(1514) Hippocampal Mitochondrial Dysfunction Persists for 7 Days in a Swine Pediatric Cardiac Arrest Model

Introduction: Following cardiac arrest (CA), mitochondrial electron transport dysfunction develops shortly after cerebral reperfusion and is a critical component of secondary brain injury. In our lab’s prior work, cerebral mitochondrial bioenergetic dysfunction was present 24h after resuscitation in a swine model of pediatric CA. We sought to examine if mitochondrial dysfunction persists at 7 days post-resuscitation to develop mechanisms of action for targeted neurotherapeutics.

Methods: 4-week-old swine (Sus scrofa domesticus) underwent 7 min of asphyxia followed by induction of ventricular fibrillation and guideline-based CPR (rate 100/min, depth of 1/3 the anterior-posterior chest diameter, intravenous epinephrine every 4 min) with defibrillation attempts beginning at 15 minutes of CPR. Successfully resuscitated animals were survived for 7 days prior to sacrifice. Cortical and hippocampal mitochondrial bioenergetic function was assessed by high-resolution respirometry (Oroboros) using established substrate and inhibitor combinations and normalized to citrate synthase activity (CS). Six age- and sex-matched shams were included as controls. Wilcoxon rank-sum test compared CA to sham animals.

Results: Of 15 CA animals, 10 achieved ROSC and 7 survived for 7 days. Hippocampal mitochondrial respiration was analyzable for 6 CA and 5 sham animals. Animals after CA demonstrated lower oxidative-phosphorylation (OX-PHOS) complex I + II capacity vs sham animals (median 3.00 IQR: [2.53-3.62] vs 4.41 [4.24-4.42] pmols O2 / (s*mg*CS) , P< 0.05). We did not detect a difference in OX-PHOS complex I capacity after CA vs shams (1.39 [1.22-1.47] vs. 1.94 [1.74-2.11], P=0.052). Complex IV capacity did not differ after CA vs sham (4.80 [4.25-5.69] vs. 5.47 [5.32-6.03], P=0.33). Similarly, there was no difference in hippocampal leak, or electron transport system capacity after CA vs. sham (P>0.05). In the cortex, no component of mitochondrial bioenergetic capacity differed between CA and sham animals (P>0.05 for all comparisons).

Conclusions: Hippocampal mitochondrial dysfunction persists 7 days after successful resuscitation from asphyxia-associated CA. Future studies should test targeted therapies to improve mitochondrial function.