Lipidomics Detection of Brain Cardiolipins in Plasma Is Associated With Outcome After Cardiac Arrest

Anthonymuthu, Tamil S.; Kenny, Elizabeth; Lamade, Andrew M.; Gidwani, Hitesh; Krehel, Nicholas; Missé, Amalea; Gao, Xiang; Amoscato, Andrew A.; Straub, Adam C.; Kagan, Valerian E.; Dezfulian, Cameron; Bayır, Hülya

doi:10.1097/ccm.0000000000003636

Cited by 21 publications

(24 citation statements)

References 40 publications

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“… 32 33 We plan an exploratory investigation into the prognostication accuracy of brain mitochondria-specific CL and CLox, biomarkers developed by our collaborators. 34 35 Finally, families could opt-in for genetic biomarker analysis in which a blood clot remaining from blood biomarker processing procedures is banked for future analysis.…”

Section: Methodsmentioning

confidence: 99%

“…Further, we will include an exploratory analysis of a brain-specific mitochondrial cardiolipin (CL) that when measured in the blood predicted outcome in adults with cardiac arrest and may have utility as a therapeutic target. 19 This manuscript describes the study design, trial management and oversight for the Personalising Outcomes after Child Cardiac Arrest (POCCA) trial.…”

Section: Introductionmentioning

confidence: 99%

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Personalising Outcomes after Child Cardiac Arrest (POCCA): design and recruitment challenges of a multicentre, observational study

et al. 2020

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IntroductionBlood and imaging biomarkers show promise in prognosticating outcomes after paediatric cardiac arrest in pilot studies. We describe the methods and early recruitment challenges and solutions for an ongoing multicentre (n=14) observational trial, Personalising Outcomes following Child Cardiac Arrest to validate clinical, blood and imaging biomarkers individually and together in a clinically relevant panel.Methods and analysisChildren (n=164) between 48 hours and 17 years of age who receive chest compressions irrespective of provider, duration, or event location and are admitted to an intensive care unit are eligible. Blood samples will be taken on days 1–3 for the measurement of brain-focused biomarkers analysed to predict the outcome. Clinically indicated and timed brain MRI and spectroscopy biomarkers will be analysed to predict the outcome. The primary outcome for the trial is survival with favourable (Vineland Adaptive Behavioural Scale score >70) outcome at 1 year. Secondary outcomes include mortality and pre-event and postdischarge measures of emotional, cognitive, physical and family functioning and health-related quality of life. Early enrollment targets were not met due to prolonged regulatory and subcontract processes. Multiple, simultaneous interventions including modification to inclusion criteria, additional sites and site visits were implemented with successful improvement in recruitment. Study procedures including outcomes and biomarker analysis are ongoing.Ethics and disseminationTwelve of 14 sites will use the centralised Institutional Review Board (IRB) at the University of Pittsburgh (PRO14030712). Two sites will use individual IRBs: Children’s Healthcare of Atlanta Institutional Review Board and Children’s Hospital of Wisconsin IRB. Parents and/or guardians are consented and children assented (when possible) by the site Primary investigator (PI) or research coordinator for enrollment. Study findings will be disseminated through scientific conferences, peer-reviewed journal publications, public study website materials and invited lectures.Trial registration numberNCT02769026.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Personalising Outcomes after Child Cardiac Arrest (POCCA): design and recruitment challenges of a multicentre, observational study

et al. 2020

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“…The pericontusional cortex was isolated from the brain and the lipids were extracted using the folch method. Total phosphate content of the lipids was quantified using the method reported previously (Anthonymuthu et al, 2019). For phospholipid analysis, samples corresponding to approximately 2.5 nanomol of total phosphate were supplemented with the appropriate internal standards (5 picomoles each of phosphatidylcholine (PC) (17:0/17:0), phosphatidylglycerol (PG) (17:0/17:0), phosphatidylinositol (PI) (16:0/16:0), CL (14:0/14:0/14:0/14:0), phosphatidylserine (PS) (17:0/17:0), phosphatidic acid (PA) (17:0/17:0), phosphatidylethanolamine (PE) (17:0/17:0)) and analyzed using LC-MS/MS.…”

Section: Lipid Extraction and Mass Spectrometry Analysismentioning

confidence: 99%

“…Brain tissue has a distinct CL profile based on the number of CL species, acyl chain lengths and degree of unsaturation (Kagan et al, 2015). We recently showed that the appearance of unique brain-type CLs in plasma could serve as a brain-specific marker of mitochondrial/tissue injury in adults after cardiac arrest (Anthonymuthu et al, 2019). Accumulation of three unique CL species [CL(70:3), CL(72:5) and CL(74:7)] correlated with neurological injury severity and functional outcome in these patients.…”

Section: Introductionmentioning

confidence: 99%

Detection of brain specific cardiolipins in plasma after experimental pediatric head injury

Anthonymuthu

Kenny

Hier

et al. 2019

Experimental Neurology

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Cardiolipin (CL) is a mitochondria-specific phospholipid that is central to maintenance and regulation of mitochondrial bioenergetic and metabolic functions. CL molecular species display great tissue variation with brain exhibiting a distinct, highly diverse CL population. We recently showed that the appearance of unique brain-type CLs in plasma could serve as a brain-specific marker of mitochondrial/tissue injury in patients after cardiac arrest. Mitochondrial dysfunction has been increasingly implicated as a critical mechanism underlying the pathogenesis of traumatic brain injury (TBI). Therefore, we hypothesized that unique, brain specific CL species from the injured brain are released to the peripheral circulation after TBI. To test this hypothesis, we performed a high-resolution mass spectrometry based phospholipidomics analysis of post-natal day (PND)-17 rat brain and plasma after controlled cortical impact. We found a time dependent increase in plasma CLs after TBI including the aforementioned brain-specific CL species early after injury, whereas CLs were significantly decreased in the injured brain. Compositional and quantitative correlational analysis suggested a possible release of CL into the systemic circulation following TBI. The identification of brain-type CLs in systemic circulation may indicate underlying mitochondrial dysfunction/loss after TBI. They may have potential as pharmacodynamics response biomarkers for targeted therapies.

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“…26 The brain-specific cardiolipin is also detected in plasma samples from patients with brain injury induced by cardiac arrest and from rats subjected to asphyxial cardiac arrest. 27 Furthermore, peroxidized cardiolipin is detected in injured brains, 28 and anticardiolipin antibody is found in the peripheral blood samples of patients with stroke 29 and TBI. 30 An obvious question is whether the cardiolipin detected in these studies are free phospholipid micelles, mitochondrial damage associated molecular patterns (mDAMPs), or exMTs.…”

Section: Traumatic Injured Brains Release Extracellular Mitochondriamentioning

confidence: 99%

Extracellular Mitochondria in Traumatic Brain Injury Induced Coagulopathy

Zhao

Zhou

et al. 2019

Semin Thromb Hemost

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Traumatic brain injury (TBI) induced coagulopathy remains a significant clinical challenge, with unmet needs for standardizing diagnosis and optimizing treatments. TBI-induced coagulopathy is closely associated with poor outcomes in affected patients. Recent studies have demonstrated that TBI induces coagulopathy, which is mechanistically distinct from the deficient and dilutional coagulopathy found in patients with injuries to the body/limbs and hemorrhagic shock. Multiple causal and disseminating factors have been identified to cause TBI-induced coagulopathy. Among these are extracellular mitochondria (exMTs) released from injured cerebral cells, endothelial cells, and platelets. These circulating exMTs not only express potent procoagulant activity but also promote inflammation, and could remain metabolically active to become a major source of oxidative stress. They activate platelets and endothelial cells to propagate TBI-induced coagulopathy and secondary tissue injury after primary traumatic impact. In this review, we discuss recent advances in our understanding of the role of exMTs in the development of TBI-induced coagulopathy.

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Lipidomics Detection of Brain Cardiolipins in Plasma Is Associated With Outcome After Cardiac Arrest

Cited by 21 publications

References 40 publications

Personalising Outcomes after Child Cardiac Arrest (POCCA): design and recruitment challenges of a multicentre, observational study

Personalising Outcomes after Child Cardiac Arrest (POCCA): design and recruitment challenges of a multicentre, observational study

Detection of brain specific cardiolipins in plasma after experimental pediatric head injury

Extracellular Mitochondria in Traumatic Brain Injury Induced Coagulopathy

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