Publikasjoner
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Stø, Kristine; Skagen, Karolina Ryeng; Bjerkeli, Vigdis; Ueland, Per Magne; Hov, Johannes Espolin Roksund & Trøseid, Marius
[Vis alle 10 forfattere av denne artikkelen]
(2026).
Gut microbiota derived indoles are altered and associate with immune activation in moderate and severe carotid stenosis.
Frontiers in Immunology.
17.
doi:
10.3389/fimmu.2026.1796312.
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Background: An imbalance of gut microbiota, their metabolites as well as inflammatory mediators have been increasingly linked to both atherosclerosis and stroke. However, data on microbiota derived tryptophan and histidine metabolites in carotid atherosclerosis are scarce.
Purpose: We investigated serum microbiota derived indoles, imidazole propionate (ImP) and trimethylamine N-oxide (TMAO), representing three distinct gut bacterial-related metabolites, in patients with carotid atherosclerosis compared with healthy controls with normal findings on carotid ultrasound. We aimed to examine their relation to plaque characteristics, immune activation markers and traditional cardiovascular risk factors.
Methods: Thirty patients scheduled for carotid endarterectomy and 18 control subjects were included in this cross-sectional study. Carotid arteries were investigated with ultrasound. Indoles, ImP and TMAO were analyzed by liquid chromatography-tandem mass spectrometry, and Lipopolysaccharide (LPS) by a Limulus Amebocyte Lysate chromogenic assay.
Results: Compared to controls, patients exhibited lower levels of indole-3-propionic acid (IPA) (p=0.004) and indole-3-acetic acid (IAA) (p = 0.030). In patients, higher levels of indole metabolites were associated with lower C-reactive protein. ImP and TMAO did not differ between patients and controls.
Conclusion: Patients with carotid atherosclerosis exhibited reduced serum concentrations of IPA and IAA, thought to have anti-inflammatory effects, and increased inflammatory markers, possibly suggesting disruptions in the gut–vascular-immune axis.
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Ryan, Stephen James; Jørstad, Øystein Kalsnes; Skjelland, Mona; Pesonen, Maiju; Simonsen, Claus Z. & Bek, Toke
[Vis alle 50 forfattere av denne artikkelen]
(2026).
A Randomized Trial of Tenecteplase in Acute Central Retinal Artery Occlusion.
New England Journal of Medicine.
ISSN 0028-4793.
394(5),
s. 442–450.
doi:
10.1056/nejmoa2508515.
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Background: Central retinal artery occlusion can result in permanent vision loss. Effective treatment is lacking.
Methods: We conducted a phase 3, double-blind, double-dummy, randomized, controlled trial involving adults with acute, nonarteritic central retinal artery occlusion who had symptom onset within 4.5 hours before treatment. Patients were assigned, in a 1:1 ratio, to receive intravenous tenecteplase (at a dose of 0.25 mg per kilogram of body weight) and oral placebo or intravenous placebo and oral aspirin (at a dose of 300 mg). The primary end point was vision recovery, defined as a best corrected visual acuity (BCVA) in the affected eye at 30 days of up to 0.7 logMAR (logarithm of the minimum angle of resolution; equivalent to ≥20/100). Key secondary visual end points were a BCVA of up to 0.5 logMAR (equivalent to ≥20/63), mean improvement in BCVA, and perimetry score at 30 days. Key safety end points included symptomatic intracranial hemorrhage, major bleeding, and death.
Results: A total of 78 patients at 16 sites in six countries underwent randomization, with 40 assigned to receive tenecteplase and 38 to receive aspirin. At 30 days, 8 patients (20%) in the tenecteplase group and 9 patients (24%) in the aspirin group had vision recovery (risk difference, −3.7 percentage points; 95% confidence interval, −22.0 to 14.7; P=0.69). The outcomes with regard to the secondary visual end points did not differ substantially between the groups. There was a greater incidence of adverse events in the tenecteplase group, including one fatal intracranial hemorrhage.
Conclusions: Intravenous tenecteplase administered within 4.5 hours after onset of central retinal artery occlusion did not result in significantly greater vision recovery at 30 days than oral aspirin but was associated with serious safety concerns. (Funded by Oslo University Hospital and others; TenCRAOS ClinicalTrials.gov number, NCT04526951; EU Clinical Trials number, 2024-517606-29-00.)
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Haavardsholm, Kathrine; Zamani, Mahtab; Skjelland, Mona Elisabeth; Ramm-Pettersen, Anette & Skagen, Karolina Ryeng
(2025).
Carotid intima-media thickness may be an early biomarker for cardiovascular risk in patients treated with ketogenic dietary therapy.
Epilepsia Open.
10(6),
s. 1860–1870.
doi:
10.1002/epi4.70152.
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Jacobsen, Daniel Pitz; Fjeldstad, Heidi; Olsen, Maria Belland; Sugulle, Meryam; Schjørlien, Therese & Skjelland, Mona Elisabeth
[Vis alle 8 forfattere av denne artikkelen]
(2025).
Postpartum levels of circulating fetal microchimeric cells are lower after early-onset preeclampsia.
Journal of Reproductive Immunology.
ISSN 0165-0378.
172.
doi:
10.1016/j.jri.2025.104646.
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Fetal cells may persist in the mother following pregnancy, termed fetal microchimerism. These cells have been attributed positive and negative effects. The number of fetal cells transferred during pregnancy appears to be higher in preeclampsia. Here, we investigate whether fetal cell presence and quantity in the maternal circulation 1–8 years postpartum is influenced by a previous preeclamptic pregnancy. We also relate fetal cells detected postpartum to fetal cells detected during pregnancy, time since index pregnancy, parity, fetal sex and maternal characteristics. A cohort of 139 women was included in the present study: 21 with previous early-onset preeclampsia, 31 with previous late-onset preeclampsia and 87 with a clinically uncomplicated index pregnancy. Circulating fetal microchimerism was detected in maternal buffy coat using qPCR, targeting alleles unique to the fetus. Pregnancy buffy coat samples were available for 129 of the 139 included women. Early-onset, but not late-onset, preeclampsia was associated with reduced quantity of fetal microchimeric cells in maternal circulation postpartum. Fetal cells detected during pregnancy, time since index pregnancy, parity, fetal sex and maternal characteristics were not predictive of microchimerism postpartum in our cohort. Our findings suggest that early-onset, but not late-onset preeclampsia, affects circulating microchimerism postpartum. Our observation that fetal microchimerism postpartum did not correlate with number of fetal cells detected during pregnancy nor time since index pregnancy supports the notion that fetal microchimerism is a dynamic phenomenon, with fetal cells moving in and out of maternal circulation and surrounding tissues, possibly affected by the current physiologic state of the mother.
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Wiedmann, Markus; Netteland, Dag Ferner; Enriquez, Brian Anthony; Nedregaard, Bård; Schjørlien, Therese & Skjelland, Mona Elisabeth
[Vis alle 8 forfattere av denne artikkelen]
(2025).
Reconsidering stroke management pathways: The role of microsurgical thrombectomy after failed endovascular therapy.
Journal of clinical neuroscience.
ISSN 0967-5868.
142.
doi:
10.1016/j.jocn.2025.111661.
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Endovascular therapy (EVT) has revolutionized acute ischemic stroke (AIS) management in patients with large vessel occlusion (LVO). Yet, EVT fails to achieve recanalization in 10–20 % of cases. In selected patients with persistent vessel occlusion, viable brain tissue, and exhausted endovascular options, microsurgical thrombectomy (MST) may offer a rescue strategy. In this opinion paper, we present two illustrative cases demonstrating MST after EVT failure—one involving vessel injury during thrombectomy, the other a calcified embolus refractory to retrieval. In both cases, complete revascularization was achieved within 5.5–7 h from symptom onset, and both patients recovered to mRS 0–1 by 3 months. Initial NIHSS scores were 13 and 17, and preoperative imaging demonstrated LVO and poor collateral status, findings typically associated with poor prognosis under conservative management. These cases demonstrate that MST, when performed promptly by experienced teams, can result in favourable outcomes in otherwise high-risk scenarios. We argue for the structured integration of MST into modern stroke workflows and propose a research framework to evaluate its role. Multidisciplinary collaboration, standardized protocols, and prospective outcome monitoring are essential to ensure safe and effective implementation.
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Hill, Michael D; Goyal, Mayank; Demchuk, Andrew M; Menon, Bijoy K; Field, Thalia S & Guest, William C
[Vis alle 99 forfattere av denne artikkelen]
(2025).
Efficacy and safety of nerinetide in acute ischaemic stroke in patients undergoing endovascular thrombectomy without previous thrombolysis (ESCAPE-NEXT): a multicentre, double-blind, randomised controlled trial.
The Lancet.
ISSN 0140-6736.
405(10478),
s. 560–570.
doi:
10.1016/S0140-6736(25)00194-1.
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Zamani, Mahtab; Skagen, Karolina Ryeng; Lindberg, Beate; Bjerkeli, Vigdis; Aukrust, Pål & Halvorsen, Bente
[Vis alle 7 forfattere av denne artikkelen]
(2024).
Relationship between fibroblast growth factor in plasma and carotid plaque neovascularization: a pilot study.
Frontiers in Immunology.
15,
s. 1–6.
doi:
10.3389/fimmu.2024.1385377.
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Background: Unstable atherosclerotic carotid plaques with intraplaque neovascularization (IPN) carry a substantial risk for ischemic stroke. Conventional ultrasound methods fall short in detecting IPN, where superb microvascular imaging (SMI) has emerged as a promising tool for both visualizing and quantification. High levels of fibroblast growth factor 23 (FGF-23) have, in observational studies, been suggested as related to cardiovascular morbidity and mortality. The association of FGF-23 to atherosclerotic carotid plaque instability remains relatively unexplored. Methods: A cohort of twenty-nine patients with ≥50% atherosclerotic carotid stenosis underwent conventional carotid ultrasound, SMI, and blood tests, including measurement of FGF-23 in plasma. Nineteen patients were characterized as symptomatic and ten as asymptomatic. Results: Our major findings were: i) Higher FGF-23 levels were strongly correlated with increased SMI-assessed IPN. ii) Neo-vessel count recorded by quantitative SMI was positively correlated to increased FGF-23 levels, but not with basic FGF levels. (iii) In contrast, traditional risk factors for plaque instability exhibited no noteworthy associations with SMI-assessed IPN or with FGF-23 levels. Conclusion: This pilot study suggest the potential of FGF-23 as a valuable marker for neovascularization and atherosclerotic carotid plaque instability as a risk factor for ischemic stroke. Further research involving larger cohorts and prospective data is necessary to understand FGF-23’s role in this context comprehensively.
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Enriquez, Brian Anthony; Skattør, Thor Håkon; Laugesen, Nicolaj Grønbæk; Truelsen, Thomas; Lund, Christian & Nome, Terje
[Vis alle 9 forfattere av denne artikkelen]
(2024).
External validation of clinical risk prediction score for elderly treated with endovascular thrombectomy.
Journal of Neurology.
ISSN 0340-5354.
271,
s. 5838–5845.
doi:
10.1007/s00415-024-12535-6.
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Background and aim: The thrombectomy in the elderly prediction score (TERPS) for functional outcome after anterior circulation endovascular therapy (EVT) in patients ≥ 80 years was recently developed. The aim of this study was to assess predictors of functional outcome in the elderly and validate the prediction model. Methods: Consecutive patients treated with EVT from the Oslo Acute Reperfusion Stroke Study were evaluated for inclusion. Clinical and radiological parameters were used to calculate the TERPS, and functional outcome were assessed at 3-month follow-up. Results: Out of 1028 patients who underwent EVT for acute ischemic stroke from January 2017 to July 2022, 218 (21.2%) patients ≥ 80 years with anterior ischemic stroke were included. Fair outcome, defined as modified Rankin scale ≤ 3 (mRS), was achieved in 117 (53.7%). In bivariate analyses, male sex (p 0.035), age (p 0.025), baseline National Institute of Health Stroke Scale (NIHSS, p < 0.001), pre-stroke mRS (p 0.002) and Alberta Stroke Program Early Computed Tomography score (ASPECTS, p 0.001) were associated with fair outcome. Significant predictors for fair outcome in regression analyses were lower pre-stroke mRS, adjusted odd ratio, (aOR) 0.67 (95% CI 0.50–0.91, p 0.01), NIHSS, aOR 0.92 (95% CI 0.87–0.97, p 0.002), and higher ASPECTS, aOR 1.22 (95% CI 1.03–1.44, p 0.023). The area under the curve (AUC) using TERPS was 0.74 (95% CI 0.67–0.80). Conclusions: The risk prediction score TERPS showed moderate performance in this external validation. Other variables may still be included to improve the model and validation using other cohorts is recommended. Trial registration: NCT06220981.
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Dyreborg, Anders; Hildebrandt, Tonje; Skjelland, Mona & Vlachos, Georgios
(2024).
Varicella-zoster-virus-myelitt som årsak til akutt funksjonssvikt.
Tidsskrift for Den norske legeforening (Tidsskriftet).
ISSN 0029-2001.
144(11).
doi:
10.4045/tidsskr.23.0674.
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Enriquez, Brian Anthony; Halling, Heidi Kristine; Lund, Christian; Tennøe, Bjørn; Brunborg, Cathrine & Skjelland, Mona
[Vis alle 8 forfattere av denne artikkelen]
(2024).
Exploring the Impact of Age and Pre-Stroke Modified Rankin Scale in Elderly Thrombectomy: A 15-Year Single-Center Experience.
Cerebrovascular Diseases Extra.
ISSN 1664-5456.
14(1),
s. 125–133.
doi:
10.1159/000540992.
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Introduction: The selection of endovascular thrombectomy (EVT) for acute ischemic stroke in the elderly remains challenging due to the underrepresentation of these patients in landmark randomized trials. The aim of this study was to assess the association between age and the pre-stroke modified Rankin scale score with functional outcomes after EVT in elderly patients aged ≥80 years. Methods: We prospectively collected data from consecutive elderly patients who underwent EVT of the anterior or posterior circulation at our institution between 2007 and 2022. Clinical and radiological parameters were analyzed using a fair outcome (mRS ≤3 or retained pre-stroke mRS score of 4) as the primary outcome. Results: In total, 307 elderly patients were included in the analysis. Fair functional outcomes were achieved in 162 (53%) patients. Eighty-four (27.4%) patients were deceased at 3-month follow-up and the mortality rate increased to 37.1% (114 deceased) at 1-year follow-up. The likelihood of achieving a fair functional outcome decreased by 8% for every 1-year age increase (OR 0.81, 95% CI 0.73–0.90). Lower National Institutes of Health Stroke Scale (OR 0.89, 95% CI 0.85–0.93, p < 0.001) and pre-stroke mRS (OR 0.67, 95% CI 0.53–0.84, p < 0.001) were associated with fair outcomes. Conclusions: EVT in elderly patients with stroke is beneficial in selected cases. Increasing age was associated with an increased risk of an mRS change to 4 or worse and death within 1 year. The pre-stroke mRS may aid clinicians in the selection of elderly patients for EVT.
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Enriquez, Brian Anthony; Nome, Terje; Nome, Cecilie; Tennøe, Bjørn; Lund, Christian & Beyer, Mona K.
[Vis alle 8 forfattere av denne artikkelen]
(2023).
Predictors of outcome after endovascular treatment for tandem occlusions: a single center retrospective analysis.
BMC Neurology.
23,
s. 1–9.
doi:
10.1186/s12883-023-03127-4.
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Background The endovascular treatment procedure in tandem occlusions (TO) is complex compared to single occlusion (SO) and optimal management remains uncertain. The aim of this study was to identify clinical and procedural factors that may be associated to efficacy and safety in the management of TO and compare functional outcome in TO and SO stroke patients. Methods This is a retrospective single center study of medium (MeVO) and large vessel occlusion (LVO) of the anterior circulation. Clinical, imaging, and interventional data were analyzed to identify predictive factors for symptomatic intracranial hemorrhage (sICH) and functional outcome after endovascular treatment (EVT) in TO. Functional outcome in TO and SO patients was compared. Results Of 662 anterior circulation stroke patients with MeVO and LVO stroke, 90 (14%) had TO. Stenting was performed in 73 (81%) of TO patients. Stent thromboses occurred in 8 (11%) patients. Successful reperfusion with modified thrombolysis in cerebral infarction (mTICI) ≥ 2b was achieved in 82 (91%). SICH occurred in seven (8%). The strongest predictors for sICH were diabetes mellitus and number of stent retriever passes. Good functional clinical outcome (mRS ≤ 2) at 90-day follow up was similar in TO and SO patients (58% vs 59% respectively). General anesthesia (GA) was associated with good functional outcome whereas hemorrhage in the infarcted tissue, lower mTICI score and history of smoking were associated with poor outcome. Conclusions The risk of sICH was increased in patients with diabetes mellitus and those with extra stent-retriever attempts. Functional clinical outcomes in patients with TO were comparable to patients with SO.
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Stø, Kristine; Skagen, Karolina Ryeng; Valeur, Jørgen; Yang, Kuan; Bjerkeli, Vigdis & Aukrust, Pål
[Vis alle 8 forfattere av denne artikkelen]
(2023).
Increased plasma levels of non-sugar sweeteners in patients with symptomatic carotid atherosclerosis.
Scandinavian Cardiovascular Journal.
ISSN 1401-7431.
57(1).
doi:
10.1080/14017431.2023.2205068.
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Purpose. The non-sugar sweeteners acesulfame K and saccharin are considered safe, but there is conflicting evidence on their effects on cardiovascular health. Materials and methods. In this explorative pilot study, we measured plasma levels of acesulfame K and saccharin in 15 patients with symptomatic carotid atherosclerosis, 18 asymptomatic patients and 15 control subjects. Fecal microbiota and short-chain fatty acids were analyzed. Dietary and medical history was assessed. Results. Symptomatic patients had higher levels of acesulfame K and saccharin compared to controls. Acesulfame K was associated with increased leukocyte count. Saccharin was associated with more severe carotid stenosis, as well as lower fecal butyric acid.
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Nome, Terje; Enriquez, Brian Anthony; Nome, Cecilie; Tennøe, Bjørn; Lund, Christian & Skjelland, Mona
[Vis alle 8 forfattere av denne artikkelen]
(2023).
Clinical outcome after thrombectomy in patients with MeVO stroke: importance of clinical and technical factors.
Journal of Neurology.
ISSN 0340-5354.
1(2),
s. 877–886.
doi:
10.1007/s00415-023-12025-1.
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Background and aims Whereas high-level evidence has been proven for safety and efficacy of endovascular treatment (EVT) in large vessel occlusion (LVO) stroke, the evidence for EVT in medium vessel occlusion (MeVO) in both sexes and different age groupremains to be answered. The aim of this study was to evaluate the importance of clinical and technical parameters, focusing on sex, age and EVT procedural factors, on functional outcome in primary MeVO (pMeVO) strokes. Methods 144 patients with pMeVO in the MCA territory from the Oslo Acute Reperfusion Stroke Study (OSCAR) were included. Clinical and radiological data were collected including 90-day mRS follow-up. Results Successful reperfusion with modified thrombolysis in cerebral infarction (mTICI) ≥ 2b was achieved in 123 patients (84%). Good functional outcome (mRS ≤ 2) at 90-day follow-up was achieved in 84 patients (61.8%). Two or more passes with stent retriever was associated with increased risk of SAH, poor mTICI and poor functional outcome. In average, women had 62 min longer ictus to recanalization time compared to men. Age over 80 years was significantly associated with poor outcome and death. Conclusion In pMeVO patients, TICI score and number of passes with stent retriever were the main technical factors predicting mRS ≤ 2. Good clinical outcome occurred almost twice as often in patients under 80 years of age compared to patients over 80 years. Women with MeVO strokes had significant longer time from ictus to recanalization; however, this did not affect the clinical outcome.
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Krzywicka, Katarzyna; Aguiar de Sousa, Diana; Cordonnier, Charlotte; Bode, Felix J.; Field, Thalia S. & Michalski, Dominik
[Vis alle 52 forfattere av denne artikkelen]
(2023).
Decompressive surgery in cerebral venous sinus thrombosis due to vaccine-induced immune thrombotic thrombocytopenia.
European Journal of Neurology.
ISSN 1351-5101.
30(5),
s. 1335–1345.
doi:
10.1111/ene.15735.
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Abstract Background and purpose Cerebral venous sinus thrombosis due to vaccine‐induced immune thrombotic thrombocytopenia (CVST‐VITT) is an adverse drug reaction occurring after severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) vaccination. CVST‐VITT patients often present with large intracerebral haemorrhages and a high proportion undergoes decompressive surgery. Clinical characteristics, therapeutic management and outcomes of CVST‐VITT patients who underwent decompressive surgery are described and predictors of in‐hospital mortality in these patients are explored. Methods Data from an ongoing international registry of patients who developed CVST within 28 days of SARS‐CoV‐2 vaccination, reported between 29 March 2021 and 10 May 2022, were used. Definite, probable and possible VITT cases, as defined by Pavord et al. (N Engl J Med 2021; 385: 1680–1689), were included. Results Decompressive surgery was performed in 34/128 (27%) patients with CVST‐VITT. In‐hospital mortality was 22/34 (65%) in the surgical and 27/94 (29%) in the non‐surgical group ( p < 0.001). In all surgical cases, the cause of death was brain herniation. The highest mortality rates were found amongst patients with preoperative coma (17/18, 94% vs. 4/14, 29% in the non‐comatose; p < 0.001) and bilaterally absent pupillary reflexes (7/7, 100% vs. 6/9, 67% with unilaterally reactive pupil, and 4/11, 36% with bilaterally reactive pupils; p = 0.023). Postoperative imaging revealed worsening of index haemorrhagic lesion in 19 (70%) patients and new haemorrhagic lesions in 16 (59%) patients. At a median follow‐up of 6 months, 8/10 of surgical CVST‐VITT who survived admission were functionally independent. Conclusions Almost two‐thirds of surgical CVST‐VITT patients died during hospital admission. Preoperative coma and bilateral absence of pupillary responses were associated with higher mortality rates. Survivors often achieved functional independence.
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Seim, Bjørn Edvard; Holt, Margrethe Flesvig; Ratajska, Aleksandra; Michelsen, Annika Elisabet; Ringseth, Monica Myklebust & Halvorsen, Bente
[Vis alle 14 forfattere av denne artikkelen]
(2022).
Markers of extracellular matrix remodeling and systemic inflammation in patients with heritable thoracic aortic diseases.
Frontiers in Cardiovascular Medicine.
9,
s. 1–9.
doi:
10.3389/fcvm.2022.1073069.
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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.<p> <p>Aims: To quantify markers of extracellular matrix (ECM) and inflammation in patients with vascular connective tissue diseases versus healthy controls. <p>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. <p>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. <p>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.
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Stø, Kristine; Valeur, Jørgen; Ueland, Thor; Malmstrøm, Gunn Helen; Bjerkeli, Vigdis & Trøseid, Marius
[Vis alle 12 forfattere av denne artikkelen]
(2022).
Fecal level of butyric acid, a microbiome-derived metabolite, is increased in patients with severe carotid atherosclerosis.
Scientific Reports.
12(1),
s. 1–9.
doi:
10.1038/s41598-022-26759-x.
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Abstract The short-chain fatty acid (SCFA) butyric acid maintains a healthy gut barrier and vascular endothelium. We aimed to investigate the association between fecal butyric acid, carotid atherosclerosis and risk factors for ischemic stroke. Patients with severe carotid atherosclerosis (i.e. ≥ 50% stenosis) (n = 43) were compared with healthy controls (n = 38). We analyzed fecal SCFAs by gas chromatography, microbiota composition by 16S rRNA sequencing, markers of gut barrier damage and inflammasome activation by immunoassay, and plasma SCFAs by ultra-high performance liquid chromatography-tandem mass spectroscopy. Patients had higher fecal butyric acid level ( p = 0.024), along with increased functional potential of microbial butyric acid production ( p = 0.031), compared with controls. Dietary fiber intake was comparable. Patients had higher levels of gut barrier damage markers CCL25 and IFABP, and the inflammasome activation marker IL-18, whereas plasma level of butyric was similar. Increased fecal butyric acid was associated with higher BMI, waist-hip ratio, HbA1c, CRP and leukocyte count. Contrary to our hypothesis, patients with severe carotid atherosclerosis had higher fecal butyric acid level, and increased microbial production, compared with controls. Gut barrier damage in patients might indicate decreased absorption of butyric acid and hence contribute to the higher fecal level.
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Schultz, Nina Haagenrud; Søraas, Arne Vasli; Sørvoll, Ingvild Hausberg; Akkøk, Cigdem Ahaein; Vetlesen, Annette & Jagjit, Bhamra Singh
[Vis alle 13 forfattere av denne artikkelen]
(2022).
Vaccine associated benign headache and cutaneous hemorrhage after ChAdOx1 nCoV-19 vaccine: A cohort study.
Journal of Stroke & Cerebrovascular Diseases.
ISSN 1052-3057.
32(1).
doi:
10.1016/j.jstrokecerebrovasdis.2022.106860.
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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<p> <p>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. <p>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. <p>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 D–dimer.
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Enriquez, Brian Anthony; Tennøe, Bjørn; Nome, Terje; Gjertsen, Øivind; Nedregaard, Bård & Sletteberg, Ruth
[Vis alle 13 forfattere av denne artikkelen]
(2022).
Mekanisk trombektomi ved akutt hjerneinfarkt.
Tidsskrift for Den norske legeforening (Tidsskriftet).
ISSN 0029-2001.
142,
s. 1–8.
doi:
10.4045/tidsskr.21.0577.
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Mekanisk trombektomi er nå standard behandling ved akutt hjerneinfarkt med okklusjon av en halsarterie og/eller intrakranial arterie. Ved denne typen okklusjoner har ofte trombolytisk behandling begrenset effekt. Behandlingsresultatet ved trombektomi er tidsavhengig, og en individualisert indikasjonsstilling er alltid nødvendig. De viktigste forutsetningene for å oppnå best mulig resultat er gode faglige prosedyrer, optimale pasientforløp, høy nevroradiologisk kompetanse og samkjørte tverrfaglige team.
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Fontaine, Margaux A. C.; Jin, Han; Gagliardi, Mick; Rousch, Mat; Wijnands, Erwin & Stoll, Monika
[Vis alle 23 forfattere av denne artikkelen]
(2022).
Blood Milieu in Acute Myocardial Infarction Reprograms Human Macrophages for Trauma Repair.
Advanced Science.
s. 1–14.
doi:
10.1002/advs.202203053.
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Acute myocardial infarction (AMI) is accompanied by a systemic trauma response that impacts the whole body, including blood. This study addresses whether macrophages, key players in trauma repair, sense and respond to these changes. For this, healthy human monocyte-derived macrophages are exposed to 20% human AMI (n = 50) or control (n = 20) serum and analyzed by transcriptional and multiparameter functional screening followed by network-guided data interpretation and drug repurposing. Results are validated in an independent cohort at functional level (n = 47 AMI, n = 25 control) and in a public dataset. AMI serum exposure results in an overt AMI signature, enriched in debris cleaning, mitosis, and immune pathways. Moreover, gene networks associated with AMI and with poor clinical prognosis in AMI are identified. Network-guided drug screening on the latter unveils prostaglandin E2 (PGE2) signaling as target for clinical intervention in detrimental macrophage imprinting during AMI trauma healing. The results demonstrate pronounced context-induced macrophage reprogramming by the AMI systemic environment, to a degree decisive for patient prognosis. This offers new opportunities for targeted intervention and optimized cardiovascular disease risk management.
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Kong, Xiang Yi; Huse, Camilla; Yang, Kuan; Øgaard, Jonas; Jimenez, Natalia Berges & Vik, Erik Sebastian
[Vis alle 24 forfattere av denne artikkelen]
(2021).
Endonuclease v regulates atherosclerosis through c-c motif chemokine ligand 2-mediated monocyte infiltration.
Journal of the American Heart Association (JAHA).
10(14).
doi:
10.1161/JAHA.120.020656.
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Background:
In cardiovascular diseases, atherosclerotic disorder are the most frequent and important with respect to morbidity and mortality. Inflammation mediated by immune cells is central in all parts of the atherosclerotic progress, and further understanding of the underlying mechanisms is needed. Growing evidence suggests that deamination of adenosine‐to‐inosine in RNA is crucial for a correct immune response; nevertheless, the role of adenosine‐to‐inosine RNA editing in atherogenesis has barely been studied. Several proteins have affinity for inosines in RNA, one being ENDOV (endonuclease V), which binds and cleaves RNA at inosines. Data on ENDOV in atherosclerosis are lacking.
Methods and Results:
Quantitative polymerase chain reaction on ENDOV mRNA showed an increased level in human carotid atherosclerotic plaques compared with control veins. Inosine‐ribonuclease activity as measured by an enzyme activity assay is detected in immune cells relevant for the atherosclerotic process. Abolishing EndoV in atherogenic apolipoprotein E‐deficient (ApoE−/−) mice reduces the atherosclerotic plaque burden, both in size and lipid content. In addition, in a brain stroke model, mice without ENDOV suffer less damage than control mice. Finally, lack of EndoV reduces the recruitment of monocytes to atherosclerotic lesions in atherogenic ApoE−/− mice.
Conclusions:
ENDOV is upregulated in human atherosclerotic lesions, and data from mice suggest that ENDOV promotes atherogenesis by enhancing the monocyte recruitment into the atherosclerotic lesion, potentially by increasing the effect of CCL2 activation on these cells.
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Wiedmann, Markus; Skattør, Thor Håkon; Stray-Pedersen, Arne; Romundstad, Luis Georg; Antal, Ellen-Ann & Marthinsen, Pål Bache
[Vis alle 16 forfattere av denne artikkelen]
(2021).
Vaccine Induced Immune Thrombotic Thrombocytopenia Causing a Severe Form of Cerebral Venous Thrombosis With High Fatality Rate: A Case Series.
Frontiers in Neurology.
12:721146,
s. 1–7.
doi:
10.3389/fneur.2021.721146.
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During a 2-week period, we have encountered five cases presenting with the combination of cerebral venous thrombosis (CVT), intracerebral hemorrhage and thrombocytopenia. A clinical hallmark was the rapid and severe progression of disease in spite of maximum treatment efforts, resulting in fatal outcome in for 4 out of 5 patients. All cases had received ChAdOx1 nCov-19 vaccine 1–2 weeks earlier and developed a characteristic syndrome thereafter. The rapid progressive clinical course and high fatality rate of CVT in combination with thrombocytopenia in such a cluster and in otherwise healthy adults is a recent phenomenon. Cerebral autopsy findings were those of venous hemorrhagic infarctions and thrombi in dural venous sinuses, including thrombus material apparently rich in thrombocytes, leukocytes and fibrin. Vessel walls were free of inflammation. Extra-cerebral manifestations included leech-like thrombi in large veins, fibrin clots in small venules and scattered hemorrhages on skin and membranes. CVT with thrombocytopenia after adenovirus vectored COVID-19 vaccination is a new clinical syndrome that needs to be recognized by clinicians, is challenging to treat and seems associated with a high mortality rate.
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Niyonzima, Nathalie; Rahman, Jubayer; Kunz, Natalie; West, Erin; Freiwald, Tilo & Desai, Jigar V.
[Vis alle 37 forfattere av denne artikkelen]
(2021).
Mitochondrial C5aR1 activity in macrophages controls IL-1β production underlying sterile inflammation.
Science immunology.
6(66),
s. eabf2489–eabf2489.
doi:
10.1126/sciimmunol.abf2489.
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While serum-circulating complement destroys invading pathogens, intracellularly active complement, termed the “complosome,” functions as a vital orchestrator of cell-metabolic events underlying T cell effector responses. Whether intracellular complement is also nonredundant for the activity of myeloid immune cells is currently unknown. Here, we show that monocytes and macrophages constitutively express complement component (C) 5 and generate autocrine C5a via formation of an intracellular C5 convertase. Cholesterol crystal sensing by macrophages induced C5aR1 signaling on mitochondrial membranes, which shifted ATP production via reverse electron chain flux toward reactive oxygen species generation and anaerobic glycolysis to favor IL-1β production, both at the transcriptional level and processing of pro–IL-1β. Consequently, atherosclerosis-prone mice lacking macrophage-specific C5ar1 had ameliorated cardiovascular disease on a high-cholesterol diet. Conversely, inflammatory gene signatures and IL-1β produced by cells in unstable atherosclerotic plaques of patients were normalized by a specific cell-permeable C5aR1 antagonist. Deficiency of the macrophage cell-autonomous C5 system also protected mice from crystal nephropathy mediated by folic acid. These data demonstrate the unexpected intracellular formation of a C5 convertase and identify C5aR1 as a direct modulator of mitochondrial function and inflammatory output from myeloid cells. Together, these findings suggest that the complosome is a contributor to the biologic processes underlying sterile inflammation and indicate that targeting this system could be beneficial in macrophage-dependent diseases, such as atherosclerosis.
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Grøan, Mathias; Ospel, Johanna; Ajmi, Soffien Chadli; Sandset, Else Charlotte; Kurz, Friedrich Martin Wilhelm & Skjelland, Mona
[Vis alle 7 forfattere av denne artikkelen]
(2021).
Time-Based Decision Making for Reperfusion in Acute Ischemic Stroke.
Frontiers in Neurology.
12.
doi:
10.3389/fneur.2021.728012.
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Decision making in the extended time windows for acute ischemic stroke can be a complex and time-consuming process. The process of making the clinical decision to treat has been compounded by the availability of different imaging modalities. In the setting of acute ischemic stroke, time is of the essence and chances of a good outcome diminish by each passing minute. Navigating the plethora of advanced imaging modalities means that treatment in some cases can be inefficaciously delayed. Time delays and individually based non-programmed decision making can prove challenging for clinicians. Visual aids can assist such decision making aimed at simplifying the use of advanced imaging. Flow charts are one such visual tool that can expedite treatment in this setting. A systematic review of existing literature around imaging modalities based on site of occlusion and time from onset can be used to aid decision making; a more program-based thought process. The use of an acute reperfusion flow chart helping navigate the myriad of imaging modalities can aid the effective treatment of patients.
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Holm, Sverre; Kared, Hassen; Michelsen, Annika Elisabet; Kong, Xiang Yi; Dahl, Tuva Børresdatter & Schultz, Nina Haagenrud
[Vis alle 21 forfattere av denne artikkelen]
(2021).
Immune complexes, innate immunity, and NETosis in ChAdOx1 vaccine-induced thrombocytopenia.
European Heart Journal.
ISSN 0195-668X.
42(39),
s. 4064–4072.
doi:
10.1093/eurheartj/ehab506.
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Aims - We recently reported five cases of vaccine-induced immune thrombotic thrombocytopenia (VITT) 7–10 days 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.<p> <p>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 myeloperoxidase–DNA complex. The thrombus had extensive infiltration of neutrophils, formation of neutrophil extracellular traps (NETs), and IgG deposits.<p> <p>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.
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Skjelland, Mona; Zamani, Mahtab; Hetlevik, Siri Opsahl; Lilleby, Vibke; Halvorsen, Bente & Skagen, Karolina Ryeng
(2020).
Increased endothelial activation in patients with mixed
connective tissue disease.
Journal of Stroke & Cerebrovascular Diseases.
ISSN 1052-3057.
29:104563(2),
s. 1–5.
doi:
10.1016/j.jstrokecerebrovasdis.2019.104563.
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Objective: Juvenile-onset mixed connective tissue disease (JMCTD) is a chronic inflammatory disease. We have previously demonstrated preclinical atherosclerosis in these patients, now exploring this further by assessing markers of endothelial dysfunction. Methods: Thirty-three patients with JMCTD and 33 age-and sex-matched controls were included. Soluble intercellular adhesion molecule-1 (sICAM-1), Il-6 and, von Willenbrand factor (vWF) were assayed from blood taken at the time of carotid ultrasound. Results: Our major findings were: (1) Levels of sICAM-1 ( P < .001), IL-6 ( P = .004), and vWF ( P = .001) were higher, whereas (2) high density lipoprotein cholesterol (<.01) and apolipoprotein A1 ( P < .01) were lower in the patient group compared to controls. Conclusions: Patients with JMCTD had significantly increased levels of markers of endothelial dysfunction.
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Lambert, Anna Tancin; Kong, Xiang Yi; Ratajczak-Tretel, Barbara; Atar, Dan; Russell, David & Skjelland, Mona Elisabet
[Vis alle 13 forfattere av denne artikkelen]
(2020).
Biomarkers Associated with Atrial Fibrillation in Patients with Ischemic Stroke: A Pilot Study from the NOR-FIB Study.
Cerebrovascular Diseases Extra.
ISSN 1664-5456.
10(1),
s. 11–20.
doi:
10.1159/000504529.
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Background and Purpose: Cardioembolic stroke due to paroxysmal atrial fibrillation (AF) may account for 1 out of 4 cryptogenic strokes (CS) and transient ischemic attacks (TIAs). The purpose of this pilot study was to search for biomarkers potentially predicting incident AF in patients with ischemic stroke or TIA. Methods: Plasma samples were collected from patients aged 18 years and older with ischemic stroke or TIA due to AF (n = 9) and large artery atherosclerosis (LAA) with ipsilateral carotid stenosis (n = 8) and age- and sex-matched controls (n = 10). Analyses were performed with the Olink technology simultaneously measuring 184 biomarkers of cardiovascular disease. For bioinformatics, acquired data were analyzed using gene set enrichment analysis (GSEA). Selected proteins were validated using ELISA. Individual receiver operating characteristic (ROC) curves and odds ratios from logistic regression were calculated. A randomForest (RF) model with out-of-bag estimate was applied for predictive modeling. Results: GSEA indicated enrichment of proteins related to inflammatory response in the AF group. Interleukin (IL)-6, growth differentiation factor (GDF)-15, and pentraxin-related protein PTX3 were the top biomarkers on the ranked list for the AF group compared to the LAA group and the control group. ELISA validated increased expression of all tested proteins (GDF-15, PTX3, and urokinase plasminogen activator surface receptor [U-PAR]), except for IL-6. 19 proteins had the area under the ROC curve (AUC) over 0.85 including all of the proteins with significant evolution in the logistic regression. AUCs were very discriminant in distinguishing patients with and without AF (LAA and control group together). GDF-15 alone reached AUC of 0.95. Based on RF model, all selected participants in the tested group were classified correctly, and the most important protein in the model was GDF-15. Conclusions: Our results demonstrate an association between inflammation and AF and that multiple proteins alone and in combination may potentially be used as indicators of AF in CS and TIA patients. However, further studies including larger samples sizes are needed to support these findings. In the ongoing NOR-FIB study, we plan further biomarker assessments in patients with CS and TIA undergoing long-term cardiac rhythm monitoring with insertable cardiac monitors.
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Niyonzima, Nathalie; Bakke, Siril Skaret; Gregersen, Ida; Holm, Sverre; Sandanger, Øystein & Orrem, Hilde Lang
[Vis alle 22 forfattere av denne artikkelen]
(2020).
Cholesterol crystals use complement to increase NLRP3 signaling pathways in coronary and carotid atherosclerosis.
EBioMedicine.
60:102985,
s. 1–13.
doi:
10.1016/j.ebiom.2020.102985.
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Background: During atherogenesis, cholesterol precipitates into cholesterol crystals (CC) in the vessel wall, which trigger plaque inflammation by activating the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome. We investigated the relationship between CC, complement and NLRP3 in patients with cardiovascular disease. Methods: We analysed plasma, peripheral blood mononuclear cells (PBMC) and carotid plaques from patients with advanced atherosclerosis applying ELISAs, multiplex cytokine assay, qPCR, immunohistochemistry, and gene profiling. Findings: Transcripts of interleukin (IL)-1beta(b) and NLRP3 were increased and correlated in PBMC from patients with acute coronary syndrome (ACS). Priming of these cells with complement factor 5a (C5a) and tumour necrosis factor (TNF) before incubation with CC resulted in increased IL-1b protein when compared to healthy controls. As opposed to healthy controls, systemic complement was significantly increased in patients with stable angina pectoris or ACS. In carotid plaques, complement C1q and C5b-9 complex accumulated around CC-clefts, and complement receptors C5aR1, C5aR2 and C3aR1 were higher in carotid plaques compared to control arteries. Priming human carotid plaques with C5a followed by CC incubation resulted in pronounced release of IL-1b, IL-18 and IL-1a. Additionally, mRNA profiling demonstrated that C5a and TNF priming followed by CC incubation upregulated plaque expression of NLRP3 inflammasome components. Interpretation: We demonstrate that CC are important local- and systemic complement activators, and we reveal that the interaction between CC and complement could exert its effect by activating the NLRP3 inflammasome, thus promoting the progression of atherosclerosis.
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Zamani, Mahtab; Skagen, Karolina Ryeng; Scott, Helge; Russell, David & Skjelland, Mona
(2020).
Advanced ultrasound methods in assessment of carotid plaque instability: a prospective multimodal study.
BMC Neurology.
20:39(1),
s. 1–8.
doi:
10.1186/s12883-020-1620-z.
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Background
A significant proportion of ischemic strokes are caused by emboli from atherosclerotic, unstable carotid artery plaques. The selection of patients for endarterectomy in current clinical practice is primarily based on the degree of carotid artery stenosis and clinical symptoms. However, the content of the plaque is known to be more important for stroke risk. Intraplaque neovascularization (IPN) has recently emerged as a possible surrogate marker for plaque instability. Neo-microvessels from the adventitial vasa vasorum grow into the full thickness of the vessel wall in an adaptive response to hypoxia, causing subsequent intraplaque haemorrhage and plaque rupture. Conventional ultrasound cannot detect IPN. Contrast-enhanced ultrasound and Superb Microvascular Imaging (SMI), have, however, shown promise in IPN assessment. Recent research using Shear Wave Elastography (SWE) has also reported reduced tissue stiffness in the artery wall (reduced mean Young’s modulus) in unstable compared to stable plaques. The purpose of this study is to identify unstable carotid artery plaques at risk of rupture and future ischemic stroke risk using multimodal assessments. Methods
Forty five symptomatic and 45 asymptomatic patients > 18 years, with > 50% carotid stenosis referred to Oslo University Hospital ultrasound lab will be included in this on-going project. Patients will undergo contrast enhanced ultrasound, SMI, carotid-MRI and PET-(18F-FDG). Contrast enhanced ultrasound will be analyzed semi-quantitatively (5-levels visual classification) and quantitatively by plotting time-intensity curve analyses to obtain plaque peak contrast enhancement intensity. Plaques removed at carotid endarterectomy will be assessed histologically and the number of microvessels, areas of inflammation, granulation, calcification, lipid and fibrosis will be measured. Discussion
This multimodality study will primarily provide information on the clinical value of advanced ultrasound methods (SMI, SWE) for the detection of unstable carotid artery plaque in comparison with other methods including contrast-enhanced ultrasound, carotid-MRI and PET-(18F-FDG) using histology as the gold standard. Secondly, findings from the methods mentioned above will be related to cerebrovascular symptoms, blood tests (leukocytes, CRP, ESR, lipoproteins and inflammatory markers) and cardiovascular risk factors at inclusion and at 1-year follow-up. The overall aim is to optimize detection of plaque instability which can lead to better preventive decisions and reduced stroke rate.
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Gregersen, Ida; Michelsen, Annika; Lunde, Ngoc Nguyen; Åkerblom, Axel; Lakic, Tatevik G. & Skjelland, Mona
[Vis alle 20 forfattere av denne artikkelen]
(2020).
Legumain in Acute Coronary Syndromes: A Substudy of the PLATO (Platelet Inhibition and Patient Outcomes) Trial.
Journal of the American Heart Association (JAHA).
e016360.
doi:
10.1161/JAHA.120.016360.
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<i>Background</i> - 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.<p><p> <i>Methods and Results</i> - 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 follow‐up. 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, 1.04–1.21), <i>P</i>=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, 1.02–1.19; <i>P</i>=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, 0.44–0.88; <i>P</i>=0.0069), including in the fully adjusted model (HR, 0.57; 95% CI, 0.37–0.88; <i>P</i>=0.0114).<p><p> <i>Conclusions</i> - 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.
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Jimenez, Ana Maria Teresa Quiles; Gregersen, Ida; Sousa, Mirta; Abbas, Azhar; Kong, Xiang Yi & Alseth, Ingrun
[Vis alle 13 forfattere av denne artikkelen]
(2020).
N6-methyladenosine in RNA of atherosclerotic plaques: An epitranscriptomic signature of human carotid atherosclerosis.
Biochemical and Biophysical Research Communications - BBRC.
ISSN 0006-291X.
533(4),
s. 631–637.
doi:
10.1016/j.bbrc.2020.09.057.
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Background More than 170 post-transcriptional RNA modifications regulate the localization, processing and function of cellular RNAs, and aberrant RNA modifications have been linked to a range of human diseases. The RNA modification landscape in atherosclerosis, the main underlying cause of cardiovascular diseases, is still largely unknown. Methods We used mass spectrometry to analyse a selection of RNA-modifying enzymes and the N6-methyladenosine (m6A) in carotid atherosclerotic lesion samples representing early and advanced stages of atherosclerosis as compared to non-atherosclerotic arteries from healthy controls. Findings (i) the detection of different levels of several enzymes involved in methylations occurring in rRNA and mRNA; (ii) these findings included changes in the levels of methyltransferases (‘writers’), binding proteins (‘readers’) and demethylases (‘erasers’) during atherosclerosis as compared to non-atherosclerotic control arteries, with generally the most prominent differences in samples from early atherosclerotic lesions; and (iii) these changes were accompanied by a marked downregulation of m6A in rRNA, the most abundant and well-studied modification in mRNA with a wide range of effects on cell biology. Interpretation We show for the first time that RNA-modifying enzymes and the well-studied RNA modification m6A are differentially regulated in atherosclerotic lesions, which potentially could help creating new prognostic and treatment strategies.
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Lunde, Ngoc Dieu Nguyen; Gregersen, Ida; Ueland, Thor; Shetelig, Christian; Holm, Sverre & Kong, Xiang Yi
[Vis alle 31 forfattere av denne artikkelen]
(2019).
Legumain is upregulated in acute cardiovascular events and associated with improved outcome – potentially related to anti-inflammatory effects on macrophages.
Atherosclerosis.
ISSN 0021-9150.
s. 1–9.
doi:
10.1016/j.atherosclerosis.2019.12.008.
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Background and aims We have previously found increased levels of the cysteine protease legumain in plasma and plaques from patients with carotid atherosclerosis. This study further investigated legumain during acute cardiovascular events. Methods Circulating levels of legumain from patients and legumain released from platelets were assessed by enzyme-linked-immunosorbent assay. Quantitative PCR and immunoblotting were used to study expression, while localization was visualized by immunohistochemistry. Results In the SUMMIT Malmö cohort (n = 339 with or without type 2 diabetes and/or cardiovascular disease [CVD], and 64 healthy controls), the levels of circulating legumain were associated with the presence of CVD in non-diabetics, with no relation to outcome. In symptomatic carotid plaques and in samples from both coronary and intracerebral thrombi obtained during acute cardiovascular events, legumain was co-localized with macrophages in the same regions as platelets. In vitro, legumain was shown to be present in and released from platelets upon activation. In addition, THP-1 macrophages exposed to releasate from activated platelets showed increased legumain expression. Interestingly, primary peripheral blood mononuclear cells stimulated with recombinant legumain promoted anti-inflammatory responses. Finally, in a STEMI population (POSTEMI; n = 272), patients had significantly higher circulating legumain before and immediately after percutaneous coronary intervention compared with healthy controls (n = 67), and high levels were associated with improved outcome. Conclusions Our data demonstrate for the first time that legumain is upregulated during acute cardiovascular events and is associated with improved outcome.
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Zamani, Mahtab; Skagen, Karolina Ryeng; Scott, Helge; Lindberg, Beate; Russell, David & Skjelland, Mona
(2019).
Carotid Plaque Neovascularization Detected With Superb Microvascular Imaging Ultrasound Without Using Contrast Media.
Stroke.
ISSN 0039-2499.
50(11),
s. 3121–3127.
doi:
10.1161/STROKEAHA.119.025496.
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Background and Purpose— A significant proportion of ischemic strokes are caused by emboli from unstable carotid artery plaques with intraplaque neovascularization (IPN) as a key feature of plaque instability. IPN is not detectable with conventional Doppler ultrasound. Contrast-enhanced ultrasound (CEUS) can visualize IPN, but its use is limited in clinical practice because it requires an intravenous injection of contrast. Superb microvascular imaging (SMI) without contrast uses an algorithm to remove clutter and motion wall artifacts while preserving low-velocity blood flow signals, enabling visualization of IPN. Our aim was to assess the feasibility of SMI for the detection of IPN. Methods— Thirty-one patients with >50% carotid stenosis were included: 22 patients were symptomatic and 9 asymptomatic. All patients underwent conventional carotid ultrasound, CEUS, SMI, and blood tests. CEUS and SMI findings were compared and correlated to histological plaque assessments after endarterectomy. Results— There was significant positive correlation between an IPN visual 5-level classification of SMI and a semiquantitative analysis of CEUS (P<0.001, r=0.911). Plaques with higher SMI grades had higher numbers of neovessels quantified at histology (P=0.041, r=0.460). Hypoechoic plaques had higher grades of IPN on both CEUS and SMI (P<0.001). Higher visual IPN counts on SMI were associated with (1) increased areas of inflammation (P=0.043, r=0.457), (2) combined rank scores of granulation tissue, inflammation and lipids (P=0.02, r=0.494) at histology, and (3) higher peak-intensity values on quantitative CEUS (P=0.042, r=0.514). Conclusions— SMI ultrasound can detect neovascularization with accuracy comparable to CEUS, suggesting SMI to be a promising noninvasive alternative to CEUS for the assessment of carotid plaque stability.
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Skagen, Karolina Ryeng; Hetlevik, Siri Opsahl; Zamani, Mahtab; Lilleby, Vibke & Skjelland, Mona
(2019).
Preclinical Carotid Athersoclerosis in Patients With Juvenile-onset Mixed Connective Tissue Disease.
Journal of Stroke & Cerebrovascular Diseases.
ISSN 1052-3057.
28(5),
s. 1295–1301.
doi:
10.1016/j.jstrokecerebrovasdis.2019.01.027.
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Jusufovic, Mirza; Skagen, Karolina Ryeng; Krohg-Sørensen, Kirsten & Skjelland, Mona
(2019).
Current medical and surgical stroke prevention therapies for patients with carotid artery stenosis.
Current Neurovascular Research.
ISSN 1567-2026.
16(1),
s. 96–103.
doi:
10.2174/1567202616666190131162811.
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Gravastrand, Caroline S.; Steinkjer, Bjørg; Halvorsen, Bente; Landsem, Anne; Skjelland, Mona & Jacobsen, Eva Astrid
[Vis alle 12 forfattere av denne artikkelen]
(2019).
Cholesterol Crystals Induce coagulation Activation through Complement-Dependent Expression of Monocytic Tissue Factor.
Journal of Immunology.
ISSN 0022-1767.
203(4),
s. 853–863.
doi:
10.4049/jimmunol.1900503.
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Cholesterol crystals (CC) are strong activators of complement and could potentially be involved in thromboinflammation through complement-coagulation cross-talk. To explore the coagulation-inducing potential of CC, we performed studies in lepirudin-based human whole blood and plasma models. In addition, immunohistological examinations of brain thrombi and vulnerable plaque material from patients with advanced carotid atherosclerosis were performed using polarization filter reflected light microscopy to identify CC. In whole blood, CC exposure induced a time- and concentration-dependent generation of prothrombin fragment 1+2 (PTF1.2), tissue factor (TF) mRNA synthesis, and monocyte TF expression. Blocking Abs against TF abolished CC-mediated coagulation, thus indicating involvement of the TF-dependent pathway. Blockade of FXII by corn trypsin inhibitor had a significant inhibitory effect on CC-induced PTF1.2 in platelet-free plasma, although the overall activation potential was low. CC exposure did not induce platelet aggregation, TF microparticle induction, or TF on granulocytes or eosinophils. Inhibition of complement C3 by CP40 (compstatin), C5 by eculizumab, or C5aR1 by PMX53 blocked CC-induced PTF1.2 by 90% and reduced TF+ monocytes from 18-20 to 1-2%. The physiologic relevance was supported by birefringent CC structures adjacent to monocytes (CD14), TF, and activated complement iC3b and C5b-9 in a human brain thrombus. Furthermore, monocyte influx and TF induction in close proximity to CC-rich regions with activated complement were found in a vulnerable plaque. In conclusion, CC could be active, releasable contributors to thrombosis by inducing monocyte TF secondary to complement C5aR1 signaling.
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Skarpengland, Tonje; Skjelland, Mona; Kong, Xiang Yi; Skagen, Karolina Ryeng; Holm, Sverre & Otterdal, Kari
[Vis alle 16 forfattere av denne artikkelen]
(2018).
Increased levels of lectin-like oxidized low-density lipoprotein receptor-1 in ischemic stroke and transient ischemic attack.
Journal of the American Heart Association (JAHA).
7:e006479(2),
s. 1–16.
doi:
10.1161/JAHA.117.006479.
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Background: Soluble lectin‐like oxidized low‐density lipoprotein receptor‐1 (sLOX‐1) has been shown to be increased in patients with acute ischemic stroke. Here, we evaluated plasma sLOX‐1 levels and vascular carotid plaque LOX‐1 (ie, OLR1) gene expression in patients with ischemic stroke and transient ischemic attack (TIA) with particular focus on their relation to time since symptom onset. Methods and Results: Plasma sLOX‐1 (n=232) and carotid plaque OLR1 gene expression (n=146) were evaluated in patients who were referred to evaluation for carotid endarterectomy, as well as in healthy control plasma (n=81). Patients were categorized according to presence of acute ischemic stroke or transient ischemic attack (n=35) ≤7 days, >7 days ≤3 months (n=90), >3 months (n=40), or no reported symptoms before study inclusion (n=67). Our major findings were the following: (1) Patients with carotid atherosclerosis had increased plasma sLOX‐1 levels as compared with controls. (2) Plaque OLR1 mRNA levels were increased in carotid plaques (n=146) compared with nonatherosclerotic vessels (ie, common iliac arteries of organ donors, n=10). (3) There were no differences in sLOX plasma levels or OLR1 gene expression when analyzed according to the time since relevant cerebral ischemic symptoms. (4) Also patients with severe carotid atherosclerosis without any previous ischemic events had raised sLOX‐1 levels. (5) Immunostaining showed colocalization between LOX‐1 and macrophages within the carotid plaques. (6) Also patients with acute stroke (within 7 days) caused by atrial fibrillation (n=22) had comparable raised sLOX‐1 levels. Conclusions: sLOX‐1 levels are elevated in patients with ischemic stroke and transient ischemic attack independent of cause and time since the ischemic event.
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Bjerknes, Silje Kristin; Toft, Mathias; Konglund, Ane; Pham, Uyen Ha Gia; Waage, Trine Rygvold & Pedersen, Lena
[Vis alle 11 forfattere av denne artikkelen]
(2018).
Multiple microelectrode recordings in STN-DBS surgery for Parkinson's disease: a randomized study.
Movement Disorders Clinical Practice.
5(3),
s. 296–305.
doi:
10.1002/mdc3.12621.
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Background: Subthalamic nucleus deep brain stimulation improves motor symptoms and fluctuations in advanced Parkinson's disease, but the degree of clinical improvement depends on accurate anatomical electrode placement. Methods used to localize the sensory‐motor part of the nucleus vary substantially. Using microelectrode recordings, at least three inserted microelectrodes are needed to obtain a three‐dimensional map. Therefore, multiple simultaneously inserted microelectrodes should provide better guidance than single sequential microelectrodes. We aimed to compare the use of multiple simultaneous versus single sequential microelectrode recordings on efficacy and safety of subthalamic nucleus stimulation. Methods: Sixty patients were included in this double‐blind, randomized study, 30 in each group. Primary outcome measures were the difference from baseline to 12 months in the MDS‐UPDRS motor score (part III) in the off‐medication state and quality of life using the Parkinson's Disease Questionnaire‐39 (PDQ‐39) scores. Results: The mean reduction of the MDS‐UPDRS III off score was 35 (SD 12) in the group investigated with multiple simultaneous microelectrodes compared to 26 (SD 10) in the single sequential microelectrode group (p = 0.004). The PDQ‐39 Summary Index did not differ between the groups, but the domain scores activities of daily living and bodily discomfort improved significantly more in the multiple microelectrodes group. The frequency of serious adverse events did not differ significantly. Conclusions: After 12 months of subthalamic nucleus stimulation, the multiple microelectrodes group had a significantly greater improvement both in MDS‐UPDRS III off score and in two PDQ‐39 domains. Our results may support the use of multiple simultaneous microelectrode recordings.
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Serrano, Sandra Espada; Stavik, Benedicte; Holm, Sverre; Sagen, Ellen Lund; Bjerkeli, Vigdis & Skjelland, Mona
[Vis alle 12 forfattere av denne artikkelen]
(2017).
Tissue factor pathway inhibitor attenuates ER stress-induced inflammation in human M2-polarized macrophages.
Biochemical and Biophysical Research Communications - BBRC.
ISSN 0006-291X.
491(2),
s. 442–448.
doi:
10.1016/j.bbrc.2017.07.070.
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Endoplasmic reticulum (ER) stress has been shown to play a key role during the initiation and clinical progression of the cardiovascular diseases, such as atherosclerosis. We have recently shown that expression of tissue factor pathway inhibitor (TFPI) in human monocyte-derived macrophages (MDMs) was induced by cholesterol crystals (CC). In the present study we aimed to determine the role of TFPI under ER stress conditions using human MDMs. qRT-PCR and immunohistochemistry analysis were performed to determine the presence of the ER stress marker CCAAT/enhancer binding protein homologous protein (CHOP) and TFPI in human carotid plaque material and also in human MDMs polarized into pro-inflammatory M1 or anti-inflammatory M2 populations. CHOP mRNA levels were upregulated in the plaques compared to healthy vessels, and CHOP protein was localized in the same area as TFPI in the plaques. Both CHOP and TFPI mRNA levels were upregulated after CC treatment, especially in the M2 phenotype, and the ER stress inhibitor 4-phenylbutyric acid (PBA) reversed this effect. Furthermore, CC treatment increased the levels of the pro-inflammatory cytokines TNF-α, IL-6, and IL-8, which for TNF-α and IL-8 was inhibited by PBA, and reduced the levels of the anti-inflammatory cytokine IL-10 in M2-polarized macrophages. Knockdown of TFPI prior to CC treatment exacerbated TNF-α and IL-6 levels, but reduced IL-8 and IL-10 levels. Our results show that CC induce TFPI and cytokine expression in M2-polarized macrophages through activation of the ER stress pathway and that TFPI has a protective effect against TNF-α and IL-6 mediated inflammation. These mechanisms may have implications for the pathogenesis of atherosclerosis.
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Bakke, Siril Skaret; Aune, Marie Hjelmseth; Niyonzima, Nathalie; Pilely, Katrine; Ryan, Liv & Skjelland, Mona
[Vis alle 13 forfattere av denne artikkelen]
(2017).
Cyclodextrin Reduces Cholesterol Crystal-Induced Inflammation by Modulating Complement Activation.
Journal of Immunology.
ISSN 0022-1767.
199(8),
s. 2910–2920.
doi:
10.4049/jimmunol.1700302.
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Cholesterol crystals (CC) are abundant in atherosclerotic plaques and promote inflammatory responses via the complement system and inflammasome activation. Cyclic oligosaccharide 2-hydroxypropyl-β-cyclodextrin (BCD) is a compound that solubilizes lipophilic substances. Recently we have shown that BCD has an anti-inflammatory effect on CC via suppression of the inflammasome and liver X receptor activation. The putative effects of BCD on CC-induced complement activation remain unknown. In this study, we found that BCD bound to CC and reduced deposition of Igs, pattern recognition molecules, and complement factors on CC in human plasma. Furthermore, BCD decreased complement activation as measured by terminal complement complex and lowered the expression of complement receptors on monocytes in whole blood in response to CC exposure. In line with this, BCD also reduced reactive oxygen species formation caused by CC in whole blood. Furthermore, BCD attenuated the CC-induced proinflammatory cytokine responses (e.g., IL-1α, MIP-1α, TNF, IL-6, and IL-8) as well as regulated a range of CC-induced genes in human PBMC. BCD also regulated complement-related genes in human carotid plaques treated ex vivo. Formation of terminal complement complex on other complement-activating structures such as monosodium urate crystals and zymosan was not affected by BCD. These data demonstrate that BCD inhibits CC-induced inflammatory responses, which may be explained by BCD-mediated attenuation of complement activation. Thus, these findings support the potential for using BCD in treatment of atherosclerosis.
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Stavik, Benedicte; Holm, Sverre; Serrano, Sandra Espada; Iversen, Nina; Sporsheim, Bjørnar & Bjerkeli, Vigdis
[Vis alle 12 forfattere av denne artikkelen]
(2017).
Increased expression of TFPI in human carotid stenosis.
Thrombosis Research.
ISSN 0049-3848.
155,
s. 31–37.
doi:
10.1016/j.thromres.2017.04.024.
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INTRODUCTION:
Tissue factor (TF) pathway inhibitor (TFPI) is the physiological inhibitor of TF induced blood coagulation and two isoforms exists, TFPIα and TFPIβ. In atherosclerotic plaques, TFPI may inhibit TF activity and thrombus formation, which is the main cause of ischemic stroke in carotid artery disease. We aimed to identify the isoforms of TFPI present in human carotid plaques and potential sources of TFPI.
MATERIALS AND METHODS:
Human atherosclerotic plaques from carotid endarterectomies were used for mRNA and immunohistochemistry analyses. hPBMCs isolated from buffy coats and THP-1 cells were differentiated and polarized into M1 or M2 macrophages, and subsequently cultured with or without cholesterol crystals (CC). mRNA and protein expression were measured with qRT-PCR and ELISA, respectively, and procoagulant activity was assessed using a two-stage chromogenic assay.
RESULTS:
TFPIα and TFPIβ mRNA levels were significantly increased in carotid plaques, whereas TF levels were unchanged as compared to healthy arteries. Antibodies against total TFPI showed elevated levels compared to antibodies against free TFPIα, both by immunohistochemical and ELISA detection in plaques. The antibody against total TFPI also co-localized with CD68 and the M1 and M2 markers CD80 and CD163, respectively. The TFPI mRNA expression was elevated and the procoagulant activity was decreased in M2 compared to M1 polarized human macrophages. TFPI was present in early foam cell formation and CC treatment increased the TFPI mRNA expression even further in M2 macrophages.
CONCLUSIONS:
Our data indicate that both isoforms of TFPI are present in advanced plaques and that anti-inflammatory M2 macrophages may be a potential source of TFPI.
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Gregersen, Ida; Sandanger, Øystein; Askevold, Erik Tandberg; Sagen, Ellen Lund; Yang, Kuan & Holm, Sverre
[Vis alle 16 forfattere av denne artikkelen]
(2017).
Interleukin 27 is increased in carotid atherosclerosis and promotes NLRP3 inflammasome activation.
PLOS ONE.
12(11).
doi:
10.1371/journal.pone.0188387.
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Aim Interleukin-27 (IL-27) is involved in different inflammatory diseases; however, its role in atherosclerosis is unclear. In this study we investigated the expression of IL-27 and its receptor in patients with carotid atherosclerosis and if IL-27 could modulate the inflammatory effects of the NLRP3 inflammasome in vitro. Methods Plasma IL-27 was measured by enzyme immunoassay in patients with carotid stenosis (n = 140) and in healthy controls (n = 19). Expression of IL-27 and IL-27R was analyzed by quantitative PCR and immunohistochemistry in plaques from patients and in non-atherosclerotic vessels. THP-1 monocytes, primary monocytes and peripheral blood mononuclear cells (PBMCs) were used to study effects of IL-27 in vitro. Results Our main findings were: (i) Plasma levels of IL-27 were significantly elevated in patients with carotid atherosclerotic disease compared to healthy controls. (ii) Gene expression of IL-27 and IL-27R was significantly elevated in plaques compared to control vessels, and co-localized to macrophages. (iii) In vitro, IL-27 increased NLRP3 inflammasome activation in monocytes with enhanced release of IL-1 β. Conclusions We demonstrate increased levels of IL-27 and IL-27R in patients with carotid atherosclerosis. Our in vitro findings suggest an inflammatory role for IL-27, which can possibly be linked to atherosclerotic disease development.
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Johnsrud, Kjersti; Skagen, Karolina Ryeng; Seierstad, Therese; Skjelland, Mona; Russell, David & Rootwelt-Revheim, Mona-Elisabeth
(2017).
18F-FDG PET/CT for the quantification of inflammation in large carotid artery plaques.
Journal of Nuclear Cardiology.
ISSN 1071-3581.
s. 1–11.
doi:
10.1007/s12350-017-1121-7.
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Skarpengland, Tonje; Holm, Sverre; Scheffler, Katja; Gregersen, Ida; Dahl, Tuva Børresdatter & Suganthan, Rajikala
[Vis alle 33 forfattere av denne artikkelen]
(2016).
Neil3-dependent base excision repair regulates lipid metabolism and prevents atherosclerosis in Apoe-deficient mice.
Scientific Reports.
6:28337.
doi:
10.1038/srep28337.
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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. Apoe−/−Neil3−/− mice on high-fat diet showed accelerated plaque formation as compared to Apoe−/− mice, reflecting an atherogenic lipid profile, increased hepatic triglyceride levels and attenuated macrophage cholesterol efflux capacity. Apoe−/−Neil3−/− 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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Varghese, Paramel G; Folkersen, Lasse; Strawbridge, Rona J.; Halvorsen, Bente; Yndestad, Arne & Ranheim, Trine
[Vis alle 17 forfattere av denne artikkelen]
(2016).
NLRP3 inflammasome expression and activation in human atherosclerosis.
Journal of the American Heart Association (JAHA).
5:e003031(5),
s. 1–14.
doi:
10.1161/JAHA.115.003031.
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Background The NLR family, pyrin domain containing 3 (NLRP3) inflammasome is an interleukin (IL)‐1β and IL‐18 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 IL‐1β release. The Swedish First‐ever myocardial Infarction study in Ac‐county (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, Apoptosis‐associated speck‐like protein containing a CARD (ASC), caspase‐1 (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. CD68‐positive 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 IL‐1β release from lipopolysaccharide‐primed 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.
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Skagen, Karolina Ryeng; Skjelland, Mona; Zamani, Mahtab & Russell, David
(2016).
Unstable carotid artery plaque: New insights and controversies in diagnostics and treatment.
Croatian Medical Journal.
ISSN 0353-9504.
57(4),
s. 311–320.
doi:
10.3325/cmj.2016.57.311.
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Jusufovic, Mirza; Sandset, Else Charlotte; Skagen, Karolina Ryeng & Skjelland, Mona
(2016).
Blood pressure lowering treatment in patients with carotid artery stenosis.
Current Medical Imaging.
ISSN 1573-4056.
12(2),
s. 148–155.
doi:
10.2174/157340211202160525010133.
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Lunde, Ngoc Nguyen Dieu; Holm, Sverre; Dahl, Tuva Børresdatter; Inass, Elyouncha; Sporsheim, Bjørnar & Gregersen, Ida
[Vis alle 12 forfattere av denne artikkelen]
(2016).
Increased levels of legumain in plasma and plaques from patients with carotid atherosclerosis.
Atherosclerosis.
ISSN 0021-9150.
257,
s. 216–223.
doi:
10.1016/j.atherosclerosis.2016.11.026.
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Background and aims
The cysteine protease legumain has been shown to be up-regulated in unstable atherosclerotic plaques. This study aims to further elucidate legumain in atherosclerosis, by examining legumain in plasma and carotid plaques from patients with carotid stenosis. Furthermore, legumain secretion from monocyte-derived macrophages treated with atherogenic lipids during macrophage polarization was studied.
Methods
Plasma levels of legumain from patients with carotid stenosis (n = 254), healthy controls (n = 91), and secreted from monocyte-derived macrophages were assessed by enzyme-linked-immunosorbent assay. Quantitative PCR and immunoblotting of legumain were performed on isolated plaques and legumain localization was visualized by immunohistochemistry and fluorescence microscopy. Monocyte-derived macrophages polarized to M1 or M2 macrophages were treated with VLDL, oxLDL or cholesterol crystals (CC) and the level of legumain analysed.
Results
Patients with carotid stenosis had significantly higher levels of plasma legumain compared with healthy controls (median 2.0 versus 1.5 ng/ml, respectively; p = 0.003), although there was no correlation between the level of legumain and the degree of stenosis, and legumain was not an independent factor to identify patients with carotid plaques. Moreover, patients with symptoms the last 2 months had higher expressions of mature legumain, cystatin C and E/M, and the macrophage markers CD80 (M1) and CD163 (M2). Legumain co-localized with both M1 and M2 macrophages within plaques, whereas legumain mRNA expression was significantly higher (p < 0.0001) in plaques compared to non-atherosclerotic arteries (controls). Furthermore, in vitro studies showed significantly increased secretion of legumain from pro-inflammatory M1 compared to pro-resolving M2 macrophages (p = 0.014), and particularly in M1 treated with CC. In plaques, legumain was localized to structures resembling foam cells.
Conclusions
Legumain is increased in both plasma and plaques of patients with carotid stenosis and might be a new and early biomarker of atherosclerosis.
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Zimmer, Sebastian; Grebe, Alena; Bakke, Siril Skaret; Bode, Niklas; Halvorsen, Bente & Ulas, Thomas
[Vis alle 25 forfattere av denne artikkelen]
(2016).
Cyclodextrin promotes atherosclerosis regression via macrophage reprogramming.
Science Translational Medicine.
ISSN 1946-6234.
8(333).
doi:
10.1126/scitranslmed.aad6100.
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Atherosclerosis is an inflammatory disease linked to elevated blood cholesterol concentrations. Despite ongoing advances in the prevention and treatment of atherosclerosis, cardiovascular disease remains the leading cause of death worldwide. Continuous retention of apolipoprotein B–containing lipoproteins in the subendothelial space causes a local overabundance of free cholesterol. Because cholesterol accumulation and deposition of cholesterol crystals (CCs) trigger a complex inflammatory response, we tested the efficacy of the cyclic oligosaccharide 2-hydroxypropyl-β-cyclodextrin (CD), a compound that increases cholesterol solubility in preventing and reversing atherosclerosis. We showed that CD treatment of murine atherosclerosis reduced atherosclerotic plaque size and CC load and promoted plaque regression even with a continued cholesterol-rich diet. Mechanistically, CD increased oxysterol production in both macrophages and human atherosclerotic plaques and promoted liver X receptor (LXR)–mediated transcriptional reprogramming to improve cholesterol efflux and exert anti-inflammatory effects. In vivo, this CD-mediated LXR agonism was required for the antiatherosclerotic and anti-inflammatory effects of CD as well as for augmented reverse cholesterol transport. Because CD treatment in humans is safe and CD beneficially affects key mechanisms of atherogenesis, it may therefore be used clinically to prevent or treat human atherosclerosis.
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Skagen, Karolina Ryeng; Skjelland, Mona; Russell, David & Jacobsen, Eva Astrid
(2015).
Large-vessel occlusion stroke: Effect of recanalization on outcome depends on the National Institutes of Health Stroke scale score.
Journal of Stroke & Cerebrovascular Diseases.
ISSN 1052-3057.
24(7),
s. 1532–1539.
doi:
10.1016/j.jstrokecerebrovasdis.2015.03.020.
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Jusufovic, Mirza; Konglund, Ane; Beyer, Mona K.; Dietrichs, Espen & Skjelland, Mona
(2014).
Deep brain stimulation in essential tremor.
Tidsskrift for Den norske legeforening (Tidsskriftet).
ISSN 0029-2001.
134,
s. 1757–1757.
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Jusufovic, Mirza; Thomassen, Lars & Skjelland, Mona
(2014).
Hjerneinfarkt ved åpent foramen ovale.
Tidsskrift for Den norske legeforening (Tidsskriftet).
ISSN 0029-2001.
134(2),
s. 180–184.
doi:
10.4045/tidsskr.13.0038.
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Gregersen, Ida; Skjelland, Mona; Holm, Sverre; Holven, Kirsten Bjørklund; Sørensen, Kirsten & Russell, David
[Vis alle 14 forfattere av denne artikkelen]
(2013).
Increased Systemic and Local Interleukin 9 Levels in Patients with Carotid and Coronary Atherosclerosis.
PLOS ONE.
8(8).
doi:
10.1371/journal.pone.0072769.
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Objective: Atherosclerosis is a chronic inflammatory disorder that involves a range of inflammatory mediators. Although interleukin (IL)-9 has been related to inflammation, there are at present no data on its role in atherosclerosis. Here we have examined IL-9 and IL-9 receptor (IL-9R) systemically and locally in patients with coronary and carotid atherosclerosis. Methods: Plasma IL-9 was quantified by enzyme immunoassay and multiplex technology. IL-9 and IL-9R mRNA were quantified by real-time RT-PCR, and their localization within the lesion was assessed by immunohistochemistry. Results: The main findings were: (i) Patients with carotid atherosclerosis had significantly raised IL-9 plasma levels compared with healthy controls (n = 28), with no differences between asymptomatic (n = 56) and symptomatic (n = 88) patients. (ii) On admission, patients with acute ST-elevation myocardial infarction (STEMI) (n = 42) had markedly raised IL-9 plasma levels which gradually declined during the first week post-MI. (iii) T cells and monocytes from patients with unstable angina (n = 17) had increased mRNA levels of IL-9 as compared with controls (n = 11). (iv) Carotid plaques (n = 68) showed increased mRNA levels of IL-9 and IL-9R compared to non-atherosclerotic vessels (n = 10). Co-localization to T cells (IL-9 and IL-9R) and macrophages (IL-9) were shown by immunohistochemistry. (v) IL-9 increased IL-17 release in peripheral blood mononuclear cells from patients with unstable angina (n = 5) and healthy controls (n = 5) with a particularly enhancing effect in cells from the patient group. Conclusion: Our findings show increased IL-9 levels in different atherosclerotic disorders both systemically and within the lesion, suggesting a role for the IL-9/IL-9R axis in the atherosclerotic process, potentially involving IL-17 mediated mechanisms. However, the functional consequences of these findings should be further investigated.
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Ryan, Stephen James; Jørstad, Øystein Kalsnes; Skjelland, Mona; Simonsen, Claus Z; Bek, Toke & Blauenfeldt, Rolf Ankerlund
[Vis alle 65 forfattere av denne artikkelen]
(2025).
Tenecteplase in Central Retinal Artery Occlusion Study (TenCRAOS): Protocol for a randomized-controlled trial.
doi:
10.1177/23969873251344199.
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Rationale:
Central retinal artery occlusion (CRAO) is an ophthalmologic emergency that, without prompt reperfusion, is associated with a high risk of permanent blindness. There is currently no evidence-based, effective treatment for CRAO.
Methods and design:
TenCRAOS is an investigator-initiated, international, multicenter, randomized controlled, double-dummy, double-blind, phase III trial testing tenecteplase (TNK) 0.25 mg/kg + placebo versus acetylsalicylic acid (ASA) 300 mg + placebo. The target population is patients diagnosed with CRAO and a best-corrected visual acuity (BCVA) of ⩾1.0 logarithm of the minimum angle of resolution (logMAR), corresponding to a decimal BCVA of ⩽0.1 or a fraction BCVA of ⩽6/60, who can be treated within 4.5 h.
Sample size:
Assuming a difference in proportion of participants reaching the primary endpoint of 20% in the placebo/ASA treatment group versus 50% in the TNK/placebo group, we need 78 participants to reach 80% power to detect the difference on a 5% significance level.
Outcomes:
The primary outcome is the proportion of participants with BCVA of ⩽0.7 logMAR in the affected eye at 30-day follow-up, corresponding to a decimal BCVA of ⩾0.2 or fraction BCVA of ⩾6/30, representing a clinically relevant improvement of BCVA of ⩾0.3 logMAR (or 15 letters). Secondary efficacy outcomes include proportion of participants with BCVA of ⩽0.5 logMAR, corresponding to a decimal BCVA of ⩾0.32 or fraction BCVA of ⩾ 6/19, self-reported vision-targeted health status, quality of life, and modified Rankin Score at 30 and 90 days. Safety outcomes include symptomatic intracranial hemorrhage, major bleeding, and mortality. Exploratory analyses include assessment with optical coherence tomography with angiography and transorbital ultrasound.
Discussion:
TenCRAOS intends to assess the efficacy and safety of systemic TNK within 4.5 h of CRAO onset.
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Stavik, Benedicte; Andresen, Marianne Seierstad; Holm, Sverre; Skjelland, Mona; Tinholt, Mari & Sandset, Per Morten
[Vis alle 8 forfattere av denne artikkelen]
(2021).
Increased levels of coagulation factor V in atherosclerotic plaques - an immune regulated response?
Research and Practice in Thrombosis and Haemostasis (RPTH).
5.
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Zamani, Mahtab; Skagen, Karolina Ryeng; Russell, David & Skjelland, Mona
(2020).
Response by Zamani et al to Letter Regarding Article, "Carotid Plaque Neovascularization Detected With Superb Microvascular Imaging Ultrasound Without Using Contrast Media".
Stroke.
ISSN 0039-2499.
51(1),
s. E12–E12.
doi:
10.1161/STROKEAHA.119.027944.
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Skagen, Karolina; Aamodt, Anne Hege; Enriquez, Brian & Skjelland, Mona Elisabet
(2020).
For lite kunnskap om blodtrykk ved hjerneinfarkt.
Tidsskrift for Den norske legeforening (Tidsskriftet).
ISSN 0029-2001.
140(9),
s. 1–3.
doi:
10.4045/tidsskr.20.0323.
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Skjelland, Mona & Mathiesen, Ellisiv B.
(2019).
Ultralydundersøkelse av precerebrale og intracerebrale arterier,
Nevrologi og nevrokirurgi. Fra barn til voksen, 7. utg..
Fagbokforlaget.
ISSN 9788245024739.
s. 125–131.
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Stavik, Benedicte; Espada, Sandra; Holm, Sverre; Bjerkeli, Vigdis; Sandset, Per Morten & Dahl, Tuva Børresdatter
[Vis alle 11 forfattere av denne artikkelen]
(2016).
Cholesterol crystals induce TFPI expression in alternatively activated human monocyte-derived macrophages.
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Atherosclerotic disease is denoted by low density lipoprotein (LDL) influx and retention in the artery intima, triggering the recruitment of monocytes causing a low grade chronic inflammation. Tissue factor (TF) pathway inhibitor (TFPI) regulates TF induced blood coagulation. Two isoforms exist, TFPIα and TFPIβ. In addition, TFPIα is also found complexed with LDL with unknown function. Moreover, ApoE-/- TFPI-/+ double KO mice display an atherogenic phenotype.
We aimed to identify the cells expressing TFPI isoforms in human atherosclerotic plaques and the function of TFPI in these cells.
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Serrano, Sandra Espada; Holm, Sverre; Bjerkeli, Vigdis; Skjelland, Mona; Dahl, Tuva Børresdatter & Iversen, Nina
[Vis alle 11 forfattere av denne artikkelen]
(2016).
ER stress conditions lead to an upregulation of TFPI and is associated with an anti-apoptotic macrophage phenotype.
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Endoplasmic reticulum (ER) stress is an important event during the initiation and clinical progression of several cardiovascular diseases, including atherosclerosis. In the present study we determined the role of tissue factor pathway inhibitor (TFPI) under ER stress conditions using human monocyte-derived macrophages (PBMC) and human carotid endarterectomies. TFPI was expressed in carotid plaques from patients with internal carotid stenosis, especially the TFPIα isoform. Moreover, TFPI colocalized with the ER stress marker CHOP in the plaques. Cholesterol crystals (CC) were used in human M1 and M2-polarized macrophages in vitro as an inducer of ER stress. CHOP and TFPI mRNA levels were upregulated after CC treatment, especially in the M2 phenotype. The ER stress inhibitor 4-Phenylbutyric acid (PBA) reversed the CC-mediated upregulation of CHOP and TFPI. Furthermore, M2-polarized macrophages incubated with CC had higher levels of Bcl-2:Bax mRNA ratios and Bcl-2 protein expression, and these effects were reversed by TFPI knockdown and PBA treatment. Our results indicate that TFPI could promote survival of the M2-polarized macrophages under ER stress conditions. These findings may have implications for the pathogenesis of atherosclerosis.
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Skagen, Karolina Ryeng; Marthinsen, Pål Bache; Skjelland, Mona & Russell, David
(2015).
Fluktuerende carotistumor.
Tidsskrift for Den norske legeforening (Tidsskriftet).
ISSN 0029-2001.
134(4).
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Zamani, Mathab; Skagen, Karolina Ryeng; Skjelland, Mona & Russell, David
(2015).
The assessment of neovscularization in carotid artery plaques and ischemic stroke using Superb Microvascular Imaging.
International Journal of Stroke.
ISSN 1747-4930.
10,
s. 1–458.
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Skagen, Karolina Ryeng; Skjelland, Mona; Scott, Helge; Hol, Per Kristian & Russell, David
(2015).
Assessment of the unstable carotid artery plaque using 3T MRI.
International Journal of Stroke.
ISSN 1747-4930.
10,
s. 1–458.
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Skagen, Karolina Ryeng; Skjelland, Mona; Russell, David & Jacobsen, Eva Astrid
(2013).
Large vessel occlusion stroke: effect of recanalization on outcome depends on NIHSS score.
Cerebrovascular Diseases.
ISSN 1015-9770.
35,
s. 178–178.
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Publisert
14. nov. 2018 12:25
- Sist endret
2. jan. 2020 11:44
