Publications by authors named "Maria Vistnes"

19 Publications

  • Page 1 of 1

Levosimendan Versus Milrinone and Release of Myocardial Biomarkers After Pediatric Cardiac Surgery: Post Hoc Analysis of Clinical Trial Data.

Pediatr Crit Care Med 2021 07;22(7):e402-e409

Department of Anesthesiology and Intensive Care Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Objectives: We compared the effect of two inodilators, levosimendan and milrinone, on the plasma levels of myocardial injury biomarkers, that is, high-sensitivity troponin T and heart-type fatty acid binding protein, and on N-terminal prohormone of brain natriuretic peptide as a biomarker of ventricular function. We hypothesized that levosimendan could attenuate the degree of myocardial injury when compared with milrinone.

Design: A post hoc, nonprespecified exploratory secondary analysis of the Milrinone versus Levosimendan-1 trial (ClinicalTrials.gov Identifier: NCT02232399).

Setting: Two pediatric tertiary university hospitals.

Patients: Infants 1-12 months old, diagnosed with ventricular septal defect, complete atrioventricular septal defect, or Tetralogy of Fallot undergoing corrective surgery with cardiopulmonary bypass.

Interventions: Seventy patients received a loading dose of either levosimendan or milrinone at the start of cardiopulmonary bypass followed by an infusion of the respective drug, which continued for 26 hours.

Measurements And Main Results: Plasma levels of the three cardiac biomarkers were measured prior to the initiation of cardiopulmonary bypass and 2, 6, and 24 hours after weaning from cardiopulmonary bypass. In both groups, the levels of high-sensitivity troponin T and heart-type fatty acid binding protein were highest at 2 hours post cardiopulmonary bypass, whereas the highest level of N-terminal prohormone of brain natriuretic peptide occurred at 24 hours post cardiopulmonary bypass. There was no significant difference in the biomarkers' plasma levels between the study groups over time. Neither was there a significant difference in the postoperative peak plasma levels of the cardiac biomarkers.

Conclusions: In this post hoc analysis of the MiLe-1 trial, there was no demonstrable difference in the postoperative cardiac biomarker profile of myocardial injury and ventricular function when comparing infants managed in the perioperative period with levosimendan versus milrinone.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PCC.0000000000002712DOI Listing
July 2021

Correlation of Body Weight and Composition With Hepatic Activities of Cytochrome P450 Enzymes.

J Pharm Sci 2021 01 19;110(1):432-437. Epub 2020 Oct 19.

Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, Oslo, Norway. Electronic address:

Obesity is associated with comorbidities of which pharmacological treatment is needed. Physiological changes associated with obesity may influence the pharmacokinetics of drugs, but the effect of body weight on drug metabolism capacity remains uncertain. The aim of this study was to investigate ex vivo activities of hepatic drug metabolizing CYP enzymes in patients covering a wide range of body weight. Liver biopsies from 36 individuals with a body mass index (BMI) ranging from 18 to 63 kg/m were obtained. Individual hepatic microsomes were prepared and activities of CYP3A, CYP2B6, CYP2C8, CYP2D6, CYP2C9, CYP2C19 and CYP1A2 were determined. The unbound intrinsic clearance (CL) values for CYP3A correlated negatively with body weight (r = -0.43, p < 0.01), waist circumference (r = -0.47, p < 0.01), hip circumference (r = -0.51, p < 0.01), fat percent (r = -0.41, p < 0.05), fat mass (r = -0.48, p < 0.01) and BMI (r = -0.46, p < 0.01). Linear regression analysis showed that CL values for CYP3A decreased with 5% with each 10% increase in body weight (r = 0.12, β = -0.558, p < 0.05). There were no correlations between body weight measures and CL values for the other CYP enzymes investigated. These results indicate reduced hepatic metabolizing capacity of CYP3A substrates in patients with increasing body weight.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.xphs.2020.10.027DOI Listing
January 2021

Obstructive sleep apnea versus central sleep apnea: prognosis in systolic heart failure.

Cardiovasc Diagn Ther 2020 Jun;10(3):396-404

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

Background: In chronic heart failure (CHF), obstructive sleep apnea (OSA) and Cheyne-Stokes respiration (CSR) are associated with increased mortality. The present study aimed to evaluate the prognostic effect of CSR compared to OSA, in otherwise similar groups of CHF patients.

Methods: Screening for sleep-disordered breathing (SDB) was conducted among patients with CHF of New York Heart Association (NYHA) class II-IV, and left ventricular ejection fraction (LVEF) of ≤45%. The study included 43 patients (4 women) with >25% CSR during sleeping time, and 19 patients (2 women) with OSA and an apnea-hypopnea index (AHI) of ≥6. Patients were followed for a median of 1,371 days. The primary endpoint was mortality, and the secondary endpoint was combined mortality and hospital admissions.

Results: Baseline parameters did not significantly differ between groups, but CSR patients were older and had higher AHI values than OSA patients. Five OSA patients (26%) died, and 14 (74%) met the combined end-point of death or hospitalization. CSR patients had significantly higher risk for both end-points, with 23 (53%) deaths [log-rank P=0.040; HR, 2.70 (1.01-7.22); P=0.047] and 40 (93%) deaths or readmissions [log-rank P=0.029; HR, 1.96 (1.06-3.63); P=0.032]. After adjustment for confounding risk factors, the association between CSR and death remained significant [HR, 4.73 (1.10-20.28); P=0.037], hospital admission rates were not significantly different.

Conclusions: Among patients with CHF, CSR was associated with higher mortality than OSA independently of age and cardiac systolic function. CSR was also an age-independent predictor of unfavorable outcome, but hospital admission rates were not significantly different between the two groups after adjustment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/cdt.2020.03.02DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7369271PMC
June 2020

The Association Between Circulating Inflammatory Markers and the Progression of Alzheimer Disease in Norwegian Memory Clinic Patients With Mild Cognitive Impairment or Dementia.

Alzheimer Dis Assoc Disord 2020 Jan-Mar;34(1):47-53

Departments of Geriatric Medicine.

Objective: Neuroinflammation may play an important role in the pathogenesis and progression of Alzheimer disease (AD). The aim of the present study was to detect whether increased inflammatory activity at baseline could predict cognitive and functional decline in patients with amnestic mild cognitive impairment (aMCI) or AD dementia after 2 years.

Methods: Serum samples from 242 memory clinic patients with an aMCI (n=88) or AD dementia (n=154) were analyzed for C-reactive protein and for 14 other inflammatory markers [interleukin (IL)-1β, interleukin-1 receptor antagonist, IL-6, IL-10, IL-12p40, IL-17a, IL-18, IL-22, IL-33, tumor necrosis factor, cluster of differentiation 40 ligand, interferon-γ, chemokine ligand (CCL) 2, and CCL4] by bead-based multiplex immunoassay. Disease progression was measured by the annual increase in the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) and annual decrease in the score on the Mini-Mental State Examination (MMSE).

Results: No association between increased levels of the inflammatory markers and change on the CDR-SB or MMSE score was found, but there was a significant difference in baseline IL-6 and interleukin-1 receptor antagonist levels between aMCI and AD dementia groups.

Conclusion: Increased levels of inflammatory markers were not associated with faster progression as measured by the annual change on the CDR-SB or MMSE score.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/WAD.0000000000000342DOI Listing
November 2020

The Effect of Levosimendan Versus Milrinone on the Occurrence Rate of Acute Kidney Injury Following Congenital Heart Surgery in Infants: A Randomized Clinical Trial.

Pediatr Crit Care Med 2019 10;20(10):947-956

Department of Anesthesiology and Intensive Care Medicine, Sahlgrenska Academy, University of Gothenburg and Queen Silvia Children's Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden.

Objectives: It has been shown that, in contrast to other inotropic agents, levosimendan improves glomerular filtration rate after adult cardiac surgery. The aim of this study was to investigate the efficacy of levosimendan, compared with milrinone, in preventing acute kidney dysfunction in infants after open-heart surgery with cardiopulmonary bypass.

Design: Two-center, double-blinded, prospective, randomized clinical trial.

Setting: The study was performed in two tertiary pediatric centers, one in Sweden (Gothenburg) and one in Finland (Helsinki).

Patients: Infants between 1 and 12 months old, diagnosed with Tetralogy of Fallot, complete atrioventricular septal defect or nonrestrictive ventricular septal defect, undergoing total corrective cardiac surgery with cardiopulmonary bypass.

Interventions: Seventy-two infants were randomized to receive a perioperative infusion of levosimendan (0.1 µg/kg/min) or milrinone (0.4 µg/kg/min). The infusion was initiated at the start of cardiopulmonary bypass and continued for 26 hours.

Measurements And Main Results: The primary outcome variable was the absolute value of serum creatinine data on postoperative day 1. Secondary outcomes included the following: 1) acute kidney injury according to the serum creatinine criteria of the Kidney Diseases: Improving Global Outcomes; 2) acute kidney injury with serum creatinine corrected for fluid balance; 3) plasma neutrophil gelatinase-associated lipocalin; 4) cystatin C; 5) urea; 6) lactate; 7) hemodynamic variables; 8) use of diuretics in the PICU; 9) need of dialysis; 10) length of ventilator therapy; and 11) length of PICU stays. There was no significant difference in postoperative serum creatinine between the treatment groups over time (p = 0.65). The occurrence rate of acute kidney injury within 48 hours was 46.9% in the levosimendan group and 39.5% in the milrinone group (p = 0.70). There were no significant differences in other secondary outcome variables between the groups.

Conclusions: Levosimendan compared with milrinone did not reduce the occurrence rate of acute kidney injury in infants after total corrective heart surgery for atrioventricular septal defect, ventricular septal defect, or Tetralogy of Fallot.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PCC.0000000000002017DOI Listing
October 2019

Annual decline in forced expiratory volume and airway inflammatory cells and mediators in a general population-based sample.

BMC Pulm Med 2019 May 9;19(1):90. Epub 2019 May 9.

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

Background: Few studies have examined the relationships between sputum inflammatory markers and subsequent annual decline in forced expiratory volume in 1 s (dFEV). This study investigated whether indices of airway inflammation are predictors of dFEV in a general population-based sample.

Methods: The study, conducted from 2003 to 2005, included 120 healthy Norwegian subjects aged 40 to 70 years old. At baseline, the participants completed a self-administered respiratory questionnaire and underwent a clinical examination that included spirometry, venous blood sampling, and induced sputum examination. From 2015 to 2016, 62 (52%) participants agreed to a follow-up examination that did not include induced sputum examination. Those with a FEV/forced vital capacity (FVC) ratio <  0.70 underwent a bronchial reversibility test. The levels of cytokines, pro-inflammatory M1 macrophage phenotypes were measured in induced sputum using bead-based multiplex analysis. The associations between cytokine levels and dFEV were then analysed.

Results: The mean dFEV was 32.9 ml/year (standard deviation 26.3). We found no associations between dFEV and the baseline indices of sputum inflammation. Seven participants had irreversible airflow limitation at follow-up. They had lower FEV1 and gas diffusion at baseline compared with the remaining subjects. Moreover, two of these individuals had a positive reversibility test and sputum eosinophilia at baseline.

Conclusions: In this cohort of presumably healthy subjects, we found no associations between sputum inflammatory cells or mediators and dFEV during 10 years of follow-up.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12890-018-0765-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6509765PMC
May 2019

Associations between Cytokine Levels and CYP3A4 Phenotype in Patients with Rheumatoid Arthritis.

Drug Metab Dispos 2018 10 10;46(10):1384-1389. Epub 2018 Jul 10.

Center for Psychopharmacology (B.M.W., E.M.), Departments of Rheumatology (S.W.S., E.L.), Internal Medicine (M.V.), and Medicinal Biochemistry (L.L.M.), Diakonhjemmet Hospital, Oslo, Norway; Institute for Experimental Medicinal Research, Oslo University Hospital, Oslo, Norway (M.V.); and Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway (E.M.).

Systemic inflammation has been linked to suppressed CYP3A4 activity. The aim of this study was to examine associations between levels of a broad selection of cytokines and CYP3A4 phenotype in patients with rheumatoid arthritis (RA). The study included 31 RA patients treated with tumor necrosis factor (TNF)- inhibitors. CYP3A4 phenotype was measured as serum concentration of 4-hydroxycholesterol (4OHC) by ultra-performance liquid chromatography-tandem mass spectrometry in samples collected prior to and 3 months after initiation of treatment with TNF- inhibitors. Serum levels of the following 21 cytokines were determined in the same samples using a bead-based multiplex immunoassay (Luminex technology): CCL2, CCL3, CXCL8, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, interferon , interleukin (IL)-1, IL-1 receptor antagonist (ra), IL-2, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12, IL-13, IL-15, IL-17A, IL-18, IL-23, and TNF- Correlations between levels of cytokines and 4OHC were assessed by Spearman's rank correlation tests. Among the investigated cytokines, three were negatively correlated with CYP3A4 phenotype during treatment with TNF- inhibitors: i.e., IL-1ra ( = -0.408, = 0.023), IL-6 ( = -0.410, = 0.022) and CXCL8 ( = -0.403, = 0.025) ( ≥ 0.3 for all other cytokines). None of the analyzed cytokines were correlated with CYP3A4 phenotype prior to TNF- inhibitor treatment ( > 0.1 for all cytokines). These findings suggest that immune responses associated with increased levels of IL-1ra, IL-6, and CXCL8 may suppress CYP3A4 metabolism. Further studies are required to evaluate these preliminary findings in different patient populations and also examine the possible molecular mechanisms behind our observations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1124/dmd.118.082065DOI Listing
October 2018

Plasma immunological markers in pregnancy and cord blood: A possible link between macrophage chemo-attractants and risk of childhood type 1 diabetes.

Am J Reprod Immunol 2018 03 20;79(3). Epub 2017 Dec 20.

Norwegian Institute of Public Health, Oslo, Norway.

Problem: Previous studies have suggested that immune perturbations during pregnancy can affect offspring type 1 diabetes (T1D) risk. We aimed to identify immunological markers that could predict offspring T1D or that were linked to T1D risk factors.

Method Of Study: We quantified selected circulating immunological markers in mid-pregnancy (interleukin [IL]-1β, IL-1ra, IL-2Rα, IL-2, -4, -5, -6, -10, -12p70, 13, -17A, GM-CSF, IFN-γ, CXCL10, CCL 2, CCL3, CCL4, TNF) and cord blood plasma (neopterin and kynurenine/tryptophan ratio) in a case-control study with 175 mother/child T1D cases (median age 5.8, range 0.7-13.0 years) and 552 controls.

Results: Pre-pregnancy obesity was positively associated with CCL4, CXCL10, kynurenine/tryptophan ratio and neopterin (P < .01). The established T1D SNPs rs1159465 (near IL2RA) and rs75352297 (near CCR2 and CCR3) were positively associated with IL-2Rα and CCL4, respectively (P < .01). There was a borderline association of CCL4 and offspring T1D risk, independent of maternal obesity and genotype. When grouping the immunological markers, there was a borderline association (P = .05) with M1 phenotype and no association between M2-, Th1-, Th2- or Th17 phenotypes and offspring T1D risk.

Conclusion: Increased mid-pregnancy CCL4 levels showed borderline associations with increased offspring T1D risk, which may indicate a link between environmental factors in pregnancy and offspring T1D risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/aji.12802DOI Listing
March 2018

Midpregnancy and cord blood immunologic biomarkers, HLA genotype, and pediatric celiac disease.

J Allergy Clin Immunol 2017 05 16;139(5):1696-1698. Epub 2016 Nov 16.

Norwegian Institute of Public Health, Oslo, Norway; Department of Pediatrics, Østfold Hospital Trust, Grålum, Norway.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaci.2016.10.016DOI Listing
May 2017

A retrospective analysis of cardiovascular outcomes in patients treated with ASV.

Scand Cardiovasc J 2017 Apr 7;51(2):106-113. Epub 2016 Dec 7.

b University of Oslo , Oslo , Norway.

Objectives: The effect of long-term adaptive servo-ventilation (ASV) on cardiovascular mortality and admission rates in patients with chronic heart failure (CHF) and Cheyne-Stokes respiration (CSR) has not been much studied. The aim of this study was primarily to investigate whether ASV therapy significantly reduced these parameters.

Design: We included 75 CHF patients on optimal medication and CSR ≥25% of sleeping time, in New York Heart Association (NYHA) classes II-IV and left ventricular ejection fraction (LVEF) ≤ 45%. Thirty-one patients were treated with ASV for >3-18 months and 44 patients served as a control group.

Results: Seven deaths (16%) in the control group and one death (3%) in the ASV treatment group had cardiovascular etiology. There was no significant difference between the two groups regarding cardiovascular death (log rank p = 0.07; HR 0.18 (95% CI 0.02-1.44), p = 0.11) and combined cardiovascular death or readmissions, but there was a trend toward better outcome regarding cardiovascular event-free survival (log rank p = 0.06; HR 0.53 (95% CI 0.27-1.05).

Conclusions: In CHF patients with CSR, 18 months ASV treatment did not significantly affect cardiovascular death or combined cardiovascular death or hospital admissions. But there was a trend toward better combined outcome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14017431.2016.1262546DOI Listing
April 2017

In active juvenile dermatomyositis, elevated eotaxin and MCP-1 and cholesterol levels in the upper normal range are associated with cardiac dysfunction.

Rheumatology (Oxford) 2014 Dec 4;53(12):2214-22. Epub 2014 Jul 4.

Institute for Experimental Medical Research, Oslo University Hospital-Ullevål, KG Jebsen Cardiac Research Center and Center for Heart Failure Research, Institute for Clinical Medicine, University of Oslo, Department of Cardiology, Oslo University Hospital-Ullevål and Section of Rheumatology, Oslo University Hospital-Rikshospitalet, Oslo, Norway.

Objective: The aim of this study was to examine the influence of chemokines and lipids on cardiac function in patients with active and inactive JDM and matched controls.

Methods: Fifty-four JDM patients were clinically examined a median 16.8 years (range 2-38) after disease onset and compared with 54 sex- and age-matched controls. Inactive disease was defined by the PRINTO criteria. Serum levels of chemokines were analysed by Luminex technology. Echocardiography was performed and analysed blinded to patient information. Long-axis strain and e' were used as parameters of systolic and diastolic function, respectively.

Results: In patients, but not in controls, eotaxin and monocyte chemoattractant protein 1 (MCP-1) correlated with systolic (r = -0.65 and r = -0.45) and diastolic (r = -0.59 and r = -0.65) function, particularly in those with active disease (systolic function, r = -0.74 and r = -0.60; diastolic function, r = -0.69 and r = -0.80). Total cholesterol level was lower in patients than controls [mean 4.19 mmol/l (s.d. 0.82) vs 4.60 (0.87), P ≤ 0.01]. However, total cholesterol levels in the upper normal range were associated with systolic (r = -0.56, P < 0.01) and diastolic (r = -0.64, P < 0.001) dysfunction and with high eotaxin and MCP-1 (r = 0.56 and r = 0.50, P < 0.01) in patients with active disease, but not in those with inactive disease or in controls (all r < ±0.2).

Conclusion: In the active disease state of JDM, eotaxin and MCP-1 were associated with cardiac dysfunction, possibly through sustained inflammation. In those with active disease and cholesterol levels in the upper normal range, eotaxin and MCP-1 might enhance susceptibility to cardiac dysfunction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/rheumatology/keu256DOI Listing
December 2014

Increased levels of eotaxin and MCP-1 in juvenile dermatomyositis median 16.8 years after disease onset; associations with disease activity, duration and organ damage.

PLoS One 2014 19;9(3):e92171. Epub 2014 Mar 19.

Institute for Experimental Medical Research, Oslo University Hospital-Ullevål, Oslo, Norway; KG Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, Oslo, Norway; Department of Cardiology, Oslo University Hospital-Ullevål, Oslo, Norway.

Objective: To compare cytokine profiles in patients with juvenile dermatomyositis (JDM) after medium to long-term follow-up with matched controls, and to examine associations between cytokine levels and disease activity, disease duration and organ damage.

Methods: Fifty-four JDM patients were examined median 16.8 years (2-38) after disease onset (follow-up) and compared with 54 sex- and age-matched controls. Cytokine concentrations in serum were quantified by Luminex technology. In patients, disease activity score (DAS), myositis damage index (MDI) and other disease parameters were collected by chart review (early parameters) and clinical examination (follow-up).

Results: Serum levels of eotaxin, monocyte chemoattractant protein-1 (MCP-1) and interferon-inducible protein 10 (IP-10) were elevated in JDM patients compared to controls (31.5%, 37.2% and 43.2% respectively, all p<0.05). Patients with active (n = 28), but not inactive disease (n = 26) had a higher level of MCP-1 than their respective controls. Levels of eotaxin and MCP-1 correlated with disease duration (r = 0.47 and r = 0.64, both p<0.001) and age in patients, but not with age in controls. At follow-up, MDI was associated with MCP-1(standardized β = 0.43, p = 0.002) after adjusting for disease duration and gender. High MDI 1 year post-diagnosis predicted high levels of eotaxin and MCP-1 at follow-up (standardized β = 0.24 and 0.29, both p<0.05) after adjusting for disease duration and gender.

Conclusion: Patients with JDM had higher eotaxin, MCP-1 and IP-10 than controls. High eotaxin and MCP-1 at follow-up was predicted by early disease parameters, and MCP-1 was associated with organ damage at follow-up, highlighting a role of these chemokines in JDM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0092171PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3960173PMC
December 2015

Pentosan polysulfate decreases myocardial expression of the extracellular matrix enzyme ADAMTS4 and improves cardiac function in vivo in rats subjected to pressure overload by aortic banding.

PLoS One 2014 3;9(3):e89621. Epub 2014 Mar 3.

Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; KG Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, Oslo, Norway.

Background: We hypothesized that cleavage of the extracellular matrix (ECM) proteoglycans versican and aggrecan by ADAMTS (a disintegrin and metalloprotease with thrombospondin motifs) proteases, which contributes to stress-induced ECM-reorganization in atherogenesis and osteoarthritis, also play a role in heart failure development.

Objectives: The primary objective was to identify alterations in expression of ADAMTS versicanases and aggrecanases during development of heart failure, while evaluation of the effects of in vivo modulation of relevant changes in ADAMTS activity constituted the secondary objective.

Methods: Myocardial levels of versican, aggrecan, and their ADAMTS cleaving proteases were examined in Wistar rats six weeks after aortic banding (AB), and versican and selected ADAMTS versicanases were further analyzed in neonatal cardiomyocytes (NCM) and cardiac fibroblasts (NFB) after stimulation by inflammatory mediators. Based on the initial findings, ADAMTS4 was selected the most promising therapeutic target. Thus, rats with AB were treated with pentosan polysulfate (PPS), a polysaccharide with known ADAMTS4-inhibitory properties, and effects on versican fragmentation, left ventricular function and geometry were evaluated.

Results: We discovered that myocardial mRNA and protein levels of ADAMTS1 and -4, and mRNA levels of versican, aggrecan, and ADAMTS8 increased after AB, and TNF-α and IL-1β synergistically increased mRNA of versican and ADAMTS4 in NCM and NFB and secretion of ADAMTS4 from NCM. Furthermore, PPS-treatment improved systolic function, demonstrated by an improved fractional shortening (vehicle 48±3% versus PPS 60±1%, p<0.01) after AB. Following PPS-treatment, we observed an ∼80% reduction in myocardial ADAMTS4 mRNA (p = 0.03), and ∼50% reduction in the extracellular amount of the p150 versican fragments (p = 0.05), suggesting reduced versicanase activity.

Conclusions: Our findings suggest that AB induces an increase in myocardial ADAMTS4 versicanase activity, and that PPS-treatment improved systolic function in the pressure-overloaded heart, holding promise as a novel therapeutic agent in heart failure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0089621PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3940660PMC
January 2015

Innate immune signaling induces expression and shedding of the heparan sulfate proteoglycan syndecan-4 in cardiac fibroblasts and myocytes, affecting inflammation in the pressure-overloaded heart.

FEBS J 2013 May 24;280(10):2228-47. Epub 2013 Feb 24.

Institute for Experimental Medical Research, Oslo University Hospital Ullevål and University of Oslo, Norway.

Sustained pressure overload induces heart failure, the main cause of mortality in the Western world. Increased understanding of the underlying molecular mechanisms is essential to improve heart failure treatment. Despite important functions in other tissues, cardiac proteoglycans have received little attention. Syndecan-4, a transmembrane heparan sulfate proteoglycan, is essential for pathological remodeling, and we here investigated its expression and shedding during heart failure. Pressure overload induced by aortic banding for 24 h and 1 week in mice increased syndecan-4 mRNA, which correlated with mRNA of inflammatory cytokines. In cardiac myocytes and fibroblasts, tumor necrosis factor-α, interleukin-1β and lipopolysaccharide through the toll-like receptor-4, induced syndecan-4 mRNA. Bioinformatical and mutational analyses in HEK293 cells identified a functional site for the proinflammatory nuclear factor-κB transcription factor in the syndecan-4 promoter, and nuclear factor-κB regulated syndecan-4 mRNA in cardiac cells. Interestingly, tumor necrosis factor-α, interleukin-1β and lipopolysaccharide induced nuclear factor-κB-dependent shedding of the syndecan-4 ectodomain from cardiac cells. Overexpression of syndecan-4 with mutated enzyme-interacting domains suggested enzyme-dependent heparan sulfate chains to regulate shedding. In cardiac fibroblasts, lipopolysaccharide reduced focal adhesion assembly, shown by immunohistochemistry, suggesting that inflammation-induced shedding affects function. After aortic banding, a time-dependent cardiac recruitment of T lymphocytes was observed by measuring CD3, CD4 and CD8 mRNA, which was reduced in syndecan-4 knockout hearts. Finally, syndecan-4 mRNA and shedding were upregulated in failing human hearts. Conclusively, our data suggest that syndecan-4 plays an important role in the immune response of the heart to increased pressure, influencing cardiac remodeling and failure progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/febs.12161DOI Listing
May 2013

Macrophage inflammatory protein-1β: a novel prognostic biomarker in atherosclerosis?

Authors:
Maria Vistnes

Cardiology 2012 20;121(3):149-51. Epub 2012 Mar 20.

Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000336484DOI Listing
July 2012

Circulating cytokine concentrations are not associated with major depressive disorder in a community-based cohort.

Gen Hosp Psychiatry 2012 May-Jun;34(3):262-7. Epub 2012 Mar 7.

Division of Medicine, Akershus University Hospital, Lørenskog, Norway.

Objective: The objective was to test the hypotheses that cytokine levels are elevated in community-residing persons at high risk for obstructive sleep apnea with major depressive disorder (MDD) compared to nondepressive persons and that cytokine levels show stronger correlations with somatic than psychological symptoms of depression.

Method: A case-control study within the cross-sectional Akershus Sleep Apnea Project was performed. Two controls matched for age, gender, metabolic syndrome and obstructive sleep apnea were drawn for each case of MDD.

Results: Group comparisons revealed no significant difference in the levels of 17 cytokines [interleukin-1β, -2,-4, -5, -6, -7, -8, -10, -12(p70), -13 and -17; tumor necrosis factor-α; interferon-γ; granulocyte colony-stimulating factor; granulocyte-monocyte colony-stimulating factor; macrophage chemoattractant protein-1 and monocyte inhibitory protein-1β] between persons with (n=34) and without MDD (n=68). There was no association between cytokines levels and MDD in multivariate regression analyses. The concentration of interleukin-4 was significantly more positively correlated with psychological than somatic symptoms (r=0.046 vs. -0.143, respectively, P=0.024), while no different correlations were observed for other cytokines.

Conclusion: The cytokine levels were not elevated in MDD, and cytokine levels were not more strongly associated with somatic than psychological symptoms of depression. The depression-specific effect on inflammation may be weak in community-based samples with prevalent somatic comorbidity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.genhosppsych.2012.01.017DOI Listing
September 2012

Chemokines regulate small leucine-rich proteoglycans in the extracellular matrix of the pressure-overloaded right ventricle.

J Appl Physiol (1985) 2012 Apr 16;112(8):1372-82. Epub 2012 Feb 16.

Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Kirkeveien 166, Oslo, Norway.

Chemokines have been suggested to play a role during development of left ventricular failure, but little is known about their role during right ventricular (RV) remodeling and dysfunction. We have previously shown that the chemokine (C-X-C motif) ligand 13 (CXCL13) regulates small leucine-rich proteoglycans (SLRPs). We hypothesized that chemokines are upregulated in the pressure-overloaded RV, and that they regulate SLRPs. Mice with RV pressure overload following pulmonary banding (PB) had a significant increase in RV weight and an increase in liver weight after 1 wk. Microarray analysis (Affymetrix) of RV tissue from mice with PB revealed that CXCL10, CXCL6, chemokine (C-X3-C motif) ligand 1 (CX3CL1), chemokine (C-C motif) ligand 5 (CCL5), CXCL16, and CCL2 were the most upregulated chemokines. Stimulation of cardiac fibroblasts with these same chemokines showed that CXCL16 increased the expression of the four SLRPs: decorin, lumican, biglycan, and fibromodulin. CCL5 increased the same SLRPs, except decorin, whereas CX3CL1 increased the expression of decorin and lumican. CXCL16, CX3CL1, and CCL5 were also shown to increase the levels of glycosylated decorin and lumican in the medium after stimulation of fibroblasts. In the pressure-overloaded RV tissue, Western blotting revealed an increase in the total protein level of lumican and a glycosylated form of decorin with a higher molecular weight compared with control mice. Both mice with PB and patients with pulmonary stenosis had significantly increased circulating levels of CXCL16 compared with healthy controls measured by enzyme immunoassay. In conclusion, we have found that chemokines are upregulated in the pressure-overloaded RV and that CXCL16, CX3CL1, and CCL5 regulate expression and posttranslational modifications of SLRPs in cardiac fibroblasts. In the pressure-overloaded RV, protein levels of lumican were increased, and a glycosylated form of decorin with a high molecular weight appeared.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/japplphysiol.01350.2011DOI Listing
April 2012

Circulating cytokine levels in mice with heart failure are etiology dependent.

J Appl Physiol (1985) 2010 May 11;108(5):1357-64. Epub 2010 Mar 11.

Institute for Experimental Medical Research, Oslo University Hospital Ullevål, and Center for Heart Failure Research, University of Oslo, Kirkeveien 166, N-0407 Oslo, Norway.

Objectives: The aim of this study was to examine whether alterations in circulating cytokine levels are dependent on the etiology of myocardial hypertrophy and heart failure (HF).

Background: Several heart diseases are associated with altered levels of circulating cytokines. Cytokines are regarded as possible therapeutic targets or biomarkers, but such approaches are currently not in clinical use. If alterations in circulating cytokines are etiology dependent, this should be taken into consideration when using cytokines as disease markers and therapeutic targets.

Methods: The serum levels of 25 cytokines were quantified with Luminex and/or ELISA in four murine models of heart disease: banding of the ascending aorta (AB) or the pulmonary artery (PB), myocardial infarction (MI), and a cardiomyopathy model with inducible cardiomyocyte-specific knockout of the sarco(endo)plasmatic reticulum Ca2+-ATPase (SERCA2KO).

Results: No increase in circulating cytokine levels were found in mice 1 wk after AB, although substantial myocardial hypertrophy was present. After 1 wk of MI, only interleukin (IL)-18 was increased. In the SERCA2KO mice with HF, circulating levels of IL-1alpha, IL-2, IL-3, IL-6, IL-9, IL-10, IL-12p40, eotaxin, granulocyte-colony stimulating factor (G-CSF), interferon-gamma, monocyte chemoattractant protein-1, macrophage inflammatory protein-1beta were increased, and in mice with PB, IL-1alpha, IL-6, G-CSF, and monokine induced by gamma-interferon showed elevated levels.

Conclusions: Serum levels of cytokines in mice with HF vary depending on the etiology. Increased serum levels of several cytokines were found in models with increased right ventricular afterload, suggesting that the cytokine responses result primarily from systemic congestion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/japplphysiol.01084.2009DOI Listing
May 2010

Multiple cytokine biomarkers in heart failure.

Expert Rev Mol Diagn 2010 Mar;10(2):147-57

Institute for Experimental Medical Research, Oslo University Hospital, Oslo, Norway.

Raised levels of circulating proinflammatory cytokines are associated with disease progression and adverse outcomes in chronic heart failure patients. Inflammatory markers may be predictive of congestive heart failure and myocardial infarction, allowing enhanced risk stratification. The profile of cytokine blood levels differs in accordance with the initiating cause and type of heart failure. Therefore, subclassification of heart failure patients based on cytokine measurements could potentially identify subgroups of patients, permitting tailored or personalized therapy. During inflammatory states, cytokine production is often regulated by activation of other cytokines, resulting in a perpetuating, complex cytokine cascade. Thus, single-assay measurement of cytokines provides limited information, and to obtain a more comprehensive picture of immune activation, multiple cytokines need to be analyzed simultaneously. With the technological development in multiplex protein analyses, multiplexing cytokines has become simple, fast and reproducible. Luminex technology represents one platform for simultaneous measurements of several cytokines, and has gained increasing interest among researchers in recent years. However, the measurement of multiple cytokines as part of a multimarker prognostic or diagnostic biomarker approach remains to be implemented in current clinical practice, as current knowledge of the underlying biology of cytokine release in heart disease is still too limited and a bioinformatic tool for interpretation of cytokine profiles is needed. Nevertheless, multiplex protein analyses are likely to constitute an important part of experimental and clinical research on heart failure and cytokines, paving the way for more accurate heart failure treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1586/erm.10.3DOI Listing
March 2010
-->