Cardiac troponin I but not cardiac troponin T induces severe autoimmune inflammation in the myocardium

Stefan Göser, Martin Andrassy, Sebastian J. Buss, Florian Leuschner, Christian H. Volz, Renate Öttl, Stefan Zittrich, Natascha Blaudeck, Stefan E. Hardt, Gabriele Pfitzer, Noel R. Rose, Hugo A. Katus, Ziya Kaya

Research output: Contribution to journalArticle

Abstract

BACKGROUND - Cardiac troponins in blood are the most preferred markers of myocardial damage. The fact that they are normally not found in the circulation provides a high level of clinical sensitivity and specificity even when cardiac lesions are small. After myocardial injury, the troponins enter the circulation, where they can be used for diagnosis of acute coronary syndromes. Thus, the cardiac troponins are paramount for disease classification and risk stratification. However, little is known about the long-term effects of the released troponins on cardiac function. METHODS AND RESULTS - In this study we prepared recombinant murine cardiac troponin I (mc-TnI) and murine cardiac troponin T and used them to immunize mice. We report that A/J mice immunized with mc-TnI developed severe inflammation of the myocardium with increased expression of inflammatory chemokines RANTES (regulated on activation normal T cell expressed and secreted), monocyte chemoattractant protein-1, macrophage inflammatory protein (MIP)-1α, MIP-1β, MIP-2, T-cell activation gene 3, and eotaxin and chemokine receptors CCR1, CCR2, and CCR5. The inflammation was followed by cardiomegaly, fibrosis, reduced fractional shortening, and 30% mortality over 270 days. In contrast, mice immunized with murine cardiac troponin T or with the control buffer showed little or no inflammation and no death. Furthermore, we demonstrate that mice preimmunized with mc-TnI before left anterior descending coronary artery ligation showed greater infarct size, more fibrosis, higher inflammation score, and reduced fractional shortening. CONCLUSIONS - Overall, our results show for the first time that provocation of an autoimmune response to mc-TnI induces severe inflammation in the myocardium followed by fibrosis and heart failure with increased mortality in mice.

Original languageEnglish (US)
Pages (from-to)1693-1702
Number of pages10
JournalCirculation
Volume114
Issue number16
DOIs
StatePublished - Oct 2006

Fingerprint

Troponin T
Troponin I
Troponin
Myocardium
Inflammation
Macrophage Inflammatory Proteins
Fibrosis
Chemokine CXCL2
T-Lymphocytes
Mortality
Chemokine CCL2
Chemokine Receptors
Cardiomegaly
Acute Coronary Syndrome
Autoimmunity
Chemokines
Transcriptional Activation
Ligation
Coronary Vessels
Buffers

Keywords

  • Heart failure
  • Inflammation
  • Myocarditis
  • Troponin

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Göser, S., Andrassy, M., Buss, S. J., Leuschner, F., Volz, C. H., Öttl, R., ... Kaya, Z. (2006). Cardiac troponin I but not cardiac troponin T induces severe autoimmune inflammation in the myocardium. Circulation, 114(16), 1693-1702. https://doi.org/10.1161/CIRCULATIONAHA.106.635664

Cardiac troponin I but not cardiac troponin T induces severe autoimmune inflammation in the myocardium. / Göser, Stefan; Andrassy, Martin; Buss, Sebastian J.; Leuschner, Florian; Volz, Christian H.; Öttl, Renate; Zittrich, Stefan; Blaudeck, Natascha; Hardt, Stefan E.; Pfitzer, Gabriele; Rose, Noel R.; Katus, Hugo A.; Kaya, Ziya.

In: Circulation, Vol. 114, No. 16, 10.2006, p. 1693-1702.

Research output: Contribution to journalArticle

Göser, S, Andrassy, M, Buss, SJ, Leuschner, F, Volz, CH, Öttl, R, Zittrich, S, Blaudeck, N, Hardt, SE, Pfitzer, G, Rose, NR, Katus, HA & Kaya, Z 2006, 'Cardiac troponin I but not cardiac troponin T induces severe autoimmune inflammation in the myocardium', Circulation, vol. 114, no. 16, pp. 1693-1702. https://doi.org/10.1161/CIRCULATIONAHA.106.635664
Göser, Stefan ; Andrassy, Martin ; Buss, Sebastian J. ; Leuschner, Florian ; Volz, Christian H. ; Öttl, Renate ; Zittrich, Stefan ; Blaudeck, Natascha ; Hardt, Stefan E. ; Pfitzer, Gabriele ; Rose, Noel R. ; Katus, Hugo A. ; Kaya, Ziya. / Cardiac troponin I but not cardiac troponin T induces severe autoimmune inflammation in the myocardium. In: Circulation. 2006 ; Vol. 114, No. 16. pp. 1693-1702.
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abstract = "BACKGROUND - Cardiac troponins in blood are the most preferred markers of myocardial damage. The fact that they are normally not found in the circulation provides a high level of clinical sensitivity and specificity even when cardiac lesions are small. After myocardial injury, the troponins enter the circulation, where they can be used for diagnosis of acute coronary syndromes. Thus, the cardiac troponins are paramount for disease classification and risk stratification. However, little is known about the long-term effects of the released troponins on cardiac function. METHODS AND RESULTS - In this study we prepared recombinant murine cardiac troponin I (mc-TnI) and murine cardiac troponin T and used them to immunize mice. We report that A/J mice immunized with mc-TnI developed severe inflammation of the myocardium with increased expression of inflammatory chemokines RANTES (regulated on activation normal T cell expressed and secreted), monocyte chemoattractant protein-1, macrophage inflammatory protein (MIP)-1α, MIP-1β, MIP-2, T-cell activation gene 3, and eotaxin and chemokine receptors CCR1, CCR2, and CCR5. The inflammation was followed by cardiomegaly, fibrosis, reduced fractional shortening, and 30{\%} mortality over 270 days. In contrast, mice immunized with murine cardiac troponin T or with the control buffer showed little or no inflammation and no death. Furthermore, we demonstrate that mice preimmunized with mc-TnI before left anterior descending coronary artery ligation showed greater infarct size, more fibrosis, higher inflammation score, and reduced fractional shortening. CONCLUSIONS - Overall, our results show for the first time that provocation of an autoimmune response to mc-TnI induces severe inflammation in the myocardium followed by fibrosis and heart failure with increased mortality in mice.",
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AU - Göser, Stefan

AU - Andrassy, Martin

AU - Buss, Sebastian J.

AU - Leuschner, Florian

AU - Volz, Christian H.

AU - Öttl, Renate

AU - Zittrich, Stefan

AU - Blaudeck, Natascha

AU - Hardt, Stefan E.

AU - Pfitzer, Gabriele

AU - Rose, Noel R.

AU - Katus, Hugo A.

AU - Kaya, Ziya

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N2 - BACKGROUND - Cardiac troponins in blood are the most preferred markers of myocardial damage. The fact that they are normally not found in the circulation provides a high level of clinical sensitivity and specificity even when cardiac lesions are small. After myocardial injury, the troponins enter the circulation, where they can be used for diagnosis of acute coronary syndromes. Thus, the cardiac troponins are paramount for disease classification and risk stratification. However, little is known about the long-term effects of the released troponins on cardiac function. METHODS AND RESULTS - In this study we prepared recombinant murine cardiac troponin I (mc-TnI) and murine cardiac troponin T and used them to immunize mice. We report that A/J mice immunized with mc-TnI developed severe inflammation of the myocardium with increased expression of inflammatory chemokines RANTES (regulated on activation normal T cell expressed and secreted), monocyte chemoattractant protein-1, macrophage inflammatory protein (MIP)-1α, MIP-1β, MIP-2, T-cell activation gene 3, and eotaxin and chemokine receptors CCR1, CCR2, and CCR5. The inflammation was followed by cardiomegaly, fibrosis, reduced fractional shortening, and 30% mortality over 270 days. In contrast, mice immunized with murine cardiac troponin T or with the control buffer showed little or no inflammation and no death. Furthermore, we demonstrate that mice preimmunized with mc-TnI before left anterior descending coronary artery ligation showed greater infarct size, more fibrosis, higher inflammation score, and reduced fractional shortening. CONCLUSIONS - Overall, our results show for the first time that provocation of an autoimmune response to mc-TnI induces severe inflammation in the myocardium followed by fibrosis and heart failure with increased mortality in mice.

AB - BACKGROUND - Cardiac troponins in blood are the most preferred markers of myocardial damage. The fact that they are normally not found in the circulation provides a high level of clinical sensitivity and specificity even when cardiac lesions are small. After myocardial injury, the troponins enter the circulation, where they can be used for diagnosis of acute coronary syndromes. Thus, the cardiac troponins are paramount for disease classification and risk stratification. However, little is known about the long-term effects of the released troponins on cardiac function. METHODS AND RESULTS - In this study we prepared recombinant murine cardiac troponin I (mc-TnI) and murine cardiac troponin T and used them to immunize mice. We report that A/J mice immunized with mc-TnI developed severe inflammation of the myocardium with increased expression of inflammatory chemokines RANTES (regulated on activation normal T cell expressed and secreted), monocyte chemoattractant protein-1, macrophage inflammatory protein (MIP)-1α, MIP-1β, MIP-2, T-cell activation gene 3, and eotaxin and chemokine receptors CCR1, CCR2, and CCR5. The inflammation was followed by cardiomegaly, fibrosis, reduced fractional shortening, and 30% mortality over 270 days. In contrast, mice immunized with murine cardiac troponin T or with the control buffer showed little or no inflammation and no death. Furthermore, we demonstrate that mice preimmunized with mc-TnI before left anterior descending coronary artery ligation showed greater infarct size, more fibrosis, higher inflammation score, and reduced fractional shortening. CONCLUSIONS - Overall, our results show for the first time that provocation of an autoimmune response to mc-TnI induces severe inflammation in the myocardium followed by fibrosis and heart failure with increased mortality in mice.

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KW - Myocarditis

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