Search

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. 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/.

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.

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.

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.

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

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

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/.

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.

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: 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

OBJECTIVES The aim of this study was to compare long-term mortality in patients undergoing primary isolated coronary artery bypass grafting who received ≥1 units of red blood cells (RBCs) or no RBCs. We hypothesized that a possible difference in long-term mortality was due to preoperative morbidity and/or postoperative morbidity. METHODS This prospective cohort study, part of the Cardiac Surgery Outcome Study (CaSOS) at St. Olavs University Hospital, Trondheim, Norway, included patients operated on from 2000 through 2014 (n = 4014) and excluded those with large intra- or postoperative blood loss or 30-day mortality. Observed mortality from 30 days to 15 years postoperatively was compared between patients who received RBC transfusion and those who did not. Cox regression analysis was performed with unadjusted models, adjusting for pre- and intraoperative covariates, and with further adjustment for postoperative complications. Sensitivity analyses were performed with propensity score matching or including 30-day mortality. RESULTS The unadjusted hazard ratio (HR) for long-term mortality was 2.10 (1.81-2.43; P

Background Several models for predicting acute kidney injury following cardiac surgery have been published, and various end-point definitions have been used. Objectives Our aim was to investigate how acute kidney injury following cardiac surgery could be most accurately predicted. Design Single-centre prospective observational study. Setting St Olav's University Hospital, Trondheim, Norway, from 2000 to 2007. Patients All 5029 adult patients undergoing cardiac surgery were considered eligible for participation. Patients who required preoperative dialysis and patients with missing information on preoperative or maximum postoperative serum creatinine concentration were excluded (n=51). A total of 4978 patients were entered into the statistical analyses. Main outcome measures Logistic regression with bootstrapping methods was applied for model development and validation, together with the area under the receiver operating characteristic curve and Hosmer-Lemeshow test. We tested different end-points, exchanged serum creatinine concentration with creatinine clearance or estimated glomerular filtration rate and added intraoperative variables. The main end-point was at least 50% increase in serum creatinine concentration, an increase in concentration by at least 26.4 μmol l(-1) (0.3 mg dl(-1)) or a new requirement for dialysis after surgery. Results The final model consisted of 11 preoperative predictors of acute kidney injury: age, BMI, lipid-lowering treatment, hypertension, peripheral vascular disease, chronic pulmonary disease, haemoglobin concentration, serum creatinine concentration, previous cardiac surgery, emergency operation and operation type. The area under the receiver operating characteristic curve was 0.819 (95% confidence interval 0.801 to 0.837), and the Hosmer-Lemeshow test P value was 0.17. Exchanging serum creatinine concentration with glomerular filtration rate or creatinine clearance slightly reduced model discrimination and the addition of intraoperative variables improved discrimination somewhat. Slight end-point definition changes had little impact. Conclusion The risk of acute kidney injury can be accurately predicted using preoperative variables. Serum creatinine concentration was more accurate than estimated glomerular filtration rate or creatinine clearance. Intraoperative variables slightly improved the model, but did not seem to outweigh the advantages of a preoperative model.

The lectin complement pathway is suggested to play a role in atherogenesis. Pentraxin-3 (PTX3), ficolin-1, ficolin-2, ficolin-3, MBL/ficolin/collectin-associated serine protease-3 (MASP-3) and MBL/ficolin/collectin-associated protein-1 (MAP-1) are molecules related to activation of the lectin complement pathway. We hypothesized that serum levels of these molecules may be associated with the incidence of myocardial infarction (MI). In a Norwegian population-based cohort (HUNT2) where young to middle-aged relatively healthy Caucasians were followed up for a first-time MI from 1995–1997 through 2008, the 370 youngest MI patients were matched by age (range 29–62 years) and gender to 370 controls. After adjustments for traditional risk factors, the two highest tertiles of PTX3 and the highest tertiles of ficolin-2 and MASP-3 were associated with MI, with odds ratios (95% confidence interval) of 1.65 (1.10–2.47) and 2.79 (1.83–4.24) for PTX3, 1.55 (1.04–2.30) for ficolin-2, and 0.63 (0.043–0.94) for MASP-3. Ficolin-1, ficolin-3 and MAP-1 were not associated with MI. In a multimarker analysis of all associated biomarkers, only PTX3 and MASP-3 remained significant. PTX-3 and MASP-3 enhanced prediction of MI compared to the traditional Framingham risk score alone (AUC increased from 0.64 to 0.68, p = 0.006). These results support the role of complement-dependent inflammation in the pathophysiology of cardiovascular disease. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ © The Author(s) 2017

Background: In the present study, we examined the effect of sample storage on the reproducibility of several inflammatory biomarkers, including high-sensitivity C-reactive protein (hsCRP), high-sensitivity interleukin-6 (hsIL6), and high-sensitivity tumor necrosis factor alpha (hsTNFα). In addition, we assessed inter- and intra-assay variability between collaborating biobanks.Methods: In total, 240 fasting plasma samples were obtained from the LifeLines biobank. Samples had been stored for less than 2 or more than 4 years at −80°C. Measurements were performed at three different laboratories. hsCRP was measured by immunonephelometry and ELISA, hsIL6, and hsTNFα samples were measured with ELISAs from two different manufacturers. For confirmation, similar analyses were performed on samples obtained from a subpopulation of 80 obese individuals. Passing–Bablok regression analysis and Bland–Altman plots were used to compare the results.Results: We observed good stability of samples stored at −80°C. hsCRP measured on the day of blood draw was similar to levels measured after more than 4 years of storage. There were small interlaboratory differences with the R&D ELISAs for hsIL6 and hsTNFα. We found a linear correlation between the Bender Medsystems ELISA and the R&D ELISA for hsIL6, with significantly higher levels measured with the R&D ELISA. Over 90% of hsTNFα samples measured with the IBL ELISA were below the detection limit of 0.13 ng/L, rendering this assay unsuitable for large-scale analysis. Similar results were found in the confirmation study.Conclusion: In summary, plasma hsCRP showed good stability in samples stored for either less than 2 years or more than 4 years at −80°C. Both the R&D and Bender Medsystems for hsIL6 measurement yielded similar results. The IBL hsTNFα assay is not suited for use in biobanking samples. Assays for the measurement of inflammatory biomarker assays should be rigorously tested before large sample sets are measured. This is a submitted manuscript of an article published by Mary Ann Liebert in Biopreservation and Biobanking, 1 Dec 2017. Locked until 1.12.2018 due to copyright restrictions.

Objective. Self-reported diagnoses of inflammatory arthritis are not accurate. The primary study aim was to ascertain self-reported diagnoses of rheumatoid arthritis (RA) and ankylosing spondylitis (AS) in the Norwegian population-based Nord-Trøndelag Health Study (HUNT) using hospital case files. The secondary aim was to provide updated estimates of the prevalence and incidence of RA and AS. Methods. All inhabitants ≥ 20 years old from the county of Nord-Trøndelag were invited. Data from 70,805 unique participants from HUNT2 (1995–1997) and HUNT3 (2006–2008) were included. For participants who self-reported RA or AS, case files from all 3 hospitals in the catchment area were evaluated using standardized diagnostic criteria. Results. Of 2703 self-reported cases of RA, 19.1% were verified in hospital files. Of 1064 self-reported cases of AS, 15.8% were verified. Of 259 cases self-reporting both RA and AS, 8.1% had RA and 5.4% had AS. Overall, a self-report of 1 or both diagnoses could not be verified in 82.1%, including 22.8% with insufficient information or no case file. The prevalence of RA was 768 (95% CI 705–835) per 100,000. The incidence of RA from HUNT2 to HUNT3 was 0.48 (0.41–0.56) per 1000 per year. The prevalence of AS was 264 (228–305) per 100,000. The incidence of AS from HUNT2 to HUNT3 was 0.19 (0.15–0.24) per 1000 per year. Conclusion. Self-reported diagnoses of RA and AS are often false-positive. The prevalence and incidence of RA were comparable to reports from similar populations. The incidence of AS was higher than previously reported in a mixed population from Norway. © 2017. This is a pre-copy-editing, author-produced PDF of an article accepted for publication in The Journal of Rheumatology following peer review. LOCKED until 1.8.2018 due to copyright restrictions. The definitive publisher-authenticated version [Self-reported diagnosis of rheumatoid arthritis or ankylosing spondylitis has low accuracy: Data from the Nord-Trøndelag Health Study] is available online at: http://www.jrheum.org/content/44/8/1134

Background In the randomized, controlled study Probiotics in the Prevention of Allergy among Children in Trondheim (ProPACT), maternal probiotic supplementation reduced the incidence of atopic dermatitis (AD) in the offspring. In the current study, we hypothesized that the effect was mediated by a shift in the T helper (Th) cells in the children. Objective To examine whether Th cell proportions were affected by maternal probiotic supplementation and thus could mediate the preventive effect of probiotics on AD. Methods A total of 415 pregnant women were randomized to ingest a combination of Lactobacillus rhamnosus GG (LGG), Bifidobacterium animalis subsp. lactis Bb-12 (Bb-12) and Lactobacillus acidophilus La-5 (La-5) or placebo, and their offspring were assessed for AD during the first 2 years of life. Peripheral blood collected at 3 months of age was analysed for regulatory T cells (n=140) and Th subsets (n=77) including Th1, Th2, Th9, Th17 and Th22. Results The proportion of Th22 cells was reduced in children in the probiotic group compared to the placebo group (median 0.038% vs 0.064%, P=.009). The difference between the probiotic and placebo groups was also observed in the children who did not develop AD during the 2-year follow-up. The proportion of Th22 cells was increased in children who developed AD compared to the children who did not develop AD (0.090% vs 0.044%, P

Objective To investigate whether a multimarker strategy combining preoperative biomarkers representing distinct pathophysiologic pathways enhances preoperative risk assessment of acute kidney injury after cardiac surgery (CSA-AKI) and increases knowledge of underlying pathogenesis. Design Prospective, cohort study. Setting Single-center tertiary referral hospital. Participants The study comprised 1,015 adults undergoing cardiac surgery with cardiopulmonary bypass. Interventions CSA-AKI was defined as≥50% increase in serum creatinine concentration, absolute increase≥26 µmol/L, or new requirement for dialysis. Preoperative and perioperative information until hospital discharge was recorded. Preoperative plasma levels of C-reactive protein, terminal complement complex, neopterin, lactoferrin, N-terminal pro-brain natriuretic peptide, and cystatin C were determined using enzyme immunoassays. Biomarkers were selected based on causal hypotheses of underlying mechanisms and were related to inflammatory, hemodynamic, or renal signaling pathways. Measurements and Main Results One hundred patients (9.9%) developed CSA-AKI. Higher baseline plasma concentrations of neopterin and N-terminal pro-brain natriuretic peptide were associated independently with CSA-AKI (p = 0.04 and p

Objective To evaluate the effects of tranexamic acid on postoperative blood loss and transfusion requirements in elderly patients undergoing combined aortic valve replacement and coronary artery bypass graft surgery (CABG). Design A prospective, randomized, double-blinded, placebo-controlled, parallel-group trial. Setting A university hospital (single institution). Participants Sixty-four patients 70 years or older undergoing combined aortic valve replacement and CABG surgery were included. One patient was withdrawn from the study after randomization by the attending surgeon because of a change in the surgical procedure. The remaining 63 patients were analyzed as intention to treat. Interventions The included patients were randomized to treatment with either tranexamic acid, 10 mg/kg, as a bolus injection before surgery followed by 1 mg/kg/h as an infusion during surgery, or a corresponding volume of 0.9% sodium chloride. Measurements and Main Results Postoperative blood loss was recorded for 16 hours. The transfusion of blood products was recorded during the entire hospital stay. The number of packed red cell transfusions given to the patients was significantly lower in the tranexamic acid group compared with the placebo group (median, 3.0 [interquartile range, 2-5] v 5.0 [3-7], p = 0.049). Conclusion Tranexamic acid reduced the number of packed red cell transfusions given to patients 70 years or older undergoing combined aortic valve replacement and CABG surgery.

Context Cardiac dysfunction following open heart surgery is a major determinant of subsequent morbidity and mortality. Objectives To develop a specific risk prediction model for postoperative cardiac dysfunction based on preoperative variables, to investigate whether prediction could be improved by inclusion of selected intraoperative variables and to compare our model with five previously published risk scores. Design Single-centre prospectively collected data. Setting Tertiary care centre, Middle Norway. Patients Four thousand nine hundred and eighty-nine patients (all eligible) undergoing open cardiac surgery from 2000 to 2007. Main outcome measures Logistic regression models for postoperative cardiac dysfunction: predictive accuracy/calibration, discrimination as shown by area under the receiver operating characteristics curve, internal validity as indicated by bootstrapping, comparison of goodness-of-fit with predictions based on alternative risk scores. Results The preoperative model included chronic cardiac insufficiency, previous myocardial infarction, previous cardiac operation, pulmonary hypertension, renal dysfunction, low haemoglobin concentration, urgent operation and operation type other than isolated coronary artery bypass surgery. The area under the curve was 0.838 [95% confidence interval (CI) 0.812-0.864]. Risk prediction was accurate apart from a slight overestimation in the 2% of highest risk patients. Inclusion of a few intraoperative variables (inotropic or vasoconstrictor drugs, plasma or red cell transfusion) improved the model slightly, increasing the area under the curve to 0.875 (95% CI 0.854-0.896) or 0.890 (95% CI 0.863-0.902) for two equivalent models. On the basis of estimated shrinkage factors of 0.94, 0.97 and 0.98, respectively, the models should behave with 6% or less error in future datasets. Our preoperative model was significantly better than the previously published risk scores (P Conclusion The preoperative model including variables obtained easily in routine clinical work performed well and was improved only slightly by inclusion of intraoperative variables. Performance was better than those of the five previously published risk scores.

A randomized open-heart surgery study comprising 30 patients was undertaken to compare the biocompatibility of Phisio-(phosphorylcholine) and PMEA-(poly-2-methoxyethyl acrylate) coated cardiopulmonary bypass (CPB) circuits and to assess the initial complement pathway activation during open-heart surgery. Blood samples were obtained at five time points, from the start of surgery to 24 hours postoperatively. The following analyses were performed: haemoglobin, lactate dehydrogenase, leukocyte and platelet counts, myeloperoxidase and neutrophil-activating peptide-2, thrombin-anti-thrombin complexes, syndecan-1 and the complement activation products C1rs-C1-inhibitor complexes, C4bc, C3bc, C3bBbP and the terminal complement complex (TCC). No significant inter-group difference was found in any parameters, except for the concentration of TCC which was moderately lower in the PMEA group at termination of CPB. Complement activation during open-heart surgery was mainly mediated through the alternative pathway. In conclusion, PMEA- and Phisio-coated circuits displayed similar biocompatibility with respect to inflammatory and haemostatic responses during and after open-heart surgery.

Background: The biocompatibility of cardiopulmonary bypass surfaces has been improved by heparin and polymer surface modifications. The present study compared the effect of two such coatings on the inflammatory reactions after open heart surgery. Methods:Thirty patients undergoing elective heart surgery were randomly assigned to receive one of two types of coated circuits: Bioline (n=15) or phosphorylcholine (Phisio, n=15). The platelet and leukocyte counts, neutrophil activation (myeloperoxidase), complement activation (C3a and TCC), concentrations of lactate dehydrogenase, 27 cytokines (including interleukins, chemokines and growth factors), thrombin-antithrombin complexes, and the endothelial cell marker syndecan-1 were analyzed at five predetermined time points until 24 hrs post operatively. Results: Most measurements were comparable in both groups. However, myeloperoxidase was significantly higher in the Bioline group (p < 0.001). Postoperative lactate dehydrogenase concentrations were significantly higher in the Phisio group (p

Activated endothelium releases the soluble adhesion molecules vascular cell adhesion molecule-1 (sVCAM-1) and intercellular adhesion molecule-1 (sICAM-1). Measurement of fluid-phase adhesion molecules is therefore used to quantify endothelial activation, but it is unclear which is the better marker. The aims of the study were to compare the relationships between mRNA, surface and total expression and released VCAM-1 and ICAM-1 in endothelial cell cultures during activation, and to compare human umbilical vein endothelial cells (HUVEC) with the microvascular cell line HMEC-1. sVCAM-1 better represented mRNA and surface expression changes in HUVEC undergoing endotoxin stimulation than did sICAM-1. Very little VCAM-1 was released from endotoxin-stimulated HMEC-1, and sICAM-1 seemed a better activation marker for these cells. During incubation of HUVEC in media with glucose concentrations of 5.6, 10.6 or 20.6 mM, VCAM-1 was released to the media in a dose-dependent way without changes in surface expression. ICAM-1 was not influenced by the glucose concentration. There are situations when VCAM-1 concentrations in the media do not mirror the surface expression on HUVEC in culture, indicating that measurements of soluble adhesion molecules may not necessarily be representative of the conditions on the cell surface. Endothelium from different locations showed varying responses with respect to VCAM-1 and ICAM-1 liberation upon endotoxin stimulation. Thus, both sVCAM-1 and sICAM-1 should be quantified in clinical studies of endothelial activation until their characteristics are better clarified.

Complement plays a vital role in the body's defence systems. Cardiopulmonary bypass induces a detrimental inflammatory reaction in which the complement system is known to participate through direct effects as well as through activation of neutrophils, platelets and endothelial cells. On the other hand, it has been suggested that in the setting of cardiopulmonary bypass, complement may be activated by neutrophils, perhaps due to fragmentation caused by the heart-lung machine. We therefore investigated whether intact or fragmented neutrophils were able to activate the complement system, and whether neutrophil-platelet interaction could influence such complement activation. Lepirudin-anticoagulated plasma was incubated at 37 degrees C with resting or activated intact neutrophils or neutrophils combined with platelets, or increasing amounts of fragmented neutrophils. Complement activation was evaluated by measurement of C1rs-C1 inhibitor complexes, C4bc, C3bBbP, C3bc, C5a and sC5b-9. We found significant activation of complement only by unphysiological doses of fragmented neutrophils or supernatant from fragmented neutrophils, consistent with a limited clinical significance related to neutrophil destruction during cardiopulmonary bypass. Unstimulated neutrophils induced C3bPBb formation but little formation of other activation products, indicating an increased C3 hydrolysis which was kept under control by regulatory mechanisms. Neutrophils and platelets combined increased classical activation and decreased alternative activation, similar to the findings with platelets alone. Our data confirm that in the setting of acute neutrophil fragmentation or activation, complement activation is much more important in the inflammatory network as an event upstream to neutrophil activation than vice versa.

We investigated the interactions between neutrophils, platelets, and artificial surfaces, and whether blocking of relevant receptors on platelets reduced unwanted activation responses in model cardiopulmonary bypass. Isolated neutrophils and platelets resuspended in heparin-anticoagulated plasma were recirculated with and without blocking antibodies to CD62P, CD42b, or junctional adhesion molecule C (JAM-C) in polyvinyl chloride tubing using a roller pump. Platelet adhesion to the tubing was inhibited by anti-CD42b and anti-CD62P, and adhesion of neutrophils by anti-JAM-C. Formation of platelet-neutrophil and platelet aggregates was reduced by anti-CD62P. Anti-JAM-C decreased platelet-neutrophil aggregation at low concentrations and platelet macroaggregates at high concentrations. Anti-CD62P increased neutrophil CD11b expression but not degranulation. Anti-JAM-C substantially increased neutrophil degranulation and slightly increased CD11b expression. Platelet activation increased when CD62P was blocked and decreased with anti-CD42b antibody. High-dose anti-JAM-C reduced platelet activation. In conclusion, inhibiting platelet and neutrophil-platelet interactions had useful effects but no single blocking antibody seemed capable of inducing only beneficial effects.

Background— Exercise training reduces the symptoms of chronic heart failure. Which exercise intensity yields maximal beneficial adaptations is controversial. Furthermore, the incidence of chronic heart failure increases with advanced age; it has been reported that 88% and 49% of patients with a first diagnosis of chronic heart failure are >65 and >80 years old, respectively. Despite this, most previous studies have excluded patients with an age >70 years. Our objective was to compare training programs with moderate versus high exercise intensity with regard to variables associated with cardiovascular function and prognosis in patients with postinfarction heart failure. Methods and Results— Twenty-seven patients with stable postinfarction heart failure who were undergoing optimal medical treatment, including β-blockers and angiotensin-converting enzyme inhibitors (aged 75.5±11.1 years; left ventricular [LV] ejection fraction 29%; V̇ o 2peak 13 mL · kg −1 · min −1 ) were randomized to either moderate continuous training (70% of highest measured heart rate, ie, peak heart rate) or aerobic interval training (95% of peak heart rate) 3 times per week for 12 weeks or to a control group that received standard advice regarding physical activity. V̇ o 2peak increased more with aerobic interval training than moderate continuous training (46% versus 14%, P Conclusions— Exercise intensity was an important factor for reversing LV remodeling and improving aerobic capacity, endothelial function, and quality of life in patients with postinfarction heart failure. These findings may have important implications for exercise training in rehabilitation programs and future studies.

Several inflammatory biomarkers are linked to cardiovascular risk. In order to investigate their coexistence and relative responses, several established and two novel markers (lactoferrin and the terminal complement complex), representing infection and central components of inflammation, were measured simultaneously in patients undergoing first-time coronary angiography.Blood samples from patients with (n=131) or without (n=103) significant coronary artery stenosis were analyzed for plasma markers representing endothelium, platelets, neutrophils, monocytes, and complement, C-reactive protein, and antibodies against the infectious agents Chlamydia pneumoniae, Helicobacter pylori, and cytomegalovirus. In multivariate logistic regression analysis, hypercholesterolemia (p0.001), increased concentrations of the neutrophil activation marker lactoferrin (p0.001) and the monocyte activation marker neopterin (p=0.012), lower concentrations of the terminal complement complex (p0.001), and antibodies against C. pneumoniae (p=0.023) were variables linked to coronary artery stenosis. In univariate analysis additional relationships were found to current smoking (p0.001), increased plasma concentrations of vascular cell adhesion molecule-1 (p=0.015), E-selectin (p0.01), myeloperoxidase (p=0.051) and endothelin-1 (p=0.053), as well as diabetes (p=0.039).Activation of multiple inflammatory pathways and C. pneumoniae infection may influence the inflammatory response in atherosclerosis. These pilot data provide an indication of the relative usefulness of various inflammatory biomarkers, indicating that the novel markers lactoferrin and the terminal complement complex warrant further investigation.

Common variable immunodeficiency disorder (CVID) is the most common symptomatic primary immunodeficiency in adults, characterized by B-cell abnormalities and inadequate antibody response. CVID patients have considerable autoimmune comorbidity and we therefore hypothesized that genetic susceptibility to CVID may overlap with autoimmune disorders. Here, in the largest genetic study performed in CVID to date, we compare 778 CVID cases with 10,999 controls across 123,127 single-nucleotide polymorphisms (SNPs) on the Immunochip. We identify the first non-HLA genome-wide significant risk locus at CLEC16A (rs17806056, P=2.0 × 10(-9)) and confirm the previously reported human leukocyte antigen (HLA) associations on chromosome 6p21 (rs1049225, P=4.8 × 10(-16)). Clec16a knockdown (KD) mice showed reduced number of B cells and elevated IgM levels compared with controls, suggesting that CLEC16A may be involved in immune regulatory pathways of relevance to CVID. In conclusion, the CLEC16A associations in CVID represent the first robust evidence of non-HLA associations in this immunodeficiency condition.

AB Purpose: It has been demonstrated that aerobic exercise induces beneficial changes in coronary atherosclerosis via reduced necrotic core and plaque burden. Clinical factors that may be associated with favorable exercise-induced intracoronary effects are unknown. Methods: This study used post hoc analysis of associations between baseline clinical variables and reductions in coronary necrotic core and plaque burden after aerobic exercise intervention. Coronary plaque characteristics were measured with grayscale and radiofrequency intravascular ultrasound in 36 patients (median age, 58.5 yr; seven women) with stable CAD (SCAD) or non-ST elevation acute coronary syndrome (NSTE-ACS). Screening of clinical variables was performed with random forest analysis followed by multivariate linear regression. Results: The only significant clinical variable for necrotic core reduction was clinical presentation of disease (SCAD vs NSTE-ACS, P = 0.011). The changes in necrotic core after exercise were -4.94 mm3 (-10.33; -1.33) in patients with SCAD and 1.03 mm3 (-4.29; 3.71) in patients with NSTE-ACS (P = 0.01). Necrotic core was reduced in 17 patients (94%) with SCAD and eight patients (44%) with NSTE-ACS (P = 0.01). R2 for the model including baseline clinical presentation and baseline necrotic core volume was 0.90. There were no significant explanatory variables for plaque burden reduction. Conclusions: Exercise-induced plaque stabilization via reduced coronary necrotic core may be strongly dependent on clinical presentation of CAD. We hypothesized that an increased proinflammatory load renders patients with NSTE-ACS more resistant to exercise-induced plaque stabilization than patients with SCAD. Furthermore, aerobic exercise may have a particular potential for inducing beneficial effects on coronary atherosclerosis in patients with SCAD compared with patients in the early phase after an acute coronary syndrome.

Activated neutrophils play a central role in the pathogenesis of postoperative organ dysfunction after surgery with cardiopulmonary bypass. The researchers used an in vitro roller pump model to investigate the relative importance of the biomaterial, platelets, plasma proteins including activated complement, and flow mode on neutrophil activation as shown by the adhesion, degranulation, and increased the surface expression of CD11b. Neutrophil adhesion to the biomaterial increased with platelet addition, but not with plasma. Biomaterial contact activated neutrophils in a serum-free buffer, but was significantly increased by activated complement. Platelets increased neutrophil degranulation in a serum-free buffer but tended to reduce it in plasma. CD11b expression increased in both media. Complement activation was higher with neutrophils alone than with neutrophils and platelets combined. The roller pump reduced neutrophil adhesion and increased degranulation compared to passive rotation. Neutrophil interaction with platelets and complement were more important for activation than biomaterial contact and use of the roller pump. Improvement of biocompatibility is dependent on modifying complement activation and platelet interaction with neutrophils.

Background Exposure of blood to artificial surfaces, as in cardiopulmonary bypass, induces an inflammatory response involving complement, leukocyte and platelet activation. To elucidate the specific role of complement in this process, studies were performed on blood circulated in polyvinyl chloride tubing in the absence and presence of complement inhibitors. Parallel experiments were performed with heparin-coated polyvinyl chloride tubing, which is known to prevent complement and cell activation. Methods A novel experimental model was used, based on human whole blood anticoagulated with lepirudin. Complement activation products, myeloperoxidase, lactoferrin, and thrombospondin were quantified in enzyme immunoassays. Leukocyte CD11b expression and leukocyte-platelet conjugates were detected by flow cytometry. Results Increased levels of C3 activation products, alternative pathway convertase, and the terminal SC5b-9 complex, combined with unchanged levels of C1rs–C1-inhibitor complexes and marginal changes in C4 activation demonstrated that complement was activated through the alternative pathway. Granulocyte and monocyte CD11b expression and granulocyte-platelet conjugate formation were efficiently attenuated by blocking either factor D, C3, C5, or C5a receptor. In contrast, monocyte-platelet conjugate formation and release of myeloperoxidase, lactoferrin, and thrombospondin were not reduced by complement inhibition. Heparin-coated polyvinyl chloride tubing efficiently reduced all inflammatory markers studied, except for C1rs–C1-inhibitor complexes, which increased, consistent with the enhancing effect of heparin on C1-inhibitor function. This effect did not, however, reduce fluid-phase classic pathway activation induced by heat-aggregated immunoglobulin G. Conclusions Leukocyte and platelet activation in response to artificial materials occur by mechanisms that vary in their dependence on complement. Heparin coating precludes both the complement-dependent and complement-independent reactions.

Neutrophil activation induces changes in the expression of surface receptors and may lead to degranulation. Surface expression of beta2-integrins, l-selectin, complement receptor 1 (CR-1), decay-accelerating factor (DAF), C5a receptor, intercellular adhesion molecule-1 (ICAM-1) and ICAM-3 was compared by flow cytometry on isolated neutrophils stimulated with phorbol 12-myristate 13-acetate (PMA), N-formyl-methionyl-leucyl-phenylalanine (FMLP), endotoxin or interleukin-8 and on neutrophils in whole blood anti-coagulated with the thrombin inhibitor lepirudin and stimulated with cobra venom factor to induce complement activation. Myeloperoxidase and lactoferrin in the supernatants were quantified in enzyme immunoassays. With high enough doses, all stimulants induced significant upregulation of beta2-integrins, CR-1 and DAF and downregulation of l-selectin. ICAM-3 was either unchanged or somewhat downregulated. Only FMLP and PMA induced significant upregulation of ICAM-1. Combined measurement of beta2-integrins and l-selectin permitted graded evaluation of early neutrophil activation. Measurement of degranulation showed no differences compared to unstimulated controls due to substantial spontaneous degranulation of isolated neutrophils by rewarming from 4 degrees C and incubation at 37 degrees C. Spontaneous activation was less in ethylenediaminetetraacetic acid-anti-coagulated blood, but calcium chelation may also inhibit the stimulated responses. There was large activation of unstimulated neutrophils in lepirudin-anti-coagulated blood at 37 degrees C, obscuring changes induced by stimulation, which may render this anti-coagulant unsuitable for studies of neutrophils.

Objective: Heart surgery with extracorporeal circulation has a marked effect on platelet function and coagulation accounting for abnormal blood loss and allegedly a low incidence of thromboembolic complications. Little is known about platelet function at the time of hospital discharge of routine patients. Methods: Blood samples from 91 patients undergoing elective heart surgery were drawn before surgery and prior to discharge. Thirty-seven patients underwent coronary artery surgery and 54 an aortic valve implantation. The mean age of patients was 69 ^ 9 years. Fifty patients were male and 41 female. Platelet function was evaluated using plasma b-thromboglobulin quantification in enzyme-linked immunosorbent assay. In addition, flow cytometric analysis of platelet ‐ monocyte conjugates and platelet ‐ neutrophil conjugates was performed. Results: The platelet count before discharge was significantly increased (265 ^ 86 vs. 212 ^ 61 £ 10 9 =l preoperatively). b-Thromboglobulin was significantly increased (176 ^ 127 vs. 79 ^ 70 ng/ml preoperatively) and flow cytometry proved a significant increase in monocyte‐ platelet aggregates (8.3 ^ 5.4% vs. 5.3 ^ 2.6% preoperatively) indicating platelet activation at the time of hospital discharge. There were no significant differences among the three subgroups coronary surgery, mechanical valve insertion and biological valve insertion. Conclusions: Heart surgery with extracorporeal circulation leads to significant platelet activation and a reactive increase in platelet count before discharge. This is in contrast to the reduced platelet function immediately postoperatively. q 2003 Elsevier Science B.V. All rights reserved.

Cardiopulmonary bypass causes a systemic inflammatory reaction, which leads to endothelial activation with increased expression of adhesion molecules. The study aim was to test whether activated endothelial cells secrete measurable amounts of soluble adhesion molecules during the time course of routine heart surgery, and whether these markers correlate with cellular activation responses. Endothelial cells from human umbilical cords were cultured by standard methods and stimulated with endotoxin. After 2 h, the expression of membrane-bound E-selectin on the cells had increased significantly ( p= 0.04), whereas soluble VCAM-1 (sVCAM-1) had increased significantly in the culture media ( p= 0.03). In agreement with these findings, sVCAM-1 increased from 399 ng/ml (median) to 581 ng/ml within 3 h postoperatively in sera from 11 patients undergoing open heart surgery ( p= 0.003). sVCAM-1, therefore, may be suitable as an early marker of endothelial activation related to the systemic inflammation after open heart surgery. The clinical significance of sVCAM-1 measurements must be further evaluated in future patient studies.

Background Sensitization toward allergens, as determined by skin prick test (SPT) or specific IgE (sIgE), is a predictor for the later presence of allergy-related disease (atopic eczema, allergic rhinoconjuctivitis and asthma). However, it is not known whether SPT or sIgE should be the preferred test. The aim of this study was to compare the predictive ability of SPT and sIgE when performed in a general population of 2-yr-old children. Methods In a prospective, longitudinal population-based study of children aged 2–6 yr, SPT and sIgE for nine common allergens were performed at 2 yr. Allergy-related disease was evaluated by clinical examination and questionnaire at 2 and 6 yr of age (n = 199). Results Skin prick test or sIgE was positive in 10.6% and 21.1% in the 2-yr-old children, respectively. The prevalence of allergy-related disease was 25.6% at 2 yr and 25.1% at 6 yr. Half of the cases at 2 yr were transient. Both SPT and sIgE were statistically significant predictors for later allergy-related disease, OR = 6.5 (95% CI 2.3–18.6) and OR = 4.1 (95% CI 1.9–9.0), respectively. Receiver operating characteristic analysis showed that SPT and sIgE had comparable predictive ability for atopic eczema, asthma or any allergy-related disease, but sIgE had better ability to predict later allergic rhinoconjunctivitis. Conclusion Sensitization at 2 yr may be useful predictors of allergy-related disease later in childhood. The predictive ability of SPT and sIgE were mainly comparable; however, it may be that sIgE is the preferred choice in young children when the aim is to predict allergic rhinoconjunctivitis.