Filaggrin Mutation Status and Prevention of Atopic Dermatitis with Maternal Probiotic Supplementation.

The World Allergy Organization recommends probiotics in the prevention of atopic dermatitis in high-risk populations. Mutations in the filaggrin gene (FLG) result in an increased risk of atopic dermatitis through disruption of the skin keratin layer. This exploratory study investigated whether the preventive effect of maternal probiotics was evident in children with and without FLG mutations. DNA was collected from children (n = 228) from the Probiotic in the Prevention of Allergy among Children in Trondheim (ProPACT) study. Samples were analysed for 3 common FLG mutations (R501X, R2447X, and 2282del4). Overall, 7% of children had heterozygous FLG mutations; each child had only one of the 3 mutations. Mutation status had no association with atopic dermatitis (RR = 1.1; 95% CI 0.5 to 2.3). The risk ratio (RR) for having atopic dermatitis following maternal probiotics was 0.6 (95% CI 0.4 to 0.9) and RR was similar if the child expressed an FLG mutation (RR = 0.6; 95% CI 0.1 to 4.1) or wildtype FLG (RR = 0.6; 95% CI 0.4 to 0.9). The preventive  effect of probiotics for atopic dermatitis was also evident in children without FLG mutation. Larger confirmatory studies are needed.

Rheumatoid arthritis, disease-modifying antirheumatic drugs and risk of major osteoporotic fracture: prospective data from the HUNT Study, Norway.

OBJECTIVES: Rheumatoid arthritis has been associated with increased fracture risk. New treatments have improved the course of the disease substantially, but it is not clear if this influences fracture risk. We examined if rheumatoid arthritis, overall and according to disease-modifying antirheumatic drugs (DMARDs), is associated with a risk of major osteoporotic fractures. METHODS: Overall, 92 285 participants in the population-based Nord-Trndelag Health Study (HUNT), Norway were included and linked with hospital records for a validated rheumatoid arthritis diagnosis (n=605), type of DMARD treatment and fracture diagnosis. Participants were followed up until the first major osteoporotic fracture, death, emigration or end of follow-up. Cox regression was used to estimate HRs for fractures among individuals with rheumatoid arthritis, overall and by DMARD treatment, compared with participants without rheumatoid arthritis. RESULTS: A total of 9670 fractures were observed during follow-up, of which 88 were among those with rheumatoid arthritis. Compared with the reference group of participants without rheumatoid arthritis, those with the disease had an HR of fracture of 1.41 (95% CI 1.13 to 1.74). The association was largely similar for users of csDMARDs (HR 1.44; 95% CI 1.15 to 1.81), whereas the association for bDMARD users was weaker and less precise (HR 1.19; 95% CI 0.64 to 2.21). CONCLUSION: Participants with rheumatoid arthritis had a 40% higher risk of fracture than participants without the disease. A similar fracture risk was observed for conventional synthetic DMARD use, whereas there was weak evidence that the use of biological DMARDs may be associated with a somewhat lower fracture risk.

Exercise training and high-sensitivity cardiac troponin-I in patients with heart failure with reduced ejection fraction.

AIMS: The aims of this sub-study of the SMARTEX trial were (1) to evaluate the effects of a 12-week exercise training programme on serum levels of high sensitivity cardiac troponin I (hs-cTnI) in patients with moderate chronic heart failure (CHF), in New York Heart Association class II-III with reduced ejection fraction (HFrEF) and (2) to explore the associations with left ventricular remodelling, functional capacity and filling pressures measured with N-terminal pro brain natriuretic peptide (NT-proBNP). METHODS AND RESULTS: In this sub-study, 196 patients were randomly assigned to high intensity interval training (HIIT, n = 70), moderate continuous training (MCT, n = 59) or recommendation of regular exercise (RRE), (n = 67) for 12 weeks. To reveal potential difference between structured intervention and control, HIIT and MCT groups were merged and named supervised exercise training (SET) group. The RRE group constituted the control group (CG). To avoid contributing factors to myocardial injury, we also evaluated changes in patients without additional co-morbidities (atrial fibrillation, hypertension, diabetes mellitus, and chronic obstructive pulmonary disease). The relationship between hs-cTnI and left ventricular end-diastolic diameter (LVEDD), VO2peak, and NT-proBNP was analysed by linear mixed models. At 12 weeks, Hs-cTnI levels were modestly but significantly reduced in the SET group from median 11.9 ng/L (interquartile ratio, IQR 7.1-21.8) to 11.5 ng/L (IQR 7.0-20.7), P = 0.030. There was no between-group difference (SET vs. CG, P = 0.116). There was a numerical but not significant reduction in hs-cTnI for the whole population (P = 0.067) after 12 weeks. For the sub-group of patients without additional co-morbidities, there was a significant between-group difference: SET group (delta -1.2 ng/L, IQR -2.7 to 0.1) versus CG (delta -0.1 ng/L, IQR -0.4 to 0.7), P = 0.007. In the SET group, hs-cTnI changed from 10.9 ng/L (IQR 6.0-22.7) to 9.2 ng/L (IQR 5.2-20.5) (P = 0.002), whereas there was no change in the CG (6.4 to 5.8 ng/L, P = 0.64). Changes in hs-cTnI (all patients) were significantly associated with changes in; LVEDD, VO2peak, and NT-proBNP, respectively. CONCLUSIONS: In patients with stable HFrEF, 12 weeks of structured exercise intervention was associated with a modest, but significant reduction of hs-cTnI. There was no significant difference between intervention group and control group. In the sub-group of patients without additional co-morbidities, this difference was highly significant. The alterations in hs-cTnI were associated with reduction of LVEDD and natriuretic peptide concentrations as well as improved functional capacity.

Identification of a regulatory pathway governing TRAF1 via an arthritis-associated non-coding variant.

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 patients with juvenile idiopathic arthritis (JIA) and 14,412 control individuals, we identified 132 plausible common non-coding variants, reduced serially by single-nucleotide polymorphism sequencing (SNP-seq), electrophoretic mobility shift, and luciferase studies to the single variant rs7034653 in the third intron of TRAF1. Genetically manipulated experimental cells and primary monocytes from genotyped donors establish that the risk G allele reduces binding of Fos-related antigen 2 (FRA2), encoded by FOSL2, resulting in reduced TRAF1 expression and enhanced tumor necrosis factor (TNF) production. Conditioning on this JIA variant eliminated 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 functional variant drives risk of inflammatory arthritis in children and adults.

Relative importance of inflammation and cardiorespiratory fitness for all-cause mortality risk in persons with rheumatoid arthritis: the population-based Trøndelag Health Study.

OBJECTIVE: Inflammation and reduced cardiorespiratory fitness (CRF) are associated with increased mortality rates in rheumatoid arthritis (RA). We aimed at directly comparing the relative importance of inflammation and reduced CRF as mediators of all-cause mortality in persons with RA compared with controls, quantifying direct and indirect (mediated) effects. METHODS: Persons with (n=223, cases) and without (n=31 684, controls) RA from the third survey of the Trøndelag Health Study (HUNT3, 2006-2008) were included. Inflammation was quantified using C reactive protein (CRP) and estimated CRF (eCRF) was calculated using published formulae. All-cause mortality was found by linkage to the Norwegian Cause of Death Registry, with follow-up from inclusion in HUNT3 until death or 31 December 2018. Data were analysed using standardised equation modelling, permitting complex correlations among variables. RESULTS: Persons with RA had increased all-cause mortality rates (24.1% vs 9.9%, p<0.001). Both eCRF (p<0.001) and CRP ≥3 mg/L (p<0.001) were mediators of this excess mortality, rendering the direct effect of RA non-significant (p=0.19). The indirect effect of RA mediated by eCRF (standardised coefficient 0.006) was approximately three times higher than the indirect effect mediated by CRP (standardised coefficient 0.002) in a model adjusted for other mortality risk factors. CONCLUSION: Even with CRP concentrations <3 mg/L in all patients with RA, excess mortality mediated by low CRF would still play an important role. Improved inflammation control in RA does not necessarily lead to better CRF. Therefore, our study strongly supports recommendations for development and implementation of exercise programmes aimed at improving CRF in persons with RA.

Systemic inflammatory proteins in offspring following maternal probiotic supplementation for atopic dermatitis prevention.

BACKGROUND: Maternal probiotic supplementation has a promising effect on atopic dermatitis (AD) prevention in infancy. In the randomised controlled study, Probiotics in the Prevention of Allergy among Children in Trondheim (ProPACT), maternal probiotics reduced the cumulative incidence of AD in their offspring by 40% at 2 years of age. However, our understanding on how probiotics prevented AD is still limited, and the role of inflammatory proteins in infants following maternal probiotic supplementation is unclear. We hypothesised that maternal probiotics lowered pro-inflammatory proteins and increased anti-inflammatory proteins in their 2-year-old children as a mechanism of AD prevention. We aimed to explore this hypothesis and the association between these proteins and the presence of AD, severity of AD, and the degree of preventive effect of probiotics. METHODS: Plasma samples were collected from 2-year-old children (n = 202) during the ProPACT study, a randomised placebo-controlled trial of maternal probiotic supplementation. These samples were analysed for 92 inflammatory proteins using a multiplex proximity extension assay. Associations between inflammatory proteins and the presence and severity of AD, and the degree of preventive effect, was estimated individually using regression analysis and then collectively using unsupervised cluster analysis. RESULTS: Several proteins were observed to differ between the groups. The probiotic group had lower CCL11 and IL-17C, while children with AD had higher IL-17C, MCP-4, uPA, and CD6. Cytokine CCL20 and IL-18 had moderate correlation (r = 0.35 and r = 0.46) with the severity of AD. The cluster analysis revealed that children in the cluster of samples with the highest value of immune checkpoint receptors and inflammatory suppressor enzymes showed the greatest AD preventive effect from probiotics. CONCLUSIONS: The proteins associated with both maternal probiotic supplementation and the presence and severity of AD warrant attention because of their potential biological relevance. Cluster analysis may provide a new insight when considering which subgroups benefit from probiotic supplementation. Larger studies are needed to confirm the results. TRIAL REGISTRATION NUMBER: The study was retrospectively registered at ClinicalTrials.gov (NCT00159523) on 12nd September 2005.

High physical activity in persons with psoriatic arthritis is associated with reduced visceral fat mass and percentage body fat: the Trøndelag Health study.

The associations of physical activity (PA) with body composition among persons with psoriatic arthritis (PsA) are not well described. The objective was to investigate associations of PA with visceral fat mass and percentage body fat in persons with PsA of different age groups. Persons with PsA (CASPAR criteria, n = 356), and controls (n = 47,470) from the Trøndelag Health Study (HUNT4, 2017-2019) were included. Visceral fat mass and percentage body fat measured using bioelectrical impedance were primary outcomes in multivariable linear regression analysis. PsA, PA (questionnaire data), and age were explanatory variables, with adjustment for sex, smoking, heart disease, lung disease, and height. An interaction term between PsA and age was included in both models. Persons with PsA had altered body composition, including higher visceral fat mass and percentage body fat, especially those < 40 years of age (p ≤ 0.01). Moderate or high PA was associated with significantly lower values of the primary outcomes. Differences were Moderate compared to low PA: 1.4 kg (95% CI 1.3, 1.5 kg) lower visceral fat mass, and 2.0% (95% CI 1.8, 2.1) lower percentage body fat. Differences were High compared to low PA: 3.2 kg (95% CI 3.1, 3.3) lower visceral fat mass and 5.0% (95% CI 4.8, 5.1%) lower percentage body fat. Persons with PsA had higher visceral fat mass and percentage body fat, especially if < 40 years, and PA was associated with lower values of both endpoints. Changes of body composition in persons with PsA may influence important health outcomes and should be addressed in clinical practice.

Calprotectin and CRP as biomarkers of cardiovascular disease risk in patients with chronic kidney disease: a follow-up study at 5 and 10 years.

Chronic kidney disease (CKD) and low-grade inflammation are associated with increased risk of cardiovascular disease (CVD). Calprotectin, a protein mainly secreted by activated neutrophils during inflammatory conditions, has been linked to CVD risk in general populations. The aim of this study was to evaluate the association of calprotectin with CVD risk in CKD patients, relative to C-reactive protein (CRP). One hundred and fifty-three patients with moderate CKD were prospectively followed up at 5 and 10 years. We used Cox regression modelling with stepwise adjustments for other relevant covariates (age, sex, cystatin C, previous CVD, systolic blood pressure, HDL cholesterol and HbA1c) to assess the association of baseline calprotectin and CRP with the risk of fatal or non-fatal CVD events. Twenty-nine and 44 patients experienced a CVD event during median follow-up of 4.8 and 10.9 years, respectively. Higher calprotectin was associated with increased CVD risk at both time points, which remained statistically significant after multivariable adjustments, including adjustment for CRP. For CRP, the associations did not remain statistically significant after final multivariable adjustments. In conclusion, we have shown that in patients with CKD, calprotectin was independently associated with the risk of future CVD events, suggesting that calprotectin may provide prognostic information of CVD risk.

The association between rheumatoid arthritis and reduced estimated cardiorespiratory fitness is mediated by physical symptoms and negative emotions: a cross-sectional study.

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.

Validation in Indonesia of two published scores for mortality prediction after cardiac surgery.

Introduction: No mortality risk prediction model has previously been validated for cardiac surgery in Indonesia. This study aimed at validating the EuroSCORE II and Age Creatinine Ejection Fraction (ACEF) score as predictors for in-hospital mortality after cardiac surgery a in tertiary center, and if necessary, to recalibrate the EuroSCORE II model to our population. Methods: This study was a single-center observational study from prospectively collected data on adult patients undergoing cardiac surgery from January 2006 to December 2011 (n = 1833). EuroSCORE II and ACEF scores were calculated for all patients to predict in-hospital mortality. Discrimination was assessed using the area under the curve (AUC) with a 95% confidence interval. Calibration was assessed with the Hosmer-Lemeshow test (HL test). Multivariable analysis was performed to recalibrate the EuroSCORE II; variables with P < 0.2 entered the final model. Results: The in-hospital mortality rate was 3.8%, which was underestimated by the EuroSCORE II (2.1%) and the ACEF score (2.4%). EuroSCORE II (AUC 0.774 (0.714-0.834)) showed good discrimination, whereas the ACEF score (AUC 0.638 [0.561-0.718]) showed poor discrimination. The differences in AUC were significant (P = 0.002). Both scores were poorly calibrated (EuroSCORE II: HL test P < 0.001, ACEF score: HL test P < 0.001) and underestimated mortality in all risk groups. After recalibration, EuroSCORE II showed good discrimination (AUC 0.776 [0.714- 0.840]) and calibration (HL test P = 0.79). Conclusions: EuroSCORE II and the ACEF score were unsuitable for risk prediction of in-hospital mortality after cardiac surgery in our center. Following recalibration, the calibration of the EuroSCORE II was greatly improved.

Persons with rheumatoid arthritis have higher barriers to physical activity than controls: a cross-sectional study using the Facilitators and Barriers to Physical Activity Questionnaire (FasBarPAQ).

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 < 0.001) and lower Total Facilitators-Barriers scores (coefficient = - 3.67, p < 0.001). HADS-D ≥ 8 was associated with lower Total scores (coefficient = - 3.32, p = 0.022), and the two higher stress score tertiles were associated with higher Barriers and lower Total scores (p = 0.023 to p < 0.001). Persons with RA reported greatly varying facilitators and barriers profiles. Seropositivity and higher patient global assessment were associated with higher Barriers scores (coefficients = 1.79, p = 0.011; 0.60, p < 0.001) and lower Total scores (coefficients = - 3.60, p = 0.003; - 0.98, p < 0.001). Persons with RA had higher barriers and lower facilitators for PA, with varying individual profiles. The new FasBarPAQ questionnaire may be a useful screening tool for healthcare providers treating persons with RA.

Safety and efficacy of plasma transfusion from exercise-trained donors in patients with early Alzheimer's disease: protocol for the ExPlas study.

INTRODUCTION: Given 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 ANALYSIS: ExPlas 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 baseline ETHICS AND DISSEMINATION: Written 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 NUMBER: EudraCT No. 2018-000148-24. CLINICALTRIALS: gov, NCT05068830.

Inflammation mediates approximately one quarter of excess relative all-cause mortality in persons with rheumatoid arthritis: the Trøndelag Health Study.

Inflammation may contribute to excess mortality in rheumatoid arthritis (RA) patients. We investigated associations to all-cause mortality of the inflammation markers high-sensitivity C-reactive protein (CRP), lactoferrin (neutrophil activation marker), and neopterin (monocyte activation marker). From the population-based Trøndelag Health Study (3rd wave 2006-2008), 316 RA patients and 43,579 controls were included. Lactoferrin and neopterin were quantified in a nested cohort (n = 283 RA patients, n = 3698 controls). Follow-up was until death found by linkage to the Norwegian Cause of Death Registry or 31.12.2018. All-cause mortality was analyzed using Cox regression and Cox regression-based mediation analysis. Having RA (hazard ratio (HR): 1.25, 95%CI: 1.00, 1.56, p = 0.048), and CRP ≥ 3 mg/L (HR: 1.50, 95%CI: 1.41, 1.60, p < 0.001) were associated with all-cause mortality. The overall excess relative mortality risk of having RA was 38%. CRP ≥ 3 mg/L mediated approximately 1/4 of this risk (p < 0.001). In the nested cohort, CRP ≥ 3 mg/L (HR: 1.51, 95%CI: 1.26, 1.80, p < 0.001) and neopterin (HR: 1.17, 95%CI: 1.01, 1.36, p = 0.031) were associated with all-cause mortality. In conclusion, CRP levels ≥ 3 mg/L mediated approximately a quarter of the 38% excess relative all-cause mortality risk associated with RA. Using definitions of RA remission with emphasis both on joint status and the level of general inflammation may help guide the most efficient treatment regimens.

Exercise Self-Efficacy and patient global assessment were associated with 6-min walk test distance in persons with rheumatoid arthritis.

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.

Associations between circulating microRNAs and coronary plaque characteristics: potential impact from physical exercise.

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.

Use of the Behavioral Regulation in Exercise Questionnaire-2 to assess motivation for physical activity in persons with rheumatoid arthritis: an observational study.

Arthritis patients may show little motivation for physical activity (PA), resulting in a sedentary lifestyle. The primary objective of the study was to investigate whether motivation for PA and fulfillment of PA recommendations were associated with cardiorespiratory fitness in patients with RA. The exploratory objective was to study whether university students could be used as controls for RA patients in future studies of PA motivation. Peak oxygen uptake (VO2peak) was measured in 93 RA patients. The patients and 354 students filled in the Behavioral Regulation in Exercise Questionnaire-2 (BREQ-2). Data were analyzed using structural equation modeling with adjustment for age and sex. The BREQ-2 scores were also compiled to an overall motivational style "Relative Autonomy Index" as previously published. Mean VO2peak for the RA patients was 32.2 (SD: 9.6) mL × min-1 × kg-1. Only 29 patients (31%) fulfilled the current recommendations for PA. BREQ-2 scores were associated with measured VO2peak (standardized coefficient 0.33, p < 0.001). Whether a person fulfilled the current recommendations for PA was a significant mediator of this effect (standardized coefficients: mediated effect; 0.22, p = 0.001, remaining direct effect; 0.11, p = 0.18). The Relative Autonomy Index also significantly predicted measured VO2peak (standardized coefficient 0.30, p < 0.001). The underlying BREQ-2 factor structure was significantly different between RA patients and university students, and comparison of scores would not be adequate. Motivation for PA was significantly associated with measured VO2peak in RA patients. The effect was mediated by whether the patient fulfilled the current recommendations for PA. Addressing and stimulating motivation is important when intervening to increase PA and cardiovascular fitness in RA patients.

Moderate continuous or high intensity interval exercise in heart failure with reduced ejection fraction: Differences between ischemic and non-ischemic etiology.

Background: Exercise for heart failure (HF) with reduced ejection fraction (HFrEF) is recommended by guidelines, but exercise mode and intensities are not differentiated between HF etiologies. We, therefore, investigated the effect of moderate or high intensity exercise on left ventricular end-diastolic diameter (LVEDD), left ventricular ejection fraction (LVEF) and maximal exercise capacity (peak VO2) in patients with ischemic cardiomyopathy (ICM) and non-ischemic cardiomyopathy (NICM). Methods: The Study of Myocardial Recovery after Exercise Training in Heart Failure (SMARTEX-HF) consecutively enrolled 231 patients with HFrEF (LVEF ≤ 35 %, NYHA II-III) in a 12-weeks supervised exercise program. Patients were stratified for HFrEF etiology (ICM versus NICM) and randomly assigned (1:1:1) to supervised exercise thrice weekly: a) moderate continuous training (MCT) at 60-70 % of peak heart rate (HR), b) high intensity interval training (HIIIT) at 90-95 % peak HR, or c) recommendation of regular exercise (RRE) according to guidelines. LVEDD, LVEF and peak VO2 were assessed at baseline, after 12 and 52 weeks. Results: 215 patients completed the intervention. ICM (59 %; n = 126) compared to NICM patients (41 %; n = 89) had significantly lower peak VO2 values at baseline and after 12 weeks (difference in peak VO2 2.2 mL/(kg*min); p < 0.0005) without differences between time points (p = 0.11) or training groups (p = 0.15). Etiology did not influence changes of LVEDD or LVEF (p = 0.30; p = 0.12), even when adjusting for sex, age and smoking status (p = 0.54; p = 0.12). Similar findings were observed after 52 weeks. Conclusions: Etiology of HFrEF did not influence the effects of moderate or high intensity exercise on cardiac dimensions, systolic function or exercise capacity. Clinical Trial Registration­URL: http://www.clinicaltrials.gov. Unique identifier: NCT00917046.

Inflammatory markers and risk of cardiovascular mortality in relation to diabetes status in the HUNT study.

Inflammatory markers have been associated with increased risk of cardiovascular mortality in general populations. We assessed whether these associations differ by diabetes status. From a population-based cohort study (n = 62,237) we included all participants with diabetes (n = 1753) and a control group without diabetes (n = 1818). Cox regression models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CI) for possible associations with cardiovascular mortality of 4 different inflammatory markers; C-reactive protein (CRP), calprotectin, neopterin and lactoferrin. During a median follow-up of 13.9 years, 728 (20.4%) died from cardiovascular disease (CVD). After adjustment for age, sex and diabetes, the associations of all inflammatory markers with risk of cardiovascular mortality were log-linear (all P ≤ 0.017 for trend) and did not differ according to diabetes status (all P ≥ 0.53 for interaction). After further adjustments for established risk factors, only CRP remained independently associated with cardiovascular mortality. HRs were 1.22 (1.12-1.32) per standard deviation higher loge CRP concentration and 1.91 (1.50-2.43) when comparing individuals in the top versus bottom quartile. The associations of CRP, calprotectin, lactoferrin and neopterin with cardiovascular mortality did not differ by diabetes, suggesting that any potential prognostic value of these markers is independent of diabetes status.

Exercise training and high-sensitivity cardiac troponin T in patients with heart failure with reduced ejection fraction.

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 < 0.001), and the reduction was maintained at 1 year with a mean reduction from BL to 1 year of 1.1 ng/L (95% confidence interval: 1.0-1.1 ng/L, P = 0.025). Randomization group was not associated with hs-cTnT at any time point (overall test: P = 0.20, MCT vs. RRE: P = 0.81, HIIT vs. RRE: P = 0.095, interaction time × randomization group: P = 0.88). Independent of time point, higher VO2peak 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.