Cardiac depression after multiple trauma – diagnostic and therapeutic effects of microRNAs

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Heart injury reflected by high serum levels of cardiac troponin frequently occurs after severe trauma and is associated with a poor overall outcome. Cardiac injuries after trauma mainly correlate with an enhanced local and systemic inflammatory response and with increased systemic activation of the innate immune system, including the release of pro-inflammatory cytokines, complement activation products and damage associated molecular patterns (DAMPs). Locally, cardiac damage after trauma is characterized by impaired calcium handling, disturbed mitochondrial function, metabolic and structural alterations, gap junction pathologies and apoptosis. miRNAs were shown to play an important role in various aspects of cardiac pathophysiology in different species in vivo and in vitro. After trauma miRNAs have been demonstrated to be differentially expressed systemically. Thus far, different molecular mechanisms of miRNA action on the heart have been described. Calcium handling, inflammation, apoptosis, NLRP3 caspase-1-induced pyroptosis and gap junctions are addressed by miRNAs. However, the potential of miRNAs as novel biomarkers for diagnosis of cardiac damage after trauma in different species and their therapeutic efficiency have not been elucidated yet. Therefore, in the proposed project the presence of miRNAs in blood, heart and urine will be assessed and correlated with myocardial damage in experimental polytrauma. Clinically highly relevant and transferable models of porcine and murine multiple trauma will be utilized. To shed light on the prognostic and diagnostic role of systemic miRNAs in the development of post-traumatic myocardial damage, systemically differentially expressed miRNA will be correlated with cardiac function, local cardiac damage, apoptosis, nitrosative and oxidative stress and with systemic and myocardial inflammation. Furthermore, in blood plasma from selected severely injured patients systemically differentially expressed miRNAs will be examined together with cardiac damage markers. Also, functional analysis of the heart via transthoracic echocardiography and electrocardiographic recordings (ECG) will be utilized to quantify cardiac damage and correlate with miRNA expression. Furthermore, the therapeutic application of miRNAs/antagomirs will be tested with regard to their potential to alleviate myocardial damage in vitro in human cardiomyocytes.