Publications by authors named "Ingebjørg Seljeflot"

242 Publications

Abdominal Adipose Tissue Associates With Adiponectin and TNFα in Middle-Aged Healthy Men.

Front Endocrinol (Lausanne) 2022 7;13:874977. Epub 2022 Jul 7.

Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital, Ullevål, Norway.

Introduction: Adipokines are highly active biopeptides involved in glucose metabolism, insulin regulation and the development and progression of obesity and its associated diseases. It includes, among others, adiponectin, visfatin and tumor necrosis factor alpha (TNFα). The sources of adipokines and their associations with glucometabolic variables are not completely understood.

Aim: In this cross-sectional study, we aimed to investigate whether gene expression levels in subcutaneous adipose tissue (SAT) of selected adipokines and their corresponding circulating levels associate with the amount of AT in superficial (sSAT), deep (dSAT) and visceral AT (VAT), assessed by computed tomography (CT). Any association with glucometabolic variables were also explored.

Methods: In 103 healthy Caucasian men, aged 39.5 years, fasting venous blood and SAT samples from the gluteal region were collected. Ninety-four of the participants underwent CT assessment of the abdominal AT, which was divided into VAT, sSAT and dSAT. Circulating levels of adipokines were measured by ELISA and AT gene-expression by PCR. Insulin sensitivity was determined by glucose clamp, assessing glucose disposal rate (GDR).

Results: Circulating adiponectin and TNFα gene expression correlated inversely and positively to the amount of AT in all three compartments (r=-0.266 to -0.276, p<0.05 for all) and (r=0.323 - 0.368, p<0.05 for all), respectively, with strongest correlations to the amount in sSAT and dSAT. When dividing AT compartments into quartiles, a tendency was observed towards lower circulating adiponectin and higher TNFα gene expression levels, respectively, with increasing amount of sSAT and dSAT. Circulating adiponectin correlated inversely to insulin, C-peptide and waist circumference (r=-456 to -0.373, p<0.001) and positively to GDR (r=0.356, p<0.001). AT-expressed visfatin correlated inversely to insulin and C-peptide (r=-0.370 and r=-0.404, p<0.001).

Conclusion: Increased amount of AT is associated with lower levels of adiponectin and increased levels of TNFα AT expression.
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http://dx.doi.org/10.3389/fendo.2022.874977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9301307PMC
July 2022

Exercise-induced change in circulating NT-proBNP could not distinguish between patients with and without coronary artery disease: the CADENCE study.

Scand Cardiovasc J 2022 12;56(1):107-113

Section of Cardiovascular and Renal research, Oslo University Hospital Ulleval, Oslo, Norway.

In patients with chest pain, exercise stress test has a moderate accuracy for coronary artery disease (CAD). Adding a reliable cardiac biomarker to the exercise test could potentially improve the precision of the test. We investigated circulating NT-proBNP levels before and during exercise stress test in patients with and without angiographically verified CAD. We hypothesized that NT-proBNP would give an additive diagnostic value to the exercise stress test. . In patients presenting with symptoms of stable CAD, venous blood samples were taken at rest and within 5 min of termination of a maximal stress test on a bicycle ergometer. All study participants underwent coronary angiography. Significant CAD was defined as ≥75% stenosis in one or more segments of the coronary arteries. . Of the 297 participants, significant CAD was found in 111 (37%) patients. Resting levels of NT-proBNP were significantly higher in patients with CAD compared with patients without CAD (74.18 vs. 56.03 ng/L),  = .005. During exercise, NT-proBNP levels increased in the total population ( < .001). The rise was, however, not significantly different between the two groups (8.24 vs. 8.51 ng/L),  = .700. Combining resting NT-proBNP with positive exercise stress test was superior to exercise test alone in predicting CAD, AUC = 0.68 vs. 0.64. . Exercise-induced change in circulating NT-proBNP could not distinguish between patients with or without CAD. However, resting levels of NT-proBNP were significantly higher in patients with CAD than those without CAD.
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http://dx.doi.org/10.1080/14017431.2022.2075562DOI Listing
December 2022

Interleukin-6 inhibition in ST-elevation myocardial infarction: Immune cell profile in the randomised ASSAIL-MI trial.

EBioMedicine 2022 Jun 30;80:104013. Epub 2022 Apr 30.

Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Department of Research and Development, Division of Emergencies and Critical Care, Oslo University Hospital, Norway. Electronic address:

Background: We recently showed that interleukin (IL)-6 inhibition by tocilizumab improves myocardial salvage in ST-elevation myocardial infarction (STEMI). However, the mechanisms for this effect are not clear.

Methods: In this exploratory sub-study of the ASSAIL-MI trial, we examined leukocyte differential counts and their relation to myocardial salvage and peak troponin T (TnT) in STEMI patients randomised to tocilizumab (n = 101) or placebo (n = 98). We performed RNA-sequencing on whole blood (n = 40) and T cells (n = 20). B and T cell subpopulations were examined by flow cytometry (n = 69).

Findings: (i) STEMI patients had higher neutrophil counts at hospitalisation compared with stable angina patients. (ii) After percutaneous coronary intervention there was a gradual decline in neutrophils, which was significantly more pronounced in the tocilizumab group. (iii) The decrease in neutrophils in the tocilizumab group was associated with improved myocardial salvage and lower peak TnT. (iv) RNA-sequencing suggested that neutrophil function was also attenuated by tocilizumab. (v) B and T cell sub-populations changed only minimally after STEMI with minor effects of tocilizumab, supported as well by RNA-sequencing analyses of T cells. (vi) However, a low CD8 count was associated with improved myocardial salvage in patients admitted to the hospital > 3 h after symptom onset.

Interpretation: Tocilizumab induced a rapid reduction in neutrophils and seemed to attenuate neutrophil function in STEMI patients potentially related to the beneficial effects of tocilizumab on myocardial salvage.

Funding: South-Eastern Norway Regional Health Authority (Nos. 2019067, 2017084), the Central Norway Regional Health Authority and Norwegian Research Council (No. 283867).
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http://dx.doi.org/10.1016/j.ebiom.2022.104013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9079006PMC
June 2022

Coagulation factors XI and XII as possible targets for anticoagulant therapy.

Thromb Res 2022 06 25;214:53-62. Epub 2022 Apr 25.

Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevål, Norway; University of Oslo, Norway; Department of Cardiology, Oslo University Hospital Ullevål, Norway.

In this review, we give an overview over observational and experimental studies supporting factors XI and XII as targets for anticoagulant therapy. The majority of observational studies on FXI report low concentrations of FXI to be protective against ischemic stroke and venous thrombosis. There is also extensive evidence from experimental and animal studies supporting FXI inhibition as a target for anticoagulant therapy, alone or in combination with other antithrombotic treatments. Four Phase 2 clinical trials on patients undergoing total knee arthroplasty showed non-inferiority or superiority of FXI inhibition compared to enoxaparin for the primary outcome, which was incidence of venous thromboembolism. One Phase 2 trial reported that FXI inhibition is associated with fewer bleeding events than apixaban. The results from observational studies on FXII are more conflicting. Some show that low FXII concentrations confer protection against thrombosis, while others have found it to be deleterious. Results from experimental studies are inconclusive, but suggest that FXII inhibition might be useful in preventing thrombosis caused by foreign objects like catheters or mechanical heart valves. One Phase 2 study not conducted on thrombosis has reported FXII inhibition as safe. In conclusion, FXI seems to be a promising target for antithrombotic therapy, both alone and in combination with existing therapies, while the potential of targeting FXII is still unclear.
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http://dx.doi.org/10.1016/j.thromres.2022.04.013DOI Listing
June 2022

Gene expression of fibrinolytic markers in coronary thrombi.

Thromb J 2022 Apr 29;20(1):23. Epub 2022 Apr 29.

Center for Clinical Heart Research, Oslo University Hospital Ullevål, Kirkeveien 166, Pb 4950 Nydalen, N-0424, Oslo, Norway.

Background: The fibrinolytic system plays an important role in coronary artery atherothrombosis, and especially circulating plasminogen-activator inhibitor (PAI) type 1 (PAI-1) associates with increased mortality, infarct size and heart failure in patients with myocardial infarction (MI). In a cross-sectional study, we aimed to study whether genes encoding tissue plasminogen activator (tPA), urinary-type plasminogen activator (uPA), PAI-1 and PAI-2 are expressed in coronary thrombi from acute ST-elevation MI (STEMI) patients. Any relations to myocardial injury measured by peak troponin T, time from symptom onset to Percutaneous Coronary Intervention (PCI), and to different cell types present in the thrombi were also explored.

Methods: Intracoronary thrombi were aspirated from 33 STEMI patients treated with primary PCI. The thrombi were snap-frozen for gene expression analyses, relatively quantified by RT PCR. Peripheral blood samples were drawn. Correlations were performed by Spearmans rho.

Results: The genes were present in 74-94% of the thrombi. Median peak troponin T was 3434 μ/L and median ischemic time 152 min. There were no significant correlations between the measured genes and troponin T, or ischemic time. Genes encoding tPA, u-PA, PAI-1 and PAI-2 all correlated significantly to the presence of monocytes/macrophages (CD68) in the thrombi (p = 0.028, p < 0.001, p = 0.003, p < 0.001). PAI-1 and PAI-2 also correlated to endothelial cells (CD31) (p = 0.002, p = 0.016). uPA associated with neutrophil granulocytes (CD 66b) (p = 0.019).

Conclusion: Genes encoding tPA, uPA, PAI-1 and PAI-2 were highly expressed in human coronary thrombi from STEMI patients, indicating fibrinolytic regulators playing active roles in the thrombi, although not related to myocardial injury. All markers related to the presence of monocytes/macrophages, indicating connection to local inflammatory cells.

Trial Registration: The study is registered at clinicaltrials.gov with identification number NCT02746822 .
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http://dx.doi.org/10.1186/s12959-022-00383-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9052700PMC
April 2022

Gut Leakage and Cardiac Biomarkers after Prolonged Strenuous Exercise.

Med Sci Sports Exerc 2022 09 25;54(9):1476-1482. Epub 2022 Apr 25.

Purpose: Transient increase in the cardiac biomarkers troponin T (cTnT) and NT-proBNP are observed during strenuous exercise, even in healthy athletes. Gut leakage, the translocation of bacterial lipopolysaccharide (LPS) into the circulation, is associated with atherosclerosis and cardiovascular disease but has also been reported after prolonged endurance exercise. We aimed to explore the link between exercise-induced gut leakage and cardiac biomarker release.

Methods: Participants in Norseman Xtreme Triathlon (Norseman) were included ( n = 44, age 43 ± 9 yr, 9 [21%] women). Blood samples were taken before and immediately after the race for the determination of biomarkers. cTnT and NT-proBNP were measured by conventional methods. Gut leakage marker LPS was measured by the kinetic, chromogenic limulus amebocyte lysate assay method, whereas LPS-binding protein (LBP), soluble cluster of differentiation 14 (sCD14), and intestinal injury marker intestinal fatty acid-binding protein (I-FABP) were measured by enzyme-linked immunosorbent assay.

Results: Median (25, 75 percentiles) finish time was 14 h 33 min (13 h 42 min, 15 h 29 min). TnT and NT-proBNP increased significantly to 38 ng·L -1 (27, 56) and 495 ng·L -1 (310, 828) after the race ( P < 0.001, both). LBP and sCD14 also increased significantly ( P < 0.001, both), as did I-FABP ( P = 0.003), whereas LPS remained unchanged ( P = 0.13). No significant correlations between changes in gut leakage markers and changes in cardiac biomarkers were observed after adjusting for multiple testing.

Conclusions: Cardiac and gut leakage biomarkers increased after Norseman Xtreme triathlon. However, changes in these biomarkers were not intercorrelated, suggesting that the exercise-induced increase in cardiac and gut leakage biomarkers occurs independently of each other.
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http://dx.doi.org/10.1249/MSS.0000000000002948DOI Listing
September 2022

Vascular Function in Norwegian Female Elite Runners: A Cross-Sectional, Controlled Study.

Sports (Basel) 2022 Mar 2;10(3). Epub 2022 Mar 2.

Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0318 Oslo, Norway.

In general, aerobic exercise has a positive impact on the vascular system, but the syndrome of relative energy-deficiency in sports (RED-S) makes this impact less clear for the athlete. The present cross-sectional controlled study aimed to investigate the vascular function in female elite long-distance runners, compared to inactive women. Sixteen female elite long-distance runners and seventeen healthy controls were recruited. Assessments of vascular function and morphology included endothelial function, evaluated by flow-mediated dilatation (FMD), vascular stiffness, evaluated with pulse wave velocity (PWV), carotid artery reactivity (CAR %), and carotid intima-media thickness (cIMT). Blood samples included hormone analyses, metabolic parameters, lipids, and biomarkers reflecting endothelial activation. RED-S risk was assessed through the low energy availability in female questionnaire (LEAF-Q), and body composition was measured by dual-energy X-ray absorptiometry (DXA). We found no significant differences in brachial FMD, PWV, CAR %, cIMT, or biomarkers reflecting endothelial activation between the two groups. Forty-four percent of the runners had a LEAF-Q score consistent with being at risk of RED-S. Runners showed significantly higher HDL-cholesterol and insulin sensitivity compared to controls. In conclusion, Norwegian female elite runners had an as good vascular function and morphology as inactive women of the same age.
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http://dx.doi.org/10.3390/sports10030037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8955513PMC
March 2022

TIMP-1 expression in coronary thrombi associate with myocardial injury in ST-elevation myocardial infarction patients.

Coron Artery Dis 2022 Sep 31;33(6):446-455. Epub 2022 Jan 31.

Center for Clinical Heart Research Oslo University Hospital Ullevål.

Background: Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) are considered important both in atherosclerosis and remodeling after acute myocardial infarction (AMI). We aimed to study genetic expression and presence of MMP-2, MMP-9, TIMP-1, TIMP-2 and the extracellular MMP-inducer (EMMPRIN) in coronary thrombi. Circulating levels and genetic expression in circulating leukocytes were also assessed, and relations to degree of myocardial injury measured by troponin T and time from symptom to PCI were explored. Expression of cell markers were also analyzed, indicating relations to cell types.

Methods: Intracoronary thrombi were aspirated from 33 patients with ST-elevation myocardial infarction (STEMI). Blood samples with Pax-gene tubes were drawn at end of PCI and the next day. RNA was isolated from thrombi and leukocytes, and genes were relatively quantified by RT-PCR. Each thrombus was preserved for histology and immunohistochemistry analyzes.

Results: Genes coding for the five markers were present in 84-100% of thrombi and immunohistochemically stained in 96-100%. Expression of TIMP-1 in thrombi and in leukocytes correlated significantly to peak troponin T ( r = 0.393 P = 0.026, r = 0.469 P = 0.006, respectively). No significant correlations between genes expressed in thrombi and time from symptom to PCI were observed. TIMP-1 was connected mainly to monocytes/macrophages in the thrombi.

Conclusion: MMP-2, MMP-9, TIMP-1, TIMP-2 and EMMPRIN were highly expressed in human coronary thrombi. The correlation between troponin T and the expression of TIMP-1 both in thrombi and in leukocytes at time of PCI indicates that TIMP-1 plays a role in myocardial damage early post-MI.
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http://dx.doi.org/10.1097/MCA.0000000000001128DOI Listing
September 2022

NETosis in Long-Term Type 1 Diabetes Mellitus and Its Link to Coronary Artery Disease.

Front Immunol 2021 5;12:799539. Epub 2022 Jan 5.

Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevål, Oslo, Norway.

Background: Neutrophil extracellular traps NETs have been linked to glucose and the pathogenesis of type 1 diabetes mellitus (T1DM). NETs also play a role in vascular inflammation and the development of coronary artery disease (CAD). The role of NETs in CAD progression in patients with long-term T1DM is unclear. We aimed to 1) investigate whether levels of circulating NETs markers were elevated in long-term T1DM subjects compared to controls, and 2) explore whether levels of NETs were related to the presence of CAD.

Material And Methods: 102 patients with > 45 years of T1DM and 75 age-matched controls were enrolled in a cross-sectional study. Median age was 62 years. Computed tomography coronary angiography (CTCA) was performed in 148 subjects without established coronary heart disease. For the current study, CAD was defined as a coronary artery stenosis >50%. Double-stranded deoxyribonucleic acid (dsDNA) was measured by a nucleic acid stain, myeloperoxidase-DNA (MPO-DNA), citrullinated histone 3 (H3Cit) and peptidylarginine deiminase 4 (PAD4) by ELISAs, while gene expression of PAD4 was measured in leukocytes from PAXgene tubes.

Results: Circulating MPO-DNA levels were significantly lower in patients with T1DM than in controls (0.17 vs 0.29 OD, p<0.001), while dsDNA, H3Cit, PAD4 and gene expression of PAD4 did not differ with respect to the presence of T1DM. There were no significant associations between NETs markers and HbA1c in the T1DM group. None of the NETs markers differed according to the presence of CAD in patients with T1DM. While all circulating NETs markers correlated significantly with circulating neutrophils in the control group (r=0.292-393, p<0.014), only H3Cit and PAD4 correlated with neutrophils in the T1DM group (r= 0.330-0.449, p ≤ 0.001).

Conclusions: In this cross-sectional study of patients with long-term T1DM and age-matched controls, circulating NETs levels were not consistently associated with the presence of T1DM or glycemic status, and did not differ according to the presence of CAD in patients with T1DM. Our results entail the possibility of altered neutrophil function and reduced NETosis in T1DM. This warrants further investigation.
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http://dx.doi.org/10.3389/fimmu.2021.799539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8767558PMC
February 2022

Changes in eicosapentaenoic acid and docosahexaenoic acid and risk of cardiovascular events and atrial fibrillation: A secondary analysis of the OMEMI trial.

J Intern Med 2022 05 4;291(5):637-647. Epub 2022 Jan 4.

Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.

Background: The cardiovascular benefit from n-3 polyunsaturated fatty acids (PUFAs) after acute myocardial infarction (AMI) is controversial, and the importance of serum eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) concentrations for clinical events is unclear.

Objectives: To assess changes in EPA and DHA serum concentrations during n-3 PUFA supplementation and their association with incident cardiovascular events.

Methods: In the OMEMI trial, elderly patients with a recent AMI were randomized to 1.8 g/day of EPA/DHA or control (corn oil) for 2 years. The primary outcome was a composite of AMI, coronary revascularization, stroke, heart failure hospitalization, or all-cause death (major adverse cardiovascular event [MACE]) and the secondary outcome was new-onset atrial fibrillation (AF).

Results: EPA and DHA measurements were available in 881 (92% of survivors) participants at randomization and study completion. EPA and DHA increased in the active treatment arm (n = 438) by a median of 87% and 16%, respectively. Greater on-treatment increases in EPA and DHA were associated with decreasing triglycerides, increasing high-density lipoprotein cholesterol, and lower baseline EPA and DHA concentrations. Greater on-treatment increases in EPA were associated with lower risk of MACE (adjusted hazard ratio 0.86 [95% confidence interval, CI, 0.75-0.99], p = 0.034), and higher risk of AF (adjusted hazard ratio (HR) 1.36 [95% CI 1.07-1.72], p = 0.011). Although there were similar tendencies for DHA changes and outcomes, these associations were not statistically significant (HR 0.84 [0.66-1.06] for MACE and 1.39 [0.90-2.13] for AF).

Conclusion: Greater on-treatment increases in EPA were associated with lower risk of MACE and higher risk of new-onset AF. These data suggest that the cardiovascular effects of increasing n-3 PUFA levels through supplements are complex, involving both potential benefits and harm.
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http://dx.doi.org/10.1111/joim.13442DOI Listing
May 2022

Soluble ST2 concentrations associate with in-hospital mortality and need for mechanical ventilation in unselected patients with COVID-19.

Open Heart 2021 12;8(2)

Department of Cardiology, Akershus University Hospital, Lorenskog, Norway

Objective: Soluble ST2 (sST2) reflects inflammation, endothelial dysfunction and myocardial fibrosis, is produced in the lungs and is an established biomarker in heart failure. We sought to determine the role of sST2 in COVID-19 by assessing pathophysiological correlates and its association to in-hospital outcomes.

Methods: We enrolled 123 consecutive, hospitalised patients with COVID-19 in the prospective, observational COVID-19 MECH study. Biobank samples were collected at baseline, day 3 and day 9. The key exposure variable was sST2, and the outcome was ICU treatment with mechanical ventilation or in-hospital death.

Results: Concentrations of sST2 at baseline was median 48 (IQR 37-67) ng/mL, and 74% had elevated concentrations (>37.9 ng/mL). Higher baseline sST2 concentrations were associated with older age, male sex, white race, smoking, diabetes, hypertension and chronic kidney disease. Baseline sST2 also associated with the presence of SARS-CoV-2 viraemia, lower oxygen saturation, higher respiratory rate and increasing concentrations of biomarkers reflecting inflammation, thrombosis and cardiovascular disease. During the hospitalisation, 8 (7%) patients died and 27 (22%) survivors received intensive care unit (ICU) treatment. Baseline sST2 concentrations demonstrated a graded association with disease severity (median, IQR): medical ward 43 (36-59) ng/mL; ICU 67 (39-104) ng/mL and non-survivors 107 (72-116) ng/mL (p<0.001 for all comparisons). These associations persisted at day 3 and day 9 .

Conclusions: sST2 concentrations associate with SARS-CoV-2 viraemia, hypoxaemia and concentrations of inflammatory and cardiovascular biomarkers. There was a robust association between baseline sST2 and disease severity that was independent of, and superior to, established risk factors. sST2 reflects key pathophysiology and may be a promising biomarker in COVID-19.

Trial Registration Number: NCT04314232.
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http://dx.doi.org/10.1136/openhrt-2021-001884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8692780PMC
December 2021

High levels of interleukin-6 are associated with final infarct size and adverse clinical events in patients with STEMI.

Open Heart 2021 12;8(2)

Department of Cardiology, Oslo University Hospital Ulleval, Oslo, Norway.

Objective: Inflammation has emerged as a new treatment target in patients with coronary artery disease and inflammation seems to play an important role in ischaemia/reperfusion injury that follows ST-elevation myocardial infarction (STEMI). We aimed to explore the role of acute and sustained interleukin 6 (IL-6) signalling, including soluble IL-6 receptor (IL-6R), with regard to infarct size, adverse remodelling and future cardiovascular events in patients with STEMI.

Methods: We included 269 patients with first-time STEMI, symptom duration <6 hours and treated with percutaneous coronary intervention. Blood sampling and cardiac MRI were performed in the acute phase and after 4 months. Clinical events and all-cause mortality were registered during 12-month and 70-month follow-up, respectively.

Results: IL-6 levels above median at all sampling points were significantly associated with increased infarct size and reduced left ventricular ejection fraction (LVEF). IL-6 levels in the highest quartile were at all sampling points associated with an increased risk of having an adverse clinical event during the first 12 months and with long-term all-cause mortality. IL-6R was not associated with infarct size, LVEF, myocardial salvage or long-term all-cause mortality.

Conclusion: Acute and sustained elevation of IL-6 measured 4 months after STEMI were associated with larger infarct size, reduced LVEF and adverse clinical events including all-cause mortality. The results add important information to the sustained role of inflammation in patients with STEMI and IL-6 as a potential target for long-term intervention.

Trial Registration Number: NCT00922675.
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http://dx.doi.org/10.1136/openhrt-2021-001869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8693166PMC
December 2021

Complement ratios C3bc/C3 and sC5b-9/C5 do not increase the sensitivity of detecting acute complement activation systemically.

Mol Immunol 2022 01 11;141:273-279. Epub 2021 Dec 11.

Department of Immunology, Oslo University Hospital and University of Oslo, Norway; Division of Emergencies and Critical Care, Oslo University Hospital, Norway. Electronic address:

Background: Complement activation plays an important pathogenic role in numerous diseases. The ratio between an activation product and its parent protein is suggested to be more sensitive to detect complement activation than the activation product itself. In the present study we explored whether the ratio between the activation product and the parent protein for C3 (C3bc/C3) and for C5 (sC5b-9/C5) increased the sensitivity to detect complement activation in acute clinical settings compared to the activation product alone.

Materials And Methods: Samples from patients with acute heart failure following ST-elevated myocardial infarction (STEMI) and from patients with out-of-hospital cardiac arrest (OHCA) were used. C3, C3bc and C5, sC5b-9 were analysed in 629 and 672 patient samples, respectively. Healthy controls (n = 20) served to determine reference cut-off values for activation products and ratios, defined as two SD above the mean.

Results: Increased C3bc/C3- and sC5b-9/C5 ratios were vastly dependent on C3bc and sC5b-9. Thus, 99.5 % and 98.1 % of the increased C3bc/C3- and sC5b-9/C5 ratios were solely dependent on increased C3bc and sC5b-9, respectively. Significantly decreased C3 and C5 caused increased ratios in only 3/600 (0.5 %) and 4/319 (1.3 %) samples, respectively. Strong correlations between C3bc and C3bc/C3-ratio and between sC5b-9 and sC5b-9/C5-ratio were found in the STEMI- (r = 0.926 and r = 0.786, respectively) and the OHCA-population (r = 0.908 and r = 0.843, respectively; p < 0.0001 for all). Importantly, sC5b-9 identified worse outcome groups better than sC5b-9/C5-ratio.

Conclusion: C3bc and sC5b-9 were sensitive markers of complement activation. The ratios of C3bc/C3 and sC5b-9/C5 did not improve detection of complement activation systemically.
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http://dx.doi.org/10.1016/j.molimm.2021.11.016DOI Listing
January 2022

Probiotics to HIV-Infected Immunological Nonresponders: Altered Mucosal Immunity and Microbial Diversity Restricted to Ileum.

J Acquir Immune Defic Syndr 2022 01;89(1):77-86

Department of Infectious Diseases, Oslo University Hospital, Oslo, Norway.

Background: HIV-infected immunological nonresponders (INRs) have increased risk of non-AIDS morbidity and compromised gut barrier immunity. Probiotics are widely used to improve health. We assessed the effects of probiotics in INRs with a comprehensive analysis of gut immunity and microbiome in terminal ileum and sigmoid colon.

Methods: The study involved clinical intervention with five-strain probiotic capsules (1.2 × 1010 CFUs/d) for 8 weeks in 20 INRs with CD4+ T-cell counts <400 cells/µL and plasma HIV RNA <50 copies/mL for more than 3.5 years. Colonoscopy with sampling of gut biopsies from terminal ileum and sigmoid colon and fecal and blood sampling were performed before and after the intervention. Flow cytometry (cytokine production, immune activation, and exhaustion), ELISA (inflammation, microbial translocation, and enterocyte damage), and 16S rRNA sequencing analyses were applied.

Results: In the terminal ileum, increased alpha diversity, increased abundance of Bifidobacterium sp., and decreased frequencies of IL-22+ CD4+ T cells were observed. The increased abundance of Bifidobacterium sp. in the terminal ileum correlated with increased fraction of CD4+ T cells in the same compartment (r = 0.54, P = 0.05) and increased CD4/CD8 ratio in peripheral blood (r = 0.49, P = 0.05). There were no corresponding changes in the sigmoid colon and no changes in fecal microbiome. Probiotic intervention did not affect peripheral blood CD4 count, viral load, or soluble markers of inflammation and microbial translocation.

Conclusions: Probiotics induced segment-specific changes in the terminal ileum but did not affect systemic CD4 counts in INRs. Further clinical studies are warranted to recommend probiotics to INRs.
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http://dx.doi.org/10.1097/QAI.0000000000002817DOI Listing
January 2022

Adiponectin in relation to exercise and physical performance in patients with type 2 diabetes and coronary artery disease.

Adipocyte 2021 12;10(1):612-620

Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevål, Norway.

Introduction: Adipokines, expressed by adipose tissue (AT), have been associated with metabolic disturbances and coronary artery disease (CAD). The impact of exercise training on the AT in patients suffering from both diabetes and CAD is unknown. To gain knowledge on changes in ATs' inflammatory profile in such a population, we investigated the effects of long-term exercise on selected adipokines and their associations with physical performance and glucometabolic variables. Adiponectin was selected based on its anti-atherogenic and anti-diabetic properties and visfatin and tumour necrosis factor (TNF) for their association with atherosclerosis and metabolic disorders. Not many studies have focused on the effects of long-term exercise training on adipokines in patients with concomitant T2DM and CAD.

Methods: Patients with type 2 diabetes and CAD (n = 137), 41-81 years, 17.2% females, were randomized in a 1:1 manner to an exercise group, who underwent 1 year of 150 min weekly combined strength and endurance exercise, or a control group. AT from the gluteal region and blood samples were obtained at baseline and after 12 months, along with a physical performance test, assessed by the VO peak. Circulating protein levels were measured by ELISA. RNA was extracted from AT and expression levels were relatively quantified by PCR.

Results: After 1 year, no significant difference in the change in the investigated markers between the intervention group and the control group was observed. Changes in circulating adiponectin and VO peak correlated in the total population (r = 0.256, p = 0.008). At baseline, circulating adiponectin and TNF correlated inversely with insulin and with C-peptide and VOpeak, respectively (p < 0.001, all).

Conclusion: In this population with concomitant diabetes and CAD, ATs' inflammatory profile remained unchanged apparently after 1 year of exercise intervention. Changes in the VOpeak were nevertheless, related to changes in circulating adiponectin levels.

Trial Registration: http://www.clinicaltrials.gov NCT01232608.
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http://dx.doi.org/10.1080/21623945.2021.1996699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8726619PMC
December 2021

One year of omega 3 polyunsaturated fatty acid supplementation does not reduce circulating prothrombotic microvesicles in elderly subjects after suffering a myocardial infarction.

Clin Nutr 2021 12 20;40(12):5674-5677. Epub 2021 Oct 20.

Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevål, 0450, Oslo, Norway; Faculty of Medicine, University of Oslo, 0372, Oslo, Norway.

Background & Aims: Circulating microvesicles (cMV) are both effectors and biomarkers of cardiovascular disease (CVD), and the effects of omega 3 polyunsaturated fatty acids (n3 PUFA) in MV shedding are not yet well known. Therefore, we aimed to investigate the effects of long-term n3 PUFA supplementation on cMV release from cells of the vascular compartment in elderly subjects at very high risk of CVD.

Methods: We included 156 elderly patients 2-8 weeks after suffering an acute myocardial infarction from the OMEMI cohort. Subjects were randomly allocated to receive 930 mg EPA + 660 mg DHA (n3 PUFA intervention) or corn oil (56% linoleic acid, 32% oleic acid, 10% palmitic acid) used as placebo daily for two years. At inclusion and after one-year follow-up, prothrombotic [annexin V (AV)] cMV derived from blood and vascular cells were phenotyped by flow cytometry.

Results: No differences were observed in the levels of cMV between the randomized groups at inclusion in the study. After one-year follow-up, total AV, platelet-derived CD61/AV, and endothelial-derived CD31/AV and CD31/CD42b/AV cMV increased significantly in both groups. In the n3 PUFA supplemented group, platelet-derived CD62P/AV, CD42b/AV and CD31/CD42b/AV; leukocyte-derived CD62L/AV, CD45/AV, and CD11b/AV, as well as endothelial derived CD146/AV, CD62E/AV, and CD309/AV cMV also increased significantly. No significant differences were however, observed in the changes of cMV levels between groups.

Conclusion: In elderly Norwegians who have suffered a recent acute myocardial infarction and treated as per guidelines, long-term supplementation with 1.8 g/day n3 PUFA does not modulate prothrombotic MV release from blood and vascular cells.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01841944.
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http://dx.doi.org/10.1016/j.clnu.2021.10.007DOI Listing
December 2021

Serum Levels of Dihomo-Gamma (γ)-Linolenic Acid (DGLA) Are Inversely Associated with Linoleic Acid and Total Death in Elderly Patients with a Recent Myocardial Infarction.

Nutrients 2021 Sep 30;13(10). Epub 2021 Sep 30.

Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0315 Oslo, Norway.

Dihomo-gamma-linolenic acid (DGLA) is an -6 polyunsaturated fatty acid (PUFA) derived from linoleic acid (LA). The LA:DGLA ratio reflects conversion from LA to DGLA. Low levels of DGLA in serum have been related to poor outcome in myocardial infarction (MI) patients. To assess the association of DGLA and LA:DGLA with total death as a primary aim and incident cardiovascular events as a secondary objective. Baseline samples from 1002 patients, aged 70 to 82 years, included 2-8 weeks after an MI and followed for 2 years, were used. Major adverse clinical events (MACE) consisted of nonfatal MI, unscheduled coronary revascularization, stroke, hospitalization for heart failure or all-cause death. Cox regression analysis was used to relate serum -6 PUFA phospholipid levels (%wt) to the risk of MACE, adjusting for the following: (1) age, sex and body mass index (BMI); (2) adding baseline cod liver oil supplementation; (3) adding prevalent hypertension, chronic kidney disease and diabetes mellitus. Median DGLA level in serum phospholipids was 2.89 (Q1-Q3 2.43-3.38) %wt. DGLA was inversely related to LA and LA:DGLA ratio. There were 208 incident cases of MACE and 55 deaths. In the multivariable analysis, the hazard ratio (HR) for the total death in the three higher quartiles (Q2-4) of DGLA as compared to Q1 was 0.54 (0.31-0.95), with = 0.03 (Model-1), 0.50 (0.28-0.91), with = 0.02 (Model-2), and 0.47 (0.26-0.84), with = 0.012 (Model-3), and non-significant for MACE. Risk of MACE (Model 3) approached borderline significance for LA:DGLA in Q2-4 vs. Q1 [HR 1.42 (1.00-2.04), = 0.052]. Low levels of DGLA were related to a high LA:DGLA ratio and risk of total death in elderly patients with recent MI.
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http://dx.doi.org/10.3390/nu13103475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8540726PMC
September 2021

Gut Leakage Markers in Response to Strenuous Exercise in Patients with Suspected Coronary Artery Disease.

Cells 2021 08 25;10(9). Epub 2021 Aug 25.

Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevål, 0424 Oslo, Norway.

Elevated levels of gut leakage markers have been shown after strenuous exercise in healthy individuals. Any association between a temporary increase in these markers and the presence of coronary artery disease (CAD) is unknown. We therefore aimed to explore circulating gut leakage markers in response to a bout of strenuous exercise in patients with symptoms of CAD. Patients referred to exercise stress testing due to symptoms of CAD were included ( = 287). A maximal exercise ECG stress test was performed and venous blood samples were drawn at rest and within five minutes after, for analysis of soluble cluster of differentiation 14 (sCD14), lipopolysaccharide-binding protein (LBP), intestinal fatty-acid binding protein (I-FABP), lipopolysaccharide (LPS) and gene expression of toll-like receptor 4 (TLR4) in circulating leukocytes. Patients then underwent coronary angiography. LPS, LBP and sCD14 increased significantly after strenuous exercise in patients with symptoms of CAD, suggesting that even short bouts of vigorous exercise are associated with gut leakage. The gene expression of TLR4 decreased significantly after exercise, possibly as a negative feedback to the increase in LPS. There were no differences in exercise-induced changes between the groups of CAD, suggesting gut leakage to be independent of the presence of CAD.
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http://dx.doi.org/10.3390/cells10092193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8466709PMC
August 2021

Reduced L-Arginine and L-Arginine-ADMA-Ratio, and Increased SDMA after Norseman Xtreme Triathlon.

Sports (Basel) 2021 Aug 31;9(9). Epub 2021 Aug 31.

Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0318 Oslo, Norway.

Endothelial vasodilatory function is dependent on the NO synthesis from L-arginine by endothelial NO-synthetase (eNOS). eNOS can be inhibited by asymmetric dimethylarginine (ADMA) by competitive inhibition on the binding site, and symmetric dimethylarginine (SDMA) can reduce the L-arginine availability intracellularly through competing for transport over the cellular membrane. To study the NO synthesis after prolonged exercise, we assessed circulatory L-arginine, the L-arginine/ADMA ratio, and SDMA before, after, and on the day after the Norseman Xtreme triathlon, an Ironman distance triathlon. We found significantly reduced levels of L-arginine and the L-arginine/ADMA ratio and increased levels of SDMA after the race (all < 0.05). L-arginine rose toward baseline levels the day after the race, but ADMA increased beyond baseline levels, and SDMA remained above baseline the day after the race. The reduced levels of L-arginine and the L-arginine/ADMA ratio, and increased SDMA, after the race indicate a state of reduced capability of NO production. Increased levels of ADMA and SDMA, and reduced L-arginine/ADMA ratio, as seen the day after the race, are known risk markers of atherosclerosis and warrant further studies.
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http://dx.doi.org/10.3390/sports9090120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8472968PMC
August 2021

Immune complexes, innate immunity, and NETosis in ChAdOx1 vaccine-induced thrombocytopenia.

Eur Heart J 2021 10;42(39):4064-4072

Research Institute of Internal Medicine, Oslo University Hospital, Postbox 4950, 0424 Oslo, Norway.

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.

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.

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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http://dx.doi.org/10.1093/eurheartj/ehab506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8385969PMC
October 2021

Rifaximin or Saccharomyces boulardii in heart failure with reduced ejection fraction: Results from the randomized GutHeart trial.

EBioMedicine 2021 Aug 28;70:103511. Epub 2021 Jul 28.

Department of Cardiology, Oslo University Hospital, Rikshospitalet, 0372 Oslo, Norway; KG Jebsen Center for Cardiac Research, University of Oslo, 0450 Oslo, Norway.

Background: The gut microbiota represents a potential treatment target in heart failure (HF) through microbial metabolites such as trimethylamine N-oxide (TMAO) and systemic inflammation. Treatment with the probiotic yeast Saccharomyces boulardii have been suggested to improve left ventricular ejection fraction (LVEF).

Methods: In a multicentre, prospective randomized open label, blinded end-point trial, we randomized patients with LVEF <40% and New York Heart Association functional class II or III, despite optimal medical therapy, to treatment (1:1:1) with the probiotic yeast Saccharomyces boulardii, the antibiotic rifaximin, or standard of care (SoC) only. The primary endpoint, the baseline-adjusted LVEF at three months, was assessed in an intention-to-treat analysis.

Findings: We enrolled a total of 151 patients. After three months' treatment, the LVEF did not differ significantly between the SoC arm and the rifaximin arm (mean difference was -1•2 percentage points; 95% CI -3•2 - 0•7; p=0•22) or between the SoC arm and the Saccharomyces boulardii arm (mean difference -0•2 percentage points; 95% CI -2•2 - 1•9; p=0•87). We observed no significant between-group differences in changes in microbiota diversity, TMAO, or C-reactive protein.

Interpretation: Three months' treatment with Saccharomyces boulardii or rifaximin on top of SoC had no significant effect on LVEF, microbiota diversity, or the measured biomarkers in our population with HF.

Funding: The trial was funded by the Norwegian Association for Public Health, the Blix foundation, Stein Erik Hagen's Foundation for Clinical Heart Research, Ada og Hagbart Waages humanitære og veldedige stiftelse, Alfasigma, and Biocodex.
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http://dx.doi.org/10.1016/j.ebiom.2021.103511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339250PMC
August 2021

Transient Reduction of FMD-Response and L-Arginine Accompanied by Increased Levels of E-Selectin, VCAM, and ICAM after Prolonged Strenuous Exercise.

Sports (Basel) 2021 Jun 17;9(6). Epub 2021 Jun 17.

Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0318 Oslo, Norway.

We assessed endothelial function by flow-mediated dilatation (FMD), levels of the NO-precursor L-arginine, and markers of endothelial inflammation before, at the finish line, and one week after the Norseman Xtreme triathlon. The race is an Ironman distance triathlon with a total elevation of 5200 m. Nine male participants were included. They completed the race in 14.5 (13.4-15.3) h. FMD was significantly reduced to 3.1 (2.1-5.0)% dilatation compared to 8.7 (8.2-9.3)% dilatation before the race ( < 0.05) and was normalized one week after the race. L-arginine showed significantly reduced levels at the finish line ( < 0.05) but was normalized one week after the race. Markers of endothelial inflammation E-Selectin, VCAM-1, and ICAM-1 all showed a pattern with increased values at the finish line compared to before the race (all < 0.05), with normalization one week after the race. In conclusion, we found acutely reduced FMD with reduced L-arginine levels and increased E-Selectin, VCAM-1, and ICAM-1 immediately after the Norseman Xtreme triathlon. Our findings indicate a transient reduced endothelial function, measured by the FMD-response, after prolonged strenuous exercise that could be explained by reduced NO-precursor L-arginine levels and increased endothelial inflammation.
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http://dx.doi.org/10.3390/sports9060086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234080PMC
June 2021

Myhre, Seljeflot and Arnesen respond.

Tidsskr Nor Laegeforen 2021 06 28;141(10). Epub 2021 Jun 28.

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http://dx.doi.org/10.4045/tidsskr.21.0470DOI Listing
June 2021

The Inflammasome Signaling Pathway Is Actively Regulated and Related to Myocardial Damage in Coronary Thrombi from Patients with STEMI.

Mediators Inflamm 2021 27;2021:5525917. Epub 2021 May 27.

Center for Clinical Heart Research, Oslo University Hospital Ullevål, Norway.

Background: The Nod-Like-Receptor-Protein-3 (NLRP3) inflammasome and the Interleukin-6 (IL-6) pathways are central mechanisms of the inflammatory response in myocardial reperfusion injury. Expanding our knowledge about the inflammasome signaling axis is important to improve treatment options. In a cross-sectional study, we aimed to study presence, localization, and genetic expression of inflammasome- and IL-6- signaling-related proteins in coronary thrombi and circulating leukocytes from ST-elevation myocardial infarction (STEMI) patients, with relation to myocardial injury and time from symptoms to PCI.

Methods: Intracoronary thrombi were aspirated from 33 STEMI patients. Blood samples were drawn. mRNA of Toll-Like-Receptor-4 (TLR4), NLRP3, caspase 1, Interleukin-1 (IL1-), Interleukin-18 (IL-18), IL-6, IL-6-receptor (IL-6R), and glycoprotein 130 (gp130) were isolated from thrombi and circulating leukocytes and relatively quantified by RT-PCR. A part of each thrombus was embedded in paraffin for histology and immunohistochemistry analyses.

Results: Genes encoding the 8 markers were present in 76-100% of thrombi. Expression of TLR4 in thrombi significantly correlated to troponin T ( = 0.455, = 0.013), as did NLRP3 ( = 0.468, = 0.024). Troponin T correlated with expression in circulating leukocytes of TLR4 ( = 0.438, = 0.011), NLRP3 ( = 0.420, = 0.0149), and IL-1 ( = 0.394, = 0.023). IL-6R expression in thrombi correlated significantly to troponin T ( = 0.434, = 0.019), whereas gp130 was inversely correlated ( = -0.398, = 0.050). IL-6 in circulating leukocytes correlated inversely to troponin T ( = -0.421, = 0.015). There were no significant correlations between genes expressed in thrombi and time from symptom to PCI.

Conclusions: The inflammasome signaling pathway was actively regulated in coronary thrombi and in circulating leukocytes from patients with STEMI, in association with myocardial damage measured by troponin T. This supports the strategy of medically targeting this pathway in treating myocardial infarction and contributes to sort out optimal timing and targets for anti-inflammatory treatment. The study is registered at clinicaltrials.gov with identification number NCT02746822.
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http://dx.doi.org/10.1155/2021/5525917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178014PMC
December 2021

Complement activation is associated with poor outcome after out-of-hospital cardiac arrest.

Resuscitation 2021 09 11;166:129-136. Epub 2021 Jun 11.

Dept. of Immunology, University of Oslo and Oslo University Hospital, Oslo, Norway; Dept. of Anaesthesiology, Division of Emergencies and Critical Care, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Dept. of Research and Development, Division of Emergencies and Critical Care, Oslo University Hospital, Oslo, Norway. Electronic address:

Background: Cardiopulmonary resuscitation after cardiac arrest initiates a whole-body ischemia-reperfusion injury, which may activate the innate immune system, including the complement system. We hypothesized that complement activation and subsequent release of soluble endothelial activation markers were associated with cerebral outcome including death.

Methods: Outcome was assessed at six months and defined by cerebral performance category scale (1-2; good outcome, 3-5; poor outcome including death) in 232 resuscitated out-of-hospital cardiac arrest patients. Plasma samples obtained at admission and day three were analysed for complement activation products C3bc, the soluble terminal complement complex (sC5b-9), and soluble CD14. Endothelial cell activation was measured by soluble markers syndecan-1, sE-selectin, thrombomodulin, and vascular cell adhesion molecule.

Results: Forty-nine percent of the patients had good outcome. C3bc and sC5b-9 were significantly higher at admission compared to day three (p < 0.001 for both) and in patients with poor compared to good outcome (p = 0.03 and p < 0.001, respectively). Unadjusted, higher sC5b-9 at admission was associated with poor outcome (odds ratio 1.08 (95% CI 1.01-1.14), p = 0.024). Adjusted, sC5b-9 was still associated with outcome, but the association became non-significant when time to return-of-spontaneous-circulation above 25 min was included as a covariate. Endothelial cell activation markers increased from admission to day three, but only sE-selectin and thrombomodulin were significantly higher in patients with poor versus good outcome (p = 0.004 and p = 0.03, respectively) and correlated to sCD14 and sC5b-9/C3bc, respectively.

Conclusion: Complement system activation, reflected by sC5b-9 at admission, leading to subsequent endothelial cell activation, was associated with poor outcome in out-of-hospital cardiac arrest patients.
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http://dx.doi.org/10.1016/j.resuscitation.2021.05.038DOI Listing
September 2021

Mortality and microbial diversity after allogeneic hematopoietic stem cell transplantation: secondary analysis of a randomized nutritional intervention trial.

Sci Rep 2021 06 2;11(1):11593. Epub 2021 Jun 2.

Department of Haematology, Oslo University Hospital, P.O. Box 4950 Nydalen, 0424, Oslo, Norway.

Gut mucosal barrier injury is common following allogeneic hematopoietic stem cell transplantation (allo-HSCT) and associated with poor clinical outcomes. Diet is critical for microbial diversity, but whether nutritional support affects microbiota and outcome after allo-HSCT is unknown. We present a secondary analysis of a randomized controlled nutritional intervention trial during allo-HSCT. We investigated if the intervention influenced gut microbiota, short-chain fatty acids (SCFAs), and markers of gut barrier functions, and if these parameters were associated with clinical outcomes. Fecal specimens were available from 47 recipients, and subjected to 16S rRNA gene sequencing. We found no significant differences between the intervention group and controls in investigated parameters. We observed a major depletion of microbiota, SCFAs, and altered markers of gut barrier function from baseline to 3 weeks post-transplant. One-year mortality was significantly higher in patients with lower diversity at 3 weeks post-HSCT, but not related to diversity at baseline. The relative abundance of Blautia genus at 3 weeks was higher in survivors. Fecal propionic acid was associated with survival. Markers of gut barrier functions were less strongly associated with clinical outcomes. Possibly, other strategies than dietary intervention are needed to prevent negative effects of gut microbiota and clinical outcomes after allo-HSCT.ClinicalTrials.gov (NCT01181076).
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http://dx.doi.org/10.1038/s41598-021-90976-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172574PMC
June 2021

Effects of intermittent negative pressure treatment on circulating vascular biomarkers in patients with intermittent claudication.

Vasc Med 2021 10 13;26(5):489-496. Epub 2021 May 13.

Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.

The aim of this study was to investigate the effects of lower extremity intermittent negative pressure (INP) treatment for 1 hour twice daily for 12 weeks, on circulating vascular biomarkers in patients with intermittent claudication. Patients were randomized to treatment with -40 mmHg INP (treatment group), or -10 mmHg INP (sham control group). Venous blood samples were collected at baseline and after 12 weeks, and concentrations of vascular adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1), E-selectin, P-selectin, von Willebrand factor (vWF), l-arginine, asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA) were analyzed. A larger proportion of the patients in the treatment group (25/31) had a reduction in vWF levels after 12 weeks, compared to the sham control group (17/30) ( = 0.043). Within the treatment group there was a significant mean (SEM) reduction in the concentration of vWF of -11% (4) ( = 0.019), whereas there was no significant change in the levels of vWF in the sham control group (1% (6); = 0.85). There were no significant differences in the change of any of the biomarker levels between the groups after 12 weeks of treatment. In conclusion, there were no differences in the change of the circulating levels of the measured biomarkers between the treatment group and the sham control group after 12 weeks of INP treatment. However, the observed changes in vWF might indicate a beneficial effect of INP treatment on endothelial activation and endothelial injury. .
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http://dx.doi.org/10.1177/1358863X211007933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8493410PMC
October 2021

Effect of intermittent and continuous caloric restriction on Sirtuin1 concentration depends on sex and body mass index.

Nutr Metab Cardiovasc Dis 2021 06 19;31(6):1871-1878. Epub 2021 Mar 19.

Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevål, Oslo, Norway; Faculty of Medicine, University of Oslo, Norway.

Background & Aims: The favorable effect of caloric restriction (CR) on health span is well known and partly mediated by the sirtuin system. Sirtuin1, a regulator of energy homeostasis in response to nutrient availability, is activated by CR. We therefore investigated effects of two different CR regimens on Sirtuin1 concentrations.

Methods & Results: The study included 112 abdominally obese subjects, randomized to intermittent or continuous CR for 1 year. Blood samples and anthropometric measures were collected at baseline and after 12 months. Sirtuin1 concentrations were measured by ELISA. Sirtuin1 correlated significantly to BMI at baseline (r = .232, p = 0.019). Mean reduction in body-weight was 8.0 and 9.0 kg after intermittent and continuous CR, respectively. After 1 year, no significant between-group differences in Sirtuin1 levels were observed according to regimen (p = 0.98) and sex (p = 0.41). An increase in median Sirtuin1 concentrations (pg/mL) [25, 75 percentiles] from baseline was observed after intermittent CR in the total population (884 [624, 1285] vs.762 [530, 1135]; p = 0.041), most marked in men (820 [623, 1250] vs. 633 [524, 926]; p = 0.016). Improvement in BMI after 1 year correlated to Sirtuin1 changes, but varied according to sex. In women, Spearman's rho = .298, p = 0.034, with stronger correlation in the intermittent CR group (r = .424, p = 0.049). In men, there was an inverse relation to Sirtuin1 changes, only in the intermittent CR group (r = -.396, p = 0.045).

Conclusions: Effects on Sirtuin1 concentrations after 1 year of CR are sex and BMI-related. Intermittent CR regimen affected Sirtuin1 to a stronger extent than continuous CR, suggesting individualized dietary intervention.
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http://dx.doi.org/10.1016/j.numecd.2021.03.005DOI Listing
June 2021

Tocilizumab increases citrullinated histone 3 in non-ST segment elevation myocardial infarction.

Open Heart 2021 05;8(1)

Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevål, Oslo, Norway.

Objective: Beyond reducing inflammation and troponin T (TnT) release, the interleukin-6 receptor antagonist tocilizumab reduces neutrophil counts in patients with non-ST segment elevation myocardial infarction (NSTEMI). It is unclear if this is related to formation of neutrophil extracellular traps (NETs), carrying inflammatory and thrombotic properties.

Methods: In a placebo-controlled trial, 117 patients with NSTEMI were randomised to a single dose of tocilizumab (n=58) or placebo (n=59) before coronary angiography. The NETs related markers double-stranded DNA (dsDNA), myloperoxidase-DNA (MPO-DNA) and citrullinated histone 3 (H3Cit) were measured at five consecutive time points during hospitalisation (days 1-3).

Results: Our major findings were: (1) H3Cit levels were significantly higher in the tocilizumab compared with the placebo group at all time points (all p<0.05), and H3Cit area under the curve (AUC) was 2.3 fold higher in the tocilizumab compared with placebo group (p<0.0001). (2) MPO-DNA and dsDNA did not differ between the groups. (3) In both treatment arms, dsDNA AUC was associated with TnT AUC. (4) Neutrophil count AUC correlated inversely to H3Cit AUC (p=0.015) in the total population.

Conclusions: In patients with NSTEMI, treatment with tocilizumab is associated with increased circulating H3Cit levels, suggesting that tocilizumab enhances NETosis. Further studies should clarify whether NETosis is a relevant side effect of tocilizumab. Regardless of tocilizumab, dsDNA associated with TnT release, indicating a link between extracellular nuclear material and myocardial injury.
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http://dx.doi.org/10.1136/openhrt-2020-001492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8112443PMC
May 2021
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