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Objective To evaluate the prognostic implications of longitudinal long-term changes beyond the biological variation of high-sensitivity cardiac troponin T (hs-cTnT) in outpatients with stable or asymptomatic cardiovascular disease (CV) and to assess possible differences in the prognostic value while using reference change value (RCV) and minimal important differences (MID) as metric for biological variation. Methods Hs-cTnT was measured at index visit and after 12 months in outpatients presenting for routine follow-up. The prognostic relevance of a concentration change of hs-cTnT values exceeding the biological variation defined by RCV and MID of a healthy population within the next 12 months following the stable initial period was determined regarding three endpoints: all-cause mortality (EP1), a composite of all-cause mortality, non-fatal myocardial infarction and stroke (EP2), and a composite of all-cause mortality, non-fatal myocardial infarction, stroke, hospitalization for acute coronary syndrome (ACS) or decompensated heart failure, and planned and unplanned percutaneous coronary interventions (PCI, EP3). Results Change in hs-cTnT values exceeding the biovariability defined by MID but not by RCV discriminated a group with a higher cardiovascular risk profile. Changes within MID were associated with uneventful course (NPV 91.6–99.7%) while changes exceeding MID were associated with a higher occurrence of all endpoints within the next 365 days indicating a 5.5-fold increased risk for EP 1 (p = 0.041) a 2.4-fold increased risk for EP 2 (p = 0.049) and a 1.9-fold increased risk for EP 3 (p Conclusions In stable outpatients MID calculated from hs-cTnT changes measured 365 ± 120 days apart are helpful to predict an uneventful clinical course. Clinical trials identifier NCT01954303. Graphic abstract

BACKGROUND: Application of the 4th version of Universal Definition of Myocardial Infarction (UDMI) to characterize rates and prognostic relevance of myocardial injury in COVID-19 disease. METHODS: This retrospective, single-centre observational study enrolled 104 patients hospitalized with SARS-CoV-2 infection. Kaplan-Meier analysis and multivariate Cox regression were used to identify influence of acute or chronic myocardial injury on a composite primary (mortality, incident acute respiratory distress syndrome, incident mechanical ventilation) and secondary endpoint (mortality, incident acute myocardial injury during hospitalization, incident venous thrombosis, pulmonary embolism or stroke). RESULTS: A total of 27 (26.0%) patients presented with chronic myocardial injury, and 19 (18.3%) with acute myocardial injury. 42 patients(40.4%) developed an incident myocardial injury during hospitalization. The presence of acute or chronic myocardial injury on admission and incident myocardial injury during hospitalization were associated with higher rates of endpoints. Independent predictors for the primary endpoint were higher severity stages according to Siddiqi et al. classification system and history of dyslipidaemia. Maximal hs-cTnT and D-dimer concentrations during hospitalization showed an association (r = 0.61). CONCLUSIONS: Objective description of myocardial injury according to the 4th UDMI in the current COVID-19 pandemic is crucial in order to discriminate patients with acute myocardial infarction and acute, chronic or incident myocardial injury.

Background To evaluate the prognostic value of eleven microRNAs (miRNAs) compared to high-sensitivity Troponin T (hs-cTnT) in patients presenting with suspected acute coronary syndrome (ACS) to the emergency department (ED). Methods 1,042 patients presenting between August 2014 and April 2017 were included. Expression levels of eleven microRNAs (miR-21-5p, miR-22-3p, miR-29a-3p, miR-92a-3p, miR-122-5p, miR-126-3p, miR-132-3p, miR-133a-3p, miR-134-5p, miR-191-3p, and miR-423-5p) were determined using RT-qPCR. All-cause mortality (ACM) and a composite of ACM, acute myocardial infarction (AMI) and stroke were defined as endpoints. Results During a median follow-up of 399 (P25-P75: 381–525) days 58 patients (5.6%) died. The composite endpoint occurred in 86 patients (8.3%). Different expression levels of miR-21-5p (median, P25-P75: 5.28 [5.14–5.51] vs. 5.16 [4.97–5.35], p = 0.0033) and miR-122-5p (median, P25-P75: 5.17 [4.81–5.49] vs. 5.35 [5.01–5.69], p = 0.0184) were observed in patients who died compared to survivors. ROC-optimized cutoff of miR-21-5p (HR, P25-P75: 3.3 [1.2–9.4], p = 0.0239), but not miR-122-5p (HR, P25-P75: 0.4 [0.2–0.8], p = 0.0116), was predictive for all-cause mortality, even after adjustment in a multivariate model. Nevertheless, addition of miR-21-5p and miR-122-5p decreased prognostic accuracy of hs-cTnT for all-cause mortality (△AUC: 0.112, p = 0.0159). Hs-cTnT admission values had a high prognostic value for ACM (AUC [95%CI] = 0.794 [0.751–0.837]) and the composite of ACM, AMI and stroke (AUC [95%CI] = 0.745 [0.695–0.794]). Conclusions Despite a different expression depending on outcomes miR-21-5p and miR-122-5p do not add prognostic information to hs-cTnT in patients presenting with suspected ACS to the ED.

Patients with unstable angina (UA) are regarded to be at low risk for future coronary events. Guidelines discourage routine coronary angiography and recommend early discharge after individualized risk stratification. The relative value of clinical risk indicators as compared to cardiac troponin (cTn) alone is unsettled in the era of high-sensitivity cardiac troponin (hsTn) assays. We aimed to investigate the clinical characteristics, therapies, and outcomes of UA patients with different hsTnT concentrations. During 12 months, 2525 patients were enrolled. UA was defined as unstable symptoms and either undetectable ( 99th percentile but not unstable symptoms carried an independent 3.25-fold (1.78–5.93) higher risk for all-cause death after adjustment for other clinical risk indicators or the GRACE score. Utilization of guideline-recommended therapies was high albeit lower than for non-ST-elevation myocardial infarction (NSTEMI). Significantly fewer patients with UA received dual antiplatelet therapy (DAPT, odds ratio (OR) 0.51 [95% CI 0.44–0.59], P

Objectives The PATHFAST hs-cTnI (high-sensitivity cardiac troponin) assay is the first point-of-care assay with a high-sensitivity designation that received FDA approval for diagnosis of myocardial infarction (MI). Testing from whole blood does not need centrifugation and therefore is faster and more convenient in the emergency room instead of plasma. However, there is sparse evidence whether point-of-care testing of Tn from whole blood is as reliable as from plasma samples. Methods We investigated the agreement between plasma and whole blood hs-cTnI by using the PATHFAST hs-cTnI assay. Hs-cTnT measured on Cobas 602 in the central laboratory and compared to a final diagnosis of NSTEMI using serial hs-cTnT served as reference. We assessed biases, limits of agreement (±1.96 SD) and coefficients of correlation, and tested the discriminatory ability of the baseline sample of plasma and whole blood hs-cTnI and plasma hs-cTnT to discriminate non-ST-segment elevation myocardial infarction (NSTEMI). Results A total of 224 paired fresh samples were collected simultaneously from 191 patients presenting with suspected acute coronary syndrome. There was an excellent correlation between plasma and whole blood hs-cTnI (r=0.99), and a very good inter-rater agreement (k=0.93) between elevated and normal plasma and whole blood results. Precision evaluation according to CLSI ep 15 revealed comparable coefficients of variation (CV) in whole blood and plasma. The discriminatory ability of baseline hs-cTnT, plasma and whole blood hs-cTnI was excellent (AUC 0.967, AUC 0.954 and AUC 0.953) without significant difference. Conclusions Whole blood can be used interchangeably with plasma for more convenient and less time and labor-consuming testing of hs-cTnI on the PATHFAST instrument.

Background/Introduction MicroRNAs (miRNAs) are promising biomarkers due to their high specificity and may facilitate differential diagnosis of patients presenting with suspected acute coronary syndrome (ACS) to the emergency department (ED). Purpose To assess the diagnostic value of eleven miRNAs for the detection of non-ST-segment elevation myocardial infarction (NSTEMI). Methods 1,042 patients presenting between August 2014 and April 2017 to the ED with suspected ACS were included. NSTEMI was diagnosed per criteria of the 4th Universal definition of myocardial infarction (UDMI) using high-sensitivity troponin T (hs-cTnT). Expression levels of eleven microRNAs (miR-21, miR-22, miR-29a, miR-92a, miR-122, miR-126, miR-132, miR-133, miR-134, miR-191, miR-423) were determined using RT-qPCR. Discrimination of NSTEMI was assessed for individual and a panel of miRNAs compared to the hs-cTnT reference using C-statistics and reclassification analysis. Results NSTEMI was diagnosed in 137 (13.1%) patients. The AUC of the hs-cTnT based reference was 0.937. In a multivariate model three miRNAs (miR-122, miR-133 and miR-134) were found to be associated with NSTEMI with AUCs between 0.506 and 0.656. A panel consisting of these miRNAs revealed an AUC of 0.662 for the diagnosis of NSTEMI. The AUC of the combination of the miRNA panel and troponin reference was significantly lower than the reference standard (AUC: 0.897 vs. 0.937, p=0.006). Despite a significant improvement of NSTEMI reclassification measured by IDI and NRI, miRNAs did not improve specificity of hs-cTnT kinetic changes for the diagnosis of NSTEMI (ΔAUC: 0.04). Conclusion Although single miRNAs are significantly associated with the diagnosis of NSTEMI a miRNA panel does not add diagnostic accuracy to the hs-cTnT reference considering baseline values and kinetic changes as recommended by 4th version of UDMI. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): German Heart Foundation/German Foundation of Heart Research.CIBERES (CB07/06/2008 to DdGC) is a project from Carlos III Health Institute. Central illustration

Journal of the American Heart Association : JAHA 10(13), e019477 (2021). doi:10.1161/JAHA.120.019477, Published by Association, New York, NY

Aims: Recent studies have found circulating concentrations of the gastrointestinal hormone GLP-1 to be an excellent predictor of cardiovascular risk in patients with myocardial infarction. This illustrates a yet not appreciated crosstalk between the gastrointestinal and cardiovascular systems, which requires further investigation. The gut-derived hormone Peptide YY (PYY) is secreted from the same intestinal L-cells as GLP-1. Relevance of PYY in the context of cardiovascular disease has not been explored. In this study, we aimed to investigate PYY serum concentrations in patients with acute myocardial infarction and to evaluate their association with cardiovascular events. Material and Methods: PYY levels were assessed in 834 patients presenting with acute myocardial infarction (553 Non-ST-Elevation Myocardial Infarction (NSTEMI) and 281 ST-Elevation Myocardial Infarction (STEMI)) at the time of hospital admission. The composite outcomes of first occurrence of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke (3-P-MACE), and all-cause mortality were assessed with a median follow-up of 338 days. Results: PYY levels were significantly associated with age and cardiovascular risk factors, including hypertension, diabetes, and kidney function in addition to biomarkers of heart failure (NT-pro BNP) and inflammation (hs-CRP). Further, PYY was significantly associated with 3-P-MACE (HR: 1.7, 95% CI: 1&ndash, 2.97, p = 0.0495) and all-cause mortality (HR: 2.69, 95% CI: 1.61&ndash, 4.47, p = 0.0001) by univariable Cox regression analyses, which was however lost after adjusting for multiple confounders. Conclusions: PYY levels are associated with parameters of cardiovascular risk as well as cardiovascular events and mortality in patients presenting with acute myocardial infarction. However, this significant association is lost after adjustment for further confounders.

Aims To assess the diagnostic value of microRNAs (miRNAs) for the detection of non-ST-segment elevation myocardial infarction (NSTEMI). Methods and results A total of 1042 patients presenting between August 2014 and April 2017 to the emergency department with the suspected acute coronary syndrome were included. Non-ST-segment elevation myocardial infarction was diagnosed per criteria of the fourth Universal definition of myocardial infarction (UDMI) using high-sensitivity troponin T (hs-cTnT). Expression levels of eleven microRNAs (miR-21, miR-22, miR-29a, miR-92a, miR-122, miR-126, miR-132, miR-133, miR-134, miR-191, and miR-423) were determined using RT-qPCR. Discrimination of NSTEMI was assessed for individual and a panel of miRNAs compared to the hs-cTnT reference using C-statistics and reclassification analysis. NSTEMI was diagnosed in 137 (13.1%) patients. The area under the curve (AUC) of the hs-cTnT based reference was 0.937. In a multivariate model, three miRNAs (miR-122, miR-133, and miR-134) were found to be associated with NSTEMI with AUCs between 0.506 and 0.656. A panel consisting of these miRNAs revealed an AUC of 0.662 for the diagnosis of NSTEMI. The AUC of the combination of the miRNA panel and troponin reference was significantly lower than the reference standard (AUC: 0.897 vs. 0.937, P = 0.006). Despite a significant improvement of NSTEMI reclassification measured by IDI and NRI, miRNAs did not improve the specificity of hs-cTnT kinetic changes for the diagnosis of NSTEMI (ΔAUC: 0.04). Conclusion Although single miRNAs are significantly associated with the diagnosis of NSTEMI a miRNA panel does not add diagnostic accuracy to the hs-cTnT reference considering baseline values and kinetic changes as recommended by the fourth version of UDMI. Clinical Trials Identifier NCT02116153

Background GLP-1 and GLP-2 (glucagon-like peptide-1/2) are gut derived hormones that are co-secreted from intestinal L-cells in response to food intake. While GLP-1 is known to induce postprandial insulin secretion, GLP-2 enhances intestinal nutrient absorption and is clinically used for the treatment of patients with short bowel syndrome. The relevance of the GLP-2 system for cardiovascular disease is unknown. Purpose The aim of this study was to assess the predictive capacity of GLP-2 for cardiovascular prognosis in patients with myocardial infarction. Methods Total GLP-2 levels, NT-proBNP concentrations and the Global Registry of Acute Coronary Events (GRACE) score were assessed at time of admission in 918 patients with myocardial infarction, among them 597 patients with NSTEMI and 321 with STEMI. The primary composite outcome of the study was the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (3-P-MACE) with a median follow-up of 311 days. Results Kaplan-Meier survival plots (separated by the median of GLP-2 with a cut-off value of 4.4 ng/mL) and univariable cox regression analyses found GLP-2 values to be associated with adverse outcome (logarithmized GLP-2 values HR: 2.87; 95% CI: 1.75–4.68; p Conclusions In patients admitted with acute myocardial infarction, GLP-2 levels are associated with adverse cardiovascular prognosis. This demonstrates a strong yet not appreciated crosstalk between the heart and the gut with relevance for cardiovascular outcome. Future studies are needed to further explore this crosstalk with the possibility of new treatment avenues for cardiovascular disease. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): German Society of Cardiology (DGK), German Research Foundation (DFG)

Background Cathepsin S is an extracellular matrix degradation enzyme that plays an important role in atherosclerotic cardiovascular disease by inducing vasa vasorum development and atherosclerotic plaque rupture. Purpose To determine the prognostic and reclassification value of baseline serum cathepsin S after adjustment for the Global Registry of Acute Coronary Events (GRACE) score, which is a clinical guideline recommended risk score in non-ST-segment elevation acute coronary syndrome (NSTE-ACS). Methods Serum cathepsin S was measured by ELISA in 1,129 consecutive patients presenting with acute symptoms to the emergency department for whom a final adjudicated diagnosis of NSTE-ACS was made. All-cause mortality or all-cause death/non-fatal myocardial infarction (MI) after a median follow-up of 21 months were evaluated as the primary or secondary study endpoint, respectively. The Net Reclassification Index (NRI) estimated the reclassification predictive value for risk of each end-point of cathepsin S over the GRACE score. Results After a median follow-up of 21 months 101 (8.95%) deaths were reported. The combined endpoint of death or non-fatal MI occurred in 176 (15.6%) patients. Dose-response curve analysis adjusted for the effect of age, gender, diabetes mellitus, high-sensitivity-cardiac troponin T, high-sensitivity C-reactive protein, revascularization and index diagnosis revealed a non-linear association of continuous cathepsin S with all-cause death (P=0.036 for non-linearity; adjusted HR=1.60 for 80th vs. 20th percentiles, P=0.038) or with the combined endpoint (P=0.008 for non-linearity, adjusted HR=1.53 for 80th vs. 20th percentiles, P=0.011). Serum cathepsin S maintained its predictive value for all-cause death (adjusted HR=1.70 highest vs. lowest tertile, 95% CI 1.03–2.82, P=0.039) after adjusting for the GRACE Score. Similarly, cathepsin S predicted the combined endpoint of all-cause death or non-fatal MI (adjusted HR=1.67 highest vs. lowest tertile, 95% CI 1.15–2.42, P=0.007) independently of the GRACE Score. When cathepsin S was added over the GRACE Score it correctly reclassified risk for all-cause death in 20% of the population (P=0.004). Similarly, serum Cathepsin S conferred a significant reclassification value over the GRACE score for all-cause death or non-fatal MI in 15.9% of the population. Conclusions Serum cathepsin S is a predictor of mortality and improves risk stratification over the GRACE score in patients with NSTE-ACS. The clinical application of cathepsin S as a novel biomarker in NSTE-ACS should be further explored and validated. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): German Heart Foundation

Background D-dimer is elevated in a variety of conditions. The purpose of this study was to assess the positive predictive value of D-dimer to rule in patients with confirmed pulmonary embolism, deep vein thrombosis, acute aortic dissection or thrombosis of the upper extremity in comparison to patients with elevated D-dimer for other reasons. Methods and results We studied 1334 patients presenting to the emergency department with pulmonary embolism (n=193), deep vein thrombosis (n=73), acute aortic dissection (n=22), thrombosis of the upper extremity (n=8) and 1038 controls. The positive predictive value was increased with higher D-dimer concentrations improving the ability to identify diseases with high thrombus burden. Patients with venous thromboembolism, acute aortic dissection and thrombosis of the upper extremity showed a maximum positive predictive value of 85.2% at a D-dimer level of 7.8 mg/L (95% confidence interval (CI) 78.1 to 90.4). The maximum positive predictive value was lower in cancer patients with venous thromboembolism, acute aortic dissection and thrombosis of the upper extremity, reaching 68.9% at a D-dimer level of 7.5 mg/L (95% CI 57.4 to 78.4). The positive likelihood ratio was very consistent with the positive predictive value. Using a cut-off level of 0.5 mg/L, D-dimer showed a high sensitivity of at least 93%, but a very low specificity of nearly 0%. Conversely, an optimised cut-off value of 4.6 mg/L increased specificity to 95% for the detection of life-threatening venous thromboembolism, acute aortic dissection or thrombosis of the upper extremity at the costs of moderate sensitivities (58% for pulmonary embolism, 41% for deep vein thrombosis, 65% for pulmonary embolism with co-existent deep vein thrombosis, 50% for acute aortic dissection and 13% for thrombosis of the upper extremity). Using the same cut-off in cancer patients, higher values were observed for sensitivity at a specificity level of more than 95%. The area under the curve for the discrimination of venous thromboembolism/acute aortic dissection/thrombosis of the upper extremity from controls was significantly higher in cancer versus non-cancer patients (area under the curve 0.905 in cancer patients, 95% CI 0.89 to 0.92, vs. area under the curve 0.857 in non-cancer patients, 95% CI 0.84 to 0.88; P=0.0349). Conclusion D-dimers are useful not only to rule out but also to rule in venous thromboembolism and acute aortic dissection with an at least moderate discriminatory ability, both in patients with and without cancer.

Aims Elevated levels of high-sensitivity cardiac troponin T (hsTnT) indicate underlying heart disease and are known to predict adverse outcomes in various patient populations. Their role in atrial fibrillation (AF) is still under debate. Methods and results This retrospective study included 2898 consecutive patients presenting with AF to the emergency department of the Department of Cardiology, Heidelberg University Hospital. Multivariable Cox regression was used to assess associations between hsTnT and mortality. Elevated hsTnT levels were associated with increased risk of all-cause mortality in all patients with AF, as well as in each subtype of AF. After adjustment for multiple risk factors, both detectable hsTnT below the 99th percentile (5-14 ng/L, adjusted hazard ratio (HR): 4.86 [95% CI: 1.77-13.34], P = 0.002) and elevated hsTnT (>14 ng/L, adjusted HR: 13.42 [95% CI: 4.95-36.40], P

Background Blood-based biomarkers may be useful in the identification of residual risk for death or acute myocardial infarction (AMI) in patients with a previous acute coronary syndrome. Cathepsin S (CTSS) is a lysosomal cysteine protease with potent elastolytic and collagenolytic activity, which plays an important role in cardiovascular disease through extracellular matrix degradation, vasa vasorum development and atherosclerotic plaque rupture. The aim of the present study was to determine the prognostic and reclassification value of baseline circulating levels of CTSS after adjustment for the Global Registry of Acute Coronary Events (GRACE) score, which is widely recommended for risk stratification in non-ST-segment elevation acute coronary syndrome (NSTE-ACS). Methods CTSS was measured in blood samples collected from 1,129 consecutive patients with adjudicated NSTE-ACS presenting at an acute chest pain unit for evaluation of a possible acute coronary syndrome. Cardiovascular (CV) death and a composite of all-cause mortality and AMI were evaluated as the primary and secondary endpoints of the study, respectively. The additive prognostic value of CTSS over the GRACE score was estimated by the Net Reclassification Index (NRI) that examines the net upward and downward reclassification into correct pre-defined risk categories. Results After a median follow-up of 21 months, 101 (8.95%) deaths were reported, of which 63 (5.6%) were of cardiac origin. The combined endpoint occurred in 176 (15.6%) patients. Patients with CTSS in the highest tertile presented the greatest risk for all-cause mortality (HR=1.84 for highest versus lowest tertile of CTSS distribution, 95% CI 1.1–3.08, P=0.02) and CV death (HR=2.5 for highest versus lowest tertile of CTSS distribution, 95% CI 1.24–5.05, P=0.011) after adjustment for age, gender, diabetes mellitus, hs-cTnT, hsCRP, revascularization and index diagnosis. Similarly, CTSS was associated with increased risk of cardiovascular death after adjusting for the GRACE Score (adjusted HR for highest versus lowest tertile of CTSS distribution=2.34, 95% CI 1.18–4.64, P=0.015). Further, CTSS predicted the combined endpoint of all-cause death or non-fatal MI independently of the GRACE Score (adjusted HR for highest versus lowest tertile of CTSS distribution=1.67, 95% CI 1.15–2.42, P=0.007). When CTSS was added over the GRACE Score, it conferred significant reclassification value for CV death (NRI=21.4%, P=0.008). Similarly, CTSS correctly reclassified risk for all-cause death or non-fatal MI (P=0.006) in 15.9% of the population. Conclusions Circulating CTSS predicts mortality and improves risk stratification of patients with NSTE-ACS over the GRACE score recommended by clinical guidelines. The clinical application of CTSS as a novel biomarker in NSTE-ACS should be further explored and validated.

Background Patients with unstable angina (UA) are regarded to be at low risk for future coronary events. Guidelines discourage routine coronary angiography and recommend early discharge after individualized risk stratification. The relative value of clinical risk indicators as compared to cardiac troponin (cTn) alone is unsettled in the era of high-sensitivity cardiac troponin (hsTn) assays. Purpose We aimed to investigate the clinical characteristics, therapies and outcomes of UA patients with different hsTnT concentrations. Methods During 12 months, 2,525 patients were enrolled. UA was defined as unstable symptoms and either undetectable ( Results A total of 280 patients (11.1%) received a diagnosis of UA. Mortality rates at 12 months were 0%, 1.9% and 6.9% in presence of undetectable, normal and stable elevated hsTnT. Elevated hsTnT >99th percentile but not unstable symptoms carried an independent 3.25-fold (1.78–5.93) higher risk for all-cause death after adjustment for other clinical risk indicators or the GRACE score. Utilization of guideline recommended therapies was high albeit lower than for non-ST-elevation myocardial infarction (NSTEMI). Significantly fewer patients with UA received dual antiplatelet therapy (DAPT, odds ratio (OR): 0.51 [95% CI: 0.44–0.59], p Conclusions The current dichotomization of patients into UA and NSTEMI is no longer appropriate. Additional risk stratification seems warranted including the presence and magnitude of hsTn concentration and additional risk indicators. Acknowledgement/Funding Research Grant by Roche Diagnostics

Background: Although the value of fast diagnostic protocols in suspected acute coronary syndrome has been validated, there is insufficient real world evidence including patients with lower pre-test probability, atypical symptoms and confounding comorbidities. The feasibility, efficacy and safety of European Society of Cardiology (ESC) 0/1 and 0/3-hour algorithms using high-sensitivity troponin T were evaluated in a consecutive cohort with suspected acute coronary syndrome. Methods: During 12 months, 2525 eligible patients were enrolled. In a pre-implementation period of 6 months, the prevalence of protocols, disposition, lengths of emergency department stay and treatments were registered. Implementation of the 0/1-hour protocol was monitored for another 6 months. Primary endpoints comprised the change of diagnostic protocols and 30-day mortality after direct discharge from the emergency department. Results: Use of the ESC 0/1-hour algorithm increased by 270% at the cost of the standard 0/3-hour protocol. After rule-out (1588 patients), 1309 patients (76.1%) were discharged directly from the emergency department, with an all-cause mortality of 0.08% at 30 days (one death due to lung cancer). Median lengths of stay were 2.9 (1.9–3.8) and 3.2 (2.7–4.4) hours using a single high-sensitivity troponin T below the limit of detection (5 ng/L) at presentation and the ESC 0/1-hour algorithm, respectively, as compared to 5.3 (4.7–6.5) hours using the ESC 0/3-hour rule-out protocol ( PConclusion: Implementation of the ESC 0/1-hour algorithm is feasible and safe, is associated with shorter emergency department stay than the ESC 0/3-hour protocol, and an increase in discharge rates. Trial registration: ClinicalTrials.gov , Unique identifier: NCT03111862.

Aims Glucagon-like peptide 1 (GLP-1) is a gut incretin hormone inducing post-prandial insulin secretion. Glucagon-like peptide 1 levels were recently found to be increased in patients with acute myocardial infarction. Glucagon-like peptide 1 receptor agonists improve cardiovascular outcomes in patients with diabetes. The aim of this study was to assess the predictive capacity of GLP-1 serum levels for cardiovascular outcome in patients with myocardial infarction. Methods and results In 918 patients presenting with myocardial infarction [321 ST-segment elevation myocardial infarction and 597 non-ST-segment elevation myocardial infarction (NSTEMI)] total GLP-1, N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and the Global Registry of Acute Coronary Events (GRACE) score were assessed at time of hospital admission. The primary composite outcome of the study was the first occurrence of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. Kaplan–Meier survival plots and univariable Cox regression analyses found GLP-1 to be associated with adverse outcome [hazard ratio (HR) of logarithmized GLP-1 values: 6.29, 95% confidence interval (CI): 2.67–14.81; P < 0.0001]. After further adjustment for age, sex, family history of cardiovascular disease, smoking, diabetes, hypertension, hypercholesterinaemia, glomerular filtration rate (GFR) CKD-EPI, hs-CRP, hs-Troponin T, and NT-proBNP levels the HR remained significant at 10.98 (95% CI: 2.63–45.90; P = 0.0010). Time-dependent receiver operating characteristic curve analyses illustrated that GLP-1 levels are a strong indicator for early events. For events up to 30 days after admission, GLP-1 proved to be superior to other biomarkers including hs-Troponin T, GFR CKD-EPI, hs-CRP, and NT-proBNP. Adjustment of the GRACE risk estimate by addition of GLP-1 increased the area under the receiver operating characteristic curve over time in NSTEMI patients. Conclusion In patients hospitalized for myocardial infarction, GLP-1 levels are associated with cardiovascular events.

Introduction Blood-based biomarkers may be useful in the identification of residual risk for death or acute myocardial infarction (AMI) in patients with a previous acute coronary syndrome. Cathepsin S (CTSS) is a lysosomal cysteine protease with potent elastolytic and collagenolytic activity, which plays an important role in cardiovascular disease through extracellular matrix degradation, vasa vasorum development and atherosclerotic plaque rupture. The aim of the present study was to determine the prognostic and reclassification value of baseline circulating levels of CTSS after adjustment for the Global Registry of Acute Coronary Events (GRACE) score, which is widely recommended for risk stratification in non-ST-segment elevation acute coronary syndrome (NSTE-ACS). Methods CTSS was measured in blood samples collected from 1,129 consecutive patients with adjudicated NSTE-ACS presenting at an acute chest pain unit for evaluation of a possible acute coronary syndrome. Cardiovascular (CV) death and a composite of all-cause mortality and AMI were evaluated as the primary and secondary endpoints of the study, respectively. The additive prognostic value of CTSS over the GRACE score was estimated by the Net Reclassification Index (NRI) that examines the net upward and downward reclassification into correct pre-defined risk categories. Results After a median follow-up of 21 months, 101 (8.95%) deaths were reported, of which 63 (5.6%) were of cardiac origin. The combined endpoint occurred in 176 (15.6%) patients. Patients with CTSS in the highest tertile presented the greatest risk for all-cause mortality (HR=1.84 for highest versus lowest tertile of CTSS distribution, 95% CI 1.1–3.08, P=0.02) and CV death (HR=2.5 for highest versus lowest tertile of CTSS distribution, 95% CI 1.24–5.05, P=0.011) after adjustment for age, gender, diabetes mellitus, hs-cTnT, hsCRP, revascularization and index diagnosis. Similarly, CTSS was associated with increased risk of cardiovascular death after adjusting for the GRACE Score (adjusted HR for highest versus lowest tertile of CTSS distribution=2.34, 95% CI 1.18–4.64, P=0.015). Further, CTSS predicted the combined endpoint of all-cause death or non-fatal MI independently of the GRACE Score (adjusted HR for highest versus lowest tertile of CTSS distribution=1.67, 95% CI 1.15–2.42, P=0.007). When CTSS was added over the GRACE Score, it conferred significant reclassification value for CV death (NRI=21.4%, P=0.008). Similarly, CTSS correctly reclassified risk for all-cause death or non-fatal MI (P=0.006) in 15.9% of the population. Conclusion Circulating CTSS predicts mortality and improves risk stratification of patients with NSTE-ACS over the GRACE score recommended by clinical guidelines. The clinical application of CTSS as a novel biomarker in NSTE-ACS should be further explored and validated. Conflict of Interest none

AimsElevated levels of high-sensitivity cardiac troponin T (hsTnT) are associated with adverse outcomes in numerous patient populations. Their value in prediction of stroke risk in patients with atrial fibrillation (AF) is in debate.MethodsThe study population included 2898 consecutive patients presenting with AF to the emergency department of the Department of Cardiology, Heidelberg University Hospital. Associations between hsTnT and stroke risk were assessed using multivariable Cox regression.ResultsElevated hsTnT levels (>14 ng/L) were associated with increased risk of stroke. Even after adjustment for various risk factors, elevated hsTnT remained independently associated with stroke risk in patients with AF, adjusted hazard ratio 2.35 [95% confidence interval (CI): 1.26-4.36] (P = 0.007). These results were consistent across important subgroups (age, renal function, ejection fraction, CHA2DS2-VASc score and main admission diagnosis). For hsTnT, area under the receiver-operating-characteristic curve (AUC) was 0.659 [95% CI: 0.575-0.742], compared to 0.610 [95% CI: 0.526-0.694] for the CHA2DS2-VASc score. Inclusion of hsTnT in the multivariable model for stroke risk prediction consisting of all variables of the CHA2DS2-VASc score was associated with a significant improvement of its discriminatory power.ConclusionElevated hsTnT levels are significantly associated with higher risk of stroke and provide prognostic information independent of CHA2DS2-VASc score variables. Measurement of hsTnT may improve prediction of stroke risk in patients presenting to an emergency department with AF as compared to risk stratification based only on clinical variables.

Background: We aimed to directly compare the diagnostic and prognostic performance of a dual maker strategy (DMS) with combined testing of copeptin and high-sensitivity (hs) cardiac troponin T (cTnT) at time of presentation with other algorithms for rapid rule-out of acute myocardial infarction (AMI). Methods: 922 patients presenting to the emergency department with suspected AMI and available baseline copeptin measurements qualified for the present TRAPID-AMI substudy. Diagnostic measures using the DMS (copeptin

Objective To evaluate the long term biological variation of high-sensitivity cardiac troponin T (hs-cTnT) in stable outpatients with cardiovascular disease (CVD). Methods After applying 8 exclusion criteria to 965 patients, hs-cTnT was measured at index visit and at a 12-month interval in 169 stable outpatients presenting for routine follow-up visits for any CVD. Stability was defined as absence of any endpoint within the follow-up period. Reference change values (RCVs) and minimal important differences (MIDs) were determined to assess biological variation of hs-cTnT. Results MID and RCV for the 12 months interval in patients were 3.8 ng/L or 44.2%, respectively. MID and transformed MID values were lower than the corresponding RCV with a value of 5.1 ng/L for the transformed RCV and 28.1% for the transformed MID. Similar patterns were shown in different subgroups as sex, age, and renal function . We observed a baseline hs-cTnT value dependent change of MID and RCV with increasing values for MID and decreasing values for RCV which converge to stable values between a baseline hs-cTNT value of 11 to 25 ng/L. Conclusions Biological variation of hs-cTnT over 12 months in stable outpatients depends on the concentration at index visit, and is consistent among important prespecified subgroups. MID shows a low biovariability over 12 months. Clinical Trials Identifier: NCT01954303

BACKGROUND Diagnostic performance of high-sensitivity cardiac troponin T (hs-cTnT) varies depending on presenting symptoms in patients with suspected acute coronary syndrome (ACS). METHODS We compared performance measures of hs-cTnT among patients admitted to the emergency department with typical chest pain (angina), dyspnea, and atypical symptoms and assessed outcomes by leading presenting symptoms. RESULTS A total of 658 patients suspected of ACS and presenting with typical chest pain (n = 241, 36.6%), dyspnea (n = 142, 21.6%), or atypical symptoms (n = 275, 41.8%) were included. Diagnostic accuracy of hs-cTnT on admission was higher among patients with typical chest pain compared to those with atypical symptoms [area under the curve (AUC) 0.823 vs AUC 0.776 vs AUC 0.705, P > 0.05 and P = 0.04]. Absolute concentration changes within 6 h improved accuracy among all subgroups, with the smallest added benefit in typical chest pain and dyspnea (ΔAUC, 0.078; P = 0.02 and 0.05, P > 0.05). During 1-year follow-up, dyspnea was associated with a higher risk of death (hazard ratio, 2.36; 95% CI, 1.26–4.43, P = 0.008) and death/AMI (hazard ratio, 2.23; 95% CI, 1.21–4.11, P = 0.01) compared to typical chest pain. Optimal discriminating values for hs-cTnT were higher among patients presenting with dyspnea compared to those with typical chest pain (91.2 vs 14.1 ng/L, P < 0.001). CONCLUSION The diagnostic performance of hs-cTnT in patients with suspected ACS depends on the leading presenting symptom. Patients admitted with dyspnea represent a high-risk cohort in which the diagnosis of ACS is less frequent and with inferior performance of serial hs-cTnT measurements. Higher hs-cTnT cutoffs at baseline and absolute changes after 6 h help to identify non-STEMI (ST segment elevation myocardial infarction) in this population.

BACKGROUND Guidelines for diagnosing acute myocardial infarction (AMI) recommend adding kinetic changes to the initial cardiac troponin (cTn) blood concentration to improve AMI diagnosis. We hypothesized that kinetic changes may not be required in patients presenting with highly abnormal cTn. METHODS Patients presenting with suspected AMI to the emergency department were enrolled in a prospective diagnostic study. We assessed the positive predictive value (PPV) of initial high-sensitivity cardiac troponin T (hs-cTnT) blood concentrations alone and in combination with kinetic changes for AMI. Predefined relative changes (δ change of ≥20%) and absolute changes (Δ change ≥9.2 ng/L) within different time intervals (1 h, 2 h, and 4–14 h after presentation) were assessed. The final diagnosis was adjudicated by 2 independent cardiologists. RESULTS Among 1282 patients, 213 (16.6%) patients had a final diagnosis of AMI. For AMI prediction, PPVs increased from 48.8% for an initial hs-cTnT >14 ng/L to 87.2% for >60 ng/L, whereas PPVs remained unchanged for higher hs-cTnT concentrations at baseline (87.1% for both >80 ng/L and >100 ng/L). With addition of 20% relative Δ change, PPVs were not further improved in patients with baseline hs-cTnT >80 ng/L using the 1-h (84.0%) and 2-h (88.9%) intervals, and only minimally when extending the interval to 4–14 h (91.2% for >80 ng/L and 90.4% for >100 ng/L, respectively). Similar findings were observed when applying absolute changes. CONCLUSIONS In chest pain patients with highly abnormal hs-cTnT concentrations at presentation, subsequent blood draws may not be required, as they do not provide incremental diagnostic value for prediction of AMI diagnosis.

Purpose The aim of this study was to test the prognostic performance of rising and falling kinetic changes of high-sensitivity cardiac troponin T (hs-cTnT) and the GRACE score. Methods Rising and falling hs-cTnT changes in an unselected emergency department population were compared. Results 635 patients with a hs-cTnT > 99th percentile admission value were enrolled. Of these, 572 patients qualified for evaluation with rising patterns ( n = 254, 44.4%), falling patterns ( n = 224, 39.2%), or falling patterns following an initial rise ( n = 94, 16.4%). During 407 days of follow-up, we observed 74 deaths, 17 recurrent AMI, and 79 subjects with a composite of death/AMI. Admission values > 14 ng/L were associated with a higher rate of adverse outcomes (OR, 95%CI:death:12.6, 1.8–92.1, p = 0.01, death/AMI:6.7, 1.6–27.9, p = 0.01). Neither rising nor falling changes increased the AUC of baseline values (AUC: rising 0.562 vs. 0.561, p = ns, falling: 0.533 vs. 0.575, p = ns). A GRACE score ≥ 140 points indicated a higher risk of death (OR, 95%CI: 3.14, 1.84–5.36), AMI (OR, 95%CI: 1.56, 0.59–4.17), or death/AMI (OR, 95%CI: 2.49, 1.51–4.11). Hs-cTnT changes did not improve the prognostic performance of a GRACE score ≥ 140 points (AUC, 95%CI: death: 0.635, 0.570–0.701 vs. 0.560, 0.470–0.649 p = ns, AMI: 0.555, 0.418–0.693 vs. 0.603, 0.424–0.782, p = ns, death/AMI: 0.610, 0.545–0.676 vs. 0.538, 0.454–0.622, p = ns). Coronary angiography was performed earlier in patients with rising than with falling kinetics (median, IQR [hours]:13.7, 5.5–28.0 vs. 20.8, 6.3–59.0, p = 0.01). Conclusion Neither rising nor falling hs-cTnT changes improve the prognostic performance of elevated hs-cTnT admission values or the GRACE score. However, rising values are more likely associated with the decision for earlier invasive strategy.

We sought to evaluate the prognostic impact of absolute and relative kinetic changes of high-sensitivity cardiac Troponin T (hs-cTnT) in comparison to baseline hs-cTnT elevations for risk stratification in acute coronary syndrome (ACS) and non-ACS conditions with increased hs-cTnT.hs-cTnT was measured serially in patients presenting with acute symptoms to our emergency department. We assessed the prognostic performance of baseline and serial hs-cTnT concentrations in all consecutive patients with ACS (n=406) or hs-cTnT increases not due to ACS (n=442) within 3-6h after admission.Mortality rates were higher, albeit not statistically, in non-ACS (53/442=12.0%) than ACS patients (36/406=8.9%). In ACS patients, receiver operating characteristics (ROC) revealed optimized cut-off values of 12.2 ng/L for absolute δ-change (AUC=0.66, p0.001), 31.2 ng/L for baseline hs-cTnT (AUC=0.71, p0.001) and 45.2 ng/L for maximal hs-cTnT (AUC=0.68, p0.001). C-statistics showed superiority of absolute δ-changes (p=0.0003), baseline hs-cTnT (p=0.04) and maximal hs-cTnT (p=0.02) compared to relative δ-changes. However, the combination of baseline hs-cTnT values with either absolute or relative δ-changes did not improve risk prediction compared to baseline hs-cTnT alone (p=n.s.). In non-ACS conditions, the ROC-optimized cut-off value of 46.2 ng/L for baseline hs-cTnT (AUC=0.661, p0.001) was superior to absolute (p=0.007) and relative δ-changes regarding prognostication (p=0.045).Our data suggest that the magnitude of baseline hs-cTnT, and not acute dynamic changes, convey superior long-term prognostic information in ACS and non-ACS conditions. Moreover, absolute and relative kinetic δ-changes of hs-cTnT do not add significant incremental value in risk assessment in both conditions.

Risk stratification of patients with cardiovascular disease remains challenging despite consideration of risk scores.We aimed to evaluate the prognostic performance of high-sensitivity cardiac troponin T in a low-risk outpatient population presenting for nonsecondary and secondary prevention. All-cause mortality, a composite of all-cause mortality, acute myocardial infarction, and stroke (end point 2), and a composite of all-cause mortality, acute myocardial infarction, stroke and rehospitalization for acute coronary syndrome, and decompensated heart failure (end point 3) were defined. The prognostic performance of high-sensitivity cardiac troponin T on index visit was compared with the PROCAM score and 3 FRAMINGHAM subscores.In 693 patients with a median follow-up of 796 days, we observed 16 deaths, 32 patients with end point 2, and 83 patients with end point 3. All risk scores performed better in the prediction of all-cause mortality in nonsecondary prevention (area under the curve [AUC]: PROCAM: 0.922 vs 0.523, P = .001, consistent for all other scores). In secondary prevention, high-sensitivity cardiac troponin T outperformed all risk scores in the prediction of all-cause mortality (ΔAUC: PROCAM: 0.319, P.001, consistent for all other scores) and performed superiorly in the prediction of end point 2 compared with the PROCAM, FRAMINGHAM-Coronary Heart Disease, and FRAMINGHAM-Hard Coronary Heart Disease scores (ΔAUC: PROCAM: 0.176, P = .047, consistent for FRAMINGHAM-Coronary Heart Disease and FRAMINGHAM-Hard Coronary Heart Disease). In nonsecondary prevention, we observed a comparable prognostic performance of high-sensitivity cardiac troponin T and multivariable risk scores. Our findings on the prediction of all-cause mortality compared with the FRAMINGHAM-Hard Coronary Heart Disease score were confirmed in an independent validation cohort on 2046 patients.High-sensitivity troponin T provides excellent risk stratification regarding all-cause mortality and all-cause mortality, acute myocardial infarction, and stroke in a secondary prevention cohort in whom risk scores perform poorly.

Background Current European guidelines recommend the use of sensitive or high-sensitivity cardiac troponin assays to reduce the minimal sampling interval from 6 to 3h. Methods We compared a 3-hour versus a 6-hour protocol for diagnosis of non-STEMI and used the 99th percentile for rule-out, and relative and absolute concentration changes for rule-in of non-STEMI. Results 459 patients with either an NSTE-ACS or elevated hs-cTnT not due to MI and hs-cTnT measurements at 0, 3 and 6h were enrolled. Among the 404 patients excluded due to an incomplete sampling protocol performance was comparable to the 459 patients with a complete sampling protocol (AUC 0.79 vs 0.80, p=ns). In the study group, non-STEMI was diagnosed in 111 cases (24.2%) and elevated hs-cTnT not due to MI was observed in 215 cases (46.8%). For rule-out of non-STEMI, NPVs were 94.9%, 98.7% and 100% on admission, at 3 and 6h with comparable performance at 3 and 6h (AUC 0.782 vs 0.790, p=ns). For rule-in a 3-hour protocol performed as well as a 6-hour protocol, with a significantly (p Conclusions Rule-in and rule-out of non-STEMI may be accomplished comparably effective at 3 or 6h. For rule-in, absolute kinetic changes perform better than relative changes at all time points. ROC-optimal absolute δ-change was 6.95ng/L at 3h and 8.9ng/L at 6h.

Current ESC guidelines for the diagnosis of myocardial infarction consider a rise and/or fall of cardiac biomarkers. However, whether rising or falling patterns of high-sensitivity cardiac troponin T (hs-cTnT) improve the discrimination of ST-elevation myocardial infarction (non-STEMI) from non-acute coronary syndromes (ACS) has not been evaluated yet.We compared protocols of rising and falling absolute and relative hs-cTnT changes in an unselected emergency department population.A total of 635 patients with unstable angina pectoris (UAP), non-STEMI, or acute symptoms and increased hs-cTnT (99th percentile) were enrolled. Of these, 572 patients met the inclusion criteria of consistently rising patterns (n=254, 44.4%), consistently falling patterns (n=224, 39.2%), or falling patterns after an initial rise (n=94, 16.4%). Final diagnoses included 66 (11.5%) patients with UAP, 141 (24.7%) patients with non-STEMI, and 365 (63.8%) patients with hs-cTnT elevations not due to ACS. Rising values were found more frequently in patients with non-STEMI, as compared to non-ACS (OR 3.69, 95% CI 2.46-5.53; p0.0001), and falling patterns were observed more frequently in patients with non-ACS conditions (OR 3.56, 95% CI 2.24-5.63; p0.001). Addition of rising but not falling changes increased diagnostic performance of hs-cTnT concentrations at presentation: positive: AUC 0.680 (95% CI 0.618-0.742) vs. 0.861 (95% CI 0.822-0.900; p0.0001), negative: AUC 0.678 (95% CI 0.545-0.812) vs. 0.741 (95% CI 0.635-0.847). A 20% criterion as proposed by ESC guidelines performed equally for positive and negative changes only when admission hs-cTnT values were considered: AUC 0.785 (95% CI 0.726-0.845) vs. AUC 0.763 (95% CI 0.681-0.845); p=ns.Detection of rising but not falling hs-cTnT values improves discrimination of non-STEMI from non-ACS in an unselected emergency department population.

Cardiac troponins (cTns) T and I are exclusively expressed at high concentrations in cardiac muscle and have emerged as the preferred biomarker in the universal definition of myocardial infarction (MI). With the recent introduction of high-sensitivity (hs) assays, diagnostic sensitivity for earlier detection of MI has substantially improved. However, lowering the diagnostic cut-off has increased the detection of myocardial injuries in various non-acute coronary syndrome (ACS) conditions, which are not related to myocardial ischemia, leading to rising difficulties in diagnosing MI in clinical situations. Several approaches, such as serial sampling and incorporation of relative or absolute δ-changes, have been proposed to overcome the limitation of decreased sensitivity for MI diagnosis with hs-cTn assays. Current consensus for rapid rule-in proposes a 20% increase within 3 or 6h when baseline cTn levels are elevated. In the case of negative baseline values, relative increases ≥50% above the 99(th) percentile were found to be adequate to improve accuracy of MI diagnosis. Besides improved diagnostic accuracy for myocardial injury, even minor cTn elevations provide important prognostic information, and increased levels of cTn are associated with adverse outcomes in both the ACS and non-ACS condition, irrespective of whether the underlying cause is an acute or chronic illness. Thus, it is highly likely that lowering the diagnostic cut-off with even more sensitive assays might improve risk stratification in both conditions.

The study sought to compare the clinical performance of two more sensitive cardiac troponin (cTn) assays, a novel high-sensitivity (hs) troponin T assay and a contemporary cTnI assay.We measured hs-cTnT (Roche TnThs) and cTnI (Siemens Centaur Ultra) on presentation in 1,384 patients with suspected acute coronary syndrome (ACS) who underwent early invasive strategy within 24 h after presentation. Kaplan-Meier, Cox proportional hazards, and receiver-operating characteristic (ROC) analysis was used to compare their prognostic performance for the prediction of all-cause death and death/MI (myocardial infarction) after a median of 271 days. We also compared the diagnostic performance of these assays on presentation for early diagnosis of non-STEMI.Both hs-cTnT and cTnI were independently predictive of long-term death (OR 3.51 vs. 2.19) and the composite of death/MI (OR 9.24 vs. 3.61), across the spectrum of ACS and in patients without ACS. When used as a continuous variable, ROC analysis demonstrated significantly higher areas under the curve (AUC) for hs-cTnT as compared to cTnI for the prediction of death/MI (0.721 vs. 0.672, P = 0.024), a trend to better prediction of all-cause death (0.721 vs. 0.672, P = 0.093) and significantly higher AUC for early diagnosis of non-STEMI (0.965 vs. 0.901, P 0.001).Using the 99th percentile cutoff for hs-cTnT and cTnI, both assays enable prediction of adverse long-term outcomes and earlier diagnosis of non-STEMI. Used as a continuous variable, the hs-cTnT assay showed superior performance compared to the cTnI assay, especially in regard to prognosis.

Objective To evaluate the prognostic performance of high-sensitivity cardiac troponin T (hs-cTnT) compared with the ESC-SCORE. Methods We included low-risk outpatients with stable cardiovascular (CV) disease categorised into need for non-secondary and secondary prevention. The prognostication of hs-cTnT at index visit was compared with the European Society of Cardiology-Systematic COronary Risk Evaluation (ESC-SCORE) with respect to all-cause mortality (ACM) and two composite endpoints (ACM, acute myocardial infarction (AMI) and stroke and ACM, AMI, stroke and rehospitalisation for acute coronary syndrome (ACS) and decompensated heart failure (DHF)). Results Within a median follow-up of 796 days, a total of 16 deaths, 32 composite endpoints of ACM, AMI and stroke and 83 composite endpoints of ACM, AMI, stroke, rehospitalisation for ACS and DHF were observed among 693 stable low-risk outpatients. Using C-statistics, measurement of hs-cTnT alone outperformed the ESC-SCORE for the prediction of ACM in the entire study population (Δarea under the curve (AUC) 0.221, p=0.0039) and both prevention groups (non-secondary: ΔAUC 0.164, p=0.0208; secondary: ΔAUC 0.264, p=0.0134). For the prediction of all other secondary endpoints, hs-cTnT was at least as effective as the ESC-SCORE, both in secondary and non-secondary prevention. Using continuous and categorical net reclassification improvement and integrated discrimination improvement, hs-cTnT significantly improved reclassification regarding all endpoints in the entire population and in the secondary prevention cohort. In non-secondary prevention, hs-cTnT improved reclassification only for ACM. The results were confirmed in an independent external cohort on 2046 patients. Conclusions Hs-cTnT is superior to the multivariable ESC-SCORE for the prediction of ACM and a composite endpoint in stable outpatients with and without relevant CV disease. Trial registration number NCT01954303; Pre-results.

Background Point of care testing (POCT) assays for cardiac troponin (cTn) are hampered by lower analytical sensitivity and thus suboptimal rule-out of myocardial infarction (MI). We investigated, whether additional measurement of copeptin using an ultrasensitive assay improves diagnostic performance of POCT for cTn T compared to a high sensitivity troponin T (hsTnT) assay. Methods 131 patients with suspected acute coronary syndrome were prospectively enrolled in our center 08/2010 to 11/2011. In blood samples obtained at presentation, ultrasensitive copeptin (Kryptor, BRAHMS) and two commercially available POCT assays, AQT90 Flex Radiometer (Radiometer) and Cobas h232 POC-System (Cobas), were tested. HsTnT (Cobas E411, Roche) at baseline and after 3 and 6h in the central laboratory served as reference. Results Copeptin improved rule-out of non-STEMI combined with all tested troponin assays. Addition of copeptin increased sensitivity of Cobas from 67.9% (95% CI: 0.506; 0.852) to 89.3% (95% CI: 0.778; 1.007) and Radiometer from 71.4% (95% CI: 0.547; 0.882) to 85.7% (95% CI: 0.728; 0.987), achieving the sensitivity of hsTnT alone at admission of 85.7% (95% CI: 0.728; 0.987). The area under the curve (AUC) of Radiometer (0.822) was numerically but insignificantly (p=0.17) higher than AUC of Cobas (0.725). Addition of copeptin increased AUC of Radiometer to 0.826 (p=0.96) and AUC of Cobas to 0.814 (p=0.20). Conclusions Additional use of ultrasensitive copeptin improves diagnostic performance of conventional sensitive POCT assays overcoming lower sensitivities at the cost of a drop of clinical specificity. When hsTn is temporarily unavailable, copeptin and POCT for cTn may allow initial evaluation at a comparable performance as hsTnT at admission.

To investigate the prognostic implications of elevated high-sensitivity cardiac troponin T (hs-cTnT) values in presumably stable ambulatory coronary artery disease patients.We conducted a retrospective, single-centre pilot observational study in a low-risk population. All patients received routine measurement of hs-cTnT at index and follow-up visits. Endpoints were all-cause mortality and a composite of all-cause mortality, acute myocardial infarction, stroke and rehospitalization for acute coronary syndrome and heart failure. Nine hundred and sixty-five consecutive patients presenting to our outpatient clinic between June 2009 and June 2010 were screened; 693 patients with a stable clinical course, at least one hs-cTnT value and at least one follow-up visit qualified for analysis. Follow-up was 796 days. Five hundred and forty-seven patients (78.9%) had hs-cTnT values below and 146 patients (21.1%) had values above 14 ng/l, which was defined to categorize high and low levels as it was reported to be the 99th percentile of a reference population. We observed 13 deaths (all-cause mortality) including four cardiovascular deaths. Age, N terminal pro-brain natriuretic peptide levels and impaired renal function were independently associated with an elevated hs-cTnT in a multivariate analysis. Hs-cTnT values14 ng/l were strongly associated with all-cause mortality (hazard ratio 12.9, 95% confidence interval (CI): 3.5-46.9, p=0.0001), the composite clinical endpoint (hazard ratio 2.35, 95% CI: 1.48-3.72, p=0.0003) and rehospitalization for heart failure (hazard ratio 3.36, 95% CI: 1.73-6.53, p=0.0004). Compared with the multivariable Framingham score hs-cTnT revealed a significantly better performance (area under the receiver operating characteristics curve (AUC) hs-cTnT: 0.882 vs. AUC Framingham score 0.639, p=0.0005).Elevated hs-cTnT levels provide excellent prognostic information regarding all-cause mortality and a combined clinical endpoint in presumably stable ambulatory coronary artery disease outpatients presenting for routine evaluation.

Cardiac troponin (cTn) is a regulatory protein of the myofibrillar thin filament of striated muscle regulating excitation–contraction coupling in the heart.w1 Among the three subunits (T, I, and C), only cardiac troponin T (cTnT) and I (cTnI) are expressed in cardiac muscle and released into blood following myocardial cell death. Several distinct pathobiological mechanisms leading to elevated troponin values have been suggested, not all of which involve myocyte necrosis.w2 cTnT or cTnI are routinely used in emergency units as the preferred biomarkers for the diagnosis of acute myocardial infarction (MI). According to joint criteria for the diagnosis of acute MI by the European Society of Cardiology/American College of Cardiology/American Heart Association/World Heart Federation Task Force, an acute MI should be diagnosed in patients with symptoms of myocardial ischaemia and detection of a rise and/or fall of cardiac biomarkers (preferentially troponins) with at least one value above the 99th percentile of the upper reference limit.1 Use of high sensitivity troponin assays allows more accurate and earlier detection of MI.2 w3 Higher analytical sensitivity increases the number of patients with analytically true positive cTn results due to non-ST elevation MI (NSTEMI) but also due to numerous acute or chronic diseases in the absence of overt ischaemic heart disease (box 1).3 w4 Box 1 ### Elevations of cardiac troponin values because of myocardial injury Injury related to primary myocardial ischaemia Plaque rupture Intraluminal coronary artery thrombus formation Injury related to supply/demand imbalance of myocardial ischaemia Tachy-/bradyarrhythmias Aortic dissection or severe aortic valve disease Hypertrophic cardiomyopathy Cardiogenic, hypovolaemic, or septic shock Severe respiratory failure Severe anaemia Hypertension with or without left ventricular hypertrophy Coronary spasm Coronary embolism or vasculitis Coronary endothelial dysfunction without significant coronary artery disease Injury not related to myocardial ischaemia Cardiac contusion, surgery, ablation, pacing, or …

Elevated cardiac troponin (cTn) has been reported to occur with AVNRT. Little is known about prevalence, kinetic changes, and possible reasons of increased cTn.We evaluated 139 consecutive patients presenting with AVNRT to the emergency department between 2006 and 2010. Cardiac troponin T (cTnT) was measured serially at baseline, after three and six hours. Patients were evaluated for the presence of structural heart disease or CAD. Troponin was defined as elevated if a value exceeded the lower limit of detection (10 ng/l) using the fourth generation cTnT, or if the value99 th percentile (14 ng/l) using the new highly sensitive cTn assay.A cTnTLLD (n = 29) or99 th percentile (n = 16) was found in 45 patients (32.4%) within the initial six hours after hospitalization. All patients were symptomatic with palpitations, chest discomfort or dyspnea. A complete cardiac evaluation was carried out, including coronary angiography in 32 patients demonstrating an underlying structural heart disease or CAD in 18 cases (56%). Significant CAD was detected in 16 cases. 8 cases required PCI during hospitalization. Elevated cTnT was seen in patients with and without structural heart disease.AVNRT is a possible reason for elevated cTnT, even in the absence of relevant structural heart disease or CAD.

The effect of age on diagnostic and prognostic performance of high-sensitivity cardiac troponin T (hs-cTnT) has not been addressed adequately, so far.High-sensitivity cardiac troponin T was measured serially in patients with acute symptoms presenting to our emergency department. We tested the diagnostic and prognostic performance of baseline and serial hs-cTnT concentrations related to age in all consecutive patients with acute coronary syndrome (ACS) (n = 342) or hs-cTnT increases not due to ACS (n = 442).Prevalence of elevated hs-cTnT in the study population was higher among patients ≥75 years compared with younger patients (89.1 % vs 73.3 %, hazard ratio [HR] 1.2, P.0001). Elevated hs-cTnT was more likely due to ACS in the younger patients (HR 1.4, P = .001) and conversely more frequently due to non-ACS conditions in the elderly patients (HR 1.3, P = .0001). Diagnostic performance of hs-cTnT using the 99th percentile was significantly superior in younger than in elderly patients (P.0001). For receiver operating characteristic-optimized cutoffs, a trend to significance was found between younger and older patients (area under the curve 0.87 vs 0.79, P = .074), with higher sensitivities (98.2 % vs 72.6%) and negative predictive values (97.3% vs. 78.5%) for patients75 years. Moreover, receiver operating characteristic-optimized cutoff values for diagnosis of non-ST-segment elevation myocardial infarction were significantly higher in elderly patients (32.9 ng/L) compared with younger patients (12.9 ng/L). The prognostic information of single and serial hs-cTnT measurements was comparably poor in both age groups, showing no better prognostic information to hs-cTnT measurement on presentation.Elevated hs-cTnT is more common in the elderly due to higher prevalence of non-ACS conditions and significantly impairs diagnostic performance in discriminating non-ST-segment elevation myocardial infarction.

BACKGROUND We evaluated kinetic changes of high-sensitivity cardiac troponin T (hs-cTnT) in patients with acute coronary syndrome (ACS) and patients with hs-cTnT increases not due to ACS to rule in or rule out non–ST-segment elevation myocardial infarction (STEMI). METHODS hs-cTnT was measured serially in consecutive patients presenting to the emergency department. Patients with ACS who had at least 2 hs-cTnT measurements within 6 h and non-ACS patients with hs-cTnT concentrations above the 99th percentile value (14 ng/L) were enrolled to compare absolute and relative kinetic changes of hs-cTnT. RESULTS For discrimination of non-STEMI (n = 165) in the entire study population (n = 784), the absolute δ change with the ROC-optimized value of 9.2 ng/L yielded an area under the curve of 0.898 and was superior to all relative δ changes (P < 0.0001). The positive predictive value for the absolute δ change was 48.7%, whereas the negative predictive value was 96.5%. In a specific ACS population with exclusion of STEMI (n = 342), the absolute δ change with the ROC-optimized value of 6.9 ng/L yielded a positive predictive value of 82.8% and a negative predictive value of 93.0%. In comparison to the ≥20% relative δ change, the ROC-optimized absolute δ change demonstrated a significantly added value for the entire study population and for the ACS cohort (net reclassification index 0.331 and 0.499, P < 0.0001). CONCLUSIONS Absolute δ changes appear superior to relative δ changes in discriminating non-STEMI. A rise or fall of at least 9.2 ng/L in the entire study population and 6.9 ng/L in selected ACS patients seems adequate to rule-out non-STEMI. However, δ-values are useful to rule-in non-STEMI only in a specific ACS population.

Impact Of Markedly Elevated Initial High -Sensitivity Cardiac Troponin T On Prediction Of Acute Myocardial Infarction In Chest Pain Patients And Additional Value Of Kinetic Changes : Results From The Trapid-AMI Study

In an earlier issue of this journal [1], we reported on early rule-out and rule-in of non-STEMI using 3 h and 6 h protocols of high sensitivity cardiac troponin T in an emergency department population. With interest, we now read a letter to the editor from Dr. Lippi [2] referring to a recent studybyCardinaels et al. [3]who found several cTnT degradation products in sera of patients admitted for STEMI and underwent primary PCI. Lippi now raised the possibility that cTnT degradation products might confound serial troponin testing that is endorsed by current ESC Guidelines on patients with non-ST segment elevationacute coronary syndromes [4]. The observationof Cardinaels et al. [3] is interesting but requires further validation of Western blot findings, as well as clinical evaluation of its clinical relevance. Lippi and Cervellin [2] suspect that antibodies of the current hsTnT assaymay fail to detect variousmolecular isoformsdue toheterogeneous immunoreactivity. For support, they refer to Cardinaels et al. [3] who demonstrated a consistentdegradationpatternusingantibodies directed against the C-terminal end of cTnTas compared to the pattern seenwith standard cTnT antibodies, but no fragments when the antibody was directed against the N-terminal end. Notably, the epitope of the cTnT assay is located centrally and thereby protected against epitope loss by protease cleavage [5,6]. In fact, this issue might be more relevant for some cTnI assays due to a higher susceptibility to posttranslational modifications, and heterogeneous epitope locations [5]. In addition to the central location of the epitope, cTnT is not prone to oxidation– reduction, phosphorylation or major modifications [5]. Nevertheless, it would be scientifically interesting to investigate the effect of degradation on measurable cTnT and cTnI concentrations over time. In clinical practice, the strength of hsTnT is earlier andmore accurate detection of NSTEMI. For STEMI, monitoring of reperfusion success is nowadays less important than in the era of fibrinolytic therapy, and estimation of infarct size using values beyond the first 24 h is not within the label. Therefore, the hsTnT assay was optimized at the low concentration range and truncated at the upper range as compared to the 4th generation cTnT assay [7]. Due to the excellent negative predictive value of hsTn assays in large clinical trials [8,9], current ESC guidelines on NSTE-ACS [4] endorse an early rule-out protocol with cTnTmeasurements on admission and after 3 h (optionally after 6 h). The finding that intact cTnT disappears 4 h after admission to the ED, and cTnT fragments start to become themajor fraction of cTnT does however not support the notion that cTnT fragments might disturb the diagnostic performance of hsTnT for early rule-out of NSTEMI. In addition, the mechanisms behind the formation of cTn degradation products remain unclear. Further work is needed to investigate the occurrenceof degradationproducts after small myocyte necrosis as compared to large STEMI with the subsequent release of large quantities of proteases, or the role of ischemia/ reperfusion injury after primary PCI. Although, the concerns of Dr. Lippi cannot be ruled out fully, his hypothesis is not supported by clinical experience where clinicians are rather confronted with issues of overdiagnosis of NSTEMI due to reduced clinical specificity rather than underdiagnosis. At least, at the moment, no data support an underestimation of MI due to epitope loss or modification, and the study by Cardinaels et al. [3] studied cTnT degradation products in a patient population that is not in the scope of troponin testing. In addition, as this is thefirst report,findings require confirmationusingmass spectroscopy followed by peptide sequencing to validate the identity of peptides. Furthermore, testing for fragments should be executed in heparin plasma, as well. Another issue raised by Dr. Lippi [2] is the analytical imprecision of hsTnT values below the LoQ which depends on the analytical platform used. Accordingly, Lippi [2] questioned the interpretation of small absolute concentration values for the diagnosis of NSTEMI. In our study [1], a diagnosis of NSTEMI was not only based on the presence of respective hsTnTchanges but required that the first or second hsTnT value exceeded the 99th percentile value of 14 ng/L. So far, the symphony is ready to be played but musicians still need to practice for harmony.

BACKGROUND: Current ESC guidelines for the diagnosis of myocardial infarction consider a rise and/or fall of cardiac biomarkers. However, whether rising or falling patterns of high-sensitivity cardiac troponin T (hs-cTnT) improve the discrimination of ST-elevation myocardial infarction (non-STEMI) from non-acute coronary syndromes (ACS) has not been evaluated yet. METHODS: We compared protocols of rising and falling absolute and relative hs-cTnT changes in an unselected emergency department population. RESULTS: A total of 635 patients with unstable angina pectoris (UAP), non-STEMI, or acute symptoms and increased hs-cTnT (>99th percentile) were enrolled. Of these, 572 patients met the inclusion criteria of consistently rising patterns (n=254, 44.4%), consistently falling patterns (n=224, 39.2%), or falling patterns after an initial rise (n=94, 16.4%). Final diagnoses included 66 (11.5%) patients with UAP, 141 (24.7%) patients with non-STEMI, and 365 (63.8%) patients with hs-cTnT elevations not due to ACS. Rising values were found more frequently in patients with non-STEMI, as compared to non-ACS (OR 3.69, 95% CI 2.46–5.53; p