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Background Identifying persons at risk for sudden cardiac death (SCD) is challenging. A comprehensive evaluation may reveal clues about the clinical, anatomical, genetic, and metabolic risk factors for SCD. Methods Seventy-one patients who had SCD (25-60 years old) without an initially apparent cause of death were evaluated at the Hennepin County Medical Examiner's office (Minneapolis, MN) from August 2001 to July 2004. We reviewed their clinic records conducted next-of-kin interviews and performed autopsy, laboratory testing, and genetic analysis for mutations in genes associated with the long QT syndrome. Results Mean age was 49.5 ± 7 years, 86% were male, and 2 subjects had history of coronary heart disease (CHD). Coronary risk factors were highly prevalent in comparison to individuals of the same age group in this community (eg, smoking 61%, hypertension 27%, hyperlipidemia 25%) but inadequately treated. On autopsy, 80% of the subjects had high-grade coronary stenoses. Acute coronary lesions and previous silent myocardial infarction (MI) were found in 27% and 34%, respectively. Furthermore, 32% of the subjects had recently smoked cigarettes, and 50% had ingested analgesics. Possible deleterious mutations of the ion channel genes were detected in 5 subjects (7%). Of these, 4 were in the sodium channel gene SCN5A. Conclusions Most of the persons who had SCD in the community had severe subclinical CHD, including undetected previous MI. Traditional coronary risk factors were prevalent and undertreated. Mutations in the long QT syndrome genes were detected in a few subjects. These findings imply that improvements in the detection and treatment of subclinical CHD in the community are needed to prevent SCD.

Background Studies addressing patients with type 2 myocardial infarction and myocardial injury, including the impact of using high-sensitivity (hs) cardiac troponin (cTn) assays on their incidence are needed. Methods Ours is a prospective, observational US cohort study. Consecutive emergency department patients with serial cTnI measurements were studied. Outcomes included 180-day mortality and major adverse cardiac events, including 2-year follow-up for those with myonecrosis. Results Among 1640 patients, using a contemporary cTnI assay, 30% (n = 497) had ≥1 cTnI >99 th percentile, with 4.7% (n = 77), 8.5% (n = 140), and 17% (n = 280) classified as type 1 myocardial infarction, type 2 myocardial infarction, and myocardial injury, respectively. Compared with patients without myonecrosis, 180-day mortality was higher for type 2 myocardial infarction (4% vs 13%, P P = .0005) and myocardial injury (4% vs 11%, P P = .02), both with mortality >20% at 2 years. Predictors of 2-year mortality for type 2 myocardial infarction included age, congestive heart failure, and beta-blockers. Relative to the contemporary cTnI assay, hs-cTnI had less myonecrosis (30% vs 26%, P = .003) and acute myocardial infarction (13.2% vs 10.8%, P = .032), including fewer type 2 myocardial infarctions (8.5% vs 6.3, P = .01), with no difference in myocardial injury (17% vs 15%, P = .1). Conclusions cTnI increases are encountered in approximately a third of patients, the majority due to nonatherothrombotic conditions. Compared with patients without myonecrosis, type 2 myocardial infarction and myocardial injury have worse short-term outcomes, with mortality rates >20% at 2 years. hs-cTnI assay does not lead to more myocardial injury or infarction.

Cardiac troponins (cTns) are established biomarkers of ischemic heart disease in humans. However, their value as biomarkers of cardiac injury from causes other than ischemic heart disease is now being explored, particularly in drug development. In a workshop sponsored by the Cardiac Troponin Biomarker Working Group of the Health and Environmental Sciences Institute, preclinical, clinical, and regulatory scientists discussed the application of cTns in their respective environments, issues in translating the preclinical application of cTn to clinical studies, and gaps in our understanding of cTn biology and pathobiology. Evidence indicates that cTns are sensitive and specific biomarkers of cardiac injury from varying causes in both animals and humans. Accordingly, monitoring cTns can help ensure patient safety during the clinical evaluation of new drugs. In addition, preclinical characterization of cardiac risk and cTns as biomarkers of that risk can guide relevant clinical application and interpretation. We summarize here the outcomes of the workshop which included consensus statements, recommendations for further research, and a proposal for a cross-disciplinary group of clinical, regulatory, and drug development scientists to collaborate in such research.

Background: We sought to determine the diagnostic accuracy of the cardiac troponin I (cTnI) VITROS® Troponin I-ES assay for early detection of acute myocardial infarction (AMI) and for risk prediction of adverse events in patients with symptoms of acute coronary syndrome (ACS). Methods: cTnI was measured on admission and approximately 6 h postadmission in 381 patients. The 99th percentile cTnI concentration (0.034 μg/L) and change [delta (δ)] between admission and follow-up concentrations were evaluated in diagnostic sensitivity and specificity calculations. Risk of cardiac event or death within 60 days was evaluated by Cox proportional hazards regression. Results: AMI occurred in 52 patients. Diagnostic sensitivities (95% CI) of admission and follow-up cTnIs for AMI were 69% (55%–81%) and 94% (84%–99%), respectively. The corresponding specificities (95% CI) were 78% (73%–82%) and 81% (77%–85%), and ROC curve areas were 0.82 vs 0.96 (P < 0.001). Deltas between admission and follow-up cTnI >30% had a sensitivity of 75% (95% CI 61%–86%) and a specificity of 91% (95% CI 87%–94%). During follow-up, 1 cardiac death, 2 noncardiac deaths, 52 AMIs, 6 coronary artery bypass grafts, and 43 percutanous coronary interventions occurred in 62 patients. A δ cTnI >30%, when added to either initial cTnI >0.034 μg/L or follow-up cTnI >0.034 μg/L, improved risk stratification for cardiac event or death (P < 0.001). Conclusions: Admission cTnI measured by the VITROS ES assay is a sensitive biomarker for detection of AMI. Utilizing >30% cTnI δ in addition to either the baseline or follow-up concentration improved both specificity and risk assessment in patients presenting with symptoms of ACS.

Background: Cardiac troponin is the preferred biomarker for detecting acute myocardial injury and infarction (MI). We studied whether multiple biomarkers of numerous pathophysiological pathways would increase the diagnostic accuracy for detecting MI. Methods: Seven biomarkers [myeloperoxidase, soluble CD40 ligand, placental growth factor, matrix metalloproteinase 9 (MMP-9), high-sensitivity C-reactive protein (hsCRP), cardiac troponin I (cTnI), N-terminal pro–B-type natriuretic peptide] and estimated glomerular filtration rate were measured in 457 patients presenting on admission with symptoms suggestive of acute coronary syndrome. Twenty-five patients (5.4%) received MI diagnoses. Clinical sensitivities and specificities were evaluated from 99th-percentile reference values. Forward and backward stepwise logistic regression modeling techniques were used to identify biomarkers that were independently predictive of MI. Results: Biomarker sensitivities ranged from 20% to 96%, and specificities ranged from 19% to 89%. MMP-9 had the highest sensitivity, but its specificity was 19%. cTnI demonstrated a sensitivity of 72% (95% CI, 51%–88%) and a specificity of 89% (95% CI, 85%–92%). In multivariate models, cTnI (P < 0.001) and either hsCRP (P = 0.009) or MMP-9 (P = 0.03) were independently predictive of MI. Addition of hsCRP or MMP-9 increased the specificity to 95% (95% CI, 92%–97%) or 91% (95% CI, 88%–94%), respectively, but reduced the sensitivity to 56% (95% CI, 35%–76%) and 68% (95% CI, 47%–85%) relative to cTnI alone. Conclusions: Our findings indicate that the most clinically accurate biomarker for the early diagnosis of MI is the use of cTnI alone, rather than a multiple-biomarker approach, when an analytically robust cardiac troponin assay based on the 99th percentile is used.

Heart blood free oxycodone concentrations in oxycodone-related and mixed drug overdose deaths were compared with those found incidentally at autopsy in medical examiner cases. Between 2000 and 2005, 67 oxycodone-positive postmortem cases were identified. Thirty of 67 cases (44.8%) were determined to be drug overdoses. Oxycodone alone was responsible for 7 of the 30 (23.3%) overdose deaths. Mean (median) oxycodone concentrations were 1.060 mg/L (0.824 mg/L) with a range of 0.270-3.390 mg/L. Three cases were accidents, three were suicides, and one was undetermined. The remaining 23 were mixed drug overdoses. Mean (median) oxycodone concentrations in these cases were 0.820 mg/L (0.470 mg/L) with a range of 0.014-3.800 mg/L. Sixteen mixed drug overdoses were accidental, and seven were suicidal. Where oxycodone was an incidental finding, 24 were natural, 6 accident, 4 suicide, 1 homicide, and 2 undetermined. The mean (median) concentrations in the incidental finding group were 0.330 mg/L (0.150 mg/L) with a range of 0.017-1.300 mg/L. In conclusion, the findings substantiate the considerable overlap that exists with blood oxycodone concentrations in cases where oxycodone alone was determined to be the cause of death compared with mixed drug overdoses and incidental findings. Free oxycodone concentrations in postmortem cases must be interpreted in the context of the deceased's past medical history and autopsy findings.

Cardiac troponin provides diagnostic and prognostic information in acute coronary syndromes, but its role in acute decompensated heart failure is unclear. The purpose of our study was to describe the association between elevated cardiac troponin levels and adverse events in hospitalized patients with acute decompensated heart failure.We analyzed hospitalizations for acute decompensated heart failure between October 2001 and January 2004 that were recorded in the Acute Decompensated Heart Failure National Registry (ADHERE). Entry criteria included a troponin level that was obtained at the time of hospitalization in patients with a serum creatinine level of less than 2.0 mg per deciliter (177 micromol per liter). A positive troponin test was defined as a cardiac troponin I level of 1.0 microg per liter or higher or a cardiac troponin T level of 0.1 microg per liter or higher.Troponin was measured at the time of admission in 84,872 of 105,388 patients (80.5%) who were hospitalized for acute decompensated heart failure. Of these patients, 67,924 had a creatinine level of less than 2.0 mg per deciliter. Cardiac troponin I was measured in 61,379 patients, and cardiac troponin T in 7880 patients (both proteins were measured in 1335 patients). Overall, 4240 patients (6.2%) were positive for troponin. Patients who were positive for troponin had lower systolic blood pressure on admission, a lower ejection fraction, and higher in-hospital mortality (8.0% vs. 2.7%, P0.001) than those who were negative for troponin. The adjusted odds ratio for death in the group of patients with a positive troponin test was 2.55 (95% confidence interval, 2.24 to 2.89; P0.001 by the Wald test).In patients with acute decompensated heart failure, a positive cardiac troponin test is associated with higher in-hospital mortality, independently of other predictive variables. (ClinicalTrials.gov number, NCT00366639 [ClinicalTrials.gov].).

Introduction Brain natriuretic peptide (BNP) is produced by the ventricles of the heart and is a biomarker for heart failure. Several commercial assays are now available. We evaluated the performance characteristics of the ARCHITECT® BNP assay. Methods We evaluated the limit of blank, limit of detection, linearity and imprecision. Method comparison studies were performed with 3 other automated BNP assays including the ADVIA Centaur®, AxSYM®, and UniCel DxI® 800 methods. Results The mean LOB and LOD of the Architect assay were 3.5 and 5.8 ng/L, respectively. Imprecision studies yielded within run CVs of 1.1 to 5.1% and total CVs of 2.3 to 5.3% using human plasma based multi-constituent controls at concentrations of 92, 500, and 3500 ng/L. The maximum deviation from the target recovery for dilution linearity was 9.6%. Concordance with other BNP assays at a 100 ng/l cutoff was 91 to 98% and κ statistics were 0.78 to 0.96. The mean difference between the Architect and Advia Centaur methods was positive. For the other methods, the mean difference with the Architect was negative. Conclusions The Architect BNP assay shows good performance characteristics with total imprecision ≤ 5.3%. It agrees well with the Advia Centaur, AxSYM, and UniCel DxI BNP assays.

We demonstrate the performance of the bioMérieux VIDAS Troponin I Ultra assay for diagnostic accuracy for detection of myocardial infarction (MI) and risk stratification.cTnI was measured in 545 patients from 2 clinical centers with symptoms suggestive of ACS at admission, with an additional specimen at 4-12 h (453 patients). The 99th percentile value (0.01 microg/l) was used to assess clinical accuracy for diagnosis of acute MI. Primary endpoint for risk stratification was first of cardiac event or death in 302 patients (one center) followed for 60 days.157 (28.8%) patients ruled in for an MI during index hospitalization. Sensitivities and specificities were 88.1% (95% CI 81.9 to 92.4%) and 79.9% (CI 75.5 to 83.6%) for baseline and 100% (CI 96.5 to 100%) and 79.4% (CI 74.4 to 83.4%) for follow-up specimens. ROC curve areas increased from 0.912 (CI 0.879 to 0.944) at baseline to 0.994 (CI 0.988 to 0.999) at second sampling (n=453, p0.01); with no differences between sites. Primary endpoint rate for the 223 patients (74%) with normal cTnI on presentation was lower than the 79 patients (26%) with cTnI0.01 ug/l (5.9% vs. 42.3%, p0.0001). The relative risk for the0.01 ug/l group was 8.9 (CI 4.6 to 17).The VIDAS cTnI assay is a sensitive diagnostic method for the early detection of MI and predicts increased risk for adverse events in patients with symptoms suggestive of ACS.

Aims The predictors and outcomes of patients with a peri-operative elevation in cardiac troponin I above the 99th percentile of normal following an elective vascular operation have not been studied in a homogeneous cohort with documented coronary artery disease. Methods and results The Coronary Artery Revascularization Prophylaxis (CARP) trial was a randomized trial that tested the benefit of coronary artery revascularization prior to vascular surgery. Among 377 randomized patients, core lab samples for peak cardiac troponin I concentrations were monitored following the vascular operation and the blinded results were correlated with outcomes. A peri-operative myocardial infarction (MI), defined by an increase in cardiac troponin I greater than the 99th percentile reference (> or =0.1 microg/L), occurred in 100 patients (26.5%) and the incidence was not dissimilar in patients with and without pre-operative coronary revascularization (24.2 vs. 28.6%; P = 0.32). By logistic regression analysis, predictors of MI (odds risk; 95%CI; P-value) were age >70 (1.84; 1.14-2.98; P = 0.01), abdominal aortic surgery (1.82; 1.09-3.03; P = 0.02), diabetes (1.86; 1.11-3.11; P = 0.02), angina (1.67; 1.03-2.64; P = 0.04), and baseline STT abnormalities (1.62; 1.00-2.6; P = 0.05). At 2.5 years post-surgery, the probability of survival in patients with and without the MI was 0.73 and 0.84, respectively (P = 0.03, log-rank test). Using a Cox proportional hazards regression analysis, a peri-operative MI in diabetic patients was a strong predictor of long-term mortality (hazards ratio: 2.43; 95% CI: 1.31-4.48; P Conclusion Among patients with coronary artery disease who undergo vascular surgery, a peri-operative elevation in cardiac troponin levels is common and in combination with diabetes, is a strong predictor of long-term mortality. These data support the utility of cardiac troponins as a means of stratifying high-risk patients following vascular operations.

Measurement of amino-terminal pro-B-type natriuretic peptide (NT-proBNP) is useful for evaluating patients with heart failure (HF).We evaluated the performance of a new automated NT-proBNP assay.The VITROS NT-proBNP assay had mean within-run and total imprecision of 1.0% and 3.4% at NT-proBNP concentrations from 67-27,500 ng/l. Acceptable linearity, functional/analytical sensitivity were demonstrated. Anticoagulant/tube types had no effect on results. Excellent sample stability and no high-dose hook were observed. High correlation between the VITROS and Elecsys methods was demonstrated (r=0.995; P.001), with 98.3% clinical concordance. VITROS NT-proBNP concentrations were significantly higher in HF subjects than those without (1210 versus 68 ng/l; P.001) and associated with HF symptom severity (P.001). The VITROS assay had AUC for HF of 0.95 (P.001), and had excellent NPV for excluding HF.The automated VITROS NT-proBNP assay demonstrates excellent analytical and clinical performance for evaluating the presence and severity of HF.

Guidelines for the preanalytical, analytical, and postanalytical phases of cardiac biomarker testing at point of care (POC) are presented. At initiation, stakeholders including emergency medicine, cardiology, primary care, and laboratory medicine should work collaboratively to develop system

Myocardial infarction is a major cause of death and disability worldwide. Coronary atherosclerosis is a chronic disease with stable and unstable periods. During unstable periods with activated inflammation in the vascular wall, patients may develop a myocardial infarction. Myocardial infarction may be a minor event in a lifelong chronic disease, it may even go undetected, but it may also be a major catastrophic event leading to sudden death or severe hemodynamic deterioration. A myocardial infarction may be the first manifestation of coronary artery disease, or it may occur, repeatedly, in patients with established disease. Information on myocardial infarction attack rates can provide useful data regarding the burden of coronary artery disease within and across populations, especially if standardized data are collected in a manner that demonstrates the distinction between incident and recurrent events. From the epidemiological point of view, the incidence of myocardial infarction in a population can be used as a proxy for the prevalence of coronary artery disease in that population. Furthermore, the term myocardial infarction has major psychological and legal implications for the individual and society. It is an indicator of one of the leading health problems in the world, and it is an outcome measure in clinical trials and observational studies. With these perspectives, myocardial infarction may be defined from a number of different clinical, electrocardiographic, biochemical, imaging, and pathological characteristics. In the past, a general consensus existed for the clinical syndrome designated as myocardial infarction. In studies of disease prevalence, the World Health Organization (WHO) defined myocardial infarction from symptoms, ECG abnormalities, and enzymes. However, the development of more sensitive and specific serological biomarkers and precise imaging techniques allows detection of ever smaller amounts of myocardial necrosis. Accordingly, current clinical practice, health care delivery systems, as well as epidemiology and clinical trials all require a …

NT-proBNP measurements aid in the evaluation of patients with suspected heart failure (HF) and may facilitate risk stratification in patients with HF and acute coronary syndrome (ACS). Point-of-care (POC) assays may provide more timely results and potentially improve patient outcomes.We evaluated the analytical performance of the Response Biomedical Corporation whole blood RAMP amino-terminal pro-B type natriuretic peptide (NT-proBNP) POC assay compared to the Roche Elecsys proBNP (NT-proBNP) assay.Intra-day and total imprecision (% CV) ranged from 5.5% to 10.3% at 140, 449 and 1675 ng/L. The lowest concentration that yields a 20% CV was 57 ng/L. The lower limit of detection was 18 ng/L. The upper limit of linearity was validated to 23,428 ng/L with an average recovery of 95%. Correlation by Passing and Bablok regression yielded RAMP=1.01 Elecsys+14.6, r=0.98 (n=540; range of Elecsys values5 to35,000). Concordance of RAMP versus Elecsys using cut-offs of 125 ng/L for subjects75 years and 450 ng/L for subjectsor =75 was 92% (95% CI 89-94%) for a group consisting of 127 apparently healthy individuals and 208 non-healthy subjects without HF, and 99% (95% CI 97-100%) for patients with HF, using the New York Heart Association (NYHA) functional classification. Overall, 80%, 87%, 97% and 100% of the RAMP results and 77%, 85%, 96% and 100% of the Elecsys results were greater than the age appropriate cut-off for NYHA I, II, III or IV groups. For both the RAMP and Elecsys results, the median NT-proBNP value was statistically correlated (increasing) with NYHA I, II, III or IV groups, respectively (p0.0001), with no significant difference between the two methods.The POC Response Biomedical RAMP NT-proBNP assay provides comparable results that measured on the FDA cleared Roche Elecsys central laboratory platform.

[Graphic][1] Myocardial infarction is a major cause of death and disability worldwide. Coronary atherosclerosis is a chronic disease with stable and unstable periods. During unstable periods with activated inflammation in the vascular wall, patients may develop a myocardial infarction. Myocardial infarction may be a minor event in a lifelong chronic disease, it may even go undetected, but it may also be a major catastrophic event leading to sudden death or severe haemodynamic deterioration. A myocardial infarction may be the first manifestation of coronary artery disease, or it may occur, repeatedly, in patients with established disease. Information on myocardial infarction attack rates can provide useful data regarding the burden of coronary artery disease within and across populations, especially if standardized data are collected in a manner that demonstrates the distinction between incident and recurrent events. From the epidemiological point of view, the incidence of myocardial infarction in a population can be used as a proxy for the prevalence of coronary artery disease in that population. Furthermore, the term myocardial infarction has major psychological and legal implications for the individual and society. It is an indicator of one of the leading health problems in the world, and it is an outcome measure in clinical trials and observational studies. With these perspectives, myocardial infarction may be defined from a number of different clinical, electrocardiographic, biochemical, imaging, and pathological characteristics. In the past, a general consensus existed for the clinical syndrome designated as myocardial infarction. In studies of disease prevalence, the World Health Organization (WHO) defined myocardial infarction from symptoms, ECG abnormalities, and enzymes. However, the development of more sensitive and specific serological biomarkers and precise imaging techniques allows detection of ever smaller amounts of myocardial necrosis. Accordingly, current clinical practice, health care delivery systems, as well as epidemiology and clinical trials all require a … [1]: /embed/inline-graphic-1.gif

Background: Peptides derived from brain natriuretic peptide (BNP) precursor (proBNP), BNP, and the N-terminal fragment of proBNP (NT-proBNP) are used as biomarkers of heart failure. It remains unclear which forms of these peptides circulate in blood and which forms are measured by assays for these natriuretic peptides. Methods: To design assays for immunodetection of proBNP, NT-proBNP, and BNP, we used a panel of BNP- and NT-proBNP–specific monoclonal antibodies (MAbs). All MAbs were tested in 2-site combinations in time-resolved fluoroimmunoassays with recombinant or synthetic antigens and plasma from heart failure (HF) patients. ProBNP and related molecules were assayed in HF plasma samples and plasma extracts by means of gel filtration fast protein liquid chromatography (FPLC) before and after protein fractionation on Sep-Pak C18 cartridges. Results: The limits of detection for BNP, proBNP, and NT-proBNP assays were 0.4, 3, and 10 ng/L, respectively. Gel filtration-FPLC studies revealed 1 peak of NT-proBNP (∼25 kDa), 1 peak of proBNP (∼37 kDa), and 2 peaks of BNP immunoreactivity, a major peak (∼37 kDa) for proBNP, and a minor peak (∼4 kDa) for BNP. In patient plasma, the molar concentration of NT-proBNP was almost 10 times that of proBNP. The mean proBNP:BNP ratio in patient plasma was 6.3, ranging from 1.8 to 10.8. Conclusions: ProBNP is the major BNP-immunoreactive form in human blood. The proBNP:BNP ratio in plasma samples is dependent on the methods used for sample handling and for the measurement of the peptides.

Cardiac troponin (cTn) assays were compared in 490 unselected patients with symptoms suggestive of acute coronary syndrome with varying renal functions for risk stratification. cTnI (Dade, Newark, NJ; Beckman, Chaska, MN; and Tosoh, South San Francisco, CA) and cTnT (Roche, Indianapolis, IN) measurements and estimated glomerular filtration rates (eGFRs) were obtained and classified along sex-derived cutoffs. The cTn levels were increased in 14% to 25% of patients. In 68%, the eGFR was 60 mL/min/1.73 m2 or more; in 17%, it was between 41 and 59; and in 15%, it was 40 or less. There were 36 deaths and 9 cardiac events. Risk stratification was significant at 30 days and 6 months (Por = .05). Relative risks ranged from 3.1 to 3.7, and cumulative event rates ranged from 22.4% to 24.2% for an increased troponin level compared with 6.7% to 8.9% for a normal level. The 6-month event rate with an eGFR less than 60 mL/min/1.73 m2 and an increased troponin level ranged from 29.9% to 50.8% compared with 4.9% to 6.6% for a normal troponin level and an eGFR greater than 60 mL/min/1.73 m2 (P.05). The eGFR in combination with an increased cTn level demonstrated the most powerful stratification.

a. Background In 1999, the National Academy of Clinical Biochemistry (NACB)1 published the first standards of laboratory practice addressing analytical and clinical recommendations for use of cardiac markers in coronary artery diseases (1). The objectives were to recommend the appropriate implementation and utilization of cardiac biomarkers, specifically for cardiac troponin (cTn), which had just gained US Food and Drug Administration (FDA) clearance as a cardiac biomarker to aid in the diagnosis of acute myocardial infarction (AMI). In 2001, the IFCC Committee on Standardization of Markers of Cardiac Damage (C-SMCD) recommended quality specifications for analytical and preanalytical factors for cTn assays (2). The objectives were intended for use by the manufacturers of commercial assays and by clinical laboratories that use cTn assays. The overall goal was to establish uniform criteria so that all cTn assays could objectively be evaluated for their analytical qualities and clinical performance. These general principles can also be applied to creatine kinase MB (CK-MB) mass and myoglobin assays by use of the analytical recommendations in this document. In this report, we provide the background for establishing updated practice guidelines with recommendations addressing analytical issues for cardiac biomarkers based on 8 years of evidence-based medical and scientific observations since the publication of the initial recommendations (1). ### recommendations: analytical aspects of acs biomarkers ALL CLASS I 1. Reference decision-limits should be established for each cardiac biomarker based on a population of normal, healthy individuals without a known history of heart disease (reference population). For cardiac troponin …

a. definition of terms Acute coronary syndrome (ACS)1 refers to a constellation of clinical symptoms caused by acute myocardial ischemia (1)(2). Owing to their higher risk for cardiac death or ischemic complications, patients with ACS must be identified among the estimated 8 million patients with nontraumatic chest symptoms presenting for emergency evaluation each year in the US (3). In practice, the terms suspected or possible ACS are often used by medical personnel early in the process of evaluation to describe patients for whom the symptom complex is consistent with ACS but the diagnosis has not yet been conclusively established (1). Patients with ACS are subdivided into 2 major categories based on the 12-lead electrocardiogram (ECG) at presentation (Fig. 1⇓ ): those with new ST-segment …

Objectives These studies describe molecular forms of circulating B-type natriuretic peptide (BNP) as well as their biological activity. Background Increased circulating levels of immunoreactive BNP correlate with the severity of heart failure and are considered a sensitive biomarker. However, little is known about the molecular forms of circulating BNP and their biological activity. Methods Western blot analysis was used to characterize immunoreactive BNP species in heart failure plasma. Recombinant proBNP was assessed for reactivity in commercially available BNP assays and cell activity by cyclic guanosine monophosphate production in vascular cells. Results Heart failure plasma contained both low- (LMW-BNP) and high-molecular-weight (HMW-BNP) forms. The LMW-BNP migrated similarly to a 32-amino acid BNP standard, whereas HMW-BNP, when deglycosylated, was similar to deglycosylated recombinant proBNP. Recombinant proBNP and BNP were equally recognized by the Triage BNP assay (Biosite, San Diego, California). Furthermore, recombinant proBNP and BNP were both recognized by the Advia Centaur BNP test (Bayer Diagnostics, Tarrytown, New York), but only recombinant proBNP was recognized by the Elecsys NTproBNP assay (Roche Diagnostics, Indianapolis, Indiana). Recombinant proBNP exerted significantly less biological activity than BNP on human endothelial and vascular smooth muscle cells. Comparison of effective concentration (50%) values indicates that proBNP is 6- to 8-fold less potent than BNP in these human cells. Conclusions This study demonstrates that proBNP, constituting a substantial portion of immunoreactive BNP in heart failure plasma, possesses significantly lower biological activity than the processed 32-amino acid hormone. These results implicate a discordance in heart failure between the high circulating levels of immunoreactive BNP and hormone activity, suggesting that some patients may be in a state of natriuretic peptide deficiency.

BACKGROUND The frequency and characteristics of myocardial infarction (MI) subtypes per the Third Universal Definition of MI (TUDMI) classification system using high-sensitivity (hs) cardiac troponin assays with sex-specific cutoffs is not well known. We sought to describe the diagnostic characteristics of type 1 (T1MI) and type 2 (T2MI) MI using an hs–cardiac troponin I (hs-cTnI) assay with sex-specific cutoffs. METHODS A total of 310 consecutive patients with serial cTnI measurements obtained on clinical indication were studied with contemporary and hs-cTnI assays. Ninety-ninth percentile sex-specific upper reference limits (URLs) for the hs-cTnI assay were 16 ng/L for females and 34 ng/L for males. The TUDMI consensus recommendations were used to define and adjudicate MI based on each URL. RESULTS A total of 127 (41%) patients had at least 1 hs-cTnI exceeding the sex-specific 99th percentiles, whereas 183 (59%) had hs-cTnI within the reference interval. Females had more myocardial injury related to supply/demand ischemia than males (39% vs 18%, P = 0.01), whereas males had more multifactorial or indeterminate injury (52% vs 33%, P = 0.05). By hs-cTnI, there were 32 (10%) acute MIs, among which 10 (3%) were T1MI and 22 (7%) were T2MI. T2MI represented 69% (22 out of 32) of all acute MIs, whereas T1MI represented 31% (10 out of 32). Ninety-five patients (31%) had an increased hs-cTnI above the 99th percentile but did not meet criteria for acute MI. The most common triggers for T2MI were tachyarrhythmias, hypotension/shock, and hypertension. By contemporary cTnI, more MIs (14 T1MI and 29 T2MI) were diagnosed. By contemporary cTnI, there were 43 MIs, 14 T1MI, and 29 T2MI. CONCLUSIONS Fewer MI diagnoses were found with the hs-cTnI assay, contrary to the commonly accepted idea that hs-cTnI will lead to excessive false-positive diagnoses.

The use of biomarkers to aid diagnosis and treatment is increasing rapidly as genomics and proteomics help us expand the number of markers we can use and as an improved understanding of the pathophysiology of cardiac disease guides their use. However, as with all rapidly expanding fields, there is the risk of excessive enthusiasm unless we are circumspect about the data that guide the clinical use of these new tools. This review focuses first on how to use troponin, which at present is the best validated of the new markers, and will hopefully provide insight into how to use this biomarker more productively by distinguishing subsets of patients and by providing an understanding of the meaning of elevations in various clinical situations. The review then discusses the use as well as the knowledge gaps associated with emerging biomarkers such as B-type natriuretic peptide and C-reactive protein, which are increasingly moving toward more productive clinical use. Finally, it reflects on some of the large number of markers that are still in development.

Introduction: High-sensitivity cardiac troponin (hs-cTn) assays have not yet been FDA cleared for clinical use in the United States (US). Pending expected approval of hs-cTn assays, which will use gender-specific cutoffs (GSC), it is relevant to recognize the causes of cTn increases using hs-cTnI assays in a US population. Our purpose was to describe the frequency of distinct etiologies of hs-cTnI assay increases using GSC. Methods: Retrospective study of 310 patients with serial hs-cTnI (Abbott ARCHITECT, 99th percentiles: F:16 ng/L; M:34 ng/L) measurements. Patients with an increased hs-cTnI were adjudicated into categories according to the 3rd Universal Definition of MI. Categories included, A: primary myocardial ischemia (i.e. plaque rupture); B: injury secondary to supply/demand imbalance; C: injury not related to myocardial ischemia (i.e. cardiac contusion, ablation, shock, surgery); D: multifactorial or indeterminate myocardial injury (i.e. heart failure, critically ill, pulmonary HTN, sepsis, stroke, renal failure, pulmonary embolism); E: Unknown. Results: 127 (41%) had an increased hs-cTnI above the GSC 99th percentile, whereas 183 (59%) had a normal hs-cTnI. The most common causes of hs-cTnI increases were: a) multifactorial or indeterminate injury - 43% among all patients and 52% in males, and b) supply/demand imbalance - 39% in women (Table). Injury related to primary myocardial ischemia was present in 10% (n=13). Females had more injury related to supply/demand ischemia than males (39% vs. 18%, p=0.01), whereas males had more multifactorial or indeterminate injury (52% vs. 33%, p=0.05). Conclusions: Most increased hs-cTnI values were explained by non-plaque rupture conditions. Males tended to have hs-cTnI increases due to multifactorial/indeterminate causes, whereas in women supply/demand imbalance was the most common etiology. Investigations are needed to better understand if etiologies of myocardial injury have gender differences.

Background: Evaluation of patients who present to the hospital with a complaint of chest pain or other signs or symptoms suggestive of acute coronary syndrome (ACS) is time-consuming, expensive, and problematic. Recent investigations have indicated that increases in biomarkers upstream from biomarkers of necrosis (cardiac troponins I and T), such as inflammatory cytokines, cellular adhesion molecules, acute-phase reactants, plaque destabilization and rupture biomarkers, biomarkers of ischemia, and biomarkers of myocardial stretch may provide earlier assessment of overall patient risk and aid in identifying patients with higher risk of an adverse event. Approach and Content: The purpose of this review is to provide an overview of the pathophysiology and clinical and analytical characteristics of several biomarkers that may have potential clinical utility to identify ACS patients. These biomarkers (myeloperoxidase, metalloproteinase-9, soluble CD40 ligand, pregnancy-associated plasma protein A, choline, ischemia-modified albumin, unbound free fatty acids, glycogen phosphorylase isoenzyme BB, and placental growth factor) have demonstrated promise and need to be more thoroughly evaluated for commercial development for implementation into routine clinical and laboratory practice. Summary: Specifications that have been addressed for cardiac troponins and natriuretic peptides will need to be addressed with the same scrutiny for the biomarkers discussed in this review. They include validating analytical imprecision and detection limits, calibrator characterization, assay specificity and standardization, preanalytical issues, and appropriate reference interval studies. Crossing boundaries from research to clinical application will require replication in multiple settings and experimental evidence supporting a pathophysiologic role and, ideally, interventional trials demonstrating that monitoring single or multiple biomarkers improves outcomes.

Background: In patients with end-stage renal disease (ESRD), the ability of single and multiple biomarker monitoring to predict adverse outcomes has not been well established. This study determined the prognostic value of multiple biomarkers for all-cause death over 2 years in 399 ESRD patients.Methods: The risk of all-cause death was determined by use of multiple biomarkers based on concentrations for a reference population (normal) and cutoffs based on tertile distributions in the ESRD group. Biomarkers studied included N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein (hsCRP; Dade Behring and Roche assays), and cardiac troponin T (cTnT; Roche) and I (cTnI; Dade Behring and Beckman Coulter assays). Relative risks of death were estimated and survival curves computed.Results: A total of 101 deaths occurred during 594 patient-years of follow-up. Increased NT-proBNP concentrations were not predictive of death on the basis of the normal cutoffs. However, tertile analysis of NT-proBNP was significantly predictive of death and had a ROC area under the curve equivalent to or better than any of the other biomarkers. Biomarkers independently predictive of survival were hsCRP (P Conclusions: Although mechanisms likely vary for causation, increased plasma hsCRP, cTnT, and cTnI above the cutoffs for our reference (normal) population were all independently predictive of subsequent death in ESRD patients. Tertile analysis for NT-proBNP also demonstrated prognostic value.

Although myocardial injury can be a significant component of multiple organ dysfunction (MODS) in association with septicemia in critically ill human patients, it is as yet an undefined clinical entity in equine septicemia. With septicemia as the leading cause of death in neonatal foals, a better understanding of the pathophysiology, diagnosis and treatment of MODS will be important in further improving survival rates. We designed a prospective study to establish normal ranges for cardiac troponin I (cTnI), T (cTnT) and CKMB mass in healthy 24–48 hour old foals, as well as septicemic neonatal foals seen over a 2-year period in a teaching hospital. We also performed a comparison of these biomarkers in surviving and non-surviving septicemic foals. Sepsis was judged on the basis of the presence of any of the 3 following criteria: blood culture positive at admission, admission sepsis score ≥11, or 3 or more sites of infection during hospitalization in foals ≤14 days of age. cTnI was measured by the ACCESS® (Beckman Coulter), cTnT was measured using the Elecsys 2010® Immunoassay (Roche), and CKMB mass measurements were performed using the Elecsys 2010®. Each parameter was described using range and 95th and 50th percentile. Comparisons were made for each parameter between normal and septic foals as well as surviving and non-surviving septic foals using the non-parametric Wilcoxon's rank sum test. Significance was set at p

Background: This study determines the analytical characteristics of the i-STAT cardiac troponin I assay (cTnI; i-STAT, Princeton, NJ), a 10-min POC assay, designed to be performed at the bedside. Methods: Three different hospitals participated in a patient specimen and analytical validation study (n=186) for the i-STAT cTnI assay carried out in real time. A total of 186 whole blood specimens (lithium heparin) were collected from patients presenting with symptoms suggestive of acute coronary syndromes (ACS) for correlation studies as well as from 162 healthy subjects for reference interval determination. Factors studied included antibody specificity, detection limit, imprecision, linearity, assay specificity, sample type stability, interferences, reference limit determination and comparison vs. the Dade Stratus CS cTnI assay. Results: Total imprecision (CV) of 10% and 20% were seen at 0.09 and 0.07 Ag/l, respectively. The detection limit was 0.02 Ag/l. The 99th percentile reference limit was 0.08 Ag/l. The assay was not affected by common interferents. An equimolar response within 5% was found for reduced and phosphorylated forms of TIC and IC complexes. Regression analysis for the i-STAT cTnI between whole blood and plasma specimens and for whole blood between the i-STAT and Stratus CS cTnI assays demonstrated slopes of 1.06 and 0.89, respectively. Conclusions: The i-STAT cTnI assay is a sensitive and precise monitor of cTnI, poised for point-of-care/near bedside clinical utilization for triage, diagnostics and risk management of acute coronary syndrome patients. D 2004 Elsevier B.V. All rights reserved.

Patients with symptoms suggestive of, but at low risk for, acute coronary syndrome (ACS), who have a negative electrocardiogram (EKG) and a single normal troponin I at 6-9 h after symptom onset are frequently discharged from our Emergency Department (ED). We sought to determine their rate of adverse cardiac events at 30 days (ACE-30), defined as cardiac death or myocardial infarction (MI), by chart review, telephone interview, or county death records. Of 663 patients, data were available for 588 (89%). Mean age was 48 years; 59% were male. There were 390 patients (66%) who complained of chest pain. Previous coronary artery disease (CAD) was reported in 145 patients (25%). Two patients (0.34%) had ACE-30, both with non-ST elevation MI. There were no cases of cardiac death. None of the patients died in Hennepin County within 30 days. At our institution, low-risk patients with symptoms suggestive of ACS who are discharged home after a normal cTnI drawn 6-9 h after symptom onset have a very low incidence of cardiac events at 30 days.

Monitoring increased plasma unbound free fatty acid (FFAu) concentrations has been proposed as a biomarker for myocardial ischemia. In the current study, 30 acute coronary syndrome (ACS) patients presenting in the emergency department, with chest pain within 12 h of onset, were clinically evaluated along with serial cardiac troponin I (cTnI) and FFAu measurements. Increased FFAu were found in 28 of 30 (93%) of ACS patients, ranging from 2.0 to 430 nM. For the nine ACS patients with myocardial infarction (MI), FFAu levels were increased at presentation for all (100%). In contrast, cTnI was increased in only 9 of 30 (30%) patients, mean 0.7 μg/L, and in only 2 of 9 (22%) MI patients, mean 1.3 μg/L. During the 24 h following admission, cTnI increased in all 9 MI patients. FFAu concentrations increased in every sample in which cTnI increased. Our findings suggest that FFAu is increased in ischemia regardless of the presence or absence of myocardial necrosis, as reflected by increased or normal cTnI, respectively.

The tissue specificity of creatine kinase (CK-MB) has been shown not to be absolute for the myocardium. Unexplained increases of plasma creatine kinase (CK-MB) occur in patients with skeletal muscle disease, confounding the diagnosis of myocardial injury. The purpose of this study was to examine the expression of CK-B as well as of the nuclear regulatory factor MyoD by Western blot and reverse transcriptase-polymerase chain reaction (RT-PCR) techniques in skeletal muscle biopsies obtained from end-stage renal disease (ESRD) patients. Quantitation of CKMB mass demonstrated a 35-fold greater concentration in skeletal muscle from ESRD patients (n=45) vs normal skeletal muscles (n=10), (p

The analytic accuracy and precision for measurement of chemical analytes in vitreous humor (VH) are critical if results are to be used in forensic pathology. The purpose of our study was to demonstrate the stability and the reproducibility of VH sodium, potassium, chloride, glucose, urea nitrogen, acetone, and beta-hydroxybutyrate in specimens obtained from both eyes in medical examiner cases. We also compared with calculated VH osmolalities. Small but significant increases were observed in VH electrolyte concentrations in specimens refrigerated 6-12 months: sodium pre 144 mmol/L, post 151 mmol/L; potassium pre 12.0 mmol/L, post 12.8 mmol/L; chloride pre 121 mmol/L, post 123 mmol/L. No differences were observed between eyes, and within-day precision for all electrolyte measurements were excellent, (

Eight million patients with chest pain present annually to emergency departments (ED).1 Five million of this group are judged to have suspected acute coronary syndromes (ACS) and are admitted to the hospital. Less than half ultimately are found to have a cardiac diagnosis, causing costly, unnecessary admissions. Three million of this group are discharged from the ED each year, and 40,000 of these are inadvertently discharged as myocardial infarctions (MI). Mortality rates of missed diagnoses in patients sent home are 2-fold greater than those patients admitted. Thus, there is a considerable amount of clinical interest and research to identify markers of myocardial ischemia that could be monitored during the early, reversible stage of ACS to assist in the appropriate triage of patients presenting with symptoms suggestive of ACS. CE update [chemistry | molecular diagnostics] Ischemia Modified Albumin Measured by the Albumin Cobalt Binding Test: A Clinical and Analytical Review

Background : Brain natriuretic peptides (BNPs) are useful in the assessment of heart failure, left ventricular dysfunction, and acute coronary syndromes. Methods : We performed a multicenter evaluation of the automated Roche NT-proBNP assay and compared its performance to the Biosite Triage BNP assay. Results : The N-terminal (1–76) pro brain natriuretic peptide (NT-proBNP) method is precise (CV≤6.1%), has a wide dynamic measuring range (30–35,000 ng/l), is free from common interferences, and does not cross-react with BNP. EDTA or heparinized plasma samples collected in glass or plastic tubes can be used, and samples are stable at room temperature or 4 °C for up to 3 days. In contrast, the Biosite BNP assay has >2-fold higher CV, and plasma samples are more labile when stored at room temperature and 4 °C. Comparison studies showed a reasonable correlation between NT-proBNP and BNP assays, with a substantially higher slope bias of 6–20 for the NT-proBNP assay. Conclusions : The automated Roche NT-proBNP assay has good analytical performance and better precision than the Biosite BNP assay. Unlike BNP, NT-proBNP is stable in EDTA plasma for 3 days at room temperature or longer at 4 °C. The Roche NT-proBNP is fully automated and will accommodate the testing of large numbers of clinical samples for assessing cardiac dysfunction.

Background: The European Society of Cardiology/American College of Cardiology (ESC/ACC) consensus document for definition of myocardial infarction (MI) is predicated on increased cardiac troponin or creatine kinase (CK) MB mass above the 99th percentile reference limit. The purpose of this study was to determine the plasma (heparin) 99th percentile reference limits for the leading in vitro diagnostic cardiac troponin and CKMB mass assays. Methods: Blood (heparin plasma) was obtained from healthy adults (n = 696; age range, 18–84 years) stratified by gender and ethnicity. Cardiac troponin I (cTnI) and T (cTnT) and CKMB mass concentrations were measured by eight assays. Reference limits were determined by nonparametric statistical analysis. Results: Two cTnI assays demonstrated at least a 1.2- to 2.5-fold higher 99th percentile for males vs females, with the mean concentrations significantly higher for males (P Conclusions: The heparin-plasma 99th percentile reference limits for cardiac troponin and CKMB mass provide an evidence base in support of the ESC, ACC, and American Heart Association guidelines for detection of myocardial injury. Selective gender and ethnic differences were demonstrated. These data allow clinicians, trialists, and epidemiologists a common point for operational use.

We evaluated the risk assessment value of a commercial cardiac troponin (cTn; Ortho Vitros ECi, Ortho-Clinical Diagnostics, Raritan, NJ) I assay in patients with symptoms of myocardial ischemia suggestive of acute coronary syndrome and compared findings with those for a commercial cTnT assay in the same population. The cTn levels were measured by both assays in plasma samples from 273 patients during 24 hours after admission. Baseline and maximum concentrations were used for risk stratification; cutoffs were the 99th percentile and 10% coefficient of variation. End points were all-cause death and cardiac events within 60 days. Relative risks (RRs) were estimated using Cox proportional hazards regression models and Kaplan-Meier curves. RRs of cardiac events and death were significantly higher with increased baseline and maximum concentrations using either cTnI cutoff. The respective mortality rates for baseline cTnI of more than 0.08 μg/L vs 0.08 μg/L or less were 17.4% vs 2.9% ( P = .001); cardiac event rates were 11.5% vs 3.6% ( P = .03). Exclusion of patients with ST-segment elevation had no significant effect on rates for either assay. Mortality was higher in the intermediate (0.09–0.2 μg/L) than in the low (≤0.08 μg/L) group for cTnI, with directionally similar results for cTnT. Our findings validate the Ortho cTnI assay as a risk stratification biomarker in patients with symptoms of myocardial ischemia.

Background: Cardiac troponins T (cTnT) and I (cTnI) are proven diagnostic and risk stratification biomarkers in patients with acute coronary syndromes. To date, no immunohistochemical studies have been performed which allow visualization of the time course and pattern of myocardial troponin egress from the myocardium during the early evolution of ischemic injury in experimental systems. Methods: We studied archival formalin-fixed, paraffin-embedded myocardium from 50 experimental animals (dogs, pigs and rats) that had undergone permanent coronary occlusion ( n =34) for 0.5–6 h or occlusion of 0.75–6 h followed by reperfusion ( n =16). Histologic sections that included ischemic and nonischemic myocardium were studied by immunohistochemistry with three different antibodies to human cTnI and one to cTnT, using a standard avidin–biotin–peroxidase system. Results: All antibodies detected cTnT or cTnI in normal myocardium and its loss from necrotic myocardium, in some cases as early as 30 min after coronary occlusion, before histologic evidence of necrosis was present. Loss was nonuniform, being greater at the periphery of the infarcts then at their central regions. Usually, loss of cTnT appeared greater than loss of cTnI. With reperfusion, findings were similar to those after permanent occlusion, except that there was a greater contrast between loss at the periphery compared to the loss in the central region. Considerable residual staining persisted for hours after occlusion, indicating delayed release over time, concordant with sustained serum elevations in patients with acute myocardial infarction. No loss of staining was observed in nonnecrotic myocardium. Conclusions: Immunohistochemical staining using antibodies to human cTnT and cTnI can be used to visualize cardiac troponins and document their loss in histologic sections of myocardium in different animal species. Loss of cTnT and cTnI occurs very early following ischemic injury and may precede histologic evidence of necrosis, but does not occur in myocardium that is not necrotic. Immunohistochemical staining of hearts for cTnT and cTnI can assist in the often difficult recognition of myocardial necrosis at autopsy, in patients suspected of dying from acute myocardial ischemia.

Objectives We determined diagnostic accuracy and risk stratification using delta changes for the cardiac troponin I (cTnI) Centaur Ultra assay for ruling out acute myocardial infarction (AMI) and for risk prediction of adverse events in patients with symptoms of acute coronary syndrome. Design and methods cTnI was measured on admission and 6–24 h in 371 patients. Optimal deltas (percent change, absolute value of percent change, change, absolute value of change) were determined from ROC curve analysis. Risk stratification was performed for cardiac events and death within 60 days. Results AMI during hospitalization occurred in 49 patients and endpoints in 11 patients. Diagnostic accuracy by ROC curve was optimal (0.96) using the absolute value of change delta. Diagnostic specificities utilizing the 99th percentile (40 ng/L) for admission and follow-up samples were 84% and 81%, compared to: [90% percent change delta] 89.7%; [66.7% absolute value of percent change delta] 85.5%, [217 ng/L change delta] 99.0% and [55 ng/L absolute value of change delta] 93.7%. All four delta values showed substantially greater risk when the initial cTn value was normal. Conclusions Utilizing delta cTnI values improves clinical specificity, diagnostic accuracy and risk assessment in patients presenting with symptoms of ACS.

Cardiovascular medicine has, in general, enthusiastically embraced new technologies and used them per appropriate guidelines. However, one area in which this has not been as much the case has been with cardiac troponin (cTn). There has been reluctance to use cTn at the suggested 99th percentile of the upper reference range (URL).1 Part of this reluctance reflects a lack of comfort with the large number of increases seen with such a sensitive probe that challenge clinicians.2 However, the reluctance to utilize cTn properly has distorted the utility of cTn in many areas,1,2 but perhaps it has caused the greatest confusion in the area of post-PCI biomarker increases as attested to by recent articles.3–5 In this area, the reluctance to give up the paradigms of the past and to use cTn per guidelines has led to confusion and inaccurate conclusions in articles published even in our most prestigious journals. This editorial from a group of researchers knowledgeable in this area attempts to articulate some of the difficulties with the interpretations thus far posed and suggest how proper use of cTn can achieve a better understanding in this important area. It does not and cannot answer all of the questions going forward but progress is only possible if we understand and properly interpret the data that presently exist. A recent article in this area published in JACC3 is an excellent example of the problems in this area. It was followed by an editorial that misconstrues most of the important concepts.4 The article utilized MR imaging post-PCI to visualize areas of cardiac injury putatively related to the procedure. Because they used a good and sensitive cTn assay and the recommended cut-off values, they found that more increases in CK-MB were associated findings of …

Background— This study determined the prevalence of increased cardiac troponin I (cTnI) and T (cTnT) in end-stage renal disease (ESRD) patients and whether an increased troponin was predictive of death. Methods and Results— Serum was obtained from 733 ESRD patients and measured for cTnI and cTnT. Relative risks were estimated using Cox proportional hazards regressions univariately and adjusted for age, time on dialysis, and coronary artery disease. Kaplan-Meier curves compared time to event data between groups. Greater percentages of patients had an increased cTnT versus cTnI at each cutoff, as follows: 99th percentile, 82% versus 6%; 10% coefficient of variation, 53% versus 1.0%; and receiver operator characteristic, 20% versus 0.4%. Increased versus normal cTnT was predictive of increased mortality using all cutoffs and only above the 99th percentile for cTnI. Two-year cumulative mortality rates increased ( P 99th percentile) cTnT were 5.0 (CI, 2.5 to 10; P P P =0.008) and 2.1 (CI, 1.3 to 3.3; P =0.007). Age, coronary artery disease, and time on dialysis were also independent predictors of mortality. Conclusions— Increases in cTnT and cTnI in ESRD patients show a 2- to 5-fold increase in mortality, with a greater number of patients having an increased cTnT.

Background The European Society of Cardiology and American College of Cardiology guidelines for redefinition of myocardial infarction suggest that the cutoff value for diagnosis of acute myocardial infarction (AMI) be the 99th percentile of the reference population at a level measured with imprecision (coefficient of variation) ≥10%. No current commercially available troponin assay meets this requirement. Accordingly, questions have been raised about how to implement cutoff values from the guidelines. The Clinical Outcomes Utilizing Revascularization and Aggressive druG Evaluation (COURAGE) trial asked for recommendations concerning the use of troponin assays for the trial. Methods Cutoff values for the various assays were obtained from package inserts or from direct communication with manufacturers. Results The cutoff value with ≥10% imprecision was above the 99th percentile of the reference range for all assays. For the present, we suggest that this value be used for clinical and clinical trial purposes. It will account for analytic variability and individual biological changes. We provide recommendations for clinical practice and clinical trials concerning how to make the diagnosis of AMI in patients with ischemic symptoms and patients who undergo percutaneous coronary intervention and coronary artery bypass surgery. Conclusions This is a first attempt to define cutoff values on the basis of the European Society of Cardiology and American College of Cardiology guidelines. These criteria will provide increased consistency until assays improve to allow full implementation of the guidelines. (Am Heart J 2002;144981-6.)

Numerous studies have evaluated cardiac troponin I (cTnI), cardiac troponin T (cTnT), and creatine kinase-MB for risk stratification of acute coronary syndrome (ACS) patients. Two metaanalyses have demonstrated the ability of cTnI or cTnT to predict adverse outcomes (1)(2). A substudy of the FRISC II trial showed that the prognostic value of cTnT in ACS patients could be attributed to its correlation with the underlying severity of coronary artery stenosis (3). Because of analytical and clinical differences among troponin assays (4)(5)(6)(7), the cardiology (8)(9) and laboratory medicine (10) communities have endorsed the need for evidence-based studies before individual assays are accepted into clinical practice. Few studies have investigated the role of point-of-care (POC) testing for assessing adverse outcomes in ACS patients. One study using qualitative POC assays for cTnI and cTnT showed both assays to be independent predictors of cardiac events at 30 days after admission in ACS patients (11). In a consensus document from the European Society of Cardiology (ESC) and the American College of Cardiology (ACC), myocardial infarction (MI) was redefined as any amount of myocardial necrosis in the presence of myocardial ischemia, as indicated by an increased cardiac troponin (I or T) above the 99th percentile of a reference population (9). Because many troponin assays lack acceptable precision at the 99th percentile cutoff and assay precision may be important for risk stratification, a revised cutoff has been recommended as the index for myocardial damage, as the lowest troponin concentration closest to the 99th percentile that can be measured with 10% imprecision (CV) (5). We investigated the prognostic value of a whole-blood quantitative POC cTnI assay for risk stratification of ACS patients admitted in routine clinical practice for all-cause death, cardiac death, and cardiac events …

Numerous studies have monitored the appearance of both cardiac and skeletal muscle proteins and enzymes after short- and long-term exercise regimens. Both animal and human exercise models have attempted to determine whether the stress of long-duration exercise, such as a marathon race (42.2 km), could cause myocardial necrosis and the release of cardiac-specific proteins, such as cardiac troponin I (cTnI) or T (cTnT) (1)(2)(3)(4). In a rat animal model, the severe stress of swimming for 5 h caused microscopic evidence of myocardial necrosis, which led to substantially increased serum cTnT concentrations (1). However, in a less stressful regimen of 1–3 h of swimming, no evidence of ischemic injury and only very minor alterations in serum cTnT concentrations were detected. Middle-aged male marathon runners had increases in inflammatory and prothrombotic markers within 4 h after completion of a race (5). Increases in cTnI were also observed (6). However, no evidence of microinfarction was found by sestamibi imaging, nor was evidence of left ventricular dysfunction found by B-natriuretic peptide testing (6). Ischemia-modified albumin (IMA), measured by the albumin cobalt-binding (ACB) test (7), is reported to predict subsequent cTnI results for patients presenting with symptoms of acute coronary syndromes. Furthermore, studies that included percutaneous transluminal coronary angioplasty as a model of transient myocardial ischemia have demonstrated that serum IMA concentrations, as measured by the ACB test, were increased very early after an ischemic event (8); thus, IMA may be a very early indicator of myocardial ischemia before necrosis. To test this hypothesis in healthy persons at very low risk for cardiac disease but at high risk for skeletal muscle damage, we studied the appearance and clearance characteristics of the IMA marker compared with cTnI, cTnT, and myoglobin in runners after a marathon race. Nineteen Caucasian runners, …

Background: Cardiac troponin I (cTnI) is a powerful tool to aid in the diagnosis of myocardial infarction and cardiac muscle damage. We describe an assay that overcomes problems of early assays that were often affected by cTnI degradation, assay interference, poor sensitivity, and imprecision.Methods: The analytical performance of the Access® AccuTnITM assay (Beckman Coulter) was evaluated at five institutions. Controls, zero calibrator, and diluted patient samples were used to determine precision, detection limit, functional sensitivity, and linearity. The 97.5 and 99 percentiles of a reference population were determined. Common interferents and heterophilic patient samples were tested. Equimolarity was determined by assaying samples with various ratios of free and complexed cTnI. Matched samples drawn into serum, EDTA, lithium heparin, and sodium heparin sample tubes were compared.Results: Total imprecision (CVs) was 4.0–8.8% between 0.40 and 31 μg/L cTnI. The detection limit was 60 μg/L and not affected by common assay interferents. An equimolar response was observed with free, complexed, phosphorylated, and dephosphorylated forms of cTnI. Results were 4% lower in serum and 14% lower in EDTA plasma than in lithium heparin plasma (P Conclusion: AccuTnI is a sensitive and precise assay for the measurement of cTnI.

Background: Because respiratory distress syndrome (RDS) affects 1% of live births, accurate and rapid assessment of markers of fetal lung maturity is critical to clinicians in deciding whether to deliver a preterm infant. Our objective was to determine the optimal diagnostic cutoff value for the TDx-FLM II assay (Abbott Laboratories) for predicting clinically significant RDS. Methods: Amniotic fluid TDx-FLM II data were collected retrospectively over 4 years. Women were included in the study if they had delivered within 72 h of TDx-FLM II testing and both the mother and infant charts could be reviewed. Women who had been treated with steroids and delivered unaffected infants were excluded from the analysis. The diagnosis of RDS was defined as infants who either were treated with surfactant and/or were placed on a ventilator and/or required continuous positive airway pressure for >1 day. Results: A total of 185 women met all entry criteria (15 RDS, 170 non-RDS). A cutoff value for a mature result of ≥45 mg/g gave a sensitivity of 100% (95% confidence interval, 82–100%) and a specificity of 90% (95% confidence interval, 78–89%). Conclusions: The TDx-FLM II appears to predict clinically significant RDS when a cutoff of ≥45 mg/g is used for mature results. Further studies will be required to confirm these findings.

This study examined the performance of single high-sensitivity cardiac troponin I (hs-cTnI) measurement strategies to rule out acute myocardial infarction.This was a prospective, observational study of consecutive patients presenting to the emergency department (n = 1631) in whom cTnI measurements were obtained using an investigational hs-cTnI assay. The goals of the study were to determine 1) negative predictive value (NPV) and sensitivity for the diagnosis of acute myocardial infarction, type 1 myocardial infarction, and type 2 myocardial infarction; and 2) safety outcome of acute myocardial infarction or cardiac death at 30 days using hs-cTnI less than the limit of detection (LoD) (1.9 ng/L) or the High-STEACS threshold (5 ng/L) alone and in combination with normal electrocardiogram (ECG).Acute myocardial infarction occurred in 170 patients (10.4%), including 68 (4.2%) type 1 myocardial infarction and 102 (6.3%) type 2 myocardial infarction. For hs-cTnILoD (27%), the NPV and sensitivity for acute myocardial infarction were 99.6% (95% confidence interval 98.9%-100%) and 98.8 (97.2%-100%). For hs-cTnI5 ng/L (50%), the NPV and sensitivity for acute myocardial infarction were 98.9% (98.2%-99.6%) and 94.7% (91.3%-98.1%). In combination with a normal ECG, 1) hs-cTnILoD had an NPV of 99.6% (98.9%-100%) and sensitivity of 99.4% (98.3%-100%); and 2) hs-cTnI5 ng/L had an NPV of 99.5% (98.8%-100%) and sensitivity of 98.8% (97.2%-100%). The NPV and sensitivity for the safety outcome were excellent for hs-cTnILoD alone or in combination with a normal ECG, and for hs-cTnI5 ng/L in combination with a normal ECG.Strategies using a single hs-cTnI alone or in combination with a normal ECG allow the immediate identification of patients unlikely to have acute myocardial infarction and who are at very low risk for adverse events at 30 days.