Identification of Cardiac Troponin I Sequence Motifs Leading to Heart Failure by Induction of Myocardial Inflammation and Fibrosis

Abstract

Background-Despite the widespread use of cardiac troponins for diagnosis of myocyte injury and risk stratification in acute cardiac disorders, little is known about the long-term effects of the released troponins on cardiac function. Recently, we showed that an autoimmune response to cardiac troponin I (cTnI) induces severe inflammation and subsequent fibrosis in the myocardium. This autoimmune disorder predisposes to heart failure and cardiac death in mice. Methods and Results-To investigate the role of cTnI-specific T cells, T cells were isolated from splenocytes of mice immunized with murine cTnI (mcTnI). Wild-type mice that received mcTnI-specific T cells showed high mcTnIspecific antibody titers, increased production of the proinflammatory cytokines interleukin-1␤ and tumor necrosis factor-␣, severe inflammation and fibrosis in the myocardium, and reduced fractional shortening. To identify the antigenic determinants of troponin I responsible for the observed inflammation, fibrosis, and heart failure, 16 overlapping 16mer to 18mer peptides covering the entire amino acid sequence of mcTnI (211 residues) were synthesized. Only mice immunized with residues 105 to 122 of mcTnI developed significant inflammation and fibrosis in the myocardium, with increased expression of the inflammatory chemokines RANTES, monocyte chemotactic protein-1, macrophage inflammatory protein-1␣, macrophage inflammatory protein-1␤, macrophage inflammatory protein-2, T-cell activation-3, and eotaxin and the chemokine receptors CCR1, CCR2, and CCR5. Mice immunized with the corresponding human cTnI residues 104 to 121 and the mcTnI residues 131 to 148 developed milder disease. Conclusions-Transfer of troponin I-specific T cells can induce inflammation and fibrosis in wild-type mice, which leads to deterioration of contractile function. Furthermore, 2 sequence motifs of cTnI that induce inflammation and fibrosis in the myocardium are characterized.

Critical role of RAGE and HMGB1 in inflammatory heart disease

“…Therefore, based on the EAM model, our results show for the first time, to our knowledge, that RAGE-ko mice are almost completely protected from developing TnI-induced autoimmune myocarditis. Ablation of RAGE resulted in significantly decreased levels of several inflammatory mediators such as chemokines, chemokine receptors, MMPs, and cytokines, which are important for the pathogenesis of autoimmune myocarditis (20). Additionally, NF-κB binding activity was reduced in immunized RAGE-ko mice.…”

“…This experimental approach enables a reproducible sterile cardiac inflammation, as described previously (1,20). Furthermore, the clinical relevance of both proteins should be investigated.…”

Troponin-Specific Autoantibody Interference in Different Cardiac Troponin I Assay Configurations

“…In addition to the measured autoantibody titers, intraindividual variation in cTnAAb epitope specificities probably affects the degree of interference. In addition, the fine speci- ficity of circulating cTnAAbs calls for more precise characterization in the light of a recently reported study (26 ) in which antibodies targeting different cTnI epitopes were associated with different pathological effects in mice.…”

Anti-cardiac troponin antibodies in clinical human disease: a systematic review

“…As previously described, in an animal model the administration of anti-cardiac troponin I antibodies induced inflammation of the myocardium, dilation of cardiac chambers with fibrosis and a higher mortality (8). In addition, the inoculation of T lymphocytes specific for cardiac troponin I in another animal model induced inflammation, fibrosis and impairment of cardiac contractility (63). In situations of myocardial ischemia the release of cardiac molecules (self-antigens) may occur and these, if recognized by the immune system, may initiate mechanisms of autoimmunity.…”