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Objectives: To evaluate the impact of age-and gender-specific cut-offs for high-sensitivity cardiac troponin T (hs-cTnT) compared to the general 99th percentile hs-cTnT cut-off on diagnosis and prognosis of acute myocardial infarction (AMI). Methods: 1282 unselected patients presenting to the emergency department with suspected AMI were enrolled as part of the TRAPID-AMI study. In the present sub-analysis, reclassification of AMI diagnosis was performed by comparing the general hs-cTnT cut-off of 14 ng/L to previously proposed age-and gender-dependent hs-cTnT 99th percentile cut-offs (28 ng/L for >= 65 years, 9 ng/L for female and 15.5 ng/L for male patients). Patients were further clinically adjudicated into acute coronary syndrome (ACS) and non-ACS. Results: For patients >= 65 years, application of age-specified cut-offs resulted in a decrease of AMI from 29.8% to 18.3% in the entire cohort (n = 557) and 54.7% to 40.9% in the ACS subcohort (n = 225). Using gender-specific cut-offs, AMI-rate increased from 16.6% to 22.6% (entire cohort, n = 477) and 62.6% to 71.7% (ACS subcohort, n = 99) in women, whereas in men, rates decreased from 23.1% to 21.1% (entire cohort, n = 805) and 48.8% to 45.9% (ACS, n = 281), respectively. Age-specified cut-offs significantly reclassified patients for outcomes of 1-month and 3-month mortality in the entire and ACS cohort (14.2% net reclassification improvement, p < 0.001, respectively). Contrary, no significant differences in outcomes could be found using gender-specific cut-offs. Conclusions: While influence of gender-specific hs-cTnT cut-offs on diagnostic and prognostic reclassification was only modest in patients with suspected AMI, age-specific cut-offs showed a significant impact and may be considered for further validation. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

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.

Current studies on reference values for high-sensitivity cardiac troponins (hs-cTn) are limited due to small study size, shortage of phenotype information and relatively young age of individuals. 827 healthy subjects (mean age 54.9y, n=421 male, n=406 female) were prospectively enrolled.

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.

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