TY - JOUR
T1 - Cardiac troponin I but not cardiac troponin T induces severe autoimmune inflammation in the myocardium
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
PY - 2006/10
Y1 - 2006/10
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.
KW - Heart failure
KW - Inflammation
KW - Myocarditis
KW - Troponin
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U2 - 10.1161/CIRCULATIONAHA.106.635664
DO - 10.1161/CIRCULATIONAHA.106.635664
M3 - Article
C2 - 17015788
AN - SCOPUS:33750200769
SN - 0009-7322
VL - 114
SP - 1693
EP - 1702
JO - Circulation
JF - Circulation
IS - 16
ER -