Identification of cardiac troponin I sequence motifs leading to heart failure by induction of myocardial inflammation and fibrosis

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 (cTnl) 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 cTnl-specific T cells, T cells were isolated from splenocytes of mice immunized with murine cTnl (mcTnl). Wild-type mice that received mcTnl-specific T cells showed high mcTnl-specific antibody titers, increased production of the proinflammatory cytokines interleukin-1β and tumor necrosis factor-α, 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 mcTnl (211 residues) were synthesized. Only mice immunized with residues 105 to 122 of mcTnl developed significant inflammation and fibrosis in the myocardium, with increased expression of the inflammatory chemokines RANTES, monocyte chemotactic protein-1, macrophage inflammatory protein-1α, macrophage inflammatory protein-1β, macrophage inflammatory protein-2, T-cell activation-3, and eotaxin and the chemokine receptors CCRl, CCR2, and CCR5. Mice immunized with the corresponding human cTnl residues 104 to 121 and the mcTnl 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 cTnl that induce inflammation and fibrosis in the myocardium are characterized.