Haemodynamic-directed cardiopulmonary resuscitation promotes mitochondrial fusion and preservation of mitochondrial mass after successful resuscitation in a pediatric porcine model

Abstract

ObjectiveCerebral mitochondrial dysfunction is a key mediator of neurologic injury following cardiac arrest (CA) and is regulated by the balance of fusion and fission (mitochondrial dynamics). Under stress, fission can decrease mitochondrial mass and signal apoptosis, while fusion promotes oxidative phosphorylation efficiency. This study evaluates mitochondrial dynamics and content in brain tissue 24h after CA between two cardiopulmonary resuscitation (CPR) strategies. InterventionsPiglets (1 month), previously randomized to three groups: (1) Std-CPR (n=5); (2) HD-CPR (n=5; goal systolic blood pressure 90mmHg, goal coronary perfusion pressure 20mmHg); (3) Shams (n=7). Std-CPR and HD-CPR groups underwent 7min of asphyxia, 10min of CPR, and standardized post-resuscitation care. Primary outcomes: (1) cerebral cortical mitochondrial protein expression for fusion (OPA1, OPA1 long to short chain ratio, MFN2) and fission (DRP1, FIS1), and (2) mitochondrial mass by citrate synthase activity. Secondary outcomes: (1) intra-arrest haemodynamics and (2) cerebral performance category (CPC) at 24h. ResultsHD-CPR subjects had higher total OPA1 expression compared to Std-CPR (1.52; IQR 1.02–1.69 vs 0.67; IQR 0.54−0.88, p=0.001) and higher OPA1 long to short chain ratio than both Std-CPR (0.63; IQR 0.46−0.92 vs 0.26; IQR 0.26−0.31, p=0.016) and shams. Citrate synthase activity was lower in Std-CPR than sham (11.0; IQR 10.15–12.29 vs 13.4; IQR 12.28–15.66, p=0.047), but preserved in HD-CPR. HD-CPR subjects had improved intra-arrest haemodynamics and CPC scores at 24h compared to Std-CPR. ConclusionsFollowing asphyxia-associated CA, HD-CPR exhibits increased pro-mitochondrial fusion protein expression, preservation of mitochondrial mass, improved haemodynamics and superior neurologic scoring compared to Std-CPR. Institutional protocol numberIAC 16-001023.