Advertisement

Neurocritical Care

, Volume 31, Issue 3, pp 486–493 | Cite as

Serum Caspase-3 Levels and Early Mortality of Patients with Malignant Middle Cerebral Artery Infarction

  • Leonardo LorenteEmail author
  • María M. Martín
  • Antonia Pérez-Cejas
  • Agustín F. González-Rivero
  • Rafael Sabatel
  • Luis Ramos
  • Mónica Argueso
  • Jordi Solé-Violán
  • Juan J. Cáceres
  • Alejandro Jiménez
  • Victor García-Marín
Original Work
  • 94 Downloads

Abstract

Purpose

Circulating caspase-3 levels at 24 h of ischemic stroke were found to be associated with poorer functional neurological outcome in a previous study. The aim of this study was to determine whether there is an association between serum caspase-3 levels and early mortality in patients with malignant middle cerebral artery infarction (MMCAI).

Methods

We included patients with MMCAI defined as computer tomography showing ischemic changes in more than 50% of the middle cerebral artery territory and Glasgow Coma Scale ≤ 8. Serum caspase-3 levels at days 1, 4, and 8 of MMCAI were determined.

Results

Non-surviving MMCAI (n = 34) showed higher serum caspase-3 levels at days 1 (p < 0.001), 4 (p = 0.001), and 8 (p = 0.01) than surviving patients (n = 34). We found that the area under the curve of serum caspase-3 levels for prediction of mortality at 30 days was 88% (95% CI = 78–95%; p < 0.001). Multiple logistic regression showed that serum caspase-3 levels were associated with 30-day mortality (OR = 51.25; 95% CI = 8.30–316.31; p < 0.001).

Conclusions

The novel and more important findings of our study were that high serum caspase-3 levels were associated with mortality in MMCAI patients.

Keywords

Caspase-3 Cerebral infarction Patients Mortality 

List of Abbreviations

APACHE

Acute Physiology and Chronic Health Evaluation

aPTT

Activated partial thromboplastin time

COPD

Chronic obstructive pulmonary disease

FIO2

Fraction inspired of oxygen

GCS

Glasgow Coma Scale

INR

International normalized ratio

PaO2

Pressure of arterial oxygen

Notes

Acknowledgements

This study was supported by a Grant (OA18/011) from Fundación DISA a la Investigación Médica 2017 (Santa Cruz de Tenerife. Spain). Funding did not have influence in the study design, the collection, analysis, and interpretation of data, the manuscript writing, and the decision to submit it for publication.

Author Contributions

LL conceived, designed and coordinated the study, participated in acquisition and interpretation of data, and drafted the manuscript. MMM, RS, LR, MA, JSV, JJC, and VGM participated in acquisition of data. APC and AFGR participated in blood determination levels. AJ participated in the interpretation of data. All authors revised the manuscript critically for important intellectual content, made the final approval of the version to be published, and agreed to be accountable for all aspects of the work.

Source of Support

This study was supported by a grant (OA18/011) from Fundación DISA a la Investigación Médica 2017 (Santa Cruz de Tenerife. Spain).

Conflicts of interest

The authors declare that they have no conflict of interests.

Ethical Approval/Informed Consent

This study was carried after the approval of Institutional Review Board of all participating hospitals and with the written informed consent from legal guardians of patients.

References

  1. 1.
    Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, Biller J, Brown M, Demaerschalk BM, Hoh B, Jauch EC, Kidwell CS, Leslie-Mazwi TM, Ovbiagele B, Scott PA, Sheth KN, Southerland AM, Summers DV, Tirschwell DL, American Heart Association Stroke Council. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2018;2018(49):e46–110.Google Scholar
  2. 2.
    Radak D, Katsiki N, Resanovic I, Jovanovic A, Sudar-Milovanovic E, Zafirovic S, Mousad SA, Isenovic ER. Apoptosis and acute brain ischemia in ischemic stroke. Curr Vasc Pharmacol. 2017;15:115–22.CrossRefGoogle Scholar
  3. 3.
    Khoshnam SE, Winlow W, Farzaneh M, Farbood Y, Moghaddam HF. Pathogenic mechanisms following ischemic stroke. Neurol Sci. 2017;38:1167–86.CrossRefGoogle Scholar
  4. 4.
    Chelluboina B, Klopfenstein JD, Gujrati M, Rao JS, Veeravalli KK. Temporal regulation of apoptotic and anti-apoptotic molecules after middle cerebral artery occlusion followed by reperfusion. Mol Neurobiol. 2014;49:50–65.CrossRefGoogle Scholar
  5. 5.
    Akpan N, Troy CM. Caspase inhibitors: prospective therapies for stroke. Neuroscientist. 2013;19:129–36.CrossRefGoogle Scholar
  6. 6.
    Chen SD, Yang DI, Lin TK, Shaw FZ, Liou CW, Chuang YC. Roles of oxidative stress, apoptosis, PGC-1α and mitochondrial biogenesis in cerebral ischemia. Int J Mol Sci. 2011;12:7199–215.CrossRefGoogle Scholar
  7. 7.
    Broughton BR, Reutens DC, Sobey CG. Apoptotic mechanisms after cerebral ischemia. Stroke. 2009;40:e331–9.CrossRefGoogle Scholar
  8. 8.
    Duan SR, Wang JX, Wang J, Xu R, Zhao JK, Wang DS. Ischemia induces endoplasmic reticulum stress and cell apoptosis in human brain. Neurosci Lett. 2010;475:132–5.CrossRefGoogle Scholar
  9. 9.
    Lorberboym M, Blankenberg FG, Sadeh M, Lampl Y. In vivo imaging of apoptosis in patients with acute stroke: correlation with blood-brain barrier permeability. Brain Res. 2006;1103:13–9.CrossRefGoogle Scholar
  10. 10.
    Qi JP, Wu AP, Wang DS, Wang LF, Li SX, Xu FL. Correlation between neuronal injury and Caspase-3 after focal ischemia in human hippocampus. Chin Med J (Engl). 2004;117:1507–12.Google Scholar
  11. 11.
    Love S, Barber R, Wilcock GK. Neuronal death in brain infarcts in man. Neuropathol Appl Neurobiol. 2000;26:55–66.CrossRefGoogle Scholar
  12. 12.
    Rami A, Sims J, Botez G, Winckler J. Spatial resolution of phospholipid scramblase 1 (PLSCR12), caspase-3 activation and DNA-fragmentation in the human hippocampus after cerebral ischemia. Neurochem Int. 2003;43:79–87.CrossRefGoogle Scholar
  13. 13.
    Mitsios N, Gaffney J, Krupinski J, Mathias R, Wang Q, Hayward S, Rubio F, Kumar P, Kumar S, Slevin M. Expression of signaling molecules associated with apoptosis in human ischemic stroke tissue. Cell Biochem Biophys. 2007;47:73–86.CrossRefGoogle Scholar
  14. 14.
    Cevik O, Adiguzel Z, Baykal AT, Somay G, Sener A. The apoptotic actions of platelets in acute ischemic stroke. Mol Biol Rep. 2013;40:6721–7.CrossRefGoogle Scholar
  15. 15.
    Rosell A, Cuadrado E, Alvarez-Sabín J, Hernández-Guillamon M, Delgado P, Penalba A, Mendioroz M, Rovira A, Fernández-Cadenas I, Ribó M, Molina CA, Montaner J. Caspase-3 is related to infarct growth after human ischemic stroke. Neurosci Lett. 2008;430:1–6.CrossRefGoogle Scholar
  16. 16.
    Lin CH, Chen M, Sun MC. Circulating apoptotic factors in patients with acute cerebral infarction. Clin Biochem. 2010;43:761–3.CrossRefGoogle Scholar
  17. 17.
    Teasdale G, Jennett B. Assessement of coma and impaired consciousness. A practical scale. Lancet. 1974;2:81–4.CrossRefGoogle Scholar
  18. 18.
    Lorente L, Martín MM, Abreu-González P, Ramos L, Argueso M, Solé-Violán J, Riaño-Ruiz M, Jiménez A. Serum malondialdehyde levels in patients with malignant middle cerebral artery infarction are associated with mortality. PLoS ONE. 2015;10:e0125893.CrossRefGoogle Scholar
  19. 19.
    Lorente L, Martín MM, González-Rivero AF, Ramos L, Argueso M, Cáceres JJ, Solé-Violán J, Jiménez A, Borreguero-León JM. Association between serum soluble CD154 levels and mortality in patients with malignant middle cerebral artery infarction. Int J Mol Sci. 2015;16:12147–58.CrossRefGoogle Scholar
  20. 20.
    Lorente L, Martín MM, Pérez-Cejas A, Ramos L, Argueso M, Solé-Violán J, Cáceres JJ, Jiménez A, García-Marín V. High serum levels of caspase-cleaved cytokeratin-18 are associated with malignant middle cerebral artery infarction patient mortality. BMC Neurol. 2018;18:32.CrossRefGoogle Scholar
  21. 21.
    Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Crit Care Med. 1985;13:818–29.CrossRefGoogle Scholar
  22. 22.
    Kleinbaum DG, Kupper LL, Nizam A, Muller KE. Polynomial regression. In: Kleinbaum DG, Kupper LL, Nizam A, editors. Applied regression analysis and other multivariable methods. CA: Duxbury Press; 1998. p. 281–316.Google Scholar
  23. 23.
    Brott T, Adams HP Jr, Olinger CP, Marler JR, Barsan WG, Biller J, Spilker J, Holleran R, Eberle R, Hertzberg V. Measurements of acute cerebral infarction: a clinical examination scale. Stroke. 1989;20:864–70.CrossRefGoogle Scholar
  24. 24.
    Rathore JA, Kango ZA, Mehraj A. Predictors of mortality after acute stroke a prospective hospital based study. J Ayub Med Coll Abbottabad. 2011;23:144–6.PubMedGoogle Scholar
  25. 25.
    Suyama K, Horie N, Hayashi K, Nagata I. Nationwide survey of decompressive hemicraniectomy for malignant middle cerebral artery infarction in Japan. World Neurosurg. 2014;82:1158–63.CrossRefGoogle Scholar
  26. 26.
    Hacke W, Schwab S, Horn M, Spranger M, De Georgia M, von Kummer R. Malignant middle cerebral artery territory infarction: clinical course and prognostic signs. Arch Neurol. 1996;53:309–15.CrossRefGoogle Scholar
  27. 27.
    Schwab S, Steiner T, Aschoff A, Schwarz S, Steiner HH, Jansen O, Hacke W. Early hemicraniectomy in patients with complete middle cerebral artery infarction. Stroke. 1998;29:1888–93.CrossRefGoogle Scholar
  28. 28.
    Serena J, Blanco M, Castellanos M, Silva Y, Vivancos J, Moro MA, Leira R, Lizasoain I, Castillo J, Dávalos A. The prediction of malignant cerebral infarction by molecular brain barrier disruption markers. Stroke. 2005;36:1921–6.CrossRefGoogle Scholar
  29. 29.
    Chen B, Wang G, Li W, Liu W, Lin R, Tao J, Jiang M, Chen L, Wang Y. Memantine attenuates cell apoptosis by suppressing the calpain-caspase-3 pathway in an experimental model of ischemic stroke. Exp Cell Res. 2017;351:163–72.CrossRefGoogle Scholar
  30. 30.
    Cho YS, Shin MS, Ko IG, Kim SE, Kim CJ, Sung YH, Yoon HS, Lee BJ. Ulinastatin inhibits cerebral ischemia-induced apoptosis in the hippocampus of gerbils. Mol Med Rep. 2015;12:1796–802.CrossRefGoogle Scholar
  31. 31.
    Liu DM, Wang ZH, Liu L, Zhang XM, Lou FL. Acetylpuerarin increases cell viability and reduces apoptosis in rat hippocampal neurons following oxygen-glucose deprivation/reperfusion. Mol Med Rep. 2013;8:1453–9.CrossRefGoogle Scholar
  32. 32.
    Guan X, Liu Z, Liu H, Yu H, Wang LE, Sturgis EM, Li G, Wei Q. A functional variant at the miR-885-5p binding site of CASP3 confers risk of both index and second primary malignancies in patients with head and neck cancer. FASEB J. 2013;27:1404–12.CrossRefGoogle Scholar
  33. 33.
    Gu S, Wu Q, Zhao X, Wu W, Gao Z, Tan X, Qian J, Chen H, Xie Y, Jin L, Han B, Lu D. Association of CASP3 polymorphism with hematologic toxicity in patients with advanced non-small-cell lung carcinoma treated with platinum-based chemotherapy. Cancer Sci. 2012;103:1451–9.CrossRefGoogle Scholar
  34. 34.
    Zhang Z, Yu X, Guo Y, Song W, Yu D, Zhang X. Genetic variant in CASP3 affects promoter activity and risk of esophageal squamous cell carcinoma. Cancer Sci. 2012;103:555–60.CrossRefGoogle Scholar
  35. 35.
    Lorente L, Martín MM, Argueso M, Ramos L, Solé-Violán J, Riaño-Ruiz M, Jiménez A, Borreguero-León JM. Serum caspase-3 levels and mortality are associated in patients with severe traumatic brain injury. BMC Neurol. 2015;15:228.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society 2019

Authors and Affiliations

  • Leonardo Lorente
    • 1
    Email author
  • María M. Martín
    • 2
  • Antonia Pérez-Cejas
    • 3
  • Agustín F. González-Rivero
    • 3
  • Rafael Sabatel
    • 4
  • Luis Ramos
    • 5
  • Mónica Argueso
    • 6
  • Jordi Solé-Violán
    • 7
  • Juan J. Cáceres
    • 8
  • Alejandro Jiménez
    • 9
  • Victor García-Marín
    • 10
  1. 1.Intensive Care UnitHospital Universitario de CanariasSanta Cruz de TenerifeSpain
  2. 2.Intensive Care UnitHospital Universitario Nuestra Señora de CandelariaSanta Cruz de TenerifeSpain
  3. 3.Laboratory DepartmentHospital Universitario de CanariasSanta Cruz de TenerifeSpain
  4. 4.Department of RadiologyHospital Universitario de CanariasSanta Cruz de TenerifeSpain
  5. 5.Intensive Care UnitHospital General La PalmaLa PalmaSpain
  6. 6.Intensive Care UnitHospital Clínico Universitario de ValenciaValenciaSpain
  7. 7.Intensive Care UnitHospital Universitario Dr. Negrín, CIBERESLas Palmas de Gran CanariaSpain
  8. 8.Intensive Care UnitHospital InsularLas Palmas de Gran CanariaSpain
  9. 9.Research UnitHospital Universitario de CanariasSanta Cruz de TenerifeSpain
  10. 10.Department of NeurosurgeryHospital Universitario de CanariasSanta Cruz de TenerifeSpain

Personalised recommendations