Abstract
We hypothesized that the enzyme arginase-1 is released into the cerebrospinal fluid (CSF) during red blood cell lysis and contributes to dysregulated metabolism of the nitric oxide (NO) precursor L-arginine during aneurysmal subarachnoid hemorrhage (SAH). This prospective case–control study included 43 patients with aneurysmal SAH and ventricular drainage for clinical reasons. Longitudinal CSF samples (99) were obtained in the course of SAH. Patients were dichotomized regarding the occurrence of cerebral vasospasm syndrome (CVS) (N = 19). Arginase-1 and the amino acids L-arginine and L-ornithine were quantified in CSF. Outcome assessments included delayed cerebral ischemia (DCI) and functional status after 3 months using the modified Rankin Scale (mRS). Arginase-1 was released into the CSF of SAH patients whereas this enzyme was undetectable in controls. Compared to patients without CVS, arginase-1 levels were higher in CVS patients until day 14 after clinical event. The well-known surrogate parameter for arginase acitivity, the L-arginine to L-ornithine ratio (Arg/Orn), correlated with CSF arginase-1 levels. Arg/Orn was reduced in patients with CVS from disease onset (days 1–3, p = 0.0009) until day 14. Logistic regression analysis of early Arg/Orn was predictive for CVS (p = 0.008) and DCI (p = 0.035), independent of age, Hunt and Hess grade, and intraventricular blood. Arg/Orn < 2.71 at disease onset predicted CVS with a sensitivity of 86.7% and specificity of 72.2%. Arg/Orn ≥ 2.71 predicted excellent functional outcome. We propose a novel mechanism contributing to NO deprivation during SAH: arginase-1 is released from erythrocytes into the CSF, leading to L-arginine consumption and reduced NO bioavailability. Furthermore, Arg/Orn is a robust predictor for occurrence of CVS, DCI, and functional outcome 3 months after aneurysmal SAH. Our data provide a novel prognostic biomarker and may contribute to the development of novel therapeutic strategies in SAH. Clinical Trial Registration-URL: http://www.drks.de. Unique identifier: DRKS00015293, date of registration: 13.09.2018.
Highlights
Despite improved surgical and endovascular treatment options for ruptured intracranial aneurysms, up to 70% of subarachnoid hemorrhage (SAH) patients develop spasms of cerebral arteries [1]
It is widely accepted that intracellular products released from lysed erythrocytes to the subarachnoid space are responsible for the development of cerebral vasospasm syndrome (CVS) and delayed cerebral ischemia (DCI) [5]
Arginase-1 was measured in cerebrospinal fluid (CSF) at a 1:4 dilution using ELISA (Hycult biotechnology) according to the manufacturers’ protocol
Summary
Despite improved surgical and endovascular treatment options for ruptured intracranial aneurysms, up to 70% of subarachnoid hemorrhage (SAH) patients develop spasms of cerebral arteries [1]. By depletion of the eNOS substrate L-arginine, arginase-1 may contribute to CVS, DCI and poor clinical outcome. SAH subarachnoid hemorrhage, CVS cerebral vasospasm syndrome, SD standard deviation, H&H Hunt and Hess grade, IQR interquartile range, IVH intraventricular hemorrhage visible within 24 h after SAH, DCI delayed cerebral infarction, mRS modified Rankin scale, *all other cases underwent endovascular coiling of disease compared to patients without CVS both during pre-CVS phase (p = 0.029, n = 9 vs 5) and CVS onset phase (p = 0.038, n = 11 vs 6).
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