Correspondence

Autoantibodies against Cardiac Troponins

N Engl J Med 2005; 352:98-100January 6, 2005

Article

To the Editor:

Cardiac troponins are preferred markers of tissue injury in acute coronary syndromes. Their specificity and the fact that only very minute amounts or none are normally found in the circulation provide high clinical sensitivity and specificity even when cardiac lesions are small. The importance of cardiac troponins in identifying high-risk patients to receive active intervention is widely recognized.1

Troponins present substantial challenges with respect to immunoassays, however. They occur as various complexes or fragments and show other forms of heterogeneity.2 In addition, we recently reported3 that serum from many patients contains an interfering factor that prevents the recognition of exogenous and endogenous cardiac troponin I. In such patients with low recovery of added cardiac troponin I, release of cardiac troponin I from injured tissue is detected poorly or only after an interval that may last more than 12 hours. This is especially true of immunoassays, in which the antibodies recognize the stable central portion (mid-fragment) of cardiac troponin I (amino acid residues 30 to 110), the analytic approach currently favored.4

We have found that this interference is due to antibodies to cardiac troponin I or its circulating complexes. We tested serum from 10 patients with low recovery of added cardiac troponin I (0 to 27 percent; median, 10.6 percent) and 10 with normal recovery (91 to 101 percent) for the presence of autoantibodies to cardiac troponin I. Samples were incubated in microtiter wells precoated with cardiac troponin I complexes. The amounts of immunoglobulin were quantified with labeled mouse antihuman antibodies. The box-plot diagram in Figure 1AFigure 1Antibodies to Cardiac Troponin I According to the Level of Recovery of Added Cardiac Troponin I Standard (Panel A) and Measurements of Cardiac Troponin I with Two Different Assays in a Patient with an Acute Coronary Syndrome (Panel B). shows a significant difference in signals between patients with low recovery and those with normal recovery.

The consequence of the presence of autoantibodies with regard to measurements of cardiac troponin I is illustrated in Figure 1B, in which two differently configured assays were used in the follow-up of a low-recovery patient with an acute coronary syndrome. The assay based on two mid-fragment antibodies had negative results for both the sample obtained at admission and that obtained after 6 to 12 hours, whereas an assay that also included antibodies outside the mid-fragment was positive in all three samples tested.

We conclude that autoantibodies to cardiac troponin I can hamper the triage of patients with acute coronary syndrome by causing delays in the detection of cardiac troponin I. At exceptionally high titers, these antibodies may totally mask the release of small amounts of cardiac troponin I. Patients with low recovery are commonly identified with mid-fragment cardiac troponin I assays, and about 10 percent have recovery of less than 50 percent.3 To avoid misclassification of patients with myocardial infarction or delays in identifying them, assays should be made sensitive enough to detect a substantially blocked signal. Preferably, alternative assays should be used to recognize autoantibody complexes. Such improvements may make it possible to use cardiac troponin I not only as a specific marker, but also as an early marker of cardiac injury.

Susann Eriksson, M.Sc.
Jukka Hellman, Ph.D.
Kim Pettersson, Ph.D.
University of Turku, FIN-20520 Turku, Finland
kim.pettersson@utu.fi

Dr. Pettersson reports being a shareholder and board member of Innotrac Diagnostics Oy (Turku, Finland), the manufacturer of the Aio cardiac troponin I kit. The novel assay mentioned in the letter is an investigational assay, but the same basic concept is now being manufactured by Innotrac Diagnostics.

4 References

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   Eriksson S, Junikka M, Laitinen P, Majamaa-Voltti K, Alfthan H, Pettersson K. Negative interference in cardiac troponin I immunoassays from a frequently occurring serum and plasma component. Clin Chem 2003;49:1095-1104
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Citing Articles (16)

Citing Articles

1. 1

   Bertil Lindahl, Per Venge, Kai M. Eggers, Rolf Gedeborg, Noora Ristiniemi, Saara Wittfooth, Kim Pettersson. (2010) Autoantibodies to cardiac troponin in acute coronary syndromes. Clinica Chimica Acta 411:21-22, 1793-1798
   CrossRef

2. 2

   Robb D. Kociol, Peter S. Pang, Mihai Gheorghiade, Gregg C. Fonarow, Christopher M. O'Connor, G. Michael Felker. (2010) Troponin Elevation in Heart Failure. Journal of the American College of Cardiology 56:14, 1071-1078
   CrossRef

3. 3

   R. Jahns. (2010) Autoantibodies against cardiac troponin I: friend or foe?. European Journal of Heart Failure 12:7, 645-648
   CrossRef

4. 4

   H.-D. Dungen, M. Platzeck, J. Vollert, J. Searle, C. Muller, J. Reiche, F. Mehrhof, R. Muller, M. Mockel. (2010) Autoantibodies against cardiac troponin I in patients with congestive heart failure. European Journal of Heart Failure 12:7, 668-675
   CrossRef

5. 5

   N. Vuilleumier, M. F. Rossier, S. Pagano, M. Python, E. Charbonney, R. Nkoulou, R. James, G. Reber, F. Mach, P. Roux-Lombard. (2010) Anti-apolipoprotein A-1 IgG as an independent cardiovascular prognostic marker affecting basal heart rate in myocardial infarction. European Heart Journal 31:7, 815-823
   CrossRef

6. 6

   Ziya Kaya, Hugo A. Katus, Noel R. Rose. (2010) Cardiac troponins and autoimmunity: Their role in the pathogenesis of myocarditis and of heart failure. Clinical Immunology 134:1, 80-88
   CrossRef

7. 7

   Florian Leuschner, Hugo A. Katus, Ziya Kaya. (2009) Autoimmune myocarditis: Past, present and future. Journal of Autoimmunity 33:3-4, 282-289
   CrossRef

8. 8

   Alberto Giannoni, Stefania Giovannini, Aldo Clerico. (2009) Measurement of circulating concentrations of cardiac troponin I and T in healthy subjects: a tool for monitoring myocardial tissue renewal?. Clinical Chemistry and Laboratory Medicine 47:10, 1167-1177
   CrossRef

9. 9

   Maciej Adamczyk, R. Jeffrey Brashear, Phillip G. Mattingly. (2009) Circulating Cardiac Troponin-I Autoantibodies in Human Plasma and Serum. Annals of the New York Academy of Sciences 1173:1, 67-74
   CrossRef

10. 10

    D. Frenkel, A. S. Pachori, L. Zhang, A. Dembinsky-Vaknin, D. Farfara, S. Petrovic-Stojkovic, V. J. Dzau, H. L. Weiner. (2009) Nasal vaccination with troponin reduces troponin specific T-cell responses and improves heart function in myocardial ischemia-reperfusion injury. International Immunology 21:7, 817-829
    CrossRef

11. 11

    J. Latva-Hirvelä, V. Kytö, A. Saraste, S. Eriksson, T. Vuorinen, K. Pettersson, P. Saukko. (2009) Development of troponin autoantibodies in experimental coxsackievirus B3 myocarditis. European Journal of Clinical Investigation 39:6, 457-462
    CrossRef

12. 12

    Pirjo Hedberg, Gitte Wennecke. (2009) A preliminary evaluation of the AQT90 FLEX TnI immunoassay. Clinical Chemistry and Laboratory Medicine 47:3, 376-378
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    F. Leuschner, J. Li, S. Goser, L. Reinhardt, R. Ottl, P. Bride, J. Zehelein, G. Pfitzer, A. Remppis, E. Giannitsis, H. A. Katus, Z. Kaya. (2008) Absence of auto-antibodies against cardiac troponin I predicts improvement of left ventricular function after acute myocardial infarction. European Heart Journal 29:16, 1949-1955
    CrossRef

14. 14

    Shih-Hung Tsai, Shi-Jye Chu, Ching-Wang Hsu, Shu-Meng Cheng, Shih-Ping Yang. (2008) Use and interpretation of cardiac troponins in the ED. The American Journal of Emergency Medicine 26:3, 331-341
    CrossRef

15. 15

    Vlad C Vasile, Allan S Jaffe. (2007) New potential uses for cardiac troponins. Biomarkers in Medicine 1:4, 491-501
    CrossRef

16. 16

    Amy K. Saenger, Allan S. Jaffe. (2007) The Use of Biomarkers for the Evaluation and Treatment of Patients with Acute Coronary Syndromes. Medical Clinics of North America 91:4, 657-681
    CrossRef