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Small Vessel Disease Is Associated with Tissue Inhibitor of Matrix Metalloproteinase-4 After Ischaemic Stroke

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Abstract

Small vessel disease (SVD) is frequent in aging and stroke patients. Inflammation and remodeling of extracellular matrix have been suggested as concurrent mechanisms of SVD. We investigated the relationship between imaging features of SVD and circulating metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in patients with ischaemic stroke. In patients treated with intravenous thrombolysis, we took blood samples before intravenous thrombolysis and 90 days after the acute stroke and analysed levels of MMPs and TIMPs. We assessed leukoaraiosis, number of lacunes and brain atrophy on pre-treatment CT scan and graded global SVD burden combining such features. We investigated associations between single features, global SVD and MMPs and TIMPs at baseline and at follow-up, retaining univariate statistically significant associations in multivariate linear regression analysis and adjusting for clinical confounders. A total of 255 patients [mean (±SD) = 68.6 (± 12.7) years, 154 (59%) males] were included, 107 (42%) had no signs of SVD; 47 (19%) had from moderate to severe SVD burden. A total of 107 (42%) patients had no signs of SVD; 47 (19%) had from moderate to severe SVD burden. After adjustment, only TIMP-4 proved associations with SVD features. Brain atrophy was associated with baseline TIMP-4 (β = 0.20;p = 0.019) and leukoaraiosis with 90 days TIMP-4 (β = 0.19; p = 0.013). Global SVD score was not associated with baseline TIMP-4 levels (β = 0.10; p = 0.072), whereas was associated with 90 days TIMP-4 levels (β = 0.21; p = 0.003). Total SVD burden was associated with higher TIMP-4 levels 90 days after stroke, whereas was not during the acute phase. Our results support a biological relationship between SVD grade and TIMP-4.

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References

  1. Pantoni L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol. 2010;9:689–701.

    Article  Google Scholar 

  2. Wardlaw JM, Smith EE, Biessels GJ, Cordonnier C, Fazekas F, Frayne R, et al. STandards for ReportIng vascular changes on nEuroimaging (STRIVE v1). Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol. 2013;12:822–38.

    Article  Google Scholar 

  3. Rosenberg GA. Inflammation and white matter damage in vascular cognitive impairment. Stroke. 2009;40:S20–3.

    Article  Google Scholar 

  4. Shoamanesh A, Preis SR, Beiser AS, Vasan RS, Benjamin EJ, Kase CS, et al. Inflammatory biomarkers, cerebral microbleeds, and small vessel disease: Framingham Heart Study. Neurology. 2015;84:825–32.

    Article  CAS  Google Scholar 

  5. Wiseman SJ, Doubal FN, Chappell FM, Valdés-Hernández MC, Wang X, Rumley A, et al. Plasma biomarkers of inflammation, endothelial function and hemostasis in cerebral small vessel disease. Cerebrovasc Dis. 2015;40:157–64.

    Article  CAS  Google Scholar 

  6. Topakian R, Garrick TR, Howe FA, et al. Blood-brain barrier permeability is increased in normal-appearing white matter in patients with lacunar stroke and leukoaraiosis. J Neurol Neurosurg Psychiatry. 2010;81:192–7.

    Article  CAS  Google Scholar 

  7. Wardlaw JM, Sandercock PAG, Dennis MS, Starr J, Kalimo H. Is breakdown of the blood-brain barrier responsible for lacunar stroke, leukoaraiosis, and dementia? Stroke. 2003;34:806–12.

    Article  CAS  Google Scholar 

  8. Candelario-Jalil E, Thompson J, Taheri S, Grossetete M, Adair JC, Edmonds E, et al. Matrix metalloproteinases are associated with increased blood-brain barrier opening in vascular cognitive impairment. Stroke. 2011;42:1345–50.

    Article  CAS  Google Scholar 

  9. Heo JH, Lucero J, Abumiya T, Koziol JA, Copeland BR, del Zoppo GJ. Matrix metalloproteinases increase very early during experimental focal cerebral ischemia. J Cereb Blood Flow Metab. 1999;19:624–33.

    Article  CAS  Google Scholar 

  10. Inzitari D, Giusti B, Nencini P, Gori AM, Nesi M, Palumbo V, et al. MAGIC study group. MMP9 variation after thrombolysis is associated with hemorrhagic transformation of lesion and death. Stroke. 2013;44:2901–3.

    Article  CAS  Google Scholar 

  11. Montaner J, Molina CA, Monasterio J, Abilleira S, Arenillas JF, Ribó M, et al. Matrix metalloproteinase-9 pretreatment level predicts intracranial hemorrhagic complications after thrombolysis in human stroke. Circulation. 2003;107:598–603.

    Article  CAS  Google Scholar 

  12. Wahlgren N, Ahmed N, Dávalos A, Ford GA, Grond M, Hacke W, Hennerici MG, Kaste M, Kuelkens S, Larrue V, Lees KR, Roine RO, Soinne L, Toni D, Vanhooren G; SITS-MOST investigators. Thrombolysis with alteplase for acute ischaemic stroke in the safe implementation of thrombolysis in stroke-monitoring study (SITS-MOST): an observational study. Lancet 2007; 369:275–282.

  13. Van Swieten JC, Hijdra A, Koudstaal PJ, van Gijn J. Grading white matter lesions on CT and MRI: a simple scale. J Neurol Neurosurg Psychiatry. 1990;53:1080–3.

    Article  Google Scholar 

  14. IST-3 collaborative group. Association between brain imaging signs, early and late outcomes, and response to intravenous alteplase after acute ischaemic stroke in the third international stroke trial (IST-3): secondary analysis of a randomised controlled trial. Lancet Neurol. 2015;14:485–96.

    Article  Google Scholar 

  15. Arba F, Leigh R, Inzitari D, Warach S, Luby M, Lees KR. On behalf of STIR/VISTA imaging collaboration. Blood-brain barrier leakage increases with small vessel disease in acute ischemic stroke. Neurology. 2017;89:2143–50.

    Article  Google Scholar 

  16. Arba F, Mair G, Carpenter T, Sakka E, Sandercock PA, Lindley RI, et al. Cerebral white matter hypoperfusion increases with small vessel disease burden. Data from the third international stroke trial. J Stroke Cerebrovasc Dis. 2017;26:1506–13.

    Article  Google Scholar 

  17. Arba F, Inzitari D, Ali M, Warach SJ, Luby M, Lees KR. STIR/VISTA imaging collaboration. Small vessel disease and clinical outcomes after IV rt-PA treatment. Acta Neurol Scand. 2017;136:72–7.

    Article  CAS  Google Scholar 

  18. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J Royal Statistical Society1995; Series B. 57:289–300.

  19. Staals J, Booth T, Morris Z, Bastin ME, Gow AJ, Corley J, et al. Total MRI load of cerebral small vessel disease and cognitive ability in older people. Neurobiol Aging. 2015;36:2806–11.

    Article  Google Scholar 

  20. Staals J, Makin SD, Doubal FN, Dennis MS, Wardlaw JM. Stroke subtype, vascular risk factors, and total MRI brain small-vessel disease burden. Neurology. 2014;83:1228–34.

    Article  Google Scholar 

  21. Arba F, Palumbo V, Boulanger JM, Pracucci G, Inzitari D, Buchan AM, et al. Leukoaraiosis and lacunes are associated with poor clinical outcomes in ischemic stroke patients treated with intravenous thrombolysis. Int J Stroke. 2016;11:62–7.

    Article  Google Scholar 

  22. Wardlaw JM, Smith C, Dichgans M. Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging. Lancet Neurol. 2013;12:483–97.

    Article  Google Scholar 

  23. Fernando MS, Simpson JE, Matthews F, Brayne C, Lewis CE, Barber R, et al. White matter lesions in an unselected cohort of the elderly: molecular pathology suggests origin from chronic hypoperfusion injury. Stroke. 2006;37:1391–8.

    Article  Google Scholar 

  24. Simpson JE, Fernando MS, Clark L, Ince PG, Matthews F, Forster G, et al. White matter lesions in an unselected cohort of the elderly: astrocytic, microglial and oligodendrocyte precursor cell responses. Neuropathol Appl Neurobiol. 2007;33:410–9.

    Article  CAS  Google Scholar 

  25. Rosenberg GA, Sullivan N, Esiri MM. White matter damage is associated with matrix metalloproteinases in vascular dementia. Stroke. 2001;32:1162–8.

    Article  CAS  Google Scholar 

  26. Aribisala BS, Wiseman S, Morris Z, Valdés-Hernández MC, Royle NA, Maniega SM, et al. Circulating inflammatory markers are associated with magnetic resonance imaging-visible perivascular spaces but not directly with white matter hyperintensities. Stroke. 2014;45:605–7.

    Article  CAS  Google Scholar 

  27. Rouhl RP, Damoiseaux JG, Lodder J, Theunissen RO, Knottnerus IL, Staals J, et al. Vascular inflammation in cerebral small vessel disease. Neurobiol Aging. 2012;33:1800–6.

    Article  CAS  Google Scholar 

  28. Romero JR, Vasan RS, Beiser AS, Au R, Benjamin EJ, DeCarli C, et al. Association of matrix metalloproteinases with MRI indices of brain ischemia and aging. Neurobiol Aging. 2010;31:2128–35.

    Article  CAS  Google Scholar 

  29. Leco KJ, Apte SS, Taniguchi GT, Hawkes SP, Khoukha R, Schultz GA, et al. Murine tissue inhibitor of metalloproteinases-4 (Timp-4): cDNA isolation and expression in adult mouse tissues. FEBS Lett. 1997;401:213–7.

    Article  CAS  Google Scholar 

  30. Ketsawatsomkron P, Keen HL, Davis DR. Lu KT, stump M, De Silva TM, Hilzendeger AM, Grobe JL, Faraci FM, Sigmund CD. Protective role for tissue inhibitor of Metalloproteinase-4, a novel peroxisome proliferator-activated receptor-γ target gene, in smooth muscle in Deoxycorticosterone acetate-salt hypertension. Hypertension. 2016;67:214–22.

    Article  CAS  Google Scholar 

  31. Radomski A, Jurasz P, Sanders EJ, Overall CM, Bigg HF, Edwards DR, et al. Identification, regulation and role of tissue inhibitor of metalloproteinases-4 (TIMP-4) in human platelets. Br J Pharmacol. 2002;137(8):1330–8.

    Article  CAS  Google Scholar 

  32. Tomimoto H, Akiguchi I, Wakita H, Osaki A, Hayashi M, Yamamoto Y. Coagulation activation in patients with Binswanger disease. Arch Neurol. 1999;56:1104–8.

    Article  CAS  Google Scholar 

  33. Iwamoto T, Kubo H, Takasaki M. Platelet activation in the cerebral circulation in different subtypes of ischaemic stroke and Binswanger's disease. Stroke. 1995;26:52–6.

    Article  CAS  Google Scholar 

  34. Wattjes MP, Henneman WJ, van der Flier WM, de Vries O, Träber F, Geurts JJ, et al. Diagnostic imaging of patients in a memory clinic: comparison of MR imaging and 64-detector row CT. Radiology. 2009;253:174–83.

    Article  Google Scholar 

  35. Potter GM, Doubal FN, Jackson CA, Chappell FM, Sudlow CL, Dennis MS, et al. Counting cavitating lacunes underestimates the burden of lacunar infarction. Stroke. 2010;4:267–72.

    Article  Google Scholar 

  36. Curtze S, Melkas S, Sibolt G, Haapaniemi E, Mustanoja S, Putaala J, et al. Cerebral computed tomography-graded white matter lesions are associated with worse outcome after thrombolysis in patients with stroke. Stroke. 2015;46:1554–60.

    Article  Google Scholar 

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Acknowledgments

We thank the hospital staff for data collection: M. Acampa, Siena; M. Bacigaluppi, Milano; A. Chiti, Pisa; A. De Boni, Vicenza; M.L. De Lodovici, Varese; F. Galati, Vibo Valentia; N. Marcello, Reggio Emilia; N. Micheletti, Verona; F. Muscia, Como; E. Paolino, Ferrara; P. Palumbo, Prato; P. Tosi, Rozzano; E. Mossello, Firenze; M.R. Tola, Ferrara; M. Torri, Firenze.

Funding

Biological Markers Associated with Acute Ischemic Stroke (MAGIC) Study was funded by grants from Italian Ministry of Health, 2006 Finalized Research Programmes (RFPS-2006-1-336520) and Ente Cassa di Risparmio di Firenze (2010.06.03).

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Correspondence to Francesco Arba.

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Study protocol was approved from local ethic committees. Each patient gave written informed consent.

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The authors declare that they have no conflict of interest.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.

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Arba, F., Piccardi, B., Palumbo, V. et al. Small Vessel Disease Is Associated with Tissue Inhibitor of Matrix Metalloproteinase-4 After Ischaemic Stroke. Transl. Stroke Res. 10, 44–51 (2019). https://doi.org/10.1007/s12975-018-0627-x

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  • DOI: https://doi.org/10.1007/s12975-018-0627-x

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