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Association between tPA therapy and raised early matrix metalloproteinase-9 in acute stroke

From the Stroke Service (M.N., K.L.F., W.J.K., M.B., M.L., P.J.K.), Department of Neurology (W.J.K., M.B., M.L.), and Biostatistics Center (H.L.), Massachusetts General Hospital and Harvard Medical School, Neuroprotection Research Laboratory (X.W., M.Z., E.H.L.) and Departments of Neurology (X.W.) and Radiology (X.W., M.Z., A.G.S.), Massachusetts General Hospital, Boston, MA; and Neurovascular Clinical Science Unit (P.J.K.), Department of Neurology, Mater Misericordiae University Hospital and University College Dublin, UK.

Address correspondence and reprint requests to Dr Kelly, Neurovascular Clinical Science Unit, Department of Neurology, Mater Misericordiae University Hospital, 71 Eccles Street, Dublin 7, UK; e-mail: pjkelly{at}partners.org; or Dr. K.L. Furie, Stroke Service, VBK 802, Department of Neurology, Massachusetts General Hospital, Fruit Street, Boston, MA 02114; e-mail: kfurie{at}partners.org.

Background: Matrix metalloproteinase-9 (MMP9) is expressed in acute ischemic stroke and up-regulated by tissue plasminogen activator (tPA) in animal models. The authors investigated plasma MMP9 and its endogenous inhibitor, tissue inhibitor of metalloproteinase (TIMP1), in tPA-treated and -untreated stroke patients.

Methods: Nonstroke control subjects and consecutive ischemic stroke patients presenting within 8 hours of onset were enrolled. Blood was sampled within 8 hours and at 24 hours, 2 to 5 days and 4 to 6 weeks. MMP9 and TIMP1 were analyzed by ELISA and gel zymography.

Results: Fifty-two cases (26 tPA treated, 26 tPA untreated) and 27 nonstroke control subjects were enrolled. Hyperacute MMP9 was elevated in tPA-treated vs tPA-untreated patients (medians 43 vs 28 ng/mL; p = 0.01). tPA therapy independently predicted hyperacute MMP9 after adjustment for stroke severity, volume, and hemorrhagic transformation (p = 0.01). There was a trend toward lower hyperacute TIMP1 levels in tPA-treated vs tPA-untreated patients (p = 0.06). Hyperacute MMP9 was correlated to poor 3-month modified Rankin Scale outcome (r = 0.58, p = 0.0005).

Conclusion: Tissue plasminogen activator independently predicted plasma matrix metalloproteinase-9 (MMP9) in the first 8 hours after human ischemic stroke. As MMP9 may be an important mediator of hemorrhagic transformation, alternative thrombolytic agents or therapeutic MMP9 inhibition may increase the safety profile of acute stroke thrombolysis.

Dr. Ning is the recipient of a Fellowship Award from the American Stroke Association. Dr. Furie is supported by an NINDS Career Development Award (K23 NS42720). Dr. Lo is supported by NINDS swards R01-NS37074, R01-NS38731, and R01-NS40529. Dr. Kelly is the recipient of a Clinical Scientist Development Award from the Doris Duke Charitable Foundation. During the period when this work was performed, he received funding from the American Stroke Association. Support was also provided by the Massachusetts General Hospital Mallinckrodt General Clinical Research Center (NIH grant no. M01-RR-01066). This work was made possible by the generous support of the Esther U. Sharp Fund, Conway Fellowship Fund, Lakeside Fund, and Levitt Fund.

Disclosure: The authors report no conflicts of interest.

Received June 1, 2005. Accepted in final form February 13, 2006.

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