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  • 1.
    Buccheri, Sergio
    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.
    Sarno, Giovanna
    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.
    Frobert, Ole
    Orebro Univ Hosp, Dept Cardiol, Orebro, Sweden.
    Gudnason, Thorarinn
    Landspitali Univ Hosp, Reykjavik, Iceland;Univ Iceland, Dept Cardiol, Reykjavik, Iceland;Univ Iceland, Cardiovasc Res Ctr, Reykjavik, Iceland.
    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.
    Lindholm, Daniel P
    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.
    Maeng, Michael
    Aarhus Univ Hosp, Dept Cardiol, Aarhus, Denmark.
    Olivecrona, Goran
    Lund Univ Hosp, Dept Cardiol, Clin Sci, Lund, Sweden.
    James, Stefan
    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.
    Assessing the Nationwide Impact of a Registry-Based Randomized Clinical Trial on Cardiovascular Practice The TASTE Trial in Perspective2019In: Circulation. Cardiovascular Interventions, ISSN 1941-7640, E-ISSN 1941-7632, Vol. 12, no 3, article id e007381Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Registry-based randomized clinical trials have emerged as useful tools to provide evidence on the comparative efficacy and safety of different therapeutic strategies. However, it remains unknown whether the results of registry-based randomized clinical trials have a sizable impact on daily clinical practice. We sought, therefore, to describe the temporal trends in thrombus aspiration (TA) use in Sweden before, during, and after dissemination of the TASTE trial (Thrombus Aspiration in ST-Elevation Myocardial Infarction in Scandinavia) results.

    METHODS AND RESULTS: From January 1, 2006, to December 31, 2017, we included all consecutive patients with ST-segment-elevation myocardial infarction undergoing percutaneous revascularization in Sweden. All patients were registered in the Swedish Coronary Angiography and Angioplasty Registry. A total of 55 809 ST-segment-elevation myocardial infarction patients were included. TA use in Sweden substantially decreased after dissemination of TASTE results (from 39.8% to 11.8% during and after TASTE, respectively). Substantial variability in TA use across treating centers was observed before TASTE (TA use ranging from 0% to 70%), but after TASTE both the interhospital variability and the frequency of TA use were markedly reduced. A constant shift in medical practice was seen about 4 months after dissemination of the TASTE trial results. Time trends for all-cause mortality and definite stent thrombosis at 30 days were not associated with variations in TA use (P values >0.05 using the Granger test).

    CONCLUSIONS: In Sweden, the results of the TASTE trial were impactful in daily clinical practice and led to a relevant decrease in TA use in ST-segment-elevation myocardial infarction patients undergoing percutaneous revascularization.

  • 2.
    Buccheri, Sergio
    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.
    Sarno, Giovanna
    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.
    Lagerqvist, Bo
    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.
    Olivecrona, Göran
    Hambraeus, Kristina
    Witt, Nils
    Lindholm, Daniel
    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.
    Erlinge, David
    Angerås, Oskar
    James, Stefan K
    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.
    Bioabsorbable polymer everolimus-eluting stents in patients with acute myocardial infarction: a report from the Swedish Coronary Angiography and Angioplasty Registry.2018In: EuroIntervention, ISSN 1774-024X, E-ISSN 1969-6213, Vol. 14, no 5, p. e562-e569Article in journal (Refereed)
    Abstract [en]

    AIMS: The clinical performance of the SYNERGY drug-eluting stent (DES) in patients with acute myocardial infarction (MI) has not been investigated in detail. We sought to report on the outcomes after SYNERGY DES (Boston Scientific, Marlborough, MA, USA) implantation in patients with MI undergoing percutaneous revascularisation (PCI).

    METHODS AND RESULTS: We included all consecutive patients with MI undergoing PCI with the SYNERGY DES and newer-generation DES (n-DES group) in Sweden. From March 2013 to September 2016, a total of 36,292 patients, of whom 39.7% presented with ST-elevation MI, were included. As compared to patients in the n-DES group (n=31,403), patients in the SYNERGY group (n=4,889) were older and presented more often with left main or three-vessel disease involvement, as well as with restenotic lesions (p<0.001 for all parameters). The Kaplan-Meier estimates of ST at two years in the SYNERGY and n-DES groups were 0.69% and 0.81%, respectively (adjusted HR 1.00, 95% CI: 0.69-1.46; p=0.99). Clinically relevant restenosis was encountered in 1.48% and 1.25% of patients in the SYNERGY and n-DES groups, respectively (adjusted HR 1.05, 95% CI: 0.81-1.37; p=0.72). No differences in the risk of all-cause death and recurrent MI were found between the two groups after adjustment (adjusted HR 1.12, 95% CI: 0.98-1.28; p=0.10, and adjusted HR 0.95, 95% CI: 0.82-1.10; p=0.49, respectively).

    CONCLUSIONS: In a large and unselected cohort of patients with MI undergoing percutaneous revascularisation with the SYNERGY DES, stent performance and clinical outcomes did not differ compared with other n-DES up to two years.

  • 3.
    Crona, Joakim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Fanola, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Lindholm, Daniel P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Antonodimitrakis, Pantelis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Granberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Effect of Temozolomide in Patients with Metastatic Bronchial Carcinoids2013In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 98, no 2, p. 151-155Article in journal (Refereed)
    Abstract [en]

    Introduction: Metastatic bronchial carcinoids are rare neoplasms, where efforts of medical treatment so far have been disappointing. A previous study from our center indicated that temozolomide might be of value. Materials and Methods: All patients with progressive metastatic bronchial carcinoid treated with tennozolomide as monotherapy at our center between 2004 and 2010 (n = 31) were included in this retrospective study. 14 tumors were classified as typical and 15 as atypical carcinoids, whereas 2 tumors could not be classified. Temozolomide was given on 5 consecutive days every 4 weeks. Toxicity was evaluable in 28 of 31 patients, and 22 patients were evaluable by RECIST 1.1. Results: There were no complete responses. A partial response was seen in 3 patients (14%), stable disease in 11(52%) and progressive disease in 7 patients (33%). Median progression-free survival was 5.3 months and median overall survival was 23.2 months from the start of temozolomide. Toxcities grade 3-4 were noted in 4 patients, thrombocytopenia (n =3) and leukopenia (n = 1). Conclusion: Temozolomide as monotherapy shows activity in metastatic bronchial carcinoids. Regimens combining tennozolomide with other agents (e.g. capecitabine and/or bevacizumab, everolimus, radiolabeled somatostatin analogues) should be further studied in these patients. Copyright (C) 2013 S. Karger AG, Basel

  • 4.
    Fukaya, Eri
    et al.
    Stanford Univ, Sch Med, Dept Surg, Div Vasc Surg, Stanford, CA 94305 USA.
    Flores, Alyssa M.
    Stanford Univ, Sch Med, Dept Surg, Div Vasc Surg, Stanford, CA 94305 USA.
    Lindholm, Daniel P
    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.
    Gustafsson, Stefan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Zanetti, Daniela
    Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, Stanford, CA 94305 USA.
    Ingelsson, Erik
    Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, Stanford, CA 94305 USA;Stanford Cardiovasc Inst, Stanford, CA USA.
    Leeper, Nicholas J.
    Stanford Univ, Sch Med, Dept Surg, Div Vasc Surg, Stanford, CA 94305 USA;Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, Stanford, CA 94305 USA;Stanford Cardiovasc Inst, Stanford, CA USA.
    Clinical and Genetic Determinants of Varicose Veins Prospective, Community-Based Study of approximate to 500 000 Individuals2018In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 138, no 25, p. 2869-2880Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Varicose veins are a common problem with no approved medical therapies. Although it is believed that varicose vein pathogenesis is multifactorial, there is limited understanding of the genetic and environmental factors that contribute to their formation. Large-scale studies of risk factors for varicose veins may highlight important aspects of pathophysiology and identify groups at increased risk for disease. METHODS: We applied machine learning to agnostically search for risk factors of varicose veins in 493 519 individuals in the UK Biobank. Predictors were further studied with univariable and multivariable Cox regression analyses (2441 incident events). A genome-wide association study of varicose veins was also performed among 337 536 unrelated individuals (9577 cases) of white British descent, followed by expression quantitative loci and pathway analyses. Because height emerged as a new candidate risk factor, we performed mendelian randomization analyses to assess a potential causal role for height in varicose vein development. RESULTS: Machine learning confirmed several known (age, sex, obesity, pregnancy, history of deep vein thrombosis) and identified several new risk factors for varicose vein disease, including height. After adjustment for traditional risk factors in Cox regression, greater height remained independently associated with varicose veins (hazard ratio for upper versus lower quartile, 1.74; 95% Cl, 1.51-2.01; P<0.0001). A genomewide association study identified 30 new genome-wide significant loci, identifying pathways involved in vascular development and skeletal/ limb biology. Mendelian randomization analysis provided evidence that increased height is causally related to varicose veins (inverse -variance weighted: odds ratio, 1.26; P=2.07x10(-16)). CONCLUSIONS: Using data from nearly a half -million individuals, we present a comprehensive genetic and epidemiological study of varicose veins. We identified novel clinical and genetic risk factors that provide pathophysiological insights and could help future improvements of treatment of varicose vein disease.

  • 5.
    Johansson, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Lindholm, Daniel
    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.
    Varenhorst, Christoph
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    James, Stefan
    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.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Barratt, Bryan J.
    AstraZeneca R&D, Alderley Pk SK10 4TF, Cheshire, England..
    Becker, Richard C.
    Acad Hlth Ctr, Div Cardiovasc Hlth & Dis, Heart Lung & Vasc Inst, Cincinnati, OH 45267 USA..
    Himmelmann, Anders
    AstraZeneca Res & Dev, S-43150 Molndal, Sweden..
    Katus, Hugo A.
    Univ Klinikum Heidelberg, Med Klin, D-69120 Heidelberg, Germany..
    Steg, Philippe Gabriel
    INSERM, Unite 1148, F-75019 Paris, France.;Hop Bichat Claude Bernard, AP HP, Dept Hosp Univ FIRE, F-75018 Paris, France.;Univ Paris Diderot, Sorbonne Paris Cite, F-75013 Paris, France.;Royal Brompton Hosp, ICMS, NHLI Imperial Coll, London SW3 6NP, England..
    Storey, Robert F.
    Univ Sheffield, Dept Cardiovasc Sci, Sheffield S10 2RX, S Yorkshire, England..
    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.
    Genome-wide association and Mendelian randomization study of NT-proBNP in patients with acute coronary syndrome2016In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 25, no 7, p. 1447-1456Article in journal (Refereed)
    Abstract [en]

    N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a strong predictor of mortality in coronary artery disease and is widely employed as a prognostic biomarker. However, a causal relationship between NT-proBNP and clinical endpoints has not been established. We have performed a genome-wide association and Mendelian randomization study of NT-proBNP. We used a discovery set of 3740 patients from the PLATelet inhibition and patient Outcomes (PLATO) trial, which enrolled 18 624 patients with acute coronary syndrome (ACS). A further set of 5492 patients, from the same trial, was used for replication. Genetic variants at two novel loci (SLC39A8 and POC1B/GALNT4) were associated with NT-proBNP levels and replicated together with the previously known NPPB locus. The most significant SNP (rs198389, pooled P = 1.07 x 10(-15)) in NPPB interrupts an E-box consensus motif in the gene promoter. The association in SLC39A8 is driven by a deleterious variant (rs13107325, pooled P = 5.99 x 10(-10)), whereas the most significant SNP in POC1B/GALNT4 (rs11105306, pooled P = 1.02 x 10(-16)) is intronic. The SLC39A8 SNP was associated with higher risk of cardiovascular (CV) death (HR = 1.39, 95% CI: 1.08-1.79, P = 0.0095), but the other loci were not associated with clinical endpoints. We have identified two novel loci to be associated with NT-proBNP in patients with ACS. Only the SLC39A8 variant, but not the NPPB variant, was associated with a clinical endpoint. Due to pleotropic effects of SLC39A8, these results do not suggest that NT-proBNP levels have a direct effect on mortality in ACS patients. PLATO Clinical Trial Registration: ; NCT00391872.

  • 6. Katus, Hugo
    et al.
    Ziegler, André
    Ekinci, Okan
    Giannitsis, Evangelos
    Stough, Wendy Gattis
    Achenbach, Stephan
    Blankenberg, Stefan
    Brueckmann, Martina
    Collinson, Paul
    Comaniciu, Dorin
    Crea, Filippo
    Dinh, Wilfried
    Ducrocq, Grégory
    Flachskampf, Frank A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Fox, Keith A A
    Friedrich, Matthias G
    Hebert, Kathy A
    Himmelmann, Anders
    Hlatky, Mark
    Lautsch, Dominik
    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, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Lindholm, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Mills, Nicholas L
    Minotti, Giorgio
    Möckel, Martin
    Omland, Torbjørn
    Semjonow, Véronique
    Early diagnosis of acute coronary syndrome2017In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 38, no 41, p. 3049-3055Article, review/survey (Refereed)
    Abstract [en]

    The diagnostic evaluation of acute chest pain has been augmented in recent years by advances in the sensitivity and precision of cardiac troponin assays, new biomarkers, improvements in imaging modalities, and release of new clinical decision algorithms. This progress has enabled physicians to diagnose or rule-out acute myocardial infarction earlier after the initial patient presentation, usually in emergency department settings, which may facilitate prompt initiation of evidence-based treatments, investigation of alternative diagnoses for chest pain, or discharge, and permit better utilization of healthcare resources. A non-trivial proportion of patients fall in an indeterminate category according to rule-out algorithms, and minimal evidence-based guidance exists for the optimal evaluation, monitoring, and treatment of these patients. The Cardiovascular Round Table of the ESC proposes approaches for the optimal application of early strategies in clinical practice to improve patient care following the review of recent advances in the early diagnosis of acute coronary syndrome. The following specific 'indeterminate' patient categories were considered: (i) patients with symptoms and high-sensitivity cardiac troponin <99th percentile; (ii) patients with symptoms and high-sensitivity troponin <99th percentile but above the limit of detection; (iii) patients with symptoms and high-sensitivity troponin >99th percentile but without dynamic change; and (iv) patients with symptoms and high-sensitivity troponin >99th percentile and dynamic change but without coronary plaque rupture/erosion/dissection. Definitive evidence is currently lacking to manage these patients whose early diagnosis is 'indeterminate' and these areas of uncertainty should be assigned a high priority for research.

  • 7.
    Lindholm, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Platelet Inhibition, Revascularization, and Risk Prediction in Non-ST-elevation Acute Coronary Syndromes2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Cardiovascular disease is the leading cause of death worldwide and ischemic heart disease is the most common manifestation. Despite improved outcomes during the last decades, patients with acute coronary syndromes (ACS) are still at substantial risk of recurrent ischemic events and mortality.

    The aims of this thesis were to investigate the effect of the novel antiplatelet agent ticagrelor versus clopidogrel in patients with non-ST-elevation ACS (NSTE-ACS), overall and in relation to initial revascularization, and to explore this effect in relation to cardiac biomarkers. The impact of timing of revascularization in non-ST-elevation myocardial infarction (NSTEMI) was also studied, by assessing risk of mortality and recurrent myocardial infarction in relation to delay of percutaneous coronary intervention (PCI) in a nation-wide cohort. Finally, a novel clinical prediction model based on angiographic findings, biomarkers, and clinical characteristics was developed to estimate risk of ischemic events after performed revascularization.

    Ticagrelor treatment compared with clopidogrel was associated with a reduction in the composite endpoint of cardiovascular death/myocardial infarction/stroke and mortality alone, without any increase in overall major bleeding, but increased non-CABG-related major bleeding. The effect of ticagrelor over clopidogrel was consistent independent of initial revascularization. Elevated high-sensitivity cardiac troponin-T predicted benefit of ticagrelor over clopidogrel, while no difference between treatments was detected at normal levels. In patients with NSTEMI, PCI treatment within two days after hospital admission was associated with lower risk of all-cause death and recurrent myocardial infarction compared with delayed PCI. The new clinical prediction model included the following variables: prior vascular disease, extent of coronary artery disease, level of N-terminal pro-B-type natriuretic peptide and estimated glomerular filtration rate; and showed good discriminatory ability for the risk prediction of cardiovascular death/myocardial infarction/stroke and cardiovascular death alone.

    In conclusion, these results show that ticagrelor reduces the risk of recurrent ischemic events and mortality in patients with NSTE-ACS when compared with clopidogrel, and this effect seems independent of performed revascularization. The results also indicate that biomarkers could be used to select patients who would benefit most from more intense platelet inhibition. Furthermore, early PCI in NSTEMI seems to be associated with improved outcome. Finally, the novel clinical prediction model based only on four variables showed good discriminatory ability, which makes it a potentially effective and simple tool for tailored treatment based on individual risk of recurrent events.

    List of papers
    1. Ticagrelor vs. clopidogrel in patients with non-ST-elevation acute coronary syndrome with or without revascularization: results from the PLATO trial
    Open this publication in new window or tab >>Ticagrelor vs. clopidogrel in patients with non-ST-elevation acute coronary syndrome with or without revascularization: results from the PLATO trial
    Show others...
    2014 (English)In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 35, no 31, p. 2083-2093Article in journal (Refereed) Published
    Abstract [en]

    Aims The optimal platelet inhibition strategy for ACS patients managed without revascularization is unknown. We aimed to evaluate efficacy and safety of ticagrelor vs. clopidogrel in the non-ST-elevation acute coronary syndrome (NSTE-ACS) subgroup of the PLATO trial, in the total cohort, and in the subgroups managed with and without revascularization within 10 days of randomization. Methods and results We performed a retrospective analysis of the primary endpoint of cardiovascular death/myocardial infarction/stroke. Among 18 624 PLATO patients, 11 080 (59%) were categorized as NSTE-ACS at randomization. During the initial 10 days, 74% had angiography, 46% PCI, and 5% CABG. In NSTE-ACS patients, the primary endpoint was reduced with ticagrelor vs. clopidogrel [10.0 vs. 12.3%; hazard ratio (HR) 0.83; 95% confidence interval (CI) = 0.74-0.93], as was myocardial infarction (6.6 vs. 7.7%; HR 0.86; 95% CI = 0.74-0.99), cardiovascular death (3.7 vs. 4.9%; HR 0.77; 95% CI = 0.64-0.93), and all-cause death (4.3 vs. 5.8%; HR 0.76; 95% CI = 0.64-0.90). Major bleeding rate was similar between treatment groups (13.4 vs. 12.6%; HR 1.07; 95% CI = 0.95-1.19), but ticagrelor was associated with an increase in non-CABG major bleeding (4.8 vs. 3.8%; HR 1.28; 95% CI = 1.05-1.56). Within the first 10 days, 5366 (48.4%) patients were managed without revascularization. Regardless of revascularization or not, ticagrelor consistently reduced the primary outcome (HR 0.86 vs. 0.85, interaction P = 0.93), and all-cause death (HR 0.75 vs. 0.73, interaction P = 0.89) with no significant increase in overall major bleeding. Conclusion In patients with NSTE-ACS, benefit of ticagrelor over clopidogrel in reducing ischaemic events and total mortality was consistent with the overall PLATO trial, independent of actually performed revascularization during the initial 10 days.

    Keywords
    Platelet inhibition, Acute coronary syndrome
    National Category
    Cardiac and Cardiovascular Systems
    Identifiers
    urn:nbn:se:uu:diva-235190 (URN)10.1093/eurheartj/ehu160 (DOI)000342232600013 ()24727884 (PubMedID)
    Available from: 2014-10-30 Created: 2014-10-29 Last updated: 2017-12-05Bibliographically approved
    2. Biomarkers in Relation to the Effects of Ticagrelor in Comparison With Clopidogrel in Non-ST-Elevation Acute Coronary Syndrome Patients Managed With or Without In-Hospital Revascularization A Substudy From the Prospective Randomized Platelet Inhibition and Patient Outcomes (PLATO) Trial
    Open this publication in new window or tab >>Biomarkers in Relation to the Effects of Ticagrelor in Comparison With Clopidogrel in Non-ST-Elevation Acute Coronary Syndrome Patients Managed With or Without In-Hospital Revascularization A Substudy From the Prospective Randomized Platelet Inhibition and Patient Outcomes (PLATO) Trial
    Show others...
    2014 (English)In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 129, no 3, p. 293-303Article in journal (Refereed) Published
    Abstract [en]

    Background Risk stratification and the use of specific biomarkers have been proposed for tailoring treatment in patients with non-ST-elevation acute coronary syndrome (NSTE-ACS). We investigated the prognostic importance of high-sensitivity troponin T (hs-TnT), N-terminal pro-brain natriuretic peptide (NT-proBNP), and growth differentiation factor-15 (GDF-15) in relation to randomized treatment (ticagrelor versus clopidogrel) and management strategy (with or without revascularization) in the NSTE-ACS subgroup of the Platelet Inhibition and Patient Outcomes (PLATO) trial. Methods and Results Of 18 624 patients in the PLATO trial, 9946 had an entry diagnosis of NSTE-ACS and baseline blood samples available. During index hospitalization, 5357 were revascularized, and 4589 were managed without revascularization. Hs-TnT, NT-proBNP, and GDF-15 were determined and assessed according to predefined cutoff levels. Median follow-up was 9.1 months. Increasing levels of hs-TnT were associated with increasing risk of cardiovascular death, myocardial infarction, and stroke in medically managed patients (P<0.001), but not in those managed invasively. NT-proBNP and GDF-15 levels were associated with the same events independent of management strategy. Ticagrelor versus clopidogrel reduced the rate of cardiovascular death, myocardial infarction, and stroke in patients with NSTE-ACS and hs-TnT 14.0 ng/L in both invasively and noninvasively managed patients; in patients with hs-TnT <14.0 ng/L, there was no difference between ticagrelor and clopidogrel in the noninvasive group Conclusions Hs-TnT, NT-proBNP, and GDF-15 are predictors of cardiovascular death, myocardial infarction, and stroke in patients with NSTE-ACS managed noninvasively, and NT-proBNP and GDF-15 also in those managed invasively. Elevated hs-TnT predicts substantial benefit of ticagrelor over clopidogrel both in invasively and noninvasively managed patients, but no apparent benefit was seen at normal hs-TnT. Clinical Trial Registration URL:http://www.clinicaltrials.gov. Unique identifier: NCT00391872.

    Keywords
    acute coronary syndrome, biological markers, blood platelets, myocardial infarction, troponin
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-219196 (URN)10.1161/CIRCULATIONAHA.113.004420 (DOI)000329880700006 ()
    Available from: 2014-02-25 Created: 2014-02-24 Last updated: 2017-12-05Bibliographically approved
    3. Timing of percutaneous coronary intervention in patients with non-ST-elevation myocardial infarction: a SWEDEHEART study
    Open this publication in new window or tab >>Timing of percutaneous coronary intervention in patients with non-ST-elevation myocardial infarction: a SWEDEHEART study
    Show others...
    2017 (English)In: European Heart Journal - Quality of Care and Clinical Outcomes, ISSN 2058-5225, E-ISSN 2058-1742, Vol. 3, no 1, p. 53-60Article in journal (Refereed) Published
    Abstract [en]

    Aims

    Although routine invasive management is recommended in NSTEMI patients, the optimal timing of the procedure is not defined. The aim of this study was to assess outcomes in relation to timing of PCI in NSTEMI patients.

    Methods and results

    This was an observational, prospective, multicentre cohort study from the SWEDEHEART registry including all Swedish PCI centres. We included 40 494 consecutive PCI-treated patients who were admitted to any coronary care unit from 2006 to 2013. The primary outcome was all-cause death, and secondary outcomes were recurrent myocardial infarction (MI), stent thrombosis, and severe in-hospital bleeding. Outcomes were assessed within 1 year from admission in relation to pre-specified cut-offs to define early PCI: within 1, 2, or 3 days. Patients who received delayed PCI, compared with those who did not, were older, and had a higher prevalence of comorbidities (hypertension, hyperlipidaemia, diabetes, and prior stroke) but showed similar angiographic findings. Cox mixed-effects models showed a lower risk of all-cause death with early PCI across all three cut-offs: HR (95% CI) of 0.88 (0.80–0.98), 0.78 (0.71–0.86), and 0.75 (0.68–0.84), for the 1-, 2-, and 3-day cut-offs, respectively. Early PCI was associated with lower risk of recurrent MI for the 2- and 3-day cut-offs, but not for the 1-day cut-off. The reported rates of severe in-hospital bleeding were low, but tended to be higher in patients receiving delayed PCI.

    Conclusion

    In patients undergoing PCI for NSTEMI, early invasive treatment is associated with lower risk of ischaemic outcomes.

    Place, publisher, year, edition, pages
    Oxford University Press, 2017
    Keywords
    cardiology, acute coronary syndromes, non-st-elevation myocardial infarction, percutaneous coronary intervention, timing
    National Category
    Cardiac and Cardiovascular Systems
    Identifiers
    urn:nbn:se:uu:diva-265012 (URN)10.1093/ehjqcco/qcw044 (DOI)000422956400009 ()28927193 (PubMedID)
    Available from: 2015-10-20 Created: 2015-10-20 Last updated: 2018-03-08Bibliographically approved
    4. Development of a novel biomarker-based clinical prediction model for major adverse cardiovascular events in revascularized patients with acute coronary syndromes
    Open this publication in new window or tab >>Development of a novel biomarker-based clinical prediction model for major adverse cardiovascular events in revascularized patients with acute coronary syndromes
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Keywords
    acute coronary syndromes, risk prediction, biomarkers
    National Category
    Cardiac and Cardiovascular Systems
    Research subject
    Cardiology
    Identifiers
    urn:nbn:se:uu:diva-265014 (URN)
    Available from: 2015-10-20 Created: 2015-10-20 Last updated: 2016-01-13
  • 8.
    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.
    Alfredsson, Joakim
    Linkoping Univ, Dept Cardiol, Linkoping, Sweden; Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden.
    Angerås, Oskar
    Sahlgrens Univ Hosp, Dept Cardiol, Gothenburg, Sweden.
    Böhm, Felix
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Div Cardiol, Stockholm, Sweden.
    Calais, Fredrik
    Orebro Univ, Dept Cardiol, Fac Hlth, Orebro, Sweden.
    Koul, Sasha
    Lund Univ, Dept Cardiol, Clin Sci, Lund, Sweden.
    Lagerqvist, Bo
    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.
    Renlund, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Sarno, Giovanna
    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.
    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.
    Timing of percutaneous coronary intervention in patients with non-ST-elevation myocardial infarction: a SWEDEHEART study2017In: European Heart Journal - Quality of Care and Clinical Outcomes, ISSN 2058-5225, E-ISSN 2058-1742, Vol. 3, no 1, p. 53-60Article in journal (Refereed)
    Abstract [en]

    Aims

    Although routine invasive management is recommended in NSTEMI patients, the optimal timing of the procedure is not defined. The aim of this study was to assess outcomes in relation to timing of PCI in NSTEMI patients.

    Methods and results

    This was an observational, prospective, multicentre cohort study from the SWEDEHEART registry including all Swedish PCI centres. We included 40 494 consecutive PCI-treated patients who were admitted to any coronary care unit from 2006 to 2013. The primary outcome was all-cause death, and secondary outcomes were recurrent myocardial infarction (MI), stent thrombosis, and severe in-hospital bleeding. Outcomes were assessed within 1 year from admission in relation to pre-specified cut-offs to define early PCI: within 1, 2, or 3 days. Patients who received delayed PCI, compared with those who did not, were older, and had a higher prevalence of comorbidities (hypertension, hyperlipidaemia, diabetes, and prior stroke) but showed similar angiographic findings. Cox mixed-effects models showed a lower risk of all-cause death with early PCI across all three cut-offs: HR (95% CI) of 0.88 (0.80–0.98), 0.78 (0.71–0.86), and 0.75 (0.68–0.84), for the 1-, 2-, and 3-day cut-offs, respectively. Early PCI was associated with lower risk of recurrent MI for the 2- and 3-day cut-offs, but not for the 1-day cut-off. The reported rates of severe in-hospital bleeding were low, but tended to be higher in patients receiving delayed PCI.

    Conclusion

    In patients undergoing PCI for NSTEMI, early invasive treatment is associated with lower risk of ischaemic outcomes.

  • 9.
    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.
    Fukaya, Eri
    Leeper, Nicholas J
    Ingelsson, Erik
    Bioimpedance and New-Onset Heart Failure: A Longitudinal Study of >500 000 Individuals From the General Population.2018In: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, ISSN 2047-9980, E-ISSN 2047-9980, Vol. 7, no 13, article id e008970Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Heart failure constitutes a high burden on patients and society, but although lifetime risk is high, it is difficult to predict without costly or invasive testing. We aimed to establish new risk factors of heart failure, which potentially could enable early diagnosis and preemptive treatment.

    METHODS AND RESULTS: We applied machine learning in the UK Biobank in an agnostic search of risk factors for heart failure in 500 451 individuals, excluding individuals with prior heart failure. Novel factors were then subjected to several in-depth analyses, including multivariable Cox models of incident heart failure, and assessment of discrimination and calibration. Machine learning confirmed many known and putative risk factors for heart failure and identified several novel candidates. Mean reticulocyte volume appeared as one novel factor and leg bioimpedance another, the latter appearing as the most important new marker. Leg bioimpedance was lower in those who developed heart failure during an up to 9.8-year follow-up. When adjusting for known heart failure risk factors, leg bioimpedance was inversely related to heart failure (hazard ratio [95% confidence interval], 0.60 [0.48-0.73] and 0.75 [0.59-0.94], in age- and sex-adjusted and fully adjusted models, respectively, comparing the upper versus lower quartile). A model including leg bioimpedance, age, sex, and self-reported history of myocardial infarction showed good discrimination for future heart failure hospitalization (Concordance index [C-index]=0.82) and good calibration.

    CONCLUSIONS: Leg bioimpedance is inversely associated with heart failure incidence in the general population. A simple model of exclusively noninvasive measures, combining leg bioimpedance with history of myocardial infarction, age, and sex provides accurate predictive capacity.

  • 10.
    Lindholm, Daniel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Holzmann, Martin
    Karolinska University Hospital, Huddinge and Karolinska Institutet, Solna, Sweden.
    Machine Learning For Improved Detection Of Myocardial Infarction In Patients Presenting With Chest Pain In The Emergency Department2018In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 71, no 11, p. 225-225Article in journal (Other academic)
  • 11.
    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.
    James, Stefan K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Andersson, Jonas
    Heartcenter, Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
    Braun, Oscar Ö
    Department of Cardiology, Clinical Sciences, Faculty of Medicine, Lund University, Skåne University Hospital, Lund, Sweden.
    Heller, Susanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Henriksson, Peter
    Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden.
    Lauermann, Jörg
    Department of Internal Medicine, Division of Cardiology, Ryhov Hospital, Jönköping, Sweden.
    Öhagen, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Varenhorst, Christoph
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Pfizer, Stockholm, Sweden.
    Caffeine and incidence of dyspnea in patients treated with ticagrelor2018In: American Heart Journal, ISSN 0002-8703, E-ISSN 1097-6744, Vol. 200, p. 141-143Article in journal (Refereed)
  • 12.
    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.
    Lindback, Johan
    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, 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.
    Becker, R. C.
    Acad Med Ctr, Heart Lung & Vasc Inst, Div Cardiovasc Hlth & Dis, Cincinnati, OH USA..
    Himmelmann, A.
    AstraZeneca, Res & Dev, Molndal, Sweden..
    Siegbahn, Agneta
    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.
    Steg, P. G.
    INSERM, U1148, Paris, France. Univ Paris Diderot, Hop Bichat, AP HP, FIRE,NHLI Imperial Coll,INSERM,U1148, Paris, France..
    Katus, H. A.
    Univ Heidelberg Hosp, Med Klin, Heidelberg, Germany..
    Varenhorst, Christoph
    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.
    Biomarker-based prediction model for recurrent ischemic events in revascularised patients with acute coronary syndromes2015In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 36, no Suppl. 1, p. 10-11Article in journal (Other academic)
  • 13.
    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.
    Lindbäck, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Armstrong, Paul W.
    Budaj, Andrzej
    Cannon, Christopher P.
    Granger, Christopher B.
    Hagström, Emil
    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.
    Held, Claes
    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.
    Koenig, Wolfgang
    Östlund, Ollie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Stewart, Ralph A.H.
    Soffer, Joseph
    White, Harvey D.
    de Winter, Robbert J.
    Steg, Philippe Gabriel
    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.
    Kleber, Marcus E.
    Dressel, Alexander
    Grammer, Tanja B.
    März, Winfried
    Wallentin, Lars
    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.
    Biomarker-Based Risk Model to Predict Cardiovascular Mortality in Patients With Stable Coronary Disease2017In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 70, no 7, p. 813-826Article in journal (Refereed)
    Abstract [en]

    Background Currently, there is no generally accepted model to predict outcomes in stable coronary heart disease (CHD).Objectives This study evaluated and compared the prognostic value of biomarkers and clinical variables to develop a biomarker-based prediction model in patients with stable CHD.Methods In a prospective, randomized trial cohort of 13,164 patients with stable CHD, we analyzed several candidate biomarkers and clinical variables and used multivariable Cox regression to develop a clinical prediction model based on the most important markers. The primary outcome was cardiovascular (CV) death, but model performance was also explored for other key outcomes. It was internally bootstrap validated, and externally validated in 1,547 patients in another study.Results During a median follow-up of 3.7 years, there were 591 cases of CV death. The 3 most important biomarkers were N-terminal pro–B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-cTnT), and low-density lipoprotein cholesterol, where NT-proBNP and hs-cTnT had greater prognostic value than any other biomarker or clinical variable. The final prediction model included age (A), biomarkers (B) (NT-proBNP, hs-cTnT, and low-density lipoprotein cholesterol), and clinical variables (C) (smoking, diabetes mellitus, and peripheral arterial disease). This “ABC-CHD” model had high discriminatory ability for CV death (c-index 0.81 in derivation cohort, 0.78 in validation cohort), with adequate calibration in both cohorts.Conclusions This model provided a robust tool for the prediction of CV death in patients with stable CHD. As it is based on a small number of readily available biomarkers and clinical factors, it can be widely employed to complement clinical assessment and guide management based on CV risk. (The Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy Trial [STABILITY]; NCT00799903)

  • 14.
    Lindholm, Daniel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Lindbäck, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    James, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Becker, Richard C
    Cornel, Jan H
    Himmelmann, Anders
    Giannitsis, Evangelos
    Harrington, Robert A
    Held, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Husted, Steen
    Katus, Hugo A
    Mahaffey, Kenneth W
    Steg, Philippe Gabriel
    Storey, Robert F
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Varenhorst, Christoph
    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, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Development of a novel biomarker-based clinical prediction model for major adverse cardiovascular events in revascularized patients with acute coronary syndromesManuscript (preprint) (Other academic)
  • 15.
    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.
    Lindbäck, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    James, Stefan
    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.
    Becker, Richard
    Cornel, Jan
    Himmelmann, Anders
    Giannitsis, Evangelos
    Harrington, Robert
    Held, Claes
    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 Public Health and Caring Sciences, Clinical Psychology in Healthcare.
    Husted, Steen
    Katus, Hugo
    Mahaffey, Kenneth
    Steg, Philippe Gabriel
    Storey, Robert
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Varenhorst, Christoph
    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.
    Prediction Of Major Bleeding In Revascularized Patients With Acute Coronary Syndromes: Development Of A Novel Biomarker-Based Clinical Prediction Model2016In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 67, no 13, p. 493-493Article in journal (Other academic)
  • 16.
    Lindholm, Daniel P
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Granberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Response to temozolomide and bevacizumab in a patient with poorly differentiated neuroendocrine carcinoma2012In: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 29, no 1, p. 301-303Article in journal (Refereed)
    Abstract [en]

    Poorly differentiated endocrine carcinomas (PDEC) are usually treated with cisplatin-based chemotherapy regimens. We here present a case with a dramatic response (both radiologically and biochemically) to the combination of temozolomide and bevacizumab, after failure of cisplatin and etoposide, with continued tumor shrinkage at 5 months. Temozolomide combined with bevacizumab might be a good treatment option in PDEC, perhaps even in a first-line setting. Prospective studies to answer this are warranted.

  • 17.
    Lindholm, Daniel P
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Hagström, Emil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    James, Stefan K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Becker, Richard C
    Cannon, Christopher P
    Himmelmann, Anders
    Katus, Hugo A
    Maurer, Gerald
    López-Sendón, José Luis
    Steg, Philippe Gabriel
    Storey, Robert F
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry. 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, Cardiology.
    Growth Differentiation Factor 15 at 1 Month After an Acute Coronary Syndrome Is Associated With Increased Risk of Major Bleeding.2017In: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, ISSN 2047-9980, E-ISSN 2047-9980, Vol. 6, no 4, article id e005580Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Growth differentiation factor-15 (GDF-15) is related to major bleeding when measured at initial presentation in patients with acute coronary syndromes (ACSs) treated with dual antiplatelet therapy. It is unknown whether follow-up measurements provide additional information. The objective of this study was to investigate whether GDF-15 measured 1 month after an ACS provides additional information beyond the baseline levels with regard to the risk of major bleeding.

    METHODS AND RESULTS: GDF-15 was measured at baseline and at 1 month after an ACS in 4049 patients included in the PLATelet inhibition and patient Outcomes (PLATO) trial. The association between 1-month GDF-15 level and non-coronary artery bypass grafting surgery-related major bleeding was assessed by a multivariable Cox model, adjusting for baseline GDF-15, age, anemia, impaired renal function, history of gastrointestinal bleeding, and sex. Elevated GDF-15 (>1800 ng/L) at 1 month was associated with an increased risk of non-coronary artery bypass grafting-related major bleeding (3.9% versus 1.2%; hazard ratio, 3.38; 95% CI, 1.89-6.06), independent of baseline GDF-15. Patients who had elevated GDF-15 levels at baseline and subsequent nonelevated GDF-15 at 1 month had a similar risk as patients who had nonelevated levels at both measurements.

    CONCLUSIONS: GDF-15 at 1 month after an ACS is related to the risk of bleeding during DAPT and provides additional information on the bleeding risk beyond baseline GDF-15 levels. GDF-15 levels may therefore be useful as part of decision support concerning long-term antithrombotic treatment in patients post-ACS.

    CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00391872.

  • 18.
    Lindholm, Daniel P
    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.
    James, Stefan K
    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.
    Bertilsson, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Becker, Richard C
    Cannon, Christopher P
    Giannitsis, Evangelos
    Harrington, Robert A
    Himmelmann, Anders
    Kontny, Frederic
    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.
    Steg, Philippe Gabriel
    Storey, Robert F
    Velders, Matthijs A
    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.
    Weaver, W Douglas
    Wallentin, Lars
    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.
    Biomarkers and Coronary Lesions Predict Outcomes after Revascularization in Non-ST-Elevation Acute Coronary Syndrome2017In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 63, no 2, p. 573-584Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Risk stratification in non-ST-elevation acute coronary syndrome (NSTE-ACS) is currently mainly based on clinical characteristics. With routine invasive management, angiography findings and biomarkers are available and may improve prognostication. We aimed to assess if adding biomarkers [high-sensitivity cardiac troponin T (cTnT-hs), N-terminal probrain-type natriuretic peptide (NT-proBNP), growth differentiation factor 15 (GDF-15)] and extent of coronary artery disease (CAD) might improve prognostication in revascularized patients with NSTE-ACS.

    METHODS: In the PLATO (Platelet Inhibition and Patient Outcomes) trial, 5174 NSTE-ACS patients underwent initial angiography and revascularization and had cTnT-hs, NT-proBNP, and GDF-15 measured. Cox models were developed adding extent of CAD and biomarker levels to established clinical risk variables for the composite of cardiovascular death (CVD)/spontaneous myocardial infarction (MI), and CVD alone. Models were compared using c-statistic and net reclassification improvement (NRI).

    RESULTS: For the composite end point and CVD, prognostication improved when adding extent of CAD, NT-proBNP, and GDF-15 to clinical variables (c-statistic 0.685 and 0.805, respectively, for full model vs 0.649 and 0.760 for clinical model). cTnT-hs did not contribute to prognostication. In the full model (clinical variables, extent of CAD, all biomarkers), hazard ratios (95% CI) per standard deviation increase were for cTnT-hs 0.93(0.81-1.05), NT-proBNP 1.32(1.13-1.53), GDF-15 1.20(1.07-1.36) for the composite end point, driven by prediction of CVD by NT-proBNP and GDF-15. For spontaneous MI, there was an association with NT-proBNP or GDF-15, but not with cTnT-hs.

    CONCLUSIONS: In revascularized patients with NSTE-ACS, the extent of CAD and concentrations of NT-proBNP and GDF-15 independently improve prognostication of CVD/spontaneous MI and CVD alone. This information may be useful for selection of patients who might benefit from more intense and/or prolonged antithrombotic treatment.

  • 19.
    Lindholm, Daniel P
    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.
    James, Stefan K
    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.
    Gabrysch, Katja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Storey, Robert F
    Department of Cardiovascular Science, University of Sheffield, Sheffield, United Kingdom.
    Himmelmann, Anders
    AstraZeneca Research and Development, Mölndal, Sweden.
    Cannon, Christopher P
    Cardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts, USA; Baim Clinical Research Institute, Boston, Massachusetts, USA.
    Mahaffey, Kenneth W
    Stanford Center for Clinical Research, Stanford School of Medicine, Stanford, California, USA.
    Steg, Philippe Gabriel
    Assistance Publique-Hôpitaux de Paris; Département Hospitalo-Universitaire FIRE, Hôpital Bichat, Paris, France; Université Paris-Diderot, Sorbonne-Paris Cité, Paris, France; NHLI Imperial College, ICMS, Royal Brompton Hospital, London, United Kingdom.
    Held, Claes
    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.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry. 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, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Association of Multiple Biomarkers With Risk of All-Cause and Cause-Specific Mortality After Acute Coronary Syndromes: A Secondary Analysis of the PLATO Biomarker Study2018In: JAMA cardiology, ISSN 2380-6583, E-ISSN 2380-6591, Vol. 3, no 12, p. 1160-1166Article in journal (Refereed)
    Abstract [en]

    Importance: Mortality remains at about 5% within a year after an acute coronary syndrome event. Prior studies have assessed biomarkers in relation to all-cause or cardiovascular deaths but not across multiple causes.

    Objective: To assess if different biomarkers provide information about the risk for all-cause and cause-specific mortality.

    Design, Setting, and Participants: The Platelet Inhibition and Patient Outcomes (PLATO) trial randomized 18 624 patients with acute coronary syndrome to ticagrelor or clopidogrel from October 2006 through July 2008. In this secondary analysis biomarker substudy, 17 095 patients participated.

    Main Outcomes and Measures: Death due to myocardial infarction, heart failure, sudden cardiac death/arrhythmia, bleeding, procedures, other vascular causes, and nonvascular causes, as well as all-cause death.

    Exposures: At baseline, levels of cystatin-C, growth differentiation factor-15 (GDF-15), high-sensitivity C-reactive protein, high-sensitivity troponin I and T, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were determined.

    Results: The median (interquartile range) age of patients was 62.0 (54.0-71.0) years. Of 17 095 patients, 782 (4.6%) died during follow-up. The continuous associations between biomarkers and all-cause and cause-specific mortality were modeled using Cox models and presented as hazard ratio (HR) comparing the upper vs lower quartile. For all-cause mortality, NT-proBNP and GDF-15 were the strongest markers with adjusted HRs of 2.96 (95% CI, 2.33-3.76) and 2.65 (95% CI, 2.17-3.24), respectively. Concerning death due to heart failure, NT-proBNP was associated with an 8-fold and C-reactive protein, GDF-15, and cystatin-C, with a 3-fold increase in risk. Regarding sudden cardiac death/arrhythmia, NT-proBNP was associated with a 4-fold increased risk and GDF-15 with a doubling in risk. Growth differentiation factor-15 had the strongest associations with other vascular and nonvascular deaths and was possibly associated with death due to major bleeding (HR, 4.91; 95% CI, 1.39-17.43).

    Conclusions and Relevance: In patients with acute coronary syndrome, baseline levels of NT-proBNP and GDF-15 were strong markers associated with all-cause death based on their associations with death due to heart failure as well as due to arrhythmia and sudden cardiac death. Growth differentiation factor-15 had the strongest associations with death due to other vascular or nonvascular causes and possibly with death due to bleeding.

    Trial Registration: ClinicalTrials.gov Identifier: NCT00391872.

  • 20.
    Lindholm, Daniel P
    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.
    James, Stefan K
    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.
    Lagerqvist, Bo
    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.
    Hlatky, Mark A
    Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA.
    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.
    New Method for Assessing the Effect of Driving Distance to Hospital Care: Using OpenStreetMap Routing in Cardiovascular Research2017In: Circulation. Cardiovascular Quality and Outcomes, ISSN 1941-7713, E-ISSN 1941-7705, Vol. 10, no 9, article id e003850Article in journal (Refereed)
  • 21.
    Lindholm, Daniel P
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Biomarkers and molecular imaging in gastroenteropancreatic neuroendocrine tumors2011In: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 43, no 12, p. 832-837Article, review/survey (Refereed)
    Abstract [en]

    Neuroendocrine gastrointestinal and pancreatic tumors (GEP-NETs) are a heterogenous group of cancers with various clinical expressions. All tumors produce and secret various amines and peptides, which can be used as tissue and circulating markers. Chromogranin A (CgA) is a general tumor marker stored in secretory granules within the tumor cell and released upon stimulation. CgA is the best general tumor marker at the moment, expressed in 80-90% in all patients with GEP-NETs. CgA and NSE are used as tissue markers for the delineation of the neuroendocrine features of the tumors, but recently also the proliferation marker Ki-67 has been included in the standard procedure for evaluation of the proliferation. GEP-NETs are classified into well differentiated neuroendocrine tumors (Ki-67<2%), well-differentiated neuroendocrine carcinoma (Ki-67 2-20%), poorly differentiated neuroendocrine carcinoma (Ki-67>20%). The molecular imaging of NETs is based on the ability of these tumor cells to express somatostatin receptors as well as the APUD features. Octreoscan has been applied for imaging and staging of the disease for more than 2 decades and will nowadays be replaced by 68Ga-DOTA-Octreotate, with higher specificity and sensitivity. 18Fluoro-DOPA and 11C-5HTP are specific tracers for NETs with high specificity and selectivity. A new potential biomarker is auto-antibodies to paraneoplastic antigen MA2, which might indicate early recurrence of carcinoids after surgery with a curative intent. Circulating tumor cells (CTC) have been applied in GEP-NETs quite recently. There is still an unmet need for new markers.

  • 22.
    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.

  • 23.
    Lindholm, Daniel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Varenhorst, Christoph
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Cannon, Christopher
    Harrington, Robert
    Himmelmann, Anders
    Maya, Juan
    Husted, Steen
    Katus, Hugo
    Steg, Philippe
    Storey, Robert
    Wallentin, Lars
    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.
    Ticagrelor versus clopidogrel in patients with non-st-elevation acute coronary syndrome: results from the PLATO trial2013In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 61, no 10, p. E1-E1Article in journal (Other academic)
  • 24.
    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.
    Varenhorst, Christoph
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Cannon, Christopher P.
    Harrington, Robert A.
    Himmelmann, Anders
    Maya, Juan
    Husted, Steen
    Steg, Philippe Gabriel
    Cornel, Jan H.
    Storey, Robert F.
    Stevens, Susanna R.
    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.
    James, Stefan K.
    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.
    Ticagrelor vs. clopidogrel in patients with non-ST-elevation acute coronary syndrome with or without revascularization: results from the PLATO trial2014In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 35, no 31, p. 2083-2093Article in journal (Refereed)
    Abstract [en]

    Aims The optimal platelet inhibition strategy for ACS patients managed without revascularization is unknown. We aimed to evaluate efficacy and safety of ticagrelor vs. clopidogrel in the non-ST-elevation acute coronary syndrome (NSTE-ACS) subgroup of the PLATO trial, in the total cohort, and in the subgroups managed with and without revascularization within 10 days of randomization. Methods and results We performed a retrospective analysis of the primary endpoint of cardiovascular death/myocardial infarction/stroke. Among 18 624 PLATO patients, 11 080 (59%) were categorized as NSTE-ACS at randomization. During the initial 10 days, 74% had angiography, 46% PCI, and 5% CABG. In NSTE-ACS patients, the primary endpoint was reduced with ticagrelor vs. clopidogrel [10.0 vs. 12.3%; hazard ratio (HR) 0.83; 95% confidence interval (CI) = 0.74-0.93], as was myocardial infarction (6.6 vs. 7.7%; HR 0.86; 95% CI = 0.74-0.99), cardiovascular death (3.7 vs. 4.9%; HR 0.77; 95% CI = 0.64-0.93), and all-cause death (4.3 vs. 5.8%; HR 0.76; 95% CI = 0.64-0.90). Major bleeding rate was similar between treatment groups (13.4 vs. 12.6%; HR 1.07; 95% CI = 0.95-1.19), but ticagrelor was associated with an increase in non-CABG major bleeding (4.8 vs. 3.8%; HR 1.28; 95% CI = 1.05-1.56). Within the first 10 days, 5366 (48.4%) patients were managed without revascularization. Regardless of revascularization or not, ticagrelor consistently reduced the primary outcome (HR 0.86 vs. 0.85, interaction P = 0.93), and all-cause death (HR 0.75 vs. 0.73, interaction P = 0.89) with no significant increase in overall major bleeding. Conclusion In patients with NSTE-ACS, benefit of ticagrelor over clopidogrel in reducing ischaemic events and total mortality was consistent with the overall PLATO trial, independent of actually performed revascularization during the initial 10 days.

  • 25.
    Patel, Riyaz S.
    et al.
    UCL, Inst Cardiovasc Sci, Fac Populat Hlth Sci, London, England;St Bartholomews Hosp, Barts Heart Ctr, London, England.
    Schmidt, Amand F.
    UCL, Inst Cardiovasc Sci, Fac Populat Hlth Sci, London, England;UMC, Dept Cardiol, Div Heart & Lungs, Utrecht, Netherlands.
    Tragante, Vinicius
    UMC, Dept Cardiol, Div Heart & Lungs, Utrecht, Netherlands.
    McCubrey, Raymond O.
    Intertermt Med Ctr, Intermt Heart Inst, Salt Lake City, UT USA.
    Holmes, Michael, V
    Univ Oxford, Clin Trial Serv Unit, Nuffield Dept Populat Hlth, Oxford, England;Univ Oxford, Epidemiol Studies Unit, Nuffield Dept Populat Hlth, Oxford, England;Univ Oxford, Med Res Council Populat Hlth Res Unit, Oxford, England;Univ Oxford, Natl Inst Hlth Res, Oxford Biomed Res Ctr, Oxford, England.
    Howe, Laurence J.
    UCL, Inst Cardiovasc Sci, Fac Populat Hlth Sci, London, England.
    Direk, Kenan
    UCL, Inst Cardiovasc Sci, Fac Populat Hlth Sci, London, England.
    Åkerblom, Axel
    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.
    Leander, Karin
    Karolinska Inst, Inst Environm Med, Stockholm, Sweden.
    Virani, Salim S.
    Baylor Coll Med, Sect Cardiovasc Res, Michael & DeBakey Vet Affairs Med Ctr, Sect Cardiol, Houston, TX 77030 USA;Baylor Coll Med, Dept Med, Sect Cardiol, Houston, TX 77030 USA.
    Kaminski, Karol A.
    Med Univ Bialystok, Dept Populat Med & Civilizat Dis Prevent, Bialystok, Poland;Med Univ Bialystok, Dept Cardiol, Bialystok, Poland.
    Muehlschlegel, Jochen D.
    UCL, Inst Cardiovasc Sci, Fac Populat Hlth Sci, London, England;St Bartholomews Hosp, Barts Heart Ctr, London, England;Harvard Med Sch, 75 Francis St, Boston, MA 02115 USA.
    Dube, Marie-Pierre
    Univ Montreal, Fac Med, Montreal, PQ, Canada.
    Allayee, Hooman
    USC, Dept Prevent Med, Los Angeles, CA USA;USC, Dept Biochem & Mol Med, Los Angeles, CA USA.
    Almgren, Peter
    Lund Univ, Dept Clin Sci, Malmo, Sweden.
    Alver, Maris
    Univ Tartu, Inst Mol & Cell Biol, Dept Biotechnol, Tartu, Estonia.
    Baranova, Ekaterina, V
    Univ Med Ctr, Div Pharmacoepidemiol & Clin Pharmacol, Utrecht, Netherlands.
    Behlouli, Hassan
    McGill Univ Hlth Ctr, Res Inst, Montreal, PQ, Canada;German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany.
    Boeckx, Bram
    Katholieke Univ Leuven, Dept Human Genet, Lab Translat Genet, Leuven, Belgium;VIB, VIB Ctr Canc Biol, Lab Translat Genet, Ghent, Belgium.
    Braund, Peter S.
    Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England;Univ Leicester, Dept Hlth Sci, Leicester, Leics, England;Glenfield Hosp, NIHR, Leicester, Leics, England.
    Breitling, Lutz P.
    McGill Univ Hlth Ctr, Res Inst, Montreal, PQ, Canada;German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany.
    Delgado, Graciela
    Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Mannheim, Germany.
    Duarte, Nubia E.
    Univ Sao Paulo, Heart Inst, Sao Paulo, Brazil.
    Dufresne, Line
    McGill Univ Hlth Ctr, Res Inst, Montreal, PQ, Canada;McGill Univ Hlth Ctr, Prevent & Genom Cardiol, Montreal, PQ, Canada.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Foco, Luisa
    Univ Lubeck, Affiliated Inst, Eurac Res, Inst Biomed, Bolzano, Italy.
    Gijsberts, Crystel M.
    UMC, Lab Expt Cardiol, Utrecht, Netherlands.
    Gong, Yan
    Univ Florida, Dept Pharmacotherapy & Translat Res, Gainesville, FL USA;Univ Florida, Ctr Pharmacogen, Gainesville, FL USA.
    Hartiala, Jaana
    USC, Dept Prevent Med, Los Angeles, CA USA;USC, Dept Biochem & Mol Med, Los Angeles, CA USA;USC, Keck Sch Med, Inst Genet Med, Los Angeles, CA USA.
    Heydarpour, Mahyar
    Brigham & Womens Hosp, Dept Anesthesiol Perioperat & Pain Med, 75 Francis St, Boston, MA 02115 USA;Harvard Med Sch, 75 Francis St, Boston, MA 02115 USA.
    Hubacek, Jaroslav A.
    Inst Clin & Expt Med, Ctr Expt Med, Prague, Czech Republic.
    Kleber, Marcus
    Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Mannheim, Germany.
    Kofink, Daniel
    UMC, Dept Cardiol, Div Heart & Lungs, Utrecht, Netherlands.
    Kuukasjarvi, Pekka
    Univ Tampere, Fac Med & Life Sci, Finnish Cardiovasc Res Ctr, Dept Cardiothorac Surg, Tampere, Finland.
    Lee, Vei-Vei
    Texas Heart Inst, Dept Biostat & Epidemiol, Houston, TX 77025 USA.
    Leiherer, Andreas
    VIVIT, Feldkirch, Austria;Private Univ Principal Liechtenstein, Triesen, Liechtenstein;Med Cent Labs, Feldkirch, Austria.
    Lenzini, Petra A.
    Washington Univ, Sch Med, Dept Genet, Stat Genom Div, St Louis, MO 63110 USA;Univ Sao Paulo, Hosp Univ, Ctr Pesquisa Clin, Sao Paulo, Brazil.
    Levin, Daniel
    Univ Dundee, Sch Med, Div Mol & Clin Med, Dundee, Scotland.
    Lyytikainen, Leo-Pekka
    Univ Tampere, Fac Med & Life Sci, Finnish Cardiovasc Res Ctr, Dept Clin Chem, Tampere, Finland;Fimlab Labs, Dept Clin Chem, Tampere, Finland.
    Martinelli, Nicola
    Univ Verona, Dept Med, Verona, Italy.
    Mons, Ute
    German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany.
    Nelson, Christopher P.
    Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England;Univ Leicester, Dept Hlth Sci, Leicester, Leics, England;Glenfield Hosp, NIHR, Leicester, Leics, England.
    Nikus, Kjell
    Univ Tampere, Fac Med & Life Sci, Finnish Cardiovasc Res Ctr, Dept Cardiol, Tampere, Finland;Tampere Univ Hosp, Dept Cardiol, Heart Ctr, Tampere, Finland.
    Pilbrow, Anna P.
    Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Sch Med, Atlanta, GA 30322 USA.
    Ploski, Rafal
    Med Univ Warsaw, Dept Med Genet, Warsaw, Poland.
    Sun, Yan, V
    Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Sch Med, Atlanta, GA 30322 USA;Emory Univ, Sch Med, Dept Biomed Informat, Atlanta, GA 30322 USA.
    Tanck, Michael W. T.
    Univ Utrecht, Dept Internal Med, Sect Gerontol & Geriatr, Utrecht, Netherlands.
    Tang, W. H. Wilson
    Cleveland Clin, Lerner Res Inst, Dept Cellular & Mol Med, Cleveland, OH 44106 USA;Cleveland Clin, Dept Cardiovasc Med, Heart & Vasc Inst & Ctr Microbiome & Human Hlth, Cleveland, OH 44106 USA.
    Trompet, Stella
    Univ Utrecht, Dept Internal Med, Sect Gerontol & Geriatr, Utrecht, Netherlands;Univ Utrecht, Dept Cardiol, Utrecht, Netherlands.
    van der Laan, Sander W.
    Univ Med Ctr, Div Pharmacoepidemiol & Clin Pharmacol, Utrecht, Netherlands;Univ Utrecht, Div Labs Pharm & Biomed Genet, Leiden Univ Med Ctr, Lab Clin Chem & Hematol, Utrecht, Netherlands.
    van Setten, Jessica
    ICIN Netherlands Heart Inst, Durrer Ctr Cardiogenet Res, Utrecht, Netherlands.
    Vilmundarson, Ragnar O.
    Ruddy Canadian Cardiovasc Genet Ctr, Ottawa, ON, Canada;Univ Ottawa, Dept Biochem Microbiol & Immunol, Ottawa, ON, Canada.
    Anselmi, Chiara Viviani
    Humanitas Clin & Res Ctr, Dept Cardiovasc Med, Milan, Italy.
    Vlachopoulou, Efthymia
    Univ Helsinki, Transplantat Lab, Med, Helsinki, Finland.
    Boerwinkle, Eric
    Univ Texas Houston, Sch Publ Hlth, Houston, TX USA.
    Briguori, Carlo
    Clin Mediterranea, Naples, Italy.
    Carlquist, John F.
    Intertermt Med Ctr, Intermt Heart Inst, Salt Lake City, UT USA;Univ Utah, Dept Internal Med, Cardiol Div, Salt Lake City, UT 84112 USA.
    Carruthers, Kathryn F.
    Univ Edinburgh, Cardiovasc Sci, Edinburgh, Midlothian, Scotland.
    Casu, Gavino
    ATS Sardegna, ASL 3, Nuoro, Italy.
    Deanfield, John
    INESSS, Unite Evaluat Cardiovasc, Montreal, PQ, Canada.
    Deloukas, Panos
    Barts & London Med Sch, William Harvey Res Inst, London, England;Queen Mary Univ London, Ctr Genom Hlth, London, England.
    Dudbridge, Frank
    BHF Cardiovasc Res Ctr, Leicester, Leics, England.
    Fitzpatrick, Natalie
    UCL, Inst Hlth Informat, Fac Populat Hlth Sci, London, England.
    Gigante, Bruna
    UMC, Dept Clin Chem & Hematol, Utrecht, Netherlands.
    James, Stefan
    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.
    Lokki, Marja-Liisa
    Univ Helsinki, Transplantat Lab, Med, Helsinki, Finland.
    Lotufo, Paulo A.
    Jagiellonian Univ, Med Coll, Dept Internal Med, Krakow, Poland.
    Marziliano, Nicola
    ATS Sardegna, ASL 3, Nuoro, Italy.
    Mordi, Ify R.
    Univ Dundee, Sch Med, Div Mol & Clin Med, Dundee, Scotland.
    Muhlestein, Joseph B.
    Univ Utah, Dept Internal Med, Cardiol Div, Salt Lake City, UT 84112 USA.
    Cheh, Chris Newton
    Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston & Program Med & Populat Genet, Brd Inst, Cambridge, MA USA;Massachusetts Gen Hosp, Ctr Human Genet Res, Boston & Program Med & Populat Genet, Brd Inst, Cambridge, MA USA.
    Pitha, Jan
    Inst Clin & Expt Med, Ctr Expt Med, Prague, Czech Republic.
    Saely, Christoph H.
    UCL, Inst Hlth Informat, Fac Populat Hlth Sci, London, England;VIVIT, Feldkirch, Austria;Private Univ Principal Liechtenstein, Triesen, Liechtenstein.
    Samman-Tahhan, Ayman
    Emory Univ, Sch Med, Dept Med, Emory Clin Cardiovasc Res Inst, Atlanta, GA USA.
    Sandesara, Pratik B.
    Emory Univ, Sch Med, Dept Med, Emory Clin Cardiovasc Res Inst, Atlanta, GA USA.
    Teren, Andrej
    Heart Ctr Leipzig, Acad Teaching Hosp Feldkirch, Dept Med & Cardiol, Leipzig, Germany;Univ Leipzig, LIFE Res Ctr Civilizat Dis, Leipzig, Germany.
    Timmis, Adam
    UCL, Inst Hlth Informat, Fac Populat Hlth Sci, London, England;St Bartholomews Hosp, Barts Heart Ctr, London, England.
    Van de Werf, Frans
    Katholieke Univ Leuven, Dept Cardiovasc Sci, Leuven, Belgium.
    Wauters, Els
    Katholieke Univ Leuven, Univ Hosp, Dept Resp Med, Resp Oncol Unit, Leuven, Belgium.
    Wilde, Arthur A. M.
    Princess Jawhara Brah Ctr Excellence Res Heredita, Jeddah, Saudi Arabia.
    Ford, Ian
    Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland.
    Stott, David J.
    Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland.
    Algra, Ale
    Univ Med Ctr, Dept Neurol & Neurosurg, Brain Ctr Rudolf Magnus, Utrecht, Netherlands;Univ Med Ctr, Dept Neurol & Neurosurg, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands.
    Andreassi, Maria G.
    CNR, Inst Clin Physiol, Pisa, Italy.
    Ardissino, Diego
    Parma Univ Hosp, Cardiol Dept, Parma, OH USA.
    Arsenault, Benoit J.
    Inst Univ cardiol & Pneumol Quebec, Ctr Rech, Quebec City, PQ, Canada;Univ Laval, Fac Med, Dept Med, Laval, PQ, Canada.
    Ballantyne, Christie M.
    Baylor Coll Med, Sect Cardiovasc Res, Michael & DeBakey Vet Affairs Med Ctr, Sect Cardiol, Houston, TX 77030 USA;Baylor Coll Med, Dept Med, Sect Cardiol, Houston, TX 77030 USA.
    Bergmeijer, Thomas O.
    St Antonius Hosp, Dept Cardiol, Nieuwegein, Netherlands.
    Bezzina, Connie R.
    Univ Amsterdam, Clin Epidemiol & Biostat, AMC Heart Ctr, Amsterdam, Netherlands.
    Body, Simon C.
    Harvard Med Sch, 75 Francis St, Boston, MA 02115 USA;Beth Israel Deaconess Med Ctr, Dept Anesthesia Pain & Crit Care, Boston, MA 02215 USA.
    Bogaty, Peter
    Inst Univ Cardiol & Pneumol Quebec, Dept Multidisciplinaire Cardiol, Serv Cardiol, Quebec City, PQ, Canada;INESSS, Unite Evaluat Cardiovasc, Montreal, PQ, Canada;Laval Univ, Inst Univ Cardiol & Pnemol Quebec, Quebec City, PQ, Canada.
    de Borst, Gert J.
    Univ Utrecht, Univ Med Ctr Utrecht, Dept Vasc Surg, Utrecht, Netherlands.
    Brenner, Hermann
    ICIN Netherlands Heart Inst, Durrer Ctr Cardiogenet Res, Utrecht, Netherlands.
    Burkhardt, Ralph
    Univ Leipzig, LIFE Res Ctr Civilizat Dis, Leipzig, Germany;Univ Hosp Regensburg, Inst Clin Chem & Lab Med, Regensburg, Germany.
    Carpeggiani, Clara
    CNR, Inst Clin Physiol, Pisa, Italy.
    Condorelli, Gianluigi
    Humanitas Clin & Res Ctr, Dept Cardiovasc Med, Milan, Italy;Humanitas Univ, Dept Biomed Sci, Milan, Italy.
    Cooper-DeHoff, Rhonda M.
    Univ Florida, Dept Pharmacotherapy & Translat Res, Gainesville, FL USA;Univ Florida, Ctr Pharmacogen, Gainesville, FL USA.
    Cresci, Sharon
    Washington Univ, Sch Med, Dept Genet, Stat Genom Div, St Louis, MO 63110 USA;Washington Univ, Sch Med, Dept Med, Cardiovasc Div, St Louis, MO 63110 USA.
    de Faire, Ulf
    Karolinska Inst, Inst Environm Med, Stockholm, Sweden.
    Doughty, Robert N.
    Univ Auckland, Heart Hlth Res Grp, Auckland, New Zealand.
    Drexel, Heinz
    VIVIT, Feldkirch, Austria;Private Univ Principal Liechtenstein, Triesen, Liechtenstein;Drexel Univ, Coll Med, Philadelphia, PA USA.
    Engert, James C.
    McGill Univ Hlth Ctr, Res Inst, Montreal, PQ, Canada;Royal Victoria Hosp, Dept Med, Div Cardiol, Montreal, PQ, Canada;McGill Univ Hlth Ctr, Prevent & Genom Cardiol, Montreal, PQ, Canada.
    Fox, Keith A. A.
    Univ Edinburgh, Cardiol, Edinburgh, Midlothian, Scotland.
    Girelli, Domenico
    Univ Verona, Dept Med, Verona, Italy.
    Hagström, Emil
    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.
    Hazen, Stanley L.
    Cleveland Clin, Lerner Res Inst, Dept Cellular & Mol Med, Cleveland, OH 44106 USA;Cleveland Clin, Dept Cardiovasc Med, Heart & Vasc Inst, Cleveland, OH 44106 USA;Cleveland Clin, Dept Cardiovasc Med, Ctr Microbiome & Human Hlth, Cleveland, OH 44106 USA.
    Held, Claes
    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.
    Hemingway, Harry
    UCL, Inst Hlth Informat, Fac Populat Hlth Sci, London, England.
    Hoefer, Imo E.
    UMC, Dept Clin Chem & Hematol, Utrecht, Netherlands.
    Hovingh, G. Kees
    Acad Med Ctr, Dept Vasc Med, Amsterdam, Netherlands.
    Johnson, Julie A.
    Univ Florida, Dept Pharmacotherapy & Translat Res, Gainesville, FL USA;Univ Florida, Ctr Pharmacogen, Gainesville, FL USA;Univ Florida, Coll Med, Div Cardiovasc Med, Gainesville, FL USA.
    De Jong, Pim A.
    Univ Med Ctr, Dept Radiol, Utrecht, Netherlands.
    Jukema, J. Wouter
    Univ Utrecht, Dept Cardiol, Utrecht, Netherlands;Inter Univ, Cardiol Inst Netherlands, Utrecht, Netherlands.
    Kaczor, Marcin P.
    Jagiellonian Univ, Med Coll, Dept Internal Med, Krakow, Poland.
    Kahonen, Mika
    Univ Tampere, Fac Med & Life Sci, Finnish Cardiovasc Res Ctr, Dept Clin Physiol, Tampere, Finland;Tampere Univ Hosp, Dept Clin Physiol, Tampere, Finland.
    Kettner, Jiri
    Inst Clin & Expt Med, Cardiol Ctr, Prague, Czech Republic.
    Kiliszek, Marek
    Mil Inst Med, Dept Cardiol & Internal Dis, Warsaw, Poland.
    Klungel, Olaf H.
    Univ Med Ctr, Div Pharmacoepidemiol & Clin Pharmacol, Utrecht, Netherlands.
    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.
    Lambrechts, Diether
    Katholieke Univ Leuven, Dept Human Genet, Lab Translat Genet, Leuven, Belgium.
    Laurikka, Jari O.
    Univ Tampere, Fac Med & Life Sci, Finnish Cardiovasc Res Ctr, Dept Cardiothorac Surg, Tampere, Finland;Tampere Univ Hosp, Heart Ctr, Dept Cardiothorac Surg, Tampere, Finland.
    Lehtimaki, Terho
    Univ Tampere, Fac Med & Life Sci, Finnish Cardiovasc Res Ctr, Dept Clin Chem, Tampere, Finland;Fimlab Labs, Dept Clin Chem, Tampere, Finland.
    Lindholm, Daniel
    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.
    Mahmoodi, Bakhtawar K.
    St Antonius Hosp, Dept Cardiol, Nieuwegein, Netherlands.
    Maitland-van der Zee, Anke H.
    Univ Med Ctr, Div Pharmacoepidemiol & Clin Pharmacol, Utrecht, Netherlands;Univ Amsterdam, Acad Med Ctr, Dept Resp Med, Clin & Expt Cardiol, Amsterdam, Netherlands.
    McPherson, Ruth
    Univ Ottawa Heart Inst, Ottawa, ON, Canada;Univ Ottawa, Dept Med, Ottawa, ON, Canada;Univ Ottawa, Dept Biochem, Ottawa, ON, Canada;Univ Ottawa, Dept Microbiol & Immunol, Ottawa, ON, Canada.
    Melander, Olle
    Lund Univ, Dept Clin Sci, Malmo, Sweden;Skane Univ Hosp, Dept Internal Med, Malmo, Sweden.
    Metspalu, Andres
    Univ Tartu, Estonian Genome Ctr, Inst Genom, Tartu, Estonia;Univ Tartu, Inst Mol & Cell Biol, Dept Biotechnol, Tartu, Estonia.
    Pepinski, Witold
    Med Univ Bialystok, Dept Forens Med, Bialystok, Poland.
    Olivieri, Oliviero
    Univ Verona, Dept Med, Verona, Italy.
    Opolski, Grzegorz
    Med Univ Warsaw, Dept Cardiol, Warsaw, Poland.
    Palmer, Colin N.
    Ninewells Hosp & Med Sch, Div Mol & Clin Med, Pat Macpherson Ctr Pharmacogenet & Pharmacogen, Dundee, Scotland.
    Pasterkamp, Gerard
    UMC, Dept Clin Chem, Utrecht, Netherlands.
    Pepine, Carl J.
    Univ Florida, Coll Med, Div Cardiovasc Med, Gainesville, FL USA.
    Pereira, Alexandre C.
    Univ Sao Paulo, Heart Inst, Sao Paulo, Brazil.
    Note, Louise
    Humanitas Univ, Dept Biomed Sci, Milan, Italy.
    Quyyumi, Arshed A.
    Emory Univ, Sch Med, Dept Med, Emory Clin Cardiovasc Res Inst, Atlanta, GA USA.
    Richards, A. Mark
    Univ Otago, Christchurch Heart Inst, Dunedin, New Zealand;Natl Univ Singapore, Cardiovasc Res Inst, Singapore, Singapore.
    Sanak, Marek
    Jagiellonian Univ, Med Coll, Dept Internal Med, Krakow, Poland.
    Scholz, Markus
    Univ Leipzig, LIFE Res Ctr Civilizat Dis, Leipzig, Germany;Univ Leipzig, Inst Med Informat Stat & Epidemiol, Leipzig, Germany.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Sinisalo, Juha
    Univ Helsinki, Helsinki Univ Hosp, Heart & Lung Ctr, Helsinki, Finland.
    Smith, J. Gustav
    Lund Univ, Dept Cardiol Clin Sci, Lund, Sweden;Skane Univ Hosp, Malmo, Sweden;Wallenberg Ctr Mol Med, Malmo, Sweden;Lund Univ, Lund Univ Diabet Ctr, Lund, Sweden.
    Spertus, John A.
    St Lukes Mid Amer Heart Inst, Kansas City, MO USA;Univ Missouri, St Lukes Hlth Syst, Kansas City, MO 64110 USA.
    Stewart, Alexandre F. R.
    Ruddy Canadian Cardiovasc Genet Ctr, Ottawa, ON, Canada;Univ Ottawa, Dept Biochem Microbiol & Immunol, Ottawa, ON, Canada.
    Szczeklik, Wojciech
    Jagiellonian Univ, Med Coll, Dept Internal Med, Krakow, Poland.
    Szpakowicz, Anna
    Med Univ Bialystok, Dept Cardiol, Bialystok, Poland.
    ten Berg, Jurrien M.
    Intertermt Med Ctr, Intermt Heart Inst, Salt Lake City, UT USA;St Antonius Hosp, Dept Cardiol, Nieuwegein, Netherlands.
    Thanassoulis, George
    Med Univ Bialystok, Dept Forens Med, Bialystok, Poland;Royal Victoria Hosp, Dept Med, Div Cardiol, Montreal, PQ, Canada;McGill Univ Hlth Ctr, Prevent & Genom Cardiol, Montreal, PQ, Canada.
    Thieiy, Joachim
    Univ Leipzig, LIFE Res Ctr Civilizat Dis, Leipzig, Germany;Univ Hosp, Clin Chem & Mol Diagnost, Inst Lab Med, Leipzig, Germany.
    van der Graaf, Yolanda
    Univ Med Ctr, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands.
    Visseren, Frank L. J.
    McGill Univ Hlth Ctr, Ctr Outcomes Res & Evaluat, Res Inst, Montreal, PQ, Canada.
    Waltenberger, Johannes
    Univ Munster, Dept Cardiovasc Med, Munster, Germany.
    Van der Harst, Pim
    Univ Groningen, Univ Med Ctr, Groningen, Netherlands.
    Tardif, Jean-Claude
    Univ Montreal, Montreal Heart Inst, Montreal, PQ, Canada;Univ Montreal, Fac Med, Montreal, PQ, Canada.
    Sattar, Naveed
    Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland.
    Lang, Chim C.
    Univ Dundee, Sch Med, Div Mol & Clin Med, Dundee, Scotland.
    Pare, Guillaume
    McMaster Univ, Dept Pathol & Mol Med, Hamilton, ON, Canada;Populat Hlth Res Inst, Hamilton, ON, Canada.
    Brophy, James M.
    McGill Univ Hlth Ctr, Res Inst, Montreal, PQ, Canada.
    Anderson, Jeffrey L.
    Intertermt Med Ctr, Intermt Heart Inst, Salt Lake City, UT USA;Univ Utah, Dept Internal Med, Cardiol Div, Salt Lake City, UT 84112 USA.
    Maerz, Winfried
    Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Mannheim, Germany;Synlab Holding Deutschland GmbH, Synlab Acad, Mannheim, Germany;Med Univ Graz, Clin Inst Med, Graz, Austria;Med Univ Graz, Chem Lab Diagnost, Graz, Austria.
    Wallentin, Lars
    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.
    Cameron, Vicky A.
    Univ Otago, Christchurch Heart Inst, Dunedin, New Zealand.
    Horne, Benjamin D.
    UMC, Lab Expt Cardiol, Utrecht, Netherlands;Univ Utah, Dept Biomed Informat, Salt Lake City, UT USA.
    Samani, Nilesh J.
    Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England;Univ Leicester, Dept Hlth Sci, Leicester, Leics, England.
    Hingorani, Aroon D.
    UCL, Inst Cardiovasc Sci, Fac Populat Hlth Sci, London, England.
    Asselbergs, Folkert W.
    UCL, Inst Cardiovasc Sci, Fac Populat Hlth Sci, London, England;UCL, Inst Hlth Informat, Fac Populat Hlth Sci, London, England;UMC, Dept Cardiol, Div Heart & Lungs, Utrecht, Netherlands.
    Association of Chromosome 9p21 With Subsequent Coronary Heart Disease Events: A GENIUS-CHD Study of Individual Participant Data2019In: Circulation: Genomic and Precision Medicine, ISSN 2574-8300, Vol. 12, no 4, article id e002471Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions about its value for stratification of residual risk.

    METHODS: A variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103 357 Europeans with established CHD at baseline from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/myocardial infarction), occurred in 13 040 of the 93 115 participants with available outcome data. Effect estimates were compared with case/control risk obtained from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) including 47 222 CHD cases and 122 264 controls free of CHD.

    RESULTS: Meta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline (GENIUSCHD odds ratio, 1.02; 95% CI, 0.99-1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D odds ratio 1.20; 95% CI, 1.18-1.22; P for interaction < 0.001 compared with the GENIUS-CHD estimate. Similarly, no clear associations were identified for additional subsequent outcomes, including all-cause death, although we found a modest positive association between chromosome 9p21 and subsequent revascularization (odds ratio, 1.07; 95% CI, 1.04-1.09).

    CONCLUSIONS: In contrast to studies comparing individuals with CHD to disease-free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development.

  • 26.
    Patel, Riyaz S.
    et al.
    UCL, Inst Cardiovasc Sci, Fac Populat Hlth Sci, London, England;St Bartholomews Hosp, Barts Heart Ctr, London, England.
    Tragante, Vinicius
    UMC Utrecht, Div Heart & Lungs, Dept Cardiol, Utrecht, Netherlands.
    Schmidt, Amand F.
    UCL, Inst Cardiovasc Sci, Fac Populat Hlth Sci, London, England;UMC Utrecht, Div Heart & Lungs, Dept Cardiol, Utrecht, Netherlands.
    McCubrey, Raymond O.
    Intermt Med Ctr, Intermt Heart Inst, Salt Lake City, UT USA.
    Holmes, Michael, V
    Univ Oxford, Nuffield Dept Populat Hlth, Med Res Council Populat Hlth Res Unit, Clin Trial Serv Unit, Oxford, England;Univ Oxford, Nuffield Dept Populat Hlth, Med Res Council Populat Hlth Res Unit, Epidemiol Studies Unit, Oxford, England;Oxford Univ Hosp, Natl Inst Hlth Res, Oxford Biomed Res Ctr, Oxford, England.
    Howe, Laurence J.
    UCL, Inst Cardiovasc Sci, Fac Populat Hlth Sci, London, England.
    Direk, Kenan
    UCL, Inst Cardiovasc Sci, Fac Populat Hlth Sci, London, England;UMC Utrecht, Div Heart & Lungs, Dept Cardiol, Utrecht, Netherlands.
    Åkerblom, Axel
    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.
    Leander, Karin
    Karolinska Inst, Inst Environm Med, Stockholm, Sweden.
    Virani, Salim S.
    Michael E DeBakey VA Med Ctr, Sect Cardiol, Houston, TX USA;Baylor Coll Med, Sect Cardiovasc Res, Dept Med, Houston, TX 77030 USA.
    Kaminski, Karol A.
    Med Univ Bialystok, Dept Populat Med & Civilizat Dis Prevent, Bialystok, Poland;Med Univ Bialystok, Dept Cardiol, Bialystok, Poland.
    Muehlschlegel, Jochen D.
    Brigham & Womens Hosp, Dept Anesthesiol Perioperat & Pain Med, 75 Francis St, Boston, MA 02115 USA;Harvard Med Sch, Boston, MA 02115 USA.
    Allayee, Hooman
    USC, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA;USC, Keck Sch Med, Dept Biochem, Los Angeles, CA USA;USC, Keck Sch Med, Dept Mol Med, Los Angeles, CA USA.
    Almgren, Peter
    Lund Univ, Dept Clin Sci, Malmo, Sweden.
    Alver, Maris
    Univ Tartu, Estonian Genome Ctr, Dept Biotechnol, Inst Genom,Inst Mol & Cell Biol, Tartu, Estonia.
    Baranova, Ekaterina, V
    Univ Utrecht, Div Pharmacoepidemiol & Clin Pharmacol, Utrecht, Netherlands.
    Behloui, Hassan
    McGill Univ, Hlth Ctr, Ctr Outcomes Res & Evaluat, Res Inst, Montreal, PQ, Canada.
    Boeckx, Bram
    Katholieke Univ Leuven, Lab Translat Genet, Dept Human Genet, Leuven, Belgium;VIB Ctr Canc Biol, Lab Translat Genet, Leuven, Belgium.
    Braund, Peter S.
    Univ Leicester, Dept Cardiovasc Sci, BHF Cardiovasc Res Ctr, Leicester, Leics, England;Glenfield Hosp, NIHR Leicester Biomed Res Ctr, Leicester, Leics, England.
    Breitling, Lutz P.
    German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany.
    Delgado, Gradela
    Heidelberg Univ, Dept Med 5, Med Fac Mannheim, Heidelberg, Germany.
    Duarte, Nubia E.
    Univ Sao Paulo, Heart Inst, Sao Paulo, Brazil.
    Dube, Marie-Pierre
    Montreal Heart Inst, Montreal, PQ, Canada;Univ Montreal, Fac Med, Montreal, PQ, Canada.
    Dufresne, Line
    McGill Univ, Hlth Ctr, Ctr Outcomes Res & Evaluat, Res Inst, Montreal, PQ, Canada;McGill Univ Hlth Ctr, Prevent & Genom Cardiol, Montreal, PQ, Canada.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Foco, Luisa
    Univ Lubeck, Inst Biomed, Eurac Res, Affiliated Inst, Bolzano, Italy.
    Scholz, Markus
    Univ Leipzig, Inst Med Informat Stat & Epidemiol, Leipzig, Germany;Univ Leipzig, LIFE Res Ctr Civilizat Dis, Leipzig, Germany.
    Gijsberts, Crystel M.
    UMC Utrecht, Lab Expt Cardiol, Utrecht, Netherlands.
    Glinge, Charlotte
    Copenhagen Univ Hosp, Rigshosp, Dept Cardiol, Heart Ctr, Amsterdam, Netherlands;Univ Amsterdam, Amsterdam UMC, Clin & Expt Cardiol, Amsterdam Cardiovasc Sci,AMC Heart Ctr, Amsterdam, Netherlands.
    Gong, Yan
    Univ Florida, Dept Pharmacotherapy & Translat Res, Ctr Pharmacogen, Gainesville, FL USA.
    Hartiala, Jaana
    USC, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA;USC, Keck Sch Med, Dept Biochem, Los Angeles, CA USA;USC, Keck Sch Med, Dept Mol Med, Los Angeles, CA USA;USC, Keck Sch Med, Inst Genet Med, Los Angeles, CA USA.
    Heydarpour, Mahyar
    Brigham & Womens Hosp, Dept Anesthesiol Perioperat & Pain Med, 75 Francis St, Boston, MA 02115 USA;Harvard Med Sch, Boston, MA 02115 USA.
    Hubacek, Jaroslav A.
    Inst Clin & Expt Med, Ctr Expt Med, Prague, Czech Republic.
    Kleber, Marcus
    Heidelberg Univ, Dept Med 5, Med Fac Mannheim, Heidelberg, Germany.
    Kofink, Daniel
    Montreal Heart Inst, Montreal, PQ, Canada.
    Kotti, Salma
    URCEST CRCEST CRB HUEP UPMC, AP HP, Dept Clin Pharmacol, Platform Clin Res East Paris, Paris, France.
    Kuukasjarvi, Pekka
    Univ Tampere, Dept Cardiothorac Surg, Tampere, Finland.
    Lee, Vei-Vei
    Texas Heart Inst, Dept Biostat & Epidemiol, Houston, TX 77025 USA.
    Leiherer, Andreas
    VIVIT, Feldkirch, Austria;Private Univ Principal Liechtenstein, Triesen, Liechtenstein;Med Cent Labs, Feldkirch, Austria.
    Lenzini, Petra A.
    Washington Univ, Sch Med, Dept Genet, Stat Genom Div, St Louis, MO 63110 USA.
    Levin, Daniel
    Univ Dundee, Div Mol & Clin Med, Sch Med, Dundee, Scotland.
    Lyytikainen, Leo-Pekka
    Univ Tampere, Dept Clin Chem, Tampere, Finland;Fimlab Labs, Dept Clin Chem, Tampere, Finland.
    Martinelli, Nicola
    Univ Verona, Dept Med, Verona, Italy.
    Mons, Ute
    German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany.
    Nelson, Christopher P.
    Univ Leicester, Dept Cardiovasc Sci, BHF Cardiovasc Res Ctr, Leicester, Leics, England;Glenfield Hosp, NIHR Leicester Biomed Res Ctr, Leicester, Leics, England.
    Nikus, Kjell
    Univ Tampere, Dept Cardiol, Tampere, Finland;Tampere Univ Hosp, Dept Cardiol, Heart Ctr, Tampere, Finland.
    Pilbrow, Anna P.
    Univ Otago, Christchurch Heart Inst, Christchurch, New Zealand.
    Ploski, Rafal
    Med Univ Warsaw, Dept Med Genet, Warsaw, Poland.
    Sun, Yan, V
    Emory Univ, Dept Epidemiol, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA;Emory Univ, Sch Med, Dept Biomed Informat, Emory Clin Cardiovasc Res Inst, Atlanta, GA 30322 USA.
    Tanck, Michael W. T.
    Univ Amsterdam, Amsterdam UMC, Clin Epidemiol & Biostat, Amsterdam, Netherlands.
    Tang, W. H. Wilson
    Cleveland Clin, Lerner Res Inst, Dept Cellular & Mol Med, Cleveland, OH 44106 USA;Cleveland Clin, Dept Cardiovasc Med, Heart & Vasc Inst, Cleveland, OH 44106 USA;Cleveland Clin, Ctr Clin Genom, Cleveland, OH 44106 USA.
    Trompet, Stella
    Cleveland Clin, Sect Gerontol & Geriatr, Dept Internal Med, Cleveland, OH 44106 USA;Leiden Univ, Dept Cardiol, Med Ctr, Leiden, Netherlands.
    van der Laan, Sander W.
    Univ Utrecht, Div Labs Pharm & Biomed Genet, Lab Clin Chem & Hematol, UMC Utrecht, Utrecht, Netherlands.
    Van Setten, Jessica
    Univ Utrecht, Div Heart & Lungs, Dept Cardiol, UMC Utrecht, Utrecht, Netherlands.
    Vilmundarson, Ragnar O.
    Univ Ottawa, Heart Inst, Ruddy Canadian Cardiovasc Genet Ctr, Ottawa, ON, Canada;Univ Ottawa, Dept Biochem Microbiol & Immunol, Ottawa, ON, Canada.
    Anselmi, Chiara Viviani
    Humanitas Clin & Res Ctr, Dept Cardiovasc Med, Milan, Italy.
    Vlachopoulou, Efthymia
    Helsinki Univ Hosp, Transplantat Lab, Helsinki, Finland;Univ Helsinki, Helsinki, Finland.
    Al Ali, Lawien
    Univ Groningen, Univ Med Ctr, Groningen, Netherlands.
    Boerwinkle, Eric
    Univ Texas Houston, Sch Publ Hlth, Houston, TX USA.
    Briguori, Carlo
    Clin Mediterranea, Naples, Italy.
    Carlquist, John F.
    Intermt Med Ctr, Intermt Heart Inst, Salt Lake City, UT USA;Univ Utah, Cardiol Div, Dept Internal Med, Salt Lake City, UT USA.
    Carruthers, Kathryn F.
    Univ Edinburgh, Cardiovasc Sci, QMRI, Edinburgh, Midlothian, Scotland.
    Casu, Gavino
    Humanitas Clin & Res Ctr, Dept Cardiovasc Med, Milan, Italy;ASSL Nuoro Osped San Francesco, ATS Sardegna, Nuoro, Italy.
    Deanfield, John
    UCL, Inst Cardiovasc Sci, Fac Populat Hlth Sci, London, England;St Bartholomews Hosp, Barts Heart Ctr, London, England.
    Deloukas, Panos
    Queen Mary Univ London, William Harvey Res Inst, Barts & London Med Sch, London, England;Queen Mary Univ London, Ctr Genom Hlth, London, England.
    Dudbridge, Frank
    Univ Leicester, Dept Hlth Sci, Leicester, Leics, England.
    Engstrom, Thomas
    Copenhagen Univ Hosp, Rigshosp, Dept Cardiol, Heart Ctr, Amsterdam, Netherlands;Lund Univ, Dept Cardiol, Lund, Sweden.
    Fitzpatrick, Natalie
    UCL, Inst Hlth Informat, Fac Populat Hlth Sci, London, England.
    Fox, Kim
    Royal Brompton Hosp, Natl Heart & Lung Inst, Imperial Coll, London, England;Royal Brompton Hosp, Natl Heart & Lung Inst, Inst Cardiovasc Med & Sci, London, England.
    Gigante, Bruna
    Karolinska Inst, Inst Environm Med, Stockholm, Sweden.
    James, Stefan
    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.
    Lokki, Marja-Liisa
    Helsinki Univ Hosp, Transplantat Lab, Helsinki, Finland;Univ Helsinki, Helsinki, Finland.
    Lotufo, Paulo A.
    Univ Sao Paulo, Hosp Univ, Ctr Pesquisa Clin, Sao Paulo, Brazil.
    Marziliano, Nicola
    ATS Sardegna, ASL Nuoro 3, Nuoro, Italy.
    Mordi, Ify R.
    Univ Dundee, Div Mol & Clin Med, Sch Med, Dundee, Scotland.
    Muhlestein, Joseph B.
    Intermt Med Ctr, Intermt Heart Inst, Salt Lake City, UT USA;Univ Utah, Cardiol Div, Dept Internal Med, Salt Lake City, UT USA.
    Newton-Cheh, Christopher
    Massachusetts Gen Hosp, Cardiovasc Res Ctr, Ctr Human Genet Res, Boston, MA 02114 USA;Broad Inst, Program Med & Populat Genet, Cambridge, MA USA.
    Pitha, Jan
    Inst Clin & Expt Med, Ctr Expt Med, Prague, Czech Republic.
    Saely, Christoph H.
    VIVIT, Feldkirch, Austria;Private Univ Principal Liechtenstein, Triesen, Liechtenstein;Acad Teaching Hosp Feldkirch, Dept Med & Cardiol, Feldkirch, Austria.
    Samman-Tahhan, Ayman
    Emory Univ, Sch Med, Div Cardiol, Dept Med,Emory Clin Cardiovasc Res Inst, Atlanta, GA 30322 USA.
    Sandesara, Pratik B.
    Emory Univ, Sch Med, Div Cardiol, Dept Med,Emory Clin Cardiovasc Res Inst, Atlanta, GA 30322 USA.
    Teren, Andrej
    Univ Leipzig, LIFE Res Ctr Civilizat Dis, Leipzig, Germany;Heart Ctr Leipzig, Leipzig, Germany.
    Timmis, Adam
    UCL, Inst Hlth Informat, Fac Populat Hlth Sci, London, England;St Bartholomews Hosp, Barts Heart Ctr, London, England.
    Van de Werf, Frans
    Katholieke Univ Leuven, Dept Cardiovasc Sci, Leuven, Belgium.
    Wauters, Els
    Univ Hosp KU Leuven, Resp Oncol Unit, Dept Resp Med, Leuven, Belgium.
    Wilde, Arthur A. M.
    Univ Amsterdam, Amsterdam UMC, Clin & Expt Cardiol, Amsterdam Cardiovasc Sci,AMC Heart Ctr, Amsterdam, Netherlands;Princess Al Jawhara Al Brahim Ctr Excellence Res, Jeddah, Saudi Arabia.
    Ford, Ian
    Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland.
    Stott, David J.
    Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland.
    Algra, Ale
    Univ Utrecht, Dept Neurol & Neurosurg, Brain Ctr Rudolf Magnus & Julius Ctr Hlth Sci & P, UMC Utrecht, Utrecht, Netherlands.
    Andreassi, Maria G.
    CNR, Inst Clin Physiol, Pisa, Italy.
    Ardissino, Diego
    Parma Univ Hosp, Cardiol Dept, Parma, Italy.
    Arsenault, Benoit J.
    Inst Univ Cardiol & Pneumol Quebec, Ctr Rech, Quebec City, PQ, Canada;Univ Laval, Dept Med, Fac Med, Laval, PQ, Canada.
    Ballantyne, Christie M.
    Baylor Coll Med, Sect Cardiovasc Res, Dept Med, Houston, TX 77030 USA.
    Bergmeijer, Thomas O.
    St Antonius Hosp, Dept Cardiol, Nieuwegein, Netherlands.
    Bezzina, Connie R.
    Univ Amsterdam, Amsterdam UMC, Clin & Expt Cardiol, Amsterdam Cardiovasc Sci,AMC Heart Ctr, Amsterdam, Netherlands.
    Body, Simon C.
    Harvard Med Sch, Boston, MA 02115 USA;Beth Israel Deaconess Med Ctr, Boston, MA USA.
    Boersma, Eric H.
    Erasmus MC, Dept Cardiol, Thoraxctr, Rotterdam, Netherlands;Erasmus Med Ctr COEUR, Cardiovasc Res Sch, Rotterdam, Netherlands.
    Bogaty, Peter
    Laval Univ, Inst Univ Cardiol & Pneumol Quebec, Quebec City, PQ, Canada.
    Bots, Michiel L.
    Univ Utrecht, Julius Ctr Hlth Sci & Primary Care, UMC Utrecht, Utrecht, Netherlands.
    Brenner, Hermann
    Heidelberg Univ, Network Aging Res, Heidelberg, Germany.
    Brugts, Jasper J.
    Erasmus MC, Dept Cardiol, Thoraxctr, Rotterdam, Netherlands.
    Burkhardt, Ralph
    Univ Leipzig, LIFE Res Ctr Civilizat Dis, Leipzig, Germany;Univ Hosp Regensburg, Inst Clin Chem & Lab Med, Regensburg, Germany.
    Carpeggiani, Clara
    CNR, Inst Clin Physiol, Pisa, Italy.
    Condorelli, Gianluigi
    Humanitas Univ, Dept Biomed Sci, Milan, Italy.
    Cooper-DeHoff, Rhonda M.
    Univ Florida, Dept Pharmacotherapy & Translat Res, Ctr Pharmacogen, Gainesville, FL USA;Univ Florida, Div Cardiovasc Med, Coll Med, Gainesville, FL USA.
    Cresci, Sharon
    Washington Univ, Sch Med, Dept Genet, Stat Genom Div, St Louis, MO 63110 USA;Washington Univ, Dept Med, Cardiovasc Div, St Louis, MO 63110 USA.
    Danchin, Nicolas
    Univ Paris 05, Hop Europeen Georges Pompidou, AP HP, Dept Cardiol, Paris, France;Univ Paris 05, FACT, Paris, France;Univ Paris 05, Paris, France.
    de Faire, Ulf
    Karolinska Inst, Inst Environm Med, Stockholm, Sweden.
    Doughty, Robert N.
    Univ Auckland, Heart Hlth Res Grp, Auckland, New Zealand.
    Drexel, Heinz
    VIVIT, Feldkirch, Austria;Private Univ Principal Liechtenstein, Triesen, Liechtenstein;Drexel Univ, Coll Med, Philadelphia, PA 19104 USA.
    Engert, James C.
    McGill Univ, Res Inst, Hlth Ctr, Montreal, PQ, Canada;McGill Univ Hlth Ctr, Prevent & Genom Cardiol, Montreal, PQ, Canada;McGill Univ Hlth Ctr, Royal Victoria Hosp, Dept Med, Div Cardiol, Montreal, PQ, Canada.
    Fox, Keith A. A.
    Univ Edinburgh, Edinburgh, Midlothian, Scotland.
    Girelli, Domenico
    Univ Verona, Dept Med, Verona, Italy.
    Grobbee, Diederick E.
    Univ Utrecht, Julius Ctr Hlth Sci & Primary Care, UMC Utrecht, Utrecht, Netherlands.
    Hagström, Emil
    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.
    Hazen, Stanley L.
    Cleveland Clin, Lerner Res Inst, Dept Cellular & Mol Med, Cleveland, OH 44106 USA;Cleveland Clin, Dept Cardiovasc Med, Ctr Microbiome & Human Hlth, Heart & Vasc Inst, Cleveland, OH 44106 USA.
    Held, Claes
    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.
    Hemingway, Harry
    UCL, Inst Hlth Informat, Fac Populat Hlth Sci, London, England.
    Hoefer, Imo E.
    UMC Utrecht, Dept Clin Chem & Hematol, Utrecht, Netherlands.
    Hovingh, G. Kees
    Acad Med Ctr, Dept Vasc Med, Amsterdam, Netherlands.
    Jabbari, Reza
    Copenhagen Univ Hosp, Rigshosp, Dept Cardiol, Heart Ctr, Amsterdam, Netherlands.
    Johnson, Julie A.
    Univ Florida, Dept Pharmacotherapy & Translat Res, Ctr Pharmacogen, Gainesville, FL USA;Univ Florida, Div Cardiovasc Med, Coll Med, Gainesville, FL USA.
    Jukema, J. Wouter
    Leiden Univ, Dept Cardiol, Med Ctr, Leiden, Netherlands;LUMC, Einthoven Lab Expt Vasc Med, Leiden, Netherlands;Interuniv Cardiol Inst Netherlands, Utrecht, Netherlands.
    Kaczor, Marcin P.
    Jagiellonian Univ, Dept Internal Med, Med Coll, Krakow, Poland.
    Kahonen, Mika
    Univ Tampere, Dept Clin Physiol, Tampere, Finland;Tampere Univ Hosp, Dept Clin Physiol, Tampere, Finland.
    Kettner, Jiri
    Inst Clin & Expt Med, Cardiol Ctr, Prague, Czech Republic.
    Kiliszek, Marek
    Mil Inst Med, Dept Cardiol & Internal Dis, Warsaw, Poland.
    Klungel, Olaf H.
    Univ Utrecht, Div Pharmacoepidemiol & Clin Pharmacol, Utrecht, Netherlands.
    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.
    Lambrechts, Diether
    Katholieke Univ Leuven, Lab Translat Genet, Dept Human Genet, Leuven, Belgium;VIB Ctr Canc Biol, Lab Translat Genet, Leuven, Belgium.
    Laurikka, Jari O.
    Univ Tampere, Dept Cardiothorac Surg, Finnish Cardiovasc Res Ctr, Fac Med & Life Sci, Tampere, Finland;Tampere Univ Hosp, Dept Cardio Thorac Surg, Heart Ctr, Tampere, Finland.
    Lehtimaki, Terho
    Univ Tampere, Dept Clin Chem, Tampere, Finland;Fimlab Labs, Dept Clin Chem, Tampere, Finland.
    Lindholm, Daniel
    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.
    Mahmoodi, B. K.
    St Antonius Hosp, Dept Cardiol, Nieuwegein, Netherlands.
    Maitland-van der Zee, Anke H.
    Univ Utrecht, Div Pharmacoepidemiol & Clin Pharmacol, Utrecht, Netherlands;Univ Amsterdam, Dept Resp Med, Acad Med Ctr, Amsterdam, Netherlands.
    McPherson, Ruth
    Univ Ottawa, Heart Inst, Ruddy Canadian Cardiovasc Genet Ctr, Ottawa, ON, Canada;Univ Ottawa, Dept Med, Ottawa, ON, Canada;Univ Ottawa, Dept Biochem, Ottawa, ON, Canada;Univ Ottawa, Dept Microbiol & Immunol, Ottawa, ON, Canada.
    Melander, Olle
    Lund Univ, Dept Clin Sci, Malmo, Sweden;Skane Univ Hosp, Dept Internal Med, Malmo, Sweden.
    Metspalu, Andres
    Univ Tartu, Estonian Genome Ctr, Dept Biotechnol, Inst Genom,Inst Mol & Cell Biol, Tartu, Estonia.
    Niemcunowicz-Janica, Anna
    Med Univ Bialystok, Dept Forens Med, Bialystok, Poland.
    Olivieri, Oliviero
    Univ Verona, Dept Med, Verona, Italy.
    Opolski, Grzegorz
    Med Univ Warsaw, Chair 1, Warsaw, Poland;Med Univ Warsaw, Dept Cardiol, Warsaw, Poland.
    Palmer, Colin N.
    Ninewells Hosp & Med Sch, Pat Macpherson Ctr Pharmacogenet & Pharmacogen, Div Mol & Clin Med, Dundee, Scotland.
    Pasterkamp, Gerard
    UMC Utrecht, Dept Clin Chem, Utrecht, Netherlands.
    Pepine, Carl J.
    Univ Florida, Div Cardiovasc Med, Coll Med, Gainesville, FL USA.
    Pereira, Alexandre C.
    Univ Sao Paulo, Heart Inst, Sao Paulo, Brazil.
    Pilote, Louise
    McGill Univ, Hlth Ctr, Ctr Outcomes Res & Evaluat, Res Inst, Montreal, PQ, Canada;McGill Univ Hlth Ctr, Dept Med, Montreal, PQ, Canada.
    Quyyumi, Arshed A.
    Emory Univ, Sch Med, Div Cardiol, Dept Med,Emory Clin Cardiovasc Res Inst, Atlanta, GA 30322 USA.
    Richards, A. Mark
    Univ Otago, Christchurch Heart Inst, Christchurch, New Zealand;Natl Univ Singapore, Cardiovasc Res Inst, Singapore, Singapore.
    Sanak, Marek
    Jagiellonian Univ, Dept Internal Med, Med Coll, Krakow, Poland.
    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.
    Simon, Tabassome
    Sorbonne Univ, Platform Clin Res East Paris URCEST CRCEST CRB HU, Dept Clin Pharmacol, AP HP,FACT, Paris, France;Paris Sorbonne Univ, UPMC Site St Antoine, Paris, France.
    Sinisalo, Juha
    Heart and Lung Centre (J.S.), Helsinki University Hospital and University of Helsinki, Finland.
    Smith, J. Gustav
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA;Lund Univ, Dept Cardiol Clin Sci, Skane Univ Hosp, Lund, Sweden;Lund Univ, Wallenberg Ctr Mol Med, Diabet Ctr, Lund, Sweden.
    Spertus, John A.
    Univ Missouri, St Lukes Mid Amer Heart Inst, Kansas City, MO 64110 USA;St Lukes Mid Amer Heart Insti, Kansas City, MO USA.
    Stender, Steen
    Copenhagen Univ Hosp, Dept Clin Biochem, Gentofte, Denmark.
    Stewart, Alexandre F. R.
    Univ Ottawa, Heart Inst, Ruddy Canadian Cardiovasc Genet Ctr, Ottawa, ON, Canada;Univ Ottawa, Dept Biochem Microbiol & Immunol, Ottawa, ON, Canada.
    Szczeklik, Wojciech
    Jagiellonian Univ, Dept Internal Med, Med Coll, Krakow, Poland.
    Szpakowicz, Anna
    Med Univ Bialystok, Dept Cardiol, Bialystok, Poland.
    Tardif, Jean-Claude
    Montreal Heart Inst, Montreal, PQ, Canada;Univ Montreal, Fac Med, Montreal, PQ, Canada.
    ten Berg, Jurrien M.
    St Antonius Hosp, Dept Cardiol, Nieuwegein, Netherlands.
    Tfelt-Hansen, Jacob
    Univ Leipzig, LIFE Res Ctr Civilizat Dis, Leipzig, Germany;Copenhagen Univ Hosp, Rigshosp, Dept Cardiol, Heart Ctr, Copenhagen, Denmark;Univ Copenhagen, Fac Med Sci, Dept Forens Med, Copenhagen, Denmark.
    Thanassoulis, George
    McGill Univ, Hlth Ctr, Ctr Outcomes Res & Evaluat, Res Inst, Montreal, PQ, Canada;McGill Univ Hlth Ctr, Prevent & Genom Cardiol, Montreal, PQ, Canada;McGill Univ Hlth Ctr, Royal Victoria Hosp, Dept Med, Div Cardiol, Montreal, PQ, Canada.
    Thiery, Joachim
    Univ Hosp, Inst Lab Med, Clin Chem & Mol Diagnost, Leipzig, Germany.
    Torp-Pedersen, Christian
    Aalborg Univ Hosp, Dept Hlth Sci & Technol, Unit Epidemiol & Biostat, Aalborg, Denmark.
    van der Graaf, Yolanda
    Univ Utrecht, Julius Ctr Hlth Sci & Primary Care, UMC Utrecht, Utrecht, Netherlands.
    Visseren, Frank L. J.
    Univ Utrecht, Dept Vasc Med, UMC Utrecht, Utrecht, Netherlands.
    Waltenberger, Johannes
    Univ Munster, Dept Cardiovasc Med, Munster, Germany.
    Weeke, Peter E.
    Herlev & Gentofte Hosp, Dept Cardiol, Hellerup, Denmark.
    Van der Harst, Pim
    Univ Groningen, Univ Med Ctr, Groningen, Netherlands.
    Lang, Chim C.
    Univ Dundee, Div Mol & Clin Med, Sch Med, Dundee, Scotland.
    Sattar, Naveed
    Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland.
    Cameron, Vicky A.
    Univ Otago, Christchurch Heart Inst, Christchurch, New Zealand.
    Anderson, Jeffrey L.
    Intermt Med Ctr, Intermt Heart Inst, Salt Lake City, UT USA;Univ Utah, Cardiol Div, Dept Internal Med, Salt Lake City, UT USA.
    Brophy, James M.
    McGill Univ, Hlth Ctr, Ctr Outcomes Res & Evaluat, Res Inst, Montreal, PQ, Canada;McGill Univ Hlth Ctr, Dept Med, Montreal, PQ, Canada.
    Pare, Guillaume
    McMaster Univ, Dept Pathol & Mol Med, Hamilton, ON, Canada;Populat Hlth Res Inst, Hamilton, ON, Canada.
    Horne, Benjamin D.
    Intermt Med Ctr, Intermt Heart Inst, Salt Lake City, UT USA;Univ Utah, Dept Biomed Informat, Salt Lake City, UT USA.
    Marz, Winfried
    Heidelberg Univ, Dept Med 5, Med Fac Mannheim, Heidelberg, Germany;Synlab Holding Deutschland GmbH, Synlab Acad, Mannheim, Germany;Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, Graz, Austria.
    Wallentin, Lars
    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.
    Samani, Nilesh J.
    Univ Leicester, Dept Cardiovasc Sci, BHF Cardiovasc Res Ctr, Leicester, Leics, England;Glenfield Hosp, NIHR Leicester Biomed Res Ctr, Leicester, Leics, England.
    Hingorani, Aroon D.
    Institute of Cardiovascular Science, Faculty of Population Health Science, University College London, United Kingdom.
    Asselbergs, Folkert W.
    UCL, Inst Cardiovasc Sci, Fac Populat Hlth Sci, London, England;UCL, Inst Hlth Informat, Fac Populat Hlth Sci, London, England;UMC Utrecht, Div Heart & Lungs, Dept Cardiol, Utrecht, Netherlands;ICIN Netherlands Heart Inst, Durrer Ctr Cardiogenet Res, Utrecht, Netherlands.
    Subsequent Event Risk in Individuals With Established Coronary Heart Disease: Design and Rationale of the GENIUS-CHD Consortium2019In: Circulation: Genomic and Precision Medicine, ISSN 2574-8300, Vol. 12, no 4, article id e002470Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The Genetics of Subsequent Coronary Heart Disease (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events, in individuals with established CHD.

    METHODS: The consortium currently includes 57 studies from 18 countries, recruiting 185 614 participants with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events.

    RESULTS: Enrollment into the individual studies took place between 1985 to present day with a duration of follow-up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (hazard ratio, 1.15; 95% CI, 1.14-1.16) per 5-year increase, male sex (hazard ratio, 1.17; 95% CI, 1.13-1.21) and smoking (hazard ratio, 1.43; 95% CI, 1.35-1.51) with risk of subsequent CHD death or myocardial infarction and differing associations with other individual and composite cardiovascular endpoints.

    CONCLUSIONS: GENIUS-CHD is a global collaboration seeking to elucidate genetic and nongenetic determinants of subsequent event risk in individuals with established CHD, to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators.

  • 27. Rao, Abhiram S
    et al.
    Lindholm, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Rivas, Manuel A
    Knowles, Joshua W
    Montgomery, Stephen B
    Ingelsson, Erik
    Large-Scale Phenome-Wide Association Study of PCSK9 Variants Demonstrates Protection Against Ischemic Stroke.2018In: Circulation-genomic and precision medicine, ISSN 2574-8300, Vol. 11, no 7, article id e002162Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: PCSK9 inhibition is a potent new therapy for hypercholesterolemia and cardiovascular disease. Although short-term clinical trial results have not demonstrated major adverse effects, long-term data will not be available for some time. Genetic studies in large biobanks offer a unique opportunity to predict drug effects and provide context for the evaluation of future clinical trial outcomes.

    METHODS: We tested the association of the PCSK9 missense variant rs11591147 with predefined phenotypes and phenome-wide, in 337 536 individuals of British ancestry in the UK Biobank, with independent discovery and replication. Using a Bayesian statistical method, we leveraged phenotype correlations to evaluate the phenome-wide impact of PCSK9 inhibition with higher power at a finer resolution.

    RESULTS: The T allele of rs11591147 showed a protective effect on hyperlipidemia (odds ratio, 0.63±0.04; P=2.32×10-38), coronary heart disease (odds ratio, 0.73±0.09; P=1.05×10-6), and ischemic stroke (odds ratio, 0.61±0.18; P=2.40×10-3) and was associated with increased type 2 diabetes mellitus risk adjusted for lipid-lowering medication status (odds ratio, 1.24±0.10; P=1.98×10-7). We did not observe associations with cataracts, heart failure, atrial fibrillation, and cognitive dysfunction. Leveraging phenotype correlations, we observed evidence of a protective association with cerebral infarction and vascular occlusion. These results explore the effects of direct PCSK9 inhibition; off-target effects cannot be predicted using this approach.

    CONCLUSIONS: This result represents the first genetic evidence in a large cohort for the protective effect of PCSK9 inhibition on ischemic stroke and corroborates exploratory evidence from clinical trials. PCSK9 inhibition was not associated with variables other than those related to LDL (low-density lipoprotein) cholesterol, atherosclerosis, and type 2 diabetes mellitus, suggesting that other effects are either small or absent.

  • 28.
    Sarno, Giovanna
    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.
    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.
    Olivecrona, Göran
    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.
    Danielewicz, Mikael
    Hambraeus, Kristina
    Lindholm, Daniel
    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.
    Råmunddal, Truls
    Witt, Nils
    James, Stefan
    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.
    Real-life clinical outcomes with everolimus eluting platinum chromium stent with an abluminal biodegradable polymer in patients from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR)2017In: Catheterization and cardiovascular interventions, ISSN 1522-1946, E-ISSN 1522-726X, Vol. 90, no 6, p. 881-887Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: No previous studies have evaluated the performance of the Synergy stent in a large real-life population.

    OBJECTIVES: To describe the initial real-life experience with a novel everolimus eluting platinum chromium stent with abluminal biodegradable polymer (SYNERGY) in unselected patients from a nationwide registry.

    METHODS: All implanted Synergy stents were compared with other new generation drug eluting stents (n-DES) with >1,000 implantations in Sweden between March 2013 and October 2015. Restenosis, definite stent thrombosis (ST), myocardial infarction (MI) and death rates were assessed using propensity score and Cox regression analyses.

    RESULTS: A total of 7,886 of Synergy stents and 64,429 other n-DES (BioMatrix, N = 1,953; Orsiro, N = 4,946; Promus Element Plus, N= 2,543; Promus Premier, N= 20,414; Xience Xpedition, N= 7,971, Resolute/Resolute Integrity, N = 19,021; Ultimaster, N = 1,156; Resolute Onyx, N = 6,425) were implanted in 42,357 procedures. Restenosis and stent thrombosis occurred in 642 and 314 cases, respectively, in the overall population at 1 year. The cumulative rate of restenosis (1.1% vs. 1.0%, adjusted HR: 1.24 95% CI: 0.88-1.75; P = 0.21) and ST (0.4% vs. 0.5%, adjusted HR: 0.97; 95% CI: 0.63-1.50; P = 0.17) up to 1 year was low in both the Synergy group and the other n-DES group. Death occurred in 5.2% versus 4.5% (adjusted HR: 1.14; 95% CI: 0.96-1.36; P = 0.11) and MI in 3.2% versus 3.5%, (adjusted HR: 1.11; 95% CI: 0.93-1.33; P = 0.24) up to 1 year.

    CONCLUSIONS: In a large real-life population the Synergy stent appears to be safe and effective with a low rate of restenosis and ST comparable with other n-DES.

  • 29.
    Varenhorst, Christoph
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Alfredsson, Joakim
    Angerås, Oskar
    Bohm, Felix
    Calais, Fredrik
    James, Stefan
    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.
    Koul, Sasha
    Lagerqvist, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Renlund, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Sarno, Giovanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Lindholm, Daniel
    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.
    Timing Of Pci In Patients With Non-St-Elevation Myocardial Infarction: A Swedeheart Study2016In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 67, no 13, p. 44-44Article in journal (Other academic)
  • 30.
    Velders, Matthijs A.
    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.
    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.
    Becker, Richard C.
    van Boven, Adrianus J.
    Himmelmann, Anders
    Husted, Steen
    Katus, Hugo A.
    Lindholm, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Morais, Joao
    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.
    Storey, Robert F.
    Wernroth, Lisa
    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.
    Biomarkers for risk stratification of patients with ST-elevation myocardial infarction treated with primary percutaneous coronary intervention: Insights from the Platelet Inhibition and Patient Outcomes trial2015In: American Heart Journal, ISSN 0002-8703, E-ISSN 1097-6744, Vol. 169, no 6, p. 879-889.e7Article in journal (Refereed)
    Abstract [en]

    Background The incremental prognostic value of admission measurements of biomarkers beyond clinical characteristics and extent of coronary artery disease (CAD) in patients treated with primary percutaneous coronary intervention (PPCI) for ST-elevation myocardial infarction (STEMI) is unclear. Methods Centrally analyzed plasma for biomarker measurements was available in 5,385 of the STEMI patients treated with PPCI in the PLATO trial. Extent of CAD was graded by operators in association with PPCI. We evaluated the prognostic value of high-sensitivity cardiac troponin T, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and growth differentiation factor 15 (GDF-15) beyond clinical characteristics and extent of CAD using Cox proportional hazards analyses, C-index, and net reclassification improvement (NRI). Outcomes were cardiovascular death (CVD) and spontaneous myocardial infarction (MI). Results Angiographic data on extent of CAD improved the prediction of CVD compared to clinical risk factors alone, increasing the C-index from 0.760 to 0.778, total NRI of 0.31. Biomarker information provided additional prognostic value for CVD beyond clinical risk factors and extent of CAD, C-indices ranging from 0.792 to 0.795 for all biomarkers, but with a higher NRI for NT-proBNP. Extent of CAD and high-sensitivity cardiac troponin T were not associated with spontaneous MI. The prediction of spontaneous MI beyond clinical characteristics and extent of CAD (C-index 0.647) was improved by both NT-proBNP (C-index 0.663, NRI 0.22) and GDF-15 (C-index 0.652, NRI 0.05). Conclusions Biomarker measurement on admission is feasible and provides incremental risk stratification in patients with STEMI treated with PPCI, with NT-proBNP and GDF-15 being most valuable due to the association with both CVD and spontaneous MI.

  • 31.
    Wallentin, Lars
    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.
    Lindholm, Daniel
    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. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    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, Cardiology.
    Becker, Richard C.
    Cannon, Christopher P.
    Cornel, Jan H.
    Himmelmann, Anders
    Giannitsis, Evangelos
    Harrington, Robert A.
    Held, Claes
    Husted, Steen
    Katus, Hugo A.
    Mahaffey, Kenneth W.
    Steg, Ph. Gabriel
    Storey, Robert F.
    James, Stefan K.
    Biomarkers in Relation to the Effects of Ticagrelor in Comparison With Clopidogrel in Non-ST-Elevation Acute Coronary Syndrome Patients Managed With or Without In-Hospital Revascularization A Substudy From the Prospective Randomized Platelet Inhibition and Patient Outcomes (PLATO) Trial2014In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 129, no 3, p. 293-303Article in journal (Refereed)
    Abstract [en]

    Background Risk stratification and the use of specific biomarkers have been proposed for tailoring treatment in patients with non-ST-elevation acute coronary syndrome (NSTE-ACS). We investigated the prognostic importance of high-sensitivity troponin T (hs-TnT), N-terminal pro-brain natriuretic peptide (NT-proBNP), and growth differentiation factor-15 (GDF-15) in relation to randomized treatment (ticagrelor versus clopidogrel) and management strategy (with or without revascularization) in the NSTE-ACS subgroup of the Platelet Inhibition and Patient Outcomes (PLATO) trial. Methods and Results Of 18 624 patients in the PLATO trial, 9946 had an entry diagnosis of NSTE-ACS and baseline blood samples available. During index hospitalization, 5357 were revascularized, and 4589 were managed without revascularization. Hs-TnT, NT-proBNP, and GDF-15 were determined and assessed according to predefined cutoff levels. Median follow-up was 9.1 months. Increasing levels of hs-TnT were associated with increasing risk of cardiovascular death, myocardial infarction, and stroke in medically managed patients (P<0.001), but not in those managed invasively. NT-proBNP and GDF-15 levels were associated with the same events independent of management strategy. Ticagrelor versus clopidogrel reduced the rate of cardiovascular death, myocardial infarction, and stroke in patients with NSTE-ACS and hs-TnT 14.0 ng/L in both invasively and noninvasively managed patients; in patients with hs-TnT <14.0 ng/L, there was no difference between ticagrelor and clopidogrel in the noninvasive group Conclusions Hs-TnT, NT-proBNP, and GDF-15 are predictors of cardiovascular death, myocardial infarction, and stroke in patients with NSTE-ACS managed noninvasively, and NT-proBNP and GDF-15 also in those managed invasively. Elevated hs-TnT predicts substantial benefit of ticagrelor over clopidogrel both in invasively and noninvasively managed patients, but no apparent benefit was seen at normal hs-TnT. Clinical Trial Registration URL:http://www.clinicaltrials.gov. Unique identifier: NCT00391872.

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