Published Online
on October 2, 2006

A more recent version of this article appeared on October 17, 2006

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Submitted on April 23, 2006
Revised on June 23, 2006
Accepted on July 14, 2006

Cardiac Troponin I but Not Cardiac Troponin T Induces Severe Autoimmune Inflammation in the Myocardium

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

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.).

^* To whom correspondence should be addressed. E-mail: ziya.kaya{at}med.uni-heidelberg.de.

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-1, 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.

Key words: heart failure • inflammation • myocarditis • troponin

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