The Analytical Performance Assessment And Clinical Application Of High-sensitivity Cardiac Troponin Assays

Background:Cardiac troponins are the preferred biomarkers for the diagnosis of acute myocardial infarction. The recognition of the high diagnostic sensitivity and specificity of cardiac troponins for the detection of myocardial injury, as well as the observation that these proteins provide valuable prognostic information concerning short- and longterm outcome and the effect of early intervention in patients with non-ST-segment elevation acute coronary syndromes, has led to the widespread adoption of troponin measurement in clinical practice. Indeed, the measurement of cardiac troponins is currently routinely performed in patients with suspected acute coronary syndromes. However, recent advances in troponin assay technology, which enable accurate detection of very low levels of circulating troponins, have not only resulted in improved diagnostic accuracy in the setting of acute coronary syndromes, but have also challenged the paradigm that troponins are not circulating in subjects without myocardial infarction. In fact, from commonly being considered an almost qualitative test ('troponin positive versus troponin negative'), the use of novel highly sensitive troponin assays has clearly demonstrated that these tests are quantitative and provide diagnostic and prognostic information across a wide range of values.Moreover, troponin testing in a variety of clinical settings has revealed that detectable circulating levels are frequently present in many disease conditions, and that elevated troponin levels are associated with poor outcome。The 99th percentile of cTn concentration in a normal reference population was emphasized in the documents of redefinition of acute myocardial infraction (AMI) in 2000 and 2007. The guidelines suggested the condition that the increases of cTn concentration in blood exceeded the 99th percentile of cTn concentration in a normal reference population (the CV of the cTn assay used be≤10% at the 99th percentile concentration) and there were symptoms of ischaemia and/or electrocardiogram changes indicative of new ischaemia may be diagnosis as AMI. Nowadays, cTn assays have been the mainstay for diagnosing AMI.The clinical application of cardiac troponin assays continues to evolve substantively. In large part, this evolution has been driven by sustained progress in the analytical performance of commercially available cTn assays. The high-sensitivity cTn assays are coming now.Part one:Objective To assess the analytical performance of hs-cTnT, the biological variation in healthy population, and establish the hs-cTnT reference interval, providing clinical information for the diagnosis of acute myocardial infarction.Methods The serum samples from 100 acute myocardial infraction patients and 474 controls were collected. The functional sensitivity, within-run and between-run imprecision were determined. The hs-cTnT assay and conventional cTnT assay were evaluated. Moreover, the biological variations in healthy volunteers were assessed.Results The functional sensitivity of hs-cTnT was 0.005μg/L. The within-run and between-run precision for lower level (0.014μg/L) was 2.97%,3.64%, respectively, and for higher level (2.500μg/L) was 0.66%,1.01%, respectively. The correlation between hs-cTnT assay and cTnT assay was good(R2=0.972, P<0.01). The 99th percentile in appearently healthy people was 0.003μg/L for less than 60 years women and 0.008μg/L for less than 60 years men, and 0.015μg/L for above 60 years women and 0.021μg/L for above 60 years men. The short-term biological variations including analytical, intraindividual, interindividual and total CVs in cardiac troponin T from 22 healthy volunteers were 3.8%,4.8%,49.9% and 58.5%, respectively, the long-term were 5.3%,6.4%,56.6% and 68.3%, respectively. Part two:Objective To evaluate the clinical application of hs-cTnT. Methods The detectable rates of hs-cTnT and con-cTnT from 147 AMI (including 122 NSTEMI) patients were compared. The related biological markers including hs-cTnT, con-cTnT, CKMB mass and MYO were determined for all samples from 481 patients with chest pain in admission, and 4h,12h,20h and 28h after admission. The receiver operating characteristic curve was used to evaluate the sensitivity and specificity of all markers. The rates of change of hs-cTnT in 4 hours from AMI group, non-AMI heart diseases group, AMI-related high risk diseases group and control group were compared with serial detecting.Results The detectable rates of hs-cTnT for AMI and NSTEMI patients were 90.3% and 91.0%, and both were significantly higher than the rates of con-cTnT which were 61.9% and 60.6%(P<0.01). In the compairation of different makers from different collecting times, hs-cTnT had the highest detectable rate. For admission sample, the area under curve of hs-cTnT, con-cTnT, CKMB mass and MYO were 0.935,0.851, 0.827 and 0.769, respectively, and the difference had statistical significance (Z1=3.13 Z2=4.46 Z3=5.62, P<0.05). Besides, the rate of change of hs-cTnT was significantly different between AMI and the other groups(χ2=166.09,P<0.01).Part three: Objective To assess the analytical performance of three sensitivity cardiac troponin I assays, and compare the clinical application. Methods The serum samples were collected from patients presenting with symptoms suggestive of acute myocardial infarction for correlation studies, and from healthy subjects for reference interval determination. The functional sensitivity of three assays were determined. The results and application in diagnosis of AMI were compared among the different assays. The clinical performance of the three sensitivity cTnI assays was evaluated. Results The functional sensitivity (CV%=10%)of the cTnl assays for Abbott, Beckman-coulter, Ortho-Clinical Diagnostics were 0.030μg/L,0.04μg/L,0.013μg/L, respectively. The 99th percentile of cTnl in healthy volunteers were 0.021μg/L,0.02μg/L, 0.026μg/L, respectively. The analytical data of receiver operating characteristic (ROC)curve showed that the area under curve (AUC)of the cTnI assays for Abbott, Beckman-coulter, Ortho-Clinical Diagnostics in diagnosis of AMI was 0.852,0.909 and 0.910, respectively. The diagnostic characteristic for AMI is not significantly deferent between the 99th percentile by our laboratory and suggested by manufacturers (P<0.01)...