| 1. |
- Aktaa, Suleman, et al.
(författare)
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Data standards for heart failure : the European Unified Registries for Heart Care Evaluation and Randomized Trials (EuroHeart)
- 2022
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Ingår i: European Heart Journal. - : Oxford University Press. - 0195-668X .- 1522-9645. ; 43:23, s. 2185-
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Tidskriftsartikel (refereegranskat)abstract
- Standardized data definitions are essential for assessing the quality of care and patient outcomes in observational studies and randomized controlled trials. The European Unified Registries for Heart Care Evaluation and Randomized Trials (EuroHeart) project of the European Society of Cardiology (ESC) aims to create contemporary pan-European data standards for cardiovascular diseases, including heart failure (HF). We followed the EuroHeart methodology for cardiovascular data standard development. A Working Group including experts in HF registries, representatives from the Heart Failure Association of the ESC, and the EuroHeart was formed. Using Embase and Medline (2016-21), we conducted a systematic review of the literature on data standards, registries, and trials to identify variables pertinent to HF. A modified Delphi method was used to reach a consensus on the final set of variables. For each variable, the Working Group developed data definitions and agreed on whether it was mandatory (Level 1) or additional (Level 2). In total, 84 Level 1 and 79 Level 2 variables were selected for nine domains of HF care. These variables were reviewed by an international Reference Group with the Level 1 variables providing the dataset for registration of patients with HF on the EuroHeart IT platform. By means of a structured process and interaction with international stakeholders, harmonized data standards for HF have been developed. In the context of the EuroHeart, this will facilitate quality improvement, international observational research, registry-based randomized trials, and post-marketing surveillance of devices and pharmacotherapies across Europe.
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| 2. |
- Ferrannini, Giulia, et al.
(författare)
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Screening for Glucose Perturbations and Risk Factor Management in Dysglycemic Patients With Coronary Artery Disease-A Persistent Challenge in Need of Substantial Improvement : A Report From ESC EORP EUROASPIRE V.
- 2020
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Ingår i: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 43:4, s. 726-733
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Dysglycemia, in this survey defined as impaired glucose tolerance (IGT) or type 2 diabetes, is common in patients with coronary artery disease (CAD) and associated with an unfavorable prognosis. This European survey investigated dysglycemia screening and risk factor management of patients with CAD in relation to standards of European guidelines for cardiovascular subjects.RESEARCH DESIGN AND METHODS: The European Society of Cardiology's European Observational Research Programme (ESC EORP) European Action on Secondary and Primary Prevention by Intervention to Reduce Events (EUROASPIRE) V (2016-2017) included 8,261 CAD patients, aged 18-80 years, from 27 countries. If the glycemic state was unknown, patients underwent an oral glucose tolerance test (OGTT) and measurement of glycated hemoglobin A1c. Lifestyle, risk factors, and pharmacological management were investigated.RESULTS: A total of 2,452 patients (29.7%) had known diabetes. OGTT was performed in 4,440 patients with unknown glycemic state, of whom 41.1% were dysglycemic. Without the OGTT, 30% of patients with type 2 diabetes and 70% of those with IGT would not have been detected. The presence of dysglycemia almost doubled from that self-reported to the true proportion after screening. Only approximately one-third of all coronary patients had completely normal glucose metabolism. Of patients with known diabetes, 31% had been advised to attend a diabetes clinic, and only 24% attended. Only 58% of dysglycemic patients were prescribed all cardioprotective drugs, and use of sodium-glucose cotransporter 2 inhibitors (3%) or glucagon-like peptide 1 receptor agonists (1%) was small.CONCLUSIONS: Urgent action is required for both screening and management of patients with CAD and dysglycemia, in the expectation of a substantial reduction in risk of further cardiovascular events and in complications of diabetes, as well as longer life expectancy.
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| 3. |
- Folkersen, Lasse, et al.
(författare)
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Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.
- 2020
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Ingår i: Nature metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 2:10, s. 1135-1148
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Tidskriftsartikel (refereegranskat)abstract
- Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.
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| 4. |
- 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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| 5. |
- 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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| 6. |
- Klaric, Lucija, et al.
(författare)
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Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19.
- 2021
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Ingår i: medRxiv : the preprint server for health sciences. - : Cold Spring Harbor Laboratory. ; , s. 1-28
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using sensitivity analyses and colocalization testing provided strong evidence to implicate the apoptosis-associated cytokine receptor FAS as a causal mediator of severe COVID-19. This effect was specific to severe disease. Using RNA-seq data from 4,778 individuals, we demonstrate that the pQTL at the FAS locus results from genetically influenced alternate splicing causing skipping of exon 6. We show that the risk allele for very severe COVID-19 increases the proportion of transcripts lacking exon 6, and thereby increases soluble FAS. Soluble FAS acts as a decoy receptor for FAS-ligand, inhibiting apoptosis induced through membrane-bound FAS. In summary, we demonstrate a novel genetic mechanism that contributes to risk of severe of COVID-19, highlighting a pathway that may be a promising therapeutic target.
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| 7. |
- Simonsson, Moa, et al.
(författare)
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Temporal trends in bleeding events in acute myocardial infarction : insights from the SWEDEHEART registry
- 2020
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Ingår i: European Heart Journal. - : Oxford University Press. - 0195-668X .- 1522-9645. ; 41:7, s. 833-843
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: To describe the time trends of in-hospital and out-of-hospital bleeding parallel to the development of new treatments and ischaemic outcomes over the last 20 years in a nationwide myocardial infarction (MI) population.METHODS AND RESULTS: Patients with acute MI (n = 371 431) enrolled in the SWEDEHEART registry from 1995 until May 2018 were selected and evaluated for in-hospital bleeding and out-of-hospital bleeding events at 1 year. In-hospital bleeding increased from 0.5% to a peak at 2% 2005/2006 and thereafter slightly decreased to a new plateau around 1.3% by the end of the study period. Out-of-hospital bleeding increased in a stepwise fashion from 2.5% to 3.5 % in the middle of the study period and to 4.8% at the end of the study period. The increase in both in-hospital and out-of-hospital bleeding was parallel to increasing use of invasive strategy and adjunctive antithrombotic treatment, dual antiplatelet therapy (DAPT), and potent DAPT, while the decrease in in-hospital bleeding from 2007 to 2010 was parallel to implementation of bleeding avoidance strategies. In-hospital re-infarction decreased from 2.8% to 0.6% and out-of-hospital MI decreased from 12.6% to 7.1%. The composite out-of-hospital MI, cardiovascular death, and stroke decreased in a similar fashion from 18.4% to 9.1%.CONCLUSION: During the last 20 years, the introduction of invasive and more intense antithrombotic treatment has been associated with an increase in bleeding events but concomitant there has been a substantial greater reduction of ischaemic events including improved survival.
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| 8. |
- Thulin, Åsa, et al.
(författare)
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Extracellular vesicles in atrial fibrillation and stroke
- 2020
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Ingår i: Thrombosis Research. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0049-3848 .- 1879-2472. ; 193, s. 180-189
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Tidskriftsartikel (refereegranskat)abstract
- Background: Atrial fibrillation (AF) is associated with a 5-fold increased risk of thromboembolic stroke. Extracellular vesicles (EVs) convey pathophysiological information and are possible biomarkers for risk of stroke. Methods: EVs were measured in 836 patients with AF (of which 280 were stroke cases) selected from the ARISTOTLE trial and in a cohort of unselected 70 year old individuals (n = 1007, reference material). EVs from platelets, leukocytes, erythrocytes and inflammatory endothelial cells were measured using flow cytometry and a solid-phase proximity ligation assay. Results: Concentrations of EVs were higher in the ARISTOTLE patients than in the PIVUS cohort for all the EV groups except EVs from endothelial cells (p < 0.0001). The distributions of the concentrations of the EVs were similar among the control group and the stroke cases for all of the sources of EVs in the ARISTOTLE study. EVs were modestly correlated with the levels of NT-ProBNP, Cystatin C, GDF-15 and D-dimer. Stronger correlations were found for platelet EVs as well as phosphatidyl serine positive EVs that were correlated with CD40 ligand in the ARISTOTLE study. Leukocyte EVs were correlated with IL-6 in both the ARISTOTLE and the PIVUS study, implicating them in different physiological processes. Conclusions: Higher levels of EVs were found in anticoagulated patients with AF and a higher risk of stroke than in a general population of similar age, possibly due to the high disease burden in AF patients. Our data with EVs representing a broad repertoire of activated blood cells in AF patients suggest that EVs are likely not a key mediator of occurrence of stroke in this population.
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| 9. |
- 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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| 10. |
- Yang, Zhijian, et al.
(författare)
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Genetic Landscape of the ACE2 Coronavirus Receptor
- 2022
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Ingår i: Circulation. - : Ovid Technologies (Wolters Kluwer Health). - 0009-7322 .- 1524-4539. ; 30:SUPPL 1, s. 36-36
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Tidskriftsartikel (refereegranskat)abstract
- Background: SARS-CoV-2, the causal agent of COVID-19, enters human cells using the ACE2 (angiotensin-converting enzyme 2) protein as a receptor. ACE2 is thus key to the infection and treatment of the coronavirus. ACE2 is highly expressed in the heart and respiratory and gastrointestinal tracts, playing important regulatory roles in the cardiovascular and other biological systems. However, the genetic basis of the ACE2 protein levels is not well understood.Methods: We have conducted the largest genome-wide association meta-analysis of plasma ACE2 levels in >28 000 individuals of the SCALLOP Consortium (Systematic and Combined Analysis of Olink Proteins). We summarize the cross-sectional epidemiological correlates of circulating ACE2. Using the summary statistics-based high-definition likelihood method, we estimate relevant genetic correlations with cardiometabolic phenotypes, COVID-19, and other human complex traits and diseases. We perform causal inference of soluble ACE2 on vascular disease outcomes and COVID-19 severity using mendelian randomization. We also perform in silico functional analysis by integrating with other types of omics data.Results: We identified 10 loci, including 8 novel, capturing 30% of the heritability of the protein. We detected that plasma ACE2 was genetically correlated with vascular diseases, severe COVID-19, and a wide range of human complex diseases and medications. An X-chromosome cis-protein quantitative trait loci-based mendelian randomization analysis suggested a causal effect of elevated ACE2 levels on COVID-19 severity (odds ratio, 1.63 [95% CI, 1.10-2.42]; P=0.01), hospitalization (odds ratio, 1.52 [95% CI, 1.05-2.21]; P=0.03), and infection (odds ratio, 1.60 [95% CI, 1.08-2.37]; P=0.02). Tissue- and cell type-specific transcriptomic and epigenomic analysis revealed that the ACE2 regulatory variants were enriched for DNA methylation sites in blood immune cells.Conclusions: Human plasma ACE2 shares a genetic basis with cardiovascular disease, COVID-19, and other related diseases. The genetic architecture of the ACE2 protein is mapped, providing a useful resource for further biological and clinical studies on this coronavirus receptor.
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