Early Effects of Prolonged Cardiac Arrest and Ischemic Postconditioning during Cardiopulmonary Resuscitation on Cardiac and Brain Mitochondrial Function in Pigs

Abstract

Background Out-of-hospital cardiac arrest (CA) is a prevalent medical crisis resulting in severe injury to the heart and brain and an overall survival of less than 10 percent. Mitochondrial dysfunction is predicted to be a key determinant of poor outcomes following prolonged CA. However, the onset and severity of mitochondrial dysfunction during CA and cardiopulmonary resuscitation (CPR) is not fully understood. Ischemic postconditioning (IPC), controlled pauses during the initiation of CPR, has been shown to improve cardiac function and neurologically favorable outcomes after fifteen minutes of CA. We tested the hypothesis that mitochondrial dysfunction develops during prolonged CA and can be rescued with IPC during CPR (IPC-CPR). Methods 63 swine were randomized to no ischemia (Naïve), nineteen minutes of ventricular fibrillation (VF) CA without CPR (Untreated VF), or fifteen minutes of CA with 4 minutes of reperfusion with either standard CPR (S-CPR) or IPC-CPR. Mitochondria were isolated from the heart and brain to quantify respiration, rate of ATP synthesis, and calcium retention capacity (CRC). Reactive oxygen species (ROS) production was quantified from fresh frozen heart and brain tissue. Results Compared to Naïve, Untreated VF induced cardiac and brain ROS overproduction concurrent with decreased mitochondrial respiratory coupling and CRC, as well as decreased cardiac ATP synthesis. Compared to VF CA, S-CPR attenuated brain ROS overproduction but had no other effect on mitochondrial function in the heart or brain. Compared to VF CA, IPC-CPR improved cardiac mitochondrial respiratory coupling and rate of ATP synthesis, and decreased ROS overproduction in the heart and brain. Conclusions Fifteen minutes of VF CA results in diminished mitochondrial respiration, ATP synthesis, CRC, and increased ROS production in the heart and brain. IPC-CPR attenuates cardiac mitochondrial dysfunction caused by prolonged VF CA after only 4 minutes of reperfusion, suggesting that IPC-CPR is an effective intervention to reduce cardiac injury. However, reperfusion with both CPR methods had limited effect on mitochondrial function in the brain, emphasizing an important physiological divergence in post-arrest recovery between those two vital organs.

Aldehyde Dehydrogenase 2 Protects Against Post-Cardiac Arrest Myocardial Dysfunction Through a Novel Mechanism of Suppressing Mitochondrial Reactive Oxygen Species Production

“…Mitochondria, as the center of energy supply and reactive oxygen species (ROS) production, play a crucial role as targets and drivers of ischemia/reperfusion injury after cardiac arrest (Penna et al, 2013;Matsuura et al, 2017). One mitochondrial feature during the ischemia/reperfusion processes is the ROS production (Zweier et al, 1987;Murphy and Steenbergen, 2008;Chouchani et al, 2014).…”

The influence of time to adrenaline administration in the Paramedic 2 randomised controlled trial

“…Unlike the heart, the brain is more sensitive to tissue ischaemia as it has no myoglobin oxygen stores [23,24]. Furthermore, CPR and vasopressors may be less effective at restoring mitochondrial function in the brain than it is at restoring cardiac mitochondrial performance [25].…”

The Commonalities and Differences in Mitochondrial Dysfunction Between ex vivo and in vivo Myocardial Global Ischemia Rat Heart Models: Implications for Donation After Circulatory Death Research

“…MPTP was induced by sequential pulses of calcium (5 nmol/min). Succinate was used as a substrate in that the CRC is much higher in mitochondria oxidizing a complex II substrate compared to a complex I substrate ( Madungwe et al, 2016 ; Matsuura et al, 2017 ). Extra-mitochondrial Ca 2+ concentration was recorded with 0.5 μM Calcium Green-5N, and fluorescence monitored with excitation and emission wavelengths set at 500 and 530 nm, respectively.…”