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Cardiac disease is the major cause of death in patients with end-stage renal disease (ESRD), accounting for about 45% of all deaths. In dialysis patients about 20% of cardiac deaths are attributed to acute myocardial infarction (AMI). The survival of dialysis patients after AMI is poor, with nearly three-quarters of patients dead at 2 years after AMI. The definition of AMI is based on symptoms, electrocardiography, and cardiac biomarkers. In the non-ESRD population, it has been recognized that sensitive markers of myocardial injury (cardiac troponin I and troponin T) define a group of patients who are increased risk for adverse cardiac outcomes and who are more likely to benefit from treatment. Elevated cardiac troponin levels in nonhospitalized ESRD patients without other evidence of ongoing myocardial ischemia may also prospectively identify a subgroup of ESRD patients at increased risk for death. This editorial is an overview of cardiac biomarkers (specifically troponin I and troponin T) in the management of acute coronary syndromes in ESRD patients. A potential role of cardiac troponin testing for risk stratification in the outpatient dialysis unit is also presented. [ABSTRACT FROM AUTHOR]

Serum cardiac troponin I measurement is preferred to creatine kinase-MB mass for the diagnosis of acute myocardial infarction in patients with renal insufficiency. Unexplained increases in cardiac troponin I in this population requires further evaluation and close follow-up. [ABSTRACT FROM AUTHOR]

Objective: We sought to validate the clinical performance of a rapid assessment pathway incorporating the Siemens Atellica IM high sensitivity cardiac troponin I (hs-cTnI) assay in patients presenting to the emergency department (ED) with suspected acute myocardial infarction (AMI)., Methods: This was a multicentre prospective observational study of adult ED patients presenting to five Australian hospitals between November 2020 and September 2021. Participants included those with symptoms of suspected AMI (without ST-segment elevation MI on presentation ECG). The Siemen's Atellica IM hs-cTnI laboratory-based assay was used to measure troponin concentrations at admission and after 2-3 hours and cardiologists adjudicated final diagnoses. The HighSTEACS diagnostic algorithm was evaluated, incorporating hs-cTnI concentrations at presentation and absolute changes within the first 2 to 3 hours. The primary outcome was index AMI, including type 1 or 2 non-ST segment elevation MI (NSTEMI) or ST-elevation MI (STEMI) following presentation. 30-day major adverse cardiac outcomes (including AMI, urgent revascularisation or cardiac death) were also reported. The trial was registered with the Australian and New Zealand Clinical Trials Registry., Results: 1994 patients were included. The average age was 56.2 years (SD = 15.6), and 44.9% were women. 118 (5.9%) patients had confirmed index AMI. The 2-hour algorithm defined 61.3% of patients as low risk. Sensitivity was 99.1% (94.0%-99.9%) and negative predictive value was 99.9% (99.3%-100%). 24.4% of patients were deemed intermediate risk. When applying the parameters for high risk, 252 (14.3%) were identified, with a specificity of 91.5% (88.7%-93.6%) and a PPV of 42.0% (35.6-48.7%)., Conclusions: A 2-hour algorithm based on the HighSTEACS strategy using the Siemens Atellica IM hs-cTnI laboratory-based assay enables safe and efficient risk assessment of emergency patients with suspected AMI., Trial Registration Number: ACTRN12621000053820., Competing Interests: Competing interests: LC has received institutional grants from Siemens, Beckman Coulter, Abbott Diagnostics, Roche, and Radiometer Pacific. She has received consulting fees from Siemens Healthineers, Abbott Diagnostics and Beckman Coulter. JHG received a fellowship from Advance Queensland. WP has received institutional grants from Siemens, Beckman Coulter, Abbott Diagnostics, Roche and Radiometer Pacific. He has received consulting fees from Pfizer, Abbott Diagnostics and institutional consultancy fees from Siemens Healthineers. MT has received funding for clinical research from Abbott, Alere, Beckman, Radiometer and Roche. Payment for speaking from Abbott, Alere and Roche, Consulting fees from Abbott, Roche and Siemens. Participation in Advisory boards of Abbott, Radiometer, Roche, and Siemens. Funding for education from Abbott, Alere and Beckman. FA: Board of Directors for HyTest Ltd; Associate Editor for Clinical Chemistry; Advisory Boards: Instrumentation Laboratory, Siemens Healthineers, Osler Diagnostics, Qorvo; Honorarium for Speaking at Industry Conferences: Siemens Healthineers, Abbott Diagnostics; principal investigator on Industry Funded Grants (non-salaried) on cardiac biomarkers through Hennepin Healthcare Research Institute: Abbott Diagnostics, Abbott POC, BD, Beckman Coulter, Ortho-Clinical Diagnostics, Roche Diagnostics, Siemens Healthcare, ET Healthcare, Qorvo., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Patients presenting with symptoms suggestive of acute coronary syndrome (ACS) contribute to a high workload and overcrowding in the Emergency Department (ED). Accelerated diagnostic protocols for non-ST-elevation myocardial infarction have proved challenging to implement. One obstacle is the turnaround time for analyzing high-sensitivity cardiac troponin (hs-cTn). In the WESTCOR-POC study (Clinical Trials number NCT05354804) we aim to evaluate safety and efficiency of a 0/1 h hs-cTn algorithm utilizing a hs-cTnI point of care (POC) instrument in comparison to central laboratory hs-cTnT measurements., Design: This is a prospective single-center randomized clinical trial aiming to include 1500 patients admitted to the ED with symptoms suggestive of ACS. Patients will receive standard investigations following the European Society of Cardiology 0/1h protocols for centralized hs-cTnT measurements or the intervention using a 0/1h POC hs-cTnI algorithm. Primary end-points are 1) Safety; death, myocardial infarction or acute revascularization within 30 days 2) Efficiency; length of stay in the ED, 3) Cost- effectiveness; total episode cost, 4) Patient satisfaction, 5) Patient symptom burden and 6) Patients quality of life. Secondary outcomes are 12-months death, myocardial infarction or acute revascularization, percentage discharged after 3 and 6 h, total length of hospital stay and all costs related to hospital contact within 12 months., Conclusion: Results from this study may facilitate implementation of POC hs-cTn testing assays and accelerated diagnostic protocols in EDs, and may serve as a valuable resource for guiding future investigations for the use of POC high sensitivity troponin assays in outpatient clinics and prehospital settings.

Importance: Most healthcare institutions require employees to be vaccinated against SARS-CoV-2 and many also require at least one booster., Objective: We determine the impact of vaccine type, demographics, and health conditions on COVID-19 vaccine side effects in healthcare professionals., Design: A COVID-19 immunity study was performed at the 2021 American Association for Clinical Chemistry Annual Scientific meeting. As part of this study, a REDCap survey with cascading questions was administered from September 9, 2021 to October 20, 2021. General questions included participant demographics, past and present health conditions, smoking, exercise, and medications. COVID-19 specific questions asked about SARS-CoV-2 vaccine status and type, vaccine-associated side effects after each dose including any boosters, previous infection with COVID-19, diagnostic testing performed, and type and severity symptoms of COVID-19., Results: There were 975 participants (47.1% male, median age of 50 years) who completed the survey. Pfizer was the most commonly administered vaccine (56.4%) followed by Moderna (32.0%) and Johnson & Johnson (7.1%). There were no significant differences in vaccine type received by age, health conditions, smoking, exercise, or type or number of prescription medications. Side effects were reported more frequently after second dose (e.g., Moderna or Pfizer) (54.1%) or single/only dose of Johnson & Johnson (47.8%). Males were significantly more likely to report no side effects ( p < 0.001), while females were significantly more likely to report injection site reactions ( p < 0.001), fatigue ( p < 0.001), headache ( p < 0.001), muscle pain ( p < 0.001), chills ( p = 0.001), fever ( p = 0.007), and nausea ( p < 0.001). There was a significant upward trend in participants reporting no side effects with increasing age ( p < 0.001). There were no significant trends in side effects among different races, ethnicities, health conditions, medications, smoking status or exercise. In multivariate logistic regressions analyses, the second dose of Moderna was associated with a significantly higher risk of side effects than both the second dose of Pfizer and the single dose of Johnson & Johnson., Conclusions and Relevance: Younger people, females, and those receiving the second dose of Moderna had more COVID-19 vaccine side effects that per self-report led to moderate to severe limitations. As reported in other studies, the increase in side effects from Moderna may be explained by higher viral mRNA concentrations but be associated with additional protective immunity., Competing Interests: Author YZ is a consultant for Thermo Fisher. Author JW is Co-PI on a US and International patent. Specificity enhancing reagents for COVID-19 Antibody Testing. Author ZZ has sponsored research supported by Novartis, Waters, Siemens, Polymedco, Waters, Roche and ET Healthcare and has received consulting/speaker fee from Siemens, Roche and ET Healthcare. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Melanson, Zhao, Kumanovics, Love, Meng, Wu, Apple, Ondracek, Schulz, Wiencek, Koch, Christenson and Zhang.)

Risk scores including the Thrombolysis in Myocardial Infarction (TIMI) score; History, Electrocardiogram, Age, Risk Factors, and Troponin (HEART) score; and Simplified Emergency Department Assessment of Chest Pain Score (sEDACS) have been used to evaluate patients with symptoms suggestive of acute myocardial infarct (AMI). This study assessed prognostic utility of cardiac risk stratification scores when augmented with a high-sensitivity cardiac troponin-I assay (hs-cTnI)., Methods: This study enrolled 2,505 suspected AMI patients at 29 hospitals in the United States from April 2015 to April 2016. Blood samples were tested for hs-cTnI on the Atellica IM TnIH Assay (Siemens Healthineers). Patients were considered low risk for death/AMI with a TIMI score = 0, HEART ≤3, sEDACS ≤15, and hs-cTnI <45 ng/L (99th percentile) at time 0 and 2-3 hours., Results: There were 2,336 patients included after exclusions for ST-segment elevation myocardial infarction or incomplete data. At 30 days, 283 patients (12.1%) had been diagnosed with AMI, and there were 24 (1.0%) deaths and 213 (9.1%) revascularizations. Of 298 patients with death or AMI, 258 (86.6%) had elevated hs-cTnI. The HEART score and sEDACS identified 34.5% and 36.6% of patients as low risk, respectively. This was significantly more than the 12.1% identified by the TIMI score (P < .01)., Conclusions: The TIMI, HEART, and sEDACS scores all identify low-risk patients when combined with hs-cTnI measurements. The HEART score and sEDACS identified more low-risk patients compared to the TIMI score. These patients could be considered for discharge from the emergency department without further testing., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Competing Interests: Competing interests: The authors are all members of the International Federation of Clinical Chemists Committee on Clinical Applications of Cardiac Bio-Markers (C-CB).

Background: The introduction of more sensitive cardiac troponin assays has led to increased recognition of myocardial injury in acute illnesses other than acute coronary syndrome. The Universal Definition of Myocardial Infarction recommends high-sensitivity cardiac troponin testing and classification of patients with myocardial injury based on pathogenesis, but the clinical implications of implementing this guideline are not well understood., Methods: In a stepped-wedge cluster randomized, controlled trial, we implemented a high-sensitivity cardiac troponin assay and the recommendations of the Universal Definition in 48 282 consecutive patients with suspected acute coronary syndrome. In a prespecified secondary analysis, we compared the primary outcome of myocardial infarction or cardiovascular death and secondary outcome of noncardiovascular death at 1 year across diagnostic categories., Results: Implementation increased the diagnosis of type 1 myocardial infarction by 11% (510/4471), type 2 myocardial infarction by 22% (205/916), and acute and chronic myocardial injury by 36% (443/1233) and 43% (389/898), respectively. Compared with those without myocardial injury, the rate of the primary outcome was highest in those with type 1 myocardial infarction (cause-specific hazard ratio [HR] 5.64 [95% CI, 5.12-6.22]), but was similar across diagnostic categories, whereas noncardiovascular deaths were highest in those with acute myocardial injury (cause specific HR 2.65 [95% CI, 2.33-3.01]). Despite modest increases in antiplatelet therapy and coronary revascularization after implementation in patients with type 1 myocardial infarction, the primary outcome was unchanged (cause specific HR 1.00 [95% CI, 0.82-1.21]). Increased recognition of type 2 myocardial infarction and myocardial injury did not lead to changes in investigation, treatment or outcomes., Conclusions: Implementation of high-sensitivity cardiac troponin assays and the recommendations of the Universal Definition of Myocardial Infarction identified patients at high-risk of cardiovascular and noncardiovascular events but was not associated with consistent increases in treatment or improved outcomes. Trials of secondary prevention are urgently required to determine whether this risk is modifiable in patients without type 1 myocardial infarction., Clinical Trial Registration: https://www.clinicaltrials.gov. Unique identifier: NCT01852123.

Background: High-sensitivity cardiac troponin I (hs-cTnI) assays have been developed that quantify lower cTnI concentrations with better precision versus earlier generation assays. hs-cTnI assays allow improved clinical utility for diagnosis and risk stratification in patients presenting to the emergency department with suspected acute myocardial infarction. We describe the High-Sensitivity Cardiac Troponin I Assays in the United States (HIGH-US) study design used to conduct studies for characterizing the analytical and clinical performance of hs-cTnI assays, as required by the US Food and Drug Administration for a 510(k) clearance application. This study was non-interventional and therefore it was not registered at clinicaltrials.gov., Methods: We conducted analytic studies utilizing Clinical and Laboratory Standards Institute guidance that included limit of blank, limit of detection, limit of quantitation, linearity, within-run and between run imprecision and reproducibility as well as potential interferences and high dose hook effect. A sample set collected from healthy females and males was used to determine the overall and sex-specific cTnI 99th percentile upper reference limits (URL). The total coefficient of variation at the female 99th percentile URL and a universally available American Association for Clinical Chemistry sample set (AACC Universal Sample Bank) from healthy females and males was used to examine high-sensitivity (hs) performance of the cTnI assays. Clinical diagnosis of enrolled subjects was adjudicated by expert cardiologists and emergency medicine physicians. Assessment of temporal diagnostic accuracy including sensitivity, specificity, positive predictive value, and negative predictive value were determined at presentation and collection times thereafter. The prognostic performance at one-year after presentation to the emergency department was also performed. This design is appropriate to describe analytical characterization and clinical performance, and allows for acute myocardial infarction diagnosis and risk assessment.

Background: International guidelines authored and endorsed by professional societies of cardiology, emergency medicine, and laboratory medicine are unanimous that the cutoff concentration for establishing a diagnosis of acute myocardial infarction be set at the 99th percentile of a healthy population. The establishment of the actual 99th percentile value is assay- and sample-dependent and is influenced by the population of individuals selected for testing. We created a sample bank that will enable manufacturers of troponin assays a consistent comparison of the 99th percentile., Methods: Participants were recruited from those attending the 2015 Annual Meeting of the AACC for the creation of a universal sample bank of apparently healthy individuals (free from uncontrolled diabetes, renal insufficiency, and heart disease). For those who met eligibility criteria and signed a written consent to participate, 60 mL blood was collected into 6 10-mL tubes each (2 serum, 3 heparin plasma, and 1 EDTA). Whole blood was tested for hemoglobin (Hb) A1c, and serum was tested for N-terminal pro-B-type natriuretic peptide (NT-proBNP) and creatinine., Results: There were a total of 764 individuals who consented during the AACC Annual Meeting. After this initial enrollment, it was determined that there was an insufficient number of male participants recruited. Under the same protocol and consent, blood from 131 additional males was collected at the University of Maryland. Samples were centrifuged, and 240 μL aliquots of the 2 serum, 3 heparin plasma, and 1 EDTA tubes were frozen at 70 °C within 2 h of collection. The labeled samples were divided into boxes containing 1 aliquot from each individual. Sets of these samples were made available for purchase to manufacturers of cardiac troponin assays. Eighty-eight samples were excluded from the database for having a high NT-proBNP (>300 ng/L), low estimated glomerular filtration rate (eGFR) (<60 mL/min/1.73 m2), high Hb A1c (≥6.5%), or preanalytical sample issues and consenting/data issues. The final total was 808 individuals (402 females and 406 males; 60% Caucasian, 26% African or African American, 11% Asian or Pacific Islander, and 3% other)., Conclusions: The creation of a bank of samples from healthy individuals enables a consistent comparison of the 99th percentile results from manufacturers of cardiac troponin assays., (© 2017 American Association for Clinical Chemistry.)

Background: Copeptin has demonstrated a role in early rule out for acute myocardial infarction (AMI) in combination with a negative troponin. However, management of patients with chest pain with a positive copeptin in the setting of a negative troponin is unclear., Methods: The multicentre CHOPIN trial enrolled 2071 patients with acute chest pain. Of these, 476 subjects with an initial negative troponin but an elevated copeptin (>14 pmol/L) were included in this study. Copeptin and troponin levels were rechecked at 2 h and the final diagnosis of AMI was made by two independent, blinded cardiologists. Follow-up at 30 days was obtained for major adverse cardiac events (MACEs), including death, AMI and urgent revascularisation., Results: Of the 476 patients analysed, 365 (76.7%) had a persistently elevated copeptin at 2 h and 111 patients (23.3%) had a copeptin that fell below the cut-off of 14 pmol/L. When the second copeptin was elevated there were 18 AMIs (4.9%) compared with 0 (0%) when the second copeptin was negative (p=0.017), yielding a negative predictive value of 100% (95% CI 96.7% to 100%). On 30-day follow-up there were 36 MACEs (9.9%) in the positive second copeptin group and 2 (1.8%) MACEs in the negative second copeptin group (p=0.006)., Conclusions: Patients with chest pain with an initial negative troponin but positive copeptin are common and carry an intermediate risk of AMI. A second copeptin drawn 2 h after presentation may help risk stratify and potentially rule out AMI in this cohort., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Objectives: Pregnancy Associated Plasma Protein A (PAPP-A)-derived N- and C-terminal fragments of IGF-binding protein-4 (NT- and CT-IGFBP-4) released from vulnerable atherosclerotic plaques are proposed to be used for cardiovascular risk assessment., Design and Methods: NT- and CT-IGFBP-4 were measured by novel immunoassays in EDTA-plasma of 180 patients admitted to the emergency department with symptoms of myocardial ischemia but without ST-segment elevation. Six-month incidence of major adverse cardiac events (MACE), including myocardial infarction, cardiac death, percutaneous coronary interventions, and coronary artery bypass grafting was recorded., Results: Sixteen patients met the endpoint. NT- and CT-IGFBP-4 were strong predictors of MACE: area under ROC curve (AUC) 0.856 and 0.809, respectively. NT-IGFBP-4 concentrations≥214μg/L and CT-IGFBP-4 concentrations≥124μg/L were associated with increased risk of future MACE: adjusted hazard ratio 13.79 and 7.93, respectively., Conclusions: IGFBP-4 fragments can be utilized as biomarkers for MACE prediction in patients with suspected myocardial ischemia., (Copyright © 2012 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Background and Objective: Discrepancies between serum and heparin plasma samples have been described for many commercial troponin assays including the cardiac troponin T (cTnT) assay. Using the current 3rd generation Elecsys Troponin T immunoassay, heparin plasma cannot be recommended for the determination of cTnT due to systematic lower test results caused by a direct interference of the immunoassay by heparin. The purpose of the multicenter study was to evaluate the analytical performance of an improved 4th generation Elecsys Troponin T immunoassay with a special focus on the comparability of cTnT results determined in heparin plasma and serum., Methods and Results: The multicenter evaluation was performed in 10 clinical laboratories according to a standardized protocol (Roche Diagnostics, Penzberg, Germany, Study No. B05P008). The Elecsys Troponin T immunoassay was performed on the Modular Analytics E170 and Elecsys 2010 systems. Intraassay imprecision (n = 21) and total imprecision (2 runs/d, 10 days, triplicate measurements) were evaluated using 2 commercial controls (Roche Diagnostics) and 6 different serum pools (cTnT: 0.0140 - 4.102 microg/L). Intraassay CVs ranged from 0.73 to 3.22%. Total imprecision CVs ranged from 3.61 to 35.45% (cTnT < 0.1 microg/L) and 1.82 to 9.09% (cTnT > 0.1 microg/L), respectively. The cut-off for myocardial necrosis was determined to be 0.03 microg/L using the 10% total imprecision CV criteria. Linearity was assessed by serial dilutions of 6 different serum samples using cTnT negative serum pools. Linearity was proven up to 21.3 microg/L (recoveries: 90% - 110%). Regression data of all comparison studies were calculated according to the method of Passing and Bablok. The method comparison between the 4th generation and the commercially available cTnT immunoassay showed highly similar results across the whole measuring range (0.01 - 25.0 microg/L): y = 1.024x -0.001, r = 0.998; n = 988. Using the commercially available cTnT reagent, the serum to heparin plasma comparison yielded a systematic bias to approximately 8% lower cTnT results in heparin plasma. However, suitable comparability was obtained using the 4th generation Elecsys cTnT assay. The regression analysis (serum vs. heparin plasma) across the studied measuring range (cTnT: 0.01 - 14 microg/L) yielded the following equation: y = 0.975x + 0.001; r = 0.986; n = 403. However, rare individual serum to matched heparin plasma samples still yielded poor comparability (deviation > 20%) using the 4th generation Elecsys Troponin T immunoassay., Conclusion: Our data confirm an excellent analytical performance of the improved troponin T immunoassay. Most importantly, no systematic bias between cTnT results determined in serum and heparin plasma was observed from data obtained in 7 evaluation sites. The performance of the 4th generation Elecsys Troponin T assay is therefore comparable to other commercially available troponin immunoassays. Further studies are necessary to investigate the cause of poor comparability of cTnT results in rare individual serum to matched heparin plasma samples.

This purpose of this study was to determine the relationships between postmortem free morphine and total morphine levels in a large series of medical examiner morphine and heroin related deaths. Free morphine, total morphine, and 6-monoacetylmorphine (6-MAM) concentrations were measured by gas chromatography-mass spectrometry (GC-MS) in 87 medical examiner cases over 20 months. The mean total morphine concentration, mean free morphine concentration, and mean percent free morphine for all cases were: 2.3 mg/L (SD 5.2 mg/L), 0.5 mg/L (SD 1.6 mg/L), and 19.4% (SD 22.8%); respectively. Regression analyses showed weak correlations between total and free morphine concentrations over the entire concentration range (0 to 36.6 m/L, r = 0.603, n = 91) and over a subset concentration range of 0 to 1.0 mg/L (r = 0.369, n = 54). Twenty-three out of 56 (41%) tested positive for 6-MAM, indicative heroin abuse cases. Lower total and free morphine concentrations and a higher percent free morphine were found in individuals with detectable 6-MAM. Comparing blood concentrations for cases with and without detectable 6-MAM demonstrated mean total morphine concentrations of 0.9 mg/L versus 2.1 mg/L (p = 0.05), mean free morphine concentrations of 0.3 mg/L versus 0.4 mg/L (p = 0.21), and mean percent free morphine of 34.7% versus 13.7% (p < 0.003), respectively. Our findings demonstrate higher free to total morphine ratios in individuals with detectable 6-MAM than in individuals without 6-MAM. The database established in this study may assist medical examiners in the evaluation of postmortem blood opiates regarding the cause of death in opiate related ingestion cases.

Background: Cardiac troponin I (cTnI) results vary 100-fold among assays. As a step toward standardization, we examined the performance of 10 candidate reference materials (cRMs) in dilution studies with 13 cTnI measurement systems., Methods: Solutions of 10 cTnI cRMs, each characterized by NIST, were shipped to the manufacturers of 13 cTnI measurement systems. Manufacturers used their respective diluents to prepare each cRM in cTnI concentrations of 1, 10, 25, and 50 microg/L. For the purpose of ranking the cRMs, the deviation of each cTnI measurement from the expected response was assessed after normalization with the 10 microg/L cTnI solution. Normalized deviations were examined in five formats. Parameters from linear regression analysis of the measured cTnI vs expected values were also used to rank performance of the cRMs., Results: The three cRMs demonstrating the best overall rankings were complexes of troponins C, I, and T. The matrices for these three cRMs values differed; one was reconstituted directly from the lyophilized form submitted by the supplier; one was submitted in liquid form, lyophilized at NIST, and subsequently reconstituted; and the third was evaluated in the liquid form received from the supplier. The cRM demonstrating the fourth best performance was a binary complex of troponins C and I supplied in lyophilized form and reconstituted before distribution., Conclusions: The cRMs demonstrating the best performance characteristics in 13 cTnI analytical systems will be included in subsequent activities of the cTnI Standardization Committee of the AACC.

Background: The ability of the N-terminal region of human albumin to bind cobalt is diminished by myocardial ischemia. The characteristics of an assay based on albumin cobalt binding were assessed in suspected acute coronary syndrome patients and in a control reference population. The ability of the Albumin Cobalt Binding (ACB) Test measurement at presentation to predict troponin-positive or -negative results 6-24 h later was also examined., Methods: We enrolled 256 acute coronary syndrome patients at four medical centers. Blood specimens were collected at presentation and then 6-24 h later. The dichotomous decision limit and performance characteristics of the ACB Test for predicting troponin-positive or -negative status 6 h-24 h later were determined using ROC curve analysis. Results for 32 patients could not be used because the time of onset of ischemia appeared to have been >3 h before presentation or was uncertain. The reference interval was determined by parametric analysis to estimate the upper 95th percentile of a reference population (n = 109) of ostensibly healthy individuals., Results: Increased cTnI was found in 35 of 224 patients. The ROC curve area for the ACB Test was 0.78 [95% confidence interval (CI), 0.70-0.86]. At the optimum decision point of 75 units/mL, the sensitivity and specificity of the ACB Test were 83% (95% CI, 66-93%) and 69% (95% CI, 62-76%). The negative predictive value was 96% (95% CI, 91-98%), and the positive predictive value was 33% (95% CI, 24-44%). The within-run CV of the ACB Test was 7.3%. Results for the reference population were normally distributed; the one-sided parametric 95th percentile was 80.2 units/mL., Conclusions: This exploratory study suggests that the ACB Test has high negative predictive value and sensitivity in the presentation sample for predicting troponin-negative or -positive results 6-24 h later.

A recently published consensus document from the European Society of Cardiology and American College of Cardiology emphasized the unique role cardiac troponin monitoring plays in redefining acute myocardial infarction. The cardiology community has now established criteria to define both the reference cutpoints and acceptable imprecision for troponin assays, which complement previous recommendations by the laboratory community. This article will review the analytical issues confronting laboratories, clinicians, and industry regarding troponin assay standardization, assay imprecision, and how clinical decision cutpoints should be established and implemented for clinical practice.

Human albumin has the ability to bind cobalt at the N-terminus. The exposure of circulating albumin to ischemic tissue alters the ability of albumin to bind cobalt, probably through a mechanism involving free-radical production. The Albumin Cobalt Binding (ACB) test measures the alteration in albumin metal binding, and elevation of the ACB test is thought to be an early indicator of myocardial ischemia. In a previous multicenter study of chest pain patients presenting to the emergency department (ED), this test demonstrated high negative predictive value and sensitivity in the sample collected at presentation for predicting cardiac troponin I (cTnI)-negative or cTnI-positive results 6-24 h later. Since the completion of that report, the European Society of Cardiology (ESC) and the American College of Cardiology (ACC) have redefined the criteria for the diagnosis of acute myocardial infarction (AMI). The data from the multicenter ACB study were re-examined using the new diagnostic criteria for AMI to determine if combining the ACB test with troponin improved the sensitivity of either assay used alone for early diagnosis of AMI. Assay values were compared to either the final discharge diagnosis made at each site or to a diagnosis of AMI using the strict application of the ESC/ACC guidelines. Using the criterion of physician's discharge diagnosis and using blood collected at ED presentation, the cTnI test alone had a sensitivity of 23.9%, and the ACB test alone had a sensitivity of 39.1%, but the sensitivity significantly increased to 55.9% (p < 0.001 over cTnI alone) when both tests were used in combination. The sensitivity of the combination of ACB and cTnI tests at the 1- to 6-h time-point was 86.7% and at the >6- to 12-h time-point was 93.5%, but they were not significantly improved over the cTnI test alone. In conclusion, using the new ESC/ACC criteria, the combination also resulted in a statistically significant higher diagnostic sensitivity on blood collected at presentation. These data indicate a possible role of the ACB test in the early triage of patients with chest pain.

Background: Validation of whole blood, point-of-care testing devices for monitoring cardiac markers to aid clinicians in ruling in and ruling out myocardial infarction (MI) is necessary for both laboratory and clinical acceptance., Methods: This study evaluated the clinical diagnostic sensitivity and specificity of the First Medical Cardiac Test device operated by nursing and laboratory personnel that simultaneously measures cardiac troponin I (cTnI), creatine kinase (CK) MB, myoglobin, and total CK on the Alpha Dx analyzer in whole blood for detection of MI. Over a 6-month period, 369 patients initially presenting to the emergency department with chest pain were evaluated for MI using modified WHO criteria. Eighty-nine patients (24%) were diagnosed with MI., Results: In whole blood samples collected at admission and at 3- to 6-h intervals over 24 h, ROC curve-determined MI decision limits were as follows: cTnI, 0.4 microgram/L; CKMB, 7.0 microgram/L; myoglobin, 180 microgram/L; total CK, 190 microgram/L. Based on peak concentrations within 24 h after presentation, the following sensitivities (+/- 95% confidence intervals) were found: cTnI, 93% +/- 5.5%; myoglobin, 81% +/- 9.7%; CKMB, 90% +/- 6.3%; total CK, 86% +/- 7.5%. Sensitivities were maximal at >90% for both cTnI and CKMB at >12 h in MI patients, without differences between ST-segment elevation and non-ST-segment elevation MI patients., Conclusions: The First Medical point-of-care device provides cardiac marker assays that can be used by laboratories and clinicians in a variety of hospital settings for ruling in and ruling out MI.

Background: The majority of laboratories measure total phenytoin concentration for therapeutic drug monitoring. However, there are substantial interindividual variations in free phenytoin concentrations, the pharmacologically active component., Methods: We describe the process and data used to implement monitoring of free phenytoin only in an urban medical center. Over a 6-week period, total and free phenytoin concentrations were measured, clinical charts reviewed, and indications for alterations in the percentage of free phenytoin fraction were determined., Results: Of the 189 phenytoin requests from 139 patients, 136 data points were analyzed. Free phenytoin concentrations were 6.8-35.3%, with 50% outside the expected range of 8-12%. Clinical indications likely responsible for variations were hypoalbuminemia, drug interactions, uremia, pregnancy, and age. Overall, 30% of patients demonstrated a discrepancy between therapeutic, subtherapeutic, or supratherapeutic concentrations between free and total phenytoin concentrations. The largest discordance (53%) occurred in the patient group with free phenytoin <8% or >12%., Conclusions: This study supports previous clinical findings that monitoring total phenytoin is not as reliable as free phenytoin as a clinical indicator for therapeutic and nontherapeutic concentrations. Thus, we recommend that therapeutic monitoring should use free phenytoin concentrations only.

The goal of this study was to determine whether the stress of forced exercise would result in injury to the myocardium. Male rats with 8% of body weight attached to the tail were forced to swim 3.5 h (3.5S), forced to swim 5 h (5S), or pretrained for 8 days and then forced to swim 5 h (T5S). Rats were killed immediately after they swam (0 h PS) and at 3 h (3 h PS), 24 h (24 h PS), and 48 h after they swam (48 h PS). Tissue homogenates of the left ventricle were analyzed by Western blot analysis for cardiac troponin T (cTnT). Serum cTnT was quantified by immunoassay. Results indicated that, in the 3.5S, 5S, and T5S groups, serum cTnT was significantly (P < 0.01) increased at 0 and 3 h PS. The 5S group demonstrated a greater increase in serum cTnT than the 3.5S group (P < 0.01) and the T5S group (P < 0.01) at 0 h PS. Western blot analysis indicated significant decreases (P < 0. 01) in myocardial cTnT in the 5S group only at 0 h PS (P < 0.01) and 3 h PS (P < 0.05). Histological evidence of localized myocyte damage demonstrated by interstitial inflammatory infiltrates consisting of neutrophils, lymphocytes, and histiocytes, as well as vesicular nuclei-enlarged chromatin patterns, was observed in left ventricle specimens from the 5S group at 24 and 48 h PS. Our findings demonstrate that stressful, forced exercise induces alterations in myocardial cTnT and that training before exercise attenuates the exercise-induced heart damage.

Propofol, a central-acting sedative agent, has been implicated in the development of rhabdomyolysis in children. We describe two adults who developed rhabdomyolysis after receiving high rates of propofol infusion. Rhabdomyolysis of both skeletal and cardiac muscle was suggested in both patients by marked increases of creatine kinase (>170 000 U/L) and cardiac troponin I (11 and 46 microg/L in patients one and two, respectively). Creatine kinase and cardiac troponin I values were highly correlated in each patent (r = 0.786 and 0.988 in patients one and two, respectively). Autopsy of one patient confirmed the diagnosis of skeletal and cardiac rhabdomyolysis.

A fully automated immunoassay for total plasma homocysteine assay was evaluated at four centers. To measure total homocysteine, oxidized forms of homocysteine in serum and plasma were reduced by dithiothreitol and assayed by a competitive fluorescence polarization technique. The assay had within-run precision from 0.9 to 3.0% and total precision from 2.8 to 4.1% for control materials with homocysteine concentrations of approximately 7, 12.5, and 25 micromol/L, a sensitivity of 0.35 micromol/L, good parallelism upon dilution, and analytical recovery ranging from 97.4 to 103.8%. The immunoassay correlated with four different HPLC assays for homocysteine, yielding a slope of 0.98, an intercept of -0.19 micromol/L, and a correlation coefficient of 0.966 for 440 paired samples. The reference range, determined with plasma samples from 609 males and 600 females, yielded a mean of 9.17+/-2.86 micromol/L, with a central 95% range of 4.78-15.43 micromol/L. The immunoassay is a suitable alternative to HPLC and may be useful in screening persons with high risk of coronary artery disease.

The use of postmortem cocaine and metabolite concentrations is a complex subject. This study was undertaken to determine (1) the usefulness of vitreous humor as a specimen, compared with blood, to quantitate cocaine and cocaine metabolites; (2) whether there is a preferential site of disposition for cocaethylene between vitreous humor and blood; and (3) if the presence of cocaethylene influences the concentration of benzoylecgonine in postmortem specimens. Cocaine, benzoylecgonine, and cocaethylene were quantitated in blood and vitreous humor by gas chromatography-mass spectrometry, and ethanol was quantitated by gas chromatography in 62 medical examiner cases. No differences were found between mean concentrations of vitreous cocaine 0.613 mg/L (standard deviation [SD] 0.994 mg/L), cocaethylene 0.027 mg/L (SD 0.59 mg/L), and ethanol 0.092 g/dL (SD 0.13 g/dL) compared to blood cocaine 0.489 mg/L (SD 1.204 mg/L), cocaethylene 0.022 mg/L (SD 0.055 mg/L), and ethanol 0.058 g/dL (SD 0.91 g/dL), respectively. However, a statistical difference was found between mean benzoylecgonine concentrations in vitreous 0.989 mg/L (SD 1.597 mg/L) and blood 1.941 mg/L (SD 2.912 mg/L) (p = 0.0004). Regression analysis demonstrated that linear relationships were present between concentrations of vitreous and blood cocaine (r = 0.854) and benzoylecgonine (r = 0.763). However, the correlation coefficients were lower for cocaethylene (r = 0.433) and ethanol (r = 0.343). There were variations between the concentrations of cocaine and metabolites both in terms of magnitude and also direction of change. Mean concentrations of benzoylecgonine in blood and vitreous were higher in cases where ethanol was absent, 2.593 mg/L (SD 3.195 mg/L) and 1.431 mg/L (SD 2.021 mg/L), compared to when ethanol was present, 1.199 mg/L (SD 2.396 mg/L) and 0.469 mg/L (SD 0.553 mg/L). This study demonstrates that vitreous humor may be used to quantitate cocaine and cocaine metabolites; however, because the concentrations of cocaethylene in vitreous humor and blood were not well correlated, vitreous humor may not be a reliable specimen for measuring cocaine and cocaine metabolite concentrations.

Creatine kinase (CK) isoenzymes are important structural and energy metabolism components in skeletal muscle. In this study, CK isoenzyme alterations were examined in male rats, with an 8% body mass weight attached to their tail. The rats were either forced to swim for 5 h (5S, n = 51), or were pre-trained for 8 days and then forced to swim for 5 h (T5S, n = 48). Rats were sacrificed either immediately (0 h PS), 3 h (3 h PS), or 48 h post-swimming (48 h PS). Serum CK was increased significantly (P < 0.01) 6.2- and 2.0-fold at 0 h PS following the 5S and T5S protocols, respectively. However, training (T5S protocol) significantly (P < 0.01) decreased CK release. Soleus and white gastrocnemius (WG) CK activity was significantly decreased following the 5S protocol (P < 0.05), but not following the T5S protocol. The CK-M activity of the soleus muscle was significantly (P < 0.05) decreased at 0 h PS following both the 5S and T5S protocols, and returned to control values at 3 h PS. The CK-M activity of the WG was significantly (P < 0.05) decreased at 0 h PS following the 5S protocol. Sarcomeric mitochondrial CK (sCK-Mit) was decreased significantly (P < 0.01) at 0 h PS (20%), 3 h PS (14%), 24 h PS (22%), and 48 h PS (15%) following the 5S protocol. However, sCK-Mit was decreased significantly (P < 0.01) only at 0 h PS (7%) following the T5S. The results of this study demonstrate that prolonged intense exercise causes a loss of skeletal muscle CK-M and sCK-Mit activity and that training prior to the prolonged intense exercise attenuates the exercise-induced CK-M and sCK-Mit loss in both red and white skeletal muscles.

Background: The expression of multiple cardiac troponin T (cTnT) isoforms has been demonstrated in diseased human skeletal muscle. However, cardiac troponin I (cTnI) expression has been described only in heart muscle. The goal of this study was to determine whether mRNA for cTnT, slow skeletal troponin T (sTnT), or cTnI was expressed in skeletal muscle biopsies obtained from patients with end-stage renal disease (ESRD) and Duchenne muscular dystrophy (DMD)., Methods: Total mRNA was extracted from healthy human heart (n = 4), healthy human skeletal muscle (n = 5), and skeletal muscle from patients with ESRD (n = 7) and DMD (n = 5). Total RNA (1 microg) was reverse-transcribed using Moloney murine leukemia virus reverse transcriptase. The reverse-transcribed cDNAs were amplified by PCR using oligonucleotide primers specific for cTnT, sTnT, and cTnI sequences (GenBank accession numbers X74819, m19308, and X54163, respectively)., Results: In all heart specimens, a 150-bp cTnT amplicon was detected. Skeletal muscle from four of seven patients with ESRD and two of five patients with DMD showed expression of a 150-bp amplicon. Using DNA sequencing and a comparison program, the 150-bp amplicons found in heart and diseased skeletal muscle specimens were 100% identical and specific to the cTnT mRNA sequence. No cTnT mRNA expression was found in healthy skeletal muscle. No evidence of sTnT mRNA was found in heart muscle. A 200-bp sTnT amplicon specific to a human sTnT sequence was detected in all skeletal muscle specimens. A 250-bp cTnI amplicon specific to the cTnI sequence was detected in all heart specimens. However, no cTnI mRNA expression was found in healthy or diseased skeletal muscle specimens. cTnT mRNA expression in both heart and diseased skeletal muscles corresponded with cTnT isoform expression, respectively, as determined by Western blot analysis., Conclusion: Our findings demonstrate cTnT mRNA expression, but no cTnI mRNA expression, by reverse transcription-PCR in diseased human skeletal muscle that expresses cTnT isoforms.

This paper reviews the tissue specificity of cardiac troponin I (cTnl), cardiac troponin T (cTnT) and creatine kinase (CK) MB in human and animal heart and skeletal muscles. Studies reveal that CK-MB can be expressed up to 20% of total CK activity in human skeletal muscle; and therefore is not 100% specific for the heart. One cTnl isoform has been described and shown to be 100% specific for the heart. While one to four cTnT isoforms are expressed in diseased and regenerating human skeletal muscle, these isoforms are not the same as the cTnT isoforms expressed in the human heart and are not detected by the cTnT diagnostic assays used in clinical practice. Representative cases are described demonstrating the role of monitoring cardiac troponins in blood for differentiating false positive CK-MB increases due to skeletal muscle injury. Further, sufficient reactivity and tissue specificity of cTnl and cTnT assays are demonstrated for use as markers of myocardial injury in laboratory animals. Monitoring cTnl and cTnT concentrations in the circulation appears poised as the new standards for detection of myocardial injury.

Background: Mechanisms that mediate cocaine-induced cardiovascular events following vasoconstriction are incompletely understood., Objective: To examine the effects of cocaine in moderate doses on hematologic and hemostatic parameters that influence blood viscosity and thrombotic potential., Methods: Changes in hemoglobin concentration, hematocrit, and red blood cell counts were measured in human subjects who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for long-term cocaine abuse, before and sequentially after moderate intranasal and intravenous doses of cocaine. Hemostatic parameters, including von Willebrand factor, fibrinolytic activity, fibrinogen, plasminogen activator inhibitor antigen, and tissue-type plasminogen activator antigen, were sequentially measured after intravenous cocaine or saline placebo with cardiac troponin subunits T and I., Results: Hemoglobin level (P= .002), hematocrit (P =.01), and red blood cell counts (P = .04) significantly increased from 4% to 6% over baseline from 10 to 30 minutes after intranasal (n = 14) and intravenous (n = 7) cocaine administration in doses of 0.9 mg/kg and 0.4 mg/kg, respectively, with no change in white blood cell or platelet counts. There was a significant increase (P =.03) in von Willebrand factor from 30 to 240 minutes, peaking at 40% over baseline following intravenous cocaine administration in a dose of 0.4 mg/kg (n = 12), with no change after 0.2 mg/kg (n = 3) or placebo (n = 6). Other hemostatic factors, creatinine, blood urea nitrogen, and cardiac troponin subunits T and I showed no changes., Conclusions: Cocaine induced a transient erythrocytosis that may increase blood viscosity while maintaining tissue oxygenation during vasoconstriction. An increase in von Willebrand factor without a compensatory change in endogenous fibrinolysis may trigger platelet adhesion, aggregation, and intravascular thrombosis.

Background: The AACC assembled a committee to identify and validate a standard creatine kinase MB isoenzyme (CK-MB) material to improve the comparability of CK-MB mass assays., Methods: Three protocols were used. In protocol I, various CK-MB materials prepared in different matrices were screened as candidate standards. In protocol II, participating manufacturers calibrated their systems with concentrates of human heart CK-MB and then tested 20 patient samples to evaluate calibration bias. In protocol III, participating manufacturers calibrated their immunoassay systems using recombinant CK-MB2 (rCK-MB2) diluted into their respective sample diluents and measured 50 samples., Results: Candidate materials showed high recovery in stripped human serum, but bias improved only from 59% to 38%. These data led to the use of human heart CK-MB diluted in each manufacturer's sample diluent. This strategy reduced bias from 31% to 15%. Because human heart CK-MB is difficult to provide, a lyophilized source of CK-MB2 was identified. rCK-MB2 was shown by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, reversed-phase HPLC, intrinsic protein fluorescence, circular dichroism, agarose gel electrophoresis, immunoreactivity studies, high and low temperature stability, and reconstituted stability to be equivalent to human heart CK-MB. Calibration of immunoassay systems with rCK-MB2 added into each respective manufacturer's sample diluent showed a 13% between-manufacturer bias., Conclusion: Lyophilized rCK-MB2 was determined suitable for use as a reference material for CK-MB mass assays.

The Sixth Conference on the "Standards of Laboratory Practice Series", sponsored by the National Academy of Clinical Biochemistry (NACB), was held on August 4-5, 1998, at the Annual Meeting of the American Association for Clinical Chemistry, in Chicago, IL. An expert committee was assembled to write recommendations on the use of cardiac markers in coronary artery diseases. The NACB Committee prepared a preliminary draft of the guidelines, made them available on the World Wide Web (www.nacb.org), and distributed them before the presentations. The recommendations were divided into four areas: the use of markers in the triage of patients with chest pain, acute coronary syndromes, clinical applications other than acute myocardial infarction and research, and assay platforms and markers of acute myocardial infarction. The recommendations were revised and subsequently re-presented in part at the "Biomarkers in Acute Cardiac Syndromes Conference", sponsored by the Jewish Hospital Heart and Lung Institute, Louisville KY, on October 16-17, 1998. This report lists each recommendation, its scientific justification, and a summary of discussions from conference participants and reviewers. Approximately 100 individuals responded to various versions of these recommendations via direct correspondences, telephone calls to Committee members, electronic mail correspondence to the Committee Chairman, or oral questions and comments raised during one of the two conference presentations. Some of the recommendations were changed to reflect the consensus opinion. In cases in which there was no consensus, the Committee included pertinent discussion without necessarily changing the original recommendations. At times, the Committee members felt that although a particular recommendation might not be the current standard of care today, they anticipate that it likely will be adopted in the near future.