title: MMP9 variation after thrombolysis is associated with hemorrhagic transformation of lesion and death.
abstract: OBJECTIVE
  Experimentally, matrix metalloproteinases (MMPs) play a detrimental role related to hemorrhagic transformation and severity of an ischemic brain lesion. Tissue-type plasminogen activator (tPA) enhances such effects. This study aimed to expand clinical evidence in this connection.
  
  
  METHODS
  We measured MMPs 1, 2, 3, 7, 8, 9, and tissue inhibitors of metalloproteinases 1, 2, 4 circulating level in blood taken before and 24 hours after tPA from 327 patients (mean age, 68.9±12.1 years; median National Institutes of Health Stroke Scale, 11) with acute ischemic stroke. Delta median values ([24 hours post tPA-pre tPA]/pre tPA) of each MMP or tissue inhibitors of metalloproteinase were analyzed across subgroups of patients undergoing symptomatic intracerebral hemorrhage, 3-month death, or 3-month modified Rankin Scale score 3 to 6.
  
  
  RESULTS
  Adjusting for major clinical determinants, only matrix metalloproteinase-9 variation proved independently associated with death (odds ratio [95% confidence interval], 1.58 [1.11-2.26]; P=0.045) or symptomatic intracerebral hemorrhage (odds ratio [95% confidence interval], 1.40 [1.02-1.92]; P=0.049). Both matrix metalloproteinase-9 and tissue inhibitors of metalloproteinase-4 changes were correlated with baseline, 24 hours, and 7 days National Institutes of Health Stroke Scale (Spearman P from <0.001 to 0.040).
  
  
  CONCLUSIONS
  Our clinical evidence corroborates the detrimental role of matrix metalloproteinase-9 during ischemic stroke treated with thrombolysis, and prompts clinical trials testing agents antagonizing its effects.
authors.affiliation: From the Stroke and Neurology Unit, Careggi University Hospital, Florence, Italy (D.I., P.N., M.N., V.P., B.P., G.P.); Department of Experimental and Clinical Medicine, Thrombosis Centre, University of Florence, Florence, Italy (B.G., A.M.G., A.A., R.A.); Neurology Unit, Ospedale di Circolo e Fondazione Macchi, University of Insubria, Varese, Italy (G.B.); SSO Stroke Unit, U.O. Neurologia d.O., DAI di Neuroscienze, Azienda Ospedaliera Integrata, Verona, Italy (P.B.); U.O. Neurologia, G. Jazzolino Hospital, Vibo Valentia, Italy (D.C.); Neurology Unit, Valduce General Hospital, Como, Italy (M.G.); Neurology Unit, Arcispedale Santa Maria Nuova, Reggio Emilia, Italy (A.N.); Neurology Unit, Misericordia e Dolce Hospital, Prato, Italy (F.M.); Istituto Neurologico Nazionale C. Mondino, Pavia, Italy (G.M.); Department of Neurosciences, Neurological Clinic, University of Pisa, Pisa, Italy (G.O.); UOC di Neurologia e "Stroke Unit", Ospedale San Bortolo, Vicenza, Italy (F.P.); U.O.C. Stroke Unit, Dipartimento di Scienze Neurologiche e Neurosensoriali, Azienda Ospedaliera Universitaria Senese, Siena, Italy (R.T.); UO Neurologia, DAI Neuroscienze-Riabilitazione, Azienda Ospedaliera-Universitaria S. Anna, Ferrara, Italy (M.R.T.); Department of Neurology, San Raffaele Scientific Institute, Milan, Italy (M.S.); and Emergency Department Stroke Unit and Department of Neurological Sciences, Sapienza University of Rome, Rome, Italy (D.T.).
authors.forename: Domenico
authors.initials: D
authors.lastname: Inzitari
authors.forename: Betti
authors.initials: B
authors.lastname: Giusti
authors.forename: Patrizia
authors.initials: P
authors.lastname: Nencini
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Gori
authors.forename: Mascia
authors.initials: M
authors.lastname: Nesi
authors.forename: Vanessa
authors.initials: V
authors.lastname: Palumbo
authors.forename: Benedetta
authors.initials: B
authors.lastname: Piccardi
authors.forename: Alessandra
authors.initials: A
authors.lastname: Armillis
authors.forename: Giovanni
authors.initials: G
authors.lastname: Pracucci
authors.forename: Giorgio
authors.initials: G
authors.lastname: Bono
authors.forename: Paolo
authors.initials: P
authors.lastname: Bovi
authors.forename: Domenico
authors.initials: D
authors.lastname: Consoli
authors.forename: Mario
authors.initials: M
authors.lastname: Guidotti
authors.forename: Antonia
authors.initials: A
authors.lastname: Nucera
authors.forename: Francesca
authors.initials: F
authors.lastname: Massaro
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Micieli
authors.forename: Giovanni
authors.initials: G
authors.lastname: Orlandi
authors.forename: Francesco
authors.initials: F
authors.lastname: Perini
authors.forename: Rossana
authors.initials: R
authors.lastname: Tassi
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Tola
authors.forename: Maria
authors.initials: M
authors.lastname: Sessa
authors.forename: Danilo
authors.initials: D
authors.lastname: Toni
authors.forename: Rosanna
authors.initials: R
authors.lastname: Abbate
mesh_terms: D000208:Acute Disease; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002545:Brain Ischemia / Q000097:blood* / Q000150:complications / Q000188:drug therapy; D002543:Cerebral Hemorrhage / Q000097:blood* / Q000209:etiology; D005260:Female; D005343:Fibrinolytic Agents / Q000627:therapeutic use; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000097:blood*; D008875:Middle Aged; D020521:Stroke / Q000097:blood* / Q000150:complications / Q000188:drug therapy; D015912:Thrombolytic Therapy; D019714:Tissue Inhibitor of Metalloproteinases / Q000097:blood; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use; D000097792:Tissue Inhibitor of Metalloproteinase-4
chemical_list: D005343:Fibrinolytic Agents; D020780:Matrix Metalloproteinase 9; D019714:Tissue Inhibitor of Metalloproteinases; D010959:Tissue Plasminogen Activator; D000097792:Tissue Inhibitor of Metalloproteinase-4; C579270:MMP9 protein, human
keywords: acute stroke; metalloproteinases; thrombolytic therapy; treatment outcome