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  • 1.
    Baron, Tomasz
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Christersson, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Hjorthén, Gustav
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hedin, Eva-Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology-Arrhythmia.
    Flachskampf, Frank
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Changes in global longitudinal strain and left ventricular ejection fraction during the first year after myocardial infarction: results from a large consecutive cohort2018In: European Heart Journal Cardiovascular Imaging, ISSN 2047-2404, E-ISSN 2047-2412, Vol. 19, no 10, p. 1165-1173Article in journal (Refereed)
    Abstract [en]

    Aims: To determine changes of global longitudinal strain (GLS) and their predictors in relation to classical echocardiographic parameters of left ventricular (LV) function, over 1 year, in consecutive patients with myocardial infarction (MI) and initially normal or impaired LV ejection fraction (EF).

    Methods and results: A total of 285 patients with MI prospectively included in the REBUS (RElevance of Biomarkers for future risk of thromb-oembolic events in UnSelected post-myocardial infarction patients) study underwent echocardiography within 72 h from admission and after 1 year. At baseline, 213 (74.7%) of MI patients had a normal EF (≥52% in men or ≥54% in women), but in 70.4% of them, an impaired GLS ( ≥ -18.0%) was observed. During 1-year follow-up, in patients with normal EF at baseline, GLS improved from -15.8% to - 17.4% (10.1% relative change); EF decreased from 62.5% to 59.9% (4.0% relative change); indexed end-diastolic volume, indexed end-systolic volume, and indexed stroke volume increased with 15.6%, 24.8%, and 10.0% of relative change, respectively (P < 0.001 for all the comparisons). In the whole cohort, initial impairment of LV function [by EF, wall motion score index (WMSI), or GLS], male gender, non-smoking, and treatment with beta-blockers were the independent predictors of GLS improvement. In the group with initially impaired EF, over 1 year GLS improved from -11.9% to - 14.8% (24.4% relative change) and EF from 44.6% to 52.6% (18.2% relative change) (P < 0.001 for both). Improvement in GLS significantly correlated with EF increase in the group with impaired EF (r = -0.41, P = 0.001) but not in the patients with normal EF (r = -0.14, P = ns).

    Conclusions: Despite diveregent evolution of GLS compared with EF and ventricular volumes, one year after MI GLS significantly improved in patients with initially both normal and impaired EF. Initial impairment of LV function (by EF, WMSI, or GLS), male gender, non-smoking, and treatment with beta-blockers were independent predictors of GLS improvement. LV remodelling was present even in patients with normal EF at baseline and during follow-up, confirming limited functional assessment by EF alone.

  • 2.
    Baron, Tomasz
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Christersson, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Johansson, K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Flachskampf, Frank A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    How frequent are signs of left ventricular dysfunction in acute myocardial infarction patients with normal ejection fraction?: Impact of the latest chamber quantification recommendations2015In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 36, no Suppl. 1, p. 937-937Article in journal (Other academic)
  • 3.
    Baron, Tomasz
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Flachskampf, Frank A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Johansson, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hedin, Eva-Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology-Arrhythmia.
    Christersson, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Usefulness of traditional echocardiographic parameters in assessment of left ventricular function in patients with normal ejection fraction early after acute myocardial infarction: results from a large consecutive cohort2016In: European Heart Journal Cardiovascular Imaging, ISSN 2047-2404, E-ISSN 2047-2412, Vol. 17, no 4, p. 413-420Article in journal (Refereed)
    Abstract [en]

    AIMS: The aim of this study was to assess the frequency of left ventricular (LV) systolic function impairment using classical echocardiographic parameters and their relation to myocardial damage in patients hospitalized for acute myocardial infarction (MI) with normal LV ejection fraction (LVEF ≥52% in males or ≥54% in females).

    METHODS AND RESULTS: All 421 consecutive patients with MI included in the REBUS (RElevance of Biomarkers for future risk of thromboembolic events in UnSelected post-myocardial infarction patients) study underwent two-dimensional and Doppler echocardiography within 72 h after admission. A normal LVEF was present in 262 (73.8%) of the 355 patients ultimately enrolled in the study. Patients with normal LVEF more often presented with non-ST-elevation myocardial infarction and had less comorbidities when compared with those with impaired LVEF. No differences in demographic factors or relevant medications were observed. Higher value of mean annular plane systolic excursion (MAPSE), lower wall motion score index (WMSI), lower LV as well as left atrial volumes characterized patients with normal LVEF. Impaired MAPSE was present in 64.4%, WMSI >1 in 72.1%, and dilated left atrium in 33.6% of those patients. Maximal cardiac troponin concentration reflecting infarct size showed the strongest association with WMSI (β = 0.35), followed by LVEF (β = -0.29), MAPSE (β = -0.25), and indexed LV end-systolic volume (β = 0.19; P < 0.001 for all the models).

    CONCLUSION: In two-third of patients with MI and normal LVEF, at least one of the other markers of systolic function was outside of the normal range. WMSI reflected the size of MI better than global LV function parameters as LVEF or MAPSE.

  • 4.
    Berglund, E.
    et al.
    Dept Publ Hlth & Clin Med, Med, Umea, Sweden..
    Thilen, U.
    Lund Univ, Dept Cardiol, Clin Sci, Lund, Sweden..
    Delborg, M.
    Univ Gothenburg, Dept Mol & Clin Med, Gothenburg, Sweden..
    Christersson, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Sorensson, P.
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Nielsen, N. -E
    Johansson, B.
    Dept Publ Hlth & Clin Med, Med, Umea, Sweden..
    High incidence of endocarditis in adults with congenital ventricular septal defect2015In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 36, no Suppl. 1, p. 457-457Article in journal (Other academic)
  • 5. Berglund, Elisabeth
    et al.
    Johansson, Bengt
    Dellborg, Mikael
    Sörensson, Peder
    Christersson, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Nielsen, Niels-Eric
    Rinnström, Daniel
    Thilén, Ulf
    High incidence of infective endocarditis in adults with congenital ventricular septal defect2016In: Heart, ISSN 1355-6037, E-ISSN 1468-201X, Vol. 102, no 22, p. 1835-1839Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Ventricular septal defects (VSDs), if haemodynamically important, are closed whereas small shunts are left without intervention. The long-term prognosis in congenital VSD is good but patients are still at risk for long-term complications. The aim of this study was to clarify the incidence of infective endocarditis (IE) in adults with VSD.

    METHODS: The Swedish registry for congenital heart disease (SWEDCON) was searched for adults with VSD. 779 patients were identified, 531 with small shunts and 248 who had the VSD previously closed. The National Patient Register was then searched for hospitalisations due to IE in adults during a 10-year period.

    RESULTS: Sixteen (2%) patients were treated for IE, 6 men and 10 women, with a mean age of 46.3±12.2 years. The incidence of IE was 1.7-2.7/1000 years in patients without previous intervention, 20-30 times the risk in the general population. Thirteen had small shunts without previous intervention. There was no mortality in these 13 cases. Two patients had undergone repair of their VSD and also aortic valve replacement before the episode of endocarditis and a third patient with repaired VSD had a bicuspid aortic valve, all of these three patients needed reoperation because of their IE and one patient died. No patient with isolated and operated VSD was diagnosed with IE.

    CONCLUSIONS: A small unoperated VSD in adults carries a substantially increased risk of IE but is associated with a low risk of mortality.

  • 6.
    Christersson, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    NOAK vid klaffsjukdom -: bara i särskilda fall2018In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 115, article id FA93Article in journal (Refereed)
  • 7.
    Christersson, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Regulation of Tissue Factor and Coagulation Activity: Translation Studies with Focus on Platelet-Monocyte Aggregates and Patients with Acute Coronary Syndrome2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Myocardial infarction (MI) is often caused by a disruption of an atherosclerotic plaque with activation of coagulation, platelets and inflammation. The aims were; to investigate whether the oral direct thrombin inhibitor, ximelagatran affected markers for coagulation, platelet and inflammation in a patient cohort with recent MI and if the coagulation markers could identify patients with increased risk of new ischemic events; to evaluate some of the mechanisms involved in formation of platelet-monocyte aggregates (PMAs).

    In a biomarker substudy patients with recent MI were randomized to 24-60 mg of ximelagatran or placebo for six months. There was a persistent dose-independent reduction of coagulation markers (F1+2, D-dimer) by ximelagatran treatment. 60 % reduced their D-dimer levels after one week and that group had less ischemic events during treatment. There was an early increase of the platelet activation marker and ximelagatran in higher doses attenuated these increased levels. Both in vivo and in vitro the direct thrombin inhibitor diminished procoagulant activity and tissue factor (TF) presenting microparticles. In contrast, the inflammatory markers increased after six months of ximelagatran treatment. The PMA-levels were elevated for long-term after MI. In vitro thrombin inhibition diminished formation of PMAs. Formation of PMAs in stimulated whole blood was P-selectin dependent and induced TF expression through phosphorylation of the Src-family member Lyn in monocytes.

    Addition of an oral direct thrombin inhibitor reduces coagulation and platelet activation markers for long-term after a MI together with reduced procoagulant activity which may contribute to the clinical benefit of the drug. Early reduction of D-dimer levels seems to be suitable to identify patients with reduced risk of new ischemic events independent of antithrombotic treatment. Circulating PMAs persist after a MI connecting coagulation to inflammation. Within these aggregates P-selectin induces TF, the main initiator of coagulation, partly through phosphorylation of Lyn.

    List of papers
    1. Long-term treatment with ximelagatran, an oral direct thrombin inhibitor, persistently reduces the coagulation activity after a myocardial infarction
    Open this publication in new window or tab >>Long-term treatment with ximelagatran, an oral direct thrombin inhibitor, persistently reduces the coagulation activity after a myocardial infarction
    Show others...
    2005 (English)In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 3, no 10, p. 2245-53Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: In the ESTEEM study, patients with a recent myocardial infarction were treated with aspirin and randomized to one of four doses (24-60 mg b.i.d) of the oral direct thrombin inhibitor ximelagatran or placebo for 6 months. Ximelagatran and aspirin reduced the risk of recurrent ischemic events compared with aspirin alone. In the present substudy we evaluated the different doses of ximelagatran on pharmacokinetics as measured by plasma concentration of the active compound melagatran and activated partial thromboplastin time (APTT) and pharmacodynamics as related by markers for coagulation activity, prothrombin fragment 1 + 2 (F1 + 2) and D-dimer. METHODS AND RESULTS: Plasma samples from 518 patients were collected before, during and after the treatment period. There was a linear dose-concentration relation at peak and trough and a linear relation between concentration and APTT (P < 0.001). F1 + 2 and D-dimer were decreased by 25% and 52% at 1 week (P < 0.001) in the ximelagatran groups compared with the placebo group and the reductions were maintained during the 6 months treatment. There were no differences detected in F1 + 2 or D-dimer levels between the different ximelagatran dosages. There was no correlation between the melagatran concentration and the change in F1 + 2 and D-dimer levels. After cessation of ximelagatran F1 + 2 and D-dimer levels returned to the initial levels. CONCLUSION: The dose of ximelagatran and APTT are linearly related to the plasma concentration of melagatran. Ximelagatran induces a sustained and stable reduction of thrombin generation and fibrin turnover without any relation to dose above 24 mg b.i.d. These properties indicate that long-term treatment with a low dose of ximelagatran may provide valuable depression of coagulation activity in aspirin treated post myocardial infarction patients.

    Keywords
    Aged, Azetidines/administration & dosage/*pharmacokinetics, Benzylamines, Biological Markers/blood, Blood Coagulation/*drug effects, Dose-Response Relationship; Drug, Female, Fibrin/metabolism, Glycine/analogs & derivatives/blood, Humans, Male, Myocardial Infarction/blood/*drug therapy, Partial Thromboplastin Time, Pharmacokinetics, Thrombin/antagonists & inhibitors/biosynthesis, Time Factors
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-10329 (URN)10.1111/j.1538-7836.2005.01557.x (DOI)16194202 (PubMedID)
    Available from: 2007-04-16 Created: 2007-04-16 Last updated: 2017-12-11Bibliographically approved
    2. Early decrease in coagulation activity after myocardial infarction is associated with lower risk of new ischemic events: Observations from the ESTEEM trial
    Open this publication in new window or tab >>Early decrease in coagulation activity after myocardial infarction is associated with lower risk of new ischemic events: Observations from the ESTEEM trial
    Show others...
    2007 (English)In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 28, no 6, p. 692-698Article in journal (Refereed) Published
    Abstract [en]

    AIM: Patients with a recent myocardial infarction have an increased risk of recurrent ischaemic events. In the ESTEEM trial, the oral direct thrombin inhibitor ximelagatran reduced the risk of new ischaemic events when compared with placebo in aspirin treated post myocardial infarction patients. Ximelagatran persistently reduced markers of coagulation activity, i.e. prothrombin fragment 1 + 2 (F1 + 2) and D-dimer levels. The aim of this substudy was to evaluate the levels of these markers and activated thromboplastin time (APTT) in relation to new ischaemic events or bleeding. METHODS AND RESULTS: In the substudy, 518 out of 1883 patients were included and within 14 days after a myocardial infarction randomized to ximelagatran or placebo for 6 months. The clinical endpoints death, myocardial infarction, severe recurrent ischaemia, ischaemic stroke, and bleeding were evaluated. The levels of F1 + 2, D-dimer, and APTT were analysed at randomization and in serial samples during the study. Ximelagatran treatment appeared to have a larger treatment effect in patients with F1 + 2 and D-dimer levels above the median at randomization with a reduction of ischaemic events from 18 to 9% (P = 0.03) for F1 + 2 and from 20 to 9% for D-dimer (P = 0.009). A reduction of D-dimer levels was found in 60% of the patients 1 week after randomization and these patients had less ischaemic events when compared with patients with unchanged or increased levels (P = 0.03) regardless of treatment. F1 + 2 and D-dimer levels were unrelated to bleeding risk. In the ximelagatran group, increased APTT was not related to ischaemic events but associated with a raised risk of bleeding. CONCLUSION: A reduction of initially high coagulation activity, as measured by the D-dimer level, in patients with recent myocardial infarction identifies patients with a decreased risk of new ischaemic events, regardless whether the reduction occurs spontaneously or is induced by pharmacological means. Patients with higher initial coagulation activity seemed to benefit most from long-term treatment with ximelagatran.

    Keywords
    Myocardial infarction, Ischaemic event, Coaguulation activity, Direct thrombin inhibitor
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-97121 (URN)10.1093/eurheartj/ehl564 (DOI)000244960400014 ()17314111 (PubMedID)
    Available from: 2008-04-25 Created: 2008-04-25 Last updated: 2017-12-14Bibliographically approved
    3. Treatment with an Oral Direct Thrombin Inhibitor Decreases Platelet Activity but Increases Markers of Inflammation in Patients with Myocardial Infarction.
    Open this publication in new window or tab >>Treatment with an Oral Direct Thrombin Inhibitor Decreases Platelet Activity but Increases Markers of Inflammation in Patients with Myocardial Infarction.
    2011 (English)In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 270, no 3, p. 215-223Article in journal (Refereed) Published
    Abstract [en]

    Background: Thrombin has a role not only in the coagulation process but also in inflammatory responses. Oral direct thrombin inhibitors (DTIs) are currently being evaluated in patients with thromboembolic diseases. Objectives:  To investigate whether an oral DTI affects markers for platelet and inflammatory activity after myocardial infarction (MI). Methods:  A total of 518 patients with MI were randomly assigned to ximelagatran treatment (four different dose groups) in combination with aspirin, or aspirin alone for 6 months. The levels of soluble (s) P-selectin, soluble tissue factor, C-reactive protein (CRP), interleukin (IL)-10 and IL-18 were analysed in serial blood samples.

    Results: sP-selectin concentration increased after 1 week and persisted at an elevated level for 6 months in all study groups (p<0.001). In the two highest ximelagatran dose groups, there was a reduced increase in sP-selectin compared to treatment with lower doses of ximelagatran and aspirin alone (p=0.01 and p=0.002, respectively). IL-18 levels did not change in the aspirin alone treatment group. By contrast, there was an elevation in IL-18 level in the lower and higher ximelagatran dose groups after 6 months (p=0.006 and p<0.001, respectively). Ximelagatran increased IL-10 levels (p=0.002) and reduced the decrease in CRP levels after 6 months compared to treatment with aspirin alone (p=0.002).

    Conclusion: A persistent elevation of platelet activity is found in patients with a recent MI after the cessation of acute antithrombotic treatment, and the addition of an oral DTI at higher doses decreases the activity. By contrast, long-term treatment with a DTI increases the levels of several markers of inflammation. Further studies with prolonged exposure of oral DTIs are needed for evaluation of the effect on inflammatory processes and to determine whether these agents influence clinical outcomes.

    Keywords
    anticoagulation treatment, antithrombotic treatment, inflammation, myocardial infarction, platelets
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-144009 (URN)10.1111/j.1365-2796.2011.02354.x (DOI)000293793600003 ()21255134 (PubMedID)
    Available from: 2011-01-26 Created: 2011-01-26 Last updated: 2017-12-11Bibliographically approved
    4. The Influence of Direct Thrombin Inhibitors on the Formation of Platelet-leukocyte Aggregates and Tissue Factor Expression
    Open this publication in new window or tab >>The Influence of Direct Thrombin Inhibitors on the Formation of Platelet-leukocyte Aggregates and Tissue Factor Expression
    2010 (English)In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 126, no 4, p. E327-E333Article in journal (Refereed) Published
    Abstract [en]

    Introduction: High concentrations of platelet-monocyte aggregates (PMAs) have been found in patients with myocardial infarction (MI). Oral direct thrombin inhibitors (DTIs) are under evaluation as long-term antithrombotic treatment. The aim was to evaluate whether DTIs affect the formation of platelet-leukocyte aggregates, TF expression and procoagulant microparticles (MPs). Material and Methods: DTIs were added to an experimental whole blood model before platelet activation with thrombin or ADP. The concentrations of PMAs, platelet-granulocyte aggregates (PGAs), the amount of platelets bound per leukocyte and MPs were investigated by flow cytometry. TF mRNA and activity were recorded in all settings. TF activity was evaluated in a MI population treated with or without an oral DTI. Results: In vitro, thrombin and ADP increased the formation of PMAs and PGAs as well as TF mRNA expression. DTIs reduced the amount platelets bound to monocytes (p = 0.02) and to granulocytes (p = 0.001) upon thrombin stimulation together with a reduction of TF mRNA. In contrast, the ADP-induced formation of PMAs, PGAs and TF mRNA was not affected by the DTIs. Both thrombin and ADP stimulation increased the amount of TF-expressing MPs, which was effectively inhibited by the DTIs (p = 0.02-0.002). In the MI population, the DTI reduced the TF activity (p<0.001). Conclusion: DTIs modulate the formation of PMAs, PGAs and the TF production therein. Together with a reduction of procoagulant MPs, these results may contribute to the clinical benefit found of oral DTIs. Targeting different mechanisms in platelet and coagulation activation may be of importance due to the lack of effect of DTIs on ADP-induced platelet-leukocyte aggregates and TF production.

    Keywords
    Direct thrombin inhibitors, Myocardial infarction, Platelet-monocyte aggregates, Tissue factor
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-134658 (URN)10.1016/j.thromres.2010.03.019 (DOI)000282160700035 ()
    Available from: 2010-12-01 Created: 2010-11-30 Last updated: 2017-12-12Bibliographically approved
    5. Tissue factor and IL8 production by P-selectin-dependent platelet-monocyte aggregates in whole blood involves phosphorylation of Lyn and is inhibited by IL10
    Open this publication in new window or tab >>Tissue factor and IL8 production by P-selectin-dependent platelet-monocyte aggregates in whole blood involves phosphorylation of Lyn and is inhibited by IL10
    2008 (English)In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 6, no 6, p. 986-994Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: P-selectin and CD40L expressed by activated platelets induce tissue factor (TF) and inflammatory cytokines in monocytes, but little is known of the cellular signaling pathways involved. The anti-inflammatory cytokine IL10 reduces atherosclerotic plaque formation. OBJECTIVES: To evaluate the importance of P-selectin upon platelet-monocyte aggregate (PMA) formation in thrombin receptor activator peptide (TRAP) stimulated whole blood, the P-selectin-P-selectin glycoprotein ligand (PSGL)-1-induced cellular signaling pathway, and the effects of IL10 on these functions. METHODS: TF, IL8, and monocyte chemotactic protein-1 (MCP-1) production, PMAs and phosphorylation of Lyn were analyzed in whole blood, purified monocytes, and vitamin D(3)-differentiated U-937 cells stimulated with TRAP or P-selectin with or without IL10. Anti-P-selectin or anti-CD40L antibodies (Abs), Src-kinases inhibitors, SU6656 or PP2, were added in some experiments. RESULTS: TRAP and P-selectin increased TF, IL8, and MCP-1 mRNA in whole blood and purified monocytes. Anti-P-selectin Ab reduced TRAP-induced PMA formation by 80 +/- 2% (P = 0.001) and production of TF (P = 0.04) and IL8 (P = 0.01). IL10 and SU6656 had no effect on PMA formation, although both significantly reduced TF (P = 0.002 and P = 0.02) and IL8 (P = 0.009 and P = 0.001) mRNA upon TRAP and P-selectin stimulation. Induced Lyn phosphorylation in monocytes was diminished by SU6656 (P = 0.02), anti-P-selectin Ab (P = 0.02), and IL10 (P = 0.03) upon TRAP or P-selectin stimulation. These results were confirmed in the vitamin D(3)-differentiated U-937 cells. CONCLUSIONS: The formation of PMAs in whole blood was P-selectin-dependent in the long term. P-selectin-PSGL-1-induced TF and IL8 expression through Lyn phosphorylation, and part of the inhibitory effect of IL10 depends on reduced phosphorylation.

    Keywords
    IL8, IL10, Lyn, platelet-monocyte aggregates, P-selectin, tissue factor
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-97124 (URN)10.1111/j.1538-7836.2008.02956.x (DOI)000255943600013 ()18363812 (PubMedID)
    Available from: 2008-04-25 Created: 2008-04-25 Last updated: 2017-12-14Bibliographically approved
  • 8.
    Christersson, Christina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Johnell, Matilda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Evaluation of microparticles in whole blood by multicolour flow cytometry assay2013In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 73, no 3, p. 229-239Article in journal (Refereed)
    Abstract [en]

    Objective

    To develop and evaluate a multicolour flow cytometry method for analysis of microparticles (MPs) in fresh whole blood without any centrifugation steps or freezing/thawing procedure.

    Materials and methods

    Flow cytometry was performed using a FC500 MPL cytometer. The compensation in the protocol was performed based on the platelet population. Polystyrene microspheres 0.50–1.27 μm were used for size position, and the MP gate was set as particles 0.5–1.0 μm. Whole blood was incubated with annexin V and antibodies to tissue factor (TF), platelets (CD41 and CD62P), monocyte (CD14) and endothelial cells (CD144). For comparison, MPs from platelet free supernatant was used. The TF activity was evaluated by Calibrated Automated Thrombogram.

    Results

    Annexin V was used to distinguish true events from background noise. For standardization, each analysis included 10,000 events in the gate of platelets. There were 622(462–1001) MPannV+/10,000 platelets and of these, 66 (49–82)/10,000 platelets expressed TF. After correction for the individual platelet counts, the amount of circulating MPannV+ was 17.1 (12.1–24.9) × 109/L in whole blood, and of these, 10% (6–12%) expressed TF. The majority of the MPs expressed CD41, and 5.6% (2.2–6.9%) of these co-expressed TF. The amount of CD41 + MPannV+ tended to correlate to the TF activity in whole blood. There was no correlation between the MPannV+ in whole blood and MPs derived from platelet free supernatant. Patients with pulmonary arterial hypertension and stable coronary artery disease had increased concentrations of CD41 + MPannV+ in whole blood.

    Conclusion

    This multicolour flow cytometry assay in whole blood mimics the in vivo situation by avoiding several procedure steps interfering with the MP count. By standardized quantification of MPs a reference interval of MPs can be created.

  • 9.
    Christersson, Christina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Johnell, Matilda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    The Influence of Direct Thrombin Inhibitors on the Formation of Platelet-leukocyte Aggregates and Tissue Factor Expression2010In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 126, no 4, p. E327-E333Article in journal (Refereed)
    Abstract [en]

    Introduction: High concentrations of platelet-monocyte aggregates (PMAs) have been found in patients with myocardial infarction (MI). Oral direct thrombin inhibitors (DTIs) are under evaluation as long-term antithrombotic treatment. The aim was to evaluate whether DTIs affect the formation of platelet-leukocyte aggregates, TF expression and procoagulant microparticles (MPs). Material and Methods: DTIs were added to an experimental whole blood model before platelet activation with thrombin or ADP. The concentrations of PMAs, platelet-granulocyte aggregates (PGAs), the amount of platelets bound per leukocyte and MPs were investigated by flow cytometry. TF mRNA and activity were recorded in all settings. TF activity was evaluated in a MI population treated with or without an oral DTI. Results: In vitro, thrombin and ADP increased the formation of PMAs and PGAs as well as TF mRNA expression. DTIs reduced the amount platelets bound to monocytes (p = 0.02) and to granulocytes (p = 0.001) upon thrombin stimulation together with a reduction of TF mRNA. In contrast, the ADP-induced formation of PMAs, PGAs and TF mRNA was not affected by the DTIs. Both thrombin and ADP stimulation increased the amount of TF-expressing MPs, which was effectively inhibited by the DTIs (p = 0.02-0.002). In the MI population, the DTI reduced the TF activity (p<0.001). Conclusion: DTIs modulate the formation of PMAs, PGAs and the TF production therein. Together with a reduction of procoagulant MPs, these results may contribute to the clinical benefit found of oral DTIs. Targeting different mechanisms in platelet and coagulation activation may be of importance due to the lack of effect of DTIs on ADP-induced platelet-leukocyte aggregates and TF production.

  • 10.
    Christersson, Christina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Johnell, Matilda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Tissue factor and IL8 production by P-selectin-dependent platelet-monocyte aggregates in whole blood involves phosphorylation of Lyn and is inhibited by IL102008In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 6, no 6, p. 986-994Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: P-selectin and CD40L expressed by activated platelets induce tissue factor (TF) and inflammatory cytokines in monocytes, but little is known of the cellular signaling pathways involved. The anti-inflammatory cytokine IL10 reduces atherosclerotic plaque formation. OBJECTIVES: To evaluate the importance of P-selectin upon platelet-monocyte aggregate (PMA) formation in thrombin receptor activator peptide (TRAP) stimulated whole blood, the P-selectin-P-selectin glycoprotein ligand (PSGL)-1-induced cellular signaling pathway, and the effects of IL10 on these functions. METHODS: TF, IL8, and monocyte chemotactic protein-1 (MCP-1) production, PMAs and phosphorylation of Lyn were analyzed in whole blood, purified monocytes, and vitamin D(3)-differentiated U-937 cells stimulated with TRAP or P-selectin with or without IL10. Anti-P-selectin or anti-CD40L antibodies (Abs), Src-kinases inhibitors, SU6656 or PP2, were added in some experiments. RESULTS: TRAP and P-selectin increased TF, IL8, and MCP-1 mRNA in whole blood and purified monocytes. Anti-P-selectin Ab reduced TRAP-induced PMA formation by 80 +/- 2% (P = 0.001) and production of TF (P = 0.04) and IL8 (P = 0.01). IL10 and SU6656 had no effect on PMA formation, although both significantly reduced TF (P = 0.002 and P = 0.02) and IL8 (P = 0.009 and P = 0.001) mRNA upon TRAP and P-selectin stimulation. Induced Lyn phosphorylation in monocytes was diminished by SU6656 (P = 0.02), anti-P-selectin Ab (P = 0.02), and IL10 (P = 0.03) upon TRAP or P-selectin stimulation. These results were confirmed in the vitamin D(3)-differentiated U-937 cells. CONCLUSIONS: The formation of PMAs in whole blood was P-selectin-dependent in the long term. P-selectin-PSGL-1-induced TF and IL8 expression through Lyn phosphorylation, and part of the inhibitory effect of IL10 depends on reduced phosphorylation.

  • 11.
    Christersson, Christina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Jönelid, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Thulin, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    The change of the amount of circulating microparticles and their association to the general atherosclerotic burden after acute coronary syndrome2015In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 13, no S2, p. 214-214, article id OR312Article in journal (Other academic)
  • 12.
    Christersson, Christina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Berglund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Oldgren, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    The utility of coagulation activity for prediction of risk of mortality and cardiovascular events in guideline-treated myocardial infarction patients2017In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 122, no 4, p. 224-233Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Despite improved treatment of myocardial infarction (MI), real-world patients still suffer substantial risk for subsequent cardiovascular events. Little is known about coagulation activity shortly after MI and whether coagulation activity markers may identify patients at increased risk despite contemporary treatment.

    OBJECTIVE: To evaluate D-dimer concentration and thrombin generation potential shortly after discharge after MI and evaluate if these markers could predict the risk of future cardiovascular and bleeding events.

    METHODS: Unselected MI patients (n = 421) were included in the observational REBUS study (NCT01102933) and followed for two years. D-dimer concentrations, thrombin peak, and endogenous thrombin potential (ETP) were analyzed at inclusion (3-5 days after MI) and at early follow-up (after 2-3 weeks).

    RESULTS: Seventy-five patients (17.8%) experienced the composite endpoint (all-cause death, MI, congestive heart failure, or all-cause stroke), and 31 patients (7.4%) experienced a clinically relevant bleeding event. D-dimer concentrations at early follow-up were associated with the composite endpoint (HR [per SD increase] 1.51 [95% CI 1.22-1.87]) and with clinically relevant bleeding (HR [per SD increase] 1.80 [95% CI 1.32-2.44]). Thrombin generation potential was not significantly associated with either the composite endpoint or with clinically relevant bleeding. Higher thrombin peak and ETP at early follow-up were both inversely associated with stroke (HR [per SD increase] 0.50 [95% CI 0.30-0.81] and 0.43 [95% CI 0.22-0.83], respectively).

    CONCLUSION: In unselected MI patients treated according to contemporary guidelines, D-dimer measurements may identify patients at increased risk of new cardiovascular and bleeding events. The inverse association of thrombin generation potential and risk of stroke has to be further investigated.

  • 13.
    Christersson, Christina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    The composition and daily variation of microparticles in whole blood in stable coronary artery disease2016In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 76, no 1Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: The knowledge of circadian variation of microparticles (MPs) in stable coronary artery disease (SCAD) is limited. The aim of this study was to evaluate the daily variation of platelet-, endothelial- and monocyte-derived MPs in whole blood and their tissue factor expression (TF) in SCAD and whether these MPs were related to other endothelial and coagulation markers.

    MATERIALS AND METHODS: Serial blood samples from patients with SCAD were collected during one day. Flow cytometry was used to evaluate the amount of large MPs 0.5-1.0 μm, positive for annexin, and their expression of CD41, CD62P, CD144, CD14 and TF. The lag time and endogenous thrombin potential (ETP) was calculated by Calibrated Automated Thrombogram and soluble (s)P-selectin, sTF and vWF by ELISA.

    RESULTS: The majority of MPs in whole blood consisted of CD41 + MPs with no significant daily variation. In contrast, the concentration of CD62P + MPs described a daily variation with the lowest concentrations found in the evening (p = 0.031). CD62P + and CD144 + MPs had the highest expression of TF, 52.6% and 42.9%, respectively, and correlated to the endothelial activity evaluated by vWF. There was a circadian rhythm of lag time (p < 0.001) and ETP (p = 0.001). The CD62P+, CD14 + and CD144 + MPs correlated to the lag time.

    CONCLUSION: The different subsets of platelet-, endothelial- and monocyte-derived MPs do not present the same circadian variation and they differ in TF expression in SCAD. The MPs from activated platelets, endothelial cells and monocytes exist in low concentrations in whole blood but are related to the endothelial and coagulation activity found in SCAD.

  • 14.
    Christersson, Christina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Oldgren, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Bylock, A.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Long-term treatment with ximelagatran, an oral direct thrombin inhibitor, persistently reduces the coagulation activity after a myocardial infarction2005In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 3, no 10, p. 2245-53Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: In the ESTEEM study, patients with a recent myocardial infarction were treated with aspirin and randomized to one of four doses (24-60 mg b.i.d) of the oral direct thrombin inhibitor ximelagatran or placebo for 6 months. Ximelagatran and aspirin reduced the risk of recurrent ischemic events compared with aspirin alone. In the present substudy we evaluated the different doses of ximelagatran on pharmacokinetics as measured by plasma concentration of the active compound melagatran and activated partial thromboplastin time (APTT) and pharmacodynamics as related by markers for coagulation activity, prothrombin fragment 1 + 2 (F1 + 2) and D-dimer. METHODS AND RESULTS: Plasma samples from 518 patients were collected before, during and after the treatment period. There was a linear dose-concentration relation at peak and trough and a linear relation between concentration and APTT (P < 0.001). F1 + 2 and D-dimer were decreased by 25% and 52% at 1 week (P < 0.001) in the ximelagatran groups compared with the placebo group and the reductions were maintained during the 6 months treatment. There were no differences detected in F1 + 2 or D-dimer levels between the different ximelagatran dosages. There was no correlation between the melagatran concentration and the change in F1 + 2 and D-dimer levels. After cessation of ximelagatran F1 + 2 and D-dimer levels returned to the initial levels. CONCLUSION: The dose of ximelagatran and APTT are linearly related to the plasma concentration of melagatran. Ximelagatran induces a sustained and stable reduction of thrombin generation and fibrin turnover without any relation to dose above 24 mg b.i.d. These properties indicate that long-term treatment with a low dose of ximelagatran may provide valuable depression of coagulation activity in aspirin treated post myocardial infarction patients.

  • 15.
    Christersson, Christina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Oldgren, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Bylock, Anders
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Early decrease in coagulation activity after myocardial infarction is associated with lower risk of new ischaemic events: observations from the ESTEEM: Reply2007In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 28, no 14, p. 1783-1783Article in journal (Refereed)
  • 16.
    Christersson, Christina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Oldgren, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Bylock, Anders
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Early decrease in coagulation activity after myocardial infarction is associated with lower risk of new ischemic events: Observations from the ESTEEM trial2007In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 28, no 6, p. 692-698Article in journal (Refereed)
    Abstract [en]

    AIM: Patients with a recent myocardial infarction have an increased risk of recurrent ischaemic events. In the ESTEEM trial, the oral direct thrombin inhibitor ximelagatran reduced the risk of new ischaemic events when compared with placebo in aspirin treated post myocardial infarction patients. Ximelagatran persistently reduced markers of coagulation activity, i.e. prothrombin fragment 1 + 2 (F1 + 2) and D-dimer levels. The aim of this substudy was to evaluate the levels of these markers and activated thromboplastin time (APTT) in relation to new ischaemic events or bleeding. METHODS AND RESULTS: In the substudy, 518 out of 1883 patients were included and within 14 days after a myocardial infarction randomized to ximelagatran or placebo for 6 months. The clinical endpoints death, myocardial infarction, severe recurrent ischaemia, ischaemic stroke, and bleeding were evaluated. The levels of F1 + 2, D-dimer, and APTT were analysed at randomization and in serial samples during the study. Ximelagatran treatment appeared to have a larger treatment effect in patients with F1 + 2 and D-dimer levels above the median at randomization with a reduction of ischaemic events from 18 to 9% (P = 0.03) for F1 + 2 and from 20 to 9% for D-dimer (P = 0.009). A reduction of D-dimer levels was found in 60% of the patients 1 week after randomization and these patients had less ischaemic events when compared with patients with unchanged or increased levels (P = 0.03) regardless of treatment. F1 + 2 and D-dimer levels were unrelated to bleeding risk. In the ximelagatran group, increased APTT was not related to ischaemic events but associated with a raised risk of bleeding. CONCLUSION: A reduction of initially high coagulation activity, as measured by the D-dimer level, in patients with recent myocardial infarction identifies patients with a decreased risk of new ischaemic events, regardless whether the reduction occurs spontaneously or is induced by pharmacological means. Patients with higher initial coagulation activity seemed to benefit most from long-term treatment with ximelagatran.

  • 17.
    Christersson, Christina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Oldgren, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Treatment with an Oral Direct Thrombin Inhibitor Decreases Platelet Activity but Increases Markers of Inflammation in Patients with Myocardial Infarction.2011In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 270, no 3, p. 215-223Article in journal (Refereed)
    Abstract [en]

    Background: Thrombin has a role not only in the coagulation process but also in inflammatory responses. Oral direct thrombin inhibitors (DTIs) are currently being evaluated in patients with thromboembolic diseases. Objectives:  To investigate whether an oral DTI affects markers for platelet and inflammatory activity after myocardial infarction (MI). Methods:  A total of 518 patients with MI were randomly assigned to ximelagatran treatment (four different dose groups) in combination with aspirin, or aspirin alone for 6 months. The levels of soluble (s) P-selectin, soluble tissue factor, C-reactive protein (CRP), interleukin (IL)-10 and IL-18 were analysed in serial blood samples.

    Results: sP-selectin concentration increased after 1 week and persisted at an elevated level for 6 months in all study groups (p<0.001). In the two highest ximelagatran dose groups, there was a reduced increase in sP-selectin compared to treatment with lower doses of ximelagatran and aspirin alone (p=0.01 and p=0.002, respectively). IL-18 levels did not change in the aspirin alone treatment group. By contrast, there was an elevation in IL-18 level in the lower and higher ximelagatran dose groups after 6 months (p=0.006 and p<0.001, respectively). Ximelagatran increased IL-10 levels (p=0.002) and reduced the decrease in CRP levels after 6 months compared to treatment with aspirin alone (p=0.002).

    Conclusion: A persistent elevation of platelet activity is found in patients with a recent MI after the cessation of acute antithrombotic treatment, and the addition of an oral DTI at higher doses decreases the activity. By contrast, long-term treatment with a DTI increases the levels of several markers of inflammation. Further studies with prolonged exposure of oral DTIs are needed for evaluation of the effect on inflammatory processes and to determine whether these agents influence clinical outcomes.

  • 18.
    Christersson, Christina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Schollin, M.
    Alexander, J. H.
    Bersh, B. J.
    Horowitz, J.
    Hylek, E. M.
    Mohan, P.
    Granger, C. B.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Increased levels of D-dimer in atrial fibrillation identify patients with higher risk of thromboembolic events and death2012In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 33, no Suppl 1, p. 969-969Article in journal (Other academic)
  • 19.
    Christersson, Christina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Thulin, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Microparticles during long-term follow-up after acute myocardial infarction: Association to atherosclerotic burden and risk of cardiovascular events2017In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 117, no 8, p. 1571-1581Article in journal (Refereed)
    Abstract [en]

    Microparticles (MPs) are formed from platelets (PMPs), endothelial cells (EMPs) and monocytes (MMPs), and in acute myocardial infarction (MI), there is an increase of MPs in the culprit artery. In this study MPs were evaluated in whole blood in 105 patients with MI at five time-points during a two-year follow-up (FU). Patients with non-ST elevated MI had higher concentrations of CD41+MPs compared to ST elevated MI patients (p=0.024). The concentrations of PMPs in whole blood increased during the time period (p<0.001), but no significant change over time was found for EMPs and MMPs. CD62P+MP counts were higher in MI patients with diabetes (p=0.020), and patients with hypertension had increased levels of CD14+MPs (p=0.004). The amount of CD62P+TF+MPs increased significantly during FU (p<0.001). Patients with atherosclerosis in three arterial beds, i.e. coronary, carotid and peripheral arteries, had lower concentrations of CD62P+TF+MPs (p=0.035) and CD144+TF+MPs (p=0.004) compared to patients with atherosclerosis in one or two arterial beds. Higher concentrations of CD62P+MPs early after MI were associated with an increased risk of cardiovascular events during FU, hazard ratio 3.32 (95 %C11.20-9.31). Only small variations in PMP, EMP and MMP concentrations were found during long-term FU after MI and their levels seem to reflect the underlying cardiovascular disease rather than the acute MI. PMPs expressing P-selectin might be a promising biomarker for predicting future cardiovascular events, but further studies are needed to confirm these results.

  • 20.
    Christersson, Christina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Andersson, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Alexander, J. H.
    Ansell, J.
    De Caterina, R.
    Gersh, B. J.
    Granger, C. B.
    Hanna, M.
    Horowitz, J. D.
    Huber, K.
    Husted, S.
    Hylek, E. M.
    Lopes, R. D.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    D-dimer and risk of thromboembolic and bleeding events in patients with atrial fibrillation: observations from the ARISTOTLE trial2014In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 12, no 9, p. 1401-1412Article in journal (Refereed)
    Abstract [en]

    BackgroundD-dimer is related to adverse outcomes in arterial and venous thromboembolic diseases. ObjectivesTo evaluate the predictive value of D-dimer level for stroke, other cardiovascular events, and bleeds, in patients with atrial fibrillation (AF) treated with oral anticoagulation with apixaban or warfarin; and to evaluate the relationship between the D-dimer levels at baseline and the treatment effect of apixaban vs. warfarin. MethodsIn the ARISTOTLE trial, 18201 patients with AF were randomized to apixaban or warfarin. D-dimer was analyzed in 14878 patients at randomization. The cohort was separated into two groups; not receiving vitaminK antagonist (VKA) treatment and receiving VKA treatment at randomization. ResultsHigher D-dimer levels were associated with increased frequencies of stroke or systemic embolism (hazard ratio [HR][Q4 vs. Q1]1.72, 95% confidence interval [CI]1.14-2.59, P=0.003), death (HR[Q4 vs. Q1]4.04, 95%CI3.06-5.33) and major bleeding (HR[Q4 vs. Q1]2.47, 95%CI1.77-3.45, P<0.0001) in the no-VKA group. Similar results were obtained in the on-VKA group. Adding D-dimer level to the CHADS(2) score improved the C-index from 0.646 to 0.655 for stroke or systemic embolism, and from 0.598 to 0.662 for death, in the no-VKA group. D-dimer level improved the HAS-BLED score for prediction of major bleeds, with an increase in the C-index from 0.610 to 0.641. There were no significant interactions between efficacy and safety of study treatment and D-dimer level. ConclusionIn anticoagulated patients with AF, the level of D-dimer is related to the risk of stroke, death, and bleeding, and adds to the predictive value of clinical risk scores. The benefits of apixaban were consistent, regardless of the baseline D-dimer level.

  • 21.
    Christersson, Christina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Andersson, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Alexander, John H
    Alings, Marco
    De Caterina, Raffaele
    Gersh, Bernard J
    Granger, Christopher B
    Halvorsen, Sigrun
    Hanna, Michael
    Huber, Kurt
    Hylek, Elaine M
    Lopes, Renato D
    Oh, Byung-Hee
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Effect of apixaban compared with warfarin on coagulation markers in atrial fibrillation.2019In: Heart, ISSN 1355-6037, E-ISSN 1468-201X, Vol. 105, no 3, p. 235-242Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Compare the effect of apixaban and warfarin on coagulation and primary haemostasis biomarkers in atrial fibrillation (AF).

    METHODS: The biomarker substudy from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation trial included 4850 patients with AF randomised to treatment with apixaban or warfarin. Sixty per cent of patients used vitamin K antagonist (VKA) within 7 days before randomisation. Prothrombin fragment 1+2 (F1+2), D-dimer, soluble CD40 ligand (sCD40L) and von Willebrand factor (vWF) antigen were analysed at randomisation and after 2 months of study treatment.

    RESULTS: In patients not on VKA treatment at randomisation, F1+2 and D-dimer levels were decreased by 25% and 23%, respectively, with apixaban, and by 59% and 38%, respectively, with warfarin (p<0.0001 for treatment differences for both). In patients on VKA at randomisation, F1+2 and D-dimer levels increased by 41% and 10%, respectively, with apixaban and decreased by 37% and 11%, respectively, with warfarin (p<0.0001 for treatment differences for both). sCD40L levels were slightly increased at 2 months, regardless of VKA or randomised treatment. Apixaban and warfarin also both reduced vWF antigen regardless of VKA treatment. The efficacy (stroke) and safety (bleeding) of apixaban compared with warfarin was similar irrespectively of biomarker levels at 2 months.

    CONCLUSIONS: Treatment with apixaban compared with warfarin for stroke prevention in patients with AF was associated with less reduction in thrombin generation and fibrin turnover. This effect of apixaban could contribute to the clinical results where apixaban was superior to warfarin both in stroke prevention and in reducing bleeding risk.

    TRIAL REGISTRATION NUMBER: NCT00412984.

  • 22.
    Dimberg, Axel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Thoracic Surgery.
    Alström, Ulrica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Thoracic Surgery.
    Ståhle, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Thoracic Surgery.
    Christersson, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Higher Preoperative Plasma Thrombin Potential in Patients Undergoing Surgery for Aortic Stenosis Compared to Surgery for Stable Coronary Artery Disease2018In: Clinical and applied thrombosis/hemostasis, ISSN 1076-0296, E-ISSN 1938-2723, Vol. 24, no 8, p. 1282-1290Article in journal (Refereed)
    Abstract [en]

    Aortic stenosis (AS) and coronary artery disease (CAD) influence the coagulation system, potentially affecting hemostasis during cardiac surgery. Our aim was to evaluate 2 preoperative global hemostasis assays, plasma thrombin potential and thromboelastometry, in patients with severe aortic valve stenosis compared to patients with CAD. A secondary aim was to test whether the assays were associated with postoperative bleeding. Calibrated automated thrombogram (CAT) in platelet-poor plasma and rotational thromboelastometry (ROTEM) in whole blood were analyzed in patients scheduled for elective surgery due to severe AS (n = 103) and stable CAD (n = 68). Patients with AS displayed higher plasma thrombin potential, both thrombin peak with median 252 nmol/L (interquartile range 187-319) and endogenous thrombin potential (ETP) with median 1552 nmol/L/min (interquartile range 1340-1838), when compared to patients with CAD where thrombin peak was median 174 nmol/L (interquartile range 147-229) and ETP median 1247 nmol/L/min (interquartile range 1034-1448; both P < .001). Differences persisted after adjustment for age, gender, comorbidity, and antithrombotic treatment. Differences observed in thromboelastometry between the groups did not persist after adjustment for baseline characteristics. Bleeding amount showed no relationship with plasma thrombin potential but weakly to thromboelastometry (R-2 = .064, P = .001). Patients with AS exhibited preoperatively increased plasma thrombin potential compared to patients with CAD. Plasma thrombin potential was not predictive for postoperative bleeding in patients scheduled for elective surgery.

  • 23. Giannitsis, Evangelos
    et al.
    Mair, Johannes
    Christersson, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Huber, Kurt
    Jaffe, Allan S
    Peacock, W Frank
    Plebani, Mario
    Thygesen, Kristian
    Möckel, Martin
    Mueller, Christian
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    How to use D-dimer in acute cardiovascular care2017In: European heart journal. Acute cardiovascular care., ISSN 2048-8726, Vol. 6, no 1, p. 69-80Article in journal (Refereed)
    Abstract [en]

    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.

  • 24.
    Henriksson, Catrin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Wernroth, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Christersson, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    An Observational Study of the Occurence of Anxiety, Depression and self-reported Quality of Life 2 Years after Myocardial Infarction2018In: Journal of Cardiology and Cardiovascular Medicine, ISSN ISSN: 2575-0143, no 3, p. 052-063Article in journal (Refereed)
    Abstract [en]

    Background: Patients with myocardial infarction (MI) often experience anxiety, depression and poor quality of life (QoL) compared with a normative population. Mood disturbances and QoL have been extensively investigated, but only a few studies have examined the long-term effects of MI on these complex phenomena.

    Aims: To examine the levels and associated predictors of anxiety, depression, and QoL in patients 2 years after MI.

    Methods: This was a single center, observational study of patients with MI (n=377, 22% women, median age 66 years). Two years after MI (2012-2014), the patients were asked to answer the Hospital Anxiety and Depression Scale (HADS) and EuroQol 5-dimension (EQ-5D-3L) questionnaires.

    Results: Most patients experienced neither anxiety (87%, 95% confidence interval [CI]: 83-90%) nor depression (94%, 95% CI: 92-97%) 2 years post-MI. Elderly patients experienced more depression than younger patients (p=0.003) and women had higher anxiety levels than men (p=0.009).

    Most patients had “no problems” with any of the EQ-5D-3L dimensions (72-98%), but 48% (95% CI: 43%-53%) self-reported at least “some problems” with pain/discomfort. In a multiple logistic regression model (EQ-5D-3L) higher age (p<0.001) and female sex (p<0.001) were associated with more pain/discomfort. Female sex (p=0.047) and prior MI (p=0.038) were associated with anxiety/depression. History of heart failure was associated with worse mobility (p=0.005) and problems with usual activities (p=0.006). The median total health status of the patients (EQ-VAS) was 78 (95% CI: 75-80)

  • 25.
    Hijazi, Ziad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Andersson, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Christersson, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ezekowitz, Justin
    Gersh, Bernard J
    Hanna, Michael
    Hohnloser, Stefan
    Horowitz, John
    Huber, Kurt
    Hylek, Elaine M
    Lopes, Renato D
    McMurray, John J V
    Granger, Christopher B
    N-Terminal Pro-B-Type Natriuretic Peptide for Risk Assessment in Patients With Atrial Fibrillation: Insights from the ARISTOTLE trial2013In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 61, no 22, p. 2274-2284Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    This study sought to assess the prognostic value of N-terminal pro–B-type natriuretic peptide (NT-proBNP) in patients with atrial fibrillation (AF) enrolled in the ARISTOTLE (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation) trial, and the treatment effect of apixaban according to NT-proBNP levels.

    BACKGROUND:

    Natriuretic peptides are associated with mortality and cardiovascular events in several cardiac diseases.

    METHODS:

    In the ARISTOTLE trial, 18,201 patients with AF were randomized to apixaban or warfarin. Plasma samples at randomization were available from 14,892 patients. The association between NT-proBNP concentrations and clinical outcomes was evaluated using Cox proportional hazard models, after adjusting for established cardiovascular risk factors.

    RESULTS:

    Quartiles of NT-proBNP were Q1:≤363, Q2:364-713, Q3:714-1250 and Q4:>1250 ng/L. During 1.8 years the annual rates of stroke or systemic embolism ranged from 0.74% in the bottom NT-proBNP quartile to 2.21% in the top quartile, adjusted hazard ratio (HR) 2.35 (95% CI 1.62-3.40, p<0.0001. Annual rates of cardiac death ranged from 0.86% in Q1 to 4.14% in Q4, adjusted HR 2.50 (1.81-3.45), p<0.0001. Adding NT-proBNP levels to the CHA2DS2VASc score improved C-statistics from 0.62 to 0.65 (p=0.0009) for stroke or systemic embolism and from 0.59 to 0.69 for cardiac death (p<0.0001). Apixaban reduced stroke, mortality, and bleeding regardless of the NT-proBNP level.

    CONCLUSIONS:

    NT-proBNP levels are often elevated in AF and independently associated with an increased risk of stroke and mortality. NT-proBNP improves risk stratification beyond the CHA2DS2VASc score and might be a novel tool for improved stroke prediction in AF. The efficacy of apixaban compared with warfarin is independent of the NT-proBNP level. (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation [ARISTOTLE].

  • 26.
    Johnston, Nina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Christersson, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Sex-Specific Research: A Key Component in Improving Prognosis After Transcatheter Aortic Valve Replacement2016In: Annals of Internal Medicine, ISSN 0003-4819, E-ISSN 1539-3704, Vol. 164, no 6, p. 442-443Article in journal (Other academic)
  • 27.
    Johnston, Nina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Jönelid, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Christersson, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Kero, Tanja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Renlund, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Schenck-Gustafsson, Karin
    Lagerqvist, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Effect of Gender on Patients With ST-Elevation and Non-ST-Elevation Myocardial Infarction Without Obstructive Coronary Artery Disease2015In: American Journal of Cardiology, ISSN 0002-9149, E-ISSN 1879-1913, Vol. 115, no 12, p. 1661-1666Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to compare the prognoses of patients with ST-segment elevation myocardial infarction (STEMI) and those with non-ST-segment elevation myocardial infarction (NSTEMI) without obstructive coronary artery disease (CAD) and the risk associated with gender for future cardiovascular events. The study population was selected from 95,849 patients who underwent coronary angiography for myocardial infarction from 2005 to 2010 and registered in the Swedish Coronary Angiography and Angioplasty Registry (SCAAR). Outcome analyses, including all-cause death, myocardial infarction, congestive heart failure, stroke, and revascularization, were performed in 2,268 patients with STEMI and 10,904 with NSTEMI without obstructive CAD (<50% stenosis). Hazard ratios and 95% confidence intervals comparing women with men were calculated for events, adjusting for cardiovascular risk factors and age. Nonobstructive CAD was found in 7% of patients with STEMI (6% men, 10% women) and in 17% of those with NSTEMI (11% men, 28% women). During a median follow-up of 2.6 years, 8% of patients with STEMI and 5% of those with NSTEMI died. Gender-associated differences in risk were observed in patients with NSTEMI, with adjusted hazard ratios lower in women than men for mortality (hazard ratio 0.90, 95% confidence interval 0.50 to 0.73) and congestive heart failure (hazard ratio 0.61, 95% confidence interval 0.52 to 0.72). In the 2 groups, women underwent less revascularization. In conclusion, nonobstructive CAD was more common in patients with NSTEMI than those with STEMI, as well as in women compared with men. Long-term mortality in patients with nonobstructive CAD was higher after STEMI than NSTEMI. The gender differences in outcomes suggest gender differences in the underlying pathogenesis of myocardial infarction without obstructive CAD.

  • 28.
    Jönelid, Birgitta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Christersson, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Hedberg, P
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Leppert, Jerzy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Lindhagen, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Oldgren, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Biomarkers in addition to clinical characteristics for prediction of peripheral artery disease in patients with recent myocardial infarctionIn: Article in journal (Other academic)
    Abstract [en]

    Abstract

    Background Few studies have examined biomarkers in CAD and peripheral artery disease (PAD), their association and the ability to predict PAD.

    Methods: Two prospectively observational studies including unselected patients with recent myocardial infarction were used for the analyses. PAD was defined as an abnormal ankle brachial index (ABI) score (<0.9 or > 1.4) on at least one side. The proximity extension assay (PEA) technique was used to simultaneously analyze 92 biomarkers with association to cardiovascular disease in samples early after an acute MI. Random forest was used to identify the biomarkers with a higher association to PAD. The additional discriminatory accuracy of adding biomarkers to clinical characteristics were analyzed by the c-statistics.

    Results:  Six biomarkers were identified associated with prediction of PAD in the REBUS cohort. Three of these could be validated in the VaMIS cohort; Tumor necrosis factor receptor (TNFR-1),  Tumor necrosis factor receptor 2 (TNFR-2) and Growth Differentiation Factor 15 (GDF-15) with an increase in c-statistics; Tnfr1:0.709 (95% CI 0.640, 0.779) and 0.746 (95% CI 0.706,0.787), Tnfr2: 0.703 (95% CI 0.633, 0.773) and 0.745 (95% CI 0.704, 0.785), GDF-15: 0.710 (95% CI 0.640, 0.781) and 0.752 (95% CI 0.711, 0.792) in the REBUS and VaMIS cohort respectively. Adding a group of biomarkers to clinical characteristics further increased the c-statistics compared to a single biomarker.

    Conclusions: Three biomarkers out of a panel of 92; TNFR-1, TNFR-2 and GDF-15 were identified associated with PAD in MI patients and could improve prediction of PAD in addition to clinical characteristics.

     

     

  • 29.
    Jönelid, Birgitta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Johnston, Nina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Berglund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Andrén, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Kragsterman, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Christersson, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Ankle brachial index most important to identify polyvascular disease in patients with non-ST elevation or ST-elevation myocardial infarction2016In: European journal of internal medicine, ISSN 0953-6205, E-ISSN 1879-0828, Vol. 30, p. 55-60Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Atherosclerosis is a systemic disease. In patients with acute myocardial infarction (MI) the extent of polyvascular disease (PvD) is largely unknown. In this study we investigate the prevalence and clinical characteristics predictive of PvD in patients with non-ST-elevation (NSTEMI) and ST-elevation (STEMI) MI.

    METHOD: 375 patients with acute MI included in the REBUS (Relevance of Biomarkers for Future Risk of Thromboembolic Events in Unselected Post-myocardial Infarction Patients) study were examined. Atherosclerotic changes were assessed in three arterial beds by coronary angiography, carotid ultrasound and ankle brachial index (ABI). Results compared findings of atherosclerosis in three arterial beds to fewer than 3 beds. PvD was defined as atherosclerosis in all three arterial beds.

    RESULTS: A medical history of MI, peripheral artery disease (PAD) or stroke was reported at admission in 17.9%, 2.1% and 3.7% of the patients, respectively. After evaluation, abnormal ABI was found in 20.3% and carotid artery atherosclerosis in 54.9% of the patients. In the total population, PvD was found in 13.8% of patients with no significant differences observed between NSTEMI and STEMI patients. Age (p<0.001), diabetes (p=0.039), previous PAD (p=0.009) and female gender (p=0.016) were associated with PvD. ABI was the most important predictor of PvD with a positive predictive value of 68.4% (95% CI 57.7-79.2%) and specificity of 92.4% (95% CI 89.5-95.4%).

    CONCLUSIONS: PvD is underdiagnosed in patients suffering from MI, both NSTEMI and STEMI. ABI is a useful and simple measurement that appears predictive of widespread atherosclerosis in these patients.

  • 30.
    Jönelid, Birgitta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Kragsterman, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Berglund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Andrén, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Johnston, Nina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Oldgren, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Christersson, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Low Walking Impairment Questionnaire score after a recent myocardial infarction identifies patients with polyvascular disease2019In: JRSM Cardiovascular Disease, ISSN 2048-0040, Vol. 8, p. 1-9Article in journal (Refereed)
    Abstract [en]

    Objectives: To evaluate whether the Walking Impairment Questionnaire score could identify patients with polyvascular disease in a population with recent myocardial infarction and their association with cardiovascular events during two-year follow-up.

    Design: A prospective observational study.

    Setting: Patients admitted to the acute coronary care unit, the Department of Cardiology, Uppsala University Hospital.

    Participants: Patients admitted with acute Non-STEMI- or STEMI-elevation myocardial infarction.

    Main outcome measures: The Walking Impairment Questionnaire, developed as a self-administered instrument to assess walking distance, speed, and stair climbing in patients with peripheral artery disease, predicts future cardiovascular events and mortality. Two hundred and sixty-three patients with recent myocardial infarction answered Walking Impairment Questionnaire. Polyvascular disease was defined as abnormal findings in the coronary- and carotid arteries and an abnormal ankle-brachial index. The calculated score for each of all three categories were divided into quartiles with the lowest score in first quartile.

    Results: The lowest (worst) quartile in all three Walking Impairment Questionnaire categories was associated with polyvascular disease, fully adjusted; distance, odds ratio (OR) 5.4 (95% confidence interval (CI) 1.8-16.1); speed, OR 7.4 (95% CI 1.5-36.5); stair climbing, OR 8.4 (95% CI 1.0-73.6). In stair climbing score, patients with the lowest (worst) score had a higher risk for the composite cardiovascular endpoint compared to the highest (best) score; hazard ratio 5.3 (95% CI 1.5-19.0). The adherence to medical treatment was high (between 81.7% and 99.2%).

    Conclusions: The Walking Impairment Questionnaire is a simple tool to identify myocardial infarction patients with more widespread atherosclerotic disease and although well treated medically, stair climbing predicts cardiovascular events.

  • 31.
    Jönelid, Birgitta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Johnston, Nina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Lindhagen, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Oldgren, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Christersson, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Biochemical biomarkers associated with peripheral artery disease contribute to prediction of outcome during long-term follow up after myocardial infarctionManuscript (preprint) (Other academic)
    Abstract [en]

    Abstract

    Background: Few studies have investigated biomarkers and their association to cardiovascular (CV) outcomes in patients with myocardial infarction (MI) and peripheral artery disease (PAD). Tumor necrosis factor receptor 1(TNFR-1), tumor necrosis factor receptor 2(TNFR-2) and growth differentiation factor 15 (GDF-15) are inflammatory biomarkers found to predict PAD.

    Aim:  To evaluate whether pathological ankle brachial index (ABI) and the group of biomarkers TNFR-1, TNFR-2 and GDF-15 analyzed early after a MI, were associated with all-cause mortality and the risk of new cardiovascular events during long-term follow up.

    Method: 388 patients with MI included in the REBUS (Relevance of Biomarkers for future risk of Thromboembolic Events in Unselected Post-myocardial Infarction Patients) study were examined with ABI to diagnose PAD (defined as an ABI score <0.9 or > 1.4 on at least one side). TNFR-1, -2 and GDF-15 was measured using the Proseek Multiplex CVD III ⁹⁶˟⁹⁶ proximity extension assay (www.olink.com/products/cvd-i and iii-panel).  The composite results for these 3 biomarkers were dichotomized into two groups (i.e high and low values) We evaluated pathological ABI and the group with higher biomarkers values with the association to long-term outcome, and if the group of biomarkers for inflammation could further improve prediction of recurrence of cardiovascular events (mortality, new acute coronary syndrome (ACS) and the composite of mortality, new ACS, stroke/TIA and PAD) after an MI.  

    Results:  The mean follow-up time was 5.5 years. After adjustment for established CV risk factors, pathological ABI was associated with a higher risk of new ACS, HR 1.97, 95 % CI 1.12-3.49, p = 0.019, and the composite endpoint; HR 1.97, 95 % CI 1.29-3.01, p=0.002, compared to patients with normal ABI. The group with the higher biomarker value was associated with a higher risk for all-cause mortality; HR 1.84, 95 % CI 1.00-3.38, p=0.049 and the composite endpoint; HR 1.62, 95 % CI 1.03-2.53, p=0.035. In the ROC analyses pathological ABI added to established CV risk factors improved the AUC for a new ACS from 0.753 (95% C.I. 0.684-0.822, p<0.001) to 0.763 (95% C.I. 0.697-0.830, p<0.001). When the group with higher biomarker values was added to  established CV risk factors  AUC for all-cause mortality increased from 0.789 (95% C-I. 0.729-0.849, p<0.001) to 0.805 (95% C.I. 0.746-0.863, p<0.001).

    Conclusion: Despite a high proportion of revascularization and guideline-recommended secondary medical treatment, both pathological ABI and the group with higher values of the inflammatory biomarkers (TNFR-1, TNFR-2, GDF-15) predictive for PAD were associated with the risk of new CV events and mortality in patients with a recent MI. The group of inflammatory biomarkers provide additional information to established risk factors in prediction of CV outcome in this cohort with recent MI.

  • 32.
    Lindholm, Daniel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Storey, Robert F.
    Univ Sheffield, Dept Cardiovasc Sci, Sheffield, S Yorkshire, England..
    Christersson, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala Univ, Dept Med Sci, Cardiol, Uppsala, Sweden..
    Halvorsen, Sigrun
    Oslo Univ Hosp Ulleval, Dept Cardiol, Oslo, Norway.;Univ Oslo, Oslo, Norway..
    Grove, Erik L.
    Aarhus Univ Hosp, Dept Cardiol, DK-8000 Aarhus, Denmark..
    Braun, Oscar O.
    Lund Univ, Skane Univ Hosp, Dept Cardiol, Lund, Sweden..
    Varenhorst, Christoph
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    James, Stefan K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Design and rationale of TROCADERO: A TRial Of Caffeine to Alleviate DyspnEa Related to ticagrelOr2015In: American Heart Journal, ISSN 0002-8703, E-ISSN 1097-6744, Vol. 170, no 3, p. 465-470Article in journal (Refereed)
    Abstract [en]

    Background Ticagrelor treatment has the side effect of increased incidence of dyspnea. Adenosine-induced dyspnea is augmented by ticagrelor and can be alleviated with the adenosine antagonist theophylline. Caffeine is a closely related xanthine derivative. Objectives The primary objective of the TROCADERO is to evaluate the effect of caffeine versus placebo on ticagrelorassociated dyspnea, measured by the visual analog scale area under the curve in patients with ongoing ticagrelor treatment after an acute coronary syndrome event. Design After a run-in period of 1 to 7 days of absence of caffeine intake, acute coronary syndrome patients with ticagrelorinduced dyspnea (planned inclusion 416) are randomized in a blinded fashion to either caffeine 200 mg twice daily or matching placebo with a treatment duration of 1 week. The primary efficacy end point is change in visual analog scale area under the curve for dyspnea, and the primary safety end point is occurrence of high on-treatment platelet reactivity measured by the VerifyNow P2Y12 assay. Conclusions This trial will determine if adenosine antagonism by caffeine can alleviate ticagrelor-related dyspnea, without impairing the antiplatelet effect of ticagrelor.

  • 33.
    Malmborg, Helena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology-Arrhythmia.
    Christersson, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Lönnerholm, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology-Arrhythmia.
    Blomström-Lundqvist, Carina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology-Arrhythmia.
    Comparison of effects on coagulation and inflammatory markers using a duty-cycled bipolar and unipolar radiofrequency pulmonary vein ablation catheter vs. a cryoballoon catheter for pulmonary vein isolation2013In: Europace, ISSN 1099-5129, E-ISSN 1532-2092, Vol. 15, no 6, p. 798-804Article in journal (Refereed)
    Abstract [en]

    AIMS:

    Thrombo-embolic events are one of the most feared complications related to atrial fibrillation (AF) ablation. Since radiofrequency (RF) energy is thought to be associated with a higher risk of thrombus formation than cryoenergy, the purpose of this study was to assess if the degree of activation of coagulation and inflammatory markers differed between ablation procedures performed with a cryoballoon catheter vs. a RF energy-based pulmonary vein ablation catheter (PVAC), respectively.

    METHODS AND RESULTS:

    Thirty patients referred for AF ablation were randomized to pulmonary vein isolation with either the cryoballoon or the PVAC. Biomarkers were studied for endothelial damage (von Willebrand factor antigen), platelet activation (soluble P-selectin), and coagulation activity [prothrombin fragment 1 + 2 (F1 + 2) and D-dimer] at five different time points during the procedure. Troponin I (Trop I) and C-reactive protein were analysed to reflect myocardial destruction and inflammatory activity. Markers of endothelial damage and platelet activation increased after ablation in both the cryo and the RF group. Similarly, the D-dimer levels increased significantly (P = 0.001) in both groups, whereas the F1 + 2 levels increased after the transseptal puncture only (P = 0.001). The overall activation of the coagulation system was, however, comparable between the groups. The cryoballoon was associated with higher Trop I compared with the PVAC (P < 0.001), but the ratios between biomarkers and Trop I were higher with the PVAC than with the cryoballoon.

    CONCLUSION:

    Even though the cryoballoon causes a higher degree of myocardial destruction than the PVAC, markers of coagulation, endothelial damage, and inflammation were comparable between the two techniques.

  • 34. Pirmohamed, Munir
    et al.
    Burnside, Girvan
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Jorgensen, Andrea L.
    Toh, Cheng Hock
    Nicholson, Toby
    Kesteven, Patrick
    Christersson, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wahlström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Stafberg, Christina
    Zhang, J. Eunice
    Leathart, Julian B.
    Kohnke, Hugo
    Maitland-van der Zee, Anke H.
    Williamson, Paula R.
    Daly, Ann K.
    Avery, Peter
    Kamali, Farhad
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    A Randomized Trial of Genotype-Guided Dosing of Warfarin2013In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 369, no 24, p. 2294-2303Article in journal (Refereed)
    Abstract [en]

    Background: The level of anticoagulation in response to a fixed-dose regimen of warfarin is difficult to predict during the initiation of therapy. We prospectively compared the effect of genotype-guided dosing with that of standard dosing on anticoagulation control in patients starting warfarin therapy.

    Methods: We conducted a multicenter, randomized, controlled trial involving patients with atrial fibrillation or venous thromboembolism. Genotyping for CYP2C9*2, CYP2C9*3, and VKORC1 (-1639GA) was performed with the use of a point-of-care test. For patients assigned to the genotype-guided group, warfarin doses were prescribed according to pharmacogenetic-based algorithms for the first 5 days. Patients in the control (standard dosing) group received a 3-day loading-dose regimen. After the initiation period, the treatment of all patients was managed according to routine clinical practice. The primary outcome measure was the percentage of time in the therapeutic range of 2.0 to 3.0 for the international normalized ratio (INR) during the first 12 weeks after warfarin initiation.

    Results: A total of 455 patients were recruited, with 227 randomly assigned to the genotype-guided group and 228 assigned to the control group. The mean percentage of time in the therapeutic range was 67.4% in the genotype-guided group as compared with 60.3% in the control group (adjusted difference, 7.0 percentage points; 95% confidence interval, 3.3 to 10.6; P<0.001). There were significantly fewer incidences of excessive anticoagulation (INR 4.0) in the genotype-guided group. The median time to reach a therapeutic INR was 21 days in the genotype-guided group as compared with 29 days in the control group (P<0.001).

    Conclusions: Pharmacogenetic-based dosing was associated with a higher percentage of time in the therapeutic INR range than was standard dosing during the initiation of warfarin therapy. 

  • 35.
    Rinnström, D.
    et al.
    Dept Publ Hlth & Clin Med, Med, Umea, Sweden..
    Dellborg, M.
    Univ Gothenburg, Dept Mol & Clin Med, Gothenburg, Sweden..
    Thilen, U.
    Lund Univ, Dept Cardiol, Clin Sci, Lund, Sweden..
    Sörensson, P.
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Nielsen, N. -E
    Christersson, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Johansson, B.
    Dept Publ Hlth & Clin Med, Med, Umea, Sweden..
    Adults with repaired coarctation of the aorta: factors associated with arterial hypertension and poor control of blood pressure2016In: EUROPEAN HEART JOURNAL, ISSN 0195-668X, Vol. 37, p. 369-369Article in journal (Refereed)
  • 36.
    Rinnström, D.
    et al.
    Umea Univ Hosp, Ctr Heart, Umea, Sweden..
    Dellborg, M.
    Univ Gothenburg, Dept Mol & Clin Med, Gothenburg, Sweden..
    Thilen, U.
    Lund Univ, Dept Cardiol, Clin Sci, Lund, Sweden..
    Sörensson, P.
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Nielsen, N. E.
    Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden..
    Christersson, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Johansson, B.
    Umea Univ Hosp, Ctr Heart, Umea, Sweden..
    Left ventricular hypertrophy in adults with previous repair of coarctation of the aorta; association with systolic blood pressure in the high normal range2016In: EUROPEAN HEART JOURNAL, ISSN 0195-668X, Vol. 37, p. 369-369Article in journal (Refereed)
  • 37.
    Rinnström, Daniel
    et al.
    Umea Univ, Ctr Heart, S-90187 Umea, Sweden.;Umea Univ, Dept Publ Hlth & Clin Med, S-90187 Umea, Sweden..
    Dellborg, Mikael
    Gothenburg Univ, Dept Mol & Clin Med, S-41124 Gothenburg, Sweden..
    Thilen, Ulf
    Lund Univ, Dept Cardiol, Clin Sci, S-22100 Lund, Sweden..
    Sörensson, Peder
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Nielsen, Niels-Eric
    Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden..
    Christersson, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Johansson, Bengt
    Umea Univ, Ctr Heart, S-90187 Umea, Sweden.;Umea Univ, Dept Publ Hlth & Clin Med, S-90187 Umea, Sweden..
    Left ventricular hypertrophy in adults with previous repair of coarctation of the aorta: association with systolic blood pressure in the high normal range2016In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 218, p. 59-64Article in journal (Refereed)
    Abstract [en]

    Background: Arterial hypertension is common in adults with repaired coarctation of the aorta (CoA). The associations between the diagnosis of hypertension, actual blood pressure, other factors affecting left ventricular overload, and left ventricular hypertrophy (LVH) are not yet fully explored in this population. Material and results: From the national register for congenital heart disease, 506 adult patients (>= 18 years old) with previous repair of CoA were identified (37.0% female, mean age 35.7 +/- 13.8 years, with an average of 26.8 +/- 12.4 years post repair). Echocardiographic data were available for all patients, and showed LVH in 114 (22.5%) of these. Systolic blood pressure (SBP) (mm Hg) (OR 1.02, CI 1.01-1.04), aortic valve disease, (OR 2.17, CI 1.33-3.53), age (years) (OR 1.03, CI 1.01-1.05), diagnosis of arterial hypertension (OR 3.02, CI 1.81-5.02), and sex (female) (OR 0.41, CI 0.24-0.72) were independently associated with LVH. There was an association with LVH at SBP within the upper reference limits [ 130, 140] mm Hg (OR 2.23, CI 1.05-4.73) that further increased for SBP > 140 mm Hg (OR 8.02, CI 3.76-17.12). Conclusions: LVH is common post repair of CoA and is associated with SBP even below the currently recommended target level. Lower target levels may therefore become justified in this population. ORCID Id: 0000-0003-0976-6910

  • 38.
    Rinnström, Daniel
    et al.
    Umea Univ, Heart Ctr, Dept Publ Hlth & Clin Med, Moritzvagen 1B, S-90342 Umea, Vasterbotten, Sweden..
    Dellborg, Mikael
    Univ Gothenburg, Dept Mol & Clin Med, Gothenburg, Sweden..
    Thilen, Ulf
    Lund Univ, Dept Cardiol Clin Sci, Lund, Sweden..
    Sörensson, Peder
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Nielsen, Niels-Erik
    Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden..
    Christersson, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Ugander, Martin
    Karolinska Univ Hosp, Karolinska Inst, Dept Clin Physiol, Stockholm, Sweden..
    Johansson, Bengt
    Umea Univ, Heart Ctr, Dept Publ Hlth & Clin Med, Moritzvagen 1B, S-90342 Umea, Vasterbotten, Sweden..
    Poor blood pressure control in adults with repaired coarctation of the aorta and hypertension: a register-based study of associated factors2017In: Cardiology in the Young, ISSN 1047-9511, E-ISSN 1467-1107, Vol. 27, no 9, p. 1708-1715Article in journal (Refereed)
    Abstract [en]

    Background: Arterial hypertension is common in adults with repaired coarctation of the aorta, and is associated with several severe complications. Aims: This study aimed to investigate the prevalence of poorly controlled (>= 140/90 mmHg) blood pressure among patients with diagnosed hypertension and to identify associated factors. Methods: In the national register for CHD, adults with repaired coarctation of the aorta and diagnosed hypertension - defined as a registry diagnosis and/or use of anti-hypertensive prescription medication - were identified. Logistic regression analysis was used to identify variables associated with poorly controlled blood pressure. Results: Of the 243 included patients, 27.2% were female, the mean age was 45.4 +/- 15.3 years, and 52.3% had poorly controlled blood pressure at the last registration. In a multivariable model, age (years) (OR 1.03, CI 1.01-1.06, p = 0.008) was independently associated with poorly controlled blood pressure and so was systolic arm-leg blood pressure gradient in the ranges [10, 20] mmHg (OR 4.92, CI 1.76-13.79, p = 0.002) to >20 mmHg (OR 9.93, CI 2.99-33.02, p < 0.001), in comparison with the reference interval [0, 10] mmHg. Patients with poorly controlled blood pressure had, on average, more types of anti-hypertensive medication classes prescribed (1.9 versus 1.5, p = 0.003). Conclusions: Poorly controlled blood pressure is common among patients with repaired coarctation of the aorta and diagnosed hypertension, despite what seems to be more intensive treatment. A systolic arm-leg blood pressure gradient is associated with poorly controlled blood pressure, even at low levels usually not considered for intervention, and may be an indicator of hypertension that is difficult to treat.

  • 39.
    Sandberg, Camilla
    et al.
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden;Umea Univ, Dept Community Med & Rehabil, Umea, Sweden.
    Johansson, Karna
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden.
    Christersson, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Hlebowicz, Joanna
    Lund Univ, Dept Cardiol, Clin Sci, Lund, Sweden.
    Thilen, Ulf
    Lund Univ, Dept Cardiol, Clin Sci, Lund, Sweden.
    Johansson, Bengt
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden.
    Sarcopenia is common in adults with complex congenital heart disease2019In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 296, p. 57-62Article in journal (Other academic)
    Abstract [en]

    Background: Adults with complex congenital heart disease (CHD) have reduced aerobic capacity and impaired muscle function. We therefore hypothesized that patients have a lower skeletal muscle mass and higher fat mass than controls. Methods: Body composition was examined with full body Dual-Energy x-ray Absorptiometry (DXA) in 73 patients with complex CHD (mean age 35.8 +/- 14.3, women n = 22) and 73 age and sex matched controls. Patients fulfilling criteria for low skeletal muscle mass in relation to their height and fat mass were defined as sarcopenic. Results: Male patients (n = 51) were shorter (177.4 +/- 6.6 cm vs. 180.9 +/- 6.7 cm, p = 0.009) and weighed less (76.0 +/- 10.8 kg vs. 82.0 +/- 12.4 kg, p = 0.01) than controls. Also, patients had a lower appendicular lean mass-index (ALM-index) (7.57 +/- 0.97 kg/m(2) vs. 8.46 +/- 0.90 kg/m(2), p < 0.001). Patients' relative tissue fat mass (27.9 +/- 7.0% vs. 25.4 +/- 8.6%, p = 0.1) did not differ. Forty-seven percent of the men (n = 24) were classified as sarcopenic. Female patients (n = 22) were also shorter (163.5 +/- 8.7 cm vs. 166.7 +/- 5.9 cm, p = 0.05) but had a higher BMI (25.7 +/- 4.2 vs. 23.0 +/- 2.5, p = 0.02) than controls. Patients also had a lower ALM-index (6.30 +/- 0.75 vs. 6.67 +/- 0.55, p = 0.05), but their relative body fat mass (40.8 +/- 7.6% vs. 32.0 +/- 7.0%, p < 0.001) were higher. Fifty-nine percent of the women (n = 13) were classified as sarcopenic. Conclusions: The body composition was altered toward lower skeletal muscle mass in patients with complex CHD. Approximately half of the patients were classified as sarcopenic. Contrary to men, the women had increased body fat and a higher BMI. Further research is required to assess the cause, possible adverse long-term effects and whether sarcopenia is preventable or treatable. (C) 2019 Elsevier B.V. All rights reserved.

  • 40. Sandberg, Camilla
    et al.
    Rinnström, Daniel
    Dellborg, Mikael
    Thilén, Ulf
    Sörensson, Peder
    Nielsen, Niels-Erik
    Christersson, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Wadell, Karin
    Johansson, Bengt
    Height, weight and body mass index in adults with congenital heart disease2015In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 187, p. 219-226Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: High BMI is a risk factor for cardiovascular disease and, in contrast, low BMI is associated with worse prognosis in heart failure. The knowledge on BMI and the distribution in different BMI-classes in adults with congenital heart disease (CHD) are limited.

    METHODS AND RESULTS: Data on 2424 adult patients was extracted from the Swedish Registry on Congenital Heart Disease and compared to a reference population (n=4605). The prevalence of overweight/obesity (BMI≥25) was lower in men with variants of the Fontan procedure, pulmonary atresia (PA)/double outlet right ventricle (DORV) and aortic valve disease (AVD) (Fontan 22.0% and PA/DORV 15.1% vs. 43.0%, p=0.048 and p<0.001) (AVD 37.5% vs. 49.3%, p<0.001). Overt obesity (BMI≥30) was only more common in women with AVD (12.8% vs. 9.0%, p=0.005). Underweight (BMI<18.5) was generally more common in men with CHD (complex lesions 4.9% vs. 0.9%, p<0.001 and simple lesions 3.2% vs. 0.6%, <0.001). Men with complex lesions were shorter than controls in contrast to females that in general did not differ from controls.

    CONCLUSION: Higher prevalence of underweight in men with CHD combined with a lower prevalence of overweight/obesity in men with some complex lesions indicates that men with CHD in general has lower BMI compared to controls. In women, only limited differences between those with CHD and the controls were found. The complexity of the CHD had larger impact on height in men. The cause of these gender differences as well as possible significance for prognosis is unknown.

  • 41.
    Sandtröm, Anette
    et al.
    Umeå Univ, Heart Ctr, Umeå, Sweden;Umeå Univ, Dept Publ Hlth & Clin Med, Umeå, Sweden.
    Sandberg, Camilla
    Umeå Univ, Heart Ctr, Umeå, Sweden;Umeå Univ, Dept Publ Hlth & Clin Med, Umeå, Sweden.
    Rinnstrom, Daniel
    Umeå Univ, Heart Ctr, Umeå, Sweden;Umeå Univ, Dept Publ Hlth & Clin Med, Umeå, Sweden.
    Engström, Gunnar
    Umeå Univ, Heart Ctr, Umeå, Sweden;Umeå Univ, Dept Publ Hlth & Clin Med, Umeå, Sweden.
    Dellborg, Mikael
    Univ Gothenburg, Dept Mol & Clin Med, Gothenburg, Sweden.
    Thilen, Ulf
    Lund Univ, Dept Cardiol Clin Sci, Lund, Sweden.
    Sörensson, Peder
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Nielsen, Niels-Erik
    Linköping Univ, Dept Med & Hlth Sci, Linköping, Sweden.
    Christersson, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Johansson, Bengt
    Umeå Univ, Heart Ctr, Umeå, Sweden;Umeå Univ, Dept Publ Hlth & Clin Med, Umeå, Sweden.
    Factors associated with health-related quality of life among adults with tetralogy of Fallot2019In: Open heart, E-ISSN 2053-3624, Vol. 6, no 1, article id UNSP e000932Article in journal (Refereed)
    Abstract [en]

    Background Due to improved care, the numbers of patients with tetralogy of Fallot (ToF) are increasing. However, long-term morbidity and need for reinterventions are concerns and also address issues of quality of life (QoL). Methods Patients with ToF and valid EuroQol-5 dimensions questionnaire (EQ-5D) were identified in the national Swedish register on congenital heart disease. EQ5D index was calculated and dichotomised into best possible health-related QoL (EQ-5D index = 1) or differed from 1. Results 288 patients met the criteria and were analysed. Univariate logistic regression showed a positive association between New York Heart Association (NYHA) class I (OR 8.32, 95% CI 3.80 to 18.21), physical activity > 3 h/ week (OR 3.34, 95% CI 1.67 to 6.66) and a better right ventricular function (OR 2.56, 95% CI 1.09 to 6.02). A negative association between symptoms (OR 0.23, 95% CI 0.13 to 0.42), cardiovascular medication (OR 0.31, 95% CI 0.18 to 0.53), age (OR 0.97, 95% CI 0.96 to 0.99) and EQ-5D index was observed. In multivariate logistic regression, NYHA I (OR 7.28, 95% CI 3.29 to 16.12) and physical activity > 3 h/ week (OR 2.27, 95% CI 1.07 to 4.84) remained associated with best possible health-related QoL. Replacing NYHA with symptoms in the model yielded similar results. Conclusion In this registry study, self-reported physical activity, staff-reported NYHA class and absence of symptoms were strongly associated with best possible health-related QoL measured by EQ-5D. Physical activity level is a potential target for intervention to improve QoL in this population but randomised trials are needed to test such a hypothesis.

  • 42.
    Siegbahn, Agneta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Christersson, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Alfredsson, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    MiR-223-3p post-transcriptionally regulates the expression of F3, the human tissue factor gene, and TF expression in acute coronary syndrome2015In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 36, no Suppl. 1, p. 335-335Article in journal (Other academic)
  • 43.
    Siegbahn, Agneta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Christersson, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Schollin, M.
    Alexander, J. H.
    Horowitz, J.
    Hylek, E. M.
    Lopes, R. D.
    Mohan, P.
    Granger, C. B.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Increased levels of D-dimer identify patients with atrial fibrillation at high risk for bleeding an ARISTOTLE substudy2012In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 33, no Suppl 1, p. 51-51Article in journal (Other academic)
  • 44. Søndergaard, Lars
    et al.
    Saraste, Antti
    Christersson, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Vahanian, Alec
    The year in cardiology 2017: valvular heart disease2018In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 39, no 8, p. 650-657Article in journal (Refereed)
  • 45.
    Thilen, M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Christersson, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Dellborg, M.
    Sahlgrens Acad, Dept Med, Gothenburg, Sweden..
    Mattsson, E.
    Karolinska Univ Hosp, Dept Cardiol, Stockholm, Sweden..
    Trzebiatowska-Krzynska, A.
    Linkoping Univ Hosp, Dept Cardiol, S-58185 Linkoping, Sweden..
    Thilen, U.
    Univ Lund Hosp, Dept Med Sci, S-22185 Lund, Sweden..
    Atrial septal defect device closure in the elderly, symptomatic benefits except for arrhythmia2015In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 36, no Suppl. 1, p. 624-625Article in journal (Other academic)
  • 46.
    Thilén, Maria
    et al.
    Halmstad Cty Hosp, Dept Med, Halmstad, Sweden..
    Christersson, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Dellborg, Mikael
    Sahlgrens Univ Hosp, Dept Med, Ostra, Sweden.;Gothenburg Univ, Sahlgrenska Acad, Inst Med, S-41124 Gothenburg, Sweden..
    Mattsson, Eva
    Karolinska Univ Hosp, Dept Cardiol, Stockholm, Sweden..
    Trzebiatowska-Krzynska, Aleksandra
    Linkoping Univ Hosp, Dept Cardiol, Linkoping, Sweden..
    Thilén, Ulf
    Lund Univ, Skane Univ Hosp, Dept Cardiol, S-22100 Lund, Sweden..
    Catheter closure of atrial septal defect in the elderly (>= 65 years): A worthwhile procedure2016In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 218, p. 25-30Article in journal (Refereed)
    Abstract [en]

    Background: Secundum atrial septal defect (ASD2) is one of the most common cardiac malformations diagnosed in adult life. Catheter closure has made treatment possible even in patients of high age. However, published outcome data for elderly patients is limited. The aim of this study was to report, on a national basis, the long-term outcome of ASD2 catheter closure in the elderly. Material and results: We report the clinical and echocardiographic outcome of catheter closure of ASD2 in 148 patients aged 65-87 years. Data was obtained from a national registry, medical records and a questionnaire. The proportion of patients in NYHAI increased from 34% to 61% (p < 0.001) one year after closure and remained stable at the latest follow-up 4,4 (SD 2,6) years post-closure. The proportion of patients with moderate/severe enlargement of the right ventricle and atrium fell from 77% and 76% to 25% and 40%, respectively, (p < 0.001) and right ventricular systolic pressure dropped significantly. Improvement of NYHA class was associated with reduced right ventricular systolic pressure but not with remodelling of the right heart. NYHA deteriorated in 9 patients, despite reduced right ventricular size. Overall, the prevalence of atrial fibrillation was unchanged after closure. Major complication rate was 2% and there was no procedure-or device-related mortality. Conclusion: Catheter closure of ASD2 in the elderly is a worthwhile procedure since it improves symptoms and has a low complication rate. However, a subset of patients do not improve, in which we suggest that concealed left ventricular dysfunction may play a causative role.

  • 47.
    Thulin, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Yan, J.
    Eindhoven Univ Technol, Inst Complex Mol Syst, Eindhoven, Netherlands..
    Åberg, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Christersson, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Kamali-Moghaddam, Masood
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sensitive detection of platelet-derived and tissue factor positive extracellular vesicles in plasma using solid-phase proximity ligation assay2018In: Cardiovascular Research, ISSN 0008-6363, E-ISSN 1755-3245, Vol. 114, p. S132-S132Article in journal (Other academic)
  • 48.
    Thulin, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Yan, Junhong
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Åberg, Mikael
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Christersson, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Kamali-Moghaddam, Masood
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Siegbahn, Agneta
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Sensitive and Specific Detection of Platelet-Derived and Tissue Factor-Positive Extracellular Vesicles in Plasma using Solid-Phase Proximity Ligation Assay2018In: Thrombosis and Haemostasis open, ISSN 2512-9465Article in journal (Refereed)
    Abstract [en]

    Extracellular vesicles (EVs) derived from blood cells are promising biomarkers for various diseases. However, they are difficult to measure accurately in plasma due to their small size. Here, we demonstrate that platelet-derived EVs in plasma can be measured using solid-phase proximity ligation assay with high sensitivity and specificity using very small sample volume of biological materials. The results correlate well with high-sensitivity flow cytometry with the difference that the smallest EVs are detected. Briefly, the EVs are first captured on a solid phase, using lactadherin binding, and detection requires recognition with two antibodies followed by qPCR. The assay, using cholera toxin subunit-B or lactadherin as capture agents, also allowed detection of the more rare population of tissue factor (TF)-positive EVs at a concentration similar to sensitive TF activity assays. Thus, this assay can detect different types of EVs with high specificity and sensitivity, and has the potential to be an attractive alternative to flow cytometric analysis of preclinical and clinical samples. Improved techniques for measuring EVs in plasma will hopefully contribute to the understanding of their role in several diseases.

  • 49. Walfridsson, U.
    et al.
    Rosenqvist, M.
    Agren, P. L.
    Andersson, P.
    Juhlin, T.
    Nilsson, C.
    Christersson, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Svensson, P.
    Assessing disease-specific patient reported outcomes within the Swedish National Quality Register AURICULA2015In: European Journal of Cardiovascular Nursing, ISSN 1474-5151, E-ISSN 1873-1953, Vol. 14, no S1, p. S87-S88, article id 239Article in journal (Other academic)
  • 50.
    Wallentin, Lars C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Christersson, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Schollin, M.
    Alexander, J. H.
    Bersh, B. J.
    Hanna, M.
    Hylek, E. M.
    McMurray, J. J. V.
    Granger, C. B.
    High sensitivity troponin-T for risk stratification in atrial fibrillation during treatment with apixaban or warfarin2012In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 33, no Suppl 1, p. 53-53Article in journal (Other academic)
12 1 - 50 of 51
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