title: Serum tissue inhibitor of matrix metalloproteinase-1 levels are associated with mortality in patients with malignant middle cerebral artery infarction.
abstract: BACKGROUND
  In the last years, circulating matrix metalloproteinases (MMP)-9 levels have been associated with functional outcome in ischemic stroke patients. However the prognostic value of circulating levels of tissue inhibitor of matrix metalloproteinases (TIMP)-1 and MMP-10 in functional outcome of ischemic stroke patients has been scarcely studied. In addition, to our knowledge, serum MMP-9, MMP-10 and TIMP-1 levels in patients with malignant middle cerebral artery infarction (MMCAI) for mortality prediction have not been studied, and these were the objectives of this study.
  
  
  METHODS
  This was a multicenter, observational and prospective study carried out in six Spanish Intensive Care Units. We included patients with severe MMCAI defined as Glasgow Coma Scale (GCS) lower than 9. We measured circulating levels of MMP-9, MMP-10, TIMP-1, in 50 patients with severe MMCAI at diagnosis and in 50 healthy subjects. Endpoint was 30-day mortality.
  
  
  RESULTS
  Patients with severe MMCAI showed higher serum levels of MMP-9 (p = 0.001), MMP-10 (p < 0.001), and TIMP-1 (p = 0.02) than healthy subjects. Non-surviving MMCAI patients (n = 26) compared to survivor ones (n = 24) showed higher circulating levels of TIMP-1 (p < 0.001), MMP-10 (p = 0.02) and PAI-1(p = 0.02), and lower MMP-9 levels (p = 0.04). Multiple binomial logistic regression analysis showed that serum TIMP-1 levels > 239 ng/mL are associated with 30-day mortality (OR = 5.82; 95% CI = 1.37-24.73; P = 0.02) controlling for GCS and age. The area under the curve for TIMP-1 as predictor of 30-day mortality was 0.81 (95% CI = 0.67-0.91; P < 0.001). We found an association between circulating levels of TIMP-1 and MMP-10 (rho = 0.45; P = 0.001), plasminogen activator inhibitor (PAI)-1 (rho = 0.53; P < 0.001), and tumor necrosis factor (TNF)-alpha (rho = 0.70; P < 0.001).
  
  
  CONCLUSIONS
  The most relevant and new findings of our study, were that serum TIMP-1 levels in MMCAI patients were associated with mortality, and could be used as a prognostic biomarker of mortality in MMCAI patients.
authors.affiliation: Intensive Care Unit, Hospital Universitario de Canarias, Ofra, s/n. La Laguna, 38320, Santa Cruz de Tenerife, Spain. lorentemartin@msn.com.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Lorente
authors.affiliation: Intensive Care Unit, Hospital Universitario Nuestra Señora de Candelaria, Crta del Rosario s/n, Santa Cruz de Tenerife, 38010, Spain. mar.martinvelasco@gmail.com.
authors.forename: María M
authors.initials: MM
authors.lastname: Martín
authors.affiliation: Intensive Care Unit, Hospital General La Palma, Buenavista de Arriba s/n, Breña Alta, La Palma, 38713, Spain. lramosgomez@gmail.com.
authors.forename: Luis
authors.initials: L
authors.lastname: Ramos
authors.affiliation: Intensive Care Unit, Hospital Insular, Plaza Dr. Pasteur s/n, Las Palmas de Gran Canaria, 35016, Spain. jcacagr@gobiernodecanarias.org.
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Cáceres
authors.affiliation: Intensive Care Unit, Hospital Universitario Dr. Negrín, Barranco de la Ballena s/n, Las Palmas de Gran Canaria, 35010, Spain. jsolvio@gobiernodecanarias.org.
authors.forename: Jordi
authors.initials: J
authors.lastname: Solé-Violán
authors.affiliation: Intensive Care Unit, Hospital Clínico Universitario de Valencia, Avda. Blasco Ibáñez n°17-19, Valencia, 46004, Spain. moni_begasa@hotmail.com.
authors.forename: Mónica
authors.initials: M
authors.lastname: Argueso
authors.affiliation: Research Unit, Hospital Universitario de Canarias, Ofra, s/n. La Laguna, 38320, Santa Cruz de Tenerife, Spain. ajimenezsosa@gmail.com.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Jiménez
authors.affiliation: Laboratory Deparment, Hospital Universitario de Canarias, Ofra, s/n. La Laguna, 38320, Santa Cruz de Tenerife, Spain. jmborreguero@hotmail.com.
authors.forename: Juan M
authors.initials: JM
authors.lastname: Borreguero-León
authors.affiliation: Atherosclerosis Research Laboratory, CIMA-University of Navarra, Avda Pío XII n°55, Pamplona, 31008, Spain. josuneor@unav.es.
authors.forename: Josune
authors.initials: J
authors.lastname: Orbe
authors.affiliation: Atherosclerosis Research Laboratory, CIMA-University of Navarra, Avda Pío XII n°55, Pamplona, 31008, Spain. josean@unav.es.
authors.forename: José A
authors.initials: JA
authors.lastname: Rodríguez
authors.affiliation: Atherosclerosis Research Laboratory, CIMA-University of Navarra, Avda Pío XII n°55, Pamplona, 31008, Spain. japaramo@unav.es.
authors.forename: José A
authors.initials: JA
authors.lastname: Páramo
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D015600:Glasgow Coma Scale; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology*; D007362:Intensive Care Units; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000097:blood*; D020780:Matrix Metalloproteinase 9 / Q000097:blood; D008875:Middle Aged; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood; D011379:Prognosis; D011446:Prospective Studies; D020521:Stroke / Q000473:pathology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D017395:Plasminogen Activator Inhibitor 1; C051321:SERPINE1 protein, human; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D014409:Tumor Necrosis Factor-alpha; D020780:Matrix Metalloproteinase 9; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1