Abstract P1053: Circulating Mitochondrial DNA Level Is A Biomarker Of Acute Myocardial Infarction And Mediates Cardiac Ischemia-reperfusion Injury

Abstract

Introduction: Ischemia/reperfusion (I/R) injury occurs after reperfusion, causing significant myocardial damage. Circulating mitochondrial DNA (mtDNA) levels are elevated in acute myocardial infarction patients, and act as Damage Associated Molecular Patterns (mtDNA DAMP) that induce inflammation via immune processes, including the toll-like receptor 9 (TLR9) pathway. However, mtDNA DAMP levels have not been measured in ST-elevation myocardial infarction (STEMI) patients before and after percutaneous coronary intervention (PCI) and the role of mtDNA DAMPs in I/R injury remains unknown. Hypothesis: Pre- and post-PCI levels of mtDNA DAMPs serve as markers of STEMI related cardiac injury. Limiting mtDNA DAMP levels by increasing autophagy or blocking their downstream effects on TLR9 will decrease cardiac I/R injury. Methods: Troponin and mtDNA DAMP levels were measured pre- and 24 hours post- PCI in 55 STEMI patients (90%-100% blockage) and compared to 37 healthy controls. MtDNA DAMP levels in cell-free plasma were measured by real-time qPCR. Using a C57BL6J mouse model of I/R injury, Tat-Beclin (TB, an autophagy inducer), ODN2088 (a TLR9 inhibitor) or negative control were given at reperfusion and infarct size, cardiac function, and mtDNA DAMP levels were determined. Results: Pre- PCI mtDNA DAMP levels were increased ~200 folds (p<0.0001) in STEMI patients compared to healthy controls; post- PCI mtDNA DAMP levels were significantly decreased in the majority of patients. In contrast, troponin T levels increased, suggesting that mtDNA DAMP levels are early markers of STEMI. Interestingly, a greater decrease in mtDNA DAMP levels was associated with shorter symptom-to-PCI time. In mice, both TB induction of autophagy and TLR9 blockage by ODN2088 decreased infarct size by ~50% and preserved systolic function. As expected, TB induction of autophagy decreased mtDNA DAMP levels, while ODN2088 had no impact on mtDNA DAMP levels. Conclusions: Circulating mtDNA DAMP level is an early marker of STEMI and may predict the success of early PCI. Moreover, limiting the downstream effects of mtDNA DAMPs via induction of autophagy or blocking their action on TLR9 ameliorates cardiac I/R injury, and thus may provide a viable therapeutic avenue for STEMI patients.