138 research outputs found
Unstable carotid artery plaque: new insights and controversies in diagnostics and treatment
Cardiovascular disease is estimated to be the leading cause
of death, globally causing 14 million deaths each year.
Stroke remains a massive public health problem and there
is an increasing need for better strategies for the prevention
and treatment of this disease. At least 20% of ischemic
strokes are thromboembolic in nature, caused by a thromboembolism
from an atherosclerotic plaque at the carotid
bifurcation or the internal carotid artery. Current clinical
guidelines for both primary and secondary prevention of
stroke in patients with carotid stenosis caused by atherosclerotic
plaques remain reliant on general patient characteristics
(traditional risk factors for stroke) and static measures
of the degree of artery stenosis. Patients with similar
traditional risk factors, however, have been found to have
different risk of stroke, and it has in recent years become
increasingly clear that the degree of artery stenosis alone
is not the best estimation of stroke risk. There is a need for
new methods for the assessment of stroke risk to improve
risk prediction for the individual patient. This review aims
to give an overview of new methods available for the identification
of carotid plaque instability and the assessment
of stroke risk
Reiseopphold, positivt eller negativt i en seleksjonsprosess?
Bakgrunnen for bacheloroppgaven er vÄr interesse for fagomrÄdet HR og Personalledelse,
med en fordypning i rekruttering og seleksjon. Temaet for oppgaven er holdningene til de
som rekrutterer, rundt et reiseopphold pÄ CV-en. Problemstillingen ble derfor fÞlgende:
âHvilke holdninger har de som rekrutterer pĂ„ et reiseopphold mellom hĂžyere utdanning og en
relevant jobb?â FormĂ„let med studiet er Ă„ belyse tematikken for de som jobber i
rekrutterings- og bemanningsbransjen. Vi valgte Ă„ avgrense oppgaven til Ă„ undersĂžke kun
hvilke holdninger de har til at den jobbsĂžkende har et reiseopphold mellom hĂžyere utdanning
og en relevant jobb. Dette valgte vi fordi mange velger Ă„ reise i denne perioden i livet.
For Ă„ besvare oppgaven har vi tatt i bruk kvalitativ metode fordi vi Ăžnsket en fordypet innsikt
fra vÄre respondenter om tematikken. Vi gjennomfÞrte derfor Ätte dybdeintervjuer med
personer som jobber med rekruttering for Ä fÄ deres syn pÄ fenomenet. Hensikten med
oppgaven er Ä fÄ et innblikk i hvordan temaet i dag vurderes av de som rekrutterer, og om det
pÄvirker seleksjonsprosessen.
Resultatene vÄre viser at respondentene hadde flere positive enn negative holdninger til et
reiseopphold. Vi oppdaget ingen fordommer eller stereotypier hos respondentene som var
rettet mot mennesker som hadde dette pÄ CV-en
Cerebral microembolization during off-pump coronary artery bypass surgery with the Symmetry aortic connector device
ObjectiveThe use of aortic connector systems for proximal vein grafts in off-pump coronary artery bypass grafting might minimize aortic manipulation by eliminating the need for partial aortic clamping. The objective of this study was to asses whether use of a Symmetry connector (St Jude Medical, Inc, St Paul, Minn) reduced intraoperative cerebral embolization.MethodsThirty-two consecutive patients underwent off-pump coronary artery bypass grafting. Sixteen patients received at least one mechanical proximal vein graft anastomosis with a Symmetry aortic connector system. Sixteen patients representing the control group underwent operations with standard suturing techniques using partial aortic clamping. During surgical intervention, all patients were monitored continuously with multifrequency transcranial Doppler scanning, which detected and differentiated cerebral emboli.ResultsThere were significantly more cerebral emboli in the Symmetry group (median, 36) compared with the control group (median, 11; P = .027). This was due to a higher number of gaseous emboli in the Symmetry group than in the control group (median, 27 vs 8; P = .014), whereas there was no significant difference regarding the number of solid emboli (median, 7 vs 3; P = .139).ConclusionUse of a Symmetry connector system during proximal vein graft anastomosis increased the number of emboli to the brain compared with a standard technique in coronary bypass surgery without cardiopulmonary bypass
Fatty Acid Binding Protein 4 Is Associated with Carotid Atherosclerosis and Outcome in Patients with Acute Ischemic Stroke
BACKGROUND AND PURPOSE: Fatty acid binding protein 4 (FABP4) has been shown to play an important role in macrophage cholesterol trafficking and associated inflammation. To further elucidate the role of FABP4 in atherogenesis in humans, we examined the regulation of FABP4 in carotid atherosclerosis and ischemic stroke. METHODS: We examined plasma FABP4 levels in asymptomatic (n = 28) and symptomatic (n = 31) patients with carotid atherosclerosis, as well as in 202 subjects with acute ischemic stroke. In a subgroup of patients we also analysed the expression of FABP4 within the atherosclerotic lesion. In addition, we investigated the ability of different stimuli with relevance to atherosclerosis to regulate FABP4 expression in monocytes/macrophages. RESULTS: FABP4 levels were higher in patients with carotid atherosclerosis, both systemically and within the atherosclerotic lesion, with particular high mRNA levels in carotid plaques from patients with the most recent symptoms. Immunostaining of carotid plaques localized FABP4 to macrophages, while activated platelets and oxidized LDL were potent stimuli for FABP4 expression in monocytes/macrophages in vitro. When measured at the time of acute ischemic stroke, high plasma levels of FABP4 were significantly associated with total and cardiovascular mortality during follow-up, although we did not find that addition of FABP4 to the fully adjusted multivariate model had an effect on the prognostic discrimination for all-cause mortality as assessed by c-statistics. CONCLUSIONS: FABP4 is linked to atherogenesis, plaque instability and adverse outcome in patients with carotid atherosclerosis and acute ischemic stroke
Vaccine associated benign headache and cutaneous hemorrhage after ChAdOx1 nCoV-19 vaccine: A cohort study
Objectives
Fatal complications have occurred after vaccination with ChAdOx1 nCoV-19, a vaccine against Covid-19. Vaccine-induced immune thrombotic thrombocytopenia (VITT) with severe outcome is characterized by venous thrombosis, predominantly in cerebral veins, thrombocytopenia and anti-PF4/polyanion antibodies. Prolonged headaches and cutaneous hemorrhages, frequently observed after the ChAdOx1 nCoV-19 vaccine, have therefore caused anxiety among vaccinees. We investigated whether these symptoms represent a mild form of VITT, with a potential for aggravation, e.g. in case of a second vaccination dose, or a different entity of vaccine complications
Materials and methods
We included previously healthy individuals who had a combination of headache and spontaneous severe cutaneous hemorrhages emerging after the 1st dose of the ChAdOx1 nCoV-19 vaccine. Twelve individuals were found to meet the inclusion criteria, and a phone interview, cerebral MRI, assessment of platelet counts, anti PF4/polyanion antibodies and other laboratory tests were performed.
Results
None of the symptomatic vaccinees had cerebral vein thrombosis, hemorrhage or other pathology on MRI. Platelet counts were within normal range and no anti-PF4/polyanion platelet activating antibodies were found. Moreover, vasculitis markers, platelet activation markers and thrombin generation were normal. Furthermore, almost all symptoms resolved, and none had recurrence of symptoms after further vaccination with mRNA vaccines against Covid-19.
Conclusions
The combination of headaches and subcutaneous hemorrhage did not represent VITT and no other specific coagulation disorder or intracranial pathology was found. However, symptoms initially mimicking VITT demand vigilance and low threshold for a clinical evaluation combined with platelet counts and Dâdimer
Markers of extracellular matrix remodeling and systemic inflammation in patients with heritable thoracic aortic diseases
Background: In approximately 20% of patients with thoracic aortic aneurysms or dissections a heritable thoracic aortic disease (HTAD) is suspected. Several monogenic connective tissue diseases imply high risk of aortic disease, including both non-syndromic and syndromic forms. There are some studies assessing inflammation and extracellular matrix remodeling in patients with non-hereditary aortic disease, but such studies in patients with hereditary diseases are scarce.
Aims: To quantify markers of extracellular matrix (ECM) and inflammation in patients with vascular connective tissue diseases versus healthy controls.
Methods: Patients with Loeys-Dietz syndrome (LDS, n = 12), Marfan syndrome (MFS, n = 11), and familial thoracic aortic aneurysm 6 (FTAA6, n = 9), i.e., actin alpha 2 (ACTA2) pathogenic variants, were recruited. Exome or genome sequencing was performed for genetic diagnosis. Several markers of inflammation and ECM remodeling were measured in plasma by enzyme immunoassays. Flow cytometry of T-cell subpopulations was performed on a subgroup of patients. For comparison, blood samples were drawn from 14 healthy controls.
Results: (i) All groups of HTAD patients had increased levels matrix metalloproteinase-9 (MMP-9) as compared with healthy controls, also in adjusted analyses, reflecting altered ECM remodeling. (ii) LDS patients had increased levels of pentraxin 3 (PTX3), reflecting systemic inflammation. (iii) LDS patients have increased levels of soluble CD25, a marker of T-cell activation.
Conclusion: Our data suggest that upregulated MMP-9, a matrix degrading enzyme, is a common feature of several subgroups of HTAD. In addition, LDS patients have increased levels of PTX3 reflecting systemic and in particular vascular inflammation
Legumain in acute coronary syndromes: A substudy of the PLATO (Platelet Inhibition and Patient Outcomes) trial
Background
The cysteine protease legumain is increased in patients with atherosclerosis, but its causal role in atherogenesis and cardiovascular disease is still unclear. The aim of the study was to investigate the association of legumain with clinical outcome in a large cohort of patients with acute coronary syndrome.
Methods and Results
Serum levels of legumain were analyzed in 4883 patients with acute coronary syndrome from a substudy of the PLATO (Platelet Inhibition and Patient Outcomes) trial. Levels were analyzed at admission and after 1 month followâup. Associations between legumain and a composite of cardiovascular death, spontaneous myocardial infarction or stroke, and its individual components were assessed by multivariable Cox regression analyses. At baseline, a 50% increase in legumain level was associated with a hazard ratio (HR) of 1.13 (95% CI, 1.04â1.21), P=0.0018, for the primary composite end point, adjusted for randomized treatment. The association remained significant after adjustment for important clinical and demographic variables (HR, 1.10; 95% CI, 1.02â1.19; P=0.013) but not in the fully adjusted model. Legumain levels at 1 month were not associated with the composite end point but were negatively associated with stroke (HR, 0.62; 95% CI, 0.44â0.88; P=0.0069), including in the fully adjusted model (HR, 0.57; 95% CI, 0.37â0.88; P=0.0114).
Conclusions
Baseline legumain was associated with the primary outcome in patients with acute coronary syndrome, but not in the fully adjusted model. The association between high levels of legumain at 1 month and decreased occurrence of stroke could be of interest from a mechanistic point of view, illustrating the potential dual role of legumain during atherogenesis and acute coronary syndrome.
Registration
URL: https://www.cliniâcaltrâials.gov; Unique identifier: NCT00391872
NLRP3 inflammasome expression and activation in human atherosclerosis
Background: The NLR family, pyrin domain containing 3 (NLRP3) inflammasome is an interleukin (IL)â1ÎČ and ILâ18 cytokine processing complex that is activated in inflammatory conditions. The role of the NLRP3 inflammasome in the pathogenesis of atherosclerosis and myocardial infarction is not fully understood.
Methods and Results: Atherosclerotic plaques were analyzed for transcripts of the NLRP3 inflammasome, and for ILâ1ÎČ release. The Swedish Firstâever myocardial Infarction study in Acâcounty (FIA) cohort consisting of DNA from 555 myocardial infarction patients and 1016 healthy individuals was used to determine the frequency of 4 single nucleotide polymorphisms (SNPs) from the downstream regulatory region of NLRP3. Expression of NLRP3, Apoptosisâassociated speckâlike protein containing a CARD (ASC), caspaseâ1 (CASP1), IL1B, and IL18 mRNA was significantly increased in atherosclerotic plaques compared to normal arteries. The expression of NLRP3 mRNA was significantly higher in plaques of symptomatic patients when compared to asymptomatic ones. CD68âpositive macrophages were observed in the same areas of atherosclerotic lesions as NLRP3 and ASC expression. Occasionally, expression of NLRP3 and ASC was also present in smooth muscle cells. Cholesterol crystals and ATP induced ILâ1ÎČ release from lipopolysaccharideâprimed human atherosclerotic lesion plaques. The minor alleles of the variants rs4266924, rs6672995, and rs10733113 were associated with NLRP3 mRNA levels in peripheral blood mononuclear cells but not with the risk of myocardial infarction.
Conclusions: Our results indicate a possible role of the NLRP3 inflammasome and its genetic variants in the pathogenesis of atherosclerosis
Immune complexes, innate immunity, and NETosis in ChAdOx1 vaccine-induced thrombocytopenia
Aims - We recently reported five cases of vaccine-induced immune thrombotic thrombocytopenia (VITT) 7â10âdays after receiving the first dose of the ChAdOx1 nCoV-19 adenoviral vector vaccine against corona virus disease 2019 (COVID-19). We aimed to investigate the pathogenic immunological responses operating in these patients.
Methods and results - We assessed circulating inflammatory markers by immune assays and immune cell phenotyping by flow cytometry analyses and performed immunoprecipitation with anti-platelet factor (PF)4 antibody in plasma samples followed by mass spectrometry from all five patients. A thrombus was retrieved from the sinus sagittal superior of one patient and analysed by immunohistochemistry and flow cytometry. Precipitated immune complexes revealed multiple innate immune pathway triggers for platelet and leucocyte activation. Plasma contained increased levels of innate immune response cytokines and markers of systemic inflammation, extensive degranulation of neutrophils, and tissue and endothelial damage. Blood analyses showed activation of neutrophils and increased levels of circulating H3Cit, dsDNA, and myeloperoxidaseâDNA complex. The thrombus had extensive infiltration of neutrophils, formation of neutrophil extracellular traps (NETs), and IgG deposits.
Conclusions - The results show that anti-PF4/polyanion IgG-mediated thrombus formation in VITT patients is accompanied by a massive innate immune activation and particularly the fulminant activation of neutrophils including NETosis. These results provide novel data on the immune response in this rare adenoviral vector-induced VITT
Neil3-dependent base excision repair regulates lipid metabolism and prevents atherosclerosis in Apoe-deficient mice
Increasing evidence suggests that oxidative DNA damage accumulates in atherosclerosis. Recently, we showed that a genetic variant in the human DNA repair enzyme NEIL3 was associated with increased risk of myocardial infarction. Here, we explored the role of Neil3/NEIL3 in atherogenesis by both clinical and experimental approaches. Human carotid plaques revealed increased NEIL3 mRNA expression which significantly correlated with mRNA levels of the macrophage marker CD68. Apoeâ/âNeil3â/â mice on high-fat diet showed accelerated plaque formation as compared to Apoeâ/â mice, reflecting an atherogenic lipid profile, increased hepatic triglyceride levels and attenuated macrophage cholesterol efflux capacity. Apoeâ/âNeil3â/â mice showed marked alterations in several pathways affecting hepatic lipid metabolism, but no genotypic alterations in genome integrity or genome-wide accumulation of oxidative DNA damage. These results suggest a novel role for the DNA glycosylase Neil3 in atherogenesis in balancing lipid metabolism and macrophage function, potentially independently of genome-wide canonical base excision repair of oxidative DNA damage
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