Search

Background: Protein biomarkers that reflect different pathophysiological pathways have been associated with the risk of adverse cardiovascular events. However, it is uncertain whether these associations are sustained with increasing years after the biomarkers are measured., Methods and Results: In this cohort study, 7745 patients with coronary heart disease who participated in the LIPID (Long-Term Intervention With Pravastatin in Ischemic Disease) trial, BNP (B-type natriuretic peptide), troponin I, cystatin-C, C-reactive protein, d-dimer and midregional proadrenomedullin were measured at baseline and after 1 year. Discrimination of plasma biomarker concentrations for cardiovascular death were evaluated in landmark analyses from 1 year for the next 5 years of the randomized trial, and for 10 additional years after trial completion. All 6 biomarkers were associated with risk of cardiovascular death (n=1903) both during and after the clinical trial (each P <0.001). C-statistics for BNP were 0.706 and 0.704; cystatin-C, 0.686 and 0.693; troponin I, 0.686 and 0.689; C-reactive protein, 0.655 and 0.684; d-dimer, 0.670 and 0.679, and midregional adrenomedullin, 0.686 and 0.688, respectively. In multivariable models, adding all 6 biomarkers to models with clinical risk factors increased the C-statistic for cardiovascular death from 0.709 to 0.775 during the clinical trial, and from 0.713 to 0.751 during 10-year follow-up after the randomized trial ( P <0.001 for both)., Conclusions: In patients with chronic coronary heart disease, biomarkers that reflect different pathophysiological pathways are associated with the risk of cardiovascular death for at least the next 15 years.

Introduction: Risk stratification scores such as the European Systematic COronary Risk Evaluation (SCORE) are used to guide individuals on cardiovascular disease (CVD) prevention. Adding high-sensitivity troponin I (hsTnI) to such risk scores has the potential to improve accuracy of CVD prediction. We investigated how applying hsTnI in addition to SCORE may impact management, outcome, and cost-effectiveness., Methods: Characteristics of 72,190 apparently healthy individuals from the Biomarker for Cardiovascular Risk Assessment in Europe (BiomarCaRE) project were included into a discrete-event simulation comparing two strategies for assessing CVD risk. The standard strategy reflecting current practice employed SCORE (SCORE); the alternative strategy involved adding hsTnI information for further stratifying SCORE risk categories (S-SCORE). Individuals were followed over ten years from baseline examination to CVD event, death or end of follow-up. The model tracked the occurrence of events and calculated direct costs of screening, prevention, and treatment from a European health system perspective. Cost-effectiveness was expressed as incremental cost-effectiveness ratio (ICER) in € per quality-adjusted life year (QALYs) gained during 10 years of follow-up. Outputs were validated against observed rates, and results were tested in deterministic and probabilistic sensitivity analyses., Results: S-SCORE yielded a change in management for 10.0% of individuals, and a reduction in CVD events (4.85% vs. 5.38%, p<0.001) and mortality (6.80% vs. 7.04%, p<0.001). S-SCORE led to 23 (95%CI: 20-26) additional event-free years and 7 (95%CI: 5-9) additional QALYs per 1,000 subjects screened, and resulted in a relative risk reduction for CVD of 9.9% (95%CI: 7.3-13.5%) with a number needed to screen to prevent one event of 183 (95%CI: 172 to 203). S-SCORE increased costs per subject by 187€ (95%CI: 177 € to 196 €), leading to an ICER of 27,440€/QALY gained. Sensitivity analysis was performed with eligibility for treatment being the most sensitive., Conclusion: Adding a person's hsTnI value to SCORE can impact clinical decision making and eventually improves QALYs and is cost-effective compared to CVD prevention strategies using SCORE alone. Stratifying SCORE risk classes for hsTnI would likely offer cost-effective alternatives, particularly when targeting higher risk groups., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: PJ and IG are fulltime employees of Abbott Diagnostics, one of the providers of diagnostic tests and the assay used in this study. This does not alter our adherence to PLOS ONE policies on sharing data and materials. NM reports conference fees from Abbott Laboratories. SB has received research funding from Abbott, Abbott Diagnostics, Bayer, Boehringer Ingelheim, Siemens, and ThermoFisher; honoraria for lectures from Abbott, Abbott Diagnostics, AstraZeneca, Bayer, Boehringer Ingelheim, Medtronic, Pfizer, Roche, Siemens Diagnostics, Siemens, and ThermoFisher; and honoraria for advisory board memberships and consulting for Boehringer Ingelheim, Bayer, Novartis, Roche, and ThermoFisher. TZ and SB are listed as co-inventor of an international patent on the use of a computing device to estimate the probability of myocardial infarction (International Publication Number WO2022043229A1). TZ is shareholder of the ART.EMIS GmbH Hamburg. VS has had research collaboration with Bayer Ltd (outside the present study). SS reports consultancy and speakers honoraria from Actelion Ltd (unrelated to the present study). All other authors have declared that no competing interests exist., (Copyright: © 2024 Jülicher et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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.

Background: In suspected myocardial infarction (MI), guidelines recommend using high-sensitivity cardiac troponin (hs-cTn)-based approaches. These require fixed assay-specific thresholds and timepoints, without directly integrating clinical information. Using machine-learning techniques including hs-cTn and clinical routine variables, we aimed to build a digital tool to directly estimate the individual probability of MI, allowing for numerous hs-cTn assays., Methods: In 2,575 patients presenting to the emergency department with suspected MI, two ensembles of machine-learning models using single or serial concentrations of six different hs-cTn assays were derived to estimate the individual MI probability (ARTEMIS model). Discriminative performance of the models was assessed using area under the receiver operating characteristic curve (AUC) and logLoss. Model performance was validated in an external cohort with 1688 patients and tested for global generalizability in 13 international cohorts with 23,411 patients., Results: Eleven routinely available variables including age, sex, cardiovascular risk factors, electrocardiography, and hs-cTn were included in the ARTEMIS models. In the validation and generalization cohorts, excellent discriminative performance was confirmed, superior to hs-cTn only. For the serial hs-cTn measurement model, AUC ranged from 0.92 to 0.98. Good calibration was observed. Using a single hs-cTn measurement, the ARTEMIS model allowed direct rule-out of MI with very high and similar safety but up to tripled efficiency compared to the guideline-recommended strategy., Conclusion: We developed and validated diagnostic models to accurately estimate the individual probability of MI, which allow for variable hs-cTn use and flexible timing of resampling. Their digital application may provide rapid, safe and efficient personalized patient care., Trial Registration Numbers: Data of following cohorts were used for this project: BACC ( www., Clinicaltrials: gov ; NCT02355457), stenoCardia ( www., Clinicaltrials: gov ; NCT03227159), ADAPT-BSN ( www.australianclinicaltrials.gov.au ; ACTRN12611001069943), IMPACT ( www.australianclinicaltrials.gov.au , ACTRN12611000206921), ADAPT-RCT ( www.anzctr.org.au ; ANZCTR12610000766011), EDACS-RCT ( www.anzctr.org.au ; ANZCTR12613000745741); DROP-ACS ( https://www.umin.ac.jp , UMIN000030668); High-STEACS ( www., Clinicaltrials: gov ; NCT01852123), LUND ( www., Clinicaltrials: gov ; NCT05484544), RAPID-CPU ( www., Clinicaltrials: gov ; NCT03111862), ROMI ( www., Clinicaltrials: gov ; NCT01994577), SAMIE ( https://anzctr.org.au ; ACTRN12621000053820), SEIGE and SAFETY ( www., Clinicaltrials: gov ; NCT04772157), STOP-CP ( www., Clinicaltrials: gov ; NCT02984436), UTROPIA ( www., Clinicaltrials: gov ; NCT02060760)., (© 2023. The Author(s).)

Background: Current guidelines recommend 0/1 h algorithms using high-sensitivity cardiac troponin (hs-cTn) for fast diagnosis of myocardial infarction (MI). Yet, for some assays, existing data is limited. We aimed to evaluate the diagnostic performance and the prognostic value of a rapid 0/1 h algorithm for the Access hs-cTnI assay., Methods: In consecutive patients presenting with suspected MI, we measured concentrations of Access hs-cTnI at presentation and after 1 hour. Final diagnosis was adjudicated independently by 2 cardiologists. Parameters for diagnostic performance were calculated, applying the recently derived European Society of Cardiology (ESC) 0/1 h algorithm for Access hs-cTnI. Additionally, we assessed the prognostic utility of Access hs-cTnI for the composite end point of all-cause mortality and incident MI at 3 years., Results: In 1879 patients, 257 non-ST-elevation MIs occurred. Application of the 0/1 h algorithm classified 44.5% as rule-out, 20.3% as rule-in, and triaged 35.1% to the observe group. High rule-out safety was confirmed with a sensitivity of 97.7% (95% CI, 95.0%-99.1%) and a negative predictive value of 99.3% (95% CI, 98.4%-99.7%). Rule-in capacity was moderate with a specificity of 88.0% (95% CI, 86.3%-89.6%) and a positive predictive value of 50.8% (95% CI, 45.7%-55.9%). After exclusion of patients with ST-elevation MI the results showed strong prognostic value, even after adjustment for cardiovascular risk factors and comorbidities, with adjusted hazard ratios of 2.51 (95% CI, 1.56-4.04) in the observe and 3.55 (95% CI, 2.18-5.79) in the rule-in group for the composite end point of all-cause mortality and incident MI at 3 years, compared to ruled-out patients., Conclusion: The ESC 0/1 h algorithm for Access hs-cTnI allows safe and efficient triage of patients with suspected MI and has strong prognostic utility up to 3 years after the initial evaluation., (© American Association for Clinical Chemistry 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Preeclampsia is associated with an elevated risk of cardiovascular disease later in life. Women with a history of preeclampsia are at risk of developing hypertension as well as ischemic heart disease. Identification of women at the highest risk is important to initiate preventive strategies. We investigated whether high-sensitivity cardiac troponin I (hs-cTnI) levels are associated with a history of early-onset preeclampsia, and with hypertension in these high-risk women., Methods: Approximately 9-10 years after pregnancy, hs-cTnI levels were measured for 339 women of the Preeclampsia Risk Evaluation in FEMales cohort, consisting of 177 women with a history of early-onset preeclampsia and 162 women with a previous uncomplicated index pregnancy. Associations were analyzed using several statistical tests and linear regression analysis., Results: The median hs-cTnI levels (IQR) were 2.50 ng/l (2.30) in women with a history of early-onset preeclampsia and 2.35 ng/l (2.50) in women without a history of preeclampsia, P = 0.53. Among women with a history of early-onset preeclampsia, the hs-cTnI levels were higher in women who were hypertensive compared with their normotensive counterparts (medians 2.60 versus 2.30; P = 0.03). In addition, blood pressure levels increased with increasing hs-cTnI levels., Conclusion: We did not find a difference in hs-cTnI levels between women with and without a history of early-onset preeclampsia. Nonetheless, hs-cTnI levels were statistically significantly higher in current hypertensive women with a history of preeclampsia compared with their normotensive counterparts. Therefore, hs-cTnI levels might improve risk prediction for women at the highest risk of cardiovascular disease.

Background and Purpose: Stroke is a common cause of death and a leading cause of disability and morbidity. Stroke risk assessment remains a challenge, but circulating biomarkers may improve risk prediction. Controversial evidence is available on the predictive ability of troponin concentrations and the risk of stroke in the community. Furthermore, reports on the predictive value of troponin concentrations for different stroke subtypes are scarce., Methods: High-sensitivity cardiac troponin I (hsTnI) concentrations were assessed in 82 881 individuals (median age, 50.7 years; 49.7% men) free of stroke or myocardial infarction at baseline from 9 prospective European community cohorts. We used Cox proportional hazards regression to determine relative risks, followed by measures of discrimination and reclassification using 10-fold cross-validation to control for overoptimism. Follow-up was based upon linkage with national hospitalization registries and causes of death registries., Results: Over a median follow-up of 12.7 years, 3033 individuals were diagnosed with incident nonfatal or fatal stroke (n=1654 ischemic strokes, n=612 hemorrhagic strokes, and n=767 indeterminate strokes). In multivariable regression models, hsTnI concentrations were associated with overall stroke (hazard ratio per 1-SD increase, 1.15 [95% CI, 1.10-1.21]), ischemic stroke (hazard ratio, 1.14 [95% CI, 1.09-1.21]), and hemorrhagic stroke (hazard ratio, 1.10 [95% CI, 1.01-1.20]). Adding hsTnI concentrations to classical cardiovascular risk factors (C indices, 0.809, 0.840, and 0.736 for overall, ischemic, and hemorrhagic stroke, respectively) increased the C index significantly but modestly. In individuals with an intermediate 10-year risk (5%-20%), the net reclassification improvement for overall stroke was 0.038 ( P =0.021)., Conclusions: Elevated hsTnI concentrations are associated with an increased risk of incident stroke in the community, irrespective of stroke subtype. Adding hsTnI concentrations to classical risk factors only modestly improved estimation of 10-year risk of stroke in the overall cohort but might be of some value in individuals at an intermediate risk.

Background Current noninvasive modalities to diagnose coronary artery disease (CAD) have several limitations. We sought to derive and externally validate a hs-cTn (high-sensitivity cardiac troponin)-based proteomic model to diagnose obstructive coronary artery disease. Methods and Results In a derivation cohort of 636 patients referred for coronary angiography, predictors of ≥70% coronary stenosis were identified from 6 clinical variables and 109 biomarkers. The final model was first internally validated on a separate cohort (n=275) and then externally validated on a cohort of 241 patients presenting to the ED with suspected acute myocardial infarction where ≥50% coronary stenosis was considered significant. The resulting model consisted of 3 clinical variables (male sex, age, and previous percutaneous coronary intervention) and 3 biomarkers (hs-cTnI [high-sensitivity cardiac troponin I], adiponectin, and kidney injury molecule-1). In the internal validation cohort, the model yielded an area under the receiver operating characteristic curve of 0.85 for coronary stenosis ≥70% ( P <0.001). At the optimal cutoff, we observed 80% sensitivity, 71% specificity, a positive predictive value of 83%, and negative predictive value of 66% for ≥70% stenosis. Partitioning the score result into 5 levels resulted in a positive predictive value of 97% and a negative predictive value of 89% at the highest and lowest levels, respectively. In the external validation cohort, the score performed similarly well. Notably, in patients who had myocardial infarction neither ruled in nor ruled out via hs-cTnI testing ("indeterminate zone," n=65), the score had an area under the receiver operating characteristic curve of 0.88 ( P <0.001). Conclusions A model including hs-cTnI can predict the presence of obstructive coronary artery disease with high accuracy including in those with indeterminate hs-cTnI concentrations.

Objectives: The aims of this study were to characterize the association of high-sensitivity cardiac troponin I (hs-cTnI) with heart failure (HF), to determine its predictive value beyond classical cardiovascular risk factors (CVRFs) and N-terminal pro-B-type natriuretic peptide, and to derive a relevant cutoff for potential clinical application., Background: HF is an important contributor to the overall burden of cardiovascular disease. Early identification of individuals at risk could be beneficial for preventive therapies., Methods: Based on the Biomarker for Cardiovascular Risk Assessment in Europe consortium, we analyzed individual-level data from 4 prospective population-based cohort studies including 48,455 individuals. Participants with myocardial infarction, HF, and stroke at baseline were excluded. We investigated the value of adding hs-cTnI to CVRFs and N-terminal pro-B-type natriuretic peptide using Cox proportional hazards survival models and for prediction by calculating C-statistics and Brier score., Results: The median age of the study population was 51 years, and the median follow-up time for occurrence of HF was 6.61 years. Cox regression models adjusted for age, sex, and CVRFs revealed a significant association of hs-cTnI with incident HF (hazard ratio: 1.42 per log [ng/l] unit change [95% confidence interval: 1.31 to 1.53]). The best predictive value was achieved in the model with CVRFs (base model) and both biomarkers (C-index = 0.862; 95% confidence interval: 0.841 to 0.882). Optimal hs-cTnI cutoff values of 2.6 ng/l for women and 4.2 ng/l for men were derived for selecting individuals at risk., Conclusions: In this large dataset from the general population, hs-cTnI could show its independence for the prognosis of HF., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To determine gender-specific reference limits of high-sensitivity (hs) cardiac troponins (cTn) and validity of hs assay designation for both genders., Methods: After screening with a questionnaire, 827 presumably healthy individuals were further selected based on clinical criteria (n = 740), clinical criteria plus cardiac imaging including stress magnetic resonance imaging or stress echocardiography (n = 726), and extended cardio-pulmonary parameters (n = 626). Blood samples were measured with hs-cTnT (Roche Diagnostics) on a cobas e602 analyzer as well as hs-cTnI (Abbott Diagnostics) on an ARCHITECT i 2000 SR . The impact of health definition, statistical methods, instrument selection and limit of detection (LoD) on overall and gender-specific 99th percentiles was assessed., Results: Median age was 56 years (50.9% female) for the total study cohort. 99th percentiles for females and males ranged between 13.1 and 13.3 ng/L and 16.8-19.9 ng/L for hs-cTnT as well as 10.3-12.5 ng/L and 27.4-29.7 ng/L for hs-cTnI depending on health definition. Utilization of stricter health definition criteria reduced the difference of the gender-specific 99th percentiles between males and females for hs-cTnT to 3.7 ng/L (males 16.8 ng/L, females 13.1 ng/L), whereas the difference rather increased for hs-cTnI to 19.4 ng/L (males 29.7 ng/L, females 10.3 ng/L). Values > LoD could be measured in the majority of males and females using hs-TnT (81.4-83.3% and 96.5-96.9%, respectively). In contrast, values > LoD could not be observed in the majority of females using hs-cTnI (38.4-41.1%)., Conclusions: In a well-phenotyped healthy cohort, reference values for hs-cTnT were slightly higher, whereas hs-cTnI cut-offs were considerably lower than previously observed. Gender differences were more pronounced in hs-cTnI than in hs-cTnT and were further reduced for hs-cTnT by application of stricter health definition criteria. Contrary to hs-cTnI, hs-cTnT fulfilled criteria for hs designation for both genders., Competing Interests: Declaration of Competing Interest E.G., honoraria for lecturers from Roche Diagnostics, BRAHMS Thermo Scientific, Bayer Vital GmbH and Mitsubishi Chemical Europe, institutional research grant from Roche Diagnostics and Daiichi Sankyo, consultant for Roche Diagnostics and BRAHMS Thermo Scientific, outside the submitted work; M.M.-H., research support by the Medical Faculty of Heidelberg University, during conduct of the study, research support from Roche Diagnostics and BRAHMS Thermo Scientific, speaker honoraria from Roche Diagnostics, non-financial support by BRAHMS Thermo Scientific, Bayer Vital GmbH, Daiichi-Sankyo, Metanomics Health GmbH and Philips Electronics, outside the submitted work; M.B., research support from AstraZeneca and travel support from BRAHMS Thermo Scientific, outside the submitted work; M.V., financial support from Bayer Vital GmbH and Daiichi Sankyo, reimbursement for travel expenses and fees associated with attending seminars and conferences by Bayer Vital GmbH, Lilly Germany, GlaxoSmithKline, Roche Diagnostics and Brahms, outside the submitted work; K.M.S., research supported by Bayer Vital GmbH, outside the submitted work; S.B., non-financial support from Abbott Diagnostics, grants and personal fees from Abbott Diagnostics, Siemens, Thermo Fisher and Roche Diagnostics, outside the submitted work; H.K., honoraria from AstraZeneca, Eli Lilly, GlaxoSmithKline, Roche Diagnostics, and Bayer, holds a Troponin T Test Invention patent jointly with Roche and receives royalties for this patent, outside the submitted work. All other authors have nothing to disclose., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Risk stratification among patients with coronary artery disease (CAD) is of considerable interest to potentially guide secondary preventive therapies. Cardiac troponins as well as C-reactive protein (hsCRP) and natriuretic peptides have emerged as biomarkers for risk stratification. The question remains if one of these biomarkers is superior in predicting adverse outcomes. Thus, we perform a head-to-head comparison between high-sensitivity troponin I (hsTnI), hsCRP, and N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with CAD. Plasma levels were measured in a cohort of 2193 patients with documented CAD. The main outcome measures were cardiovascular (CV) death and/or nonfatal myocardial infarction (MI). During a median follow-up of 3.8 years, all three biomarkers were associated with cardiovascular death and/or MI. After adjustments for conventional cardiovascular risk factors, the hazard ratio (HR) per standard deviation (SD) for the prediction of CV death and/or nonfatal MI was 1.39 [95% CI: 1.24-1.57, p < 0.001] for hsTnI, 1.41 [95% CI: 1.24-1.60, p < 0.001] for hsCRP, and 1.64 [95% CI: 1.39-1.92, p < 0.001] for NT-proBNP. However, upon further adjustments for the other two biomarkers, only NT-proBNP was still associated with the combined endpoint with an HR of 1.47 [95% CI: 1.19-1.82, p < 0.001]. Conclusively, NT-proBNP is reliably linked to CV death and MI in patients with CAD and provides incremental value beyond hsCRP and hsTnI.

Background: Increasing numbers of patients are presenting worldwide to emergency departments with suspected myocardial infarction. The use of point-of-care troponin assays might enable faster decision-making in this high-risk population and reduce the burden on emergency facilities. Here, we evaluate the diagnostic performance of a point-of-care high-sensitivity troponin I assay., Methods: We conducted a prospective cohort study including patients presenting to the emergency department with suspected myocardial infarction from July 2013 to July 2016. A diagnostic algorithm for a high-sensitivity troponin I point-of-care assay was developed in a derivation data set with 669 patients and validated in an additional 610 patients., Results: The derived 0/1 h algorithm for the point-of-care assay consisted of an admission troponin I <4 ng/L and a δ from 0 h to 1 h <3 ng/L for rule out and an admission troponin I ≥90 ng/L or a δ from 0 h to 1 h ≥20 ng/L for rule in of non-ST-elevation myocardial infarction. Application to the validation cohort showed a negative predictive value of 99.7% (95% CI, 98.1%-100.0%) and 48.0% of patients ruled out, whereas 14.6% were ruled in with a positive predictive value of 86.5% (95% CI, 77.6%-92.8%). The diagnostic performance of the point-of-care high-sensitivity assay was highly comparable to guideline-recommended use of a laboratory-based high-sensitivity troponin assay., Conclusions: The clinical application of a 0/1 h diagnostic algorithm based on a high-sensitivity troponin I point-of-care assay is safe, and diagnostic performance is comparable to a laboratory-based high-sensitivity troponin I assay., (© 2019 American Association for Clinical Chemistry.)

: High-sensitivity troponin has proven to be a promising biomarker for the prediction of future adverse cardiovascular events. We aimed to assess the prognostic value of high-sensitivity troponin I (hs-TnI) on admission in patients with suspected acute myocardial infarction (AMI) analyzed by a novel (Singulex Clarity cTnI) and established hs-TnI assay (ARCHITECT STAT hs-TnI, Abbott). Hs-TnI was measured in a total of 2332 patients from two prospective cohort studies presenting to the emergency department with suspected AMI. The prognostic impact for overall and cardiovascular mortality of both hs-TnI assays was assessed in the total patient cohort as well as in the subgroups of patients with AMI ( n = 518) and without AMI (non-AMI) ( n = 1814). Patients presenting with highest hs-TnI levels showed higher overall and cardiovascular mortality rates compared to those with lower troponin levels, irrespective of the assay used. Both hs-TnI assays indicated association with overall mortality according to adjusted hazard ratio (HR) among the entire study population (HR for Singulex assay: 1.16 (95% CI 1.08-1.24) and HR for Abbott assay: 1.17 (95% CI 1.09-1.25)). This finding was particularly pronounced in non-AMI patients, whereas no association between hs-TnI and overall mortality was found in AMI patients for either assay. In non-AMI patients, both assays equally improved risk prediction for cardiovascular mortality beyond conventional cardiovascular risk factors. Hs-TnI is independently predictive for adverse outcomes in patients with suspected AMI, especially in the subset of patients without confirmed AMI. There was no difference between the established and the novel assay in the prediction of mortality., Competing Interests: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the article; and decision to submit the article for publication.

Purpose: Established diagnostic thresholds for high-sensitivity cardiac troponins (hs-cTn) might not apply for elderly patients as they are elevated irrespective of the presence of an acute myocardial infarction (AMI). Aim of the present study was to investigate hs-cTnI in elderly patients with suspected AMI and to calculate optimized diagnostic cutoffs. Material and methods: Data from a prospective multi-centre study and from a second independent prospective single-centre cohort study were analysed. A number of 2903 patients were eligible for further analysis. Patients > 70 years were classified as elderly. hs-cTnI was measured upon admission. Results: Around 34.7% of 2903 patients were classified as elderly. Around 22.5% of elderly patients were finally diagnosed with AMI. Elderly patients had higher hs-cTnI levels at admission irrespective of the final diagnosis ( p  < 0.001). According to the AUROC, hs-cTnI was a strong marker for detection of AMI in elderly patients. Application of the 99th percentile cutoffs showed a substantially lower specificity in elderly. By using optimized thresholds, specificity was improved to levels as in younger patients in both cohorts but accompanied with a decrease in sensitivity. Conclusions: hs-cTnI levels have a lower specificity for detecting AMI in elderly patients. This lower specificity can be improved by using hs-cTnI thresholds optimized for elderly patients.

Aims: Troponin is the gold-standard for diagnostic evaluation of patients with suspected myocardial infarction (MI). We aimed to evaluate the diagnostic and prognostic performance of a new ultra-sensitivity troponin I (us-TnI) assay in patients with suspected MI., Methods and Results: 1534 patients with suspected MI were included. Us-TnI measurements were performed directly on admission and after one hour. One-year rates of mortality and incident MI were assessed. For diagnostic evaluation the negative and positive predictive value (NPV/PPV) using admission us-TnI concentrations and 0/1h delta were calculated. For rule-out an NPV > 99.5% (100% for single-admission-value) and for rule-in a PPV > 80% was targeted. Internal derivation/validation was used. In the derivation dataset 155/767 (20.2%) patients were diagnosed with having non-ST-elevation MI (NSTEMI). For rule-out of NSTEMI an us-TnI < 1 ng/L directly on admission resulted in an NPV of 100.0% (CI 98.2-100.0). Using serial sampling an admission us-TnI < 2 ng/L and a 0/1h delta < 1 ng/L resulted in an NPV of 99.7% (CI 98.4-100.0) and ruled-out NSTEMI in 46.8% of all patients. The respective one-year rate of death or MI was 0.6%. For rule-in of NSTEMI an us-TnI ≥ 25 ng/L on admission or a 0/1h delta ≥ 6 ng/L resulted in a PPV of 81.3% (CI 73.7-87.5) and ruled-in NSTEMI in 18.5% of all patients. The one-year event rate was 12.7%. Results were similar in 767 patients from the validation cohort., Conclusion: Application of an us-TnI assay allows the accurate triage of a large proportion of patients with suspected MI using a 0/1h algorithm., Trial Registration: www.clinicaltrials.gov (NCT02355457)., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The soluble urokinase-type plasminogen activator receptor (suPAR) is a new marker for immune activation and inflammation and may provide diagnostic value on top of established biomarkers in patients with suspected acute myocardial infarction (AMI). Here, we evaluate the diagnostic potential of suPAR levels on top of high-sensitivity troponin I (hs-TnI) in a cohort of patients with suspected AMI. A total of 1220 patients presenting to the emergency department with suspected AMI were included, of whom 245 were diagnosed with AMI. Median suPAR levels at admission were elevated in subjects with AMI compared to non-AMI (3.8 ng/mL vs 3.3 ng/mL, p = 0.001). In C-statistics, the area under the curve (AUC) regarding the diagnosis of AMI was low (0.57 at an optimized cut-off of 3.7 ng/mL). Moreover, baseline suPAR levels on top of troponin values at admission and hour 1 reduced the number of patients who were correctly ruled-out as non-AMI, and who were correctly ruled-in as AMI. Our study shows that circulating levels of suPAR on top of high-sensitivity troponin I do not improve the early diagnosis of AMI., Competing Interests: Neumann received honoraria from Siemens and Abbott Diagnostics. Blankenberg received honoraria from Abbott Diagnostics, Siemens, Thermo Fisher, and Roche Diagnostics and is a consultant for Thermo Fisher. Westermann reports personal fees from Bayer, Boehringer-Ingelheim, Berlin Chemie, Astra Zeneca, Biotronik and Novartis. Karakas received consultancy fees outside of the scope of this manuscript from Vifor Pharma, Amgen, Sanofi, and Astra-Zeneca, and furthermore, grant support from Abbott Diagnostics, Adrenomed AG and Vifor Pharma.

Background Patients with chronic kidney disease ( CKD ) are at high risk of myocardial infarction. Cardiac troponins are the biomarkers of choice for the diagnosis of acute myocardial infarction ( AMI ) without ST -segment elevation ( NSTE ). In patients with CKD , troponin levels are often chronically elevated, which reduces their diagnostic utility when NSTE - AMI is suspected. The aim of this study was to derive a diagnostic algorithm for serial troponin measurements in patients with CKD and suspected NSTE - AMI . Methods and Results Two cohorts, 1494 patients from a prospective cohort study with high-sensitivity troponin I (hs- cTnI ) measurements and 7059 cases from a clinical registry with high-sensitivity troponin T (hs- cTnT ) measurements, were analyzed. The prospective cohort comprised 280 CKD patients (estimated glomerular filtration rate <60 mL/min/1.73 m 2 ). The registry data set contained 1581 CKD patients. In both cohorts, CKD patients were more likely to have adjudicated NSTE - AMI than non- CKD patients. The specificities of hs- cTnI and hs- cTnT to detect NSTE - AMI were reduced with CKD (0.82 versus 0.91 for hs- cTnI and 0.26 versus 0.73 for hs- cTnT ) but could be restored by applying optimized cutoffs to either the first or a second measurement after 3 hours. The best diagnostic performance was achieved with an algorithm that incorporates serial measurements and rules in or out AMI in 69% (hs- cTnI ) and 55% (hs- cTnT ) of CKD patients. Conclusions The diagnostic performance of high-sensitivity cardiac troponins in patients with CKD with suspected NSTE - AMI is improved by use of an algorithm based on admission troponin and dynamic changes in troponin concentration.

The use of cardiac troponins (cTn) is the gold standard for diagnosing myocardial infarction. Independent of myocardial infarction (MI), however, sex, age and kidney function affect cTn levels. Here we developed a method to adjust cTnI levels for age, sex, and renal function, maintaining a unified cut-off value such as the 99 th percentile. A total of 4587 individuals enrolled in a prospective longitudinal study were used to develop a model for adjustment of cTn. cTnI levels correlated with age and estimated glomerular filtration rate (eGFR) in males/females with r age  = 0.436/0.518 and with r eGFR  = -0.142/-0.207. For adjustment, these variables served as covariates in a linear regression model with cTnI as dependent variable. This adjustment model was then applied to a real-world cohort of 1789 patients with suspected acute MI (AMI) (N = 407). Adjusting cTnI showed no relevant loss of diagnostic information, as evidenced by comparable areas under the receiver operator characteristic curves, to identify AMI in males and females for adjusted and unadjusted cTnI. In specific patients groups such as in elderly females, adjusting cTnI improved specificity for AMI compared with unadjusted cTnI. Specificity was also improved in patients with renal dysfunction by using the adjusted cTnI values. Thus, the adjustments improved the diagnostic ability of cTnI to identify AMI in elderly patients and in patients with renal dysfunction. Interpretation of cTnI values in complex emergency cases is facilitated by our method, which maintains a single diagnostic cut-off value in all patients.

Background: Rule-out of non-ST-elevation myocardial infarction is based on consecutive measurements of cardiac troponins using the 99th percentile of the respective assay as cutoff. The new ESC guidelines alternatively offer rapid 1h algorithms with lower cutoffs than the 99th percentile for rule-out of non-ST-elevation myocardial infarction. We aimed to compare a recently introduced 1h algorithm based on a high-sensitivity cardiac troponin I (hs-TnI) cutoff of 6ng/L at 0h and 1h to the current standard of care using the 99th percentile (27ng/L) as cutoff with reference to follow-up events in a large chest pain cohort., Methods: Hs-TnI was measured at three time points (0h, 1h and 3h) in 1625 patients presenting with suspected myocardial infarction to the emergency department of the University-Medical Center Hamburg-Eppendorf. Seventy-five patients with ST-elevation myocardial infarction were excluded from the analysis. All-cause mortality, cardiac death, acute myocardial infarction, revascularization and cardiac rehospitalization after 12months were assessed., Results: Patients ruled out by the 1h algorithm showed significantly less cardiac rehospitalizations (12.84% vs. 17.66%; p<0.001), and overall mortality (1.30% vs 3.46%, p<0.001) compared to using the 99th percentile as cutoff. The majority of deaths were caused by non-cardiac reasons. Cardiac deaths were rare using the 1h algorithm (0.21%)., Conclusion: The commonly used 99th percentile as cutoff neglects patients with a high risk in the setting of acute chest pain., Trial Registration: www.clinicaltrials.gov (NCT02355457)., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objective: There is a clinical need for early and accurate diagnosis of acute myocardial infarction (AMI). Current European Society of Cardiology (ESC) guidelines recommend diagnosis of non-ST-elevation AMI based on serial troponin measurements. We aimed to challenge the ESC guidelines using 1) a high-sensitivity troponin I (hs-TnI) baseline cutoff, 2) an absolute hs-TnI change after 1 hour and 3) additional application of an ischemic ECG., Methods: 1,516 patients with suspected AMI presenting to the emergency department were included. Hs-TnI was measured directly at admission, after 1 and 3 hours. We investigated baseline concentrations, absolute changes of hs-TnI and additional application of an ischemic ECG to diagnose AMI. A positive predictive value (PPV) of more than 85% was targeted., Results: The median age of the study population was 65 years; 291 patients were diagnosed with AMI. The PPV of the 3-hours ESC algorithm was 85.5% (CI 79.7, 90.1) and 65.8% (CI 60.5,70.8) for the 1-hour algorithm. Using a high baseline hs-TnI concentration of 150 ng/L resulted in a PPV of 87.8% (CI 80.9,92.9). Alternatively, a hs-TnI change of 20 ng/L after 1 hour, resulted in a PPV of 86.5% (80.9,91.0), respectively for the diagnosis of AMI. Additional use of an ischemic ECG increased the PPV to 90.5% (CI 83.2,95.3), while reducing the efficacy., Conclusion: The diagnosis of AMI based on hs-TnI is challenging. The application of absolute hs-TnI changes after 1 hour may facilitate rapid rule-in of patients., Trial Registration: www.clinicaltrials.gov (NCT02355457).

Cardiac troponin and N-terminal pro-brain natriuretic peptide (NT-proBNP) are known to associate with incident dementia. The purpose of our study was to examine whether high-sensitivity cardiac troponin I (hs-TnI) and NT-proBNP are associated with incident dementia and Alzheimer's disease (AD) independently of each other. Our study was a part of the national population-based health examination survey, FINRISK 1997, with a total sample of 7114 subjects, including 407 incident dementia cases and 319 AD cases during the follow-up time of 18 years. Using multivariate Cox regression analyses, we calculated the hazard ratios (HR) for hs-TnI and NT-proBNP. Analyses were adjusted for the previously known dementia/AD risk factors, including the apoE genotype. NT-proBNP was independently associated with incident dementia (HR 1.32, 95% CI 1.17-1.49) and AD (HR 1.30, 95% CI 1.13-1.5). Hs-TnI was also associated with incident dementia (HR 1.12, 95% CI 1.02-1.23), but not independent of NT-proBNP (HR 1.10, 95% CI 0.99-1.21). Hs-TnI was not associated with incident AD. The results remained similar in cause-specific Cox regression models and among subjects over 40 years of age. NT-proBNP and hs-TnI improved the reclassification of dementia risk in 10 years follow-up, and hs-TNI also in 18 years of follow-up. Neither hs-TnI nor NT-proBNP was able to outperform each other in risk reclassification of dementia. Both cardiovascular biomarkers, NT-proBNP and hs-TnI, were associated with incident dementia independently of traditional dementia risk factors including the apoE genotype. NT-proBNP was also associated with AD. Both markers offered a better dementia risk reclassification compared with traditional risk factors.

Background: The determination of cardiac troponin is essential for diagnosing myocardial infarction. A troponin I assay has recently been developed that provides the highest analytical sensitivity to date., Methods: The analysis included 1560 patients with chest pain, of whom 1098 were diagnosed with non-coronary chest pain, 189 with unstable angina pectoris and 273 with non-ST-segment elevation myocardial infarction. The troponin I concentration was determined on admission (0 hours) and 3 hours later. The diagnostic algorithm incorporated troponin I elevation above the gender-specific 99th percentile as well as predefined relative or absolute 3-hour changes in the troponin I concentration (delta)., Results: The diagnostic criterion of troponin I above the 99th percentile resulted in a negative predictive value of 98.0% and 98.2% in men and women, respectively. For rule-in of non-ST-segment elevation myocardial infarction, the use of absolute deltas yielded higher positive predictive values and sensitivities compared to relative deltas. With detection rates of about 85% and 82% in men and women, respectively, non-ST-segment elevation myocardial infarction was diagnosed with a positive predictive value close to 84% in men and 80% in women., Conclusions: The investigational troponin I assay provides an excellent non-ST-segment elevation myocardial infarction rule out. With gender-specific differences, the application of absolute changes in troponin concentration was superior to relative changes to rule in patients with non-ST-segment elevation myocardial infarction.

Aims: Serial measurements of high-sensitivity troponin are used to rule out acute myocardial infarction (AMI) with an assay specific cutoff at the 99th percentile. Here, we evaluated the performance of a single admission troponin with a lower cutoff combined with a low risk electrocardiogram (ECG) to rule out AMI., Methods: Troponin I measured with a high-sensitivity assay (hs-TnI) was determined at admission in 1040 patients presenting with suspected AMI (BACC study). To rule out AMI we calculated the negative predictive value (NPV) utilizing the optimal hs-TnI cutoff combined with a low risk ECG. The results were validated in 3566 patients with suspected AMI [2-h Accelerated Diagnostic Protocol to Assess Patients With Chest Pain Symptoms Using Contemporary Troponins as the Only Biomarker (ADAPT) studies]. Patients were followed for 6 or 12 months., Results: 184 of all patients were diagnosed with AMI. An hs-TnI cutoff of 3 ng/L resulted in a NPV of 99.3% (CI 97.3-100.0), ruling out 35% of all non-AMI patients. Adding the information of a low risk ECG resulted in a 100% (CI 97.5-100.0) NPV (28% ruled out). The 2 validation cohorts replicated the high NPV of this approach. The follow-up mortality in the ruled out population was low (0 deaths in BACC and Stenocardia, 1 death in ADAPT)., Conclusions: A single hs-TnI measurement on admission combined with a low risk ECG appears to rule out AMI safely without need for serial troponin testing., Trial Registration: www.clinicaltrials.gov (NCT02355457)., (© 2016 American Association for Clinical Chemistry.)

Background: High-sensitivity troponin I (hs-cTnI) concentrations reflect myocardial stress. The role of hs-cTnI in predicting long-term changes in the risk of cardiovascular disease (CVD) in general populations is not clearly defined., Methods: We investigated whether the change in 3 repeated measures of hs-cTnI collected 5 years apart in a prospective Danish study (3875 participants, initially aged 30-60 years, 51% female, disease free at baseline) improves 10-year prediction of incident CVD compared to using a single most recent hs-cTnI measurement. The change process was modelled using a joint (longitudinal and survival) model and compared to a Cox model using a single hs-cTnI measure adjusted for classic CVD risk factors, and evaluated using discrimination statistics., Results: Median hs-cTnI concentrations changed from 2.6 ng/L to 3.4 ng/L over 10 years. The change in hs-cTnI predicts 10-year risk of CVD (581 events); the joint model gave a hazard ratio of 1.31 per interquartile difference in hs-cTnI (95% CI 1.15-1.48) after adjustment for CVD risk factors. However, the joint model performed only marginally better (c-index improvement 0.0041, P = 0.03) than using a single hs-cTnI measure (c-index improvement 0.0052, P = 0.04) for prediction of CVD, compared to a model incorporating CVD risk factors without hs-cTnI (c-index 0.744)., Conclusions: The change in hs-cTnI in 5-year intervals better predicts risk of CVD in the general population, but the most recent measure of hs-cTnI, (at 10 years) is as effective in predicting CVD risk. This simplifies the use of hs-cTnI as a prognostic marker for primary prevention of CVD in the general population., (© 2016 American Association for Clinical Chemistry.)

Background: Natriuretic peptides are the standard biomarker for risk stratification in cardiovascular disease. Novel biomarkers of cardiovascular stress might allow refinement in risk stratification for patients with acute coronary syndrome (ACS). We tested the performance of these novel biomarkers for cardiovascular risk stratification in patients who presented with ACS., Methods: In the AtheroGene study, 873 patients presented with ACS in the emergency department. Biomarkers measured were: B-type natriuretic peptide (BNP), N-terminal pro BNP (NT-proBNP), midregional proatrial natriuretic peptide, midregional proadrenomedullin (MR-proADM), copeptin, and troponin I. The median follow-up time was 4 years and during this time 50 patients died from cardiac causes., Results: Cox regression analysis for the continuous variables NT-proBNP and BNP showed a hazard ratio (HR) of 1.9 and 1.8, respectively, for 1 SD increase (P < 0.001 and P = 0.003) in the fully adjusted model. Novel biomarkers with MR-proADM had an HR of 3.2, followed by midregional proatrial natriuretic peptide with an HR of 1.9 (both P < 0.001), and copeptin with an HR of 1.6 (P < 0.001). C-index revealed MR-proADM as the best discriminator for identifying patients with the outcome with a C-index = 0.8, and C-index was 0.72 for NT-proBNP (P for comparison = 0.017). Integrated discrimination improvement for MR-proADM was 0.059 compared with NT-proBNP (P = 0.016), thus providing background that MR-proADM was better to identify persons with the outcome. Troponin I levels at the time of admission were not significant for risk stratification., Conclusions: In patients who present with ACS the novel biomarker, MR-proADM was the best predictor for outcome. MR-proADM adds modest information and is useful for risk prediction in ACS patients., (Copyright © 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Importance: Rapid and accurate diagnosis of acute myocardial infarction (AMI) currently constitutes an unmet need., Objective: To test a 1-hour diagnostic algorithm to diagnose AMI using a high-sensitivity troponin I assay with a new cutoff level of 6 ng/L., Design, Setting, and Participants: The Biomarkers in Acute Cardiac Care study is a prospective study that investigated the application of the troponin I assay for the diagnosis of AMI in 1040 patients presenting to the emergency department with acute chest pain from July 19, 2013, to December 31, 2014. Results were validated in 2 independent cohorts of 4009 patients. Final follow-up was completed on July 1, 2015, and data were assessed from July 2 to December 15, 2015., Exposure: Acute chest pain suggestive of AMI., Main Outcomes and Measures: Accurate diagnosis or exclusion of AMI and 12-month mortality in patients with acute chest pain., Results: Of the 1040 patients included from the study cohort, 673 (64.7%) were male and had a median age of 65 (interquartile range, 52-75) years. With application of a low troponin I cutoff value of 6 ng/L, the rule-out algorithm showed a high negative predictive value of 99.8% (95% CI, 98.6%-100.0%) after 1 hour for non-ST-segment elevation MI type 1. The 1-hour approach was comparable to a 3-hour approach. Similarly, a rule-in algorithm based on troponin I levels provided a high positive predictive value with 82.8% (95% CI, 73.2%-90.0%). Moreover, application of the cutoff of 6 ng/L resulted in lower follow-up mortality (1.0%) compared with the routinely used 99th percentile (3.7%) for this assay. Two independent cohorts further validated the performance of this algorithm with high negative and positive predictive values., Conclusions and Relevance: Patients with possible AMI can be triaged within 1 hour after admission with no loss of safety compared with a 3-hour approach, when a low and sensitive cutoff is applied. This concept enables safe discharge or rapid treatment initiation after 1 hour.

Background: Common ECG criteria such as ST-segment changes are of limited value in patients with suspected acute myocardial infarction (AMI) and bundle branch block or wide QRS complex. A large proportion of these patients do not suffer from an AMI, whereas those with ST-elevation myocardial infarction (STEMI) equivalent AMI benefit from an aggressive treatment. Aim of the present study was to evaluate the diagnostic information of cardiac troponin I (cTnI) in hemodynamically stable patients with wide QRS complex and suspected AMI., Methods: In 417 out of 1818 patients presenting consecutively between 01/2007 and 12/2008 in a prospective multicenter observational study with suspected AMI a prolonged QRS duration was observed. Of these, n = 117 showed significant obstructive coronary artery disease (CAD) used as diagnostic outcome variable. cTnI was determined at admission., Results: Patients with significant CAD had higher cTnI levels compared to individuals without (median 250ng/L vs. 11ng/L; p<0.01). To identify patients needing a coronary intervention, cTnI yielded an area under the receiver operator characteristics curve of 0.849. Optimized cut-offs with respect to a sensitivity driven rule-out and specificity driven rule-in strategy were established (40ng/L/96ng/L). Application of the specificity optimized cut-off value led to a positive predictive value of 71% compared to 59% if using the 99th percentile cut-off. The sensitivity optimized cut-off value was associated with a negative predictive value of 93% compared to 89% provided by application of the 99th percentile threshold., Conclusion: cTnI determined in hemodynamically stable patients with suspected AMI and wide QRS complex using optimized diagnostic thresholds improves rule-in and rule-out with respect to presence of a significant obstructive CAD.

Background: Cardiovascular biomarkers might help to identify fetuses or pregnancies at risk., Aim: To examine the umbilical cord neonatal and maternal levels of cardiovascular biomarkers at the time of delivery, and to correlate maternal and fetal biomarker levels to each other, to gestational age and to delivery mode., Study Design: In a prospective, observational, cross-sectional, single-center study biomarkers were measured in paired maternal and umbilical venous cord blood samples., Subjects: The sample cohort included 66 sets of fetal and maternal blood samples (11 after multiple gestation, 53 after cesarean section, 17 after exposure to labor)., Outcome Measures: Midregional pro-adrenomedullin (MRproADM), midregional-pro atrial natriuretic peptide (MRproANP), brain natriuretic peptide (BNP), n-terminal-pro brain natriuretic peptide (NTproBNP), copeptin, and high sensitive troponin I (hsTnI) levels were measured., Results: Mean ± SEM for biomarker levels in umbilical venous/maternal blood were: MRproADM [nmol/L] 1.02 ± 0.04/1.24 ± 0.08, MRproANP [pmol/L] 215.53 ± 12.96/54.65 ± 3.41, BNP [pg/mL] 32.02 ± 3.37/19.76 ± 3.29, NTproBNP [pg/mL] 1228.94 ± 91.73/71.48 ± 8.65, copeptin [pmol/L] 103.42 ± 22.89/10.41 ± 1.71, and hsTnI [pg/mL] 13.54 ± 5.17/4.91 ± 2.37. Fetal MRproANP, NTproBNP, and BNP were inversely correlated with gestational age. Maternal and fetal MRproANP (r=0.472, p=0.002) and copeptin (r=0.572, p<0.001) levels were correlated, whereas there was no feto-maternal correlation for the other biomarkers. Fetal copeptin was elevated after exposure to labor., Conclusions: Biomarker levels appear to be regulated independently in mother and fetus. Fetal biomarkers are influenced by gestational age and delivery mode. In this study on term and near term pregnancies without specific fetal pathology, correlation between paired maternal and fetal biomarker levels was weak or not demonstrable., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: The limit of detection (LoD) is the minimal amount of a substance that can be consistently detected. In the diagnosis of acute myocardial infarction (AMI) many patients present with troponin concentrations below the LoD of contemporary sensitive cardiac troponin I (cs-cTnI) assays. These censored values below the LoD influence the diagnostic performance of these assays compared to highly sensitive cTnI (hs-cTnI) assays. Therefore we assessed the impact of a new approach for interpolation of the left-censored data of a cs-cTnI assay in the evaluation of patients with suspected AMI., Methods: Our posthoc analysis used a real world cohort of 1818 patients with suspected MI. Data on cs-cTnI was available in 1786 patients. As a comparator the hs-cTnI version of the assay was used. To reconstruct quantities below the LoD of the cs-cTnI assay, a gamma regression approach incorporating the GRACE (Global Registry of Acute Coronary Events) score variables was used., Results: Censoring of cs-cTnI data below the LoD yielded weaker diagnostic information [area under the curve (AUC), 0.781; 95% CI, 0.731-0.831] regarding AMI compared to the hs-cTnI assay (AUC, 0.949; CI, 0.936-0.961). Use of our model to estimate cs-cTnI values below the LoD showed an AUC improvement to 0.921 (CI, 0.902-0.940). The cs-cTnI LoD concentration had a negative predictive value (NPV) of 0.950. An estimated concentration that was to be undercut by 25% of patients presenting with suspected AMI was associated with an improvement of the NPV to 0.979., Conclusions: Estimation of values below the LoD of a cs-cTnI assay with this new approach improves the diagnostic performance in evaluation of patients with suspected AMI., (© 2015 American Association for Clinical Chemistry.)

Background: The introduction of modern troponin assays has facilitated diagnosis of acute myocardial infarction due to improved sensitivity with corresponding loss of specificity. Atrial fibrillation (AF) is associated with elevated levels of troponin. The aim of the present study was to evaluate the diagnostic performance of troponin I in patients with suspected acute coronary syndrome and chronic AF., Methods: Contemporary sensitive troponin I was assayed in a derivation cohort of 90 patients with suspected acute coronary syndrome and chronic AF to establish diagnostic cut-offs. These thresholds were validated in an independent cohort of 314 patients with suspected myocardial infarction and AF upon presentation. Additionally, changes in troponin I concentration within 3 hours were used., Results: In the derivation cohort, optimized thresholds with respect to a rule-out strategy with high sensitivity and a rule-in strategy with high specificity were established. In the validation cohort, application of the rule-out cut-off led to a negative predictive value of 97 %. The rule-in cut-off was associated with a positive predictive value of 88 % compared with 71 % if using the 99th percentile cut-off. In patients with troponin I levels above the specificity-optimized threshold, additional use of the 3-hour change in absolute/relative concentration resulted in a further improved positive predictive value of 96 %/100 %., Conclusions: Troponin I concentration and the 3-hour change in its concentration provide valid diagnostic information in patients with suspected myocardial infarction and chronic AF. With regard to AF-associated elevation of troponin levels, application of diagnostic cut-offs other than the 99th percentile might be beneficial.

Background: The 99th percentile of cardiac troponin levels, determined in a reference population, is accepted as threshold for diagnosis of acute myocardial infarction (AMI). However, there is no common consensus of how to define the reference population. The aim of the present study was to determine 99th percentile reference values, determined by a high-sensitivity assay (hsTnI), according to different health status and cardiovascular risk factor prevalence in a large population-based sample., Methods: Troponin I was determined using the Abbott ARCHITECT STAT highly sensitive troponin I immunoassay in 4138 participants of the Gutenberg Health Study., Results: hsTnI was detectable in 81.6% of all individuals. The 99th percentile of the overall population was 27 ng/L. Age and gender had a prominent influence on these values. Exclusion of individuals with elevated natriuretic peptide levels or cardiac abnormalities resulted in lower 99th percentile values, whereas exclusion of individuals with an impaired estimated glomerular filtration rate (eGFR) or with prevalent coronary artery disease/myocardial infarction (CAD/MI) did not result in a meaningful change., Conclusions: Troponin I, measured by a high-sensitivity assay, can be reliably detected in the vast majority of the general population. hsTnI values were dependent on age, gender as well as structural and functional cardiac abnormalities.

Background: Aim of the study was to analyze the correlation of high-sensitivity assayed troponin I with cardiac and vascular structure and function in a large population-based cohort., Methods: In a sample of 4,139 subjects (2,099 men, 2,040 women, age 35-74 years) from the population-based Gutenberg Health Study, troponin I was measured with a high-sensitivity assay that had a limit of detection of 1.9 pg/mL., Results: In the study cohort, 3,405 subjects had detectable troponin I concentrations [82.3% overall, 89.9% men (N = 1,888), 74.4% women (N = 1,517)]. All analyses were adjusted for age. The strongest correlate between detectable troponin I and measures of cardiac phenotypes was observed for left ventricular mass (p < 0.001) and left ventricular end-diastolic diameter (p < 0.001) for both, women and men. Left ventricular ejection fraction was inversely correlated with troponin I (p value <0.001 in men and 0.0013 in women), also measures of diastolic dysfunction as represented by Tei index and E/E' correlated with detectable troponin I concentrations (p < 0.001 for both gender). With respect to vascular structure and function, troponin I correlated with mean intima-media thickness of the carotid artery (p < 0.001 in men and p = 0.013 in women) but showed only borderline correlation with measures of vascular function represented by flow-mediated dilation (p = 0.05 in women and p = 0.018 in men) and arterial stiffness., Conclusions: Troponin I assessed by a high-sensitivity assay correlated with measures of left ventricular hypertrophy and systolic and diastolic function, whereas its correlation with vascular phenotypes was only of weak magnitude.

Aims: Our aim was to test the prediction and clinical applicability of high-sensitivity assayed troponin I for incident cardiovascular events in a general middle-aged European population., Methods and Results: High-sensitivity assayed troponin I was measured in the Scottish Heart Health Extended Cohort (n = 15 340) with 2171 cardiovascular events (including acute coronary heart disease and probable ischaemic strokes), 714 coronary deaths (25% of all deaths), 1980 myocardial infarctions, and 797 strokes of all kinds during an average of 20 years follow-up. Detection rate above the limit of detection (LoD) was 74.8% in the overall population and 82.6% in men and 67.0% in women. Troponin I assayed by the high-sensitivity method was associated with future cardiovascular risk after full adjustment such as that individuals in the fourth category had 2.5 times the risk compared with those without detectable troponin I (P < 0.0001). These associations remained significant even for those individuals in whom levels of contemporary-sensitivity troponin I measures were not detectable. Addition of troponin I levels to clinical variables led to significant increases in risk prediction with significant improvement of the c-statistic (P < 0.0001) and net reclassification (P < 0.0001). A threshold of 4.7 pg/mL in women and 7.0 pg/mL in men is suggested to detect individuals at high risk for future cardiovascular events., Conclusion: Troponin I, measured with a high-sensitivity assay, is an independent predictor of cardiovascular events and might support selection of at risk individuals.

Background: Diagnosis of acute myocardial infarction (AMI) according to the universal definition is based on ischemic symptoms, imaging findings and elevated myocardial necrosis markers, preferably cardiac troponin I/T with diagnostic threshold representing the 99th percentile of a reference population. It is not clearly defined if this should be an unselected population-based or a healthy cohort with respect to cardiac diseases. Aim of the current study was to describe the distribution of troponin I using a sensitive assay and to evaluate the impact of cardiac diseases and cardiovascular risk factors in apparently healthy individuals., Methods: Troponin I was determined using a contemporary sensitive assay (TnI Ultra, Siemens) with 10% coefficient of variation (0.03 ng/mL) below the published 99th percentile (0.04 ng/mL) in 5000 participants (49.2% female) of the Gutenberg Health Study, a community-based, prospective, observational single-center cohort study. The calculated 99 th percentile cut-offs were tested in 1818 patients with suspected AMI., Results: Troponin I concentration representing the 99th percentile of the overall study population was 0.04 ng/mL. Excluding individuals with prevalent cardiovascular disease lowers the 99th percentile to 0.034 ng/mL. Exclusion of individuals with traditional risk factors or elevated natriuretic peptide leads to further reduction with 0.029/0.028 ng/mL. These lower cut-offs detect more patients at risk in individuals with suspected AMI. Correlations of troponin I with age, gender and traditional risk factors were observed., Conclusions: Troponin I concentrations in apparently healthy individuals are dependent on prevalent cardiovascular diseases, traditional risk factors, gender and age. Application of corresponding cut-offs in diagnosis of AMI alters the group of patients potentially at risk., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Context: Introduction of highly sensitive troponin assays into clinical practice has substantially improved the evaluation of patients with chest pain., Objective: To evaluate the diagnostic performance of a highly sensitive troponin I (hsTnI) assay compared with a contemporary troponin I (cTnI) assay and their serial changes in the diagnosis of acute myocardial infarction (AMI)., Design, Setting, and Patients: A total of 1818 patients with suspected acute coronary syndrome were consecutively enrolled at the chest pain units of the University Heart Center Hamburg, the University Medical Center Mainz, and the Federal Armed Forces Hospital Koblenz, all in Germany, from 2007 to 2008. Twelve biomarkers including hsTnI (level of detection, 3.4 pg/mL) and cTnI (level of detection, 10 pg/mL) were measured on admission and after 3 and 6 hours., Main Outcome Measures: Diagnostic performance for AMI of baseline and serial changes in hsTnI and cTnI results at 3 hours after admission to the emergency department., Results: Of the 1818 patients, 413 (22.7%) were diagnosed as having AMI. For discrimination of AMI, the area under the receiver operating characteristic (ROC) curve was 0.96 (95% CI, 0.95-0.97) for hsTnI on admission and 0.92 (95% CI, 0.90-0.94) for cTnI on admission. Both were superior to the other evaluated diagnostic biomarkers. The use of hsTnI at admission (with the diagnostic cutoff value at the 99th percentile of 30 pg/mL) had a sensitivity of 82.3% and a negative predictive value (for ruling out AMI) of 94.7%. The use of cTnI (with the diagnostic cutoff value at the 99th percentile of 32 pg/mL) at admission had a sensitivity of 79.4% and a negative predictive value of 94.0%. Using levels obtained at 3 hours after admission, the sensitivity was 98.2% and the negative predictive value was 99.4% for both hsTnI and cTnI assays. Combining the 99th percentile cutoff at admission with the serial change in troponin concentration within 3 hours, the positive predictive value (for ruling in AMI) for hsTnI increased from 75.1% at admission to 95.8% after 3 hours, and for cTnI increased from 80.9% at admission to 96.1% after 3 hours., Conclusions: Among patients with suspected acute coronary syndrome, hsTnI or cTnI determination 3 hours after admission may facilitate early rule-out of AMI. A serial change in hsTnI or cTnI levels from admission (using the 99th percentile diagnostic cutoff value) to 3 hours after admission may facilitate an early diagnosis of AMI.

Background: Cardiac troponin testing is central to the diagnosis of acute myocardial infarction. We evaluated a sensitive troponin I assay for the early diagnosis and risk stratification of myocardial infarction., Methods: In a multicenter study, we determined levels of troponin I as assessed by a sensitive assay, troponin T, and traditional myocardial necrosis markers in 1818 consecutive patients with suspected acute myocardial infarction, on admission and 3 hours and 6 hours after admission., Results: For samples obtained on admission, the diagnostic accuracy was highest with the sensitive troponin I assay (area under the receiver-operating-characteristic curve [AUC], 0.96), as compared with the troponin T assay (AUC, 0.85) and traditional myocardial necrosis markers. With the use of the sensitive troponin I assay (cutoff value, 0.04 ng per milliliter) on admission, the clinical sensitivity was 90.7%, and the specificity was 90.2%. The diagnostic accuracy was virtually identical in baseline and serial samples, regardless of the time of chest-pain onset. In patients presenting within 3 hours after chest-pain onset, a single sensitive troponin I assay had a negative predictive value of 84.1% and a positive predictive value of 86.7%; these findings predicted a 30% rise in the troponin I level within 6 hours. A troponin I level of more than 0.04 ng per milliliter was independently associated with an increased risk of an adverse outcome at 30 days (hazard ratio, 1.96; 95% confidence interval, 1.27 to 3.05; P=0.003)., Conclusions: The use of a sensitive assay for troponin I improves early diagnosis of acute myocardial infarction and risk stratification, regardless of the time of chest-pain onset., (2009 Massachusetts Medical Society)

Aims The differentiation of type 1 and type 2 myocardial infarction (T1MI, T2MI) is important, but challenging in the emergency department. We aimed to investigate the clinical characteristics and cardiovascular outcome of T2MI patients and to develop a clinical decision tool to differentiate T1MI and T2MI patients. Methods and results We prospectively enrolled 1548 patients with suspected MI. All patients were followed for up to 2 years to assess mortality. We used logistic regression with backward step-down selection to determine the most important predictors of T2MI. Based on these regression coefficients, we developed a diagnostic prediction model (score) to diagnose T2MI. T2MI was the final diagnosis of 99 patients. Patients with T2MI showed a high 1-year mortality rate (13.8%), which equals that of T1MI patients (9.4%). Female sex (Beta 1.27 [95% confidence interval; CI 0.67-1.90]), not having radiating chest pain (Beta 1.62 [CI 0.96-2.34]) and a baseline high-sensitivity troponin I concentration ≤ 40.8 ng/L (Beta 1.30 [CI 0.74-1.89]) were the strongest predictors for T2MI. Their combination resulted in an area under the curve of 0.71 to discriminate T1MI and T2MI. The binary score based on this model assigns one point to each of the predictors. Patients with the highest score value of 3 had a 72% probability of T2MI. Conclusion T2MI patients are a heterogeneous population with high-cardiovascular risk. A score based on laboratory and clinical parameters might help to differentiate T1MI and T2MI patients. The additional use of this score in clinical routine needs to be investigated prospectively. [ABSTRACT FROM AUTHOR]

BACKGROUND: Preeclampsia shares numerous risk factors with cardiovascular diseases. Here, we aimed to assess the potential utility of high-sensitivity cardiac troponin I (hs-cTnI) values during pregnancy in predicting preeclampsia occurrence. METHODS: This study measured hs-cTnI levels in 3721 blood samples of 2245 pregnant women from 4 international, prospective cohorts. Three analytical approaches were used: (1) a cross-sectional analysis of all women using a single blood sample, (2) a longitudinal analysis of hs-cTnI trajectories in women with multiple samples, and (3) analyses of prediction models incorporating hs-cTnI, maternal factors, and the sFlt-1 (soluble fms-like tyrosine kinase 1)/PlGF (placental growth factor) ratio. RESULTS: Women with hs-cTnI levels in the upper quarter had higher odds ratios for preeclampsia occurrence compared with women with levels in the lower quarter. Associations were driven by preterm preeclampsia (odds ratio, 5.78 [95% CI, 2.73–12.26]) and remained significant when using hs-cTnI as a continuous variable adjusted for confounders. Betweentrimester hs-cTnI trajectories were independent of subsequent preeclampsia occurrence. A prediction model incorporating a practical hs-cTnI level of detection cutoff (≥1.9 pg/mL) alongside maternal factors provided comparable performance with the sFlt-1/PlGF ratio. A comprehensive model including sFlt-1/PlGF, maternal factors, and hs-cTnI provided added value (cross-validated area under the receiver operator characteristic, 0.78 [95% CI, 0.73–0.82]) above the sFlt-1/PlGF ratio alone (cross-validated area under the receiver operator characteristic, 0.70 [95% CI, 0.65–0.76]; P=0.027). As assessed by likelihood ratio tests, the addition of hs-cTnI to each prediction model significantly improved the respective prediction model not incorporating hs-cTnI, particularly for preterm preeclampsia. Net reclassification improvement analyses indicated that incorporating hs-cTnI improved risk prediction predominantly by correctly reclassifying women with subsequent preeclampsia occurrence. CONCLUSIONS: These exploratory findings uncover a potential role for hs-cTnI as a complementary biomarker in the prediction of preeclampsia. After validation in prospective studies, hs-cTnI, alongside maternal factors, may either be considered as a substitute for angiogenic biomarkers in health care systems where they are sparce or unavailable, or as an enhancement to established prediction models using angiogenic markers. [ABSTRACT FROM AUTHOR]

Air pollution and traffic noise are detrimental to cardiovascular health. However, the effects of different sources of these exposures on cardiovascular biomarkers remain unclear. We explored the associations of long-term exposure to source-specific air pollution (vehicular exhausts and residential woodsmoke) at low concentrations and road-traffic noise with systemic inflammation and cardiovascular disease biomarkers. Modeled outdoor exposure to fine particulate matter (aerodynamic diameter ≤2.5 μm; PM 2.5) from vehicular exhausts and residential woodsmoke, nitrogen dioxide (NO 2) from road traffic, and road-traffic noise were linked to the home addresses of the participants (Finnish residents aged 25–74) in the FINRISK study 1997–2012. The participants were located in the cities of Helsinki, Vantaa, and the region of Turku, Finland. The outcomes were high-sensitivity C-reactive protein (CRP), a biomarker for systemic inflammation, and cardiovascular disease biomarkers N-terminal pro-B-type natriuretic peptide (NT-proBNP) and troponin I. We performed cross-sectional analyses with linear and additive models and adjusted for potential confounders. We found no association between PM 2.5 from vehicular exhausts (% CRP difference for 1 μg/m3 increase in PM 2.5 : −0.9, 95% confidence interval, CI: −7.2, 5.8), or from residential woodsmoke (% difference: −8.1, 95% CI: −21.7, 7.9) and CRP (N = 4147). Road-traffic noise >70 dB tended to be positively associated with CRP (% CRP difference versus noise reference category of ≤45 dB: 18.3, 95% CI: −0.5, 40.6), but the association lacked significance and robustness (N = 7142). Otherwise, we found no association between road-traffic noise and CRP, nor between NO 2 from road traffic and NT-proBNP (N = 1907) or troponin I (N = 1951). Long-term exposures to source-specific, fairly low-level air pollution from vehicular exhausts and residential woodsmoke, or road-traffic noise were not associated with systemic inflammation and cardiovascular disease biomarkers in this urban area. • We studied air pollution from wood combustion and road traffic, and traffic noise. • Air pollution was not associated with cardiovascular disease biomarkers. • There may be a lower threshold for the effects of air pollution. • Road-traffic noise was also not associated with the outcomes. • Efficient home sound insulation has likely contributed to the finding. [ABSTRACT FROM AUTHOR]

Background: Discrimination among patients with type 1 myocardial infarction (T1MI), type 2 myocardial infarction (T2MI), and myocardial injury is difficult.Objectives: The aim of this study was to investigate the discriminative value of a 29-biomarker panel in an emergency department setting.Methods: Patients presenting with suspected myocardial infarction (MI) were recruited. The final diagnosis in all patients was adjudicated on the basis of the fourth universal definition of MI. A panel of 29 biomarkers was measured, and multivariable logistic regression analysis was used to evaluate the associations of these biomarkers with the diagnosis of MI or myocardial injury. Biomarkers were chosen using backward selection. The model was internally validated using bootstrapping.Results: Overall, 748 patients were recruited (median age 64 years), of whom 138 had MI (107 T1MI and 31 T2MI) and 221 had myocardial injury. In the multivariable model, 4 biomarkers (apolipoprotein A-II, N-terminal prohormone of brain natriuretic peptide, copeptin, and high-sensitivity cardiac troponin I) remained significant discriminators between T1MI and T2MI. Internal validation of the model showed an area under the curve of 0.82. For discrimination between MI and myocardial injury, 6 biomarkers (adiponectin, N-terminal prohormone of brain natriuretic peptide, pulmonary and activation-regulated chemokine, transthyretin, copeptin, and high-sensitivity troponin I) were selected. Internal validation showed an area under the curve of 0.84.Conclusions: Among 29 biomarkers, 7 were identified to be the most relevant discriminators between subtypes of MI or myocardial injury. Regression models based on these biomarkers allowed good discrimination. (Biomarkers in Acute Cardiac Care [BACC]; NCT02355457). [ABSTRACT FROM AUTHOR]

Cardiac troponin blood levels are frequently elevated in patients with impaired renal function. Their predictive value for the severity of stable coronary artery disease (CAD) remains unclear in these cases. Therefore, we aimed to evaluate the blood levels of high-sensitivity troponin T and I (hsTnT/I) and their association with the severity of stable CAD in patients with chronic kidney disease. Overall, 2209 patients with suspected stable CAD undergoing invasive coronary angiography were included in an ongoing prospective cohort study. We identified 595 patients with impaired renal function defined as an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2. Coronary morphology was assessed by the number of affected major coronary vessels (CAD classification), SYNTAX, and Gensini scores. hsTnT/I blood levels were measured by three latest-generation assays (Roche Diagnostics Elecsys, Abbott ARCHITECT STAT, and Singulex Clarity). Ordinal logistic regression for the severity of CAD adjusted by classical cardiovascular risk factors and eGFR were performed with each troponin assay as an independent variable. Mean age was 72.9 ± 9.8 years (33.6% female). Median eGFR was 47.5 ml/min/1.73 m2 (interquartile range [IQR] 34.9, 54.1). For the association of Roche-hsTnT, Abbott-hsTnI, and Singulex-hsTnI with the CAD classification, odds ratios per standard deviation (OR) were 1.27 (95% confidence interval [CI] 1.07–1.51), 1.21 (CI 1.02–1.44), and 1.24 (CI 1.04–1.47), respectively. The associations for the investigated assays with SYNTAX and Gensini scores, respectively, were OR 1.40, CI 1.11–1.78 and OR 1.24, CI 1.01–1.51 (Roche-hsTnT), OR 1.42, CI 1.12–1.78 and OR 1.25, CI 1.02–1.52 (Abbott-hsTnI), OR 1.38, CI 1.09–1.74 and OR 1.25, CI 1.02–1.53 (Singulex-hsTnI). In patients with impaired renal function, blood levels of hsTnT/I were significantly associated with the severity of stable CAD. These findings may help clinicians guide further diagnostic assessment. Image 1 • High-sensitivity troponins (hsTn) are elevated in patients with chronic kidney disease (CKD). • The association of elevated hsTn with coronary artery disease (CAD) remains unclear in CKD. • The present study demonstrates higher hsTn blood levels in patients with CAD. • hsTn are associated with the severity of CAD even after adjustment for CV risk factors and eGFR. [ABSTRACT FROM AUTHOR]