Serum proteome profiles in patients treated with targeted temperature management after out-of-hospital cardiac arrest

Abstract

Background Definition of temporal serum proteome profiles after out-of-hospital cardiac arrest may identify biological processes associated with severe hypoxia–ischaemia and reperfusion. It may further explore intervention effects for new mechanistic insights, identify candidate prognostic protein biomarkers and potential therapeutic targets. This pilot study aimed to investigate serum proteome profiles from unconscious patients admitted to hospital after out-of-hospital cardiac arrest according to temperature treatment and neurological outcome. Methods Serum samples at 24, 48, and 72 h after cardiac arrest at three centres included in the Target Temperature Management after out-of-hospital cardiac arrest trial underwent data-independent acquisition mass spectrometry analysis (DIA-MS) to find changes in serum protein concentrations associated with neurological outcome at 6-month follow-up and targeted temperature management (TTM) at 33 °C as compared to 36 °C. Neurological outcome was defined according to Cerebral Performance Category (CPC) scale as “good” (CPC 1–2, good cerebral performance or moderate disability) or “poor” (CPC 3–5, severe disability, unresponsive wakefulness syndrome, or death). Results Of 78 included patients [mean age 66 ± 12 years, 62 (80.0%) male], 37 (47.4%) were randomised to TTM at 36 °C. Six-month outcome was poor in 47 (60.3%) patients. The DIA-MS analysis identified and quantified 403 unique human proteins. Differential protein abundance testing comparing poor to good outcome showed 19 elevated proteins in patients with poor outcome (log2-fold change (FC) range 0.28–1.17) and 16 reduced proteins (log2(FC) between − 0.22 and − 0.68), involved in inflammatory/immune responses and apoptotic signalling pathways for poor outcome and proteolysis for good outcome. Analysis according to level of TTM showed a significant protein abundance difference for six proteins [five elevated proteins in TTM 36 °C (log2(FC) between 0.33 and 0.88), one reduced protein (log2(FC) − 0.6)] mainly involved in inflammatory/immune responses only at 48 h after cardiac arrest. Conclusions Serum proteome profiling revealed an increase in inflammatory/immune responses and apoptosis in patients with poor outcome. In patients with good outcome, an increase in proteolysis was observed, whereas TTM-level only had a modest effect on the proteome profiles. Further validation of the differentially abundant proteins in response to neurological outcome is necessary to validate novel biomarker candidates that may predict prognosis after cardiac arrest.

Improvement in Outcomes and Prevention of Multiple Organ Dysfunction Syndrome After Cardiac Arrest and Successful Cardiopulmonary Resuscitation by Systemic Administration of Bumetanide in Male Mice

“…Going a step further, we identified 2 proteins, NGAL and angiotensinogen, that were also significantly differentiated in the comparison between good and poor neuroprognostication in human serum proteomic studies at 24 hours after ROSC. 28 The expression level and spatial expression characteristics of NGAL (Figure 6C through 6E) and CD14 (Figure S5) in brain were examined by immunofluorescence. We found the cerebral expression of NGAL was extremely low in the sham-operated mice (Figure 7C), and increased expression were found after CA/CPR (Figure 7D and 7E).…”

“…Firstly, it is scarcely possible to obtain brain samples for protein detecting in clinical practice, and serum is the most widely used and most accessible sample for detection of prognostication. Previous clinical studies have shown the serous detectability of NGAL and angiotensinogen, 28 and a further challenge is focusing on the cerebral-specific quantification of release of these biomarkers.…”

“…We identified 10 potential markers associated with neuroprognostication, and further, we identified NGAL and angiotensinogen are the common DEPs at 24 hours after resuscitation combined with serum proteome profiles from CA patients. 28 Angiotensinogen, mainly expressed in astrocytes and neurons in brain, is the precursor of angiotensin which is the part of renin-angiotensin system. 41 Increased cerebral angiotensin may have various effects.…”

Peptide set test: a peptide-centric strategy to infer differentially expressed proteins

“…We applied a 70% rule to filter missing values, retaining only analytes identified in at least 70% of samples. Our decision aligns with the original publications and common practices in proteomics, where researchers often opt for filtering strategies without imputation to handle missing values ( Yang et al 2015 , De Marchi et al 2016 , Messner et al 2020 , Hristova et al 2023 , Lileikyte et al 2023 ). Gene ontology enrichment analysis was performed using the enrichGO function() in the clusterProfiler R package ( Yu et al 2012 , Wu et al 2021 ).…”

Therapeutic potential of mitochondrial transplantation in modulating immune responses post-cardiac arrest: a narrative review

“…A recent study of serum samples collected from Swedish patients enrolled in the targeted temperature management (TTM) trial has identified additional, potential biomarkers through proteomic analysis [ 52 ]. Comparing patients with good and poor neurological outcome 6 months following CA, the study proposed the utility of proteins known to be implicated in immune programs, including kallistatin and angiotensinogen, in neuroprognostication and treatment monitoring.…”