Abstract 1362: Degradation of Cardiac Troponins in Atrial Fibrillation is Calpain-dependent

Abstract

Background: The self-perpeptuation of atrial fibrillation (AF) is caused by myocyte remodeling including degradation of cardiac troponins. Additionally, we observed enhanced calpain activity in human AF and in the tachypaced cell model for AF. We assessed the hypothesis that calpain plays a role in the degradation of cardiac troponins during AF. Methods: The tachypaced HL-1 atrial myocyte model was used to investigate degradation of endogenous cardiac troponin T, I and C (cTnT, cTnI, cTnC) as well as actin by Western-blotting. To study degradation of human cTnT, myocytes were transfected with V5-C-human cTnT. Inhibitors of calpain, caspase and proteasome were applied to study the underlying mechanism for degradation. In vivo cTn degradation was studied in atrial tissue from AF and sinus rhythm (SR) patients by Western-blotting. Results: Tachypacing (P, 3Hz) significantly and gradually induced the degradation of cTnT (Fig A ), cTnI and cTnC, compared to control (C, 1Hz), while actin were unaffected. The degradation was prevented by calpain inhibitor PD150606 (20μM), whereas caspase (CAS) and proteasome (MG) inhibition was not effective (Fig C ). Tachypacing of V5-C-human cTnT transfected HL-1 myocytes resulted in a specific degradation fragment of 25kDa, which was prevented by PD (Fig B ). In vivo, persistent AF was associated with specific degradation of cTnT, I and C, compared to patients with SR or paroxysmal AF. Actin levels were not changed. Conclusions: AF induces specific degradation of all cTn isoforms, which is mediated by calpain. Activation of calpain may represent a key component in linking cTn degradation, contractile dysfunction and the self-perpetuation of AF.