Abstract W MP28: Early Elevation of Plasma Soluble Fms-Like Tyrosine Kinase-1 is Associated With Poor Functional Outcome After Subarachnoid Hemorrhage

Abstract

Background: Vasospasm (VSP) and brain injury following subarachnoid hemorrhage (SAH) are associated with tissue hypoxia and vascular endothelial growth factor (VEGF) release. Soluble Fms-like tyrosine kinase-1 (sFlt-1), a truncated soluble form of VEGF receptor-1, is an endogenous VEGF inhibitor released in response to hypoxia and nitric oxide deficiency. SFlt-1 is anti-angiogenic and mediates endothelial dysfunction. We hypothesize sFlt-1 elevation may be associated with VSP and poor SAH outcome. Methods: We prospectively enrolled consecutive SAH subjects, banked serial blood samples, and evaluated their modified Rankin scores (mRS) at 3 month intervals. Poor functional outcome was defined as mRS>2. Angiographic VSP was defined as >50% reduction in caliber of any vessel on post-SAH day 7 cerebral angiogram. In 63 SAH subjects, we compared plasma sFlt-1 by ELISA on post-SAH days 3 and 5 by VSP and outcome status using Wilcoxon rank sum or Student’s t-test depending on data distribution. Bonferroni correction was used for multiple comparisons. Logistic regression was used to adjust for confounders. Associations were measured using Pearson’s or Spearman’s correlation depending on data distribution. Results: Twenty-seven subjects (43%) had poor 3-month outcome and 31 (49%) developed VSP. Elevated sFlt-1 level on post-SAH day 3 was associated with poor 3-month outcome (p=0.02) while post-SAH day 5 sFlt-1 level showed no association. SFlt-1 levels were not associated with Hunt and Hess (HH) or Fisher grades or with VSP. SFlt-1 was inversely correlated to VEGF (p=0.04, r=0.26). Post-SAH day 3 sFlt-1 level was independently associated with poor SAH outcome after adjustment for HH grade, age, and VEGF level (p=0.03). VEGF was not associated with VSP or SAH outcome. Conclusion: Early elevation of plasma sFlt-1 on post-SAH day 3 is independently associated with poor 3-month SAH outcome after adjustment for clinical predictors of SAH outcome and for VEGF. Inverse correlation suggests possible negative feedback control between sFlt-1 and VEGF in SAH. Future studies are necessary to determine the source of sFlt-1 in SAH and its role in SAH-associated brain injury. Replication in a larger cohort is necessary to validate sFlt-1 as a potential biomarker for SAH outcome.