Published Online
on June 9, 2005

A more recent version of this article appeared on July 1, 2005

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Submitted on February 16, 2005
Revised on March 21, 2005
Accepted on April 26, 2005

A Matrix Metalloproteinase Protein Array Reveals a Strong Relation Between MMP-9 and MMP-13 With Diffusion-Weighted Image Lesion Increase in Human Stroke

Anna Rosell MSc; José Alvarez-Sabín MD, PhD; Juan F. Arenillas MD, PhD; Alex Rovira MD; Pilar Delgado MD; Israel Fernández-Cadenas MSc; Anna Penalba; Carlos A. Molina MD, PhD; and Joan Montaner MD, PhD^*

From the Neurovascular Research Laboratory, Neurovascular Unit and Neuroimaging Unit, Neurology Department, Universitat Autònoma de Barcelona, Hospital Vall d’Hebron, Barcelona, Spain.

^* To whom correspondence should be addressed. E-mail: 31862jmv{at}comb.es.

Background and Purpose--Matrix metalloproteinases (MMPs) are involved in tissue destruction produced by the neuroinflammatory response that follows ischemic stroke. In the present study we use an MMP array to investigate the blood levels of several MMPs in stroke patients and its relation with brain tissue damage and neurological outcome.

Methods--Twenty-four patients with middle cerebral artery occlusion who received thrombolytic therapy were included. Blood samples were drawn before tissue plasminogen activator treatment and an MMP array (multiplex enzyme-linked immunosorbent assay [ELISA]) was performed including gelatinases (MMP-2 and MMP-9), collagenases (MMP-1, MMP-8, and MMP-13), stromelysines (MMP-3 and MMP-10), and MMP endogen inhibitors (TIMP-1 and TIMP-2). To assess tissue lesion a serial multimodal MRI study was performed (pretreatment and at 24 hours).

Results--Neither initial diffusion lesion nor hypoperfused volume was associated with metalloproteinase expression within the first 3 hours after stroke onset. Nevertheless, a strong correlation was found between MMP-9 and MMP-13 with diffusion-weighted image (DWI) lesion expansion (r=0.54, P=0.05 and r=0.60, P=0.017, respectively). Baseline levels of both MMP-9 (OR, 14;95% CI, 1.5 to 131; P=0.019) and MMP-13 (OR, 73; 95% CI, 3.9 to 1388; P=0.004) were independent predictors of final increase in brain infarct volume at 24 hours.

Conclusions--Our results demonstrate that within the neuroinflammatory response, high levels of MMP-9 and MMP-13 are involved in DWI lesion growth despite thrombolytic therapy, suggesting its ultra-early role in brain injury.

Key words: fibrinolysis • metalloproteinase • magnetic resonance imaging, diffusion-weighted • stroke • tissue plasminogen activator

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