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Increased platelet mitochondrial respiration after cardiac arrest and resuscitation as a potential peripheral biosignature of cerebral bioenergetic dysfunction

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Abstract

Cardiac arrest (CA) results in a sepsis-like syndrome with activation of the innate immune system and increased mitochondrial bioenergetics. Objective: To determine if platelet mitochondrial respiration increases following CA in a porcine pediatric model of asphyxia-associated ventricular fibrillation (VF) CA, and if this readily obtained biomarker is associated with decreased brain mitochondrial respiration. CA protocol: 7 min of asphyxia, followed by VF, protocolized titration of compression depth to systolic blood pressure of 90 mmHg and vasopressor administration to a coronary perfusion pressure greater than 20 mmHg. Primary outcome: platelet integrated mitochondrial electron transport system (ETS) function evaluated pre- and post-CA/ROSC four hours after return of spontaneous circulation (ROSC). Secondary outcome: correlation of platelet mitochondrial bioenergetics to cerebral bioenergetic function. Platelet maximal oxidative phosphorylation (OXPHOSCI+CII), P < 0.02, and maximal respiratory capacity (ETSCI+CII), P < 0.04, were both significantly increased compared to pre-arrest values. This was primarily due to a significant increase in succinate-supported respiration through Complex II (OXPHOSCII, P < 0.02 and ETSCII, P < 0.03). Higher respiration was not due to uncoupling, as the LEAKCI + CII respiration (mitochondrial respiration independent of ATP-production) was unchanged after CA/ROSC. Larger increases in platelet mitochondrial respiratory control ratio (RCR) compared to pre-CA RCR were significantly correlated with lower RCRs in the cortex (P < 0.03) and hippocampus (P < 0.04) compared to sham respiration. Platelet mitochondrial respiration is significantly increased four hours after ROSC. Future studies will identify mechanistic relationships between this serum biomarker and altered cerebral bioenergetics function following cardiac arrest.

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Acknowledgments

We would like to thank Melissa Byro, Ryan Morgan and George Bratinov for their technical assistance.

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Authors and Affiliations

  1. Anesthesiology and Critical Care Medicine, The Children’s Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, 34th & Civic Center Blvd., Philadelphia, PA, 19104, USA

    Michael A. Ferguson, Robert M. Sutton, Robert A. Berg & Todd J. Kilbaugh

  2. Mitochondrial Medicine, Department of Clinical Sciences, Lund University, BMC A13, SE-221 84, Lund, Sweden

    Michael Karlsson & Fredrik Sjövall

  3. Department of Emergency Medicine, Perelman School of Medicine at the University of Pennsylvania, The Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA, 19104, USA

    Lance B. Becker

  4. School of Engineering and Applied Science, Department of Bioengineering, University of Pennsylvania, 210 South 33rd Street, Philadelphia, PA, 19104, USA

    Susan S. Margulies

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  1. Michael A. Ferguson
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Correspondence to Todd J. Kilbaugh.

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This study was funded by, the National Institute of Child Health and Human Development (RMS K23), NIH U01 NS069545, NIH R01 NS039679, the Laerdal Foundation for Acute Care Medicine, and CHOP Critical Care Medicine Endowed Chair Funds.

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Michael Karlsson has received salary support from NeuroVive Pharmaceutical AB.

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Ferguson, M.A., Sutton, R.M., Karlsson, M. et al. Increased platelet mitochondrial respiration after cardiac arrest and resuscitation as a potential peripheral biosignature of cerebral bioenergetic dysfunction. J Bioenerg Biomembr 48, 269–279 (2016). https://doi.org/10.1007/s10863-016-9657-9

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