Translational Stroke Research

, Volume 10, Issue 1, pp 44–51 | Cite as

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

  • Francesco Arba
  • Benedetta Piccardi
  • Vanessa Palumbo
  • Betti Giusti
  • Patrizia Nencini
  • Anna Maria Gori
  • Alice Sereni
  • Mascia Nesi
  • Giovanni Pracucci
  • Giorgio Bono
  • Paolo Bovi
  • Enrico Fainardi
  • Domenico Consoli
  • Antonia Nucera
  • Francesca Massaro
  • Giovanni Orlandi
  • Francesco Perini
  • Rossana Tassi
  • Maria Sessa
  • Danilo Toni
  • Rosanna Abbate
  • Domenico Inzitari
  • on behalf of the MAGIC Study Group
Original Article


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.


Small 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.

Ethical Approval

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.

Supplementary material

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Francesco Arba
    • 1
    • 2
  • Benedetta Piccardi
    • 1
    • 2
  • Vanessa Palumbo
    • 2
  • Betti Giusti
    • 3
  • Patrizia Nencini
    • 2
  • Anna Maria Gori
    • 3
  • Alice Sereni
    • 3
  • Mascia Nesi
    • 2
  • Giovanni Pracucci
    • 1
  • Giorgio Bono
    • 4
  • Paolo Bovi
    • 5
  • Enrico Fainardi
    • 6
  • Domenico Consoli
    • 7
  • Antonia Nucera
    • 8
  • Francesca Massaro
    • 9
  • Giovanni Orlandi
    • 10
  • Francesco Perini
    • 11
  • Rossana Tassi
    • 12
  • Maria Sessa
    • 13
  • Danilo Toni
    • 14
  • Rosanna Abbate
    • 15
  • Domenico Inzitari
    • 16
  • on behalf of the MAGIC Study Group
  1. 1.Department of NEUROFARBA, Neuroscience SectionUniversity of FlorenceFlorenceItaly
  2. 2.Stroke Unit and NeurologyCareggi University HospitalFlorenceItaly
  3. 3.Department of Experimental and Clinical Medicine, Atherothrombotic Diseases Center, AOU CareggiUniversity of FlorenceFlorenceItaly
  4. 4.Stroke Unit, Department of NeurologyOspedale di Circolo e Fondazione MacchiVareseItaly
  5. 5.SSO Stroke Unit, Department of NeurosciencesAzienda Ospedaliera IntegrataVeronaItaly
  6. 6.Department of NeuroradiologyCareggi University HospitalFlorenceItaly
  7. 7.U.O. NeurologiaG. Jazzolino HospitalVibo ValentiaItaly
  8. 8.Department of Clinical Neurological Sciences, London Health Sciences CentreWestern UniversityLondonCanada
  9. 9.Neurology UnitSanto Stefano HospitalPratoItaly
  10. 10.Department of Neurosciences, Neurological ClinicUniversity of PisaPisaItaly
  11. 11.UOC di Neurologia e Stroke UnitOspedale San BortoloVicenzaItaly
  12. 12.U.O.C. Stroke Unit, Dipartimento di Scienze Neurologiche e NeurosensorialiAzienda Ospedaliera Universitaria SeneseSienaItaly
  13. 13.U.O. Neurologia, DAI Neuroscienze-RiabilitazioneAzienda Ospedaliera-Universitaria S. AnnaFerraraItaly
  14. 14.Emergency Department Stroke Unit, Department of Neurological SciencesSapienza University of RomeRomeItaly
  15. 15.Centro Studi Medicina Avanzata (CESMAV)FlorenceItaly
  16. 16.Institute of NeuroscienceItalian National Research CouncilFlorenceItaly

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