BACKGROUND:For suspected acute coronary syndrome (ACS), guidelines recommend using high-sensitivity troponins (hs-cTn) in accelerated diagnostic pathways (ADPs) with 0/1-hour recommended over 0/3-hour ADP. However, implementation of these ADPs, with universal use of hs-cTns, has not been directly compared in randomized trials OBJECTIVES: This study sought to compare the efficiency and safety of the European Society of Cardiology (ESC) 0/1-hour and a 0/3-hour ADP when implemented in real-world clinical practice. METHODS:This pragmatic, randomized, noninferiority implementation trial compared the safety and efficiency of clinician decision making using these 2 pathways. To prevent incorporation bias, an independent hs-cTnI was used for formal adjudication using the fourth universal definition of myocardial infarction (MI). Efficiency was judged by the proportion of patients discharged within 4 hours. The safety endpoint was major adverse cardiac events (MACE) within 30 days (adjudicated index or representation type 1 MI, cardiovascular death, and urgent coronary revascularization) for those who were considered not to have ACS and discharged. The noninferiority margin, for absolute difference in sensitivity, between the ESC 0/1-hour and the 0/3-hour ADP was set at 3%, assessed with a 1-sided 97.5% CI. RESULTS:From December 2021 to July 2024, of 13,983 screened 3,543 individual patients with suspected ACS were recruited and consented from 2 major emergency departments in North-West England, with 100% follow-up achieved for all representations to any national hospital. The median age was 60 years (IQR: 49.5-70.5 years), 53% were men, 6.7%, and 7.6% had adjudicated index type 1 MI and MACE within 30 days, respectively. The turnaround time from sample to result for central laboratory hs-cTnT was 81 minutes (IQR: 69-101 minutes). The proportion of patients discharged within 4 hours was relatively low and did not differ substantially (21.8% vs 19.2%, P = 0.07). In addition, the 0/1-hour pathway was noninferior for safety, in patients discharged, compared with the 0/3-hour pathway, absolute difference in sensitivity was +4.2% (1-sided 97.5% CI: -2.5) in favor of the 0/1-hour pathway. The calculated sensitivities were 93.7% (95% CI: 88.4%-97.1%) vs 89.5% (95% CI: 82.7%-94.3%), respectively. CONCLUSIONS:Implementation of the ESC 0/1-hour pathway failed to discharge significantly more patients within 4 hours of presentation compared with the 0/3-hour ADP. In addition, The ESC 0/1-hour was noninferior to the 0/3-hour hs-cTn pathway for safety of discharge, although safety for both pathways was less than that imputed by observational studies. This trial demonstrates that perceived benefits to emergency department efficiency of a reduced sampling interval are mitigated by central laboratory turnaround times as well as system constraints. (Pragmatic Randomised Trial of the ESC 0/​1 Versus 0/​3 Hour Troponin Pathway [MACROS2]; NCT05322395).

BACKGROUND:Sex-specific diagnostic thresholds for high-sensitivity cardiac troponin (hs-cTn) assays are recommended by international guidelines for the diagnosis of myocardial infarction (MI). We assessed the performance of sex-specific single-sample rule-out thresholds for identifying low-risk patients in the emergency department. METHODS:The derivation cohort comprised patients ≥18 years presenting with suspected MI to 2 Norwegian hospitals between 2015 and 2020 with 0-hour hs-cTnT (Roche) and high-sensitivity cardiac troponin I (Abbott and Siemens) measurements available. The primary endpoint was type 1 MI at index encounter. Diagnoses were adjudicated using assay-specific criteria per the Fourth Universal Definition of Myocardial Infarction. Sex-specific single-sample rule-out thresholds were derived, compared with guideline-recommended uniform thresholds, and externally validated in an independent and comparable British cohort. RESULTS:Among 1896 patients [median age 62 (25th-75th percentile 52-72) years; 39% female], MI occurred in 12.5%-12.8% males and 8.8%-9.2% females, depending on the adjudication assay.For each assay, more females had hs-cTn concentrations below the uniform single-sample thresholds, yet these thresholds did not achieve >99% sensitivity in females. Sex-specific adjustment achieved >99% sensitivity at cutoffs of <4 and <7 ng/L (Roche); <1 and <6 ng/L (Abbott); <2 and <7 ng/L (Siemens) for females and males, respectively. Sex-specific thresholds reduced rule-out proportions in females (from 29%-60% to 10%-32%) and increased them in males (from 17%-53% to 45%-64%). Trends were similar in the validation cohort of 1948 patients. CONCLUSIONS:Uniform single-sample rule-out thresholds reveal marked sex differences in MI risk stratification. Sex-specific hs-cTn thresholds could improve safety in females and efficiency in males. CLINICALTRIALS.GOV REGISTRATION NUMBERS:NCT02620202; NCT01852123.

There have been considerable developments in the analytic precision of cardiac troponins in the last three decades. Whilst there has been near-universal uptake of this technology, there is considerable variability in how to assess acute chest pain patients using high-sensitivity cardiac troponins. This review describes the historical narrative for cardiac troponins and details the evidence base behind decision rules, such as single sample rule-out, single sample rule-in, and accelerated diagnostic protocols (ADPs). There is particular focus on the European Society of Cardiology (ESC) 0/1 and 0/3 h and the high-STEACS ADPs. The ESC 0/3 h ADP appears to have reduced rule-out safety compared to both the ESC 0/1 h and high-STEACS ADP. However, whilst high-STEACS performed well in its validation population, external validation in the US has been less impressive and warrants further investigation. The ESC 0/1 h pathway has demonstrated strong rule-out performance, helped by its observational zone. However, real world implementation studies comparing these ADPs are required to understand their impact on Emergency Department efficiency and the safety of clinician decision-making.

A challenge in the implementation of rapid risk-stratification algorithms for patients with suspected acute coronary syndrome is the turnaround time for cardiac troponin (cTn) from blood sampling to reporting of results. Measurement of cTn in whole blood using point of care (POC) offers a solution. There is lack of consensus on how these instruments should be assessed and deployed when implemented into routine practice. A pragmatic strategy is needed to balance the requirement for appropriate evaluation, validation and local verification of POC high sensitivity (hs) cTn assays whilst avoiding unnecessary duplication of previously conducted work using central laboratory assays. The International Federation of Clinical Chemistry and Laboratory Medicine Committee on Clinical Application of Cardiac Bio-Markers (IFCC C-CB) has developed an educational document to provide practical suggestions as to how hs-cTn POC assays may be implemented in acute health care settings and networks. The objective of this document is to provide a pragmatic framework for implementation of such systems. The article describes the validation and verification procedures and outlines what should be the responsibility of the manufacturers and provides recommendations on how a local verification may be undertaken before instruments are implemented into routine clinical practice.

Myocardial infarction remains a significant cause of mortality globally. High-sensitivity cardiac troponin is an essential criterion in the fourth universal definition of myocardial infarction. Our understanding of the structure and release mechanisms of troponin has been updated over the last decade, facilitated by ever more sensitive assays. This review initially outlines the structure and function of the troponin complex, then details the currently proposed mechanisms of release and elimination of troponin. It concludes by using this updated understanding to critique the current universal definition of myocardial infarction and injury.

STUDY OBJECTIVE:To compare the effectiveness of high-sensitivity cardiac troponin (hs-cTn) point-of-care testing to central laboratory hs-cTn measurements when investigating patients presenting to the emergency department (ED) with symptoms of acute coronary syndrome. METHODS:The WESTCOR point-of-care study was a single-center prospective randomized controlled trial where we randomized patients presenting with possible acute coronary syndrome in a 1:1 fashion to receive either 0/1-hour centralized hs-cTnT measurements (control) or 0/1-hour point-of-care hs-cTnI testing (intervention). We defined length of stay (LOS) in the ED as the primary endpoint and the minimum clinically meaningful difference as 15 minutes. RESULTS:We included 1,494 patients in the final analysis, 728 in the point-of-care group, and 766 in the control group. The median (interquartile range) age was 61 (22) years, and 635 (42.5%) were women. Median LOS in the ED was 174 (95% confidence interval [CI] 167 to 181) and 180 (95% CI 175 to 189) minutes in the point-of-care and control group, respectively, resulting in a reduction in median LOS of 6 minutes (95% CI -4 to 17). Acute myocardial infarction, death, or acute revascularization occurred in 83/728 (11.4%) of point-of-care and 72/766 (9.4%) of control patients. CONCLUSIONS:We found that implementing point-of-care hs-cTnI testing in the ED with a 0/1-hour diagnostic algorithm did not lead to a clinically meaningful reduction in ED LOS. We observed no difference in the incidence of myocardial infarction, acute coronary revascularization, or death during 30 days follow-up.

Measurement of high sensitivity cardiac troponin (hs-cTn) I using cartridge-based systems at the point of care (POC) requires an appropriate quality control system. The optimal strategy for this currently remains unclear. We report the results of our experience with such a system with measurement over 842 days. The Mersey Acute Coronary syndrome Rule Out Study (MACROS-2). MACROS-2 is a two-centre, pragmatic, randomised controlled trial (RCT) comparing the rule out of non ST-elevation myocardial infarction (NSTEMI), using the European Society of Cardiology (ESC) 0/1 or 0/3 hour diagnostic algorithms (ClinicalTrials.gov Identifier: NCT05322395). The inclusion period was 13/4/22-29/07/2024. Upon presentation with symptoms compatible with NSTEMI, the patient had blood drawn at presentation for central laboratory high sensitive cardiac troponin(hs-cTn) T (roche , elecsys [clinical biomarker in use]), but an additional research sample was drawn for immediate analysis in the ED (emergency department) of whole blood (EDTA tube) Quidel TriageTrueTM hs-cTn I test on the Quidel Triage Meterpro device. This process was repeated for any serial samples. The device includes two on-board quality control (QC) checks on the analytical process. Internal liquid QC was performed using manufacturer supplied EDTA plasma-based QC material. Both alow control (target 25 ng/L) and high control (target 500 ng/L) were use by expert laboratory operators with regular checks on a weekly basis. For plasma, the analytical range is 0.1-1000 ng/L, limit of detection (LoD) is 1.5 ng/L, limit of quantitation (LoQ) at 20% coefficient of variation (CV) 2.1 ng/L and at 10% CV 4.6ng/L. 99th percentile overall 20.5 ng/L. All IQC was downloaded to a central repository for analysis. Over 842 days 539triage true POC tests were run on patient samples and 382 QC samples. An invalid test result on first analysis occurred in 56/5391 (1%). On repeat analysis there were 24 analytical failures giving a total failure rate of 24/5291 (0.4%). 328 (165 low, 162 high) QC samples were run. There were 7 lots for the low QC and 9 lots for a high QC over 21 reagent lots. eight expert laboratory operators undertook IQC. For the low control, 4/165 (2.5%) samples exceeded the two standard deviation (SD) limit and none exceeded 3 SD. Mean value was 25.4 ng/L with a mean CV of 9.7%. There was only one analytical failure in the high control with only 2 (1.2% exceeded 2 SD and none 3 SD’s. The mean value was 519 ng/L with a mean CV of 9.5%. Time series regression analysis across reagent batches showed no evidence of significant lot to lot variation or evidence of QC drift across the entire period of the study. Analytical reliability of the system was robust. QC stability with time suggests that following lot verification, QC frequency can be such that only the midpoint and towards the end of a particular batch is measured.

BACKGROUND:There is increasing awareness of the differing characteristics of troponin subunits. CASE SUMMARY:We present a case where an elevation of high-sensitivity troponin T (hs-cTnT) (>6× 99th percentile) beyond the single-sample rule-in threshold led to an erroneous diagnosis of acute coronary syndrome (ACS). After exhaustive biochemical tests proving chronic myocardial injury, we also determined that 4 different high sensitivity assays for troponin I revealed values well below their respective 99th percentiles. This uniquely highlights the difference in troponin subunit characteristics in chronic myocyte injury and dispels any notion that the difference relates to assay characteristics. DISCUSSION:Chronic elevations of hs-cTnT can be sufficiently large to surpass single rule-in thresholds in some ACS pathways, but this case stresses the importance of the delta value regardless of the degree of elevation of the presentation sample. In cases of diagnostic doubt for ACS, clinicians should consider measuring hs-cTnI as an alternative troponin.

BACKGROUND:Approximately 90% of patients presenting to the emergency department with suspected acute coronary syndrome have acute myocardial infarction excluded, but they remain at risk of major adverse cardiovascular events. This study assessed the long-term outcomes of such patients, focusing on the incremental value of multiple biomarkers combined with clinical risk scores for risk stratification. METHODS:In this prospective observational study, 487 patients with suspected acute coronary syndrome but excluded acute myocardial infarction were recruited from a large urban hospital, with a median follow-up of 5.8 years. The primary end point was major adverse cardiovascular events, including adjudicated type 1 myocardial infarction, unstable angina requiring urgent revascularization, and cardiovascular death. Biomarkers assessed were hs-cTnT (high-sensitivity cardiac troponin T), hs-cTnI (high-sensitivity cardiac troponin I), HFABP (heart-type fatty acid binding protein), GDF-15 (growth differentiation factor 15), NT-proBNP (N-terminal prohormone of brain naturetic peptide), galectin-3, and hs-CRP (high-sensitivity C-reactive protein (). Statistical methods included receiver operating characteristic analysis, Kaplan-Meier curves, net reclassification index, and Cox proportional hazards models to evaluate biomarker utility independently and combined with Thrombolysis in Myocardial Infarction and History, ECG, Age, Risk Factors, Troponin scores. RESULTS:Of the 487 patients (median age 56 years; 44% female), 9.9% experienced major adverse cardiovascular events. Annualized major adverse cardiovascular events rates for patients with troponin levels below the limit of detection were 0.5% (hs-cTnT) and 0.7% (hs-cTnI), with no cardiovascular deaths over 5 years. Both hs-cTnT and hs-cTnI levels modestly enhanced risk stratification when added to Thrombolysis in Myocardial Infarction or History, ECG, Age, Risk Factors, Troponinscores. Of the non-necrosis biomarkers, only GDF-15 demonstrated independent prognostic value in multivariable models. CONCLUSIONS:Hs-cTnT, hs-cTnI, and GDF-15 improve the long-term risk stratification of the History, ECG, Age, Risk Factors, Troponinand Thrombolysis in Myocardial Infarction scores in patients with suspected acute coronary syndrome and acute myocardial infarction excluded. Hs-cTn of either type at or below limit of detection was associated with excellent short- and long-term outcomes. REGISTRATION:URL: https://clinicaltrials.gov; Unique identifier: NCT03628586.

This chapter addresses clinical enzymology and biomarkers. Enzyme assays for diagnosing diseases depend on an increase in the activity or amount of enzyme present when a particular tissue is affected by illness and leakage or release of the enzyme into the blood. Enzymes are examples of biomarkers, which are biological molecules whose concentrations alter when there is disease. Cardiac disease occurs when the blood vessels supplying the heart become blocked. The principal biomarkers of cardiac damage are the cardiac troponins. The combination of a change (appearance) of cardiac troponin in the blood, plus changes in the electrocardiogram (ECG) and clinical features, can be used to diagnose and classify acute heart disease into stable angina, unstable angina, and myocardial infarction (MI). Meanwhile, natriuretic peptides are biomarkers of cardiac failure and can be used to diagnose both acute and chronic heart failure.

There is increasing awareness of the differing characteristics of troponin subunits. We present a case where an elevation of high-sensitivity troponin T (hs-cTnT) (>6× 99th percentile) beyond the single-sample rule-in threshold led to an erroneous diagnosis of acute coronary syndrome (ACS). After exhaustive biochemical tests proving chronic myocardial injury, we also determined that 4 different high sensitivity assays for troponin I revealed values well below their respective 99th percentiles. This uniquely highlights the difference in troponin subunit characteristics in chronic myocyte injury and dispels any notion that the difference relates to assay characteristics. Chronic elevations of hs-cTnT can be sufficiently large to surpass single rule-in thresholds in some ACS pathways, but this case stresses the importance of the delta value regardless of the degree of elevation of the presentation sample. In cases of diagnostic doubt for ACS, clinicians should consider measuring hs-cTnI as an alternative troponin.

INTRODUCTION:Expression of the cytokine growth differentiation factor 15 (GDF-15) is up-regulated in conditions of tissue injury and stress. We evaluated if GDF-15 predicts obstructive coronary artery disease (CAD) or need for revascularization within 30 days and 12 months in low/intermediate risk patients with acute chest pain. MATERIALS AND METHODS:We included 537 hospitalized patients who had high-sensitivity troponin T (hs-cTnT) < 99th percentile and underwent coronary CT angiography (CCTA). Odds ratios (ORs) and 95 % confidence intervals (CI) were calculated by logistic regression analyses and are reported per standard deviation increment of GDF-15 (log-transformed). RESULTS:The median (25th-75th percentile) age was 56 (49-65) years, 217 (40.4 %) were women, 83 (15.5 %) had obstructive CAD at CCTA. In total 49 (9.1 %) patients underwent revascularization within 30 days and 52 (9.7 %) within 12 months. In age and sex adjusted analysis GDF-15 was a significant predictor with ORs (95 % CI) of 1.35 (1.05-1.73), 1.39 (1.06-1.83) and 1.41 (1.07-1.84) for obstructive CAD, revascularization within 30 days and 12 months, respectively. However, after adjustment for clinical covariables, the ORs of GDF-15 were no longer statistically significant for either outcome (P ≥ 0.07). Adding hs-cTnT levels alone to the age and sex adjusted model also rendered the ORs of GDF-15 non-significant (P ≥ 0.31). CONCLUSIONS:In patients with acute chest pain but without acute myocardial infarction, GDF-15 did not substantially improve the identification of obstructive CAD or need for revascularization within 30 days and 12 months. Our findings question the clinical usefulness of GDF-15 for prognostication of low-risk patients with acute chest pain.

Aims This prospective, two-centre study derived and validated predictive algorithms for the Siemens Atellica IM high-sensitivity cardiac troponin I (hs-cTnI) assay in the emergency department (ED). Methods and results Algorithms for predicting 30-day myocardial infarction (MI) Types 1 and 2 and death or non-ST-elevation MI (NSTEMI, Types 1 and 2) at index admission were developed from a derivation cohort of 1896 patients and validated using a synthetic data set with nearly 1 million patient cases. Performance was compared with the European Society of Cardiology algorithms for hs-cTnT (Roche Diagnostics) and hs-cTnI (Abbott Diagnostics). An admission hs-cTnI concentration < 5 ng/L had a negative predictive value (NPV) and sensitivity for 30-day MI or death of 99.5-99.7% and 98.1-98.8%, respectively, in the derivation cohort and validation data set. The NPV and sensitivity were >= 99.7% and >= 98.8% for ruling out index NSTEMI. A 0- to 1-h algorithm with baseline hs-cTnI concentration < 10 ng/L and Delta change < 3 ng/L had NPV of >= 99.5% and sensitivity >= 97.3% for predicting 30-day MI or death and a >= 99.5% sensitivity and NPV for index NSTEMI. Rule-in algorithms of either 0-h hs-cTnI >= 120 ng/L or 0- to 1-h Delta change >= 12 ng/L had positive predictive value >= 73% and specificity > 96% for 30-day MI or death and index NSTEMI. The results were comparable with established hs-cTn algorithms. Conclusion This study presents Siemens Atellica hs-cTnI algorithms for diagnosis and risk prediction in the ED with performance comparable with established hs-cTnT (Roche) and hs-cTnI (Abbott) algorithms.

OBJECTIVES:To assess the imprecision and stability of the point-of-care troponin I assay in the Emergency Department and its correlation and bias to two central laboratory troponin I assays (Siemens Atellica and Abbott Alinity). METHODS:Imprecision and stability testing was performed on opportunistically selected samples using whole blood in the emergency department by non-laboratory trained personnel. Assay comparisons were undertaken on samples taken from participants of the Mersey Acute Coronary syndrome Rule Out Study. RESULTS:The coefficient of variation (95 % confidence interval), at the 99th percentile for the point-of-care assay, was 8.1 % (6.1-12.1 %) but with a wide confidence interval reflective of considerable scatter at values just below the 99th percentile. The 10 % limit of quantification was 7.5 ng/L (1.7-61.8 ng/L). All samples met the ≤2 ng/L stability criteria for a duration of 4 h and under. The point-of-care assay very strongly correlated and had a negative bias with the Siemens Atellica and Abbott Alinity assays, Pearson's R=0.99 and 0.95, mean difference -29.7 ng/L and -13.3 ng/L respectively. CONCLUSIONS:The Siemens VTLi point-of-care assay fulfils high-sensitivity criteria when operated by non-laboratory trained staff using whole blood in its intended environment. Lithium heparin samples are likely stable up to 4 h. Significant bias between the point-of-care and two central laboratory assays negates the use of these assays interchangeably.

Background Cardiac troponin measurements are indispensable for the diagnosis of myocardial infarction and provide useful information for long-term risk prediction of cardiovascular disease. Accelerated diagnostic pathways prevent unnecessary hospital admission, but require reporting cardiac troponin concentrations at low concentrations that are sometimes below the limit of quantification. Whether analytical imprecision at these concentrations contributes to misclassification of patients is debated. Content The International Federation of Clinical Chemistry Committee on Clinical Application of Cardiac Bio-Markers (IFCC C-CB) provides evidence-based educational statements on analytical and clinical aspects of cardiac biomarkers. This mini-review discusses how the reporting of low concentrations of cardiac troponins impacts on whether or not assays are classified as high-sensitivity and how analytical performance at low concentrations influences the utility of troponins in accelerated diagnostic pathways. Practical suggestions are made for laboratories regarding analytical quality assessment of cardiac troponin results at low cutoffs, with a particular focus on accelerated diagnostic pathways. The review also discusses how future use of cardiac troponins for long-term prediction or management of cardiovascular disease may require improvements in analytical quality. Summary Clinical guidelines recommend using cardiac troponin concentrations as low as the limit of detection of the assay to guide patient care. Laboratories, manufacturers, researchers, and external quality assessment providers should extend analytical performance monitoring of cardiac troponin assays to include the concentration ranges applicable in these pathways.