Domenico Inzitari1, Betti Giusti, Patrizia Nencini, Anna Maria Gori, Mascia Nesi, Vanessa Palumbo, Benedetta Piccardi, Alessandra Armillis, Giovanni Pracucci, Giorgio Bono, Paolo Bovi, Domenico Consoli, Mario Guidotti, Antonia Nucera, Francesca Massaro, Giuseppe Micieli, Giovanni Orlandi, Francesco Perini, Rossana Tassi, Maria Rosaria Tola, Maria Sessa, Danilo Toni, Rosanna Abbate. 1. 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.).
Abstract
BACKGROUND AND PURPOSE: 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.
BACKGROUND AND PURPOSE: 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.
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