Small Vessel Disease Is Associated with Tissue Inhibitor of Matrix Metalloproteinase-4 After Ischaemic Stroke
- 88 Downloads
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.
KeywordsSmall vessel disease Matrix metalloproteinase Tissue inhibitor of matrix metalloproteinase Acute stroke
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.
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).
Compliance with Ethical Standards
Study protocol was approved from local ethic committees. Each patient gave written informed consent.
Conflict of Interest
The authors declare that they have no conflict of interest.
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.
- 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.CrossRefGoogle 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.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.CrossRefGoogle 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.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.CrossRefGoogle Scholar