Citations

Abstract Background The clinical use and interpretation of cardiac troponins (cTn) in pediatric patients is heterogeneous. Content This review is based on an appraisal and synthesis of the available literature and discussions between International Federation of Clinical Chemistry and Laboratory Medicine Committee on Clinical Application of Cardiac Biomarkers members and pediatricians, cardiologists, emergency department physicians, and laboratorians. It aims to summarize current knowledge and best practices related to cTn measurements in pediatric patients, including which percentile should be applicable as the upper reference limit, and the influence of age, sex, and physiology on circulating concentrations. Preanalytical and analytical precautions, and a consensus on optimal interpretation of the reported results are discussed. Summary Current studies report high cTn concentrations in healthy infants and newborns. The nadir is reached at 1–3 years at which time concentrations gradually increase, reaching adult levels through puberty. The incidence of myocardial injury is reported to be low and dependent on whether the 97.5th or 99th percentile is chosen as the upper reference limit. The main clinical indication for testing appears to be suspicion of myo/pericarditis or traumatic chest injury. On occasion, cTn is measured in cases of possible heart failure and/or myocardial ischemia. There is heterogeneity among the limited clinical studies published. Most of the data are retrospective, and the current suggestions for clinical practice are thus largely based on expert opinion. More research is needed regarding all aspects of cTn testing in children, and suggestions for future research are included at the end of this review.

Abstract Background High-sensitivity cardiac troponin (hs-cTn) assays are recommended for the diagnosis of acute myocardial infarction. Here, we characterize the analytical performance of a next-generation hs-cTn assay, Elecsys® Troponin T hs Gen 6 (Roche Diagnostics International). Methods Surplus lithium-heparin plasma or serum samples from patients or healthy volunteers were run on Cobas® e 801, e 402, and Pro analyzers. Limits of blank (LoB), limits of detection (LoD), and limits of quantitation (LoQ) were determined according to CLSI EP17-A2, with target values of 1.0 and 1.5 ng/L for LoB/LoD and 3.0 ng/L (10% CV) and 1.5 ng/L (20% CV) for LoQ, respectively. Precision was measured, per CLSI EP17-A2, using 3 QC samples (approximately 4, 30, and 220 ng/L), 12 native samples, and 3 reagent lots. Linearity, per CLSI EP06-Ed2, was determined by diluting samples with cardiac troponin T (cTnT) concentration above the measuring range with a low/blank sample. Interference (per Glick) with endogenous and assay components at 5 cTnT concentrations was assessed. Results Measured values for LoB, LoD, and LoQ at 10% and 20% CV were 0.1 to 0.7 ng/L, 0.3 to 1.4 ng/L, 1.0 to 2.9 ng/L, and 0.4 to 1.2 ng/L, respectively. Repeatability CVs were 1.0 to 5.8% for mean cTnT concentrations of 2.6 to 9230 ng/L in lithium-heparin plasma. High precision was shown across lots, and linearity was observed across the measuring range (1.5 to 9500 ng/L, all Pearson's r = 1.00). No interferences were observed, specified up to ≤1000 mg/dL hemoglobin, ≤50 mg/dL [≤855 µmol/L] icterus/bilirubin, and ≤1200 ng/mL biotin. Conclusions The analytical performance characterization of the assay demonstrated high sensitivity, high precision at the low end and across the measuring range, and resistance to interference.

Abstract 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.

Abstract Background/Introduction Macrotroponin refers to high-molecular-weight troponin complexes bound to immunoglobulins, shown to cause persistently elevated troponin values often unrelated to myocardial injury. We hypothesized that its frequency might increase with age and differ between men and women, reflecting potential age-related cardiac changes and sex-specific risk profiles. Purpose To assess whether macrotroponin frequency varies across age groups and by sex within the upper sex-specific 90th percentile of troponin values in a healthy Danish reference population. Methods Among 1,307 participant samples with normal-range NT-proBNP, HbA1c, and eGFR ≥90 mL/min/1.73m2, 147 samples with troponin I within the upper levels of the sex-specific 90th percentile for the Siemens Atellica assay were further tested for macrotroponin I using Protein A/G immunoglobulin depletion and sucrose gradient ultracentrifugation. Samples were only deemed macrotroponin-positive by concordantly positive results. After excluding 29 samples with low troponin values due to analytical dilution constraints, 118 participants remained. Macrotroponin I frequency was compared across three age groups (<40, 40–60, and >60 years) and between sexes. Logistic regression was used to adjust for creatinine levels. Results Of 118 samples tested (48% females), macrotroponin I was present in 88 (75%), with similar frequencies in women (80%) and men (77%). Macrotroponin I frequency did not differ significantly across age groups (p=0.26) or between sexes (p>0.5) (Table 1, Figure 1). Logistic regression revealed no significant associations between macrotroponin I and age group, sex, or creatinine levels (all p > 0.5). Conclusion Macrotroponin I was highly frequent in the highest troponin ranges in a healthy reference population and showed no relationship with age or sex. The presence of macrotroponin I may impact clinical management in a considerable number of patients, but further investigation is required in clinical studies.

Abstract Background Measurement of cardiac troponin (cTn) using high-sensitivity assays is recommended for the diagnosis of myocardial infarction. We determined sex-specific and uniform 99th percentile upper reference limits (URLs) using the new Elecsys® Troponin T high-sensitivity Gen 6 assay in a global, healthy reference range cohort. Methods Lithium-heparin plasma and serum samples were prospectively collected from apparently healthy individuals aged ≥20 years across 34 global sites in the United States, Europe, China, and Japan. cTnT was measured using the Troponin T high-sensitivity Gen 6 assay on the Cobas® e 801 analyzer. Exclusion criteria were defined according to the 2022 IFCC guidance. Uniform and sex-specific 99th percentile URLs and nonparametric 95% CIs were determined in plasma and serum separately and combined. Results The final study population comprised 4147 participants (52.5% female) with a median (25th–75th percentiles) age of 48.0 (33.0–59.0) years; 45.8%, 47.9%, 5.2%, and 1.1% were White, Asian, Black, and other/unknown, respectively. For sample matrices combined (n = 8294), 81.0% and 99.2% of cTnT values were above the limit of detection in females and males, respectively. Sex-specific 99th percentile URLs (95% CI) were 18 (16–23) ng/L for females and 32 (28–35) ng/L for males; the uniform 99th percentile URL was 27 (24–31) ng/L. URLs were comparable in plasma and serum samples. Conclusions This study determined sex-specific and uniform 99th percentile URLs for the Troponin T high-sensitivity Gen 6 assay that were comparable irrespective of the matrix used in a large, global, healthy reference population.

Abstract Object Transdermal biosensors may provide an alternative to conventional blood-based biomarker measurement. Our purpose was to determine the binary correlation between transdermal (Infrasensor™; RCE, Inc, Carlsbad, CA) and conventional blood-based measurements. Methods This was a secondary analysis from a previously published observational cardiac troponin I (cTnI) study performed to establish the upper reference level of cTnI, at 10 US hospitals. After obtaining informed consent, 2 cohorts of patients were enrolled: 1) those who completed a health assessment questionnaire and appeared healthy, and 2) those with a known elevated cTnI per the local hospital standard assay. All blood lab analyses were performed at the University of Maryland Medical Center, Baltimore, MD. Normal was defined as cTnI <53.48 ng/L (male) or 34.11 ng/L (female) using the Siemens Atellica IM assay (Siemens Medical Solutions, Mountain View, CA), NT-proBNP <450 pg/mL (>75 years) or <124 pg/mL (<75 years), creatinine >1.17 mg/dL (male) or >0.95 mg/dL (female), and HbA1c <6.4%. The Infrasensor was placed on the patient’s wrist for measurement and blood drawn for analysis at approximately the same time. Results Of 840 enrolled patients, the median (IQR) age was 46 (30,57), 416 (49.5%) were female, 10.36% Hispanic, 6.7% Asian, 12.9% African American, and 69.1% White. Elevated lab tests were 102 hscTnI’s, 156 NTproBNP’s, 37 HbA1C’s, and 163 creatinine’s. Significant binary correlations were found between all transdermal signals and the corresponding lab blood levels Conclusion Infrasensor transcutaneous measurement demonstrates similar results as that obtained from blood testing in the central laboratory. Capsule The Infrasensor (RCE, Inc, Carlsbad, CA, USA) is rapid point of care transcutaneous biomarker measurement device. This study evaluated its ability to provide qualitative results for troponin I, NTproBNP, creatinine, and HbA1c levels in 840 patients. Significant correlations were found between all transdermal signals and the corresponding binary lab blood levels.

Abstract Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening hematological disorder affecting ≈24 per 1,000,000 people in the US. Iptacopan, the first orally administered monotherapy for PNH, received US Food and Drug Administration approval in December 2023. APPRISE-PNH is a data platform designed to capture comprehensive real-world information on iptacopan-treated patients with PNH. The aim of this study was to describe patient profiles and assess treatment patterns and clinical outcomes among iptacopan-treated patients (age ≥18 years) with PNH in the US real-world setting. Methods: The present interim analysis of APPRISE-PNH includes data from patients enrolled between July 2, 2024, and June 13, 2025, with additional data collection expected through 2025. Duration of therapy was measured from the date of iptacopan initiation (index) until discontinuation or data cutoff, whichever occurred first. Treatment adherence was measured using the medication possession ratio (MPR; ratio of the total days' supply to days covered) and the proportion of days covered (PDC; ratio of days with supply to days covered). Clinical outcomes were assessed during follow-up including hemoglobin (Hb; change from pre-index to highest level post index, proportion of patients with Hb increase ≥2 g/dL, and proportion of patients with Hb normalization to ≥12 g/dL), lactate dehydrogenase (LDH) (change from pre-index to lowest level post index and proportion of patients with LDH reduction &lt;1.5× upper limit of normal [ULN]), and number of red blood cell (RBC) transfusions. Results: Among 52 patients enrolled as of June 13, 2025, the median age was 53.7 years, 38% were male, and 60% were covered by commercial insurance. Overall, 25% of patients (n=13) were complement inhibitor (CI) naive at the time of iptacopan initiation, while 75% (n=39) were treatment experienced and had received ≥1 prior CI therapy for PNH (77% ravulizumab, 46% eculizumab, 26% pegcetacoplan). All patients received iptacopan 200 mg twice daily, per the product label; the median (IQR) duration of iptacopan therapy was 9.8 (5.0-12.8) months. At the time of data cutoff, 2 patients discontinued therapy (1 due to provider decision, 1 due to death). The median (IQR) MPR and PDC were 105.2% (100.6%-110.7%) and 97.3% (92.7%-99.5%), respectively. Among the 52 patients enrolled in APPRISE-PNH, 42 patients had medical records available at the time of data cutoff. Of the 23 of 42 patients (55%) with Hb values available pre- and post index at the time of data cutoff, 4 were CI treatment naive (median [IQR] pre-index Hb, 9.9 [9.1-10.2] g/dL) and 19 were CI treatment experienced (median [IQR] pre-index Hg, 10.7 [8.9-12.2] g/dL). The median (IQR) change from pre-index to highest value post-index was similar for both groups (1.6 [0.8-2.3] g/dL and 1.6 [0.6-3.4] g/dL, respectively). However, among the CI treatment–experienced patients, those with pre-index Hb &lt;12 g/dL (n=11) experienced a greater improvement than those with pre-index Hb ≥12 g/dL (n=8), with median (IQR) of 3.3 (2.2-4.5) g/dL vs 0.4 (0.1-1.3) g/dL, respectively. Overall, 12 of 23 patients (52%) achieved a Hb increase ≥2 g/dL, and 17 of 23 (74%) achieved Hb normalization to ≥12 g/dL. Among the 18 of 42 patients (43%) with LDH values available pre- and post index, the median (IQR) change from pre-index to lowest post-index value was −41.5 (−155.8 to 2.5) U/L. Among those with clinical data, most patients (38 of 42; 90%) did not require RBC transfusions during follow-up and 4 had evidence of an RBC transfusion over the follow-up period; 2 of 4 patients requiring transfusions had aplastic anemia and/or myelodysplastic syndrome. At the time of data cutoff, no patients with clinical data available had evidence of a major adverse vascular event (including thrombosis, transient ischemic attack, stroke, and major bleeding) over the follow-up period. Conclusions: These data represent early insights into the real-world use of iptacopan and related Hb response in US patients with PNH. Adherence to iptacopan was high, and iptacopan treatment improved Hb and LDH parameters, providing comprehensive hemolysis control. Enrollment is currently ongoing; data on additional patients with longer follow-up are forthcoming.