CIRI After Early Recanalization

  • Qingmeng Chen
  • Min Lou
Part of the Springer Series in Translational Stroke Research book series (SSTSR)


Even with rapid reperfusion therapy for acute ischemic stroke, there is still a potential risk of clinical deterioration, such as cerebral hemorrhage, infarct growth or brain edema after early recanalization, which is so-called “reperfusion injury”. Blood-brain barrier (BBB) damage, inflammatory responses and leukocyte recruitment are believed as main pathophysiological mechanisms. With the development of neuroimage, several novel neuroimaging markers had been reported. Hyperintense acute reperfusion marker (HARM) and quantitative methods including Patlak algorithm, relative recirculation (rR) on enhanced neuroimage can evaluate the damage of BBB, which may induce cerebral hemorrhage. Postischemic hyperperfusion and “no-reflow phenomenon”, which correlate with infarct growth, are observed on perfusion image. Ischemic conditioning therapy, immunosuppressive agents and hypothermia treatment may have potential therapeutic values in future.


Stroke Recanalization Reperfusion injury 


  1. 1.
    Dalkara T, Arsava EM. Can restoring incomplete microcirculatory reperfusion improve stroke outcome after thrombolysis? J Cereb Blood Flow Metab. 2012;32:2091–9.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Molina CA, Saver JL. Extending reperfusion therapy for acute ischemic stroke: emerging pharmacological, mechanical, and imaging strategies. Stroke. 2005;36:2311–20.CrossRefPubMedGoogle Scholar
  3. 3.
    Bai J, Lyden PD. Revisiting cerebral postischemic reperfusion injury: new insights in understanding reperfusion failure, hemorrhage, and edema. Int J Stroke. 2015;10(2):143–52.CrossRefPubMedGoogle Scholar
  4. 4.
    Janardhan V, Qureshi AI. Mechanisms of ischemic brain injury. Curr Cardiol Rep. 2004;6:117–23.CrossRefPubMedGoogle Scholar
  5. 5.
    Warach S, Latour LL. Evidence of reperfusion injury, exacerbated by thrombolytic therapy, in human focal brain ischemia using a novel imaging marker of early bloodbrain barrier disruption. Stroke. 2004;35:2659–61.CrossRefPubMedGoogle Scholar
  6. 6.
    Kahles T, Luedike P, Endres M, et al. NADPH oxidase plays a central role in blood-brain barrier damage in experimental stroke. Stroke. 2007;38:3000–6.CrossRefPubMedGoogle Scholar
  7. 7.
    Belayev L, Busto R, Zhao W, Ginsberg MD. Quantitative evaluation of blood-brain barrier permeability following middle cerebral artery occlusion in rats. Brain Res. 1996;739:88–96.CrossRefPubMedGoogle Scholar
  8. 8.
    Rosenberg GA, Estrada EY, Dencoff JE. Matrix metalloproteinases and TIMPs are associated with blood-brain barrier opening after reperfusion in rat brain. Stroke. 1998;29:2189–95.CrossRefPubMedGoogle Scholar
  9. 9.
    Kuroiwa T, Ting P, Martinez H, Klatzo I. The biphasic opening of the blood-brain barrier to proteins following temporary middle cerebral artery occlusion. Acta Neuropathol. 1985;68:122–9.CrossRefPubMedGoogle Scholar
  10. 10.
    Abo-Ramadan U, Durukan A, Pitkonen M, et al. Post-ischemic leakiness of the blood-brain barrier: a quantitative and systematic assessment by Patlak plots. Exp Neurol. 2009;219:328–33.CrossRefPubMedGoogle Scholar
  11. 11.
    Strbian D, Durukan A, Pitkonen M, et al. The blood-brain barrier is continuously open for several weeks following transient focal cerebral ischemia. Neuroscience. 2008;153:175–81.CrossRefPubMedGoogle Scholar
  12. 12.
    Schaller B, Graf R. Cerebral ischemia and reperfusion: the pathophysiologic concept as a basis for clinical therapy. J Cereb Blood Flow Metab. 2004;24(4):351–71.CrossRefPubMedGoogle Scholar
  13. 13.
    Shen Q, Du F. Spatiotemporal characteristics of postischemic hyperperfusion with respect to changes in T1, T2, diffusion, angiography, and blood-brain barrier permeability. J Cereb Blood Flow Metab. 2011;31:2076–85.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Lin LH, Cao S, Yu L, Cui J, Hamilton WJ, Liu PK. Upregulation of base excision repair activity for 8-hydroxy-2-deoxyguanosine in the mouse brain after forebrain ischemia-reperfusion. J Neurochem. 2000;74:1098–105.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Folbergrova J, Zhao Q, Katsura KI, Siesjo BK. N-tert-butylalpha phenylnitorne improves recovery of brain energy state in rats following transient focal ischemia. Proc Natl Acad Sci U S A. 1995;92:5057–61.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Yang Y, Estrada EY, Thompson JF, et al. Matrix metalloproteinase mediated disruption of tight junction proteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat. J Cereb Blood Flow Metab. 2007;27:697–709.CrossRefPubMedGoogle Scholar
  17. 17.
    Jordan J, Segura T, Brea D, Galindo MF, Castillo J. Inflammation as therapeutic objective in stroke. Curr Pharm Des. 2008;14:3549–64.CrossRefPubMedGoogle Scholar
  18. 18.
    Lassen NA. The luxury-perfusion syndrome and its possible relation to acute metabolic acidosis localized within the brain. Lancet. 2:1113–5.CrossRefGoogle Scholar
  19. 19.
    Berne RM, Rubio R. Regulation of coronary bloodlow. Adv Cardiol. 1974;12:303–17.CrossRefPubMedGoogle Scholar
  20. 20.
    Cipolla MJ, Chan SL. Postischemic reperfusion causes smooth muscle calcium sensitization and vasoconstriction of parenchymal arterioles. Stroke. 2014;45(8):2425–30.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Graf R, Lottgen J. Dynamics of postischemic perfusion following transient MCA occlusion in cats determined by sequential PET. J Cereb Blood Flow Metab. 17:S323.Google Scholar
  22. 22.
    Chelluboina B, Klopfenstein JD. Temporal regulation of apoptotic and anti-apoptotic molecules after middle cerebral artery occlusion followed by reperfusion. Mol Neurobiol. 2014;49(1):50–65.CrossRefPubMedGoogle Scholar
  23. 23.
    Patlak CS, Blasberg RG. Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. Generalizations. J Cereb Blood Flow Metab. 1985;5:584–90.CrossRefPubMedGoogle Scholar
  24. 24.
    Jiang Q, Ewing JR. Quantitative evaluation of BBB permeability after embolic stroke in rat using MRI. J Cereb Blood Flow Metab. 2005;25(5):583–92.CrossRefPubMedGoogle Scholar
  25. 25.
    Lupo JM, Cha S, Chang SM, et al. Dynamic susceptibility-weighted perfusion imaging of high-grade gliomas: characterization of spatial heterogeneity. AJNR Am J Neuroradiol. 2005;26:1446–54.PubMedGoogle Scholar
  26. 26.
    Thornhill RE, Chen S. Contrast-enhanced MR imaging in acute ischemic stroke: T2* measures of blood-brain barrier permeability and their relationship to T1 estimates and hemorrhagic transformation. AJNR Am J Neuroradiol. 2010;31(6):1015–22.CrossRefPubMedGoogle Scholar
  27. 27.
    Kidwell CS, Saver JL. Late secondary ischemic injury in patients receiving intraarterial thrombolysis. Ann Neurol. 2002;52(6):698–703.CrossRefPubMedGoogle Scholar
  28. 28.
    Yu S, Liebeskind DS, UCLA Stroke Investigators. Postischemic hyperperfusion on arterial spin labeled perfusion MRI is linked to hemorrhagic transformation in stroke. J Cereb Blood Flow Metab. 2015;35(4):630–7.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Neumann-Haefelin T, Kastrup A. Serial MRI after transient focal cerebral ischemia in rats: dynamics of tissue injury, blood-brain barrier damage, and edema formation. Stroke. 2000;31(8):1965–72; discussion 1972–3.CrossRefPubMedGoogle Scholar
  30. 30.
    Olah L, Wecker S. Secondary deterioration of apparent diffusion coefficient after 1-hour transient focal cerebral ischemia in rats. J Cereb Blood Flow Metab. 2000;20(10):1474–82.CrossRefPubMedGoogle Scholar
  31. 31.
    Phan TG, Wright PM. Salvaging the ischaemic penumbra: more than just reperfusion? Clin Exp Pharmacol Physiol. 2002;29(1–2):1–10.CrossRefPubMedGoogle Scholar
  32. 32.
    Zhang RL, Chopp M. Temporal profile of ischemic tissue damage, neutrophil response, and vascular plugging following permanent and transient (2H) middle cerebral artery occlusion in the rat. J Neurol Sci. 1994;125:3–10.CrossRefPubMedGoogle Scholar
  33. 33.
    Fischer EG, Ames A III. Reassessment of cerebral capillary changes in acute global ischemia and their relationship to the “no-reflow phenomenon”. Stroke. 1977;8(1):36–9.CrossRefPubMedGoogle Scholar
  34. 34.
    Matsuo Y, Onodera H, Shiga Y, et al. Correlation between myeloperoxidase-quantified neutrophil accumulation and ischemic brain injury in the rat. Effects of neutrophil depletion. Stroke. 1994;25:1469–75.CrossRefGoogle Scholar
  35. 35.
    Relton JK, Sloan KE, Frew EM, et al. Inhibition of alpha4 integrin protects against transient focal cerebral ischemia in normotensive and hypertensive rats. Stroke. 2001;32:199–205.CrossRefPubMedGoogle Scholar
  36. 36.
    Liesz A, Zhou W, Mracsko E, et al. Inhibition of lymphocyte trafficking shields the brain against deleterious neuroinflammation after stroke. Brain. 2011;134(Pt 3):704–20.CrossRefPubMedGoogle Scholar
  37. 37.
    Kleinschnitz C, Schwab N, Kraft P, et al. Early detrimental T-cell effects in experimental cerebral ischemia are neither related to adaptive immunity nor thrombus formation. Blood. 2010;115:3835–42.CrossRefPubMedGoogle Scholar
  38. 38.
    Haussen DC, Nogueira RG. Infarct growth despite fullreperfusion in endovascular therapy for acute ischemic stroke. J Neurointerv Surg. 2016;8(2):117–21.CrossRefPubMedGoogle Scholar
  39. 39.
    Cho TH, Nighoghossian N. Reperfusion within 6 hours outperforms recanalization in predicting penumbra salvage, lesion growth, final infarct, and clinical outcome. Stroke. 2015;46(6):1582–9.CrossRefPubMedGoogle Scholar
  40. 40.
    Price CJ, Menon DK. Cerebral neutrophil recruitment, histology, and outcome in acute ischemic stroke: an imaging-based study. Stroke. 2004;35(7):1659–64.CrossRefPubMedGoogle Scholar
  41. 41.
    McAteer MA, Akhtar AM. An approach to molecular imaging of atherosclerosis, thrombosis, and vascular inflammation using microparticles of iron oxide. Atherosclerosis. 2010;209(1):18–27.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Barber PA, Foniok T, Kirk D, et al. MR molecular imaging of early endothelial activation in focal ischemia. Ann Neurol. 2004;56:116–20.CrossRefPubMedGoogle Scholar
  43. 43.
    Kidwell CS, Saver JL. Diffusion-perfusion MRI characterization of post-recanalization hyperperfusion in humans. Neurology. 2001;57(11):2015–21.CrossRefPubMedGoogle Scholar
  44. 44.
    Khatri R, McKinney AM. Blood-brain barrier, reperfusion injury, and hemorrhagic transformation in acute ischemic stroke. Neurology. 2012;79(13 Suppl 1):S52–7.CrossRefPubMedGoogle Scholar
  45. 45.
    Heo JH, Han SW. Free radicals as triggers of brain edema formation after stroke. Free Radic Biol Med. 2005;39(1):51–70.CrossRefPubMedGoogle Scholar
  46. 46.
    Mayanagi K, Gáspár T. The mitochondrial K(ATP) channel opener BMS-191095 reduces neuronal damage after transient focal cerebral ischemia in rats. J Cereb Blood Flow Metab. 2007;27:348–55.CrossRefPubMedGoogle Scholar
  47. 47.
    Gáspár T, Snipes JA. ROS-independent preconditioning in neurons via activation of mitoK(ATP) channels by BMS-191095. J Cereb Blood Flow Metab. 2008;28(6):1090–103.CrossRefPubMedGoogle Scholar
  48. 48.
    Fan YY, Hu WW. Postconditioning-induced neuroprotection, mechanisms and applications in cerebral ischemia. Neurochem Int. 2017.
  49. 49.
    Zhao H, Sapolsky RM. Interrupting reperfusion as a stroke therapy: ischemic postconditioning reduces infarct size after focal ischemia in rats. J Cereb Blood Flow Metab. 2006;26:1114–21.CrossRefPubMedGoogle Scholar
  50. 50.
    Liu JF, Zhang CF. Systematic review and meta analysis of the efficacy of sphingosine-1-phosphate (S1P) receptor agonist FTY720 (fingolimod) in animal models of stroke. Int J Neurosci. 2013;123(3):163–9.CrossRefPubMedGoogle Scholar
  51. 51.
    Zhu ZL, Fu Y. Combination of the immune modulator fingolimod with alteplase in acute ischemic stroke. Circulation. 2015;132:1104–12.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Hong JM, Lee JS. Therapeutic hypothermia after recanalization in patients with acute ischemic stroke. Stroke. 2014;45(1):134–40.CrossRefPubMedGoogle Scholar
  53. 53.
    Chen J, Liu L. Endovascular hypothermia in acute ischemic stroke: pilot study of selective intra-arterial cold saline infusion. Stroke. 2016;47(7):1933–5.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Qingmeng Chen
    • 1
  • Min Lou
    • 1
  1. 1.Department of Neurology, School of MedicineThe 2nd Affiliated Hospital of Zhejiang UniversityHangzhouChina

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