or conservative treatment strategy in patients with non-ST-elevation acute coronary syndrome and a normal value of high sensitivity troponin at randomisation : A Platelet Inhibition and Patient Outcomes (PLATO) trial biomarker substudy.
  • 2017
  • Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 2048-8726 .- 2048-8734. ; 6:6, s. 500-510
  • Tidskriftsartikel (refereegranskat)abstract
    • AIMS: Current guidelines for patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) recommend early invasive treatment in intermediate-to-high risk patients based on medical history, electrocardiogram (ECG) and elevated troponin. Patients with normal levels of cardiac troponin measured with a high-sensitivity method (cTnT-hs) might not benefit from early invasive procedures.METHODS AND RESULTS: In this Prospective Randomized Platelet Inhibition and Patient Outcomes (PLATO) blood-core substudy, 1232 patients presented with NSTE-ACS had a high sensitivity cardiac troponin T (cTnT-hs) level <99(th) percentile (<14 ng/l) at randomisation. The outcomes in relation to a planned invasive (n=473) vs planned conservative treatment (n=759), were evaluated by adjusted Cox proportional hazard analyses. In patients with a normal cTnT-hs at randomisation, regardless of randomised treatment, a planned invasive vs conservative treatment was associated with a 2.3-fold higher risk (7.3% vs 3.4%, p=0.0028) for cardiovascular (CV) death or myocardial infarction (MI), driven by higher rates of procedure-related MI (3.4% vs 0.1%), while there were no differences in rates of CV death (1.3% vs 1.3%, p=0.72) or spontaneous MI (3.0% vs 2.1%, p=0.28). There were significantly more major bleeds (hazard ratio (HR) 2.98, p<0.0001), mainly due to coronary artery bypass graft (CABG)-related (HR 4.05, p<0.0001) and non-CABG procedural-related major bleeding events (HR 5.31, p=0.0175), however there were no differences in non-procedure-related major bleeding (1.5% vs 1.9%, p=0.45). Findings were consistent for patients with a normal cTnI-hs at randomisation.CONCLUSIONS: In patients with NSTE-ACS and normal cTnT-hs, a planned early invasive treatment strategy was associated with increased rates of procedure-related MI and bleeding but no differences in long-term spontaneous MI, non-procedure-related bleeding or mortality.
  • Gregersen, Ida, et al. (författare)
  • Legumain in Acute Coronary Syndromes : A Substudy of the PLATO (Platelet Inhibition and Patient Outcomes) Trial
  • 2020
  • Ingår i: Journal of the American Heart Association. - : WILEY. - 2047-9980 .- 2047-9980. ; 9:17
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: The cysteine protease legumain is increased in patients with atherosclerosis, but its causal role in atherogenesis and cardiovascular disease is still unclear. The aim of the study was to investigate the association of legumain with clinical outcome in a large cohort of patients with acute coronary syndrome. METHODS AND RESULTS : Serum levels of legumain were analyzed in 4883 patients with acute coronary syndrome from a substudy of the PLATO (Platelet Inhibition and Patient Outcomes) trial. Levels were analyzed at admission and after 1 month follow-up. Associations between legumain and a composite of cardiovascular death, spontaneous myocardial infarction or stroke, and its individual components were assessed by multivariable Cox regression analyses. At baseline, a 50% increase in legumain level was associated with a hazard ratio (HR) of 1.13 (95% CI, 1.04-1.21),P=0.0018, for the primary composite end point, adjusted for randomized treatment. The association remained significant after adjustment for important clinical and demographic variables (HR, 1.10; 95% CI, 1.02-1.19;P=0.013) but not in the fully adjusted model. Legumain levels at 1 month were not associated with the composite end point but were negatively associated with stroke (HR, 0.62; 95% CI, 0.44-0.88;P=0.0069), including in the fully adjusted model (HR, 0.57; 95% CI, 0.37-0.88;P=0.0114). CONCLUSIONS: Baseline legumain was associated with the primary outcome in patients with acute coronary syndrome, but not in the fully adjusted model. The association between high levels of legumain at 1 month and decreased occurrence of stroke could be of interest from a mechanistic point of view, illustrating the potential dual role of legumain during atherogenesis and acute coronary syndrome. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00391872.
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