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

Intensive Care Medicine Experimental · 14 authors, 9 centres

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FIDELITY 98%

POPULATION78 unconscious patients admitted to hospital after out-of-hospital cardiac arrest (mean age 66±12 years, 80% male) from three centres in the Scania region of Sweden, included in the TTM trial

INTERVENTIONTargeted temperature management (TTM) at 33°C (n=41) or 36°C (n=37)

COMPARISONPoor neurological outcome (CPC 3-5, n=47) vs. good neurological outcome (CPC 1-2, n=31) at 6 months; TTM 33°C vs. 36°C

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TL;DR

This pilot study used mass spectrometry to analyze serum proteome profiles in 78 patients after out-of-hospital cardiac arrest, comparing those with poor versus good neurological outcome and those treated with targeted temperature management at 33°C versus 36°C. Poor outcome was associated with elevated proteins involved in inflammatory/immune responses and apoptosis, while good outcome was linked to increased proteolysis; temperature management had only a modest effect on the proteome. These findings identify candidate prognostic biomarkers and suggest that inflammatory and apoptotic pathways are key drivers of poor neurological outcome after cardiac arrest.

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**Background:** Adverse outcomes after out-of-hospital cardiac arrest (OHCA) are largely due to cerebral and cardiac dysfunction from whole-body ischaemia and reperfusion injury. Targeted temperature management (TTM) has been used for neuroprotection, but the TTM trial showed no benefit of 33°C over 36°C. Proteomic profiling may identify biological processes, biomarkers, and therapeutic targets. This pilot study aimed to investigate serum proteome profiles in OHCA patients according to temperature treatment and neurological outcome.

**Methods:** Serum samples from 78 patients (mean age 66±12 years, 80% male) from three Swedish centres in the TTM trial were collected at 24, 48, and 72 hours after return of spontaneous circulation (ROSC). Patients were randomized to TTM at 33°C (n=41) or 36°C (n=37). Neurological outcome at 6 months was assessed using the Cerebral Performance Category (CPC) scale: good (CPC 1-2, n=31) or poor (CPC 3-5, n=47). Data-independent acquisition mass spectrometry (DIA-MS) identified and quantified 403 unique human proteins after filtering out those missing in >30% of samples. Differential protein abundance was analyzed using linear models with false discovery rate (FDR) correction (adjusted p<0.05). Gene Ontology (GO) enrichment and pathway analyses were performed.

**Key Results:** - **Neurological outcome:** 35 proteins were differentially abundant between poor and good outcome across time points (29 at 24h, 6 at 48h, 8 at 72h). Nineteen proteins were elevated in poor outcome (log2-fold change [FC] range 0.28–1.17), including complement component 7 (C7) and insulin-like growth factor-binding protein 2 (IGFBP2) at all three time points, and IGFBP4 at 24 and 72h. Sixteen proteins were reduced in poor outcome (log2FC range −0.22 to −0.68), including inter-alpha-trypsin inhibitor heavy chain H1 (ITIH1) at 24 and 48h, and vitamin K-dependent protein Z (PROZ) and afamin (AFM) at 24 and 72h. Three proteins had log2FC >1: ribonuclease pancreatic (RNASE1) at 24h, IGFBP2 at 48h, and immunoglobulin heavy variable 3-23 (IGHV3-23) at 72h. GO analysis showed elevated proteins in poor outcome were enriched for 'positive regulation of immune response', 'amyloid fibre formation', 'metal ion homeostasis', and 'regulation of apoptotic signalling pathway'. Reduced proteins in poor outcome were enriched for 'glycerolipid metabolic process', 'complement and coagulation cascades', 'regulation of inflammatory response', and 'regulation of proteolysis'. - **Temperature management:** Only six proteins were significantly different between TTM groups, all at 48h. Five were elevated in the 36°C group (log2FC 0.33–0.88): angiogenin (ANG), proprotein convertase subtilisin/kexin type 9 (PCSK9), inter-alpha-trypsin inhibitor heavy chain family member 4 (ITIH4), ficolin-2 (FCN2), and collagen alpha-1(VI) chain (COL6A1). One protein, mannan-binding lectin serine protease 1 (MASP1), was reduced in the 36°C group (log2FC −0.6). GO terms for elevated proteins included 'humoral immune response', 'opsonisation', and 'cholesterol homeostasis'. - **Interaction analysis:** Only extracellular superoxide dismutase (EC-SOD) showed a significant interaction between outcome and temperature at 48h (p_interaction<0.001, adjusted p=0.17). EC-SOD was elevated in poor outcome patients in the 36°C group but not in the 33°C group.

**Clinical Implications:** This pilot study demonstrates that serum proteome profiling can identify distinct biological processes associated with neurological outcome after OHCA. Poor outcome is characterized by heightened inflammatory/immune responses and apoptosis, while good outcome is associated with increased proteolysis. The minimal effect of TTM on the proteome supports the clinical finding of no significant difference in outcomes between 33°C and 36°C. The identified proteins, such as IGFBP2, PROZ, and EC-SOD, are candidate biomarkers that warrant validation in larger, prospective cohorts. Limitations include the small sample size, potential batch effects, and the inability to detect low-abundance brain-specific markers like neuron-specific enolase. Future studies should use targeted MS approaches and consider earlier or more intensive temperature interventions.

PICO

PPOPULATION

78 unconscious patients admitted to hospital after out-of-hospital cardiac arrest (mean age 66±12 years, 80% male) from three centres in the Scania region of Sweden, included in the TTM trial

IINTERVENTION

Targeted temperature management (TTM) at 33°C (n=41) or 36°C (n=37)

OOUTCOME

Differential serum protein abundance at 24, 48, and 72 hours after return of spontaneous circulation, measured by data-independent acquisition mass spectrometry (DIA-MS)

STUDY TYPE

RCT

SPECIALTY

ophthalmology

SUMMARISED BY

AI pipeline

FIDELITY CHECK

98% · A

ORIGINAL PAPER

PMC10350448

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

Intensive Care Medicine Experimental

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ABSTRACT

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 (log 2 -fold change (FC) range 0.28–1.17) and 16 reduced proteins (log 2 (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 (log 2 (FC) between 0.33 and 0.88), one reduced protein (log 2 (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. Supplementary Information The online version contains supplementary material available at 10.1186/s40635-023-00528-0. Keywords: Out-of-hospital cardiac arrest, Heart arrest, Proteomics, Prognostication, Temperature control, Hypothermia, Targeted temperature management

CITATION EXPORT

Gabriele Lileikyte, Anahita Bakochi, Ashfaq Ali et al.. Serum proteome profiles in patients treated with targeted temperature management after out-of-hospital cardiac arrest. Intensive Care Medicine Experimental. (2023). https://doi.org/10.1186/s40635-023-00528-0

AUTHORS

14 · 9 CENTRES

Gabriele Lileikyte, Anahita Bakochi, Ashfaq Ali, Marion Moseby-Knappe, Tobias Cronberg, Hans Friberg, Gisela Lilja, Helena Levin, Filip Årman, Sven Kjellström, Josef Dankiewicz, Christian Hassager, Johan Malmström, Niklas Nielsen

1Department of Clinical Sciences Lund, Anaesthesia and Intensive Care, Lund University, Helsingborg Hospital, Svartbrödragränden 3, 251 87 Helsingborg, Sweden
2Swedish National Infrastructure for Biological Mass Spectrometry (BioMS), Lund University, Lund, Sweden
3Department of Clinical Sciences Lund, Infection Medicine, Lund University, Lund, Sweden
4National Bioinformatics Infrastructure Sweden (NBIS), SciLifeLab, Department of Immunotechnology, Lund University, Lund, Sweden
5Department of Clinical Sciences Lund, Neurology, Lund University, Skåne University Hospital, Lund, Sweden
6Department of Clinical Sciences Lund, Anaesthesia and Intensive Care, Lund University, Skåne University Hospital, Malmö, Sweden
7Department of Clinical Sciences Lund, Department of Research and Education, Lund University, Skåne University Hospital, Lund, Sweden
8Department of Clinical Sciences Lund, Cardiology, Lund University, Skåne University Hospital, Lund, Sweden
9Department of Cardiology, Rigshospitalet and Dept of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark