Abstract P1039: Overexpressing Mitochondrial Transcription Factor A Protects Against Myocardial 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. Patients who survive CA frequently develop multi-system injury, including cardiac dysfunction and reduced cardiac ejection fraction (EF). Nearly 25% of these patients die from cardiogenic shock. This cardiac injury is primarily attributed to ischemia-reperfusion injury. Mitochondria make up 30% of the heart by volume and are a major site of ischemia-reperfusion damage. Such damage affects mitochondrial DNA (mtDNA), but these changes may be limited by manipulating mitochondrial transcription factor A (TFAM). 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 with potassium chloride, followed by cardiopulmonary resuscitation. Surviving mice were assessed by echocardiography at 1-day, 1-week, and 4-weeks and monitored for survival over the time 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%) compared to WT mice (38.49±3.76%) at one day and improved survival over 4 weeks. Bulk-RNA sequencing implicated changes to ribosomal expression and protein synthesis in the arrest TFAM OE mice. Western blot analysis of 1-day post-arrest hearts demonstrated increased expression of multiple heat shock proteins and increased phosphorylation of eukaryotic translation initiation factor 4E-binding protein (4E-BP1), 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, a novel potential pathway for improving outcomes after arrest.