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Temperature Variability Does Not Attenuate the Beneficial Effects of Therapeutic Hypothermia on Cellular Apoptosis and Endoplasmic Reticulum Stress in the Cerebral Cortex of a Swine Cardiac Arrest Model

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Abstract

Background

Endoplasmic reticulum stress (ERS) plays a vital role in mediating apoptosis in the brain following cardiac arrest (CA). Studies have shown that therapeutic hypothermia (TH) provides neuroprotection through anti-apoptosis; however, the effects of temperature variability in TH on the brain remain unclear. In this study, we investigated the different effects of temperature variability through extracorporeal membrane oxygenation on apoptosis and ERS in the brain following CA.

Methods

Eighteen male domestic pigs underwent 6-min duration of no-flow induced by ventricular fibrillation. Extracorporeal cardiopulmonary resuscitation was then performed, and the return of spontaneous circulation (ROSC) was achieved. The animals were randomly assigned to the following groups: normothermia, non-temperature variability, and temperature variability. TH (core temperature, 33–35 °C) was maintained for 24 h post-ROSC, and the animals were rewarmed for 8 h. Quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry for Bax and Bcl-2 transcripts and proteins, respectively, were used to investigate apoptosis in the cerebral cortex. Expression levels of the ERS molecules, GRP78 and CHOP, were also detected by qRT-PCR, and cellular morphology was evaluated using transmission electron microscopy.

Results

qRT-PCR and immunohistochemistry results revealed that TH significantly increased the expression levels of Bcl-2 and GRP78 and decreased that of Bax and CHOP than under normothermia conditions. Compared to the non-temperature variability group, temperature variability did not decrease the expression levels of Bcl-2 and GRP78 and not increase the levels of Bax and CHOP. Endoplasmic reticulum ultrastructural changes were significantly improved under TH. No statistical difference was observed between the temperature variability and non-temperature variability groups.

Conclusion

TH can reduce neuronal apoptosis by ERS, while temperature variability does not attenuate this beneficial effect.

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Abbreviations

ERS:

Endoplasmic reticulum stress

CA:

Cardiac arrest

TH:

Therapeutic hypothermia

ECMO:

Extracorporeal membrane oxygenation

VF:

Ventricular fibrillation

ECPR:

Extracorporeal cardiopulmonary resuscitation

ROSC:

Return of spontaneous circulation

qRT-PCR:

Quantitative real-time polymerase chain reaction

References

  1. Lemiale V, Dumas F, Mongardon N, et al. Intensive care unit mortality after cardiac arrest: the relative contribution of shock and brain injury in a large cohort. Intensive Care Med. 2013;39(11):1972–80.

    Article  Google Scholar 

  2. Callaway CW, Donnino MW, Fink EL, et al. Part 8: post-Cardiac Arrest Care: 2015 American Heart Association Guidelines Update For Cardiopulmonary Resuscitation And Emergency Cardiovascular Care. Circulation. 2015;132(18 Suppl 2):S465–82.

    Article  Google Scholar 

  3. Mackowiak PA. Drug fever: mechanisms, maxims and misconceptions. Am J Med Sci. 1987;294(4):275–86.

    Article  CAS  Google Scholar 

  4. Gaussorgues P, Gueugniaud PY, Vedrinne JM, et al. Bacteremia following cardiac arrest and cardiopulmonary resuscitation. Intensive Care Med. 1988;14(5):575–7.

    Article  CAS  Google Scholar 

  5. Tommasi E, Lazzeri C, Bernardo P, et al. Cooling techniques in mild hypothermia after cardiac arrest. J Cardiovasc Med (Hagerstown). 2017;18(7):459–66.

    Article  Google Scholar 

  6. Suffoletto B, Peberdy MA, van der Hoek T, et al. Body temperature changes are associated with outcomes following in-hospital cardiac arrest and return of spontaneous circulation. Resuscitation. 2009;80(12):1365–70.

    Article  Google Scholar 

  7. Shinozaki K, Oda S, Sadahiro T, et al. Duration of well-controlled core temperature correlates with neurological outcome in patients with post-cardiac arrest syndrome. Am J Emerg Med. 2012;30(9):1838–44.

    Article  Google Scholar 

  8. Nobile L, Lamanna I, Fontana V, et al. Greater temperature variability is not associated with a worse neurological outcome after cardiac arrest. Resuscitation. 2015;96:268–74.

    Article  Google Scholar 

  9. Nayeri A, Bhatia N, Holmes B, et al. Temperature variability during targeted temperature management is not associated with neurological outcomes following cardiac arrest. Am J Emerg Med. 2017;35(6):889–92.

    Article  Google Scholar 

  10. Pinichjindasup A, Homvises B, Muengtaweepongsa S. Therapeutic hypothermia with extracorporeal membrane oxygenation (ECMO) and surface cooling in post-cardiac arrest patients: 4 case reports. J Med Assoc Thail. 2014;97:S223–7.

    Google Scholar 

  11. Jaw SP, Su DD, Truong DD. Expression of Bcl-2 and Bax in the frontoparietal cortex of the rat following cardiac arrest. Brain Res Bull. 1995;38(6):577–80.

    Article  CAS  Google Scholar 

  12. Nozari A, Safar P, Stezoski SW, et al. Critical time window for intra-arrest cooling with cold saline flush in a dog model of cardiopulmonary resuscitation. Circulation. 2006;113(23):2690–6.

    Article  Google Scholar 

  13. Gong P, Hua R, Zhang Y, et al. Hypothermia-induced neuroprotection is associated with reduced mitochondrial membrane permeability in a swine model of cardiac arrest. J Cereb Blood Flow Metab. 2013;33(6):928–34.

    Article  CAS  Google Scholar 

  14. Suh GJ, Kwon WY, Kim KS, et al. Prolonged therapeutic hypothermia is more effective in attenuating brain apoptosis in a Swine cardiac arrest model. Crit Care Med. 2014;42(2):e132–42.

    Article  Google Scholar 

  15. Gong P, Li CS, Hua R, et al. Mild hypothermia attenuates mitochondrial oxidative stress by protecting respiratory enzymes and upregulating MnSOD in a pig model of cardiac arrest. PLoS ONE. 2012;7(4):e35313.

    Article  CAS  Google Scholar 

  16. Stuss DT, Levine B. Adult clinical neuropsychology: lessons from studies of the frontal lobes. Annu Rev Psychol. 2002;53:401–33.

    Article  Google Scholar 

  17. Püttgen HA, Geocadin R. Predicting neurological outcome following cardiac arrest. J Neurol Sci. 2007;261(1–2):108–17.

    Article  Google Scholar 

  18. Tahsili-Fahadan P, Farrokh S, Geocadin RG. Hypothermia and brain inflammation after cardiac arrest. Brain Circ. 2018;4(1):1–13.

    Article  Google Scholar 

  19. Wu L, Sun HL, Gao Y, et al. Therapeutic hypothermia enhances cold-inducible RNA-binding protein expression and inhibits mitochondrial apoptosis in a rat model of cardiac arrest. Mol Neurobiol. 2017;54(4):2697–705.

    Article  CAS  Google Scholar 

  20. Nguyen TP, Chen MH, Li N, et al. PD98059 protects brain against cells death resulting from ROS/ERK activation in a cardiac arrest rat model. Oxid Med Cell Longev. 2016;2016:3723762.

    Google Scholar 

  21. Rasheva VI, Domingos PM. Cellular responses to endoplasmic reticulum stress and apoptosis. Apoptosis. 2009;14(8):996–1007.

    Article  Google Scholar 

  22. Kim I, Xu W, Reed JC. Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities. Nat Rev Drug Discov. 2008;7(12):1013–30.

    Article  CAS  Google Scholar 

  23. Walter P, Ron D. The unfolded protein response: from stress pathway to homeostatic regulation. Science. 2011;334(6059):1081–6.

    Article  CAS  Google Scholar 

  24. Zhang K, Kaufman RJ. From endoplasmic-reticulum stress to the inflammatory response. Nature. 2008;454(7203):455–62.

    Article  CAS  Google Scholar 

  25. Marciniak SJ, Yun CY, Oyadomari S, et al. CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev. 2004;18(24):3066–77.

    Article  CAS  Google Scholar 

  26. Liu X, Wang M, Chen H, et al. Hypothermia protects the brain from transient global ischemia/reperfusion by attenuating endoplasmic reticulum response-induced apoptosis through CHOP. PLoS ONE. 2013;8(1):e53431.

    Article  CAS  Google Scholar 

  27. Cordoza M, Thompson H, Bridges E, et al. Association between target temperature variability and neurologic outcomes for patients receiving targeted temperature management at 36 C after cardiac arrest: a retrospective cohort study. Ther Hypothermia Temp Manag. 2020. https://doi.org/10.1089/ther.2020.0005.

    Article  PubMed  Google Scholar 

  28. Yannopoulos D, Zviman M, Castro V, et al. Intra-cardiopulmonary resuscitation hypothermia with and without volume loading in an ischemic model of cardiac arrest. Circulation. 2009;120(14):1426–35.

    Article  Google Scholar 

  29. Nielsen N, Wetterslev J, Cronberg T, et al. Targeted temperature management at 33 °C versus 36 °C after cardiac arrest. N Engl J Med. 2013;369(23):2197–206.

    Article  CAS  Google Scholar 

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Acknowledgements

We gratefully acknowledge the support of National Natural Science Foundation of China for this research, Grant Number 81927808, grant recipient Wenkui Yu. We would like to thank Editage (www.editage.cn) for English language editing.

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Authors and Affiliations

  1. Department of Critical Care Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing, 210008, Jiangsu Province, China

    Beiyuan Zhang, Qin Gu, Xiancheng Chen, Yong You, Ming Chen, Yajun Qian, Yan Chen & Wenkui Yu

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  1. Beiyuan Zhang
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  2. Qin Gu
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Correspondence to Wenkui Yu.

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Source of support

We received the support of National Natural Science Foundation of China for this research, grant number 81927808.

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The authors declare that they have no conflict of interest.

Human and Animal Rights

All applicable institutional and/or national guidelines for the care and use of animals were followed. The experiment was conducted in conformity with the guidance suggestions for the care and use of laboratory animals formulated by the Ministry of Science and Technology of the People’s Republic of China.

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Zhang, B., Gu, Q., Chen, X. et al. Temperature Variability Does Not Attenuate the Beneficial Effects of Therapeutic Hypothermia on Cellular Apoptosis and Endoplasmic Reticulum Stress in the Cerebral Cortex of a Swine Cardiac Arrest Model. Neurocrit Care 34, 769–780 (2021). https://doi.org/10.1007/s12028-020-01083-2

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  • DOI: https://doi.org/10.1007/s12028-020-01083-2

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