MaryAnn M. Murakami

Determination of 19 Cardiac Troponin I and T Assay 99th Percentile Values from a Common Presumably Healthy Population

BACKGROUNDnBetween-assay comparability of 99th percentiles for cardiac troponin concentrations has not been assessed systematically in a single population for a large number of assays.nnnMETHODSnWe determined 99th percentiles for 19 cardiac troponin assays in heparin plasma samples from a population of 272 and 252 presumably healthy males and females, respectively. The assays evaluated included 1 cardiac troponin T (cTnT) assay from Roche and 18 cTnI assays from Abbott, Alere, Beckman, bioMerieux, Instrumentation Laboratory, Ortho-Clinical Diagnostics, Singulex, Siemens, and Roche. Five of these assays were categorized as high-sensitivity, 9 as sensitive-contemporary, and 5 as point-of-care (POC) assays.nnnRESULTSnFor high-sensitivity cTnI (hs-cTnI) assays 99th percentiles varied from 23 to 58 ng/L. At least 80% of individuals had measurable hs-cTnI, whereas only 25% had measurable high-sensitivity cTnT. All high-sensitivity cardic troponin assays had 99th percentiles that were 1.2-2.4-fold higher in males than females. For the 9 sensitive-contemporary cTnI assays, 99th percentiles varied from 12 to 392 ng/L, and only the Beckman assay gave measurable concentrations in a substantial portion of the population (35% vs ≤6% for the others). Seven of these 9 assays had 1.3-5.0-fold higher 99th percentiles for males than females. For 5 cTnI POC assays, 99th percentiles varied from <10 to 40 ng/L. The Instrumentation Laboratory assay gave measurable results in 27.8% of study participants vs ≤6% for the others. Correlations were generally poor among assays.nnnCONCLUSIONSnAmong cardiac troponin assays 99th percentile concentrations appear to differ. High-sensitivity assays provide measurable cardiac troponin results in a substantially greater fraction of presumably healthy individuals.

Defining the serum 99th percentile in a normal reference population measured by a high-sensitivity cardiac troponin I assay☆

OBJECTIVESnThis study determined the serum 99th percentile reference value for cTnI measured using the high sensitivity Erenna cTnI assay.nnnDESIGN AND METHODSnSerum was obtained from healthy adults (n=348); aged 18-76 years of which 147 were males and 201 were females. Nonparametric analysis was performed to determine the 99th percentiles.nnnRESULTSnFor all subjects, the 99th percentile was 10.19 ng/L; mean concentration=1.45 ng/L, range=0.2 to 34.56 ng/L. By gender, the male and female 99th percentile values were as follows: male=16.58 ng/L, mean concentration=1.72 ng/L, and female=9.36 ng/L, mean concentration=1.25 ng/L, respectively (p=0.108).nnnCONCLUSIONncTnI measured by the high-sensitivity Erenna cTnI assay measured 100% of normal subjects, allowing prospective diagnostic and risk assessment studies to be performed, which are essential for the early detection of cardiac disease and for the management of patients presenting with symptoms suggestive of acute coronary syndrome.

Cardiac troponin changes to distinguish type 1 and type 2 myocardial infarction and 180-day mortality risk

Aims: To determine the ability of serial cardiac troponin (cTnI) changes (delta) to distinguish type 1 and type 2 myocardial infarction (MI) (excluding all ST-segment elevation MIs (STEMIs)) and describe the diagnostic accuracy and 180-day mortality in MI versus no-MI patients. Methods and results: Serial cTnIs were measured in 1112 consecutive patients without STEMI and within 6h of presentation to a United States emergency department: 856 (77%) with no MI, 66 (6%) type 1 MI, and 190 (17%) type 2 MI. Of the 0 to 3h and 0 to 6h absolute and relative cTnI changes, only the distribution of absolute change from 0 to 6h was significantly different between type 1 and type 2 MI: median (interquartile range) 311 (1430) ng/l vs. 80 (330) ng/l, p=0.03. Neither the absolute concentration change nor the absolute percent change from either 0 h to 3h (areas under the curves (AUCs) 0.57 and 0.54 respectively) or 0 h to 6h (AUCs 0.60 and 0.51) improved on the performance of the individual cTnI results at 3h (AUC 0.60) or 6h (AUC 0.62), respectively. After adjusting for age, and histories of heart failure and renal insufficiency, those with type 2 MI (hazard ratio 2.9, 95% confidence interval (CI) 1.4–5.9, p=0.004) and those with no index MI and cTnImax0–6h > 34 ng/l (2.5, CI 1.1–6.0, p=0.04) had increased risk of death within 180 days compared with those with no MI and cTnImax 0–6h ≤ 34 ng/l. Conclusion: Delta cTnI did not aid in distinguishing type 1 MI from the more common type 2 MI. Patients diagnosed with type 2 MIs, which represented more than half of all index MIs, had increased risk of death after discharge.

Canine myocardial creatine kinase isoenzymes after chronic coronary artery occlusion.

BackgroundCreatine kinase (CK) exists as three cytosolic isoenzymes, CK-MM, CK-MB, and CK-BB, and one mitochondrial isoenzyme. Animal and human observations suggest that the CK-MB content of myocardium is dynamic and may increase in response to ischemia, but the response of the myocardial CK system to chronic coronary artery occlusion is not well-defined. Methods and ResultsWe measured serial changes in myocardial total CK, percent CK-MB, and percent CK-BB before and 3 weeks after coronary artery occlusion in 17 pentobarbitalanesthetized dogs. Tissue biopsies were obtained from the left anterior descending (LAD) coronary artery myocardium, the right coronary artery (RCA) myocardium, and the circumflex coronary artery myocardium at baseline and 3 weeks after LAD occlusion (n =6), RCA occlusion (n =5), and no coronary artery occlusion (n =6). Tissue samples were assayed for total CK, percent CK-MB, and percent CK-BB. Samples were also examined by electron microscopy for evidence of ischemic myopathy. Total myocardial CK activity did not change over 3 weeks. Percent CK-MB increased significantly in the tissue supplied by the occluded artery (4.1-fold in dogs with LAD occlusion and 6.7-fold in dogs with RCA occlusion). Percent CK-BB did not change. Dogs with LAD occlusion had ultrastructural evidence of myopathic fibers interspersed with normal fibers in the LAD myocardium. Dogs with RCA occlusion had no ultrastructural evidence of myopathic fibers in the RCA myocardium. ConclusionsChronic coronary artery occlusion causes a pronounced change in the canine myocardial CK system that is limited to the tissue supplied by the occluded coronary artery. These biochemical alterations do not correlate with any cellular ultrastructural changes. Myocardial CK-MB content is dynamic, varies geographically within the heart, and increases rapidly after coronary artery occlusion. (Circulation 1991;84:333–340)

Performance characteristics of the ARCHITECT Galectin-3 assay.

OBJECTIVESnGalectin-3 is an emerging biomarker that is commonly increased in patients with heart failure and/or patients at risk for cardiovascular disease. We evaluated the Galectin-3 assay on the Abbott ARCHITECT i1000(SR) and ARCHITECT i2000(SR) at 2 testing sites.nnnDESIGN AND METHODSnImprecision (%CV), interference, limits of blank (LoB), detection (LoD), and quantitation (LoQ), linearity, method comparison to an ELISA method, comparisons between plasma and serum, and reference intervals were evaluated. Imprecision was performed based on two runs of duplicate testing conducted daily. Verification of LoB, LoD, and LoQ was performed according to Clinical and Laboratory Standards Institute guidelines. Linearity was evaluated by making 5 dilutions of a high patient EDTA plasma pool with a low patient pool. Reference intervals were established using EDTA plasma collected from self-reported healthy volunteers. A second lot of reagent was used at one site for method comparison and imprecision studies.nnnRESULTSnTotal CVs were ≤6.0%. A positive interference was observed for hemolyzed samples over 2.0 g/L hemolysate. The LoB ranged from 0.1 to 0.3 ng/mL, the LoD from 1.4 to 2.1 ng/mL and the LoQ from 3.0 to 3.3 ng/mL. Linearity studies had slopes and correlation coefficients equal to 1.0. Comparison of the i1000(SR) and i2000(SR) to the ELISA method demonstrated slopes of 1.0 to 1.2 and correlation coefficients of 0.93 to 0.97. The 97.5th percentile of the reference interval was 18.7 and 17.9 ng/mL for the i1000(SR) and i2000(SR), respectively.nnnCONCLUSIONSnThe Abbott Galectin-3 assay demonstrated acceptable analytical performance on both the ARCHITECT i1000(SR) and ARCHITECT i2000(SR).

Diagnostic performance of four point of care cardiac troponin I assays to rule in and rule out acute myocardial infarction

OBJECTIVEnThis study evaluated the diagnostic performance of four point-of-care (POC) cardiac troponin I (cTnI) assays compared to a central laboratory cTnI assay for detecting myocardial injury and diagnosing acute myocardial infarction (AMI).nnnDESIGN AND METHODSnPlasma obtained at admission, 3 h, and 6 h post-admission in 169 patients presenting with symptoms suggestive of acute coronary syndrome (ACS) was studied. cTnI concentrations were measured on the Instrumentation Laboratory prototype GEM Immuno, Radiometer AQT90, Mitsubishi PATHFAST, Abbott i-STAT and the Ortho-Clinical Diagnostic Vitros assays. MI was determined based on 99th percentiles according to Universal MI guidelines.nnnRESULTSnFor ruling in MI at presentation (0 h), the GEM Immuno (sensitivity 63%, specificity 85%) and PATHFAST (sensitivity 53%, specificity 86%) were comparable to the OCD (sensitivity 68%, specificity 81%), and significantly better (p<0.05) than the AQT90 (sensitivity 26%, specificity 93%) and i-STAT (sensitivity 32%, specificity 92%). cTnI concentrations and serial rising patterns after MI differed by each assay. Negative predictive values were >90% and ROC AUCs were >0.90 after 6h for all assays. Detection of myocardial injury in non-ischemic pathologies accounted for lower than 100% specificity for MI.nnnCONCLUSIONncTnI is a sensitive biomarker for detection of myocardial injury. The analytical variability that exists between POC cTnI assays demonstrates substantial diagnostic differences for ruling in and ruling out MI in patients presenting with symptoms suggestive of ACS.

N-terminal and C-terminal fragments of IGFBP-4 as novel biomarkers for short-term risk assessment of major adverse cardiac events in patients presenting with ischemia.

OBJECTIVESnPregnancy 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.nnnDESIGN AND METHODSnNT- 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.nnnRESULTSnSixteen 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.nnnCONCLUSIONSnIGFBP-4 fragments can be utilized as biomarkers for MACE prediction in patients with suspected myocardial ischemia.

The diagnostic utility ofcardiac biomarkers in detecting myocardial infarction

Cardiac biomarkers, eg, cardiac troponin, have become the standard test in combination with clinical and electrocardiographic findings for physicians to conduct prompt and effective triage of patients presenting with chest pain. Cardiac biomarkers are protein components of cell structures that are released into circulation when myocardial injury occurs. The purpose of this article is multifold. First, to identify specific cardiac biomarkers and review current guidelines based on study findings on the diagnostic utility of cardiac biomarkers in detecting myocardial infarction. Recent guidelines of the European Society of Cardiology, the American College of Cardiology, the American Heart Association, and the National Academy of Clinical Biochemistry were examined, as well as relevant studies relating to the development of these guidelines. Second, to analyze the clinical significance of cardiac biomarker measurements and the challenges with existing cardiac biomarker assays. Third, to discuss our findings regarding our evaluation of the analytical performance of a chemiluminescent microparticle immunoassay for the quantitative determination of cardiac troponin I in human serum and plasma on an automated immunoassay instrument system (ARCHITECT) to aid in the diagnosis of myocardial infarction.

ROLE OF DELTA CARDIAC TROPONIN I TO DISTINGUISH BETWEEN TYPE I NSTEMI AND TYPE II MYOCARDIAL INFARCTION

Numerous pathologies aside from ACS are associated with an increased cardiac troponin (cTn). We hypothesized that delta cTn would be useful for improving diagnostic accuracy and distinguishing outcomes of spontaneous MI (type 1) versus MI secondary to supply/demand imbalance (type 2).nnWe

GENDER DIFFERENCES IN MORTALITY AMONG PATIENTS WITH SUPPLY-DEMAND TYPE 2 MYOCARDIAL INFARCTION, TYPE 1 MYOCARDIAL INFARCTION AND NON-MI CARDIAC TROPONIN I INCREASES

Supply-demand type 2 myocardial infarction (T2MI) is frequently encountered. Little is known about gender differences in patients with T2MI in contrast to type 1 MI (T1MI) and non-MI troponin (cTn) increases. We sought to compare mortality according to gender among these groups.nnRetrospective study