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Open Access 01-06-2019 | Original Article

Large Vessel Vasospasm Is Not Associated with Cerebral Cortical Hypoperfusion in a Murine Model of Subarachnoid Hemorrhage

Authors: Axel Neulen, Simon Meyer, Andreas Kramer, Tobias Pantel, Michael Kosterhon, Svenja Kunzelmann, Hermann Goetz, Serge C. Thal

Published in: Translational Stroke Research | Issue 3/2019

Abstract

Clinical studies on subarachnoid hemorrhage (SAH) have shown discrepancies between large vessel vasospasm, cerebral perfusion, and clinical outcome. We set out to analyze the contribution of large vessel vasospasm to impaired cerebral perfusion and neurological impairment in a murine model of SAH. SAH was induced in C57BL/6 mice by endovascular filament perforation. Vasospasm was analyzed with microcomputed tomography, cortical perfusion by laser SPECKLE contrast imaging, and functional impairment with a quantitative neuroscore. SAH animals developed large vessel vasospasm, as shown by significantly lower vessel volumes of a 2.5-mm segment of the left middle cerebral artery (MCA) (SAH 5.6 ± 0.6 nL, sham 8.3 ± 0.5 nL, p < 0.01). Induction of SAH significantly reduced cerebral perfusion of the corresponding left MCA territory compared to values before SAH, which only recovered partly (SAH vs. sham, 15 min 35.7 ± 3.1 vs. 101.4 ± 10.2%, p < 0.01; 3 h, 85.0 ± 8.6 vs. 121.9 ± 13.4, p < 0.05; 24 h, 75.3 ± 4.6 vs. 110.6 ± 11.4%, p < 0.01; 72 h, 81.8 ± 4.8 vs. 108.5 ± 14.5%, n.s.). MCA vessel volume did not correlate significantly with MCA perfusion after 72 h (r = 0.34, p = 0.25). Perfusion correlated moderately with neuroscore (24 h: r = − 0.58, p < 0.05; 72 h: r = − 0.44, p = 0.14). There was no significant correlation between vessel volume and neuroscore after 72 h (r = − 0.21, p = 0.50). In the murine SAH model, cerebral hypoperfusion occurs independently of large vessel vasospasm. Neurological outcome is associated with cortical hypoperfusion rather than large vessel vasospasm.

Steiner T, Juvela S, Unterberg A, Jung C, Forsting M, Rinkel G, et al. European Stroke Organization guidelines for the management of intracranial aneurysms and subarachnoid haemorrhage. Cerebrovasc Dis. 2013;35(2):93–112. https://doi.org/10.1159/000346087.CrossRefPubMed

Diringer MN, Bleck TP, Claude Hemphill J 3rd, Menon D, Shutter L, Vespa P, et al. Critical care management of patients following aneurysmal subarachnoid hemorrhage: recommendations from the Neurocritical Care Society’s Multidisciplinary Consensus Conference. Neurocrit Care. 2011;15(2):211–40. https://doi.org/10.1007/s12028-011-9605-9.CrossRefPubMed

Connolly ES, Jr., Rabinstein AA, Carhuapoma JR, Derdeyn CP, Dion J, Higashida RT, Hoh BL, Kirkness CJ, Naidech AM, Ogilvy CS, Patel AB, Thompson BG, Vespa P, American Heart Association Stroke C, Council on Cardiovascular R, Intervention, Council on Cardiovascular N, Council on Cardiovascular S, Anesthesia, Council on Clinical C. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/american Stroke Association. Stroke. 2012;43(6):1711–37. https://doi.org/10.1161/STR.0b013e3182587839.CrossRef

Macdonald RL. Delayed neurological deterioration after subarachnoid haemorrhage. Nat Rev Neurol. 2014;10(1):44–58. https://doi.org/10.1038/nrneurol.2013.246.CrossRefPubMed

Kamp MA, Heiroth HJ, Beseoglu K, Turowski B, Steiger HJ, Hanggi D. Early CT perfusion measurement after aneurysmal subarachnoid hemorrhage: a screening method to predict outcome? Acta Neurochir Suppl. 2012;114:329–32. https://doi.org/10.1007/978-3-7091-0956-4_63.CrossRefPubMed

Schubert GA, Seiz M, Hegewald AA, Manville J, Thome C. Acute hypoperfusion immediately after subarachnoid hemorrhage: a xenon contrast-enhanced CT study. J Neurotrauma. 2009;26(12):2225–31. https://doi.org/10.1089/neu.2009.0924.CrossRefPubMed

Pearl JD, Macdonald RL. Vasospasm after aneurysmal subarachnoid hemorrhage: need for further study. Acta Neurochir Suppl. 2008;105:207–10.CrossRefPubMed

Macdonald RL, Higashida RT, Keller E, Mayer SA, Molyneux A, Raabe A, et al. Randomized trial of clazosentan in patients with aneurysmal subarachnoid hemorrhage undergoing endovascular coiling. Stroke. 2012;43(6):1463–9. https://doi.org/10.1161/STROKEAHA.111.648980.CrossRefPubMed

Macdonald RL, Kassell NF, Mayer S, Ruefenacht D, Schmiedek P, Weidauer S, et al. Clazosentan to overcome neurological ischemia and infarction occurring after subarachnoid hemorrhage (CONSCIOUS-1): randomized, double-blind, placebo-controlled phase 2 dose-finding trial. Stroke. 2008;39(11):3015–21. https://doi.org/10.1161/STROKEAHA.108.519942.CrossRefPubMed

10.

Macdonald RL, Higashida RT, Keller E, Mayer SA, Molyneux A, Raabe A, et al. Randomised trial of clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid hemorrhage undergoing surgical clipping (CONSCIOUS-2). Acta Neurochir Suppl. 2013;115:27–31. https://doi.org/10.1007/978-3-7091-1192-5_7.CrossRefPubMed

11.

Etminan N, Vergouwen MD, Ilodigwe D, Macdonald RL. Effect of pharmaceutical treatment on vasospasm, delayed cerebral ischemia, and clinical outcome in patients with aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis. J Cereb Blood Flow Metab. 2011;31(6):1443–51. https://doi.org/10.1038/jcbfm.2011.7.CrossRefPubMedPubMedCentral

12.

Altay T, Smithason S, Volokh N, Rasmussen PA, Ransohoff RM, Provencio JJ. A novel method for subarachnoid hemorrhage to induce vasospasm in mice. J Neurosci Methods. 2009;183(2):136–40. https://doi.org/10.1016/j.jneumeth.2009.06.027.CrossRefPubMedPubMedCentral

13.

Froehler MT, Kooshkabadi A, Miller-Lotan R, Blum S, Sher S, Levy A, et al. Vasospasm after subarachnoid hemorrhage in haptoglobin 2-2 mice can be prevented with a glutathione peroxidase mimetic. J Clin Neurosci. 2010;17(9):1169–72. https://doi.org/10.1016/j.jocn.2010.04.014.CrossRefPubMed

14.

Momin EN, Schwab KE, Chaichana KL, Miller-Lotan R, Levy AP, Tamargo RJ. Controlled delivery of nitric oxide inhibits leukocyte migration and prevents vasospasm in haptoglobin 2-2 mice after subarachnoid hemorrhage. Neurosurgery. 2009;65(5):937–45; discussion 945. https://doi.org/10.1227/01.NEU.0000356974.14230.B8.CrossRefPubMed

15.

McGirt MJ, Lynch JR, Parra A, Sheng H, Pearlstein RD, Laskowitz DT, et al. Simvastatin increases endothelial nitric oxide synthase and ameliorates cerebral vasospasm resulting from subarachnoid hemorrhage. Stroke. 2002;33(12):2950–6.CrossRefPubMed

16.

Kamii H, Kato I, Kinouchi H, Chan PH, Epstein CJ, Akabane A, et al. Amelioration of vasospasm after subarachnoid hemorrhage in transgenic mice overexpressing CuZn-superoxide dismutase. Stroke. 1999;30(4):867–71. discussion 872CrossRefPubMed

17.

Smithason S, Moore SK, Provencio JJ. Systemic administration of LPS worsens delayed deterioration associated with vasospasm after subarachnoid hemorrhage through a myeloid cell-dependent mechanism. Neurocrit Care. 2012;16(2):327–34. https://doi.org/10.1007/s12028-011-9651-3.CrossRefPubMedPubMedCentral

18.

Provencio JJ, Altay T, Smithason S, Moore SK, Ransohoff RM. Depletion of Ly6G/C(+) cells ameliorates delayed cerebral vasospasm in subarachnoid hemorrhage. J Neuroimmunol. 2011;232(1–2):94–100. https://doi.org/10.1016/j.jneuroim.2010.10.016.CrossRefPubMed

19.

Provencio JJ, Fu X, Siu A, Rasmussen PA, Hazen SL, Ransohoff RM. CSF neutrophils are implicated in the development of vasospasm in subarachnoid hemorrhage. Neurocrit Care. 2010;12(2):244–51. https://doi.org/10.1007/s12028-009-9308-7.CrossRefPubMedPubMedCentral

20.

Yagi K, Lidington D, Wan H, Fares JC, Meissner A, Sumiyoshi M, et al. Therapeutically targeting tumor necrosis factor-alpha/sphingosine-1-phosphate signaling corrects myogenic reactivity in subarachnoid hemorrhage. Stroke. 2015;46(8):2260–70. https://doi.org/10.1161/STROKEAHA.114.006365.CrossRefPubMed

21.

Terpolilli NA, Feiler S, Dienel A, Muller F, Heumos N, Friedrich B, et al. Nitric oxide inhalation reduces brain damage, prevents mortality, and improves neurological outcome after subarachnoid hemorrhage by resolving early pial microvasospasms. J Cereb Blood Flow Metab. 2016;36(12):2096–107. https://doi.org/10.1177/0271678X15605848.CrossRefPubMed

22.

Friedrich B, Muller F, Feiler S, Scholler K, Plesnila N. Experimental subarachnoid hemorrhage causes early and long-lasting microarterial constriction and microthrombosis: an in-vivo microscopy study. J Cereb Blood Flow Metab. 2012;32(3):447–55. https://doi.org/10.1038/jcbfm.2011.154.CrossRefPubMed

23.

Han BH, Vellimana AK, Zhou ML, Milner E, Zipfel GJ. Phosphodiesterase 5 inhibition attenuates cerebral vasospasm and improves functional recovery after experimental subarachnoid hemorrhage. Neurosurgery. 2012;70(1):178–86; discussion 186-177. https://doi.org/10.1227/NEU.0b013e31822ec2b0.CrossRefPubMed

24.

Muroi C, Fujioka M, Okuchi K, Fandino J, Keller E, Sakamoto Y, et al. Filament perforation model for mouse subarachnoid hemorrhage: surgical-technical considerations. Br J Neurosurg. 2014;28(6):722–32. https://doi.org/10.3109/02688697.2014.918579.CrossRefPubMed

25.

Nittel N (2012) PhD thesis. https://www.edocubuni-muenchende/15329/1/Nittel_Nadinepdf

26.

Thal SC, Sporer S, Klopotowski M, Thal SE, Woitzik J, Schmid-Elsaesser R, et al. Brain edema formation and neurological impairment after subarachnoid hemorrhage in rats. Laboratory investigation J Neurosurg. 2009;111(5):988–94. https://doi.org/10.3171/2009.3.JNS08412.CrossRefPubMed

27.

Feiler S, Friedrich B, Scholler K, Thal SC, Plesnila N. Standardized induction of subarachnoid hemorrhage in mice by intracranial pressure monitoring. J Neurosci Methods. 2010;190(2):164–70. https://doi.org/10.1016/j.jneumeth.2010.05.005.CrossRefPubMed

28.

Neulen A, Pantel T, Kosterhon M, Kirschner S, Brockmann MA, Kantelhardt SR, et al. A segmentation-based volumetric approach to localize and quantify cerebral vasospasm based on tomographic imaging data. PLoS One. 2017;12(2):e0172010. https://doi.org/10.1371/journal.pone.0172010.CrossRefPubMedPubMedCentral

29.

Dorr A, Sled JG, Kabani N. Three-dimensional cerebral vasculature of the CBA mouse brain: a magnetic resonance imaging and micro computed tomography study. Neuroimage. 2007;35(4):1409–23. https://doi.org/10.1016/j.neuroimage.2006.12.040.CrossRefPubMed

30.

Neulen A, Kosterhon, M., Pantel, T., Kirschner, S., Goetz, H., Brockmann, M. A., Kantelhardt, S. R., Thal, S. C. A Volumetric Method for Quantification of Cerebral Vasospasm in a Murine Model of Subarachnoid Hemorrhage (In-press (2018)) A Volumetric Method for Quantification of Cerebral Vasospasm in a Murine Model of Subarachnoid Hemorrhage. J Vis Exp (Pending Publication) e57997. https://doi.org/10.3791/57997

31.

Friedrich B, Michalik R, Oniszczuk A, Abubaker K, Kozniewska E, Plesnila N. CO2 has no therapeutic effect on early microvasospasm after experimental subarachnoid hemorrhage. J Cereb Blood Flow Metab. 2014;34(8):e1–6. https://doi.org/10.1038/jcbfm.2014.96.CrossRefPubMed

32.

Pickard JD, Murray GD, Illingworth R, Shaw MD, Teasdale GM, Foy PM, et al. Effect of oral nimodipine on cerebral infarction and outcome after subarachnoid haemorrhage: British aneurysm nimodipine trial. BMJ. 1989;298(6674):636–42.CrossRefPubMedPubMedCentral

33.

Stein SC, Browne KD, Chen XH, Smith DH, Graham DI. Thromboembolism and delayed cerebral ischemia after subarachnoid hemorrhage: an autopsy study. Neurosurgery. 2006;59(4):781–7; discussion 787-788. https://doi.org/10.1227/01.NEU.0000227519.27569.45.CrossRefPubMed

34.

Uhl E, Lehmberg J, Steiger HJ, Messmer K. Intraoperative detection of early microvasospasm in patients with subarachnoid hemorrhage by using orthogonal polarization spectral imaging. Neurosurgery. 2003;52(6):1307–15. disacussion 1315–1307CrossRefPubMed

35.

Attwell D, Buchan AM, Charpak S, Lauritzen M, Macvicar BA, Newman EA. Glial and neuronal control of brain blood flow. Nature. 2010;468(7321):232–43. https://doi.org/10.1038/nature09613.CrossRefPubMedPubMedCentral

36.

Matta BF, Mayberg TS, Lam AM. Direct cerebrovasodilatory effects of halothane, isoflurane, and desflurane during propofol-induced isoelectric electroencephalogram in humans. Anesthesiology. 1995;83(5):980–5. discussion 927A.CrossRefPubMed

Title: Large Vessel Vasospasm Is Not Associated with Cerebral Cortical Hypoperfusion in a Murine Model of Subarachnoid Hemorrhage
Authors: Axel Neulen
Simon Meyer
Andreas Kramer
Tobias Pantel
Michael Kosterhon
Svenja Kunzelmann
Hermann Goetz
Serge C. Thal
Publication date: 01-06-2019
Publisher: Springer US
Published in: Translational Stroke Research / Issue 3/2019
Print ISSN: 1868-4483
Electronic ISSN: 1868-601X
DOI: https://doi.org/10.1007/s12975-018-0647-6

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Large Vessel Vasospasm Is Not Associated with Cerebral Cortical Hypoperfusion in a Murine Model of Subarachnoid Hemorrhage

Abstract

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