| 1. |
- Becher, Nina, et al.
(författare)
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Anticoagulation with edoxaban in patients with long atrial high-rate episodes ≥24 h
- 2024
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Ingår i: European Heart Journal. - : Oxford University Press. - 0195-668X .- 1522-9645. ; 45:10, s. 837-849
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND AIMS: Patients with long atrial high-rate episodes (AHRE) ≥ 24 hours and stroke risk factors are often treated with anticoagulation for stroke prevention. Anticoagulation has never been compared to no anticoagulation in these patients.METHODS: This secondary prespecified analysis of NOAH-AFNET 6 examined interactions between AHRE duration at baseline and anticoagulation with edoxaban compared to placebo in patients with AHRE and stroke risk factors. The primary efficacy outcome was a composite of stroke, systemic embolism, or cardiovascular death. The safety outcome was a composite of major bleeding and death. Key secondary outcomes were components of these outcomes and ECG-diagnosed atrial fibrillation.RESULTS: AHRE ≥24 hours were present at baseline in 259/2389 patients enrolled in NOAH-AFNET 6 (11%, 78 ± 7 years old, 28% women, CHA2DS2-VASc score 4). Clinical characteristics were not different from patients with shorter AHRE. During a median follow-up of 1.8 years, the primary outcome occurred in 9/132 patients with AHRE ≥24 hours (4.3%/patient-year, 2 strokes) treated with anticoagulation and in 14/127 patients treated with placebo (6.9%/patient-year, 2 strokes). AHRE duration did not interact with the efficacy (p-interaction = 0.65) or safety (p-interaction = 0.98) of anticoagulation. Analyses including AHRE as a continuous parameter confirmed this. Patients with AHRE ≥24 hours developed more ECG-diagnosed atrial fibrillation (17.0%/patient-year) than patients with shorter AHRE (8.2%/patient-year; p < 0.001).CONCLUSIONS: This hypothesis-generating analysis does not find an interaction between AHRE duration and anticoagulation therapy in patients with device-detected AHRE and stroke risk factors. Further research is needed to identify patients with long AHRE at high stroke risk.
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| 2. |
- Bertaglia, Emanuele, et al.
(författare)
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Atrial high-rate episodes : prevalence, stroke risk, implications for management, and clinical gaps in evidence
- 2019
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Ingår i: Europace. - : Oxford University Press (OUP). - 1099-5129 .- 1532-2092. ; 21:10, s. 1459-1467
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Forskningsöversikt (refereegranskat)abstract
- Self-terminating atrial arrhythmias are commonly detected on continuous rhythm monitoring, e.g. by pacemakers or defibrillators. It is unclear whether the presence of these arrhythmias has therapeutic consequences. We sought to summarize evidence on the prevalence of atrial high-rate episodes (AHREs) and their impact on risk of stroke. We performed a comprehensive, tabulated review of published literature on the prevalence of AHRE. In patients with AHRE, but without atrial fibrillation (AF), we reviewed the stroke risk and the potential risk/benefit of oral anticoagulation. Atrial high-rate episodes are found in 10-30% of AF-free patients. Presence of AHRE slightly increases stroke risk (0.8% to 1%/year) compared with patients without AHRE. Atrial high-rate episode of longer duration (e.g. those >24 h) could be associated with a higher stroke risk. Oral anticoagulation has the potential to reduce stroke risk in patients with AHRE but is associated with a rate of major bleeding of 2%/year. Oral anticoagulation is not effective in patients with heart failure or survivors of a stroke without AF. It remains unclear whether anticoagulation is effective and safe in patients with AHRE. Atrial high-rate episodes are common and confer a slight increase in stroke risk. There is true equipoise on the best way to reduce stroke risk in patients with AHRE. Two ongoing trials (NOAH-AFNET 6 and ARTESiA) will provide much-needed information on the effectiveness and safety of oral anticoagulation using non-vitamin K antagonist oral anticoagulants in patients with AHRE.
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| 3. |
- Dichtl, Wolfgang
(författare)
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Inflammatory transcription factors in atherosclerosis
- 2000
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Transcription factors such as nuclear factor-kB (NF-kB), activator protein-1 (AP-1) and peroxisome proliferator-activated receptors (PPARs) may play important roles in atherogenesis, by regulating chronic subclinical vascular inflammation. In the first study, we showed that VLDL activates the proinflammatory transcription factor NF-kB in endothelial cells both in vitro and in vivo. Oxidation of VLDL reduced its capacity to activate NF-kB in vitro, whereas free fatty acids such as linoleic and oleic acid activated NF-kB to the same extent as VLDL. Intravenous injection of human VLDL (6 mg protein per kg) into rats resulted in arterial activation of NF-kB as assessed by electrophoretic mobility shift assay. Aortic endothelial cells showed positive nuclear staining for the activated RelA (p65) subunit of NF-kB at 6 to 24 hours after injection. There was also a parallel expression of the adhesion molecules ICAM-1 and VCAM-1, as well as the cytokine TNF-alpha Pretreatment of the rats with diet containing 1% of the antioxidant probucol for 8 weeks did not inhibit arterial activation of NF-kB in response to injection of VLDL. Moreover, injection of triglycerides (10% Intralipid, 5 ml/kg) activated arterial expression of NF-kB to the same extent as VLDL. The upregulation of endothelial VCAM-1 expression by linoleic acid in vitro was shown to be NF-kB dependent (study 2), as assessed by cells tranfected with a nonphosphorylatable IkB construct (IkB-alpha deletion mutant lacking amino acids 1-37). These results suggest that linoleic acid derived from VLDL particles promotes the development of atherosclerotic lesions by activation of the proinflammatory transcription factor NF-kB. VLDL enhances PAI-1 production in cultured endothelial cells, and there is also a close relation between high plasma levels of PAI-1 and hypertriglyceridemia. In the third study, we showed that acute VLDL elevation in the circulation stimulates PAI-1 production in the vascular cells also in vivo. Both endothelial cells and medial smooth muscle cells appeared to be responsible for increased PAI-1 production due to accumulated VLDL particles. Within the rat PAI-1 promoter we identified a sequence (-589 to -571) with 74% homology with the recently described VLDL responsive element in the human PAI-1 promoter (-675 to -657) and adjacent to a 4G motif presumably corresponding to the human 4G/5G polymorphism. Transient transfection studies showed that VLDL exerts its stimulatory effects on rat PAI-1 gene expression in vascular cells by interaction with promoter sequences located within bp –656 and –505. Electrophoretic mobility shift assays showed that VLDL stimulates the binding of unidentified protein(s) to this element. PAI-1 produced by endothelial cells predisposes to thrombosis, the hallmark of acute coronary syndroms. PAI-1 produced by vascular smooth muscle cells (SMCs) inhibits proteolysis by decreasing plasmin-dependent activation of metalloproteinases. The later effect increases matrix accumulation and reduces matrix degradation and inhibits SMC migration from the media into developing atherosclerotic lesions. In the fourth study, oxidized LDL was characterized as a possible candidate responsible for the increased PAI-1 production of SMCs within the plaque. Lysophosphatidylcholine formed during the oxidation of LDL appeared to be the mediating substance, by activating PAI-1 transcription through increased AP-1 activity. Alpha 1-Antitrypsin (AAT), the main physiological inhibitor of proteinases, undergoes conformational changes after inactivation of a target enzyme, yielding a cleaved hydrophobic C-terminal peptide (C-36) which forms amyloid fibrils. In study 5, this C-36 peptide but not native AAT nor related fibrils was found to activate PPAR-alpha, PPAR-gamma, NF-kB and AP-1 in human monocytes. Furthermore, C-36 peptide was detected in carotid atherosclerotic plaques.
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| 4. |
- Dichtl, Wolfgang, et al.
(författare)
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Linoleic acid-stimulated vascular adhesion molecule-1 expression in endothelial cells depends on nuclear factor-kappaB activation.
- 2002
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Ingår i: Metabolism, Clinical and Experimental. - : Elsevier BV. - 1532-8600 .- 0026-0495. ; 51:3, s. 327-333
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Tidskriftsartikel (refereegranskat)abstract
- Endothelial activation is an important step in atherogenesis. In addition to established cardiovascular risk factors, such as hypercholesterolemia, hypertension, diabetes mellitus, and homocysteinemia, high plasma levels of triglyceride-rich lipoproteins may be an important cause of endothelial activation as well. Free fatty acids hydrolyzed from core triglycerides of these particles can exert both pro- and anti-inflammatory effects on the vascular wall. omega-3 fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been shown to inhibit cytokine-induced endothelial activation. In contrast, we and others have previously shown that the omega-6 fatty acid linoleate activates transcription factor nuclear factor-kappaB (NF-kappaB) in endothelial cells. In this study, we show that linoleic acid stimulates vascular adhesion molecule-1 (VCAM-1) protein and mRNA expression in cultured human endothelial cells, as assessed by immunofluorescence and Northern blotting. Release of shedded soluble VCAM-1 from cultured human endothelial cells was also increased by the addition of linoleic acid, as determined by enzyme-linked immunosorbent assay (ELISA). By use of cultured rat aortic endothelial cells transfected with an IkappaB super-repressor (DeltaN2 cells), we provide evidence that NF-kappaB signalling is required in the linoleic acid-induced VCAM-1 expression in endothelial cells, whereas other transcription factors appear to be involved in the increased endothelial plasminogen activator inhibitor-1 (PAI-1) production in response to linoleic acid. These findings suggest that diets rich in linoleic acid may be proinflammatory and thus atherogenic by activating vascular endothelial cells.
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| 5. |
- Dichtl, Wolfgang, et al.
(författare)
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Oxidized LDL and lysophosphatidylcholine stimulate plasminogen activator inhibitor-1 expression in vascular smooth muscle cells
- 1999
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Ingår i: Arteriosclerosis, Thrombosis, and Vascular Biology. - : Ovid Technologies (Wolters Kluwer Health). - 1079-5642 .- 1524-4636. ; 19:12, s. 32-3025
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Tidskriftsartikel (refereegranskat)abstract
- Plasminogen activator inhibitor-1 (PAI-1) functions as an important regulator of fibrinolysis by inhibiting both tissue-type and urokinase-type plasminogen activator. PAI-1 is produced by smooth muscle cells (SMCs) in atherosclerotic arteries, but the mechanisms responsible for induction of PAI-1 in SMCs are less well understood. In cultured human aortic SMCs, PAI-1 mRNA expression and protein secretion were increased after incubation with oxidized low-density lipoprotein (LDL) and the lipid peroxidation product lysophosphatidylcholine, whereas the effects of native LDL on PAI-1 production and release were more variable and did not reach statistical significance. The effect of LDL on arterial expression of PAI-1 in vivo was also studied in an animal model. Intravenous injection of human LDL in Sprague-Dawley rats resulted in accumulation of apolipoprotein B in the aorta within 12 hours as assessed by immunohistochemical testing. Epitopes specific for oxidized LDL began to develop in the aorta 12 hours after injection of LDL and peaked at 24 hours; this peak was accompanied by intense expression of PAI-1 immunoreactivity in the media. Also, increased aortic expression of PAI-1 mRNA after LDL injection was detected by using in situ hybridization. The transcription factor activator protein-1, which is known to bind to the promoter of the PAI-1 gene, was activated in the aortic wall 24 hours after LDL injection as assessed by electrophoretic mobility shift assay. Pretreatment of LDL with the antioxidant probucol decreased expression of oxidized LDL and PAI-1 immunoreactivity and activator protein-1 induction in the aorta but did not affect expression of apolipoprotein B immunoreactivity. These findings demonstrate that LDL oxidation enhances secretion of PAI-1 from cultured SMCs and that a similar mechanism may be involved in vascular expression of PAI-1.
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| 6. |
- Linz, Dominik, et al.
(författare)
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Longer and better lives for patients with atrial fibrillation : the 9th AFNET/EHRA consensus conference
- 2024
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Ingår i: Europace. - : Oxford University Press. - 1099-5129 .- 1532-2092. ; 26:4
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Recent trial data demonstrate beneficial effects of active rhythm management in patients with atrial fibrillation (AF) and support the concept that a low arrhythmia burden is associated with a low risk of AF-related complications. The aim of this document is to summarize the key outcomes of the 9th AFNET/EHRA Consensus Conference of the Atrial Fibrillation NETwork (AFNET) and the European Heart Rhythm Association (EHRA).Methods and results: Eighty-three international experts met in Munster for 2 days in September 2023. Key findings are as follows: (i) Active rhythm management should be part of the default initial treatment for all suitable patients with AF. (ii) Patients with device-detected AF have a low burden of AF and a low risk of stroke. Anticoagulation prevents some strokes and also increases major but non-lethal bleeding. (iii) More research is needed to improve stroke risk prediction in patients with AF, especially in those with a low AF burden. Biomolecules, genetics, and imaging can support this. (iv) The presence of AF should trigger systematic workup and comprehensive treatment of concomitant cardiovascular conditions. (v) Machine learning algorithms have been used to improve detection or likely development of AF. Cooperation between clinicians and data scientists is needed to leverage the potential of data science applications for patients with AF.Conclusions: Patients with AF and a low arrhythmia burden have a lower risk of stroke and other cardiovascular events than those with a high arrhythmia burden. Combining active rhythm control, anticoagulation, rate control, and therapy of concomitant cardiovascular conditions can improve the lives of patients with AF. Graphical Abstract
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| 7. |
- Stollenwerk, Maria, et al.
(författare)
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Very low density lipoprotein potentiates tumor necrosis factor-alpha expression in macrophages.
- 2005
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Ingår i: Atherosclerosis. - : Elsevier BV. - 1879-1484 .- 0021-9150. ; 179:2, s. 247-254
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Tidskriftsartikel (refereegranskat)abstract
- High levels of the triacylglycerol-rich lipoproteins, very low density lipoprotein (VLDL) and intermediate density lipoprotein (IDL) have been identified as independent risk factors for coronary heart disease, and inflammation is thought to contribute to atherosclerosis and its complications. To understand how dyslipidemia promotes inflammation, we have characterised the effects of VLDL treatment on production of tumor necrosis factor-α (TNF) by human monocyte-derived macrophages. VLDL strongly potentiated lipopolysaccharide (LPS)-induced expression of TNF mRNA and secretion of TNF protein. VLDL activated mitogen-activated protein kinase-ERK kinase 1/2 (MEK1/2), and potentiated LPS-induced MEK1/2 activation. The MEK1/2 inhibitor U0126 strongly diminished TNF expression, indicating that MEK1/2 plays a central role in the regulation of TNF expression. VLDL did not activate transcription factors NF-κB and PPAR-γ, but it activated AP-1 at least as potently as LPS, and potentiated LPS-induced activation of AP-1. The inhibitor U0126 completely prevented this potentiation. Inhibition of AP-1 by decoy oligonucleotides abolished potentiation of TNF secretion by VLDL. In conclusion, VLDL treatment potentiates TNF expression in macrophages by activation of MEK1/2 and AP-1. These findings suggest that triacylglycerol-rich lipoproteins are involved in inflammatory processes associated with atherosclerosis.
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| 8. |
- Toennis, Tobias, et al.
(författare)
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The influence of atrial high-rate episodes on stroke and cardiovascular death : an update
- 2023
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Ingår i: Europace. - : Oxford University Press. - 1099-5129 .- 1532-2092. ; 25:7
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Tidskriftsartikel (refereegranskat)abstract
- Atrial high-rate episodes (AHRE) are atrial tachyarrhythmias detected by continuous rhythm monitoring by pacemakers, defibrillators, or implantable cardiac monitors. Atrial high-rate episodes occur in 10-30% of elderly patients without atrial fibrillation. However, it remains unclear whether the presence of these arrhythmias has therapeutic consequences. The presence of AHRE increases the risk of stroke compared with patients without AHRE. Oral anticoagulation would have the potential to reduce the risk of stroke in patients with AHRE but is also associated with a rate of major bleeding of & SIM;2%/year. The stroke rate in patients with AHRE appears to be lower than the stroke rate in patients with atrial fibrillation. Wearables like smart-watches will increase the absolute number of patients in whom atrial arrhythmias are detected. It remains unclear whether anticoagulation is effective and, equally important, safe in patients with AHRE. Two randomized clinical trials, NOAH-AFNET6 and ARTESiA, are expected to report soon. They will provide much-needed information on the efficacy and safety of oral anticoagulation in patients with AHRE.
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