Abstract WMP114: Increased Big Endothelin-1 in Human Cerebrospinal Fluid is Associated with Vasospasm and Poor 3-month Outcome Following Subarachnoid Hemorrhage

Abstract

Background Big endothelin (ET) is the precursor to ET-1, a potent vasoconstrictive peptide associated with vasospasm (VSP) in SAH. However, ET-1’s very short half-life limits its utility as a clinical biomarker. Big ET mediates in vitro microvascular vasoconstriction and has slower clearance, therefore may be a better candidate biomarker. We hypothesize that elevated CSF Big ET-1 is associated with VSP and poor outcome in SAH. Methods We prospectively enrolled consecutive SAH subjects, banked serial CSF samples, and evaluated their modified Rankin scores (mRS) via telephone follow-up every 3 months. 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 49 SAH subjects, we compared CSF big ET by ELISA on post-SAH days 1, 3, 5, and 7 with respect to VSP and outcome using student’s t-test or Wilcoxon rank sum test depending on data normality. Logistic regression was used to adjust for important confounders. Results CSF big ET elevation on post-SAH day 1 is associated with poor 3-month outcome (4.2 vs. 2.0 ng/mL, p=0.0048), and big ET elevation on post-SAH day 3 shows trend towards association with poor 3-month outcome (1.15 vs. 3.09 pg/mL, p=0.057). CSF big ET level on post-SAH day 1 is significantly associated with 3-month outcome (p<0.0001) after adjusting for age, Hunt and Hess (HH) and Fisher grades and aneurysm treatment modality by logistic regression. CSF big ET elevation on post-SAH day 7 is associated with VSP (5.2 vs. 3.9 pg/mL, p=0.045). Logistic regression shows CSF big ET level on post-SAH day 7 is significantly associated with VSP (p=0.02) after adjusting for age, HH and Fisher grades and aneurysm treatment modality. Conclusion Early elevation of CSF big ET is strongly and independently associated with SAH 3-month outcome after adjustment for important clinical confounders. CSF big ET elevation on post-SAH day 7 is also independently associated with angiographic VSP. A larger study with a replication cohort is necessary to validate big ET as a biomarker for SAH outcome and VSP. Further studies with concomitant measurements of endothelin-converting enzyme and ET-1 are necessary to elucidate the role of CSF big ET in VSP and brain injury following SAH.