The relationship between workload and exercise-induced cardiac troponin elevations is influenced by non-obstructive coronary atherosclerosis.

The relationship between exercise-induced troponin elevation and non-obstructive coronary artery disease (CAD) is unclear. This observational study assessed non-obstructive CAD's impact on exercise-induced cardiac Troponin I (cTnI) elevation in middle-aged recreational athletes. cTnI levels of 40 well-trained recreational athletes (73% males, 50 ± 9 years old) were assessed by a high-sensitive cTnI assay 24 h before, and at 3 and 24 h following two high-intensity exercises of different durations; a cardiopulmonary exercise test (CPET), and a 91-km mountain bike race. Workload was measured with power meters. Coronary computed tomography angiography was used to determine the presence or absence of non-obstructive (<50% obstruction) CAD. A total of 15 individuals had non-obstructive CAD (Atherosclerotic group), whereas 25 had no atherosclerosis (normal). There were higher post-exercise cTnI levels following the race compared with CPET, both at 3 h (77.0 (35.3-112.4) ng/L vs. 11.6 (6.4-22.5) ng/L, p < 0.001) and at 24 h (14.7 (6.7-16.3) vs. 5.0 (2.6-8.9) ng/L, p < 0.001). Absolute cTnI values did not differ among groups. Still, the association of cTnI response to power output was significantly stronger in the CAD versus Normal group both at 3 h post-exercise (Rho = 0.80, p < 0.001 vs. Rho = -0.20, p = 0.33) and 24-h post-exercise (Rho = 0.87, p < 0.001 vs. Rho = -0.13, p = 0.55). Exercise-induced cTnI elevation was strongly correlated with exercise workload in middle-aged athletes with non-obstructive CAD but not in individuals without CAD. This finding suggests that CAD influences the relationship between exercise workload and the cTnI response even without coronary artery obstruction.

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.

Prognostic value of growth differentiation factor-15 3 months after an acute chest pain admission.

OBJECTIVE: Growth differentiation factor-15 (GDF-15) is a predictor of death and cardiovascular events when measured during index hospitalisation in patients with acute chest pain. This study investigated the prognostic utility of measuring GDF-15 3 months after an admission with suspected non-ST-elevation acute coronary syndrome (NSTE-ACS). METHODS: GDF-15 was measured at baseline and 3 months after admission in 758 patients admitted with suspected NSTE-ACS. Patients were followed for a median of 1540 (IQR: 1087-1776) days after the 3-month visit. The primary endpoint was all-cause mortality, while the secondary composite endpoint included all-cause mortality, incident myocardial infarction and heart failure hospitalisation during follow-up. RESULTS: In patients with GDF-15 ≥1200 pg/mL (n=248), 18% died and 25% met the composite endpoint. In patients with GDF-15 <1200 pg/mL (n=510), 1.7% died and 4% met the composite endpoint. The GDF-15 concentration (log2 transformed) at 3 months was significantly associated with all-cause mortality (adjusted HR: 2.2, 95% CI: 1.4 to 3.3, p<0.001) and the composite endpoint (adjusted HR: 1.9, 95% CI: 1.4 to 2.7, p<0.001), independently of traditional risk factors and baseline troponin T. A 10% change in GDF-15 concentration from baseline to the 3-month visit was associated with increased risk of all-cause mortality (HR: 1.06, 95% CI: 1.01 to 1.13, p=0.031), adjusting for baseline GDF-15 concentrations. CONCLUSIONS: High GDF-15 concentrations 3 months after admission for suspected NSTE-ACS are associated with long-term mortality and cardiovascular events, independent of traditional risk factors and troponin T. A change in GDF-15 concentration can provide prognostic information.

Prognostic significance of chronic myocardial injury diagnosed by three different cardiac troponin assays in patients admitted with suspected acute coronary syndrome.

OBJECTIVES: Chronic myocardial injury (CMI) is defined as stable concentrations of cardiac troponin T or I (cTnT or cTnI) above the assay-specific 99th percentile upper reference limit (URL) and signals poor outcome. The clinical implications of diagnosing CMI are unclear. We aimed to assess prevalence and association of CMI with long-term prognosis using three different high-sensitivity cTn (hs-cTn) assays. METHODS: A total of 1,292 hospitalized patients without acute myocardial injury had cTn concentrations quantified by hs-cTn assays by Roche Diagnostics, Abbott Diagnostics and Siemens Healthineers. The median follow-up time was 4.1 years. The prevalence of CMI and hazard ratios for mortality and cardiovascular (CV) events were calculated based on the URL provided by the manufacturers and compared to the prognostic accuracy when lower percentiles of cTn (97.5, 95 or 90), limit of detection or the estimated bioequivalent concentrations between assays were used as cutoff values. RESULTS: There was no major difference in prognostic accuracy between cTnT and cTnI analyzed as continuous variables. The correlation between cTnT and cTnI was high (r=0.724-0.785), but the cTnT assay diagnosed 3.9-4.5 times more patients with having CMI based on the sex-specific URLs (TnT, n=207; TnI Abbott, n=46, TnI Siemens, n=53) and had higher clinical sensitivity and AUC at the URL. CONCLUSIONS: The prevalence of CMI is highly assay-dependent. cTnT and cTnI have similar prognostic accuracy for mortality or CV events when measured as continuous variables. However, a CMI diagnosis according to cTnT has higher prognostic accuracy compared to a CMI diagnosis according to cTnI.

Klotho and Fibroblast Growth Factor 23 Are Independent of Vitamin D, and Unlike Vitamin D, Are Not Associated With Graft- and Patient Survival After Kidney Transplantation.

Short-term survival after kidney transplantation is excellent but long-term survival remains suboptimal. The aim of the study was to explore the relationship between soluble α-Klotho (sKlotho) and intact fibroblast growth factor 23 (iFGF23) measured 8 wk and 1 y posttransplant with long-term graft- and patient survival in a cohort of kidney transplant recipients with deficient and nondeficient vitamin D (25[OH]D) levels. Methods: Vitamin D, sKlotho, and iFGF23 were measured 8 wk and 1 y posttransplant in 132 recipients transplanted between November 2012 and October 2013. Results: Of the 132 kidney transplant recipients, 49 had deficient vitamin D levels (<30 nmol/L) and 83 had nondeficient vitamin D levels (≥30 nmol/L) at 8 wk posttransplant. The mean age was 51 y and the median follow-up was 7.4 y. At 1 y posttransplant, vitamin D increased significantly. There were no significant differences in sKlotho or iFGF23 levels between the 2 vitamin D groups neither at 8 wk nor 1 y. sKlotho increased significantly and iFGF23 decreased significantly in the whole cohort. During the follow-up, there were 36 graft losses (27%) and 27 deaths (20%). Ninety-four percent of the transplant recipients with nondeficient vitamin D levels were alive with a well-functioning graft after 5 y using Kaplan-Meier survival estimates, compared with 84% of the patients with deficient vitamin D levels (P = 0.014). Klotho and FGF23 levels did not influence graft- and patient survival. Conclusions: In this nationwide cohort of kidney transplant recipients, long-term graft- and patient survival were significantly better in patients with vitamin D ≥30 nmol/L 8 wk posttransplant compared with those with vitamin D <30 nmol/L. sKlotho levels increased and iFGF23 levels decreased from 8 wk to 1 y posttransplant. Klotho and FGF23 levels were not associated with graft- and patient survival.

Growth Differentiation Factor 15: A Prognostic Marker in Patients with Acute Chest Pain without Acute Myocardial Infarction.

BACKGROUND: Acute chest pain is associated with an increased risk of death and cardiovascular events even when acute myocardial infarction (AMI) has been excluded. Growth differentiation factor-15 (GDF-15) is a strong prognostic marker in patients with acute chest pain and AMI, but the prognostic value in patients without AMI is uncertain. This study sought to investigate the ability of GDF-15 to predict long-term prognosis in patients presenting with acute chest pain without AMI. METHODS: In total, 1320 patients admitted with acute chest pain without AMI were followed for a median of 1523 days (range: 4 to 2208 days). The primary end point was all-cause mortality. Secondary end points included cardiovascular (CV) death, future AMI, heart failure hospitalization, and new-onset atrial fibrillation (AF). RESULTS: Higher concentrations of GDF-15 were associated with increased risk of death from all causes (median concentration in non-survivors vs survivors: 2124 pg/mL vs 852 pg/mL, P < 0.001), and all secondary end points. By multivariable Cox regression, GDF-15 concentration ≥4th quartile (compared to <4th quartile) remained an independent predictor of all-cause death (adjusted hazard ratio (HR): 2.75; 95% CI, 1.69-4.45, P < 0.001), CV death (adjusted HR: 3.74; 95% CI, 1.31-10.63, P = 0.013), and heart failure hospitalization (adjusted HR: 2.60; 95% CI, 1.11-6.06, P = 0.027). Adding GDF-15 to a model consisting of established risk factors and high-sensitivity cardiac troponin T (hs-cTnT) led to a significant increase in C-statistics for prediction of all-cause mortality. CONCLUSIONS: Higher concentrations of GDF-15 were associated with increased risk of mortality from all causes and risk of future CV events.

Hepcidin analysis in pneumonia: Comparison of immunoassay and LC-MS/MS.

BACKGROUND: The iron-regulatory hormone hepcidin is a promising biomarker to differentiate anaemia of inflammation from iron deficiency. Plasma hepcidin concentrations increase substantially during inflammation, and the amount of smaller, non-biologically active isoforms of hepcidin increase in inflammatory conditions. These smaller isoforms are measured in some, but not all analytical methods. Thus, we evaluated the comparability of two analytical methods with different isoform selectivity during and after acute-phase pneumonia as a highly inflammatory model disease. METHODS: Blood samples from a cohort of 267 hospitalized community-acquired pneumonia patients collected at admission and a 6-week follow-up were analysed. Hepcidin was measured in plasma by an immunoassay, which recognizes all hepcidin isoforms, and a liquid chromatography tandem mass spectrometry (LC-MS/MS), which selectively measures the bioactive hepcidin-25. Additionally, a subset of serum samples was analysed by LC-MS/MS. RESULTS: Hepcidin measurements by immunoassay were higher compared with LC-MS/MS. The relative mean difference of hepcidin plasma concentrations between the two analytical methods was larger in admission samples than in follow-up samples (admission samples <200 ng/mL: 37%, admission samples >200 ng/mL: 78%, follow-up samples >10 ng/mL: 22%). During acute-phase pneumonia, serum concentrations were on average 22% lower than plasma concentrations when measured by LC-MS/MS. CONCLUSIONS: Immunoassay measured higher hepcidin concentrations compared with LC-MS/MS, with more pronounced differences in high-concentration samples during acute-phase pneumonia. These findings should be considered in local method validations and in future harmonization and standardization optimization of hepcidin measurements.

Glycated albumin and post-transplant diabetes mellitus in kidney transplant recipients.

BACKGROUND: Post-transplant diabetes mellitus is one of the most important cardiovascular risk factors after solid organ transplantation. Factors other than hyperglycaemia found in patients post-transplant, affect the level of haemoglobin A1c (HbA1c), and new markers of hyperglycaemia are needed. Our aim was to establish a 95% reference interval for glycated albumin in kidney transplant recipients, and to compare glycated albumin concentrations to the diagnostic criteria for diabetes mellitus post-transplant using oral glucose tolerance test and HbA1c. METHODS: A total of 341 non-diabetic kidney transplant recipients aged ≥18 years who underwent an oral glucose tolerance test at 8 weeks and 1 year after transplantation were included. Glycated albumin was determined by liquid chromatography coupled with tandem mass spectrometry. RESULTS: The 95% reference interval for glycated albumin was 8.2 (90% CI: 7.2-8.5) to 12.8% (90% CI: 12.2-13.5) which is not significantly different from our laboratory's 95% reference interval for persons without diabetes. At both 8 weeks and 1 year after transplantation, 35 patients (10.3%) fulfilled one, two or all three diagnostic criteria for diabetes mellitus. One year after transplantation, eight additional patients had glycated albumin concentration >12.8%. CONCLUSION: Our findings are in accordance with the notion that kidney transplant recipients form glycation end products like normal controls as estimated by glycated albumin and HbA1c. Further studies should address glycated albumin as a supplemental tool for the diagnosis of post-transplant diabetes mellitus in kidney transplant recipients.

Glycated albumin and continuous glucose monitoring metrics across pregnancy in women with pre-gestational diabetes.

INTRODUCTION: Glycated albumin (GA), a biomarker reflecting short-term glycaemia, may be useful to assess glycaemic control in pregnancy. We examined the association between GA and continuous glucose monitoring (CGM) metrics across gestation. METHODS: In this prospective cohort study including 40 women with pre-gestational diabetes, blood samples for analysis of GA and glycated haemoglobin A1c (HbA1c) were collected at pregnancy week 12, 20, 24, 28, 32 and 36. In the CGM-group (n = 19), CGM data were collected from first trimester until pregnancy week 36. Receiver operating characteristic (ROC) curves were used to assess the accuracy of GA and HbA1c to detect poor glycaemic control, using CGM metrics as the reference standard. This study was conducted at Stavanger University Hospital, Norway, in 2016-2018. RESULTS: Glycaemic control improved across gestation with more time spent in target range, coinciding with decreased glycaemic variability and lower mean GA level. There was statistically significant correlation between GA and most CGM metrics. The area under the ROC curves (AUC) for detecting time in range <70% and time above range >25% for the pregnancy glucose target 63-140 mg/dl (3.5-7.8 mmol/L) were 0.78 and 0.82 for GA, whereas AUCs of 0.60 and 0.72 were found for HbA1c, respectively. CONCLUSIONS: Higher GA levels were associated with less time spent in target range, more time spent in the above range area and increased glycaemic variability. GA was more accurate than HbA1c to detect time above range >25% and time in range <70%.

Kinetics of 2 different high-sensitive troponins during targeted temperature management in out-of-hospital cardiac arrest patients with acute myocardial infarction: a post hoc sub-study of a randomised clinical trial.

INTRODUCTION: Short term hypothermia has been suggested to have cardio protective properties in acute myocardial infarction (AMI) by reducing infarct size as assessed by troponins. There are limited data on the kinetics of these biomarkers in comatose out-of-hospital cardiac arrest (OHCA) patients, with and without AMI, undergoing targeted temperature management (TTM) in the ICU. PURPOSE: The aim of this post hoc analyses was to evaluate and compare the kinetics of two high-sensitivity cardiac troponins in OHCA survivors, with and without acute myocardial infarction (AMI), during TTM of different durations [24 h (standard) vs. 48 h (prolonged)]. METHODS: In a sub-cohort (n = 114) of the international, multicentre, randomized controlled study "TTH48" we measured high-sensitive troponin T (hs-cTnT), high-sensitive troponin I (hs-cTnI) and CK-MB at the following time points: Arrival, 24 h, 48 h and 72 h from reaching the target temperature range of 33 ± 1 °C. All patients diagnosed with an AMI at the immediate coronary angiogram (CAG)-18 in the 24-h group and 25 in the 48-h group-underwent PCI with stent implantation. There were no stent thromboses. RESULTS: Both the hs-cTnT and hs-cTnI changes over time were highly influenced by the cause of OHCA (AMI vs. non-AMI). In contrast to non-AMI patients, both troponins remained elevated at 72 h in AMI patients. There was no difference between the two time-differentiated TTM groups in the kinetics for the two troponins. CONCLUSION: In comatose OHCA survivors with an aetiology of AMI levels of both hs-cTnI and hs-cTnT remained elevated for 72 h, which is in contrast to the well-described kinetic profile of troponins in normotherm AMI patients. There was no difference in kinetic profile between the two high sensitive assays. Different duration of TTM did not influence the kinetics of the troponins. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT01689077, 20/09/2012.

Predictors of long-term symptom burden and quality of life in patients hospitalised with chest pain: a prospective observational study.

OBJECTIVE: To describe the magnitude and predictors of symptom burden (SB) and quality of life (QoL) 3 months after hospital admission for acute chest pain. DESIGN: Prospective observational study. SETTING: Single centre, outpatient follow-up. PARTICIPANTS: 1506 patients. OUTCOMES: Scores reported for general health (RAND-12), angina-related health (Seattle Angina Questionnaire 7 (SAQ-7)) and dyspnoea (Rose Dyspnea Scale) 3 months after hospital admission for chest pain. METHODS: A total of 1506 patients received questionnaires assessing general health (RAND-12), angina-related health (SAQ-7) and dyspnoea (Rose Dyspnea Scale) 3 months after discharge. Univariable and multivariable regression models identified predictors of SB and QoL scores. A mediator analysis identified factors mediating the effect of an unstable angina pectoris (UAP) diagnosis. RESULTS: 774 (52%) responded. Discharge diagnoses were non-ST elevation myocardial infarction (NSTEMI) (14.2%), UAP (17.1%), non-coronary cardiac disease (6.6%), non-cardiac disease (6.3%) and non-cardiac chest pain (NCCP) (55.6%). NSTEMI had the most favourable, and UAP patients the least favourable SAQ-7 scores (median SAQ7-summary; 88 vs 75, p<0.001). NCCP patients reported persisting chest pain in 50% and dyspnoea in 33% of cases. After adjusting for confounders, revascularisation predicted better QoL scores, while UAP, current smoking and hypertension predicted worse outcome. NSTEMI and UAP patients who were revascularised reported higher scores (p<0.05) in SAQ-7-QL, SAQ7-PL, SAQ7-summary (NSTEMI) and all SAQ-7 domains (UAP). Revascularisation altered the unstandardised beta value (>±10%) of an UAP diagnosis for all SAQ-7 and RAND-12 outcomes. CONCLUSIONS: Patients with NSTEMI reported the most favourable outcome 3 months after hospitalisation for chest pain. Patients with other diseases, in particular UAP patients, reported lower scores. Revascularised NSTEMI and UAP patients reported higher QoL scores compared with patients receiving conservative treatment. Revascularisation mediated all outcomes in UAP patients. TRIAL REGISTRATION NUMBER: NCT02620202.

Association between symptoms and risk of non-ST segment elevation myocardial infarction according to age and sex in patients admitted to the emergency department with suspected acute coronary syndrome: a single-centre retrospective cohort study.

OBJECTIVES: Evaluate the association between symptoms and risk of non-ST segment elevation myocardial infarction (NSTEMI) in patients admitted to an emergency department with suspected acute coronary syndrome based on sex and age. DESIGN: Post hoc analysis of a prospective observational study conducted between September 2015 and May 2019. SETTING: University hospital in Norway. PARTICIPANTS: 1506 participants >18 years of age (39.6% women and 31.0% 70 years of age or older). FINDINGS: The OR for NSTEMI was 9.4 if pain radiated to both arms, 3.0 if exertional chest pain was present during the last week and 2.9 if pain occurred during activity. Men had significantly lower OR compared with women if pain was dependent of position, respiration or palpation (OR 0.17 vs 0.53, p value for interaction 0.047). Patients <70 years had higher predictive value than older patients if they reported exertional chest pain the last week (OR 4.08 vs 1.81, 95%, p value for interaction 0.025) and lower if pain radiated to the left arm (OR 0.73 vs 1.67, p value for interaction 0.045). CONCLUSIONS: Chest pain with radiation to both arms, exertional chest pain during the last week and pain during activity had the strongest predictive value for NSTEMI. The differences in symptom presentation and risk of NSTEMI between sex and age groups were small. TRIAL REGISTRATION NUMBER: WESTCOR study ClinicalTrials.gov (NCT02620202).

Glycated albumin in pregnancy: LC-MS/MS-based reference interval in healthy, nulliparous Scandinavian women and its diagnostic accuracy in gestational diabetes mellitus.

Glycated albumin (GA) may be a useful biomarker of glycemia in pregnancy. The aim of this study was to establish the reference interval (RI) for GA, analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS), in healthy, nulliparous pregnant women. In addition, we assessed the accuracy of GA and glycated hemoglobin A1c (HbA1c) in the diagnosis of gestational diabetes mellitus (GDM). Finally, we explored the prevalence of GDM in healthy nulliparas, comparing three diagnostic guidelines (WHO-1999, WHO-2013 and the Norwegian guideline). The study was carried out at Stavanger University Hospital, Norway, and included a study population of 147 pregnant nulliparous women. An oral glucose tolerance test (OGTT) was performed and used as the gold standard for GDM diagnosis. Blood samples for analysis of GA and HbA1c were collected at pregnancy week 24-28. A nonparametric approach was chosen for RI calculation, and receiver operating characteristic (ROC) curves were used to evaluate the diagnostic performance of GA and HbA1c. The established RI for GA in 121 pregnant women was 7.1-11.6%. The area under the ROC curves (AUCs) were 0.531 (GA) and 0.627 (HbA1c). According to the WHO-1999, WHO-2013 and the Norwegian guideline, respectively, 24 (16%), 36 (24%) and 21 (14%) women were diagnosed with GDM. Only nine women (6%) fulfilled the GDM-criteria of all guidelines. In conclusion, we established the first LC-MS/MS-based RI for GA in pregnant women. At pregnancy weeks 24-28, neither GA nor HbA1c discriminated between those with and without GDM. Different women were diagnosed with GDM using the three guidelines.

Hepcidin predicts 5-year mortality after community-acquired pneumonia.

BACKGROUND: Virtually all living organisms, including microbes and humans, depend on iron to survive and grow. During an infection, the plasma level of iron and several iron-related proteins change substantially. We hypothesized that iron and iron-related proteins could predict short- and long-term outcomes in community-acquired pneumonia. METHODS: Blood samples from a prospective cohort of 267 in-patients with community-acquired pneumonia were analysed for hepcidin, ferritin, iron, transferrin, transferrin saturation, and soluble transferrin receptor at admission and 6-weeks post-discharge. Adverse short-term outcome was defined as admission to intensive care unit or death within 30 days, and long-term outcome was assessed as 5-year overall mortality. Logistic regression, Kaplan Meier survival curves, and Cox regression models with cut-offs at median for the potential biomarkers were used for statistical evaluation. RESULTS: Low admission levels of hepcidin predicted 5-year overall mortality, independently of age, sex, comorbid conditions, and anaemia. Low levels of ferritin at admission as well as low levels of iron and transferrin saturation and high levels of soluble transferrin receptor at the 6-week follow-up were predictors of 5-year overall mortality in univariable, but not in multivariable analyses. Neither of these potential biomarkers predicted adverse short-term outcomes. CONCLUSIONS: In hospitalized patients with community-acquired pneumonia, low levels of hepcidin at admission predicted 5-year overall mortality, but not short-term adverse outcome.

Adding stress biomarkers to high-sensitivity cardiac troponin for rapid non-ST-elevation myocardial infarction rule-out protocols.

AIMS: This study tested the hypothesis that combining stress-induced biomarkers (copeptin or glucose) with high-sensitivity cardiac troponin (hs-cTn) increases diagnostic accuracy for non-ST-elevation myocardial infarction (NSTEMI) in patients presenting to the emergency department. METHODS AND RESULTS: The ability to rule-out NSTEMI for combinations of baseline hs-cTnT or hs-cTnI with copeptin or glucose was compared with the European Society of Cardiology (ESC) hs-cTnT/I-only rule-out algorithms in two independent (one Norwegian and one international multicentre) diagnostic studies. Among 959 patients (median age 64 years, 60.5% male) with suspected NSTEMI in the Norwegian cohort, 13% had NSTEMI. Adding copeptin or glucose to hs-cTnT/I as a continuous variable did not improve discrimination as quantified by the area under the curve {e.g. hs-cTnT/copeptin 0.91 [95% confidence interval (CI) 0.89-0.93] vs. hs-cTnT alone 0.91 (95% CI 0.89-0.93); hs-cTnI/copeptin 0.85 (95% CI 0.82-0.87) vs. hs-cTnI alone 0.93 (95% CI 0.91-0.95)}, nor did adding copeptin <9 mmol/L or glucose <5.6 mmol/L increase the sensitivity of the rule-out provided by hs-cTnT <5 ng/L or hs-cTnI <4 ng/L in patients presenting more than 3 h after chest pain onset (target population in the ESC-0 h-algorithm). The combination decreased rule-out efficacy significantly (both P < 0.01). These findings were confirmed among 1272 patients (median age 62 years, 69.3% male) with suspected NSTEMI in the international validation cohort, of which 20.7% had NSTEMI. A trend towards increased sensitivity for the hs-cTnT/I/copeptin combinations (97-100% vs. 91-97% for the ESC-0 h-rule-out cut-offs) was observed in the Norwegian cohort. CONCLUSION: Adding copeptin or glucose to hs-cTnT/I did not increase diagnostic performance when compared with current ESC guideline hs-cTnT/I-only 0 h-algorithms.

Diagnostic Performance of Novel Troponin Algorithms for the Rule-Out of Non-ST-Elevation Acute Coronary Syndrome.

BACKGROUND: The European Society of Cardiology (ESC) rule-out algorithms use cutoffs optimized for exclusion of non-ST elevation myocardial infarction (NSTEMI). We investigated these and several novel algorithms for the rule-out of non-ST elevation acute coronary syndrome (NSTE-ACS) including less urgent coronary ischemia. METHOD: A total of 1504 unselected patients with suspected NSTE-ACS were included and divided into a derivation cohort (n = 988) and validation cohort (n = 516). The primary endpoint was the diagnostic performance to rule-out NSTEMI and unstable angina pectoris during index hospitalization. The secondary endpoint was combined MI, all-cause mortality (within 30 days) and urgent (24 h) revascularization. The ESC algorithms for high-sensitivity cardiac troponin T (hs-cTnT) and I (hs-cTnI) were compared to different novel low-baseline (limit of detection), low-delta (based on the assay analytical and biological variation), and 0-1-h and 0-3-h algorithms. RESULTS: The prevalence of NSTE-ACS was 24.8%, 60.0% had noncardiac chest pain, and 15.2% other diseases. The 0-1/0-3-h algorithms had superior clinical sensitivity for the primary endpoint compared to the ESC algorithm (validation cohort); hs-cTnT: 95% vs 63%, and hs-cTnI: 87% vs 64%, respectively. Regarding the secondary endpoint, the algorithms had similar clinical sensitivity (100% vs 94%-96%) but lower clinical specificity (41%-19%) compared to the ESC algorithms (77%-74%). The rule-out rates decreased by a factor of 2-4. CONCLUSION: Low concentration/low-delta troponin algorithms improve the clinical sensitivity for a combined endpoint of NSTEMI and unstable angina pectoris, with the cost of a substantial reduction in total rule-out rate. There was no clear benefit compared to ESC for diagnosing high-risk events.

Myocardial inefficiency is an early indicator of exercise-induced myocardial fatigue.

Background: The effect of prolonged, high-intensity endurance exercise on myocardial function is unclear. This study aimed to determine the left ventricular (LV) response to increased exercise duration and intensity using novel echocardiographic tools to assess myocardial work and fatigue. Materials and methods: LV function was assessed by echocardiography before, immediately, and 24 h after a cardiopulmonary exercise test (CPET) and a 91-km mountain bike leisure race. Cardiac Troponin I (cTnI) was used to assess myocyte stress. Results: 59 healthy recreational athletes, 52 (43-59) years of age, 73% males, were included. The race was longer and of higher intensity generating higher cTnI levels compared with the CPET (p < 0.0001): Race/CPET: exercise duration: 230 (210, 245)/43 (40, 45) minutes, mean heart rate: 154 ± 10/132 ± 12 bpm, max cTnI: 77 (37, 128)/12 (7, 23) ng/L. Stroke volume and cardiac output were higher after the race than CPET (p < 0.005). The two exercises did not differ in post-exercise changes in LV ejection fraction (LVEF) or global longitudinal strain (GLS). There was an increase in global wasted work (p = 0.001) following the race and a persistent reduction in global constructive work 24 h after exercise (p = 0.003). Conclusion: Increased exercise intensity and duration were associated with increased myocardial wasted work post-exercise, without alterations in LVEF and GLS from baseline values. These findings suggest that markers of myocardial inefficiency may precede reduction in global LV function as markers of myocardial fatigue.

Determinants of Interindividual Variation in Exercise-Induced Cardiac Troponin I Levels.

Background Postexercise cardiac troponin levels show considerable interindividual variations. This study aimed to identify the major determinants of this postexercise variation in cardiac troponin I (cTnI) following 3 episodes of prolonged high-intensity endurance exercise. Methods and Results Study subjects were recruited among prior participants in a study of recreational cyclists completing a 91-km mountain bike race in either 2013 or 2014 (first race). In 2018, study participants completed a cardiopulmonary exercise test 2 to 3 weeks before renewed participation in the same race (second race). Blood was sampled before and at 3 and 24 hours following all exercises. Blood samples were analyzed using the same Abbot high-sensitivity cTnI STAT assay. Fifty-nine individuals (aged 50±9 years, 13 women) without cardiovascular disease were included. Troponin values were lowest before, highest at 3 hours, and declining at 24 hours. The largest cTnI difference was at 3 hours following exercise between the most (first race) (cTnI: 200 [87-300] ng/L) and the least strenuous exercise (cardiopulmonary exercise test) (cTnI: 12 [7-23] ng/L; P<0.001). The strongest correlation between troponin values at corresponding times was before exercise (r=0.92, P<0.0001). The strongest correlations at 3 hours were between the 2 races (r=0.72, P<0.001) and at 24 hours between the cardiopulmonary exercise test and the second race (r=0.83, P<0.001). Participants with the highest or lowest cTnI levels showed no differences in race performance or baseline echocardiographic parameters. Conclusions The variation in exercise-induced cTnI elevation is largely determined by a unique individual cTnI response that is dependent on the duration of high-intensity exercise and the timing of cTnI sampling. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02166216.

Regular consumption of cod liver oil is associated with reduced basal and exercise-induced C-reactive protein levels; a prospective observational trial : A NEEDED (The North Sea Race Endurance Exercise Study) 2014 sub-study.

BACKGROUND: Dietary supplement use among recreational athletes is common, with the intention of reducing inflammation and improving recovery. We aimed to describe the relationship between omega-3 fatty acid supplement use and inflammation induced by strenuous exercise. METHODS: C-reactive protein (CRP) concentrations were measured in 1002 healthy recreational athletes before and 24 h after a 91-km bicycle race. The use of omega-3 fatty acid supplements was reported in 856 out of 1002 recreational athletes, and the association between supplement use and the exercise-induced CRP response was assessed. RESULTS: Two hundred seventy-four subjects reported regular use of omega-3 fatty acid supplements. One hundred seventy-three of these used cod liver oil (CLO). Regular users of omega-3 fatty acid supplements had significantly lower basal and exercise-induced CRP levels as compared to non-users (n = 348, p < 0.001). Compared to non-users, regular users had a 27% (95% confidence interval (CI): 14-40) reduction in Ln CRP response (unadjusted model, p < 0.001) and 16% (95% CI: 5-28, p = 0.006) reduction after adjusting for age, sex, race duration, body mass index, delta creatine kinase, MET hours per week, resting heart rate and higher education. CLO was the primary driver of this response with a 34% (95% CI: 19-49) reduction (unadjusted model, p < 0.001) compared to non-users. Corresponding numbers in the adjusted model were 24% (95% CI: 11-38, p < 0.001). CONCLUSION: Basal CRP levels were reduced, and the exercise-induced CRP response was attenuated in healthy recreational cyclists who used omega-3 fatty acid supplements regularly. This effect was only present in regular users of CLO. TRIAL REGISTRATION: NCT02166216 , registered June 18, 2014 - Retrospectively registered.