Characterization of mitochondrial injury after cardiac arrest (COMICA)

Abstract

Introduction Mitochondrial injury post-cardiac arrest has been described in pre-clinical settings but the extent to which this injury occurs in humans remains largely unknown. We hypothesized that increased levels of mitochondrial biomarkers would be associated with mortality and neurological morbidity in post-cardiac arrest subjects. Methods We performed a prospective multicenter study of post-cardiac arrest subjects. Inclusion criteria were comatose adults who suffered an out-of-hospital cardiac arrest. Mitochondrial biomarkers were measured at 0, 12, 24, 36 and 48 hours after return of spontaneous circulation as well as in healthy controls. Results Out of 111 subjects enrolled, 102 had evaluable samples at 0 hours. Cardiac arrest subjects had higher baseline cytochrome c levels compared to controls (2.18 ng/mL [0.74, 7.74] vs. 0.16 ng/mL [0.03, 0.91], p<0.001), and subjects who died had higher 0 hours cytochrome c levels compared to survivors (3.66 ng/mL [1.40, 14.9] vs. 1.27 ng/mL [0.16, 2.37], p<0.001). There were significantly higher RNAase P (3.3 [1.2, 5.7] vs. 1.2 [0.8, 1.2], p<0.001) and B2M (12.0 [1.0, 22.9], vs. 0.6 [0.6, 1.3], p<0.001) levels in cardiac arrest subjects at baseline compared to the control subjects. There were no differences between survivors and non-survivors for mitochondrial DNA, nuclear DNA, or cell free DNA. Conclusions Cytochrome C was increased in post-cardiac arrest subjects compared to controls, and in post-cardiac arrest non-survivors compared to survivors. Nuclear DNA and cell free DNA was increased in plasma of post-cardiac arrest subjects. There were no differences in mitochondrial DNA, nuclear DNA, or cell free DNA between survivors and non-survivors. Mitochondrial injury markers showed mixed results in post-arrest period. Future research needs to investigate these differences.

Plasma Cytochrome c Detection Using a Highly Sensitive Electrochemiluminescence Enzyme-Linked Immunosorbent Assay

“…They used human cytochrome c capture and detection antibodies, but the cytochrome c used for their standard curve was not reported. A recent report by Donnino et al 23 applied an ECL technique based on MSD platform for cytochrome c measurement and reported a value of 0.7 ng/mL for healthy controls which is 14-fold less than our study. They used capture and detection antibodies specific for humans, but their standard human cytochrome c was obtained from eBioscience and ours was from Sigma, which could have explained the discrepancy.…”

“…The assay was first developed to measure human plasma cytochrome c in samples obtained in patients with sepsis and after cardiac arrest as part of a collaboration with clinical investigators at Beth Israel Deaconess Medical Center, Boston, MA. 22 , 23 We then used our method to measure plasma cytochrome c in patients with blunt trauma as part of a collaborative study between Advocate Lutheran General Hospital and our Resuscitation Institute that also included samples obtained from healthy human volunteers at our University for determining reference values. We then adapted our method to measure plasma cytochrome c in rats subjected to ventricular fibrillation (VF) and cardiopulmonary resuscitation (CPR) from 2 different series of experiments.…”

Preliminary observations in systemic oxygen consumption during targeted temperature management after cardiac arrest

“…This injury is characterized by a pro-inflammatory state with high levels of circulating cytokines and oxygen-derived free radicals, 13 which have been shown to mediate mitochondrial damage. 1,14,15 As the mitochondrion is responsible for the utilization of oxygen for cell respiration, quantification of VO 2 may afford insight into a patient’s physiology and mitochondrial status, which by extension may aid in post-arrest prognostication or potentially guide future treatments.…”

The effect of 50% compared to 100% inspired oxygen fraction on brain oxygenation and post cardiac arrest mitochondrial function in experimental cardiac arrest

“…Biomarkers of mitochondrial injury have recently been studied in human OHCA patients, indicating a differences between OHCA patients and controls, but without difference in survivors compared to non-survivors. 29 The results of the current study need to be interpreted taking into account both strengths and limitations. This experimental study was performed on pigs, which are considered to be a good large animal model for modelling CA.…”