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• BSC's cardiac troponin cutoff concentrations for myocardial infarction: “Back to the Future"
  Alan H. Wu
  Published on: 23 November 2015

• Published on: 23 November 2015

  BSC's cardiac troponin cutoff concentrations for myocardial infarction: “Back to the Future"

  • Alan H. Wu, Professor, Laboratory Medicine
  • Other Contributors:
    • Fred Apple, Allan S. Jaffe, Marcello Galvani

  Dear Editor,

  We read with great interest the British Cardiac Society’s (BCS) recommendations regarding proposed nomenclature for acute coronary syndromes (ACS) [1]. These experts attempt to alter the new definition of myocardial infarction (MI) established by the European Society of Cardiology (ESC) /American College of Cardiology (ACC) that rely predominately on increased concentrations of serum biomarkers of...

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  Dear Editor,

  We read with great interest the British Cardiac Society’s (BCS) recommendations regarding proposed nomenclature for acute coronary syndromes (ACS) [1]. These experts attempt to alter the new definition of myocardial infarction (MI) established by the European Society of Cardiology (ESC) /American College of Cardiology (ACC) that rely predominately on increased concentrations of serum biomarkers of myocardial necrosis when there is evidence of myocardial ischemia (symptoms, electrocardiographic changes, intervention, or pathology) [2]. While the recommendations are well written and thus may help clinicians understand the spectrum of acute coronary syndromes; in our opinion, there are apt to increase the existing confusion [3-6] with regard to the appropriate cut off values for troponin T and I.

  These recommendations move us backwards, not forwards. In 1999, the National Academy of Clinical Biochemistry (NACB) and the International Federation of Clinical Chemistry (IFCC) recognized the inadequacy of the 1971 World Health Organization's (WHO) definition of MI with the development of highly sensitive (non-enzyme) protein markers such as cardiac troponin [7,8].

  These laboratory medicine groups recognized the diagnostic importance of detecting minor myocardial increases in troponin in patients with symptoms suggestive of MI, since these patients have on-going myocardial damage. They were also aware that such elevations stratify patients at high very short-term risk for death (e.g., during hospitalization) and recurrent MI, similar in frequency to other non-Q- wave MIs. The NACB and IFCC suggested two cutoff concentrations for cardiac troponin. The first one was established using receiver operating characteristic (ROC) curve analysis to select an optimum cutoff to differentiate between unstable angina and WHO-defined MI. Although widely practiced at the time, this first cutoff recommendation was not evidence- based, as there were no prospective studies to validate this approach, purposefully lowered to be useful for risk stratification. The second (lower) cutoff was set at the 97.5th percentile of a healthy reference population. These guidelines stopped short of redefining MI and suggested that this was the prerogative of international cardiology organizations. In 2000, the ESC/ACC subsequently recommended the use of a single cutoff for MI diagnosis at the 99th percentile of a healthy reference population, a value that was slightly higher than the 97.5th percentile. The redefinition of MI by the ESC/ACC and endorsed by other groups such as the Italian Federation of Cardiology, [9] the IFCC, and the international epidemiology community [10] simplified the criteria by obviating the need for multiple troponin cutoffs.

  The BCS Working Group now has recommended a return to two cutoff concentrations. They suggest that patients with “ACS with clinical MI” are defined as cTnT >1.0 ng/ml and cTnI (AccuTnI) >0.5 ng/ml. It is alleged that these cutoffs approximates the traditional WHO definition of MI, but some of them are very different from what the NACB indicated would fulfill this criterion. They further suggest that patients with detectable troponin values at concentrations below these MI cutoff limits be designated as having “ACS with myocyte necrosis.” Although no concentrations were cited, the working group intimated that the 99th percentile could be used as the lower limit of this rage if the assay had acceptable precision (i.e., coefficient of variance of less than 10%). Patients with “ACS with unstable angina” would then have ECG evidence or history of coronary disease but with undetectable troponin concentrations.

  The return to a two-cutoff designation is a departure from the concept that when there is evidence of myocardial injury induced by ischemia that MI has occurred. This deviates from the well established data that the release of serum biomarkers into blood reflects the continuum of ACS disease severity. There is no pathophysiologic basis with which to subdivide troponin-positive patients into those with myocyte necrosis vs. MI. Moreover, from a risk stratification view, the risk of adverse events is also continuous, i.e., there is no troponin threshold for which cardiovascular risk becomes exponentially increased (as for example, total cholesterol).

  The Working Group recommended values of 1.0 ng/ml for cTnT and 0.5 ng/ml for cTnI is without evidence and are apparently based on unpublished personnel communications. In fact, while the 0.5 ng/ml cutoff for the Beckman AccuTnI agrees with the manufacturer’s ROC cutpoint, the 1.0 ng/ml for Roche cTnT is 3 to 10-fold higher than the manufacturer’s recommendation [11]. Assuming the values provided by the companies are data driven, it is likely that this suggestion will widen the differences in the frequency of the diagnosis of AMI between cTnT and cTnI assays [10,12]. Furthermore, the concept that one can determine similar cutoff values by relying on their relationship to the values for cTnT (only 1 assay manufactured by Roche) and for cTnI with the Beckman assay (one of more than a dozen assays in the international marketplace) ignore the important facts that individual assays use different antibodies, different chemical matrixes, and thus will give different signals for the troponin [11]. While harmonization is possible, complete standardization will likely never be possible given these differences in commercial assays.

  Finally, although we agree with the Working Group that there is a continuous relationship between troponin and MI disease severity, there is only limited data that suggests that the higher cutoff provides indirect evidence of left ventricular dysfunction [13,14]. Such a statement is particularly surprising given the marked disparity chosen between the cTnT ROC value and the one for cTnI. Until data to support this apporach is forth coming, we would argue that such a determination might best rely on for B-type natiruretic peptide15 or NT-proBNP16 or imaging techniques rather than troponin. The international community needs to be educated that all cardiac troponin assays are not created equal and that absolute cardiac troponin concentrations cannot be assumed to be interchangeable for diagnosis, risk stratification, and therapeutic decisions.

  References

  (1). Fox FAA, Birkhead J, Wilcox R, et al. British Cardiac Society Working Group on the definition of myocardial infarction. Heart 2004;90:603-9.

  (2). Joint European Society of Cardiology/American College of Cardiology Committee. Myocardial infarction redefined—a consensus document of the joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. J Am Coll Cardiol 2000;36:959-69.

  (3). Norris RM. Dissent from the consensus on the redefinition of myocardial infarction.[comment]. Eur Heart J. 2001; 22:1626-7.

  (4). Tormey W, Birkhead JS, Norris RM, et al. Redefinition of myocardial infarction. Lancet 2001; 358:764.

  (5). Richards AM, Lainchbury JG, Nicholls MG. Unsatisfactory redefinition of myocardial infarction. Lancet 2001;357:1635-6.

  (6). Tunstall-Pedoe H. Redefinition of myocardial infarction by a consensus dissenter.[comment]. J Am Coll Cardiology 2001; 37:1472-4.

  (7). Wu AHB, Apple FS, Gibler WB, Jesse RL, et al. National Academy of Clinical Biochemistry Standards of Laboratory Practice: Recommendations for use of cardiac markers in coronary artery diseases. Clin Chem 1999;45:1104-21.

  (8). Panteghini M, Apple FS, Christenson RH, et al. Proposals from IFCC Committee on Standardization of Markers of Cardiac Damage (C-SMCD): recommendations on use of biochemical markers of cardiac damage in acute coronary syndromes. Scan J Clin Lab Invest 1999;59 (suppl):103-12.

  (9). Galvani M, Panteghini M, Ottani F, et al. The new definitionl of myocardial infarction: analysis of the ESC/ACC Consensus Document and relections on its applicability to the Italian Health System. Ital Heart J 2002;3:543-57.

  (10). Luepker RV, Apple FS, Christenson RH, et al. Case definitions for acute coronary heart disease in epidemiology and clinical research studies. Circulation 2003;108: 2543-9.

  (11). Apple FS, Wu AHB, Jaffe AS. European Society of Cardiology and American College of Cardiology guidelines for redefinition of myocardial infarction: how to use existing assays clinically and for clinical trials. Am Heart J 2002;144:981-6.

  (12). Lin JC, Apple FS, Murakami MM, et al. Rates of positive cardiac troponin I and creatine kinase MB among patients hospitalized for suspected acute coronary syndromes. Clin Chem 2004;50: 333-8.

  (13). Rao AC, Collinson PO, Canepa-Anson R et al. Troponin T measurement after myocardial infarction can identify left ventricular ejection of less than 40%. Heart 1998;80:223-5.

  (14). Panteghini M, Cuccia C, Bonetti G, Giubbini R, Pagani F, Bonini E. Single-point cardiac troponin T at coronary care unit discharge after myocardial infarction correlates with infarct size and ejection fraction. Clin Chem 2002;48:1432-6.

  (15). Morrow DA, de Lemos JA, Sabatine MS, et al. Evaluation of B-type natriuretic peptide for risk assessment in unstable angina/non-ST- elevation myocardial infarction: B-type natriuretic peptide and prognosis in TACTICS-TIMI 18. J Am Coll Cardiol 2003; 41:1264-72.

  (16).Jernberg T, Stridsberg M, Venge P, et al. N-terminal pro brain natriuretic peptide on admission for early risk stratification of patients with chest pain and no ST-segment elevation. J Am Coll Cardiol 2003

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  Conflict of Interest:
  None declared.

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