title: Unbalanced Metalloproteinase-9 and Tissue Inhibitors of Metalloproteinases Ratios Predict Hemorrhagic Transformation of Lesion in Ischemic Stroke Patients Treated with Thrombolysis: Results from the MAGIC Study.
abstract: BACKGROUND
  Experimentally, metalloproteinases (MMPs) play a detrimental role related to the severity of ischemic brain lesions. Both MMPs activity and function in tissues reflect the balance between MMPs and tissue inhibitors of metalloproteinases (TIMPs). We aimed to evaluate the role of MMPs/TIMPs balance in the setting of rtPA-treated stroke patients.
  
  
  METHODS
  Blood was taken before and 24-h after rtPA from 327 patients (mean age 68 years, median NIHSS 11) with acute ischemic stroke. Delta median values of each MMP/TIMP ratio [(post rtPA MMP/TIMP-baseline MMP/TIMP)/(baseline MMP/TIMP)] were analyzed related to symptomatic intracranial hemorrhage (sICH) according to NINDS criteria, relevant hemorrhagic transformation (HT) defined as confluent petechiae within the infarcted area or any parenchymal hemorrhage, stroke subtypes (according to Oxfordshire Community Stroke Project) and 3-month death. The net effect of each MMP/TIMP ratio was estimated by a logistic regression model including major clinical determinants of outcomes.
  
  
  RESULTS
  Adjusting for major clinical determinants, only increase in MMP9/TIMP1 and MMP9/TIMP2 ratios remained significantly associated with sICH (odds ratio [95% confidence interval], 1.67 [1.17-2.38], p = 0.005; 1.74 [1.21-2.49], p = 0.003, respectively). Only relative increase in MMP9/TIMP1 ratio proved significantly associated with relevant HT (odds ratio [95% confidence interval], 1.74 [1.17-2.57], p = 0.006) with a trend toward significance for MMP9/TIMP2 ratio (p = 0.007).
  
  
  CONCLUSIONS
  Our data add substantial clinical evidence about the role of MMPs/TIMPs balance in rtPA-treated stroke patients. These results may serve to generate hypotheses on MMPs inhibitors to be administered together with rtPA in order to counteract its deleterious effect.
authors.affiliation: Neuroscience Section, Department of Neurofarba, University of Florence , Florence , Italy.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Piccardi
authors.affiliation: Stroke Unit, Department of Neurology, Careggi University Hospital , Florence , Italy.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Palumbo
authors.affiliation: Stroke Unit, Department of Neurology, Careggi University Hospital , Florence , Italy.
authors.forename: Mascia
authors.initials: M
authors.lastname: Nesi
authors.affiliation: Stroke Unit, Department of Neurology, Careggi University Hospital , Florence , Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Nencini
authors.affiliation: Department of Experimental and Clinical Medicine, Atherothrombotic Diseases Center, AOU Careggi, University of Florence , Florence , Italy.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Gori
authors.affiliation: Department of Experimental and Clinical Medicine, Atherothrombotic Diseases Center, AOU Careggi, University of Florence , Florence , Italy.
authors.forename: Betti
authors.initials: B
authors.lastname: Giusti
authors.affiliation: Neuroscience Section, Department of Neurofarba, University of Florence , Florence , Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Pracucci
authors.affiliation: Neuroscience Section, Department of Neurofarba, University of Florence , Florence , Italy.
authors.forename: Paolina
authors.initials: P
authors.lastname: Tonelli
authors.affiliation: Neuroscience Section, Department of Neurofarba, University of Florence , Florence , Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Innocenti
authors.affiliation: Department of Experimental and Clinical Medicine, Atherothrombotic Diseases Center, AOU Careggi, University of Florence , Florence , Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Sereni
authors.affiliation: Department of Experimental and Clinical Medicine, Atherothrombotic Diseases Center, AOU Careggi, University of Florence , Florence , Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Sticchi
authors.affiliation: Emergency Department Stroke Unit, Department of Neurological Sciences, Sapienza University of Rome , Rome , Italy.
authors.forename: Danilo
authors.initials: D
authors.lastname: Toni
authors.affiliation: SSO Stroke Unit, U.O. Neurologia d.O., DAI di Neuroscienze, Azienda Ospedaliera Integrata , Verona , Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Bovi
authors.affiliation: Neurology Unit, Valduce General Hospital , Como , Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Guidotti
authors.affiliation: U.O. Neurologia, DAI Neuroscienze-Riabilitazione, Azienda Ospedaliera-Universitaria S. Anna , Ferrara , Italy.
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Tola
authors.affiliation: U.O. Neurologia, G. Jazzolino Hospital , Vibo Valentia , Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Consoli
authors.affiliation: Istituto Neurologico Nazionale C. Mondino , Pavia , Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Micieli
authors.affiliation: U.O.C. Stroke Unit, Dipartimento di Scienze Neurologiche e Neurosensoriali, Azienda Ospedaliera Universitaria Senese , Siena , Italy.
authors.forename: Rossana
authors.initials: R
authors.lastname: Tassi
authors.affiliation: Department of Neurosciences, Neurological Clinic, University of Pisa , Pisa , Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Orlandi
authors.affiliation: UOC di Neurologia e "Stroke Unit", Ospedale San Bortolo , Vicenza , Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Perini
authors.affiliation: Neurology Unit, Arcispedale Santa Maria Nuova , Reggio Emilia , Italy.
authors.forename: Norina
authors.initials: N
authors.lastname: Marcello
authors.affiliation: Department of Clinical Neurological Sciences, London Health Sciences Centre, Western University , London, ON , Canada.
authors.forename: Antonia
authors.initials: A
authors.lastname: Nucera
authors.affiliation: Neurology Unit, Misericordia e Dolce Hospital , Prato , Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Massaro
authors.affiliation: Stroke Unit, Department of Neurology, Ospedale di Circolo e Fondazione Macchi , Varese , Italy.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: DeLodovici
authors.affiliation: Stroke Unit, Department of Neurology, Ospedale di Circolo e Fondazione Macchi , Varese , Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Bono
authors.affiliation: Department of Neurology, Istituti Ospitalieri , Cremona , Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Sessa
authors.affiliation: Department of Experimental and Clinical Medicine, Atherothrombotic Diseases Center, AOU Careggi, University of Florence , Florence , Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Abbate
authors.affiliation: Neuroscience Section, Department of Neurofarba, University of Florence , Florence , Italy ; Institute of Neuroscience, Italian National Research Council , Florence , Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Inzitari
keywords: death; hemorrhagic transformation; metalloproteinases; stroke; stroke subtypes; thrombolytic therapy; tissue inhibitor of metalloproteinases