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Aims: Cardiac troponin plays an essential role in the management of non-ST segment elevation acute coronary syndrome (NSTE-ACS). However, it is not clear whether troponin concentrations provide guidance regarding the initiation of prognostically beneficial cardiovascular medications [i.e. betablockers, renin-angiotensin-aldosterone system (RAAS) inhibitors, and statins] in NSTE-ACS., Methods and Results: Registry-based study investigating three NSTE-ACS cohorts (n = 43 075, 40 162, and 46 698) with elevated high-sensitivity cardiac troponin concentrations >14 ng/L. Cox proportional regression models with the addition of interaction terms were used to analyse the interrelations of high-sensitivity cardiac troponin T (hs-cTnT) concentrations, new initiated medications with the respective three drug classes, and long-term risk of all-cause mortality and major adverse events (MAE). Betablockers were associated with risk reductions of 8 and 5% regarding all-cause mortality and MAE, respectively. There was no evidence of an interaction with hs-cTnT concentrations. RAAS inhibitors were associated with 13 and 8% risk reductions, respectively, with a weak interaction between hs-cTnT and MAE (Pinteraction = 0.016). However, no increasing prognostic benefit was noted at hs-cTnT concentrations >100 ng/L. Statins were associated with 38 and 32% risk reductions, respectively, with prognostic benefit across the entire range of hs-cTnT concentrations, and with a weak interaction regarding MAE (Pinteraction = 0.011)., Conclusion: Cardiovascular medications provide different prognostic benefit in patients with NSTE-ACS with elevated hs-cTnT, and there was some evidence of greater treatment effects regarding MAE along with higher hs-cTnT concentrations. However, hs-cTnT appears only to have limited value overall for customizing such treatments., Competing Interests: Conflict of interest: K.M.E. has served as a consultant for Roche Diagnostics. L.L. and B.L. had no conflicts to disclose., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Importance: Identification of individuals at high risk for atherosclerotic cardiovascular disease within the population is important to inform primary prevention strategies., Objective: To evaluate the prognostic value of routinely available cardiovascular biomarkers when added to established risk factors., Design, Setting, and Participants: Individual-level analysis including data on cardiovascular biomarkers from 28 general population-based cohorts from 12 countries and 4 continents with assessments by participant age. The median follow-up was 11.8 years., Exposure: Measurement of high-sensitivity cardiac troponin I, high-sensitivity cardiac troponin T, N-terminal pro-B-type natriuretic peptide, B-type natriuretic peptide, or high-sensitivity C-reactive protein., Main Outcomes and Measures: The primary outcome was incident atherosclerotic cardiovascular disease, which included all fatal and nonfatal events. The secondary outcomes were all-cause mortality, heart failure, ischemic stroke, and myocardial infarction. Subdistribution hazard ratios (HRs) for the association of biomarkers and outcomes were calculated after adjustment for established risk factors. The additional predictive value of the biomarkers was assessed using the C statistic and reclassification analyses., Results: The analyses included 164 054 individuals (median age, 53.1 years [IQR, 42.7-62.9 years] and 52.4% were women). There were 17 211 incident atherosclerotic cardiovascular disease events. All biomarkers were significantly associated with incident atherosclerotic cardiovascular disease (subdistribution HR per 1-SD change, 1.13 [95% CI, 1.11-1.16] for high-sensitivity cardiac troponin I; 1.18 [95% CI, 1.12-1.23] for high-sensitivity cardiac troponin T; 1.21 [95% CI, 1.18-1.24] for N-terminal pro-B-type natriuretic peptide; 1.14 [95% CI, 1.08-1.22] for B-type natriuretic peptide; and 1.14 [95% CI, 1.12-1.16] for high-sensitivity C-reactive protein) and all secondary outcomes. The addition of each single biomarker to a model that included established risk factors improved the C statistic. For 10-year incident atherosclerotic cardiovascular disease in younger people (aged <65 years), the combination of high-sensitivity cardiac troponin I, N-terminal pro-B-type natriuretic peptide, and high-sensitivity C-reactive protein resulted in a C statistic improvement from 0.812 (95% CI, 0.8021-0.8208) to 0.8194 (95% CI, 0.8089-0.8277). The combination of these biomarkers also improved reclassification compared with the conventional model. Improvements in risk prediction were most pronounced for the secondary outcomes of heart failure and all-cause mortality. The incremental value of biomarkers was greater in people aged 65 years or older vs younger people., Conclusions and Relevance: Cardiovascular biomarkers were strongly associated with fatal and nonfatal cardiovascular events and mortality. The addition of biomarkers to established risk factors led to only a small improvement in risk prediction metrics for atherosclerotic cardiovascular disease, but was more favorable for heart failure and mortality.

Objectives: Biomarker concentrations and their changes during acute coronary syndrome (ACS) provide clinically useful information on pathophysiological processes, e.g. myocardial necrosis, hemodynamic stress and inflammation. However, current evidence on temporal biomarker patterns early during ACS is limited, and studies investigating multiple biomarkers are lacking., Methods: We measured concentrations of high-sensitivity cardiac troponin T (hs-cTnT) and I (hs-cTnI), NT-terminal pro-B-type natriuretic peptide, C-reactive protein, and growth-differentiation factor-15 (GDF-15) in plasma samples obtained at randomization in ACS patients from the PLATelet inhibition and patient Outcomes (PLATO) trial. Linear regressions with interaction analyses were used to investigate the associations of biomarker concentrations with the time from symptom onset and to model temporal biomarker concentration patterns., Results: The study population consisted of 16,944 patients (median age 62 years; 71.3 % males) with 6,853 (40.3 %) having ST-elevation myocardial infarction (STEMI) and 10,141 (59.7 %) having non-ST-elevation ACS (NSTE-ACS). Concentrations of all biomarkers were associated with time from symptom onset (p interaction <0.001), apart for GDF-15 (p interaction =0.092). Concentration increases were more pronounced in STEMI compared to NSTE-ACS. Temporal biomarker patterns for hs-cTnT and hs-cTnI were different depending on sex whereas biomarker patterns for the other biomarkers were similar in cohorts defined by age and sex., Conclusions: Temporal concentration patterns differ for various biomarkers early during ACS, reflecting the variability in the activation and duration of different pathophysiological processes, and the amount of injured myocardium. Our data emphasize that the time elapsed from symptom onset should be considered for the interpretation of biomarker results in ACS., (© 2024 the author(s), published by De Gruyter, Berlin/Boston.)

Background: Sex-differences in the pathobiology of myocardial infarction are well established but incompletely understood. Improved knowledge on this topic may help clinicians to improve management of men and women with myocardial infarction., Methods: In this registry-based cohort study (SWEDEHEART), we analyzed 175 circulating biomarkers reflecting various pathobiological axes in 856 men and 243 women admitted to Swedish coronary care units because of myocardial infarction. Two multimarker panels were applied (Proximity Extension Assay [Olink Bioscience], Multiple Reaction Monitoring mass spectrometry). Lasso analysis (penalized logistic regression), multiple testing-corrected Mann-Whitney tests and Cox regressions were used to assess sex-differences in the concentrations of these biomarkers and their implications on all-cause mortality and major adverse events (median follow-up up to 6.6 years)., Results: Biomarkers provided a very high discrimination between both sexes, when considered simultaneously (c-statistics 0.972). Compared to women, men had higher concentrations of six biomarkers with the most pronounced differences seen for those reflecting atherogenesis, myocardial necrosis and metabolism. Women had higher concentrations of 14 biomarkers with the most pronounced differences seen for those reflecting activation of the renin-angiotensin-aldosterone axis, inflammation and for adipokines. There were no major variations between sexes in the associations of these biomarkers with outcome., Conclusions: Severable sex-differences exist in the expression of biomarkers in patients with myocardial infarction. While these differences had no impact on outcome, our data suggest the presence of various sex-related pathways involved in the development of coronary atherosclerosis, the progression to plaque rupture and acute myocardial damage, with a greater heterogeneity in women., Competing Interests: The authors have declared that no competing interests exist.

Background: Around 5%-10% of patients with myocardial infarction (MI) present with nonobstructive coronary arteries (MINOCA). We aimed to assess pathophysiological mechanisms in MINOCA by extensively evaluating cardiovascular biomarkers in the stable phase after an event, comparing MINOCA patients with cardiovascular healthy controls and MI patients with obstructive coronary artery disease (MI-CAD)., Methods: Ninety-one biomarkers were measured with a proximity extension assay 3 months after MI in 97 MINOCA patients, 97 age- and sex-matched MI-CAD patients, and 98 controls. Lasso analyses (penalized logistic regression models) and adjusted multiple linear regression models were used for statistical analyses., Results: In the Lasso analysis (MINOCA vs MI-CAD), 8 biomarkers provided discriminatory value: P-selectin glycoprotein ligand 1, C-X-C motif chemokine 1, TNF-related activation-induced cytokine, and pappalysin-1 (PAPPA) with increasing probabilities of MINOCA, and tissue-type plasminogen activator, B-type natriuretic peptide, myeloperoxidase, and interleukin-1 receptor antagonist protein with increasing probabilities of MI-CAD. Comparing MINOCA vs controls, 7 biomarkers provided discriminatory value: N-terminal pro-B-type natriuretic peptide, renin, NF-κ-B essential modulator, PAPPA, interleukin-6, and soluble urokinase plasminogen activator surface receptor with increasing probabilities of MINOCA, and agouti-related protein with increasing probabilities of controls. Adjusted multiple linear regression analyses showed that group affiliation was associated with the concentrations of 7 of the 8 biomarkers in the comparison MINOCA vs MI-CAD and 5 of the 7 biomarkers in MINOCA vs controls., Conclusions: Three months after the MI, the biomarker concentrations indicated greater inflammatory activity in MINOCA patients than in both MI-CAD patients and healthy controls, and a varying degree of myocardial dysfunction among the 3 cohorts., (© 2019 American Association for Clinical Chemistry.)

Background: There is increasing interest in measurements of cardiovascular (CV) biomarker concentrations for risk prediction in the general population. We investigated the prognostic utility of a panel of novel CV biomarkers including biomarker changes over time., Methods: We measured concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP), midregional proadrenomedullin, high-sensitivity cardiac troponin I, growth-differentiation factor-15 (GDF-15), soluble ST2 (sST2), and galectin-3 at baseline and 5 years later in 1016 elderly individuals participating in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Assessed outcomes included all-cause mortality and fatal and nonfatal CV events (in participants without CV disease at baseline) during 10 years of follow-up., Results: GDF-15 exhibited the strongest association with all-cause mortality (n = 158) with a hazard ratio (HR) per 1-SD increase in standardized ln GDF-15 of 1.68 (95% CI, 1.44-1.96). NT-proBNP was the only biomarker to predict CV events (n = 163; HR 1.54 [95% CI, 1.30-1.84]). GDF-15 and NT-proBNP also improved metrics of discrimination and reclassification of the respective outcomes. Changes in GDF-15 concentrations between 70 and 75 years predicted all-cause mortality whereas changes in NT-proBNP predicted both outcomes. The other biomarkers and their temporal changes provided only moderate prognostic value apart from sST2 which had a neutral relationship with adverse events., Conclusions: Evaluation of temporal changes in GDF-15 and NT-proBNP concentrations improves risk prediction in an elderly population. These findings are of considerable interest given the emphasis on biomarkers as tools to identify and monitor at-risk individuals with preclinical and potentially modifiable stages of CV disease., (© 2015 American Association for Clinical Chemistry.)

Aims: The increasing importance of cardiac disease has generated an interest in improved screening strategies regarding preclinical cardiac abnormalities and employing measurement of circulating biomarkers. This review focuses on the utility of the B-type natriuretic peptides (NP) and the cardiac troponins (cTns) for this purpose., Results: Both the NPs and the cTns are closely related to cardiac structural and functional abnormalities that may progress to symptomatic heart disease, e.g., left ventricular (LV) hypertrophy, LV systolic and diastolic dysfunction. Both biomarkers provide incremental information to each other. However, biomarker results may be confounded by several non-cardiac conditions, and decision thresholds and recommendations on further clinical work-up are as yet not specified. Furthermore, cost issues will probably preclude widespread biomarker screening in general populations., Conclusions: Measurement of the NPs or cTns is an attractive option for screening for cardiac abnormalities. This may be particularly effective in patients at higher risk for developing overt heart disease. Nevertheless, appropriate diagnostic and therapeutic responses to biomarker results need to be defined before routine screening can be recommended in the community setting.

Objectives: Patients with unrecognized myocardial infarction (UMI) scars detected by delayed-enhanced magnetic resonance imaging (DE-MRI) have a decreased left ventricular ejection fraction and an increased left ventricular mass. N-terminal pro-brain natriuretic peptide (NT-proBNP) is a marker of heart failure, and troponin I (TnI) is a marker of myocardial injury. The primary aim of this study was to investigate whether NT-proBNP plasma levels (in addition to ejection fraction) differed in patients with UMI scars compared with normal participants. The second aim was to compare whether the TnI levels differed in those two groups., Methods: Data from the Prospective Investigation of Vasculature in Uppsala Seniors study were used. The participants who had undergone cardiac MRI were included in this study (n=248). Patients were divided into three groups depending on the existence of a myocardial infarction (MI) scar in DE-MRI and their earlier history of MI. In all the patients, a peripheral blood sample was collected and the plasma levels of NT-proBNP and TnI were determined., Results: Patients with UMI had higher plasma levels of NT-proBNP (median 140.2 ng/l; 25th-75th percentiles: 79-225.5) than no-MI participants (median 94.9 ng/l; 25th-75th percentiles: 59.2-144.2; P=0.01) and lower levels than patients with recognized MI (median 310.4 ng/l; 25th-75th percentiles: 122.6-446.5; P=0.02). Plasma TnI values did not differ among the three groups., Conclusion: Patients with UMI scars detected by DE-MRI have increased plasma levels of NT-proBNP that is known to correlate with an increased risk of future cardiovascular adverse events.

Background: Myeloperoxidase (MPO) has been listed as a potentially useful risk marker in acute coronary syndrome. However, its clinical utility in patients with acute chest pain is not yet defined., Design and Methods: MPO (Architect, Abbott Diagnostics) was measured in 120 healthy controls and 303 chest pain patients who had been admitted to the coronary care units of three Swedish hospitals., Results: Chest pain patents had significantly higher median MPO levels compared to healthy controls (120.6 vs. 78. 9 pmol/L; p<0.001). However, MPO was not useful for the diagnosis of myocardial infarction (c-statistics 0.61 [95% CI 0.54-0.67]), and Cox regression analysis revealed no independent association between MPO and mortality (adjusted hazard ratio 1.3 [95% CI 0.8-2.0]) or the composite endpoint (adjusted hazard ratio 1.1 [95% CI 0.8-1.5]) after a median follow-up of 4.9 years., Conclusions: MPO provided no clinically relevant information in the present population of chest pain patients., ((c) 2009 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Aims: Growth-differentiation factor-15 (GDF-15) has emerged as a biomarker of increased mortality and recurrent myocardial infarction (MI) in patients diagnosed with non-ST-elevation acute coronary syndrome. We explored the usefulness of GDF-15 for early risk stratification in 479 unselected patients with acute chest pain., Methods and Results: Sixty-nine per cent of the patients presented with GDF-15 levels above the previously defined upper reference limit (1200 ng/L). The risks of the composite endpoint of death or (recurrent) MI after 6 months were 1.3, 5.1, and 12.6% in patients with normal (<1200 ng/L), moderately elevated (1200-1800 ng/L), or markedly elevated (>1800 ng/L) levels of GDF-15 on admission, respectively (P < 0.001). By multivariable analysis that included clinical characteristics, ECG findings, peak cardiac troponin I levels within 2 h (cTnI(0-2 h)), N-terminal pro-B-type natriuretic peptide, C-reactive protein, and cystatin C, GDF-15 remained an independent predictor of the composite endpoint. The ability of the ECG combined with peak cTnI(0-2 h) to predict the composite endpoint was markedly improved by addition of GDF-15 (c-statistic, 0.74 vs. 0.83; P < 0.001)., Conclusion: GDF-15 improves risk stratification in unselected patients with acute chest pain and provides prognostic information beyond clinical characteristics, the ECG, and cTnI.

Background: Early risk stratification of patients with chest pain may be improved by combining cardiac Troponin I (cTnI) results and ECG findings with markers of left-ventricular dysfunction, inflammation or renal function., Methods: Serial measurements of cTnI were prospectively performed in 452 chest pain patients with a non-diagnostic ECG for AMI and admitted to the coronary care unit. NT-pro BNP, CRP, cystatin C and creatinine-clearance were retrospectively analyzed in admission samples. The prognostic value of these markers alone and in different combinations together with ECG findings was evaluated by multivariate logistic regression models., Results: During follow-up, 14 deaths and 21 myocardial (re)-infarctions occurred. Independent predictors for the combined endpoint of death or (re)-infarction were peak cTnI >or=0.1 microg/L within 24 h (OR 3.9; 95% confidence interval [CI]1.5-10.4), cystatin C >or=1.28 mg/L (OR 5.6; 95% CI 1.9-16.3) and NT-pro BNP >or=550 ng/L (OR 2.7; 95% CI 1.0-7.3). At 2 h from admission, a combination of cTnI >or=0.1 microg/L, an abnormal ECG and NT-pro BNP or cystatin C as a third variable resulted in a similar stratification of patients to different risk groups., Conclusion: cTnI, NT-pro BNP and cystatin C are strong risk predictors in patients with chest pain. For pragmatic reasons, a combination of cTnI >or=0.1 microg/L, ECG findings and a marker of renal function, preferably cystatin C, appears to be most appropriate for early risk stratification of these patients.

Differences in biomarkers reflective of pathobiology and prognosis between ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI) are incompletely understood and may offer insights for tailoring of treatment. This registry-based study included 538 STEMI and 544 NSTEMI patients admitted 2008–2014. Blood samples were collected day 1–3 after admission and 175 biomarkers were analyzed using Proximity Extension Assay and Multiple Reaction Monitoring mass spectrometry. Adjusted Lasso analysis (penalized logistic regression model) was used to select biomarkers that discriminated STEMI from NSTEMI patients. Biomarkers identified by the Lasso analysis were then evaluated in adjusted Cox regressions for associations with death or major adverse cardiovascular events. Biomarkers strongly discriminated STEMI and NSTEMI when considered simultaneously in adjusted Lasso analysis (c-statistic 0.764). Eleven biomarkers independently discriminated STEMI and NSTEMI; seven showing higher concentrations in STEMI: myoglobin, N-terminal pro-B-type natriuretic peptide, serum amyloid A-1 and A-2 protein, ST2 protein, interleukin-6 and chitinase-3-like protein 1; and four showing higher concentrations in NSTEMI: fibroblast growth factor 23, membrane-bound aminopeptidase P, tumor necrosis factor-related activation-induced cytokine and apolipoprotein C-I. During up to 6.6 years of prognostic follow-up, none of these biomarkers exhibited different associations with adverse outcome between STEMI and NSTEMI. In the acute setting, biomarkers indicated greater myocardial dysfunction and inflammation in STEMI, whereas they displayed a more diverse pathophysiologic pattern in NSTEMI patients. These biomarkers were similarly prognostic in STEMI and NSTEMI patients. The results do not support treating STEMI and NSTEMI patients differently based on the concentrations of these biomarkers. [ABSTRACT FROM AUTHOR]

Background: Higher body mass index (BMI) is associated with better outcome compared with normal weight in patients with HF and other chronic diseases. It remains uncertain whether the apparent protective role of obesity relates to the absence of comorbidities. Therefore, we investigated the effect of BMI on outcome in younger patients without co-morbidities as compared to older patients with co-morbidities in a large heart failure (HF) population. Methods: In an individual patient data analysis from pooled cohorts, 5,819 patients with chronic HF and data available on BMI, co-morbidities and outcome were analysed. Patients were divided into four groups based on BMI (i.e. ≤ 18.5 kg/m2, 18.5–25.0 kg/m2; 25.0–30.0 kg/m2; 30.0 kg/m2). Primary endpoints included all-cause mortality and HF hospitalization-free survival. Results: Mean age was 65 ± 12 years, with a majority of males (78%), ischaemic HF and HF with reduced ejection fraction. Frequency of all-cause mortality or HF hospitalization was significantly worse in the lowest two BMI groups as compared to the other two groups; however, this effect was only seen in patients older than 75 years or having at least one relevant co-morbidity, and not in younger patients with HF only. After including medications and N-terminal pro-B-type natriuretic peptide and high-sensitivity cardiac troponin concentrations into the model, the prognostic impact of BMI was largely absent even in the elderly group with co-morbidity. Conclusions: The present study suggests that obesity is a marker of less advanced disease, but does not have an independent protective effect in patients with chronic HF. Categories of BMI are only predictive of poor outcome in patients aged > 75 years or with at least one co-morbidity (bottom), but not in those aged < 75 years without co-morbidities (top). The prognostic effect largely disappears in multivariable analyses even for the former group. These findings question the protective effect of obesity in chronic heart failure (HF). [ABSTRACT FROM AUTHOR]

Background: Myocardial infarction with nonobstructive coronary arteries (MINOCA) is a heterogeneous condition. Recent studies suggest that MINOCA patients may have a proinflammatory disposition. The role of inflammation in MINOCA may thus be distinct to myocardial infarction with significant coronary artery disease (MI‐CAD). Hypothesis: We hypothesized that inflammation reflected by C‐reactive protein (CRP) levels might carry unique clinical information in MINOCA. Methods: This retrospective registry‐based cohort study (SWEDEHEART) included 9916 patients with MINOCA and 97 970 MI‐CAD patients, used for comparisons. Multivariable‐adjusted regressions were applied to investigate the associations of CRP levels with clinical variables, all‐cause mortality and major cardiovascular events (MACE) during a median follow‐up of up to 5.3 years. Results: Median admission CRP levels in patients with MINOCA and MI‐CAD were 5.0 (interquartile range 2.0–9.0) mg/dl and 5.0 (interquartile range 2.1–10.0 mg/dl), respectively. CRP levels in MINOCA exhibited independent associations with various cardiovascular risk factors, comorbidities and estimates of myocardial damage. The association of CRP with peripheral artery disease tended to be stronger compared to MI‐CAD. The associations with female sex, renal dysfunction and myocardial damage were stronger in MI‐CAD. CRP independently predicted all‐cause mortality in MINOCA (hazard ratio 1.22 [95% confidence interval 1.17–1.26]), similar to MI‐CAD (p interaction = 0.904). CRP also predicted MACE (hazard ratio 1.08 [95% confidence interval 1.04–1.12]) but this association was weaker compared to MI‐CAD (p interaction<.001). Conclusions: We found no evidence indicating the presence of a specific inflammatory pattern in acute MINOCA compared to MI‐CAD. However, CRP levels were independently, albeit moderately associated with adverse outcome. [ABSTRACT FROM AUTHOR]

Aims: N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP), high‐sensitivity troponin T (hs‐TnT) and soluble suppression of tumorigenesis‐2 (sST2) predict outcome in chronic heart failure (HF). We assessed the influence of age on circulating levels and prognostic significance of these biomarkers. Methods and results: Individual data from 5301 patients with chronic HF and NT‐proBNP, hs‐TnT, and sST2 data were evaluated. Patients were stratified according to age: <60 years (n = 1332, 25%), 60–69 years (n = 1628, 31%), 70–79 years (n = 1662, 31%), and ≥ 80 years (n = 679, 13%). Patients (median age 66 years, 75% men, median left ventricular ejection fraction 28%, 64% with ischaemic HF) had median NT‐proBNP 1564 ng/L, hs‐TnT 21 ng/L, and sST2 29 ng/mL. Age independently predicted NT‐proBNP and hs‐TnT, but not sST2. The best NT‐proBNP and hs‐TnT cut‐offs for 1‐year and 5‐year all‐cause and cardiovascular mortality and 1‐ to 12‐month HF hospitalization increased with age, while the best sST2 cut‐offs did not. When stratifying patients according to age‐ and outcome‐specific cut‐offs, this stratification yielded independent prognostic significance over NT‐proBNP levels only, or the composite of NT‐proBNP and hs‐TnT, and improved risk prediction for most endpoints. Finally, absolute NT‐proBNP, hs‐TnT, and sST2 levels predicted outcomes independent of age, sex, left ventricular ejection fraction category, ethnic group, and other variables. Conclusions: Soluble ST2 is less influenced by age than NT‐proBNP or hs‐TnT; all these biomarkers predict outcome regardless of age. The use of age‐ and outcome‐specific cut‐offs of NT‐proBNP, hs‐TnT and sST2 allows more accurate risk stratification than NT‐proBNP alone or the combination of NT‐proBNP and hs‐TnT. [ABSTRACT FROM AUTHOR]

Background Cardiac troponin (cTn) is the biomarker of choice for assessment of patients with acute coronary syndromes. Guidelines recommend the cTn 99th percentile derived from a cardiovascular healthy reference population as decision threshold. The importance of standardized criteria for the composition of such a reference population is well acknowledged. In this analysis, we investigated to which extent different statistical methods might have bearing on the calculated cTnI 99th percentile. Methods cTnI (Abbott) 99th percentiles were determined in 521 cardiovascular healthy community-dwelling subjects using the nonparametric method, the Harrell-Davis bootstrap method and the robust method together with different tests to identify potential outliers (Dixon, Tukey, Reed) and different statistical softwares. Results The cTnI 99th percentiles (nonparametric method) were 37 ng/L (total population), 42 ng/L (men) and 25 ng/L (women). These estimates differed by − 7.4% to + 5.7% using the Harrell-Davis bootstrap method and were up to 64.1% lower using the robust method. For the robust method, cTnI 99th percentiles varied by 44.2% depending on the applied software. The method of Tukey classified nine subjects as outliers while no outlier was detected using the other methods. Excluding these nine subjects resulted in up to 60.2% lower cTnI 99th percentiles. Conclusions Our results emphasize the need of a standardized statistical approach to calculate cTnI 99th percentiles. Our findings support the use of the nonparametric method and a conservative approach to detect outliers. This requires that the assessed population is sufficiently large and well selected on the basis of stringently applied clinical criteria. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Pentraxin 3 (PTX3) is the prototype of the long pentraxin family. PTX3 is involved in inflammatory processes affecting the cardiovascular system, and PTX3 levels have been shown to be elevated and independently prognostic in ST-elevation myocardial infarction. Data on PTX3 levels in non-ST-elevation acute coronary syndrome (NSTE-ACS), in contrast, are limited. The aim of the present analysis was to investigate the implications of PTX3 levels in a fairly large sample of NSTE-ACS patients and in comparison to levels of C-reactive protein (CRP). Design and methods: We measured levels of PTX3 and CRP in both 82 healthy controls and 401 NSTE-ACS patients from the GUSTO IV study, and studied the associations of these biomarkers to clinical data and 1-year mortality. Results: NSTE-ACS patients had significantly higher median PTX3 levels compared to healthy controls (3.8 vs. 1.9μg/L; p<0.001). PTX3 levels in patients with NSTE-ACS were independently related to female sex and cardiac troponin T levels, but not to age or cardiovascular risk factors. PTX3 levels were higher in patients who died within 1year but did not emerge as an independent predictor of 1-year mortality (adjusted OR 1.2 [95% CI 0.6–2.3]). This was in contrast to CRP (adjusted OR 1.5 [95% CI 1.1–2.3]). Neither PTX3 nor CRP yielded significant discriminative value regarding mortality prediction. Conclusions: PTX3 levels are elevated in NSTE-ACS. However, the prognostic information provided by PTX3 levels is limited and inferior compared to CRP. Our data, thus, do not support the measurement of PTX3 in patients with NSTE-ACS. [Copyright &y& Elsevier]

Abstract: Background: The mid-regional part of the prohormone of adrenomedullin (MR-proADM) is emerging as a novel risk indicator in patients with cardiac disease. We investigated MR-proADM levels and their changes over 5years in elderly community-dwellers, together with the underlying cardiovascular and metabolic conditions, and the prognostic implications of these measurements. Methods and results: MR-proADM was analyzed using a sandwich immunoassay (Thermo Fisher Scientific) in participants from the PIVUS study. Measurements were performed at 70 (n=1002) and 75years of age (n=795) together with various measurements of other markers of cardiovascular function. In cross-sectional analyses, MR-proADM was independently related to current smoking, renal dysfunction, obesity, lower left-ventricular ejection fraction, and higher levels of N-terminal pro-B-type natriuretic peptide and C-reactive protein. There were no independent associations to other cardiovascular risk factors or vascular pathologies. MR-proADM levels predicted all-cause mortality during 8.0years of follow-up independent of cardiovascular risk indicators (adjusted HR 5.1 [95% CI 2.8–9.5]; p<0.001) using results obtained at 70 and 75years as updated covariates. Baseline MR-proADM levels improved prognostic discrimination (IDI=0.018 [p=0.001]). Also the change in MR-proADM levels over time independently predicted all-cause mortality occurring after 75years (adjusted HR 13.4 [95% CI 3.5–50.5]; p<0.001). Conclusions: MR-proADM levels in the elderly integrate information on several relevant aspects in cardiovascular disease, namely cardiovascular risk factors including obesity, low-grade inflammation, renal dysfunction and left-ventricular abnormalities. Furthermore, MR-proADM and its changes over time predicted mortality, and might provide utility as an indicator of the overall cardiovascular risk burden. [Copyright &y& Elsevier]

Abstract: Background: Measurement of high-sensitive cardiac troponin (hs-cTn) has facilitated the early diagnostic assessment of chest pain patients. However, the information obtained from hs-cTnT levels might be improved when combined with results of other biomarkers of myocardial injury. Methods: We measured admission levels of hs-cTnT (Roche Diagnostics), heart-type fatty-acid binding protein (H-FABP; Randox Laboratories) and copeptin using a novel ultra-sensitive (us) assay (Thermo Fisher Scientific) in 360 chest pain patients with a non-diagnostic ECG. Non-STEMI was defined according to the Universal Definition using cardiac troponin I (Stratus CS; Siemens Healthcare Diagnostics) as biochemical gold standard. Results: Non-STEMI was diagnosed in 128 (36%) patients. Hs-cTnT had a greater diagnostic accuracy regarding non-STEMI (C-statistics 0.84) compared to H-FABP (C-statistics 0.80; p=0.04) and us-copeptin C-statistics(0.62; p<0.001). Compared to hs-cTnT alone, no increase in the C-statistics was noted for the combination of hs-cTnT with H-FABP (0.85; p=0.43) or with us-copeptin (0.84; p=0.88). Due to suboptimal sensitivities and/or specificities, neither H-FABP nor us-copeptin dichotomized at commonly applied diagnostic thresholds added information to hs-cTnT that would have facilitated early diagnostic assessment. Conclusions: Hs-cTnT provides an excellent early diagnostic accuracy regarding non-STEMI already on admission. Neither H-FABP nor us-copeptin perform better or provide diagnostic increment to hs-cTnT levels. [Copyright &y& Elsevier]

Background. Growth-differentiation factor-15 (GDF-15) has recently emerged as a risk predictor in patients with cardiac diseases. GDF-15 is commonly related to cardiovascular risk factors, inflammatory activity and cardiac abnormalities. However, it is not clear whether it might be an indicator of vascular pathologies as well. Methods. Circulating levels of GDF-15 were measured in 1004 elderly community dwellers participating in the PIVUS study. The relations of GDF-15 to biomarkers of endothelial activation (E-selectin, P-selectin, ICAM-1, VCAM-1), extracellular matrix degradation (MMP-9, TIMP-1), coagulatory activity (D-dimer, von Willebrand factor, prothrombin fragment 1 ++ 2, factor VIIa), and fibrinolytic activity (PAI-1 activity, tPA-antigen) were assessed by multiple linear regressions. Results. The median GDF-15 level was 1135 ng/L. By linear correlation analysis, GDF-15 exhibited a moderate relation to von Willebrand factor (r == 0.30), and weak, albeit significant relations (r == 0.13-0.29) to E-selectin, P-selectin, ICAM-1, VCAM-1, MMP-9, TIMP-1, D-dimer, PAI-1 activity and tPA-antigen. The relations to the assessed biomarkers of endothelial activation, TIMP-1, D-dimer and von Willebrand factor remained significant applying multiple linear regression models adjusted for clinical covariates and echocardiographic data. There were no significant relations between GDF-15 and biomarkers solely reflecting coagulatory activity. Conclusions. In the elderly, GDF-15 reflects endothelial activation and vascular inflammation and thus, multiple pathways involved in the development and progression of atherosclerosis. [ABSTRACT FROM AUTHOR]

The article presents a study which examined the role of growth-differentiation factor-15 (GDF-15) for long-term risk prediction in patients stabilized after an episode of non-ST-segment-elevation acute coronary syndrome. Results show that GDF-15 levels slightly decreased at randomization. GDF-15 was also related to cardiovascular risk factors and biochemical markers such as renal dysfunction and inflammation.

Objectives: The aim of this study was to assess risk prediction by different biomarkers in patients with an ongoing non–ST-segment elevation acute coronary syndrome (NSTE-ACS) and after clinical stabilization. Background: Different biomarkers reflect different aspects of the pathobiology in NSTE-ACS. However, there is little information regarding their relative prognostic value during the time course of disease. Methods: The N-terminal pro-brain natriuretic peptide (NT-proBNP), C-reactive protein (CRP), cardiac troponin I (cTnI), and the estimated glomerular filtration rate (eGFR) were measured at randomization and after 6 weeks and 6 months in 877 NSTE-ACS patients included in the FRISC (FRagmin and fast revascularization during InStability in Coronary artery disease) II trial. The biomarkers'' prognostic value during 5-year follow-up was evaluated by Cox regression models, calculation of the c-statistics, and estimation of the net reclassification improvement (NRI). Results: Among the biomarkers measured at randomization, NT-proBNP was the strongest predictor for mortality (adjusted hazard ratio [HR]: 1.7; 95% confidence interval [CI]: 1.3 to 2.1; p < 0.001). Even during follow-up, NT-proBNP demonstrated the strongest association to the composite end point of death/myocardial infarction (adjusted HR at 6 weeks: 1.5; 95% CI: 1.3 to 1.7; p < 0.001; adjusted HR at 6 months: 1.4; 95% CI: 1.2 to 1.7; p = 0.001). Even CRP was independently predictive at 6 months for the composite end point (adjusted HR: 1.3; 95% CI: 1.1 to 1.5; p = 0.003). Only 6-week results of NT-proBNP provided significant incremental prognostic value to established risk indicators regarding the composite end point (c-statistics 0.69 [p = 0.03]; NRI 0.11 [p = 0.03]). Conclusions: The NT-proBNP is an independent risk predictor in patients with ongoing NSTE-ACS and after clinical stabilization. The CRP exhibits increasing predictive value at later measurements. However, only NT-proBNP provided incremental prognostic value and might therefore be considered as a complement for early follow-up controls after NSTE-ACS. [Copyright &y& Elsevier]

The aim of the present study was to evaluate whether B-type natriuretic peptides (BNPs) could serve as screening markers for the detection of preclinical vascular disease in the community. BNP and N-terminal–pro-BNP were analyzed in 1,000 subjects aged 70 years participating in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study and were related to different measures of endothelial function and activation, arterial compliance, carotid atherosclerosis, and echocardiographic findings. The median levels were 42.0 ng/L for BNP and 110.7 ng/L for N-terminal–pro-BNP. On adjusted multivariate analysis, the 2 BNPs were related to increased left ventricular mass and impaired left ventricular systolic and diastolic function but not to any of the other assessed entities reflecting preclinical vascular disease. In conclusion, BNPs are strong markers of increased left ventricular mass and impaired cardiac performance but cannot be regarded as useful screening markers for the detection of preclinical states of vascular disease in elderly subjects. [Copyright &y& Elsevier]

The Universal Definition of Myocardial Infarction (acute myocardial infarction [AMI]) requires detection of increasing or decreasing cardiac biomarkers (preferably cardiac troponin) with ≥1 value >99th percentile, together with either clinical symptoms, new ischemic electrocardiographic changes, or typical imaging findings indicative of myocardial necrosis as diagnostic criteria for AMI. However, a small cardiac troponin elevation together with ST-T segment abnormalities may also occur in clinically stable populations. Accordingly, 0.6% of elderly subjects from a community sample (PIVUS Study) and 6.7% of patients stabilized after an acute coronary syndrome (FRISC II Study) would have been labeled AMI following the Universal Definition of AMI when diagnostic classification had been based on a single cardiac troponin I result. In conclusion, our results emphasized the importance of a significant change in cardiac troponin to avoid misdiagnosis of AMI. [Copyright &y& Elsevier]

Using high-sensitivity cardiac troponin (hs-cTn) assays with sex-specific 99th percentiles may improve management of patients with suspected acute myocardial infarction (AMI). We investigated the impact of transitioning from a conventional troponin I assay to a high-sensitivity assay with sex-specific thresholds, in patients with suspected acute coronary syndrome admitted to Swedish coronary care units. Based on data from SWEDEHEART registry (females, n = 4,819/males, n = 7,670), we compared periods before and after implementation of hs-cTnI assay (Abbott) using sex-specific 99th percentiles. We investigated differences on discharge diagnosis, in-hospital examinations, treatments, and clinical outcome. Upon implementation of the hs-cTnI assay, proportion of patients with troponin levels above diagnostic AMI threshold increased in women and men by 24.3% versus 14.8%, respectively. Similarly, incidence of AMI increased by 11.5% and 9.8%. Diagnostic interventions and treatments increased regardless of sex. However, these associations did not persist following multivariable adjustment, probably due to the effect of temporal management trends during the observation period. Overall, no risk reduction on major adverse cardiovascular events was observed (HR: 0.91 [95% CI 0.80–1.03], P = 0.126). The implementation of hs-cTnI assay together with sex-specific 99th percentiles was associated with an increase in incidence of AMI regardless of sex, but had no major impact on clinical management and prognosis. [ABSTRACT FROM AUTHOR]

The objective was to evaluate the hypothesis that growth-differentiation factor 15 (GDF-15) is an independent marker of the long-term risk for both cardiovascular disease and cancer morbidity beyond clinical and biochemical risk factors. Plasma obtained at age 71 was available from 940 subjects in the Uppsala Longitudinal Study of Adult Men (ULSAM) cohort. Complete mortality and morbidity data were obtained from public registries. At baseline there were independent associations between GDF-15 and current smoking, diabetes mellitus, biomarkers of cardiac (high-sensitivity troponin-T, NT-proBNP) and renal dysfunction (cystatin-C) and inflammatory activity (C-reactive protein), and previous cardiovascular disease (CVD). During 10 years follow-up there occurred 265 and 131 deaths, 115 and 46 cardiovascular deaths, and 185 and 86 events with coronary heart disease mortality or morbidity in the respective total cohort (n=940) and non-CVD (n=561) cohort. After adjustment for conventional cardiovascular risk factors, one SD increase in log GDF-15 were, in the respective total and non-CVD populations, associated with 48% (95%CI 26 to 73%, p<0.001) and 67% (95%CI 28 to 217%, p<0.001) incremental risk of cardiovascular mortality, 48% (95%CI 33 to 67%, p<0.001) and 61% (95%CI 38 to 89%, p<0.001) of total mortality and 36% (95%CI 19 to 56%, p<0.001) and 44% (95%CI 17 to 76%, p<0.001) of coronary heart disease morbidity and mortality. The corresponding incremental increase for cancer mortality in the respective total and non-cancer disease (n=882) population was 46% (95%CI 21 to 77%, p<0.001) and 38% (95%CI 12 to 70%, p<0.001) and for cancer morbidity and mortality in patients without previous cancer disease 30% (95%CI 12 to 51%, p<0.001). In conclusion, in elderly men, GDF-15 improves prognostication of both cardiovascular, cancer mortality and morbidity beyond established risk factors and biomarkers of cardiac, renal dysfunction and inflammation. [ABSTRACT FROM AUTHOR]

Background Biomarkers may be of value to identify individuals at risk of developing atrial fibrillation (AF). Using a multimarker approach, this study investigated if the biomarkers; NT-proBNP, high-sensitivity cardiac troponin (hs-cTn), growth differentiation factor-15 (GDF-15), cystatin C and high-sensitivity C-reactive protein (CRP) are independent predictors for incident AF. Methods Blood samples were collected from 883 individuals in the Uppsala Longitudinal Study of Adult Men (ULSAM) and 978 individuals in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Participants were followed for 10–13 years with n = 113 incident AF cases in ULSAM and n = 148 in PIVUS. The associations between biomarkers and incident AF were analysed in Cox proportional hazards regression models. Results The hazard ratio (HR) for incident AF was significant for all five biomarkers in unadjusted analyses in both cohorts. Only NT-proBNP remained significant when adjusting for cardiovascular risk factors and the other biomarkers (HR (1SD) 2.05 (1.62–2.59) (ULSAM) and 1.56 (1.30–1.86) (PIVUS), both p < 0.001). The C-index improved from 0.64 to 0.69 in ULSAM and from 0.62 to 0.68 in PIVUS, by adding NT-proBNP to cardiovascular risk factors (both p < 0.001). The C-index of the CHARGE-AF risk score increased from 0.62 to 0.68 (ULSAM) and 0.60 to 0.66 (PIVUS) by addition of NT-proBNP (p < 0.001). Conclusions Using a multimarker approach NT-proBNP was the strongest predictor of incident AF in two cohorts, and improved risk prediction when added to traditional risk factors. NT-proBNP significantly improved the predictive ability of the novel CHARGE-AF risk score, although the predictive value remained modest. [ABSTRACT FROM AUTHOR]

Background Both unrecognized myocardial infarction (UMI) and elevated levels of biomarkers are common in patients with stable coronary artery disease (CAD). The objective of this study was to determine the association between levels of cardiac biomarkers, UMI and extent of CAD in patients with stable CAD. Methods A total of 235 patients (median age: 65 years; 34% women) with stable CAD without previously known myocardial infarction were examined with late gadolinium enhancement cardiovascular magnetic resonance imaging and coronary angiography. Blood samples were drawn at enrolment and high sensitivity cardiac troponin I (cTnI), NT-proBNP and Galectin-3 were analyzed. Results UMI was detected in 58 patients (25%). The median levels of cTnI, NT-proBNP and Galectin-3 were significantly higher in patients with UMI compared to those without, (p < 0.001, p = 0.006 and p = 0.033, respectively). After adjustment for cardiovascular risk factors, left ventricular ejection fraction and renal function, cTnI remained independently associated with the presence of UMI (p = 0.031) and the extent of CAD (p = 0.047). Neither NT-proBNP, nor Galectin-3, was independently associated with UMI or extent of CAD. Conclusions The independent association between levels of cTnI and UMI indicates a common pathophysiological pathway for the cTnI elevation and development of UMI. Clinical Trial Registration ClinicalTrials.gov ( NCT01257282 ). [ABSTRACT FROM AUTHOR]