Abstract 294: Alterations in Cerebral Mitochondrial Dynamics and Mitochondrial Mass After Successful Cardiopulmonary Resuscitation in a Porcine Model of Pediatric Cardiac Arrest

Abstract

Introduction: A critical convergence point for neurologic injury following cardiac arrest is cerebral mitochondrial (Mt) dysfunction, regulated by Mt dynamics (balance of fusion and fission). Both fusion and fission are important to Mt homeostasis under normal conditions; however, under stress fission can decrease Mt mass and signal apoptosis, while fusion promotes oxidative phosphorylation efficiency. Our group has previously shown hemodynamic directed CPR (HD-CPR) improves Mt bioenergetics compared to AHA depth-guided CPR (DG-CPR), which correlated with better neurologic function. Hypothesis: Compared to DG-CPR, HD-CPR will result in cerebral cortical protein expression consistent with Mt fusion and preservation of mitochondrial mass 24 hours post-ROSC. Methods: One-month-old piglets were designated into three groups: 1) DG-CPR (n=5); 2) HD-CPR (n=5; goal SBP 90 mmHg, goal coronary perfusion pressure 20mmHg); 3) Shams (n=7). Groups 1 and 2 underwent 7 minutes of asphyxia, VF, 10-20 min of CPR, and post-ROSC therapies to maintain hemodynamic, oxygenation and ventilation goals. The primary outcomes were immunoblot quantification of cortical proteins for fusion (Opa-1, Opa-1 long to short chain ratio, MFN-2), fission (DRP-1), and citrate synthase activity for Mt mass. Groups shown as median and IQR and analyzed by Kruskal-Wallis, then Dunn’s multiple comparisons. Results: HD-CPR subjects had increased total Opa-1 expression compared to sham (1.52 [1.02,1.69] vs. 0.47 [0.34,0.51], p=0.001). Opa-1 long to short chain ratio was higher in HD-CPR than both sham (0.64 [0.46,0.92] vs. 0.28 [0.25,0.36], p=0.025) and DG-CPR (0.26 [0.26,0.31], p=0.018). There were no differences in MFN-2 or DRP-1 expression between groups. Mt mass was lower in DG-CPR than sham (11.02 [10.15,12.29] vs. 13.9 [12.35,15.63], p=0.029), but preserved in HD-CPR. Discussion: Piglets treated with HD-CPR exhibited protein expression consistent with Mt fusion, as evidenced by upregulation of total Opa-1, elevated Opa-1 long to short chain ratio, and preservation of Mt mass compared to standard AHA depth guided CPR strategy. We speculate that neurotherapeutics that target Mt dynamics could further improve brain Mt bioenergetics and neurologic function after pediatric CA.