on November 6, 2003
Published online before print November 6, 2003, doi: 10.1161/01.STR.0000098648.54429.1C
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Submitted on June 2, 2003
From the Neurovascular Research Laboratory, Stroke Unit (J.M., I.F.-C., C.A.M., J.A., M.R, M.Q., J.A-S.), Vascular Biology and Hemostasis Unit (J.M.), Lipid Research Unit (P.C.), and Centre d’Investigacions en Bioquimica i Biologia Molecular CIBBIM (A.L.A.), Vall d’Hebron Hospital. Barcelona, Spain. * To whom correspondence should be addressed. E-mail: 31862jmv{at}comb.es.
Background and Purpose--Matrix metalloproteinase-9 (MMP-9) expression, related to blood-brain barrier disruption, has been implicated in the appearance of hemorrhagic transformation (HT) after tissue plasminogen activator (tPA) treatment in stroke patients. Because an in vitro functional polymorphism of the promoter region of MMP-9 gene (C-1562T) has been described, we hypothesize that patients carrying this mutation might have higher MMP-9 levels and greater susceptibility to developing HT when receiving tPA. Methods--We studied strokes involving the middle cerebral artery territory of 61 patients who received tPA <3 hours after stroke onset. Blood samples were obtained before tPA administration. Plasmatic MMP-9 determinations were performed (enzyme-linked immunosorbent assay, ng/mL), and C-1562T genotype was determined by polymerase chain reaction. Healthy age-matched control subjects were used to study allele distribution (n=59). Hemorrhagic events were classified according to CT criteria (petechial hemorrhagic infarctions [HI,1 to 2] and large parenchymal hemorrhages [PH,1 to 2]). Results--Allele distribution was similar in patients and control subjects (CC/CT/TT: 72.3/27.7/0% versus 79.7/20.3/0%, respectively; P=0.37). Among patients, mutation carriers (CT/TT alleles) had similar rates of HT and PH than noncarriers (HT: 23.1% versus 38.2%, P=0.49; PH: 15.4% versus 17.6%, P=1.0). Although the highest MMP-9 level corresponded to patients who later developed a PH (PH, 191.4 ng/mL; non-PH, 68.05 ng/mL; P=0.022), no relation between MMP-9 mutation presence and plasmatic levels was found (CC, 127.12 ng/mL; CT/TT, 46.31 ng/mL; P=0.11). Conclusions--Although MMP-9 level predicts PH appearance after tPA treatment, no relationship exists with the C-1562T polymorphism, probably because this mutation is not functional in response to cerebral ischemia in vivo.
Accepted on July 16, 2003
Safety Profile of Tissue Plasminogen Activator Treatment Among Stroke Patients Carrying a Common Polymorphism (C-1562T) in the Promoter Region of the Matrix Metalloproteinase-9 Gene
Joan Montaner MD, PhD*;
Key words: hemorrhagic transformation • metalloproteinases • polymorphism • stroke • thrombolysis
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