Increased cerebral mitochondrial dysfunction and reactive oxygen species with cardiopulmonary bypass

Abstract

OBJECTIVES Neurodevelopmental injury after cardiac surgery using cardiopulmonary bypass (CPB) for congenital heart defects is common, but the mechanism behind this injury is unclear. This study examines the impact of CPB on cerebral mitochondrial reactive oxygen species (ROS) generation and mitochondrial bioenergetics. METHODS Twenty-three piglets (mean weight 4.2 ± 0.5 kg) were placed on CPB for either 1, 2, 3 or 4 h (n = 5 per group) or underwent anaesthesia without CPB (sham, n = 3). Microdialysis was used to measure metabolic markers of ischaemia. At the conclusion of CPB or 4 h of sham, brain tissue was harvested. Utilizing high-resolution respirometry, with simultaneous fluorometric analysis, mitochondrial respiration and ROS were measured. RESULTS There were no significant differences in markers of ischaemia between sham and experimental groups. Sham animals had significantly higher mitochondrial respiration than experimental animals, including maximal oxidative phosphorylation capacity of complex I (OXPHOSCI) (3.25 ± 0.18 vs 4-h CPB: 1.68 ± 0.10, P < 0.001) and maximal phosphorylating respiration capacity via convergent input through complexes I and II (OXPHOSCI+CII) (7.40 ± 0.24 vs 4-h CPB: 3.91 ± 0.20, P < 0.0001). At 4-h, experimental animals had significantly higher ROS related to non-phosphorylating respiration through complexes I and II (ETSCI+CII) than shams (1.08 ± 0.13 vs 0.64 ± 0.04, P = 0.026). CONCLUSIONS Even in the absence of local markers of ischaemia, CPB is associated with decreased mitochondrial respiration relative to shams irrespective of duration. Exposure to 4 h of CPB resulted in a significant increase in cerebral mitochondrial ROS formation compared to shorter durations. Further study is needed to improve the understanding of cerebral mitochondrial health and its effects on the pathophysiology of neurological injury following exposure to CPB.

Proton magnetic resonance spectroscopy assessment of neonatal brain metabolism during cardiopulmonary bypass surgery

“…The finding of increased Lac during DHCA was consistent with previous reports of high Lac levels as measured by microdialysis 44 ; however, the dynamic MRS measurements also permitted measurement of both the Lac production rate and Lac/Glc ratios. Although reduction of brain glucose and increase of Lac were generally consistent with previous DHCA studies, 44 we observed a large deviation during CA from the stoichiometric predicted glycolytic value of ΔLac/ΔGlc of 2, whereby, under anaerobic conditions, each Glu molecule should generate two Lac molecules.…”

Chronic hypoxemia induces mitochondrial respiratory complex gene expression in the fetal sheep brain

“…Therapies that target various aspects of mitochondrial function and ROS production have been shown to decrease synaptic plasticity, improve communication deficits, and motor impairments in patients with congenital mitochondrial deficits 31 and thus may represent a potential focal point for future interventions in children with CHD. Furthermore, how complex I adapts to additional stressors such a cardiopulmonary bypass 32 or sudden increase in oxygen tension in the brain postpartum, either during mechanical ventilation and perioperative, is a critical knowledge gap, as increased oxygen tension postoperatively could provide more cellular fuel for ROS production following conformational dynamic changes of complex I discovered in this study.…”

4,7-Didehydro-neophysalin B Protects Rat Lung Epithelial Cells against Hydrogen Peroxide-Induced Oxidative Damage through Nrf2-Mediated Signaling Pathway

“…Studies have shown that the damage caused by oxidative stress is mediated by reactive oxygen species which plays an important role in neurodegenerative diseases [ 20 , 21 ]. H 2 O 2 produced in the body during metabolism is equivalent to reactive oxygen species and can aggravate the body oxidative stress injury [ 22 , 23 ]. The results of this study showed that H 2 O 2 induced oxidative damage and apoptosis in RLE-6TN cells which was reduced by 4,7-didehydro-neophysalin B treatment as shown in Figure 2(c) .…”