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Letters to the Editor |
Hennepin County Medical Center, University of Minnesota, School of Medicine, Department of Laboratory Medicine, and Pathology, Minneapolis, MN
aAddress correspondence to this author at: Hennepin County Medical Center, Clinical Laboratories P4, 701 Park Ave., Minneapolis, MN 55415. Fax 612-904-4229; e-mail fred.apple{at}co.hennepin.mn.us.
To the Editor:
Several international expert panels, including the European Society of Cardiology, the American College of Cardiology, American Heart Association, the IFCC, the COURAGE trials group, the Italian Federation of Cardiology, and the American Heart Association and World Heart Federation Councils on Epidemiology and Prevention, have endorsed the concept that increased cardiac troponin I or T (cTnI or cTnT) should be defined as a measurement above the 99th percentile concentration of a reference population (1)(2)(3)(4)(5)(6)(7). Furthermore, an increased cTnI or cTnT value is considered indicative of myocardial injury (cell death) and, in the clinical setting of ischemia, is considered evidence of myocardial infarction and a high-risk profile for adverse cardiac and noncardiac events.
Previously, work from our laboratory reported on heparin plasma 99th percentile reference limits for both cTnT and seven cTnI assays (8). However, because heparin plasma is known to cause a negative bias compared with some, but not all cTnI and cTnT assays, reference limit determinations in serum would also be useful because serum and heparin plasma are the most commonly used specimen types in clinical practice. Preanalytical considerations suggest the use of plasma for reducing turnaround times. In addition, a recent study of imprecision for cardiac troponin assays to determine the lowest concentration that meets a 10% total imprecision (CV) was predicated on serum (9), with the goal to assess the size of the gap between the 99th percentile reference limit and the lowest troponin concentration that provides a 10% CV.
Although several studies have published serum-based 99th percentile reference limits for individual assays, no study has used the same population to evaluate reference limits for numerous cardiac troponin assays. The purpose of this study was to determine (using nonparametric statistics) the 99th percentile reference limit, based on samples from 403 healthy volunteers.
After receiving Institutional Review Board approval and having participants complete a health questionnaire ruling out any past or current history of heart disease, we collected nonanticoagulated blood (Becton Dickinson Vacutainer SST Gel and Clot Activator tube), separated the serum, and froze it at –70 °C. We recruited 215 females (53%) and 188 (47%) males, of whom 168 were African American (42%), 181 were Caucasian (45%), and 54 were of other ethnicities (13%). Ages ranged from 30 to 84 years (median, 49 years). As shown in Table 1
, not all assays were performed on all samples because of limited specimen volumes. To verify lack of interference by heterophile antibodies, we screened selected samples with high cardiac troponin by a commercial heterophile antibody blocking system (Scantibodies Laboratories). Shown in Table 1
are the serum 99th percentile limits for six cTnI assays and one cTnT assay for all participants, as well as a breakdown for males and females.
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For cTnI, the reference limits ranged from 0.03 µg/L (Dade Dimension) to 1.1 µg/L (Abbott AxSYM), a 36-fold difference. We found significant differences between males and females for the Beckman Access, Ortho cTnI Vitros ECi, and Bayer Centaur cTnI assays. All cTnT concentrations were 
0.015 µg/L, with the overall 99th percentile limit being <0.01 µg/L. Only the Ortho Vitros ECi cTnI showed a significant difference by ethnicity.
Our results for serum are similar to those obtained in our previous study on 99th percentile reference limits for plasma (8): (a) results obtained with different cTnI assays vary considerably because of differences in standardization and in the antibodies used (10); and (b) there is evidence of gender and ethnic variation. In general, the current serum reference concentrations (n 403 individuals) compared with our previous plasma findings in a larger population (n 696 individuals) were not predictably higher for all assays, as has been suggested in several Food and Drug Administration-cleared package inserts and previous literature (4)(8)(11)(12). The findings also demonstrate that only one of seven assays (Beckman) gave a 99th percentile concentration (0.05 µg/L) close to the previously reported total 10% imprecision concentration (0.06 µg/L) (9). Thus it is possible that some of the gender differences may be related to assay imprecision. A limitation of this study, however, was that matched serum and plasma samples were not available for analysis. Overall, our findings add to the literature to assist in setting reference limits for the cardiac troponin assays available from the major in vitro diagnostic manufacturers. Further investigations are necessary to explore gender and ethnic differences that may impact diagnostic or risk stratification decisions in patients with acute coronary syndrome (13)(14)(15)(16)(17).
References
The following articles in journals at HighWire Press have cited this article:
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  J. R Tate, W. Ferguson, R. Bais, K. Kostner, T. Marwick, and A. Carter The determination of the 99th centile level for troponin assays in an Australian reference population Ann Clin Biochem, May 1, 2008; 45(3): 275 - 288. [Abstract] [Full Text] [PDF]
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 Y. Le Manach, G. Godet, P. Coriat, C. Martinon, M. Bertrand, M.-H. Fleron, and B. Riou The Impact of Postoperative Discontinuation or Continuation of Chronic Statin Therapy on Cardiac Outcome After Major Vascular Surgery Anesth. Analg., June 1, 2007; 104(6): 1326 - 1333. [Abstract] [Full Text] [PDF]
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 D. A. Waxman, S. Hecht, J. Schappert, and G. Husk A Model for Troponin I as a Quantitative Predictor of In-Hospital Mortality J. Am. Coll. Cardiol., November 7, 2006; 48(9): 1755 - 1762. [Abstract] [Full Text] [PDF]
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 N. A. Khan, B. R. Hemmelgarn, M. Tonelli, C. R. Thompson, and A. Levin Response to Letter Regarding Article by Khan et al, "Prognostic Value of Troponin T and I Among Asymptomatic Patients With End-Stage Renal Disease: A Meta-Analysis" Circulation, May 23, 2006; 113(20): e776 - e776. [Full Text] [PDF]
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 M. N. Fahie-Wilson, D. J. Carmichael, M. P. Delaney, P. E. Stevens, E. M. Hall, and E. J. Lamb Cardiac Troponin T Circulates in the Free, Intact Form in Patients with Kidney Failure Clin. Chem., March 1, 2006; 52(3): 414 - 420. [Abstract] [Full Text] [PDF]
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 L. Babuin and A. S. Jaffe Troponin: the biomarker of choice for the detection of cardiac injury Can. Med. Assoc. J., November 8, 2005; 173(10): 1191 - 1202. [Abstract] [Full Text] [PDF]
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N. A. Abbas, R. I. John, M. C. Webb, M. E. Kempson, A. N. Potter, C. P. Price, S. Vickery, and E. J. Lamb Cardiac Troponins and Renal Function in Nondialysis Patients with Chronic Kidney Disease Clin. Chem., November 1, 2005; 51(11): 2059 - 2066. [Abstract] [Full Text] [PDF]
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