Abstract 16: Cardiac Mitochondrial Transcription Factor A Overexpression Protects Against Stunning and Improves Mortality in a Mouse Model of Cardiac Arrest

Abstract

Background: Cardiac arrest (CA) affects over 600,000 Americans every year and is associated with overwhelming mortality. After CA, myocardial stunning is a common occurrence leading to reduced cardiac output, and nearly 25% of CA die from cardiogenic shock. This cardiac injury is driven by ischemia-reperfusion injury. Mitochondria make up 30% of the heart by volume and are highly prone to ischemia-reperfusion damage. This damage may impair mitochondrial DNA (mtDNA), which is necessary for maintaining mitochondrial function. Mitochondrial transcription factor A (TFAM) can bind and protect mtDNA from damage. In this study, we investigated the role of cardiac-specific TFAM overexpression on cardiac function after CA in a mouse model. Methods: Wild-type (WT) and transgenic mice featuring cardiac-specific TFAM overexpression (TFAM OE) were subjected to 8-min of asystole by direct injection of potassium chloride and were revived by cardiopulmonary resuscitation. Surviving mice were assessed by echocardiography and monitored for survival over 4 weeks frame. Hearts were collected and sent for bulk RNA sequencing as well as assessment of mtDNA copy number, mitochondrial morphology, and protein expression. Results: TFAM OE mice express 40% more TFAM than WT littermates. TFAM OE mice had protected cardiac EF (51.11±2.95%) one day after CA when compared to WT mice (38.49±3.76%) and improved survival over 4 weeks. Bulk-RNA sequencing implicated dramatic changes to ribosomal expression and protein synthesis in the arrest TFAM OE mice. Western blot analysis of 1-day post-arrest hearts demonstrated increased markers of mRNA translation, including increased phosphorylation of eukaryotic translation initiation factor 4E-binding protein (4E-BP1) and ribosomal protein S6, suggesting that TFAM OE mice support protein translation to aid in cardiac recovery after arrest. Conclusions: Cardiac TFAM overexpression protects cardiac function and survival after cardiac arrest. Early evidence suggests that this protection may be mediated by supporting protein translation, which may offer a novel pathway for improving outcomes after arrest.