Targeting Oxygen-Induced Mitochondrial Fission to Improve Post-Resuscitation Outcomes Following Cardiac Arrest

Sudden cardiac arrest (CA) is a leading cause of death, and post-resuscitation injury risks survival in the days following. Recent studies suggest excessive oxygen following CA may contribute to poor outcomes. We hypothesize that oxygen-mediated mitochondrial injury is caused by Dynamin-Related Protein 1 (Drp1), and if we target Drp1, it can alleviate oxygen toxicity, improving survival and recovery. To test this hypothesis, a mouse model of CA is utilized, in which the mice undergo 12 minutes of asystole followed by cardiopulmonary resuscitation (CPR). One hour after resuscitation, mice are separated into groups, receiving hyperoxia (33% O2), hypoxia (10% O2), or normoxia (21% O2) for 6 hours, 24 and 240 hours post-resuscitation, mitochondrial function, cardiac function, neurological scores, and survival rates are assessed. Then Drp1 GTPase inhibitor is administered. Hyperoxic mice showed significantly lower 10-day survival rates (15%) than hypoxic mice (92%, p < 0.05). Hyperoxic mice also showed reduced myocardial fractional shortening and neurological scores (p < 0.05), and increased expression of Drp1 in the heart. In hyperoxic mice the Drp1 inhibitor significantly improved survival, myocardial function, and neurological scores, suggesting that oxygen-induced mitochondrial injury can be reduced with lower oxygen saturation and Drp1-driven mitochondrial fission can improv outcomes.