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Objectives Persons with rheumatoid arthritis (RA) have lower cardiorespiratory fitness (CRF) than healthy individuals. We sought to identify variables explaining the association between RA status and reduced CRF. Methods RA patients recruited from two Norwegian hospitals and blood donors recruited as controls filled in questionnaires about physical activity, physical symptoms, and psychological factors. Estimated CRF (eCRF) was calculated from non-exercise models. The relationship between RA status and reduced eCRF was explored with structural equation modelling. The latent variables physical symptoms (based on morning stiffness, joint pain, and pain in neck, back, or hips) and negative emotions (based on Hospital Anxiety and Depression Scale’s Depression score and Cohen’s perceived stress scale) were included as possible mediators between RA status and eCRF in separate and combined models adjusted for age and sex. Results Two-hundred-and-twenty-seven RA patients and 300 controls participated. The patients were older and had lower eCRF than controls (age- and sex-adjusted mean difference: 1.7 mL/kg/min, p=0.002). Both latent variables were significant mediators of the association between RA and reduced eCRF when included in separate models. The latent variables mediated 74% of the total effect of RA on eCRF in the combined model. Standardized coefficients: direct effect of RA -0.024 (p=0.46), indirect effect through physical symptoms -0.034 (p=0.051), and indirect effect through negative emotions -0.034 (p=0.039). Conclusion Both physical symptoms and negative emotions mediated the association between RA and reduced eCRF with similar effect sizes. To successfully increase CRF in RA patients, both physical and psychological factors should be addressed. Key Points• The RA patients in the present study had 1.7 mL/kg/min lower mean estimated cardiorespiratory fitness (CRF) compared to healthy controls.• Mediation analysis demonstrated that physical symptoms and negative emotions mediated 74% of the total negative effect of RA on estimated CRF in a combined, adjusted model.• This suggests that both physical and psychological factors should be addressed when supporting RA patients in improving their CRF.

TRAF1/C5 was among the first loci shown to confer risk for inflammatory arthritis in the absence of an associated coding variant, but its genetic mechanism remains undefined. Using ImmunoChip data from 3,939 juvenile idiopathic arthritis (JIA) patients and 14,412 controls, we identified 132 plausible common non-coding variants, reduced serially by SNP-seq, electrophoretic mobility shift, and luciferase studies to the single variant rs7034653 in the third intron ofTRAF1. Genetically manipulated experimental cells and primary monocytes from genotyped donors establish that the risk G allele reduces binding of Fos-Related Antigen 2 (FRA2), resulting in reduced TRAF1 expression and enhanced TNF production. Conditioning on this variant eliminates attributable risk for rheumatoid arthritis, implicating a mechanism shared across the arthritis spectrum. These findings reveal that rs7034653, FRA2, and TRAF1 mediate a pathway through which a non-coding causal variant drives risk of inflammatory arthritis in children and adults.

Facilitators and barriers to performing physical activity (PA) may vary among persons with rheumatoid arthritis (RA) as well as between RA patients and healthy individuals. Primary objective: To investigate associations of presence of RA and levels of stress and depression with scores for facilitators and barriers to PA, using a new questionnaire (FasBarPAQ). Secondary objectives: investigate inter-individual score differences in persons with RA, and associations with RA disease-specific variables. Persons with RA from two outpatient clinics (n = 203) and blood donor controls (n = 293) filled in the new 14-item FasBarPAQ questionnaire, the Hospital Anxiety and Depression Scale depression scale (HADS-D), Cohen’s perceived stress scale, and questions regarding PA. Clinical data, and self-reported disease activity and physical function were collected for the persons with RA. Data were analyzed using linear and logistic regression. RA was associated with lower Facilitators scores (coefficient = − 1.30, p = 0.015), higher Barriers scores (coefficient = 2.36, p p p = 0.022), and the two higher stress score tertiles were associated with higher Barriers and lower Total scores (p = 0.023 to p p = 0.011; 0.60, p p = 0.003; − 0.98, p

Introduction Low functional capacity is related to future loss of daily function and cardiovascular events. The present study explored the associations of patient-reported outcome measures (PROMs) and disease-specific measures with functional capacity as measured by the 6-min walk test (6MWT) in persons with rheumatoid arthritis (RA). Methods Seventy-nine participants from rheumatology outpatient clinics were included. The distance walked during the 6MWT (6MWD) was the dependent variable in multivariable regression analyses. Model 1 included the independent variables sex, age (in tertiles to improve model fit), and body mass index (BMI). Building on Model 1, Model 2 added smoking, patient global assessment (PGA), Exercise Self-Efficacy, Hospital Anxiety and Depression Scale’s Depression score, and Cohen’s Perceived Stress Scale score, whereas Model 3 added smoking, disease duration, present use of glucocorticosteroids, seropositivity, Disease Activity Score 28—C-Reactive Protein (DAS28-CRP), and a comorbidity variable. Results Median age was 65 years, 76% were female, and median 6MWD was 493 m. In Model 1, BMI and age were significantly associated with the 6MWD (R2 = 0.42). In Model 2, PGA and Exercise Self-Efficacy were also significantly associated with the 6MWD, with standardized regression coefficients of − 0.21 (p = 0.03) and 0.26 (p = 0.004) respectively (R2 = 0.54). The RA-specific variables in Model 3 were not significantly associated with the 6MWD (R2 = 0.49). Conclusion The PROMs PGA and Exercise Self-Efficacy were significantly associated with functional capacity as measured by the 6MWT in persons with RA, whereas disease-specific measures such as DAS28-CRP and disease duration were not. Key Points• Functional capacity measured with the 6-minute walk test was significantly associated with body mass index, age, patient global assessment, and Exercise Self-Efficacy in persons with RA.• Patient-reported outcome measures explained more of the variation in functional capacity than objective or composite measures of disease and are relevant measures in clinical follow-up.• Techniques that enhance self-efficacy for exercise should be incorporated into clinical practice to promote physical activity.

Primary aim: Compare change in estimated cardiorespiratory fitness (eCRF change) in rheumatoid arthritis (RA) patients with population-based age- and sex-matched controls during ~ 11-year follow-up and identify variables associated with eCRF change. Secondary aim: Compare eCRF level in RA patients and controls. eCRF change from the second (HUNT2 1995–1997) to the third (HUNT3 2006–2008) surveys of the Norwegian Trøndelag Health Study was compared between RA patients (n = 188) and controls (n = 26,202) attending both surveys. Predictors of eCRF change were identified by Lasso regression followed by multiple linear regression. Mean eCRF level in RA patients (n = 436) and controls (n = 67,910) was compared using age-adjusted linear regression stratified on sex, as well as two-sample t tests including RA patients (n = 432) and controls (n = 59,124) who attended either HUNT2, HUNT3 or both HUNT2 and HUNT3. The mean eCRF decline from HUNT2 to HUNT3 in RA patients was 8.3 mL min−1 kg−1 versus 6.7 mL min−1 kg−1 in controls (p p p −1 kg−1; HUNT3: − 5.0 mL min−1 kg−1; men HUNT2: − 1.8 mL min−1 kg−1; HUNT3: − 4.0 mL min−1 kg−1. Higher age at baseline was associated with faster decline in eCRF. This change was more pronounced in RA patients than controls, indicating a larger negative effect on fitness of aging in RA. RA patients had lower eCRF compared to healthy individuals.

OBJECTIVES Our goal was to investigate long-term mortality associated with red blood cell (RBC) transfusion among patients with anaemia undergoing cardiac surgery when adjusting for known risk factors. METHODS Adults with preoperative anaemia as defined by World Health Organization criteria undergoing open-heart surgery from 2000 through 2017 were included. Cox regression was performed for long-term mortality (30 days–5 years), comparing patients who received ≥1 unit of RBC with those who did not. Unadjusted and multivariable analyses adjusted for risk factors were performed. RESULTS The study included 1859 patients, 1525 (82%) of whom received RBC transfusion. A total of 370 (19.9%) deaths were registered between 30 days and 5 years; 88 patients (23.8%) died between 30 days and 1 year. The unadjusted hazard ratio (HR) associated with RBC transfusion was 2.09 (1.49–2.93, P CONCLUSIONS No statistically significant association between RBC transfusion and long-term mortality was found when we adjusted for known risk factors. This study suggests that the observed difference in mortality in this patient group is largely due to patient-related risk factors.

Persons with rheumatoid arthritis (RA) or diabetes have increased risk of cardiovascular disease (CVD) and higher death rates compared to the general population. This study used data from the population-based Nord-Trøndelag Health Study (HUNT) and the Norwegian Cause of Death registry to compare all-cause mortality rates for RA or diabetes patients to the general population. We used Cox regression with age as time variable, adjusting for sex, smoking, body mass index, hypertension, total cholesterol, creatinine and previous CVD. To achieve proportional hazards, an interaction term with an age group variable (≤75 years or >75 years) was included for diabetes, smoking and previous CVD. Median follow-up was 18.1 years. Mortality occurred for 123 (32%) of the RA patients, 1,280 (44%) of the diabetes patients, 17 (52%) of the patients with both diseases and 11,641 (18%) of the controls. Both diseases were associated with statistically significantly increased mortality rates. The hazard ratio (HR) for RA was 1.24 (95% CI: 1.03-1.44). The HR of diabetes was 1.82 (1.60-2.04) for individuals ≤75 years old and 1.49 (1.39-1.59) for individuals >75 years. Diabetes had a significantly higher HR for death than RA for participants ≤75 years, but not significantly different for participants >75 years. © The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

microRNAs (miRs) are involved in different steps in the development of atherosclerosis and are proposed as promising biomarkers of coronary artery disease (CAD). We hypothesized that circulating levels of miRs were associated with coronary plaque components assessed by radiofrequency intravascular ultrasound (RF-IVUS) before and after aerobic exercise intervention. Thirty-one patients with CAD treated with percutaneous coronary intervention (PCI) previously included in a randomized trial with aerobic interval training (AIT) or moderate continuous training (MCT) as post-PCI intervention were included. Coronary plaque characteristics by grayscale and RF-IVUS and predefined circulating candidate miRs in plasma were analyzed at baseline and follow-up. Associations between miRs and coronary plaque composition, and the potential effect from exercise, were analyzed using linear regression. Circulating levels of miR-15a-5p, miR-30e-5p, miR-92a-3p, miR-199a-3p, miR-221-3p, and miR-222-3p were associated with baseline coronary necrotic core volume. Following exercise intervention, decreased levels of miR-15a-5p, miR-93-5p, and miR-451a, and increased levels of miR-146a-5p were associated with an observed regression of coronary plaque burden. A mirPath prediction tool identified that genes regulated by miR-15a-5p, miR-199a-3p, and miR-30e-5p were significantly overrepresented in pathways related to fatty acid biosynthesis and fatty acid metabolism. This exploratory study demonstrated six miRs associated with coronary necrotic core, a marker of plaque vulnerability. In addition, changes in four miRs were associated with a regression of coronary plaque burden following exercise intervention. These novel findings may identify potential future biomarkers of CAD and coronary plaque composition.

IntroductionGiven that exercise training reduces the risk of developing Alzheimer’s disease (AD), induces changes in the blood composition and has widespread systemic benefits, it is reasonable to hypothesise that exercised plasma (ExPlas) may have rejuvenative properties. The main objective is to test safety and tolerability of transfusing ExPlas from young, healthy, fit adults to patients with mild cognitive impairment (MCI) or early AD. The study is a pilot for a future efficacy study. The key secondary objectives are examining the effect of plasma transfusions on cognitive function, fitness level, vascular risk profile, assessment of cerebral blood flow and hippocampal volume, quality of life, functional connectivity assessed by resting state functional MRI and biomarkers in blood and cerebrospinal fluid.Methods and analysisExPlas is a double-blinded, randomised controlled clinical single-centre trial. Patients up to 75 years of age with diagnosis early symptomatic phase AD will be recruited from two Norwegian hospitals. ExPlas is plasma drawn by plasmapheresis once a month for 4 months, from a total of 30 fit male donors (aged 18–40, BMI≤27 kg/m2 and maximal oxygen uptake>55 mL/kg/min). All units will be virus inactivated by the Intercept method in accordance with procedures at St. Olavs University Hospital. Comparison with isotonic saline allows differentiation from a non-blood product. The main study consists of 6 rounds of examinations in addition to 12 plasma transfusions divided over three 4-week periods during study year-1. It is also planned to conduct follow-up examinations 2 and 5 years after baselineEthics and disseminationWritten informed consent will be obtained from all participants and participation is voluntary. All participants have a next of kin who will follow them throughout the study to represent the patient’s interest. The study is approved by the Regional Committee for Medical and Health Research Ethics (REK 2018/702) and the Norwegian Medicines Agency (EudraCT No. 2018-000148-24). The study will be published in an open access journal and results will be presented at numerous national and international meetings as well as on social media platforms.Trial registration numberEudraCT No. 2018-000148-24. ClinicalTrials.gov, NCT05068830

Objective Investigate important clinical and operative variables associated with increases in cardiac troponin T (cTnT) as indicators of myocardial injury after coronary artery bypass grafting (CABG). Design Prospective cohort study. Setting Single university hospital. Participants The study comprised 626 patients undergoing isolated CABG from April 2008 through April 2010 with a validation cohort (n = 686) from 2015-2017. Interventions None. Measurements and Main Results Perioperative variables were registered prospectively. The extent of diffuse coronary atherosclerosis and significant stenoses were assessed with preoperative coronary angiography. Mixed model analysis was used to construct a statistical model explaining the course of cTnT concentrations. The model was adjusted for preoperative and intraoperative/postoperative myocardial infarction (MI) for independent assessment of additional variables. Clinical factors associated with increased cTnT concentrations during and after CABG were longer duration of cardiopulmonary bypass (p < 0.001), higher preoperative creatinine (p < 0.001), New York Heart Association functional classification IV (p = 0.006), reduced LVEF (p = 0.034), higher preoperative C-reactive protein (p = 0.049), and intraoperative/postoperative MI (p < 0.001). Factors associated with decreasing cTnT concentrations during CABG were higher BSA (p < 0.001) and a recent preoperative MI (p < 0.001). The extent of diffuse coronary atherosclerosis and significant stenoses were not associated with changes in cTnT (p = 0.35). Results were similar in the validation cohort. Conclusions Left ventricular ejection fraction, New York Heart Association classification, kidney function, inflammation status, duration of cardiopulmonary bypass, body surface area, and preoperative MI were associated with the cTnT rise-and-fall pattern related to myocardial injury after CABG. Information regarding these variables may be valuable when using cTnT in the diagnostic workup of postoperative MI. (C) 2019 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/)Journal of Cardiothoracic and Vascular Anesthesia 33 (2019) 3309 3319Contents lists available atScienceDirectJournal of Cardiothoracic and Vascular Anesthesiajournal homepage:www.jcvaonline.com

ObjectivesInvestigate if low cardiorespiratory fitness (CRF) was associated with and acted as a mediator of excess all-cause mortality rate in persons suffering from rheumatoid arthritis (RA) compared with the general population.MethodsAll-cause mortality was analysed using Cox regression modelling in patients with RA (n=348) and controls (n=60 938) who took part in the second (1995–1997) and third (2006–2008) waves of the longitudinal population-based Trøndelag Health Study in Norway. A mediation analysis was performed to investigate if excess relative risk of mortality in RA was mediated by low estimated CRF (eCRF).ResultsDuring the follow-up until 31 December 2018 (mean 19.3 years), the mortality rate among patients with RA (n=127, 36.5%) was higher than among controls (n=12 942, 21.2%) (pConclusionsLow eCRF was an important mediator of the increased all-cause mortality rate found in RA. Our data indicate that patients with RA should be given advice to perform physical activity that increases CRF, along with optimised treatment with antirheumatic drugs, from the time of diagnosis.

Aims: Whether an exercise training intervention is associated with reduction in long-term high-sensitivity cardiac troponin T (hs-cTnT) concentration (a biomarker of subclinical myocardial injury) in patients with heart failure with reduced ejection fraction (HFrEF) is unknown. The aims were to determine (i) the effect of a 12 week endurance exercise training intervention with different training intensities on hs-cTnT in stable patients with HFrEF (left ventricular ejection fraction ≤ 35%) and (ii) associations between hs-cTnT and peak oxygen uptake (VO2peak). Methods and results: In this sub-study of the SMARTEX-HF trial originally including 261 patients from nine European centres, 213 eligible patients were included after withdrawals and appropriate exclusions [19% women, mean age 61.2 years (standard deviation: 11.9)], randomized to high-intensity interval training (HIIT; n = 77), moderate continuous training (MCT; n = 63), or a recommendation of regular exercise (RRE; n = 73). Hs-cTnT measurements and clinical data acquired before (BL) and after a 12 week exercise training intervention (12 weeks) and at 1 year follow-up (1 year) were analysed using multivariable mixed models. Baseline hs-cTnT was above the 99th percentile upper reference limit of 14 ng/L in 35 (48%), 35 (56%), and 49 (64%) patients in the RRE, MCT, and HIIT groups, respectively. Median hs-cTnT was 16 ng/L at BL, 14 ng/L at 12 weeks, and 14 ng/L at 1 year. Hs-cTnT was statistically significantly reduced at 12 weeks in a model adjusted for randomization group, centre and VO2peak, and after further adjustment in the final model that also included age, sex, creatinine concentrations, N-terminal pro-brain natriuretic peptide, smoking, and heart failure treatment. The mean reduction from BL to 12 weeks in the final model was 1.1 ng/L (95% confidence interval: 1.0–1.2 ng/L, P 2peak correlated with lower hs-cTnT (mean reduction over all time points: 0.2 ng/L per increasing mL·kg−1·min−1, P = 0.002), without between-group differences (P = 0.19). Conclusions: In patients with stable HFrEF, a 12 week exercise intervention was associated with reduced hs-cTnT in all groups when adjusted for clinical variables. Higher VO2peak correlated with lower hs-cTnT, suggesting a positive long-term effect of increasing VO2peak on subclinical myocardial injury in HFrEF, independent of training programme.

OBJECTIVES Our goal was to study long-term observed and relative survival after first-time aortic valve replacement surgery with or without concomitant coronary artery bypass surgery with reference to valve morphology (i.e. bicuspid vs tricuspid). METHODS Consecutive patients (n = 5086) from 3 Swedish hospitals, operated on between 1 January 2005 and 31 December 2016, were included. The 30-day mortality (n = 116, 2.3%) was excluded from the analysis of long-term observed and relative survival (n = 4970). Observed survival was analysed using Cox regression. Relative survival was calculated as the ratio between observed and expected survival based on data from the general Swedish population, matched for age, sex and calendar year. Risk factors for death were explored using multivariable analysis. RESULTS During the follow-up (median 4.7 years) period, 1157 (23%) patients died. Observed survival excluding 30-day mortality was 96.6%, 82.7% and 57.6% after 1, 5 and 10 years. Compared with the general Swedish population, the relative 1-, 5- and 10-year survival rates were 99.0%, 97.5% and 89.0%. Bicuspid morphology was independently associated with higher observed and relative long-term survival. Renal dysfunction, diabetes, chronic obstructive pulmonary disease, heart failure, smoking and atrial fibrillation were associated with higher long-term mortality. Combined surgery was not associated with higher observed or relative mortality. CONCLUSIONS Patients with a bicuspid morphology had better prognosis, matching that of the general population. With increased age, long-term relative survival compared favourably with survival in the general Swedish population. Adding coronary artery bypass surgery to an aortic valve replacement procedure did not affect long-term outcome., Bicuspid aortic valve is the most common congenital heart condition and leads to premature valve failure in a significant number of patients [1].

Objectives. The normal aortic diameter (AD) varies with gender, age and body surface area (BSA). The aortic size index (ASI) is defined as the AD divided by BSA. The primary aim of this study was t...

Persons with rheumatoid arthritis (RA) have increased risk of myocardial infarction (MI). Overlapping associations with MI of weighted genetic risk scores (wGRS) for coronary artery disease (CAD) and RA is unknown in a population-based setting. Data from the prospective Nord-Trøndelag Health Study (HUNT2: 1995–1997 and HUNT3: 2006–2008) were used. wGRS added each participant’s carriage of all risk variants weighted by the coefficient from published association studies. Published wGRS for CAD and RA were analysed in Cox regression with MI as outcome, age as analysis time, and censoring at the first MI, death, or 31.12.2017. 2609 of 61,465 participants developed MI during follow-up (mean 17.7 years). The best-fitting wGRS for CAD and RA included 157 and 27 single-nucleotide polymorphisms, respectively. In multivariable analysis including traditional CAD risk factors, the CAD wGRS was associated with MI [hazard ratio = 1.23 (95% CI 1.18–1.27) for each SD increase, p

The purpose of the present study was to investigate the edge vascular response in patients treated with second-generation drug-eluting stents (DES) after 3 months of aerobic exercise intervention. Thirty-two patients with significant coronary artery disease underwent percutaneous coronary intervention with DES implantation prior to randomization to aerobic interval training (AIT, 14 patients) versus moderate continuous training (MCT, 18 patients). Plaque changes were assessed using grayscale and radiofrequency intravascular ultrasound at baseline and follow-up. The main endpoints were changes in plaque burden and necrotic core content in the 5-mm proximal and distal stent edges. Plaque burden in the distal stent edges decreased significantly in both groups (AIT: − 3.3%; MCT: − 0.4%, p = 0.01 for both), and more in the AIT group (p = 0.048). Necrotic core content decreased significantly in the distal stent edges in both groups (− 2.1 mm3 in AIT, − 0.3 mm3 in MCT, p = 0.01 for both), and more in the AIT group (p = 0.03). There were no significant changes in proximal stent edges or in in-stent geometry at follow-up. In this small study of patients treated with DES implantation, 3 months of aerobic exercise training demonstrated decreased plaque burden and necrotic core content in the distal stent edges, with larger reductions in the AIT group.

Circulating compounds such as drugs and nutritional components might adhere to the oxygenator fibers and tubing during ECMO support. This study evaluated the amount of nutritional supplements adsorbed to the ECMO circuit under controlled ex vivo conditions. Six identical ECMO circuits were primed with fresh human whole blood and maintained under physiological conditions at 36 °C for 24 h. A dose of nutritional supplement calculated for a 70 kg patient was added. 150 mL volume was drawn from the priming bag for control samples and kept under similar conditions. Blood samples were obtained at predetermined time points and analyzed for concentrations of vitamins, minerals, lipids, and proteins. Data were analyzed using mixed models with robust standard errors. No significant differences were found between the ECMO circuits and the controls for any of the measured variables: cobalamin, folate, vitamin A, glucose, minerals, HDL cholesterol, LDL cholesterol, total cholesterol, triglycerides or total proteins. There was an initial decrease and then an increase in the concentration of cobalamin and folate. Vitamin A concentrations decreased in both groups over time. There was a decrease in concentration of glucose and an increased concentration of lactate dehydrogenase over time in both groups. There were no significant alterations in the concentrations of nutritional supplements in an ex vivo ECMO circuit compared to control samples. The time span of this study was limited, thus, clinical studies over a longer period of time are needed. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Background Depression is associated with cardiovascular diseases, but the evidence is scarce regarding depression and risk of abdominal aortic aneurysms ( AAA ). The aim was to determine whether individuals with depressive symptoms have increased risk of AAA . Methods and Results This population‐based prospective study included 59 136 participants (52.4% women) aged 50 to 106 years from the HUNT (Norwegian Nord‐Trøndelag Health Study). Symptoms of depression were assessed using the depression subscale of the Hospital Anxiety and Depression Scale ( HADS ). During a median follow‐up of 13 years, there were 742 incident cases of AAA (201 women). A total of 6401 individuals (12.3%) reported depressive symptoms (defined as HADS depression scale [ HADS ‐D]) ≥8) (52.5% women). The annual incidence rate of AAA was 1.0 per 1000 individuals. At all ages, the estimated proportion of individuals diagnosed with AAA was higher among those with depressive symptoms (log‐rank test, P HADS ‐D ≥8 were older than those with HADS ‐DP P AAA than those without (hazard ratio, 1.32, 95% CI 1.08–1.61, P =0.007). Conclusions This study shows that individuals with depressive symptoms have significantly higher risk of incident AAA , after adjustments for established risk factors.

Objectives To evaluate selection methods among published single-nucleotide polymorphisms (SNPs) associated with RA to construct predictive genetic risk scores (GRSs) in a population-based setting. Methods The Nord-Trøndelag Health (HUNT) Study is a prospective cohort study among the whole adult population of northern Trøndelag, Norway. Participants in HUNT2 (1995–1997) and HUNT3 (2006–2008) were included (489 RA cases, 61 584 controls). The initial SNP selection from relevant genome-wide studies included 269 SNPs from 30 studies. Following different selection criteria, SNPs were weighted by published odds ratios. The sum of each person’s carriage of all weighted susceptibility variants was calculated for each GRS. Results The best-fitting risk score included 27 SNPs [weighted genetic risk score 27 (wGRS27)] and was identified using P-value selection criterion ≤5 × 10−8, the largest possible SNP selection without high linkage disequilibrium (r2 Conclusion Constructing a wGRS based on a smaller selection of informative SNPs improved predictive ability. Even with a relatively high AUC, the low PPV illustrates that there was a large overlap in risk variants among RA patients and controls, precluding clinical usefulness.

Background Patients with rheumatoid arthritis (RA) have higher mortality rates than the general population, primarily from cardiovascular disease (CVD). Diabetes is an acknowledged risk factor for early death, mainly due to CVD. The reported risk for CVD is increased for both patients with RA and diabetes, however the effect of diabetes appears to be greater than that of RA (1). Objectives To assess whether the increase in all-cause mortality rates in patients with RA and patients with diabetes are similar, compared to the general population. Methods Data were obtained from the 2nd and 3rd survey of the population-based Nord Trondelag Health Study (HUNT) and the Norwegian National Cause of Death Registry. The RA diagnoses have previously been validated (2). The definition of diabetes was self-reported diabetes, self-reported use of antidiabetica, or non-fasting blood glucose level >11.1 mmol/L. The participants were followed from their participation in HUNT to death or to 31.12.2014, whichever came first. Participants with other types of inflammatory arthritis or missing data for any of the variables in the model were excluded. Furthermore, the patients with both RA and diabetes were not included in the analysis (n=33). Participants with neither RA nor diabetes were defined as controls. RA patients, diabetes patients and controls were compared using Cox proportional hazard regression modelling, with age as the time scale. The model was adjusted for sex, smoking status, previous CVD, body mass index (BMI), hypertension, total cholesterol and creatinine. To obtain proportional hazards, an interaction term with age ≤75 years vs >75 years was included for diabetes, smoking and previous CVD. The effects of the groups were compared using overlap of confidence intervals. Results There were 123 (32%) deaths in the RA group, 1280 (44%) deaths in the diabetes groups and 11,641 (18%) deaths in the control group. The hazard ratio (HR) for RA was 1.24 (95% confidence interval: CI 1.02-1.46, p-value 0.013). The HR for diabetes was 1.82 (CI 1.60-2.05, p-value 75 years. RA patients had a significantly lower HR compared to diabetes patients for age ≤75 years, but not for age >75 years. Conclusion Patients with RA or diabetes had significantly higher mortality rates than controls, with larger HR for diabetes than for RA. The HR for RA was significantly lower than for diabetes for patients ≤75 years, but not for patients >75 years. This may be due to survival bias in diabetes patients >75 years. References 1 Curtis, J. R. et al., Is Rheumatoid Arthritis a Cardiovascular Risk-Equivalent to Diabetes Mellitus? Arthritis Care Res, 2018. 70(11): p.1694-1699 2 Videm, V, et al., Self-reported Diagnosis of Rheumatoid Arthritis or Ankylosing Spondylitis has Low Accuracy: Data from the Nord-Trondelag Health Study. J Reumatol, 2017. 44(8):p.1134-1141 Disclosure of Interests Ingrid Saether Houge: None declared, Mari Hoff: None declared, Ranjeny Thomas Grant/research support from: Janssen Biotec Inc, Merck and Co, Consultant for: Janssen Biotec Inc, Speakers bureau: Janssen, Merck, Vibeke Videm: None declared

Background RA patients are deconditioned and on average have decreased cardiorespiratory fitness (CRF, peak oxygen uptake) compared to the general population (1). This may contribute to an increased risk of cardiovascular disease (CVD). Because CRF is associated with cardiovascular health, it is important to assess. For the general population, various equations exist for estimation of CRF (eCRF) without the need of a resource-intensive cardiopulmonary exercise test. Objectives Compare eCRF of people without RA to eCRF of RA patients, using recognized equations for eCRF (2,3) based on gender, age, resting heart rate, waist circumference and self-reported physical activity. Methods Among participants with self-reported RA in the second and third surveys of the Norwegian population-based Nord-Trondelag Health Study (HUNT2 and 3)(4), RA patients were identified from hospital case files using standardized diagnostic criteria (5). The mean eCRF of participants with and without RA were calculated and the 95% confidence intervals (CI) compared. Conclusion The eCRF CIs of RA patients and participants without RA were overlapping in all age categories except for men aged 60-69 years in HUNT 3 (Table1). This is contradictory to previous findings where RA patients were deconditioned compared to healthy controls (1). A probable explanation is that equations for eCRF were developed from healthy populations, and therefore overestimate eCRF in RA patients. For better CVD risk management including CRF as an important risk factor, an equation for eCRF developed specifically for RA patients is needed. References [1] Munsterman T, et al. BMC Musculoskelet Disord. 2012;13:202. [2] Nes BM, et al. Med Sci Sports Exerc. 2014;46(6):1159-65. [3] Nauman J, et al. Mayo Clin Proc. 2017;92(2):218-27. [4] Krokstad S, et al. Int J Epidemiol. 2013;42(4):968-77. [5] Videm V, et al. J Rheumatol. 2017;44(8):1134-41 Disclosure of Interests None declared

Objective.The genetic component of ankylosing spondylitis (AS) development is ∼90%. Of the known heritability, ∼20% is explained by HLA-B27, and 113 identified AS-associated single-nucleotide polymorphisms (SNP) account for ∼7.4%. The objectives were to construct a weighted genetic risk score (wGRS) using currently known genome-wide susceptibility SNP, and to evaluate its predictive ability for AS in the Norwegian population-based Nord-Trøndelag Health Study (HUNT).Methods.AS cases (n = 164) and controls (n = 49,032) were from the second (1995–1997) and third (2006–2008) waves of the HUNT study, to which the entire adult population of the northern region of Trøndelag was invited. A wGRS based on 110 SNP weighted by published OR for AS was constructed, representing each person’s carriage of all risk variants. Logistic regression models including the wGRS alone or in combination with HLA-B27 carrier state and other adjustment variables (sex, age, smoking, body mass index, and hypertension) were developed. Discrimination among models was compared using area under the curve (AUC).Results.The wGRS was associated with AS (OR 1.7, 95% CI 1.4–2.1), but showed low discrimination (AUC 0.62, 95% CI 0.58–0.67). HLA-B27 was significantly associated with AS (OR 50, 95% CI 32–81), showing high discrimination (AUC 0.88, 95% CI 0.85–0.90). Combining the wGRS and HLA-B27 improved prediction (AUC 0.90, 95% CI 0.87–0.92; p < 0.001 vs wGRS alone, p < 0.01 vs HLA-B27 alone). Further inclusion of adjustment variables gave a small improvement (AUC 0.91, 95% CI 0.89–0.94; p = 0.03).Conclusion.Prediction in a population-based setting based on all currently known AS susceptibility SNP was better than HLA-B27 carrier state alone, although the improvement was small and of uncertain clinical value.

ObjectivePatients with rheumatoid arthritis (RA) suffer from more cardiovascular disease (CVD), and develop cardiovascular risk factors at an earlier age than the general population. Cardiorespiratory fitness (CRF) is an important predictor of cardiovascular health. There are few data regarding CRF of RA patients, measured as peak oxygen uptake (VO2peak) by the gold standard method; cardiopulmonary exercise testing. We compared CRF in RA patients to those from a healthy population, and investigated if risk factors for CVD and RA-specific variables including subjective and objective disease activity measures were associated with CRF in RA patients.MethodsVO2peak tests of RA patients (n=93) were compared to those of an age-matched and gender-matched healthy population (n=4631) from the Nord-Trøndelag Health Study. Predictors of VO2peak were found using Lasso (least absolute shrinkage and selection operator) regression, followed by standardised multiple linear regression.ResultsWomen with RA ≥40 years and men with RA aged 40–49 years or 60–69 years had up to 20% lower CRF than the healthy population in the same age groups. By relative importance, body mass index (standardised coefficient=−0.25, p2=0.82, gender-adjusted and age-adjusted).ConclusionCRF in RA patients was lower than in a healthy population. CRF was associated with common risk factors for CVD and the PGA score. Focusing on fitness in RA patients may improve cardiovascular health.

Purpose This study aimed to investigate baseline, exercise testing, and exercise training-mediated predictors of change in peak oxygen uptake (V˙O2peak) from baseline to 12-wk follow-up (ΔV˙O2peak) in a post hoc analysis from the SMARTEX Heart Failure trial. Methods We studied 215 patients with heart failure with left ventricular ejection fraction (LVEF) ≤35%, and New York Heart Association (NYHA) classes II-III who were randomized to either supervised high-intensity interval training with exercise target intensity of 90%-95% of peak heart rate (HRpeak) or supervised moderate continuous training (MCT) with target intensity of 60%-70% of HRpeak, or who received a recommendation of regular exercise on their own. Predictors of ΔV˙O2peak were assessed in two models: a logistic regression model comparing highest and lowest tertiles (baseline parameters) and a multivariate linear regression model (test/training/clinical parameters). Results The change in V˙O2peak in response to the interventions (ΔV˙O2peak) varied substantially, from -8.50 to +11.30 mL·kg·min. Baseline NYHA (class II gave higher odds vs III; odds ratio (OR), 7.1 (2.0-24.9); P = 0.002), LVEF (OR per percent, 1.1 (1.0-1.2); P = 0.005), and age (OR per 10 yr, 0.5 (0.3-0.8); P = 0.003) were associated with ΔV˙O2peak.In the multivariate linear regression, 34% of the variability in ΔV˙O2peak was explained by the increase in exercise training workload, ΔHRpeak between baseline and 12-wk posttesting, age, and ever having smoked. Conclusion Exercise training response (ΔV˙O2peak) correlated negatively with age, LVEF, and NYHA class. The ability to increase workload during the training period and increased ΔHRpeak between baseline and the 12-wk test were associated with a positive outcome.

C-reactive protein, neopterin and lactoferrin are biomarkers of atherosclerotic disease. We aimed to assess changes in these biomarkers after conservative and surgical weight loss interventions in individuals with morbid obesity, to evaluate associations between biomarker changes and changes in body mass index and HbA1c, and to study associations between changes in the biomarkers. C-reactive protein, neopterin and lactoferrin were measured before and after conservative weight loss intervention and bariatric surgery. Data were analysed with mixed models. 137 individuals (mean age 43 years) were included. Body mass index decreased from 42.1kg/m2 to 38.9kg/m2 after the conservative intervention, and further to 30.5kg/m2 after bariatric surgery. All biomarkers decreased after the conservative weight loss intervention. C-reactive protein and lactoferrin continued to decrease following bariatric surgery whereas neopterin remained stable. After adjustments for change in body mass index and HbA1c, all biomarkers decreased signifcantly after the conservative weight loss intervention, whereas none changed after bariatric surgery. There were no consistent correlations between changes in C-reactive protein, neopterin and lactoferrin. In conclusion, biomarkers of atherosclerosis decreased after weight loss interventions but had diferent trajectories. Neopterin, a marker related to atherosclerotic plaque stability, decreased after conservative weight loss but not following bariatric surgery. © The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/)

Objective The delayed development of abdominal aortic aneurysm (AAA) in women compared with men might be secondary to a protective effect from endogenous estrogens. The role of postmenopausal hormone therapy remains unclear. The aim of the present study was to evaluate the effect of female sex hormones compared with other risk factors associated with AAA through a long-term study of a large female cohort. Methods The present prospective cohort study included 20,024 postmenopausal women from the Norwegian Nord-Trondelag Health Study. A total of 201 cases of AAA were identified during a median follow-up period of 18 years (295,554 person-years; 1995-2014). The data were recorded from questionnaires, physical measurements, medical records, blood sample test results, and the Norwegian Cause of Death Registry. The effect of risk factors was evaluated in a multiple Cox regression analysis. Multiple imputation was performed for missing data (n = 50 data sets). The serum estradiol concentrations in women with and without incidental AAAs were compared. The median interval from blood sample collection to the AAA diagnosis was 7 years. Results Current smokers had >10-fold increased risk of incident AAA during the follow-up period (hazard ratio [HR], 10.9; 95% confidence interval [CI], 7.4-16.1). Positive associations were found for hypertension (HR, 2.0; 95% CI, 1.4-3.0) and coronary heart disease (HR, 2.2; 95% CI, 1.6-3.2). The HR associated with the current use of postmenopausal hormone therapy was 0.58 (95% CI, 0.6-1.5). No substantial difference in estradiol concentrations was found between women with and without AAA (P = .075). Conclusions The effect of female sex hormones on the risk of incident AAAs in women, as evaluated by the serum concentrations of estradiol and the use of postmenopausal hormone therapy, is clinically less important than the strong associations found with smoking, hypertension, and coronary heart disease.

Objective To investigate whether C-reactive protein (CRP, a general marker of inflammation), neopterin (activated macrophages), lactoferrin (activated neutrophils), and endothelial function (flow-mediated vasodilation [FMD]) are associated with cardiorespiratory fitness (peak oxygen uptake [VO2peak]), sex, body mass index (BMI), and the metabolic syndrome (MetSyn) in a healthy adult population. Patients and Methods This was a cross-sectional association study based on the population-based HUNT3 Fitness Study performed from May 15, 2007, through June 23, 2008. Seven hundred forty self-reported healthy respondents (327 women) identified as having the MetSyn were age- and sex-matched with 692 controls (307 women) from the same cohort. Associations between the inflammatory biomarkers and VO2peak, FMD, and the MetSyn were analyzed by multivariate linear regression. Results The CRP level was negatively associated with VO2peak (P Conclusion The CRP level was strongly associated with VO2peak and the MetSyn, but not with FMD. The associations among inflammation, VO2peak, and the MetSyn were strongly influenced by sex and BMI. These data support that low cardiorespiratory fitness should be considered an etiologic factor contributing to systemic inflammation and that reducing body weight and improving VO2peak are methods that may positively affect CRP levels.

Background Mortality rates are higher in RA patients compared to the general population, mostly due to cardiovascular disease (CVD). Cardiorespiratory fitness (CRF) is inversely associated with CVD, but little is known about CRF levels in RA patients. Objectives To study the association between CRF in RA patients (measured as VO2peak), and CVD risk factors and RA-specific clinical variables. Methods 93 patients were recruited from a hospital rheumatology outpatient clinic. VO2peak was measured by ergospirometry during a treadmill test. Tender and swollen joint count, height, weight, waist circumference, resting heart rate, blood pressure and hsCRP were measured. RA characteristics and information on comorbidity were recorded from an interview and from medical records. Based on a previously published index weighting frequency, intensity and duration of self-reported physical activity (PA) (1), patients were categorized into four different PA categories (table 1). VO2peak was analyzed using multivariate linear regression, adjusting for age and gender. All participants signed an informed consent and the regional ethics committee approved the study. Results Conclusions We observed a strong association between common CVD risk factors (inactivity, high BMI, high resting heart rate) and lower CRF in RA patients, similar to published findings from the general population. Patients in the “Active” and “Very active” PA categories showed significantly higher VO2peak, whereas RA-specific variables such as seropositivity, disease activity, disease duration and medications had no impact on VO2peak. We cannot exclude a selection bias because more fit patients could be more likely to participate in the study. Reference [1]Nes BM, Janszky I, Vatten LJ, Nilsen TI, Aspenes ST, Wisloff U. Estimating VO2peak from a nonexercise prediction model: the HUNT Study, Norway. Med Sci Sports Exerc2011;43(11):2024–30. Acknowledgements: The VO2peak testing was performed at the core facility NeXt Move, NTNU – Norwegian University of Science and Technology. Disclosure of Interest: None declared

Background The genetic component of AS development is estimated to ~90%. About 20% of the known heritability for AS is attributed to HLA-B27 and about 7.4% to 113 SNPs found in genome-wide association studies,1 with a further ~60% of heritability determined by as yet unmapped variants. Objectives To evaluate whether a weighted genetic risk score (wGRS) developed based on the currently identified SNPs is predictive of AS in the Norwegian population-based Nord-Trondelag Health Study (HUNT). Methods HUNT invited the entire adult population of Nord-Trondelag county. We used data from HUNT2 (1995–97) and HUNT3 (2006–8). AS cases were diagnosed from hospital records using the Modified New York Criteria. Participants with other inflammatory arthritis were excluded, leaving 181 AS cases and 55 586 controls. Genotyping was performed with Illumina HumanCoreExome arrays. Imputation was performed with Minimac3 based on European ancestry data. Imputed or genotyped data were available for 110 (97%) of the 113 SNPs. We used rs4349859 to indicate HLA-B27 carrier state (positive/negative). The wGRS was calculated by addition of risk alleles and weighting by the published OR from,1 representing each person’s carriage of all risk variants. Data were analysed using logistic regression. Four models were compared using AUC analysis: 1) the wGRS only; 2) HLA-B27 only; 3) the wGRS and HLA-B27; 3) the wGRS, HLA-B27, age, gender, BMI, hypertension, and smoking (never/previous/present). HUNT had ethical approval and participants gave informed consent. Results At baseline, mean age for cases was 43 years, 61% were men and 87% were HLA-B27 positive. The corresponding figures for controls were 46 years, 47% men and 12.7% HLA-B27 positive. The mean wGRS was 14.37 (range: 10.93 to 17.41). The wGRS alone was associated with AS (OR=1.7 for one unit increase, p Conclusions The wGSR was associated with AS, but had low predictive ability in a population-based setting. HLA-B27 was a much better predictor. Addition of clinical variables only slightly improved prediction, in accordance with the high genetic component in AS pathophysiology. Discovery and inclusion of more genetic risk variants, epigenetic factors, other demographic factors, and interaction terms, in addition to more efficient statistical approaches such as genome-wide risk score development, could improve prediction. Study limitations are false positive- or –negative AS diagnoses and potential selection bias of participants in HUNT. Reference [1] Ellinghaus D, et al. Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci. Nature Genetics2016;48(5):510–18. Disclosure of Interest None declared

Background: Observational studies have shown consistent associations between higher circulating 25-hydroxyvitamin D [25(OH)D] levels and favorable serum lipids. We sought to investigate if such associations were causal. Methods: A Mendelian randomization (MR) study was conducted on a population-based cohort comprising 56435 adults in Norway. A weighted 25(OH)D allele score was generated based on vitamin D-increasing alleles of rs2282679, rs12785878 and rs10741657. Linear regression analyses of serum lipid levels on the allele score were performed to assess the presence of causal associations of serum 25(OH)D with the lipids. To quantify the causal effects, the inverse-variance weighted method was used for calculating MR estimates based on summarized data of individual single-nucleotide polymorphisms. The MR estimate with 95% confidence interval (CI) represents percentage difference in the lipid level per genetically determined 25 nmol/L increase in 25(OH)D. Results: The 25(OH)D allele score demonstrated a clear association with high-density lipoprotein (HDL) cholesterol (p=0.007) but no association with total or non-HDL cholesterol or triglycerides (p ≥0.27). The MR estimate showed 2.52% (95% CI 0.79 to 4.25%) increase in HDL cholesterol per genetically determined 25 nmol/L increase in 25(OH)D, which was stronger than the corresponding estimate of 1.83% (95% CI 0.85 to 2.81%) from the observational analysis. The MR estimates for total cholesterol (0.60%, 95% CI -0.73 to 1.94%), non-HDL cholesterol (0.04%, 95% CI -1.79 to 1.88%) and triglycerides (-2.74%, 95% CI -6.16 to 0.67%) showed no associations. Conclusions: MR analysis of data from a population-based cohort suggested a causal and positive association between serum 25(OH)D and HDL cholesterol. Potential causal associations of serum 25-hydroxyvitamin D with lipids: a Mendelian randomization approach of the HUNT study This is a post-peer-review, pre-copyedit version of an article published in [European Journal of Epidemiology (EJE)]. The final authenticated version is available online at: https://doi.org/10.1007/s10654-018-0465-x

BackgroundWhile efficacy of combination treatment with methotrexate (MTX), sulfasalazine (SSZ) and hydroxychloroquine (HCQ) (triple therapy') has been shown in clinical trials, few studies have examined its longevity in a real-life setting.

Background Severe post-operative bleeding in cardiac surgery is associated with increased morbidity and mortality. We hypothesized that variation in genetic susceptibility contributes to post-operative bleeding in addition to clinical factors. Methods We included 1036 adults undergoing cardiac surgery with cardiopulmonary bypass. Two different endpoints for excessive post-operative bleeding were used, either defined as blood loss exceeding 2 ml/kg/h the first 4 h post-operatively or a composite including bleeding, transfusions, and reoperations. Twenty-two single nucleotide polymorphisms (SNPs) central in the coagulation and fibrinolysis systems or in platelet membrane receptors were genotyped, focusing on replication of earlier non-replicated findings and exploration of potential novel associations. Using logistic regression, significant SNPs were added to a model with only clinical variables to evaluate whether the genetic variables provided additional information. Results Univariate tests identified rs1799809 (located in the promoter region of the PROC gene), rs27646 and rs1062535 (in the ITGA2 gene), rs630014 (in the ABO gene), and rs6048 (in the F9 gene) as significantly associated with excessive post-operative bleeding (P