Proteomics identify pathogenesis and novel biomarkers for monitoring and early prognostication of brain injury after cardiac arrest: a randomized animal study

Abstract

Aim

Post-cardiac arrest brain injury (PCABI) is the leading cause of death and disability after resuscitation. This study aimed to investigate the pathogenesis and novel biomarkers for monitoring the progression and early prognostication of PCABI.

Methods

Mouse model of PCABI was induced by hyperkalemia-induced asystole and successful resuscitation. Young adult male C57BL/6 mice were randomized into sham-operation or asystole/resuscitation. The sham-operated mice were selected as control. Neurological examinations were performed at 24 h after resuscitation, and three groups were set: control (n = 4), severe PCABI (n = 3), and mild PCABI (n = 3). Cerebral cortexes were collected for data-independent acquisition-proteomic analyses. The pathogenesis and potential biomarkers were identified through the pairwise comparisons of three subgroups and subsequent bioinformatics analyses. Human serum proteomes profiles, extracted from a published work of the second analysis of TTM-trial, were used for joint analyses to identify the common and clinically relevant biomarkers at the same timepoint. Experimental and external validation were performed to verify the association between novel biomarkers and neural death in PCABI.

Results

The proteomic analysis identified and quantified 7,745 proteins. The most prominent proteomic changes were related to response to external stimulus, stress response, regulation of biological and metabolic process, endomembrane system, and inflammatory response in the PCABI progression. 10 potential biomarkers were identified by the pairwise comparisons of three groups, and lipocalin-2 and angiotensinogen are common biomarkers with human studies at 24 h after resuscitation. Experimental validation verified that lipocalin-2 was closely associated with neurodegeneration in PCABI.

Conclusions

Stress, inflammatory, and metabolic responses play important roles in the progression of PCABI. Lipocalin-2 is a novel biomarker for monitoring and early neuroprognostication at 24 h after resuscitation.