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- Grip, Lars, 1952, et al.
(författare)
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From European to National guidelines on heart disease
- 2011
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Ingår i: Scandinavian Cardiovascular Journal. - : Informa UK Limited. - 1401-7431 .- 1651-2006. ; 45:1, s. 3-13
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Forskningsöversikt (refereegranskat)abstract
- Background/aims. Guidelines from the European Society of Cardiology are important tools for defining and establishing current standards of care for various heart diseases. The aim of the present paper is to describe the process of how these international guidelines may be transformed and implemented at a national level in Sweden. Methods/results. The structure and process behind the national guidelines for heart diseases in Sweden and their relationship to the underlying European guidelines are described and differences between the national and European levels highlighted. We also give examples of how the scientific values of health care measures are weighted against health economic perspectives and integrated in a prioritization process. Compared to the European guidelines, the Swedish national guidelines have a broader economic perspective and aim to ensure that health care is cost effective and provided to all Swedish citizens on equal terms. Discussion. When certain health care measures are implemented, the national process can result in other priorities than could be expected from the European guidelines alone. On the other hand, a forceful implementation may be facilitated by the societal context in which these national guidelines are produced.
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| 4. |
- 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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| 5. |
- 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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- Oldgren, Jonas, et al.
(författare)
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Myocardial damage, coagulation activity and the response to thrombin inhibition in unstable coronary artery disease.
- 2004
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Ingår i: Thrombosis and haemostasis. - 0340-6245. ; 91:2, s. 381-7
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Tidskriftsartikel (refereegranskat)abstract
- Unstable coronary artery disease is in most cases associated with plaque rupture, activation of the coagulation system and subsequent intracoronary thrombus formation which may cause myocardial cell damage. The aim of the present analysis was to assess the relation between troponin T, markers of coagulation activity, i.e. prothrombin fragment 1+2, thrombin-antithrombin complex, soluble fibrin and D-dimer, and ischemic events, i.e. death, myocardial (re-)infarction or refractory angina. 320 patients with unstable coronary artery disease were randomized to 72 hours infusion with inogatran, a low molecular weight direct thrombin inhibitor, or unfractionated heparin. Patients with elevated troponin levels had higher levels of prothrombin fragment 1+2, soluble fibrin and D-dimer before, during, and at 24 hours after cessation of anticoagulant treatment. These troponin-positive patients tended to have worse short-term clinical outcome, without relation to markers of coagulation activity. Troponin-negative patients with unchanged or early increased thrombin generation during treatment had a cluster of ischemic events within 24 hours after cessation of the study drug. The 30-day ischemic event rate was 19 % in troponin-negative patients with unchanged or early increased prothrombin fragment 1+2, and 5.7 % in patients with decreased prothrombin fragment 1+2, p=0.006, and similarly 15 % in troponin-negative patients with unchanged or early increased thrombin-antithrombin complex and 4.5 % in patients with decreased thrombin-antithrombin complex, p=0.02. In conclusion, in unstable coronary artery disease a troponin elevation indicates higher risk and higher coagulation activity. However, among the troponin negative patients, with a lower risk and lower coagulation activity, a part of the patients seem to be non-responders to treatment with a thrombin inhibitor expressed as unchanged or raised coagulation activity and a raised risk of ischemic events early after cessation of treatment.
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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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| 9. |
- Alexander, John H., et al.
(författare)
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Apixaban, an oral, direct, selective factor Xa inhibitor, in combination with antiplatelet therapy after acute coronary syndrome : results of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) trial
- 2009
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Ingår i: Circulation. - 0009-7322 .- 1524-4539. ; 119:22, s. 2877-2885
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: After an acute coronary syndrome, patients remain at risk of recurrent events. Apixaban, an oral direct factor Xa inhibitor, is a novel anticoagulant that may reduce these events but also poses a risk of bleeding. METHODS AND RESULTS: Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) was a phase 2, double-blind, placebo-controlled, dose-ranging study. Patients (n=1715) with recent ST-elevation or non-ST-elevation acute coronary syndrome were randomized to 6 months of placebo (n=611) or 1 of 4 doses of apixaban: 2.5 mg twice daily (n=317), 10 mg once daily (n=318), 10 mg twice daily (n=248), or 20 mg once daily (n=221). Nearly all patients received aspirin; 76% received clopidogrel. The primary outcome was International Society of Thrombosis and Hemostasis major or clinically relevant nonmajor bleeding. A secondary outcome was cardiovascular death, myocardial infarction, severe recurrent ischemia, or ischemic stroke. At the recommendation of the Data Monitoring Committee, the 2 higher-dose apixaban arms were discontinued because of excess total bleeding. Compared with placebo, apixaban 2.5 mg twice daily (hazard ratio, 1.78; 95% confidence interval, 0.91 to 3.48; P=0.09) and 10 mg once daily (hazard ratio, 2.45; 95% confidence interval, 1.31 to 4.61; P=0.005) resulted in a dose-dependent increase in major or clinically relevant nonmajor bleeding. Apixaban 2.5 mg twice daily (hazard ratio, 0.73; 95% confidence interval, 0.44 to 1.19; P=0.21) and 10 mg once daily (hazard ratio, 0.61; 95% confidence interval, 0.35 to 1.04; P=0.07) resulted in lower rates of ischemic events compared with placebo. The increase in bleeding was more pronounced and the reduction in ischemic events was less evident in patients taking aspirin plus clopidogrel than in those taking aspirin alone. CONCLUSIONS: We observed a dose-related increase in bleeding and a trend toward a reduction in ischemic events with the addition of apixaban to antiplatelet therapy in patients with recent acute coronary syndrome. The safety and efficacy of apixaban may vary depending on background antiplatelet therapy. Further testing of apixaban in patients at risk of recurrent ischemic events is warranted.
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