| 1. |
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| 2. |
- Winkler, TW, et al.
(författare)
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Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals
- 2022
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Ingår i: Communications biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 5:1, s. 580-
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Tidskriftsartikel (refereegranskat)abstract
- Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (nDM = 178,691, nnoDM = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.
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| 3. |
- Turcot, Valerie, et al.
(författare)
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Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity
- 2018
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 50:1, s. 26-41
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are similar to 10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed similar to 7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
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| 4. |
- Justice, Anne E., et al.
(författare)
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Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution
- 2019
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:3, s. 452-469
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Tidskriftsartikel (refereegranskat)abstract
- Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF >= 5%) and nine low-frequency or rare (MAF < 5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.
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| 5. |
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| 6. |
- Patel, Riyaz S., et al.
(författare)
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Association of Chromosome 9p21 With Subsequent Coronary Heart Disease Events : A GENIUS-CHD Study of Individual Participant Data
- 2019
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Ingår i: Circulation. - 2574-8300. ; 12:4
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 7. |
- Patel, Riyaz S., et al.
(författare)
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Subsequent Event Risk in Individuals With Established Coronary Heart Disease : Design and Rationale of the GENIUS-CHD Consortium
- 2019
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Ingår i: Circulation. - 2574-8300. ; 12:4
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 8. |
- Gorski, Mathias, et al.
(författare)
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Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies
- 2022
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Ingår i: Kidney International. - : Elsevier. - 0085-2538 .- 1523-1755. ; 102:3, s. 624-639
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Tidskriftsartikel (refereegranskat)abstract
- Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genomewide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR- baseline (11 novel, one known for this phenotype), including nine variants robustly associated across models were identified. All loci for eGFR-decline were known for cross-sectional eGFR and thus distinguished a subgroup of eGFR loci. Seven of the nine variants showed variant- by-age interaction on eGFR cross section (further about 350,000 individuals), which linked genetic associations for eGFR-decline with agedependency of genetic cross- section associations. Clinically important were two to four-fold greater genetic effects on eGFR-decline in high-risk subgroups. Five variants associated also with chronic kidney disease progression mapped to genes with functional in- silico evidence (UMOD, SPATA7, GALNTL5, TPPP). An unfavorable versus favorable nine-variant genetic profile showed increased risk odds ratios of 1.35 for kidney failure (95% confidence intervals 1.03- 1.77) and 1.27 for acute kidney injury (95% confidence intervals 1.08-1.50) in over 2000 cases each, with matched controls). Thus, we provide a large data resource, genetic loci, and prioritized genes for kidney function decline, which help inform drug development pipelines revealing important insights into the age-dependency of kidney function genetics.
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| 9. |
- Lopes, Renato D., et al.
(författare)
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Highlights from the III International Symposium of Thrombosis and Anticoagulation (ISTA), October 14-16, 2010, Sao Paulo, Brazil
- 2011
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Ingår i: Journal of Thrombosis and Thrombolysis. - : Springer Science and Business Media LLC. - 0929-5305 .- 1573-742X. ; 32:2, s. 242-266
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Tidskriftsartikel (refereegranskat)abstract
- To discuss and share knowledge around advances in the care of patients with thrombotic disorders, the Third International Symposium of Thrombosis and Anticoagulation was held in So Paulo, Brazil, from October 14-16, 2010. This scientific program was developed by clinicians for clinicians, and was promoted by four major clinical research institutes: the Brazilian Clinical Research Institute, the Duke Clinical Research Institute of the Duke University School of Medicine, the Canadian VIGOUR Centre, and the Uppsala Clinical Research Center. Comprising 3 days of academic presentations and open discussion, the symposium had as its primary goal to educate, motivate, and inspire internists, cardiologists, hematologists, and other physicians by convening national and international visionaries, thought-leaders, and dedicated clinician-scientists. This paper summarizes the symposium proceedings.
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| 10. |
- Wallentin, Lars, 1943-, et al.
(författare)
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Early invasive versus non-invasive treatment in patients with non-ST-elevation acute coronary syndrome (FRISC-II) : 15 year follow-up of a prospective, randomised, multicentre study
- 2016
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Ingår i: The Lancet. - : ELSEVIER SCIENCE INC. - 0140-6736 .- 1474-547X. ; 388:10054, s. 1903-1911
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Tidskriftsartikel (refereegranskat)abstract
- Background The FRISC-II trial was the first randomised trial to show a reduction in death or myocardial infarction with an early invasive versus a non-invasive treatment strategy in patients with non-ST-elevation acute coronary syndrome. Here we provide a remaining lifetime perspective on the effects on all cardiovascular events during 15 years' follow-up. Methods The FRISC-II prospective, randomised, multicentre trial was done at 58 Scandinavian centres in Sweden, Denmark, and Norway. Between June 17, 1996, and Aug 28, 1998, we randomly assigned (1:1) 2457 patients with non-ST-elevation acute coronary syndrome to an early invasive treatment strategy, aiming for revascularisation within 7 days, or a non-invasive strategy, with invasive procedures at recurrent symptoms or severe exercise-induced ischaemia. Plasma for biomarker analyses was obtained at randomisation. For long-term outcomes, we linked data with national health-care registers. The primary endpoint was a composite of death or myocardial infarction. Outcomes were compared as the average postponement of the next event, including recurrent events, calculated as the area between mean cumulative count-of-events curves. Analyses were done by intention to treat. Findings At a minimum of 15 years' follow-up on Dec 31, 2014, data for survival status and death were available for 2421 (99%) of the initially recruited 2457 patients, and for other events after 2 years for 2182 (89%) patients. During follow-up, the invasive strategy postponed death or next myocardial infarction by a mean of 549 days (95% CI 204-888; p= 0.0020) compared with the non-invasive strategy. This effect was larger in non-smokers (mean gain 809 days, 95% CI 402-1175; p(interaction) = 0.0182), patients with elevated troponin T (778 days, 357-1165; p (interaction) = 0.0241), and patients with high concentrations of growth differentiation factor-15 (1356 days, 507-1650; p (interaction) = 0.0210). The difference was mainly driven by postponement of new myocardial infarction, whereas the early difference in mortality alone was not sustained over time. The invasive strategy led to a mean of 1128 days (95% CI 830-1366) postponement of death or next readmission to hospital for ischaemic heart disease, which was consistent in all subgroups (p< 0.0001). Interpretation During 15 years of follow-up, an early invasive treatment strategy postponed the occurrence of death or next myocardial infarction by an average of 18 months, and the next readmission to hospital for ischaemic heart disease by 37 months, compared with a non-invasive strategy in patients with non-ST-elevation acute coronary syndrome. This remaining lifetime perspective supports that an early invasive treatment strategy should be the preferred option in most patients with non-ST-elevation acute coronary syndrome.
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| 11. |
- Wuttke, Matthias, et al.
(författare)
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A catalog of genetic loci associated with kidney function from analyses of a million individuals
- 2019
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Ingår i: Nature Genetics. - : NATURE PUBLISHING GROUP. - 1061-4036 .- 1546-1718. ; 51:6, s. 957-972
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Tidskriftsartikel (refereegranskat)abstract
- Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
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| 12. |
- Zhao, J. H., et al.
(författare)
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Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets
- 2023
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Ingår i: Nature Immunology. - : Springer Nature. - 1529-2908 .- 1529-2916. ; 24:9, s. 1540-1551
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Tidskriftsartikel (refereegranskat)abstract
- Circulating proteins have important functions in inflammation and a broad range of diseases. To identify genetic influences on inflammation-related proteins, we conducted a genome-wide protein quantitative trait locus (pQTL) study of 91 plasma proteins measured using the Olink Target platform in 14,824 participants. We identified 180 pQTLs (59 cis, 121 trans). Integration of pQTL data with eQTL and disease genome-wide association studies provided insight into pathogenesis, implicating lymphotoxin-alpha in multiple sclerosis. Using Mendelian randomization (MR) to assess causality in disease etiology, we identified both shared and distinct effects of specific proteins across immune-mediated diseases, including directionally discordant effects of CD40 on risk of rheumatoid arthritis versus multiple sclerosis and inflammatory bowel disease. MR implicated CXCL5 in the etiology of ulcerative colitis (UC) and we show elevated gut CXCL5 transcript expression in patients with UC. These results identify targets of existing drugs and provide a powerful resource to facilitate future drug target prioritization. Here the authors identify genetic effectors of the level of inflammation-related plasma proteins and use Mendelian randomization to identify proteins that contribute to immune-mediated disease risk.
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| 13. |
- Aktaa, Suleman, et al.
(författare)
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Data standards for transcatheter aortic valve implantation : the European Unified Registries for Heart Care Evaluation and Randomised Trials (EuroHeart).
- 2023
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Ingår i: European Heart Journal - Quality of Care and Clinical Outcomes. - : Oxford University Press. - 2058-5225 .- 2058-1742. ; 9:5, s. 529-536
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Standardized data definitions are necessary for the quantification of quality of care and patient outcomes in observational studies and randomised controlled trials (RCTs). The European Unified Registries for Heart Care Evaluation and Randomised Trials (EuroHeart) project of the European Society of Cardiology (ESC) aims to create pan-European data standards for cardiovascular diseases and interventions, including transcatheter aortic valve implantation (TAVI).METHODS AND RESULTS: We followed the EuroHeart methodology for cardiovascular data standard development. A Working Group of 29 members representing 12 countries was established and included a patient representative, as well as experts in the management of valvular heart disease from the European Association of Percutaneous Cardiovascular Interventions (EAPCI), the European Association of Cardiovascular Imaging (EACVI) and the Working Group on Cardiovascular Surgery. We conducted a systematic review of the literature and used a modified Delphi method to reach consensus on a final set of variables. For each variable, the Working Group provided a definition, permissible values and categorized the variable as mandatory (Level 1) or additional (Level 2) based on its clinical importance and feasibility. In total, 93 Level 1 and 113 Level 2 variables were selected, with the level 1 variables providing the dataset for registration of patients undergoing TAVI on the EuroHeart IT platform.CONCLUSION: This document provides details of the EuroHeart data standards for TAVI processes of care and in-hospital outcomes. In the context of EuroHeart, this will facilitate quality improvement, observational research, registry-based RCTs and post-marketing surveillance of devices and pharmacotherapies.
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| 14. |
- Batra, Gorav, et al.
(författare)
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Biomarker-Based Prediction of Recurrent Ischemic Events in Patients With Acute Coronary Syndromes
- 2022
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Ingår i: Journal of the American College of Cardiology. - : Elsevier. - 0735-1097 .- 1558-3597. ; 80:18, s. 1735-1747
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: In patients with acute coronary syndrome (ACS), there is residual and variable risk of recurrent ischemic events.OBJECTIVES: This study aimed to develop biomarker-based prediction models for 1-year risk of cardiovascular (CV) death and myocardial infarction (MI) in patients with ACS undergoing percutaneous coronary intervention.METHODS: We included 10,713 patients from the PLATO (A Comparison of Ticagrelor [AZD6140] and Clopidogrel in Patients With Acute Coronary Syndrome) trial in the development cohort and externally validated in 3,508 patients from the TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) trial. Variables contributing to risk of CV death/MI were assessed using Cox regression models, and a score was derived using subsets of variables approximating the full model.RESULTS: There were 632 and 190 episodes of CV death/MI in the development and validation cohorts. The most important predictors of CV death/MI were the biomarkers, growth differentiation factor 15, and N-terminal pro-B-type natriuretic peptide, which had greater prognostic value than all candidate variables. The final model included 8 items: age (A), biomarkers (B) (growth differentiation factor 15 and N-terminal pro-B-type natriuretic peptide), and clinical variables (C) (extent of coronary artery disease, previous vascular disease, Killip class, ACS type, P2Y12 inhibitor). The model, named ABC-ACS ischemia, was well calibrated and showed good discriminatory ability for 1-year risk of CV death/MI with C-indices of 0.71 and 0.72 in the development and validation cohorts, respectively. For CV death, the score performed better, with C-indices of 0.80 and 0.84 in the development and validation cohorts, respectively.CONCLUSIONS: An 8-item score for the prediction of CV death/MI was developed and validated for patients with ACS undergoing percutaneous coronary intervention. The ABC-ACS ischemia score showed good calibration and discrimination and might be useful for risk prediction and decision support in patients with ACS. (A Comparison of Ticagrelor [AZD6140] and Clopidogrel in Patients With Acute Coronary Syndrome [PLATO]; NCT00391872; Trial to Assess the Effects of Vorapaxar [SCH 530348; MK-5348] in Preventing Heart Attack and Stroke in Participants With Acute Coronary Syndrome [TRACER]; NCT00527943)
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| 15. |
- Batra, Gorav, et al.
(författare)
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Data standards for atrial fibrillation/flutter and catheter ablation : The European Unified Registries for Heart Care Evaluation and Randomized Trials (EuroHeart)
- 2023
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Ingår i: European Heart Journal - Quality of Care and Clinical Outcomes. - : Oxford University Press. - 2058-5225 .- 2058-1742. ; 9:6, s. 609-620
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Standardized data definitions are essential for monitoring and assessment of care and outcomes in observational studies and randomized controlled trials (RCTs). The European Unified Registries for Heart Care Evaluation and Randomized Trials (EuroHeart) project of the European Society of Cardiology aimed to develop contemporary data standards for atrial fibrillation/flutter (AF/AFL) and catheter ablation.METHODS AND RESULTS: We used the EuroHeart methodology for development of data standards and formed a Working Group comprising 23 experts in AF/AFL and catheter ablation registries, as well as representatives from the European Heart Rhythm Association and EuroHeart. We conducted a systematic literature review of AF/AFL and catheter ablation registries and data standard documents to generate candidate variables. We used a modified Delphi method to reach consensus on a final variable set. For each variable, the Working Group developed permissible values and definitions, and agreed as to whether the variable was mandatory (Level 1) or additional (Level 2). In total, 70 Level 1 and 92 Level 2 variables were selected and reviewed by a wider Reference Group of 42 experts from 24 countries. The Level 1 variables were implemented into the EuroHeart IT platform as the basis for continuous registration of individual patient data.CONCLUSION: By means of a structured process and working with international stakeholders, harmonized data standards for AF/AFL and catheter ablation for AF/AFL were developed. In context of the EuroHeart project, this will facilitate country-level quality of care improvement, international observational research, registry-based RCTs and post-marketing surveillance of devices and pharmacotherapies.
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| 16. |
- Becker, Richard C, et al.
(författare)
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Bleeding complications with the P2Y12 receptor antagonists clopidogrel and ticagrelor in the PLATelet inhibition and patient Outcomes (PLATO) trial
- 2011
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 32:23, s. 2933-2944
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Tidskriftsartikel (refereegranskat)abstract
- AimsMore intense platelet-directed therapy for acute coronary syndrome (ACS) may increase bleeding risk. The aim of the current analysis was to determine the rate, clinical impact, and predictors of major and fatal bleeding complications in the PLATO study.Methods and resultsPLATO was a randomized, double-blind, active control international, phase 3 clinical trial in patients with acute ST elevation and non-ST-segment elevation ACS. A total of 18 624 patients were randomized to either ticagrelor, a non-thienopyridine, reversibly binding platelet P2Y(12) receptor antagonist, or clopidogrel in addition to aspirin. Patients randomized to ticagrelor and clopidogrel had similar rates of PLATO major bleeding (11.6 vs. 11.2%; P = 0.43), TIMI major bleeding (7.9 vs. 7.7%, P = 0.56) and GUSTO severe bleeding (2.9 vs. 3.1%, P = 0.22). Procedure-related bleeding rates were also similar. Non-CABG major bleeding (4.5 vs. 3.8%, P = 0.02) and non-procedure-related major bleeding (3.1 vs. 2.3%, P = 0.05) were more common in ticagrelor-treated patients, primarily after 30 days on treatment. Fatal bleeding and transfusion rates did not differ between groups. There were no significant interactions for major bleeding or combined minor plus major bleeding between treatment groups and age ≥75 years, weight <60 kg, region, chronic kidney disease, creatinine clearance <60 mL/min, aspirin dose >325 mg on the day of randomization, pre-randomization clopidogrel administration, or clopidogrel loading dose.Conclusion Ticagrelor compared with clopidogrel was associated with similar total major bleeding but increased non-CABG and non-procedure-related major bleeding, primarily after 30 days on study drug treatment. Fatal bleeding was low and did not differ between groups.
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| 17. |
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| 18. |
- Eggers, Kai M, et al.
(författare)
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Relations of growth-differentiation factor-15 to biomarkers reflecting vascular pathologies in a population-based sample of elderly subjects
- 2012
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Ingår i: Scandinavian Journal of Clinical and Laboratory Investigation. - : Informa UK Limited. - 0036-5513 .- 1502-7686. ; 72:1, s. 45-51
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Tidskriftsartikel (refereegranskat)abstract
- Background. Growth-differentiation factor-15 (GDF-15) has recently emerged as a risk predictor in patients with cardiac diseases. GDF-15 is commonly related to cardiovascular risk factors, inflammatory activity and cardiac abnormalities. However, it is not clear whether it might be an indicator of vascular pathologies as well.Methods.Circulating levels of GDF-15 were measured in 1004 elderly community dwellers participating in the PIVUS study. The relations of GDF-15 to biomarkers of endothelial activation (E-selectin, P-selectin, ICAM-1, VCAM-1), extracellular matrix degradation (MMP-9, TIMP-1), coagulatory activity (D-dimer, von Willebrand factor, prothrombin fragment 1 + 2, factor VIIa), and fibrinolytic activity (PAI-1 activity, tPA-antigen) were assessed by multiple linear regressions.Results. The median GDF-15 level was 1135 ng/L. By linear correlation analysis, GDF-15 exhibited a moderate relation to von Willebrand factor (r = 0.30), and weak, albeit significant relations (r = 0.13-0.29) to E-selectin, P-selectin, ICAM-1, VCAM-1, MMP-9, TIMP-1, D-dimer, PAI-1 activity and tPA-antigen. The relations to the assessed biomarkers of endothelial activation, TIMP-1, D-dimer and von Willebrand factor remained significant applying multiple linear regression models adjusted for clinical covariates and echocardiographic data. There were no significant relations between GDF-15 and biomarkers solely reflecting coagulatory activity.Conclusions.In the elderly, GDF-15 reflects endothelial activation and vascular inflammation and thus, multiple pathways involved in the development and progression of atherosclerosis.
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| 19. |
- Held, Claes, 1956-, et al.
(författare)
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Ticagrelor Versus Clopidogrel in Patients With Acute Coronary Syndromes Undergoing Coronary Artery Bypass Surgery Results From the PLATO (Platelet Inhibition and Patient Outcomes) Trial
- 2011
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Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 57:6, s. 672-684
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Tidskriftsartikel (refereegranskat)abstract
- Objectives The purpose of this study is to evaluate the efficacy and safety of ticagrelor and clopidogrel in patients with acute coronary syndrome undergoing coronary artery bypass graft surgery (CABG), as a post-randomization strategy. Background Ticagrelor is a novel, reversibly binding, oral, direct-acting P2Y(12)-receptor antagonist. In the PLATO (Platelet Inhibition and Patient Outcomes) trial, which randomized 18,624 patients with acute coronary syndromes, ticagrelor compared with clopidogrel significantly reduced the risk of the primary composite end point of cardiovascular (CV) death, myocardial infarction, or stroke (hazard ratio [HR]: 0.84; 95% confidence interval [CI]: 0.77 to 0.92; p < 0.001). This report investigated the outcomes of patients treated with CABG during the trial. Methods In total, 1,899 patients underwent CABG post-randomization. The protocol recommended ticagrelor/placebo to be withheld for 24 to 72 h and clopidogrel/placebo for 5 days preoperatively. In all, 1,261 patients underwent CABG and were receiving study drug treatment <7 days before surgery. The statistical analysis was based on events occurring from the CABG procedure until the end of the study, excluding 3 patients with CABG after study end. Results In the 1,261 patient cohort, the relative reduction of primary composite end point at 12 months (10.6% [66 of 629] with ticagrelor versus 13.1% [79 of 629] with clopidogrel; HR: 0.84; 95% CI: 0.60 to 1.16; p = 0.29) was consistent with the results of the whole trial. Total mortality was reduced from 9.7% (58 of 629) to 4.7% (29 of 629; HR: 0.49; 95% CI: 0.32 to 0.77; p < 0.01), CV death from 7.9% (47 of 629) to 4.1% (25 of 629; HR: 0.52; 95% CI: 0.32 to 0.85; p < 0.01), and non-CV death numerically from 2.0% to 0.7% (p = 0.07). There was no significant difference in CABG-related major bleeding between the randomized treatments. Conclusions In the subgroup of patients undergoing CABG within 7 days after the last study drug intake, ticagrelor compared with clopidogrel was associated with a substantial reduction in total and CV mortality without excess risk of CABG-related bleeding.
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| 20. |
- Kapelios, Chris J, et al.
(författare)
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Association between loop diuretic dose changes and outcomes in chronic heart failure : observations from the ESC-EORP Heart Failure Long-Term Registry.
- 2020
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Ingår i: European Journal of Heart Failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 22:8, s. 1424-1437
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Guidelines recommend down-titration of loop diuretics (LD) once euvolaemia is achieved. In outpatients with heart failure (HF), we investigated LD dose changes in daily cardiology practice, agreement with guideline recommendations, predictors of successful LD down-titration and association between dose changes and outcomes.METHODS AND RESULTS: We included 8130 HF patients from the ESC-EORP Heart Failure Long-Term Registry. Among patients who had dose decreased, successful decrease was defined as the decrease not followed by death, HF hospitalization, New York Heart Association class deterioration, or subsequent increase in LD dose. Mean age was 66 ± 13 years, 71% men, 62% HF with reduced ejection fraction, 19% HF with mid-range ejection fraction, 19% HF with preserved ejection fraction. Median [interquartile range (IQR)] LD dose was 40 (25-80) mg. LD dose was increased in 16%, decreased in 8.3% and unchanged in 76%. Median (IQR) follow-up was 372 (363-419) days. Diuretic dose increase (vs. no change) was associated with HF death [hazard ratio (HR) 1.53, 95% confidence interval (CI) 1.12-2.08; P = 0.008] and nominally with cardiovascular death (HR 1.25, 95% CI 0.96-1.63; P = 0.103). Decrease of diuretic dose (vs. no change) was associated with nominally lower HF (HR 0.59, 95% CI 0.33-1.07; P = 0.083) and cardiovascular mortality (HR 0.62, 95% CI 0.38-1.00; P = 0.052). Among patients who had LD dose decreased, systolic blood pressure [odds ratio (OR) 1.11 per 10 mmHg increase, 95% CI 1.01-1.22; P = 0.032], and absence of (i) sleep apnoea (OR 0.24, 95% CI 0.09-0.69; P = 0.008), (ii) peripheral congestion (OR 0.48, 95% CI 0.29-0.80; P = 0.005), and (iii) moderate/severe mitral regurgitation (OR 0.57, 95% CI 0.37-0.87; P = 0.008) were independently associated with successful decrease.CONCLUSION: Diuretic dose was unchanged in 76% and decreased in 8.3% of outpatients with chronic HF. LD dose increase was associated with worse outcomes, while the LD dose decrease group showed a trend for better outcomes compared with the no-change group. Higher systolic blood pressure, and absence of (i) sleep apnoea, (ii) peripheral congestion, and (iii) moderate/severe mitral regurgitation were independently associated with successful dose decrease.
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| 21. |
- Lind, Lars, et al.
(författare)
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Growth-differentiation factor-15 is an independent marker of cardiovascular dysfunction and disease in the elderly : results from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) Study
- 2009
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 30:19, s. 2346-2353
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Growth-differentiation factor-15 (GDF-15) is emerging as an independent prognostic biomarker in patients with cardiovascular (CV) disease. Little is known about the pathophysiological basis for the close association of GDF-15 to future CV events. We hypothesized that GDF-15 is related to underlying CV pathologies. METHODS AND RESULTS: To relate the levels of GDF-15 to indices of CV dysfunction and disease in elderly individuals, serum levels of GDF-15 were measured in 1004 subjects aged 70 years from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Carotid intima-media thickness and plaque burden, and left ventricular (LV) geometry and function were assessed by ultrasound. Endothelial function was evaluated in forearm resistance vessels and in the brachial artery by venous occlusion plethysmography and ultrasound imaging, respectively. Elevated levels of GDF-15 were related to several CV risk factors (male gender, current smoking, body mass index, waist circumference, diabetes, fasting glucose, triglycerides, and low HDL cholesterol). After adjustment for CV risk factors, increased levels of GDF-15 were associated with reduced endothelium-dependent vasodilation in resistance vessels, plaque burden, LV mass and concentric LV hypertrophy, reduced LV ejection fraction, and clinical manifestations of coronary artery disease and heart failure. CONCLUSION: GDF-15 carries information on CV dysfunction and disease that is not captured by traditional CV risk factors in elderly individuals.
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| 22. |
- Mahmoodi, Bakhtawar K., et al.
(författare)
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Association of Factor V Leiden With Subsequent Atherothrombotic Events A GENIUS-CHD Study of Individual Participant Data
- 2020
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Ingår i: Circulation. - : Ovid Technologies (Wolters Kluwer Health). - 0009-7322 .- 1524-4539. ; 142:6, s. 546-555
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Tidskriftsartikel (refereegranskat)abstract
- Background: Studies examining the role of factor V Leiden among patients at higher risk of atherothrombotic events, such as those with established coronary heart disease (CHD), are lacking. Given that coagulation is involved in the thrombus formation stage on atherosclerotic plaque rupture, we hypothesized that factor V Leiden may be a stronger risk factor for atherothrombotic events in patients with established CHD.Methods: We performed an individual-level meta-analysis including 25 prospective studies (18 cohorts, 3 case-cohorts, 4 randomized trials) from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) consortium involving patients with established CHD at baseline. Participating studies genotyped factor V Leiden status and shared risk estimates for the outcomes of interest using a centrally developed statistical code with harmonized definitions across studies. Cox proportional hazards regression models were used to obtain age- and sex-adjusted estimates. The obtained estimates were pooled using fixed-effect meta-analysis. The primary outcome was composite of myocardial infarction and CHD death. Secondary outcomes included any stroke, ischemic stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality.Results: The studies included 69 681 individuals of whom 3190 (4.6%) were either heterozygous or homozygous (n=47) carriers of factor V Leiden. Median follow-up per study ranged from 1.0 to 10.6 years. A total of 20 studies with 61 147 participants and 6849 events contributed to analyses of the primary outcome. Factor V Leiden was not associated with the combined outcome of myocardial infarction and CHD death (hazard ratio, 1.03 [95% CI, 0.92-1.16];I-2=28%;P-heterogeneity=0.12). Subgroup analysis according to baseline characteristics or strata of traditional cardiovascular risk factors did not show relevant differences. Similarly, risk estimates for the secondary outcomes including stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality were also close to identity.Conclusions: Factor V Leiden was not associated with increased risk of subsequent atherothrombotic events and mortality in high-risk participants with established and treated CHD. Routine assessment of factor V Leiden status is unlikely to improve atherothrombotic events risk stratification in this population.
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| 23. |
- Szummer, Karolina, et al.
(författare)
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Relations between implementation of new treatments and improved outcomes in patients with non-ST-elevation myocardial infarction during the last 20 years : experiences from SWEDEHEART registry 1995 to 2014
- 2018
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Ingår i: European Heart Journal. - : OXFORD UNIV PRESS. - 0195-668X .- 1522-9645. ; 39:42, s. 3766-3776
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Tidskriftsartikel (refereegranskat)abstract
- Aims We assessed the changes in short- and long-term outcomes and their relation to implementation of new evidence- based treatments in all patients with non-ST-elevation myocardial infarction (NSTEMI) in Sweden over 20 years. Methods and results Cases with NSTEMI (n = 205 693) between 1995 and 2014 were included from the nationwide Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART) registry. During 20 years in-hospital invasive procedures increased from 1.9% to 73.2%, percutaneous coronary intervention or coronary artery bypass grafting 6.5% to 58.1%, dual antiplatelet medication 0% to 72.7%, statins 13.3% to 85.6%, and angiotensin-converting enzyme inhibitors/angiotensin II receptor blocker 36.8% to 75.5%. The standardized 1-year mortality ratio compared with a control population decreased from 5.53 [95% confidence interval (CI) 5.30-5.75] to 3.03 (95% CI 2.89-3.19). If patients admitted the first 2 years were modelled to receive the same invasive treatments as the last 2 years the expected mortality/ myocardial infarction (MI) rate would be reduced from 33.0% to 25.0%. After adjusting for differences in baseline characteristics, the change of 1-year cardiovascular death/MI corresponded to a linearly decreasing odds ratio trend of 0.930 (95% CI 0.926-0.935) per 2-year period. This trend was substantially attenuated [0.970 (95% CI 0.964-0.975)] after adjusting for changes in coronary interventions, and almost eliminated [0.988 (95% CI 0.982-0.994)] after also adjusting for changes in discharge medications. Conclusion In NSTEMI patients during the last 20 years, there has been a substantial improvement in long-term survival and re- duction in the risk of new cardiovascular events. These improvements seem mainly explained by the gradual uptake and widespread use of in-hospital coronary interventions and evidence-based long-term medications.
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