Published online before print October 2, 2006, doi: 10.1161/CIRCULATIONAHA.106.635664
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(Circulation. 2006;114:1693-1702.)
© 2006 American Heart Association, Inc.
Heart Failure |
Cardiac Troponin I but Not Cardiac Troponin T Induces Severe Autoimmune Inflammation in the Myocardium
From the Department of Internal Medicine III, University of Heidelberg, Heidelberg, Germany (S.G., M.A., S.B., F.L., C.H.V., R.Ö., S.E.H., H.A.K., Z.K.); Institute of Vegetative Physiology, University of Cologne, Cologne, Germany (S.Z., N.B., G.P.); and Departments of Pathology and Molecular Microbiology and Immunology, Johns Hopkins Medical Institutions, Baltimore, Md (N.R.R.).
Correspondence to Ziya Kaya, MD, Department of Internal Medicine III, Cardiology, University of Heidelberg, 69120 Heidelberg, Germany. E-mail ziya.kaya{at}med.uni-heidelberg.de
Received April 23, 2006; revision received June 23, 2006; accepted July 14, 2006.
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)–1
, MIP-1ß, 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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