Publications by authors named "Ivana Hollan"

45 Publications

Antirheumatic treatment is associated with reduced serum Syndecan-1 in Rheumatoid Arthritis.

PLoS One 2021 9;16(7):e0253247. Epub 2021 Jul 9.

Norwegian University of Science and Technology, Gjøvik, Norway.

The endothelial glycocalyx (EG) is essential for proper function of the endothelium and for vascular integrity, but its role in premature atherogenesis in rheumatoid arthritis (RA) has not been studied yet. EG impairment can play a role in pathogenesis of vascular disease, and one of its characteristics is shedding of syndecan-1 from endothelial cells. Syndecan-1 shedding is mediated by matrix metalloproteinase-9 (MMP-9) and counteracted by tissue inhibitor of metalloproteinases (TIMP)-1. Cardiovascular disease risk in RA is reversible by disease modifying antirheumatic drugs (DMARDs), but the exact modes of action are still unclear. Therefore, we examined effects of DMARDs on syndecan-1, MMP-9 and TIMP-1 in RA patients, and searched for associations between these parameters and inflammatory activity. From the observational PSARA study, we examined 39 patients starting with methotrexate (MTX) monotherapy (in MTX naïve patients, n = 19) or tumor necrosis factor inhibitors (TNFi) in combination with MTX (in MTX non-responders, n = 20) due to active RA. Serum syndecan-1, MMP-9 and TIMP-1 were measured at baseline and after six weeks of treatment. Serum syndecan-1 (p = 0.008) and TIMP-1 (p<0.001) levels decreased after six weeks of anti-rheumatic treatment. Levels of MMP-9 also decreased, but the difference was not statistically significant. The improvement in syndecan-1 levels were independent of changes in inflammatory activity. There was no significant difference in changes in syndecan-1 levels from baseline to 6 weeks between the MTX and TNFi groups, however the change was significant within the MTX group. Six weeks of antirheumatic treatment was associated with reduction in serum levels of syndecan-1, which might reflect reduced syndecan-1 shedding from EG. Thus, it is possible that EG-preserving properties of DMARDs might contribute to their cardioprotective effects. These effects may be at least partly independent of their anti-inflammatory actions. Our findings do not support the notion that syndecan-1 shedding in RA is mediated mainly by increased MMP-9 or decreased TIMP-9 serum concentration.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0253247PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270157PMC
July 2021

Antirheumatic therapy is not associated with changes in circulating N-terminal pro-brain natriuretic peptide levels in patients with autoimmune arthritis.

PLoS One 2021 25;16(6):e0253793. Epub 2021 Jun 25.

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

Background: Patients with autoimmune arthritis (AA) are at increased risk for impaired cardiac function and heart failure. This may be partly due to the effect of inflammation in heart function. The impact of antirheumatic drugs on cardiac dysfunction in AA remains controversial. Therefore, we aimed to examine effects of antirheumatic treatment on serum N-terminal pro-brain natriuretic peptide (NT-proBNP) in AA patients and its relationship to inflammatory markers.

Methods: We examined 115 patients with AA (64 rheumatoid arthritis (RA), 31 psoriatic arthritis and 20 ankylosis spondylitis) starting with methotrexate (MTX) monotherapy or tumor necrosis factor inhibitors (TNFi) with or without MTX co-medication. NT-proBNP (measured in serum by ECLIA from Roche Diagnostics), and other clinical and laboratory parameters were evaluated at baseline, after 6 weeks and 6 months of treatment.

Results: NT-proBNP levels did not change significantly after 6 weeks and 6 months of antirheumatic therapy (pbaseline-6weeks = 0.939; pbaseline-6months = 0.485), although there was a modest improvement from 6 weeks to 6 months in the MTX only treatment group (median difference = -18.2 [95% CI = -32.3 to -4.06], p = 0.013). There was no difference in the effects of MTX monotherapy and TNFi regimen on NT-proBNP levels. The changes in NT-proBNP after antirheumatic treatment positively correlated with changes in C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Baseline NT-proBNP levels were related to baseline CRP and ESR levels, and some other established markers of disease activities in crude analyses.

Conclusion: Circulating levels of NT-proBNP were related to established inflammatory markers at baseline, and the changes in NT-proBNP after antirheumatic treatment were positively related to these markers. Nevertheless, antirheumatic therapy did not seem to affect NT-proBNP levels compared to baseline, even though inflammatory markers significantly improved.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0253793PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232407PMC
June 2021

Biologics and atherosclerotic cardiovascular risk in rheumatoid arthritis: a review of evidence and mechanistic insights.

Expert Rev Clin Immunol 2021 Apr 15;17(4):355-374. Epub 2021 Apr 15.

Division of Rheumatology, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.

: Cardiovascular disease is a leading comorbidity in rheumatoid arthritis. Timely introduction of biologic therapies in a treat-to-target approach has optimized disease-related outcomes and attenuated accrual of comorbidities, including cardiovascular risk.: A literature search in MEDLINE (via PubMed) was performed between January 2009 and November 2020. This manuscript explores recent developments in atherosclerotic cardiovascular risk in RA compared with non-RA individuals; it synopsizes differences in vascular function and inflammation, prevalence, burden, vulnerability, and progression of atherosclerotic plaque and their underlying cellular and molecular mechanisms. Finally, it reviews the recent literature on cardioprotective benefits of biologics and draws mechanistic links with inhibition of new plaque formation, stabilization of high-risk lesions and improvement in endothelial function, arterial stiffness, lipid metabolism, and traditional cardiac risk factors.: Increasing evidence points to a solid cardioprotective influence of earlier, longer, and ongoing use of biologic treatments in RA. Nevertheless, the precise mechanistic effects of plaque progression and remodeling, vascular stiffness, endothelial dysfunction, lipid metabolism, and traditional cardiac risk factors are less rigorously characterized.
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http://dx.doi.org/10.1080/1744666X.2021.1899809DOI Listing
April 2021

Epicardial Adipose Tissue Volume As a Marker of Subclinical Coronary Atherosclerosis in Rheumatoid Arthritis.

Arthritis Rheumatol 2021 Feb 14. Epub 2021 Feb 14.

Harbor-UCLA Medical Center and Lundquist Institute for Biomedical Innovation, Torrance, California.

Objective: To assess epicardial adipose tissue volume (EATV) and its link to coronary atherosclerosis and plaque morphology in patients with rheumatoid arthritis (RA) and in age- and sex-matched controls.

Methods: Computed tomography angiography was used to evaluate EATV and coronary plaque in 139 RA patients and 139 non-RA controls. All models assessing the effect of EATV on plaque were adjusted for age, sex, hypertension, diabetes, dyslipidemia, smoking status, family history of coronary artery disease, and obesity (body mass index of ≥30 kg/m ). Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated.

Results: Mean ± SD log-transformed EATV was similar in patients with RA (4.69 ± 0.36) and controls (4.70 ± 0.42). EATV was higher in RA patients with atherosclerosis compared to those without atherosclerosis (P = 0.046). In stratified analyses, EATV was associated with the number of segments with plaque in RA patients (rate ratio 1.20 [95% CI 1.01-1.41] per 1-SD increment of log-unit increase in EATV) but not in controls (P for interaction = 0.089). Likewise, EATV (per 1-SD log-unit increase) was related to the presence of multivessel or obstructive disease (OR 1.63 [95% CI 1.04-2.61]), noncalcified plaque (OR 1.78 [95% CI 1.17-2.70]), and vulnerable plaque (OR 1.77 [95% CI 1.03-3.04]) in RA patients but not in controls (P for interaction ≤ 0.048 for each). Among RA patients, EATV was associated with the number of segments with plaque in those with RA for <10 years who did not develop any cardiovascular risk factors and who were not obese (P for interaction ≤ 0.017).

Conclusion: Despite similar EATVs in RA patients and controls, EATVs were associated with greater plaque burden and presence of plaques with a noncalcified component and vulnerability features only in RA patients. EAT may be more pathogenic in RA and play a role in early-stage atherosclerosis. Its value as a biomarker of subclinical atherosclerosis and cardiovascular risk in RA warrants further studies.
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http://dx.doi.org/10.1002/art.41693DOI Listing
February 2021

Methotrexate attenuates vascular inflammation through an adenosine-microRNA-dependent pathway.

Elife 2021 Jan 8;10. Epub 2021 Jan 8.

Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, United States.

Endothelial cell (EC) activation is an early hallmark in the pathogenesis of chronic vascular diseases. MicroRNA-181b () is an important anti-inflammatory mediator in the vascular endothelium affecting endotoxemia, atherosclerosis, and insulin resistance. Herein, we identify that the drug methotrexate (MTX) and its downstream metabolite adenosine exert anti-inflammatory effects in the vascular endothelium by targeting and activating expression. Both systemic and endothelial-specific -deficient mice develop vascular inflammation, white adipose tissue (WAT) inflammation, and insulin resistance in a diet-induced obesity model. Moreover, MTX attenuated diet-induced WAT inflammation, insulin resistance, and EC activation in a -dependent manner. Mechanistically, MTX attenuated cytokine-induced EC activation through a unique adenosine-adenosine receptor A3-SMAD3/4- signaling cascade. These findings establish an essential role of endothelial in controlling vascular inflammation and that restoring in ECs by high-dose MTX or adenosine signaling may provide a potential therapeutic opportunity for anti-inflammatory therapy.
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http://dx.doi.org/10.7554/eLife.58064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840179PMC
January 2021

Personalized medicine in rheumatoid arthritis: How immunogenicity impacts use of TNF inhibitors.

Autoimmun Rev 2020 May 12;19(5):102509. Epub 2020 Mar 12.

Istituto Auxologico Italiano, IRCCS, Experimental Laboratory of Immuno-rheumatology, Milan, Italy; Department of Clinical Sciences and Community Health, University of Milan, Italy.

Up to 40% of patients treated with tumor necrosis factor alpha inhibitors (TNFi) do not respond to therapy. Testing drug bioavailability and/or anti-drug antibody (ADAb) levels may justify dosage adjustment or switch to different drugs, enabling a personalized medicine approach. We report a multicenter cross-sectional study on different methods [ELISA and a cell based functional assay (reporter gene assay - RGA)] for drug/ADAb detection, and on the relationship between drug bioavailability and ADAb. 163 patients with rheumatoid arthritis (RA) treated with infliximab (IFX; n = 67), adalimumab (ADL; n = 49) or etanercept (ETA; n = 47) were tested for drug and ADAb levels. Furthermore, we report prospective data from additional 70 patients (59 RA and 11 juvenile idiopathic arthritis - JIA) tested for drug and ADAb levels at baseline (T0) and after 3 (T3) and 6 months (T6) of treatment with ADL or ETA only. IFX-treated patients were not included because of the increasing use of IFX biosimilars. Stringent inclusion criteria were used in order to avoid unwanted variables in both studies; none of the patients used TNFi before the study, and TNFi was used only in combination with methotrexate. Clinical response was defined according to EULAR response criteria. The two assays performed comparably in the comparison study. Accordingly, ELISA was selected for the prospective study because of its feasibility in the clinical setting. The cross-sectional study found ADAb in IFX and ADL treated groups only, that were associated with a decrease in pharmacological drug availability in the blood. Comparable results were found for the ADL-treated group in the prospective study which also showed a relationship between drug/ADAb levels and the loss of clinical response. Altogether our findings support drug and anti-drug Ab monitoring in the real-world clinical setting thus enabling individualized treatment and reducing disability in chronic inflammatory arthritis.
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http://dx.doi.org/10.1016/j.autrev.2020.102509DOI Listing
May 2020

NETs analysed by novel calprotectin-based assays in blood donors and patients with multiple myeloma or rheumatoid arthritis: A pilot study.

Scand J Immunol 2020 May 4;91(5):e12870. Epub 2020 Mar 4.

Department of Immunology and Transfusion Medicine, Oslo University Hospital (OUH), Oslo, Norway.

Two novel enzyme-linked immunosorbent assays (ELISAs), designed to detect complexes containing DNA, leucocyte calprotectin and S100A12 proteins, were generated for improved specificity and rapid measurement of neutrophil extracellular traps (NETs). The assays were applied on plasma and serum samples from blood donors for establishment of reference values, and from patients with multiple myeloma (MM) or rheumatoid arthritis (RA) in order to examine putatively increased values in the two different inflammatory conditions. Although NETs were hardly detectable in healthy individuals, NET levels were as expected highly and statistically significantly increased in RA patients. The detection of statistically significantly increased NET levels in MM is a novel finding.
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http://dx.doi.org/10.1111/sji.12870DOI Listing
May 2020

Benefits of higher resistance-training volume are related to ribosome biogenesis.

J Physiol 2020 02 15;598(3):543-565. Epub 2020 Jan 15.

Section for Health and Exercise Physiology, Department of Public Health and Sport Sciences, Inland Norway University of Applied Sciences, Elverum, Norway.

Key Points: For individuals showing suboptimal adaptations to resistance training, manipulation of training volume is a potential measure to facilitate responses. This remains unexplored. Here, 34 untrained individuals performed contralateral resistance training with moderate and low volume for 12 weeks. Moderate volume led to larger increases in muscle cross-sectional area, strength and type II fibre-type transitions. These changes coincided with greater activation of signalling pathways controlling muscle growth and greater induction of ribosome synthesis. Out of 34 participants, thirteen displayed clear benefit of MOD on muscle hypertrophy and sixteen showed clear benefit of MOD on muscle strength gains. This coincided with greater total RNA accumulation in the early phase of the training period, suggesting that ribosomal biogenesis regulates the dose-response relationship between training volume and muscle hypertrophy. These results demonstrate that there is a dose-dependent relationship between training volume and outcomes. On the individual level, benefits of higher training volume were associated with increased ribosomal biogenesis.

Abstract: Resistance-exercise volume is a determinant of training outcomes. However not all individuals respond in a dose-dependent fashion. In this study, 34 healthy individuals (males n = 16, 23.6 (4.1) years; females n = 18, 22.0 (1.3) years) performed moderate- (3 sets per exercise, MOD) and low-volume (1 set, LOW) resistance training in a contralateral fashion for 12 weeks (2-3 sessions per week). Muscle cross-sectional area (CSA) and strength were assessed at Weeks 0 and 12, along with biopsy sampling (m. vastus lateralis). Muscle biopsies were also sampled before and 1 h after the fifth session (Week 2). MOD resulted in larger increases in muscle CSA (5.2 (3.8)% versus 3.7 (3.7)%, P < 0.001) and strength (3.4-7.7% difference, all P < 0.05. This coincided with greater reductions in type IIX fibres from Week 0 to Week 12 (MOD, -4.6 percentage points; LOW -3.2 percentage points), greater phosphorylation of S6-kinase 1 (p85 S6K1 , 19%; p70 S6K1 , 58%) and ribosomal protein S6 (37%), greater rested-state total RNA (8.8%) and greater exercise-induced c-Myc mRNA expression (25%; Week 2, all P < 0.05). Thirteen and sixteen participants, respectively, displayed clear benefits in response to MOD on muscle hypertrophy and strength. Benefits were associated with greater accumulation of total RNA at Week 2 in the MOD leg, with every 1% difference increasing the odds of MOD benefit by 7.0% (P = 0.005) and 9.8% (P = 0.002). In conclusion, MOD led to greater functional and biological adaptations than LOW. Associations between dose-dependent total RNA accumulation and increases in muscle mass and strength point to ribosome biogenesis as a determinant of dose-dependent training responses.
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http://dx.doi.org/10.1113/JP278455DOI Listing
February 2020

Inflammatory cell infiltrates, hypoxia, vascularization, pentraxin 3 and osteoprotegerin in abdominal aortic aneurysms - A quantitative histological study.

PLoS One 2019 8;14(11):e0224818. Epub 2019 Nov 8.

Department of Vascular Surgery, University Hospital in Pilsen, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic.

Information about the tissue characteristics of abdominal aortic aneurysms (AAAs), some of which may be reflected in the serum, can help to elucidate AAA pathogenesis and identify new AAA biomarkers. This information would be beneficial not only for diagnostics and follow-up but also for potential therapeutic intervention. Therefore, the aim of our study was to compare the expression of structural proteins, immune factors (T and B lymphocytes, macrophages, neutrophils and pentraxin 3 (PTX3)), osteoprotegerin (OPG), microvessels and hypoxic cells in AAA and nonaneurysmal aortic walls. We examined specimens collected during surgery for AAA repair (n = 39) and from the abdominal aortas of kidney donors without AAA (n = 8). Using histochemical and immunohistochemical methods, we quantified the areas positive for smooth muscle actin, desmin, elastin, collagen, OPG, CD3, CD20, MAC387, myeloperoxidase, PTX3, and hypoxia-inducible factor 1-alpha and the density of CD31-positive microvessels. AAA samples contained significantly less actin, desmin, elastin and OPG, more collagen, macrophages, neutrophils, T lymphocytes, B lymphocytes, hypoxic cells and PTX3, and a greater density of vasa vasorum (VV) than those in non-AAA samples. Hypoxia positively correlated with actin and negatively correlated with collagen. Microvascular density was related to inflammatory cell infiltrates, hypoxia, PTX3 expression and AAA diameter. The lower OPG expression in AAAs supports the notion of its protective role in AAA remodeling. AAA contained altered amounts of structural proteins, implying reduced vascular elasticity. PTX3 was upregulated in AAA and colocalized with inflammatory infiltrates. This evidence supports further evaluation of PTX3 as a candidate marker of AAA. The presence of aortic hypoxia, despite hypervascularization, suggests that hypoxia-induced neoangiogenesis may play a role in AAA pathogenesis. VV angiogenesis of the AAA wall increases its vulnerability.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0224818PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839860PMC
March 2020

Lipid management in rheumatoid arthritis: a position paper of the Working Group on Cardiovascular Pharmacotherapy of the European Society of Cardiology.

Eur Heart J Cardiovasc Pharmacother 2020 04;6(2):104-114

Immunorheumatology Research Laboratory, Istituto Auxologico Italiano, Via Ariosto, 14, 20145 Milan, Italy.

Rheumatoid arthritis (RA) is associated with increased cardiovascular morbidity, partly due to alterations in lipoprotein quantity, quality and cell cholesterol trafficking. Although cardiovascular disease significantly contributes to mortality excess in RA, cardiovascular prevention has been largely insufficient. Because of limited evidence, optimal strategies for lipid management (LM) in RA have not been determined yet, and recommendations are largely based on expert opinions. In this position paper, we describe abnormalities in lipid metabolism and introduce a new algorithm for estimation of cardiovascular risk (CVR) and LM in RA. The algorithm stratifies patients according to RA-related factors impacting CVR (such as RA activity and severity and medication). We propose strategies for monitoring of lipid parameters and treatment of dyslipidaemia in RA (including lifestyle, statins and other lipid-modifying therapies, and disease modifying antirheumatic drugs). These opinion-based recommendations are meant to facilitate LM in RA until more evidence is available.
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http://dx.doi.org/10.1093/ehjcvp/pvz033DOI Listing
April 2020

Tumor necrosis factor inhibitors are associated with reduced complement activation in spondylarthropathies: An observational study.

PLoS One 2019 23;14(7):e0220079. Epub 2019 Jul 23.

Lillehammer Hospital for Rheumatic Diseases, Lillehammer, Norway.

Background: The complement system is involved in pathogenesis of cardiovascular disease, and might play a role in accelerated atherogenesis in spondylarthropathies (SpA). Hence, we examined complement activation in SpA, and its relationship to antirheumatic treatment, inflammatory and cardiovascular markers.

Methods: From PSARA, a prospective observational study, we examined 51 SpA patients (31 psoriatic arthritis (PsA), and 20 ankylosing spondylitis (AS)), starting tumor necrosis factor (TNF) inhibitor alone (n = 25), combined with methotrexate (MTX) (n = 10), or MTX monotherapy (n = 16). Complement activation was determined by the soluble terminal complement complex (sC5b-9), inflammation by erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), and endothelial function by finger plethysmography (Endopat) at baseline, after 6 weeks and 6 months of treatment.

Results: SpA patients had sC5b-9 levels at (PsA) or above (AS) the upper limit of the estimated reference range. Median sC5b-9 levels decreased significantly from baseline to 6 weeks, with no significant difference between the AS and PsA group. Notably, a significant reduction in sC5b-9 was observed after administration of TNF inhibitor ± MTX, whereas no significant changes were observed in patients treated with MTX alone. Between 6 weeks and 6 months, sC5b-9 remained stable across all subgroups. Reduction in sC5b-9 was independently related to decreased ESR and CRP, and to increased high density cholesterol and total cholesterol. Reduction in sC5b-9 from baseline to 6 weeks was associated with improved EF in age and gender adjusted analyses.

Conclusion: TNF-inhibition, but not MTX monotherapy, led to rapid and sustained reduction of complement activation in SpA. Thus, the observed decrease in cardiovascular morbidity in patients treated with TNF-inhibitors might be partly due to its beneficial effect on complement.

Trial Registration: Clinical Trials (NCT00902005), retrospectively registered on the 14th of May 2009.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0220079PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6650069PMC
February 2020

Blood biomarker panel recommended for personalized prediction, prognosis, and prevention of complications associated with abdominal aortic aneurysm.

EPMA J 2019 Jun 3;10(2):125-135. Epub 2019 Jun 3.

5Department of Immunochemistry Diagnostics, University Hospital and Faculty of Medicine in Pilsen, Pilsen, Czech Republic.

The aim of the study was to evaluate the ability of following biomarkers as diagnostic tools and risk predictors of AAA: C-reactive protein, interleukin-6, pentraxin-3, galectin-3, procollagen type III N-terminal peptide, C-terminal telopeptide of type I collagen, high-sensitive troponin I, and brain natriuretic peptide. Seventy-two patients with an AAA and 100 healthy individuals were enrolled into the study. We assessed individual biomarker performance and correlation between the AAA diameter and biomarker levels, and also, a multivariate logistic regression was used to design a possible predictive model of AAA growth and rupture risk. We identified following four parameters with the highest potential to find a useful place in AAA diagnostics: galectin-3, pentraxin-3, interleukin-6, and C-terminal telopeptide of type I. The best biomarkers in our evaluation (galectin-3 and pentraxin-3) were AAA diameter-independent. With the high AUC and AAA diameter correlation, the high-sensitive troponin I can be used as an independent prognostic biomarker of the upcoming heart complications in AAA patients. Authors recommend to add biomarkers as additional parameters to the current AAA patient management. Main addition value of biomarkers is in the assessment of the AAA with the smaller diameter. Elevated biomarkers can change the treatment decision, which would be done only based on AAA diameter size. The best way how to manage the AAA patients is to create a reliable predictive model of AAA growth and rupture risk. A created multiparameter model gives very promising results with the significantly higher efficiency compared with the use of the individual biomarkers.
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http://dx.doi.org/10.1007/s13167-019-00173-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562056PMC
June 2019

MicroRNA-615-5p Regulates Angiogenesis and Tissue Repair by Targeting AKT/eNOS (Protein Kinase B/Endothelial Nitric Oxide Synthase) Signaling in Endothelial Cells.

Arterioscler Thromb Vasc Biol 2019 07 16;39(7):1458-1474. Epub 2019 May 16.

From the Cardiovascular Division, Department of Medicine (B.L., W.W., D.O., H.L., H.S.C., S.H., X.L., S.N.A., N.L., I.H., K.C., M.W.F.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

Objective- In response to tissue injury, the appropriate progression of events in angiogenesis is controlled by a careful balance between pro and antiangiogenic factors. We aimed to identify and characterize microRNAs that regulate angiogenesis in response to tissue injury. Approach and Results- We show that in response to tissue injury, microRNA-615-5p (miR-615-5p) is rapidly induced and serves as an antiangiogenic microRNA by targeting endothelial cell VEGF (vascular endothelial growth factor)-AKT (protein kinase B)/eNOS (endothelial nitric oxide synthase) signaling in vitro and in vivo. MiR-615-5p expression is increased in wounds of diabetic db/db mice, in plasma of human subjects with acute coronary syndromes, and in plasma and skin of human subjects with diabetes mellitus. Ectopic expression of miR-615-5p markedly inhibited endothelial cell proliferation, migration, network tube formation in Matrigel, and the release of nitric oxide, whereas miR-615-5p neutralization had the opposite effects. Mechanistic studies using transcriptomic profiling, bioinformatics, 3' untranslated region reporter and microribonucleoprotein immunoprecipitation assays, and small interfering RNA dependency studies demonstrate that miR-615-5p inhibits the VEGF-AKT/eNOS signaling pathway in endothelial cells by targeting IGF2 (insulin-like growth factor 2) and RASSF2 (Ras-associating domain family member 2). Local delivery of miR-615-5p inhibitors, markedly increased angiogenesis, granulation tissue thickness, and wound closure rates in db/db mice, whereas miR-615-5p mimics impaired these effects. Systemic miR-615-5p neutralization improved skeletal muscle perfusion and angiogenesis after hindlimb ischemia in db/db mice. Finally, modulation of miR-615-5p expression dynamically regulated VEGF-induced AKT signaling and angiogenesis in human skin organoids as a model of tissue injury. Conclusions- These findings establish miR-615-5p as an inhibitor of VEGF-AKT/eNOS-mediated endothelial cell angiogenic responses and that manipulating miR-615-5p expression could provide a new target for angiogenic therapy in response to tissue injury. Visual Overview- An online visual overview is available for this article.
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http://dx.doi.org/10.1161/ATVBAHA.119.312726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594892PMC
July 2019

Levels of Lipoprotein (a) in patients with coronary artery disease with and without inflammatory rheumatic disease: a cross-sectional study.

BMJ Open 2019 05 10;9(5):e030651. Epub 2019 May 10.

Rheumatology Department, Hospital for Rheumatic Diseases, Lillehammer, Norway.

Objectives: Patients with various inflammatory rheumatic diseases (IRDs) have increased risk of atherothrombotic disease. Lipoprotein (a) (Lp(a)) is a risk factor for atherosclerosis but its role in IRD with accompanying coronary artery disease (CAD) is still unclear. We aimed to examine if serum Lp(a) levels differed between CAD patients with and without accompanying IRD.

Design: A cross-sectional observational, patient-based cohort study.

Setting: Referred centre for coronary artery bypass grafting in the South Eastern part of Norway.

Participants: 67 CAD patients with IRD (CAD/IRD) and 52 CAD patients without IRD (CAD/non-IRD). All patients were Caucasians, aged >18 years, without any clinically significant infection or malignancy.

Methods: Lp(a) levels in serum were analysed by particle enhanced immunoturbidimetric assay, and Lp(a) levels were related to clinical and biochemical characteristics of the patient population.

Results: We found no differences in serum levels of Lp(a) between CAD patients with and without IRD. In general, we found that Lp(a) correlated poorly with clinical and biochemical parameters including C reactive protein with the same pattern in the CAD/non-IRD and CAD/IRD groups.

Conclusions: Our data do not support a link between inflammation and Lp(a) levels in CAD and in general Lp(a) levels were not correlated with other risk factors for cardiovascular disease.
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http://dx.doi.org/10.1136/bmjopen-2019-030651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6530453PMC
May 2019

MicroRNA-135a-3p regulates angiogenesis and tissue repair by targeting p38 signaling in endothelial cells.

FASEB J 2019 04 22;33(4):5599-5614. Epub 2019 Jan 22.

Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Angiogenesis is a critical process in repair of tissue injury that is regulated by a delicate balance between pro- and antiangiogenic factors. In disease states associated with impaired angiogenesis, we identified that miR-135a-3p is rapidly induced and serves as an antiangiogenic microRNA (miRNA) by targeting endothelial cell (EC) p38 signaling in vitro and in vivo. MiR-135a-3p overexpression significantly inhibited EC proliferation, migration, and network tube formation in matrigel, whereas miR-135-3p neutralization had the opposite effects. Mechanistic studies using transcriptomic profiling, bioinformatics, 3'-UTR reporter and miRNA ribonucleoprotein complex -immunoprecipitation assays, and small interfering RNA dependency studies revealed that miR-135a-3p inhibits the p38 signaling pathway in ECs by targeting huntingtin-interacting protein 1 (HIP1). Local delivery of miR-135a-3p inhibitors to wounds of diabetic db/db mice markedly increased angiogenesis, granulation tissue thickness, and wound closure rates, whereas local delivery of miR-135a-3p mimics impaired these effects. Finally, through gain- and loss-of-function studies in human skin organoids as a model of tissue injury, we demonstrated that miR-135a-3p potently modulated p38 signaling and angiogenesis in response to VEGF stimulation by targeting HIP1. These findings establish miR-135a-3p as a pivotal regulator of pathophysiological angiogenesis and tissue repair by targeting a VEGF-HIP1-p38K signaling axis, providing new targets for angiogenic therapy to promote tissue repair.-Icli, B., Wu, W., Ozdemir, D., Li, H., Haemmig, S., Liu, X., Giatsidis, G., Cheng, H. S., Avci, S. N., Kurt, M., Lee, N., Guimaraes, R. B., Manica, A., Marchini, J. F., Rynning, S. E., Risnes, I., Hollan, I., Croce, K., Orgill, D. P., Feinberg, M. W. MicroRNA-135a-3p regulates angiogenesis and tissue repair by targeting p38 signaling in endothelial cells.
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http://dx.doi.org/10.1096/fj.201802063RRDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6436660PMC
April 2019

Differential expression of vitamin D associated genes in the aorta of coronary artery disease patients with and without rheumatoid arthritis.

PLoS One 2018 23;13(8):e0202346. Epub 2018 Aug 23.

Department of Research, Innlandet Hospital Trust, Brumunddal, Norway.

Background: Vitamin D has an important role in the immune system, and has been linked to rheumatoid arthritis (RA) and coronary artery disease (CAD). The exact mechanisms by which vitamin D is involved in these processes are still unclear. Therefore, we wanted to search for differences in expression of genes involved in the vitamin D receptor (VDR) activation pathway and genes that are known to alter upon vitamin D stimulation, in the aortic adventitia of CAD patients with and without RA.

Methods: Affymetrix microarray was used to determine gene expression profile in surgical specimens from the adventitia of the ascending aorta of CAD patients with RA (n = 8) and without RA (n = 8) from the Feiring Heart Biopsy Study.

Results: We identified three vitamin D associated genes that were differentially expressed between RA and non-RA patients: Growth arrest and DNA-damage-inducible protein 45 alpha (GADD45A) (FC = 1.47; p = 0.006), Nuclear Receptor Co-repressor 1 (NCOR1) (FC = 1,21; p = 0.005) and paraoxonases 2 (PON2) (FC = -1.37; p = 0.01). High expression of GADD45A in RA tissues was confirmed by real-time qRT-PCR. GADD45A expression correlated with plasma levels of 1,25(OH)2D3 (rs = 0.69; p = 0.003).

Conclusions: Microarray analyses revealed higher expression of GADD45A and NCOR1; and lower expression of PON2 in the aortic adventitia of RA than non-RA patients. Further studies are needed to elucidate if and how GADD45A, NCOR1 and PON2 are involved in the development of accelerated atherosclerosis in RA. In theory, some of these factors might have proatherogenic effects whereas others might reflect an underlying vascular pathology promoting atherogenesis (such as vascular stress).
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0202346PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6107153PMC
February 2019

Effect of anti-rheumatic treatment on selenium levels in inflammatory arthritis.

J Trace Elem Med Biol 2018 Sep 3;49:91-97. Epub 2018 May 3.

Lillehammer Hospital for Rheumatic Diseases, Norway; Department of Research, Innlandet Hospital Trust, Brumunddal, Norway; Harvard Medical School, Boston, USA; Brigham and Women's Hospital, Boston, USA.

Objectives: The reason for increased cardiovascular risk in inflammatory arthritis (IA) is unclear. Interestingly, selenium-deficiency is suspected to contribute to the development of cardiovascular disease (CVD) in the general population. Although the reference range of serum selenium (s-selenium) is 50-120 μg/L, there are indications that levels up to 85 μg/L might not be sufficient for optimal cardioprotection. Our aim was to examine s-selenium levels in rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS), to evaluate the effect of anti-rheumatic treatment on s-selenium levels, and to assess relationships between s-selenium levels and clinical and laboratory parameters including markers of disease activity and CVD risk.

Methods: We examined 64 patients with RA, 40 with PsA and 26 with AS starting with methotrexate (MTX) monotherapy or anti-tumor necrosis factor therapy (anti-TNF) with or without methotrexate (anti-TNF ± MTX) due to active disease. S-selenium, inflammatory biomarkers, endothelial function (EF) and other variables were examined at baseline and after 6 weeks and 6 months of treatment.

Results: In the total IA group, s-selenium increased within 6 weeks of anti-rheumatic treatment, and thereafter the levels remained stable until the end of the 6 months follow-up period. There were no significant differences in s-selenium changes between the three diagnostic groups and between the two treatment regimens. Changes in s-selenium were negatively related to changes in C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), but there were no significant relationships to any other of the examined risk parameters for CVD including EF.

Conclusion: IA patients had s-selenium within the reference range, but below the level that might be necessary for optimal CVD protection. Anti-rheumatic treatment had a relatively rapid and sustained effect on s-selenium levels. The increase in s-selenium was related to reduction in inflammatory activity. In theory, anti-rheumatic drugs might improve s-selenium levels through inhibition of pro-inflammatory processes or through other mechanisms. Although we have not revealed any significant relationships between s-selenium and CVD risk parameters, the role of suboptimal s-selenium levels in pathogenesis of premature CVD in IA cannot be ruled out.
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http://dx.doi.org/10.1016/j.jtemb.2018.05.001DOI Listing
September 2018

Response: Complex issue of lipoprotein functions in rheumatoid arthritis.

Heart 2018 05;104(9):786

Faculty of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

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http://dx.doi.org/10.1136/heartjnl-2017-312678DOI Listing
May 2018

Methotrexate and anti-tumor necrosis factor treatment improves endothelial function in patients with inflammatory arthritis.

Arthritis Res Ther 2017 Oct 17;19(1):232. Epub 2017 Oct 17.

Lillehammer Hospital for Rheumatic Diseases, Lillehammer, Norway.

Background: Inflammatory arthritis (IA), including rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA), leads to increased cardiovascular disease occurrence probably due to atherosclerosis. One of the first stages in atherogenesis is endothelial dysfunction (ED). Therefore, we aimed to compare endothelial function (EF) in patients with IA, and to examine the effects of methotrexate (MTX) monotherapy and antitumor necrosis factor (anti-TNF) treatment with or without MTX comedication (anti-TNF ± MTX) on EF.

Methods: From the PSARA observational study, all patients with RA (n = 64), PsA (n = 29), and AS (n = 20) were evaluated for EF. In patients with ED at baseline (n = 40), we evaluated changes in the Reactive Hyperemic Index (RHI) after 6 weeks and 6 months of antirheumatic therapy.

Results: In IA patients with ED, RHI significantly improved after 6 weeks (p < 0.001) and 6 months (p < 0.001) of treatment, independent of changes in disease activity parameters. After 6 months, RHI had improved more in the MTX group than in the anti-TNF ± MTX group, and the difference remained statistically significant after adjustments for potential confounders. Among patients with active RA, AS, and PsA, those with AS appeared to have the worst endothelial function, although they were the youngest.

Conclusion: Treatment with MTX and anti-TNF ± MTX was associated with a relatively fast improvement of EF in IA patients with ED, independent of change in disease activity. Therefore, modes of action other than the anti-inflammatory effect may contribute to the EF improvement. After 6 months, the EF improvement was more pronounced in the MTX group than in the anti-TNF ± MTX group.

Trial Registration: Clinicaltrials, NCT00902005 . Registered on 13 May 2009.
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http://dx.doi.org/10.1186/s13075-017-1439-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5646156PMC
October 2017

Expression of High Mobility Group Protein B1 in Cardiac Tissue of Elderly Patients with Coronary Artery Disease with or without Inflammatory Rheumatic Disease.

Gerontology 2017 21;63(4):337-349. Epub 2017 Apr 21.

Unit of Rheumatology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.

Background: It is known from clinical practice and observational studies that elderly patients with a diagnosis of inflammatory rheumatic diseases (IRD) bear a significantly increased risk for cardiovascular diseases such as coronary artery disease (CAD) and heart failure. The molecular mechanism, however, is still not known. Recently, high mobility group protein B1 (HMGB1), a ubiquitous, highly conserved single polypeptide expressed in all mammal eukaryotic cells, has been identified to mediate myocardial dysfunction in vitro once released from the nuclei of cardiomyocytes.

Objective: To investigate whether HMGB1 and its receptors are expressed in cardiac muscles of elderly patients with CAD with or without IRD.

Methods: HMGB1 and its 3 well-known receptors, receptor for advanced glycation end products, Toll-like receptor 2 (TLR2), and TLR4, were examined by immunohistochemistry on myocardial biopsy specimens from 18 elderly patients with CAD (10 with IRD, 8 without IRD). Furthermore, total HMGB1 protein levels were measured by Western blot from the cardiac biopsies in 5 patients with and 5 without IRD.

Results: Pathologic cytosolic HMGB1 in cardiomyocytes was massively recorded in all patients with IRD, but only slightly expressed in 1 patient without IRD. Total HMGB1 levels were also consistently lower in myocardial muscle biopsies of patients with IRD compared to those without IRD. Furthermore, all 3 HMGB1 receptors were expressed in cardiomyocytes of all patients.

Conclusion: The increased cytosolic expression of HMGB1 in cardiomyocytes and the lower total amount of HMGB1 in the cardiac specimens of IRD patients is consistent with a greater release of HMGB1 from the myocardial nuclei in IRD than non-IRD individuals. Thus, the HMGB1 signaling pathways may be more easily activated in elderly CAD patients with concomitant IRD and trigger a detrimental inflammatory process causing severe cardiovascular problems. Therefore, targeting HMGB1 in IRD patients might reduce the risk for cardiovascular events.
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http://dx.doi.org/10.1159/000471763DOI Listing
April 2018

Plasma complement and vascular complement deposition in patients with coronary artery disease with and without inflammatory rheumatic diseases.

PLoS One 2017 31;12(3):e0174577. Epub 2017 Mar 31.

Department of Rheumatology, Lillehammer Hospital for Rheumatic Diseases, Lillehammer, Norway.

Purpose: Inflammatory rheumatic diseases (IRD) are associated with accelerated coronary artery disease (CAD), which may result from both systemic and vascular wall inflammation. There are indications that complement may be involved in the pathogenesis of CAD in Systemic Lupus Erythematosus (SLE) and Rheumatoid Arthritis (RA). This study aimed to evaluate the associations between circulating complement and complement activation products with mononuclear cell infiltrates (MCI, surrogate marker of vascular inflammation) in the aortic media and adventitia in IRDCAD and non-IRDCAD patients undergoing coronary artery bypass grafting (CABG). Furthermore, we compared complement activation product deposition patterns in rare aorta adventitial and medial biopsies from SLE, RA and non-IRD patients.

Methods: We examined plasma C3 (p-C3) and terminal complement complexes (p-TCC) in 28 IRDCAD (SLE = 3; RA = 25), 52 non-IRDCAD patients, and 32 IRDNo CAD (RA = 32) from the Feiring Heart Biopsy Study. Aortic biopsies taken from the CAD only patients during CABG were previously evaluated for adventitial MCIs. The rare aortic biopsies from 3 SLE, 3 RA and 3 non-IRDCAD were assessed for the presence of C3 and C3d using immunohistochemistry.

Results: IRDCAD patients had higher p-TCC than non-IRDCAD or IRDNo CAD patients (p<0.0001), but a similar p-C3 level (p = 0.42). Circulating C3 was associated with IRD duration (ρ, p-value: 0.46, 0.03). In multiple logistic regression analysis, IRD remained significantly related to the presence and size of MCI (p<0.05). C3 was present in all tissue samples. C3d was detected in the media of all patients and only in the adventitia of IRD patients (diffuse in all SLE and focal in one RA).

Conclusion: The independent association of IRD status with MCI and the observed C3d deposition supports the unique relationship between rheumatic disease, and, in particular, SLE with the complement system. Exaggerated systemic and vascular complement activation may accelerate CVD, serve as a CVD biomarker, and represent a target for new therapies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0174577PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5375133PMC
August 2017

Acute effects of post-absorptive and postprandial moderate exercise on markers of inflammation in hyperglycemic individuals.

Eur J Appl Physiol 2017 Apr 2;117(4):787-794. Epub 2017 Mar 2.

Department of Community Medicine, Institute of Health and Society, University of Oslo, PB 1130 Blindern, 0318, Oslo, Norway.

Purpose: Systemic inflammation is involved in the development of several diseases, including cardiovascular disease and type 2 diabetes. It is known that vigorous exercise affects systemic inflammation, but less is known about exercise at lower intensities. Hyperglycemia can also entail pro-inflammatory responses; however, postprandial hyperglycemia is blunted if the meal is followed by exercise. Hypotheses were: (1) moderate physical exercise acutely affects levels of C-reactive protein (CRP) and serum soluble vascular cell adhesion molecule 1 (sVCAM-1) in hyperglycemic individuals and (2) the effect depends on whether the activity is performed in a post-absorptive or postprandial state.

Methods: Twelve participants diagnosed with hyperglycemia, but not using anti-diabetic medication, underwent three test days in a randomized cross-over study; 1 control day without exercise, 1 day with 60 min of treadmill walking ending 30 min before breakfast, and 1 day with an identical bout of activity 30 min after the start of breakfast. Food intake was strictly standardized and venous blood for CRP, and sVCAM-1 analysis was sampled at standardized timepoints during the first 3.5 h after breakfast and once 24 h later.

Results: Merged data from the two exercise days showed that sVCAM-1 increased from baseline (4 ± 16 ng/mL) compared to the control condition (-28 ± 47 ng/mL, ES = 0.7, p = 0.024). There was no statistically significant difference in changes in sVCAM-1 levels between the two exercise test days. Exercise did not affect CRP values.

Conclusion: Moderate exercise increases sVCAM-1 in hyperglycemic individuals, whereas it does not affect CRP.
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http://dx.doi.org/10.1007/s00421-017-3576-2DOI Listing
April 2017

Anti-rheumatic treatment is not associated with reduction of pentraxin 3 in rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis.

PLoS One 2017 22;12(2):e0169830. Epub 2017 Feb 22.

Lillehammer Hospital for Rheumatic Diseases, Lillehammer, Norway.

Background: Pentraxin 3 is proposed to be a marker of inflammation and cardiovascular risk, but its role in inflammatory rheumatic diseases (IRDs) is still uncertain. Therefore, we wanted to examine if anti-rheumatic treatment reduced serum PTX3 (s-PTX3) levels in IRDs, and if s-PTX3 levels were related to other markers of inflammation and to endothelial function (EF).

Methods: We examined s-PTX3, EF and established inflammatory biomarkers in 114 IRD patients from the PSARA study before and after 6 weeks and 6 months of treatment with methotrexate (MTX) or anti-tumor necrosis factor alpha (anti-TNF) therapy with or without MTX co-medication.

Results: s-PTX3 levels in all IRD diagnoses were above the upper limit of the reference range. In contrast to established inflammatory markers, in particular CRP and ESR, s-PTX3 levels did not change significantly after 6 weeks and 6 months of anti-rheumatic therapy. There was no difference in change in s-PTX3 levels from baseline to 6 weeks and 6 months between MTX monotherapy and anti-TNF regimens. CRP, ESR and EF were not related to changes in s-PTX3 neither in crude nor adjusted analyses.

Conclusion: IRD patients have increased s-PTX3 levels, which, in contrast to other inflammatory markers, do not seem to improve within 6 months of therapy with MTX and/or anti-TNF. Thus, s-PTX3 might reflect a persisting immune process, even a causal factor of inflammation, not inhibited by the standard anti-rheumatic treatment. Furthermore, even though s-PTX3 is thought to be a strong predictor of cardiovascular prognosis, it was not related to EF.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0169830PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5321277PMC
August 2017

Metabolic abnormalities in patients with inflammatory rheumatic diseases.

Best Pract Res Clin Rheumatol 2016 10 9;30(5):901-915. Epub 2016 Nov 9.

Lillehammer Hospital for Rheumatic Diseases, Norway Hospital for Rheumatic Diseases, Department of Rheumatology, Lillehammer, and Innlandet Hospital Trust, Department of Research, Brumunddal, Norway; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Patients with rheumatoid arthritis (RA) experience an increased cardiometabolic risk factor burden that is substantially driven by systemic inflammation. This occurs less consistently in patients with ankylosing spondylitis (AS). Psoriatic arthritis most strongly associates with excess adiposity and metabolic risk. RA patients also often have systemic inflammation-induced proinflammatory high-density lipoprotein (HDL) cholesterol particles and lean/muscle mass loss in association with increased adiposity, a condition termed rheumatoid cachexia, which further enhances cardiovascular risk. The presence of proinflammatory HDL and lean mass loss was also reported in patients with AS. Individualized aerobic and resistance exercise programs can improve body composition and metabolic risk factor profiles in RA and AS. Future studies should assess how long-term lifestyle changes can be effectuated and if these can influence cardiovascular events in inflammatory rheumatic diseases. Herein, we review the current evidence on metabolic abnormalities in inflammatory arthritis. We propose management strategies and a research agenda.
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http://dx.doi.org/10.1016/j.berh.2016.10.001DOI Listing
October 2016

Improvement of Ice Hockey Players' On-Ice Sprint With Combined Plyometric and Strength Training.

Int J Sports Physiol Perform 2017 Aug 5;12(7):893-900. Epub 2016 Dec 5.

Background: Combined plyometric and strength training has previously been suggested as a strategy to improve skating performance in ice hockey players. However, the effects of combined plyometric and strength training have not previously been compared with the effects of strength training only.

Purpose: To compare the effects of combined plyometric and strength training on ice hockey players' skating sprint performance with those of strength training only.

Methods: Eighteen participants were randomly assigned to 2 groups that completed 5 strength-training sessions/wk for 8 wk. One group included plyometric exercises at the start of 3 sessions/wk (PLY+ST), and the other group included core exercises in the same sessions (ST). Tests of 10- and 35-m skating sprints, horizontal jumping, 1-repetition-maximum (1 RM) squat, skating multistage aerobic test (SMAT), maximal oxygen consumption, repeated cycle sprints, and body composition were performed before and after the intervention.

Results: The participants increased their 1RM squat, lean mass, and body mass (P < .05), with no difference between the groups. Furthermore, they improved their 3×broad jump, repeated cycle sprint, and SMAT performance (P < .05), with no difference between the groups. PLY+ST gained a larger improvement in 10-m on-ice sprint performance than ST (P < .025).

Conclusion: Combining plyometric and strength training for 8 wk was superior to strength training alone at improving 10-m on-ice sprint performance in high-level ice hockey players.
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http://dx.doi.org/10.1123/ijspp.2016-0262DOI Listing
August 2017

Inflammatory cell infiltrates in the heart of patients with coronary artery disease with and without inflammatory rheumatic disease: a biopsy study.

Arthritis Res Ther 2016 10 12;18(1):232. Epub 2016 Oct 12.

Hospital for Rheumatic Diseases, Lillehammer, Norway.

Background: The cause of premature cardiovascular disease (CVD) in inflammatory rheumatic diseases (IRDs) has not been fully elucidated. As inflammation may play a role, we wanted to compare the occurrence and extent of inflammatory cell infiltrates (ICIs), small vessel vasculitis, and the amount of adipose tissue and collagen in cardiac biopsies taken from patients with coronary artery disease with and without IRDs.

Methods: From among the Feiring Heart Biopsy Study subjects, we selected patients undergoing coronary artery bypass grafting from whom paraffin-embedded, formalin-fixed specimens from the right atrium were available. The sample comprised 48 patients with IRD and 40 non-IRD patients. Hematoxylin and eosin staining was used to examine the presence and location of ICIs and vasculitis, and Lendrum (Martius yellow, scarlet, and blue) staining was carried out for collagen and adipose tissue.

Results: Epicardial ICIs were found in 27 (56 %) patients with IRD and 24 (60 %) non-IRD patients. There were no significant differences between patients with IRD and non-IRD patients in the amount of cardiac ICIs and adipose tissue, but patients with IRD had more collagen in the myocardium than non-IRD patients. Small vessel vasculitis was not observed in any cardiac specimen. Patients with epicardial ICIs were, on average, 7 years younger than those without.

Conclusions: Our results do not support the notion that inflammation in cardiac peri-, epi-, and myocardium plays a more important role in CVD of patients with IRD than non-IRD patients. The increased amount of collagen in the myocardium of patients with IRD suggests differences in extracellular matrix composition and/or mass, which might play a role in cardiac remodeling, and represent targets for novel therapies against heart failure.
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http://dx.doi.org/10.1186/s13075-016-1136-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5059899PMC
October 2016

Omentin concentrations are independently associated with those of matrix metalloproteinase-3 in patients with mild but not severe rheumatoid arthritis.

Rheumatol Int 2017 Jan 30;37(1):3-11. Epub 2016 Jul 30.

Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.

Omentin is an adipokine that reportedly protects against cardiometabolic risk. We investigated the relationships between omentin concentrations and subclinical cardiovascular disease in rheumatoid arthritis (RA). Omentin concentrations were measured in 213 (104 black; 109 white) RA patients. Relationships of omentin levels with those of endothelial activation markers, ultrasound determined carotid intima-media thickness and plaque, and matrix metalloproteinase (MMP)-2, -3 and -9 that mediate altered plaque stability, were identified in confounder adjusted multivariate regression models. Omentin concentrations were inversely associated with MMP-3 levels [β = -364 (0.113), p = 0.002]. This relationship was influenced by population origin, RA activity and the erythrocyte sedimentation rate and joint deformity count (interaction p value = 0.009, 0.04, 0.04 and 0.007, respectively). Accordingly, the omentin-MMP-3 concentration relationship was reproduced in white [β (SE) = -0.450 (0.153), p = 0.0004)] but not black patients [β (SE) = -0.099 (0.195), p = 0.6)], in participants with disease remission or mild disease activity [β (SE) = -0.411 (0.139), p = 0.004] but not with moderate or severe RA activity [β (SE) = -0.286 (0.202), p = 0.2], and in those with a small [β (SE) = -0.534 (0.161), p = 0.001] but not large erythrocyte sedimentation rate [-0.212 (0.168), p = 0.2] and without [β (SE) = -0.554 (0.165), p = 0.0001] but not with large joint deformity counts [-0.110 (0.173), p = 0.5]. Omentin levels were unrelated to endothelial activation and atherosclerosis. Among patients with RA, a lack of plaque stabilizing effects by omentin may contribute to the reported link between severe disease and increased cardiovascular risk. The association between concentrations of omentin and MMP-3 is population specific in RA.
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http://dx.doi.org/10.1007/s00296-016-3541-0DOI Listing
January 2017

Brief Report: Proatherogenic Cytokine Microenvironment in the Aortic Adventitia of Patients With Rheumatoid Arthritis.

Arthritis Rheumatol 2016 06;68(6):1361-6

University of Glasgow, Glasgow, UK.

Objective: Patients with rheumatoid arthritis (RA) are at increased risk of developing cardiovascular disease (CVD) via mechanisms that have not yet been defined. Inflammatory pathways, in particular within the vascular adventitia, are implicated in the pathogenesis of primary CVD but could be amplified in RA at the local tissue level. The aim of this study was to examine the aortic adventitia of coronary artery disease (CAD) patients with or without RA to determine the cytokine profile contained therein.

Methods: Aortic adventitia and internal thoracic artery biopsy specimens obtained from 19 RA patients and 20 non-RA patients undergoing coronary artery bypass graft surgery were examined by immunohistochemistry.

Results: Interleukin-18 (IL-18), IL-33, and tumor necrosis factor (TNF) were expressed in aortic adventitia biopsy specimens from both groups, and expression of these cytokines was significantly higher in RA patients. In RA patients, IL-33 expression in endothelial cells correlated positively with the number of swollen joints, suggesting a link between the systemic disease state and the local vascular tissue microlesion.

Conclusion: The presence of the proinflammatory cytokines IL-18, IL-33, and TNF may play a role in the inflammatory process within the adventitia that contributes to plaque formation and destabilization. In theory, the amplified expression of these cytokines may contribute to the known increased occurrence and severity of CAD in patients with RA.
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http://dx.doi.org/10.1002/art.39574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4920270PMC
June 2016

Impairment of Performance Variables After In-Season Strength-Training Cessation in Elite Cyclists.

Int J Sports Physiol Perform 2016 Sep 24;11(6):727-735. Epub 2016 Aug 24.

The current study investigated the effects of 8 wk of strength-training cessation after 25 wk of strength training on strength- and cycling-performance characteristics. Elite cyclists were randomly assigned to either 25 wk of endurance training combined with heavy strength training (EXP, n = 7, maximal oxygen uptake [V̇O] 77 ± 6 mL . kg . min; 3 × 4-10 RM, 1 to 2 d/wk) or to endurance training only (CON, n = 7, V̇O 73 ± 5 mL . kg . min). Thereafter, both groups performed endurance training only for 8 wk, coinciding with the initial part of the competition season. Data were assessed for practical significance using magnitude-based inferences. During the 25-wk preparatory period, EXP had a larger positive impact on maximal isometric half-squat force, squat jump (SJ), maximal aerobic power (W), power output at 4 mmol/L [La], and mean power in 30-s Wingate test than did CON (ES = 0.46-0.74). Conversely, during the 8-wk competition period EXP had a reduction in SJ, W, and mean power in the 30-s Wingate test compared with CON (ES = 0.49-0.84). The present findings suggest rapid decline of adaptations on termination of strength training during the first 8 wk of the competition period in elite cyclists.
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http://dx.doi.org/10.1123/ijspp.2015-0372DOI Listing
September 2016

Rapid Anti-Inflammatory Effects of Gonadotropin-Releasing Hormone Antagonism in Rheumatoid Arthritis Patients with High Gonadotropin Levels in the AGRA Trial.

PLoS One 2015 13;10(10):e0139439. Epub 2015 Oct 13.

Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Rheumatology, Oslo University Hospital, Oslo, Norway.

Objectives: Gonadotropin-releasing hormone (GnRH) and pituitary gonadotropins, which appear to be proinflammatory, undergo profound secretory changes during events associated with rheumatoid arthritis (RA) onset, flares, or improvement e.g. menopausal transition, postpartum, or pregnancy. Potential anti-inflammatory effects of GnRH-antagonists may be most pronounced in patients with high GnRH and gonadotropin levels. Therefore, we investigated the efficacy and safety of a GnRH-antagonist, cetrorelix, in RA patients with high gonadotropin levels.

Methods: We report intention-to-treat post hoc analyses among patients with high gonadotropin levels (N = 53), i.e. gonadotropin levels>median, from our proof-of-concept, double-blind AGRA-study (N = 99). Patients with active longstanding RA, randomized to subcutaneous cetrorelix (5mg days1-2; 3mg days 3-5) or placebo, were followed through day 15. Only predefined primary and secondary endpoints were analyzed.

Results: The primary endpoint, Disease Activity Score of 28-joint counts with C-reactive protein (DAS28-CRP), improved with cetrorelix compared with placebo by day 5 (-1.0 vs. -0.4, P = 0∙010). By day 5, more patients on cetrorelix achieved at least a 20% improvement in the American College of Rheumatology scale (44% vs. 19%, P = 0.049), DAS28-CRP≤3.2 (24% vs. 0%, P = 0.012), and European League against Rheumatism 'Good-responses' (19% vs. 0%, P = 0.026). Tumor necrosis factor-α, interleukin-1β, interleukin-10, and CRP decreased with cetrorelix (P = 0.045, P = 0.034, P = 0.020 and P = 0.042 respectively) compared with placebo by day 15. Adverse event rates were similar between groups.

Conclusions: GnRH-antagonism produced rapid anti-inflammatory effects in RA patients with high gonadotropin levels. GnRH should be investigated further in RA.

Trial Registration: ClinicalTrials.gov NCT00667758.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0139439PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4603957PMC
June 2016
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