Abstract 1583: Identification of Cardiac Troponin I Sequence Motifs Leading to Heart Failure by Inducing Myocardial Inflammation and Fibrosis
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 induces severe inflammation and subsequent fibrosis in the myocardium. This autoimmune disorder predisposes in mice to heart failure and cardiac death. To investigate the role of cTnI-specific T-cells, T-cells were isolated from splenocytes of mice immunized with murine cardiac troponin I (mcTnI). WT mice receiving mcTnI-specific T-cells showed high mcTnI-specific antibody titers, increased production of pro-inflammatory cytokines IL-1β and TNF-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 16–18mer peptides covering the entire amino acid sequence of mcTnI (211 residues) were synthesized. Only mice immunized with the residues 105–122 of mcTnI developed significant inflammation and fibrosis in the myocardium with increased expression of inflammatory chemokines RANTES, MCP-1, MIP-1α, MIP-1β, MIP-2, TCA-3, eotaxin and chemokine receptors CCR1, CCR2, CCR5. Mice immunized with the corresponding human cTnI residues 104 –121 and the mcTnI residues 131–148 developed milder disease. Transfer of troponin I-specific T-cells can induce inflammation and fibrosis in WT mice leading to deterioration of contractile function. Furthermore, two sequence motifs of cTnI that induce inflammation and fibrosis in the myocardium could be characterized.