Moderated Poster Session - Heart245The involvement of TWEAK and FN14 in murine autoimmune myocarditis246Sympathetic neurons that innervate the heart locally modulate cardiomyocyte trophic and electrophysiological properties247W4R variant of CSRP3 leads to the expression of a novel alternate reading frame protein due to alternative splicing248Glucocorticoid intervention prenatally: effects on fetal heart maturation249Uncoupling of myofilament Ca2+-sensitivity from troponin I phosphorylation by hypertrophic and dilated cardiomyopathy mutations can be reversed by EGCG and related Hsp90 inhibitors250Investigating inherited HCM caused by SCO2 and PRKAG2 mutations using the patients' induced pluripotent stem cell-derived cardiomyocytes

Background: Myocarditis, defined as an inflammation of the myocardium, can be caused by autoimmune reactions. To study these immune reactions our group developed a mouse model of experimental autoimmune myocarditis (EAM). Little is known about the role of the innate immune system in the pathogenesis of this autoimmune disorder. However, it was already observed that the cytokine tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor-inducible 14 (FN14) play a pivotal role in different inflammatory diseases. Thus, we studied the involvement of TWEAK and FN14 in the development of inflammatory cardiomyopathy. Methods and Results: A/J mice were immunised with cardiac troponine I (cTnI) to induce an EAM followed by cardiomegaly, fibrosis and reduced ejection fraction (EF). To determine the severity of myocardial damage hsTnT levels were measured. Here, mice lacking FN14 (FN14-/-) displayed a significantly lower hsTnT level compared to wildtype (wt) littermates (FN14-/-: 625±193pg/mL vs. wt: 3119±1047pg/mL). Furthermore, transthoracic echocardiography showed an improved EF (FN14-/-: 79±3% vs. wt: 75±3%). Histological examination of heart sections demonstrated less inflammation and fibrosis of the myocardium in FN14-/- -mice (inflammation score: FN14-/-: 2.64±0.39 vs. wt: 3.56±0.53; fibrosis score: FN14-/-: 2.46±0.55 vs. wt: 3.22±0.66). Moreover, lower cTnI antibody titers were detectable in ELISA. In contrast, TWEAK-/- -mice displayed a higher hs-TnT level (TWEAK-/-: 3749±1423pg/mL vs. wt: 1171± 499pg/mL), a decreased EF (TWEAK-/-: 79±2% vs. wt: 84±2%), severe inflammation and fibrosis (inflammation score: TWEAK-/-: 3.43±0.65 vs. wt: 2.57±0.53; fibrosis score: TWEAK-/-: 3.29±0.75 vs. wt: 2.43±0.57) and higher cTnI antibody titers compared to wt littermates. Conclusion: TWEAK and FN14 may play an important role in the pathogenesis of autoimmune myocarditis. While the absence of FN14 led to a better disease outcome, mice lacking TWEAK are heavily affected by cTnI immunisation and showed an increased impairment of cardiac function. This result refers to a TWEAK-independent FN14 signalling cascade, which seems to be involved in disease development. Thus, inhibition of FN14 might represent a novel therapeutic strategy in the treatment of inflammatory cardiomyopathy.