Abstract 2834: Elevated Blood and Cerebrospinal Fluid Matrix Metalloproteinase-9 is Associated with Poor 3-month Outcome Following Subarachnoid Hemorrhage

Abstract

Background There is growing evidence supporting the role of inflammation in early brain injury (EBI) and cerebral vasospasm following subarachnoid hemorrhage (SAH). Matrix Metalloproteinases (MMP) are released by inflammatory cells and can mediate EBI via disruption of the extracellular matrix. MMPs also cleave endothelin-1 (ET-1) into strongly vasoactive fragments and may thereby mediate vasospasm, which can further worsen SAH outcome. We hypothesize that elevated MMP-9 in human cerebrospinal fluid (CSF) is associated with vasospasm and SAH outcome, and therefore a potential clinical biomarker. Methods We prospectively enrolled consecutive SAH subjects, banked serial blood and CSF samples, and evaluated their 3- and 6-month modified Rankins scores (mRS) via telephone follow-up. Angiographic vasospasm was defined as >50% reduction in vessel caliber on angiography on post-SAH day 6-8. Poor outcome was defined as mRS>2. We compared blood and CSF MMP-9 by ELISA on post SAH days 0-1, 2-3, 4-5, 6-8, and 10-14 in a cohort of SAH subjects (N=35) with respect to vasospasm and to 3-month outcome. Continuous variables were compared using student t-test or Wilcoxan rank sum test depending on data normality. Repeated measurements were analyzed using longitudinal regression. Results The study population had a mean age of 53 years and has 54% female. Sixty percent of subjects presented with Hunt and Hess grade of 3 and above. Fifty-four percent developed vasospasm and 32% achieved poor 3-month outcome. Elevation of CSF MMP-9 throughout post SAH days 0-14 was associated with poor 3-month outcome (p=0.008). Specifically, elevated CSF MMP-9 on post SAH day 2-3 (p=0.05) and blood MMP-9 on post SAH day 4-5 (p=0.045) were associated with poor 3-month outcome ( Figure 1 ). Blood MMP-9 correlated strongly with blood leukocyte count (r=0.56, p=0.007). Neither CSF nor blood MMP-9 correlated with vasospasm. Conclusion Early elevation of CSF and blood MMP-9 are associated with poor 3-month outcome but not with vasospasm in SAH. Leukocytes are likely a significant source of blood but not CSF MMP-9. Blood and CSF MMP-9 may mediate neuronal death in SAH via mechanisms independent of angiographic vasospasm. Further studies are necessary to determine the source of CSF MMP-9 and the mechanism by which it mediates poor outcome in SAH. Larger prospective studies are necessary to validate CSF MMP-9 as a predictive biomarker for SAH outcome.