Department of Neurology, University Hospital Bonn, Venusberg-Campus 1, 53127, Bonn, Germany.
Department of Anaesthesiology and Intensive Care, University Hospital Bonn, Bonn, Germany.
Transl Stroke Res. 2022 Jun;13(3):382-390. doi: 10.1007/s12975-021-00944-y. Epub 2021 Oct 2.
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.
我们假设，在红细胞裂解过程中，精氨酸酶-1 会释放到脑脊液（CSF）中，并导致蛛网膜下腔出血（SAH）期间一氧化氮（NO）前体 L-精氨酸的代谢失调。这项前瞻性病例对照研究纳入了 43 名因临床原因行脑室引流的动脉瘤性 SAH 患者。在 SAH 期间，共获得了 99 份纵向 CSF 样本。根据是否发生脑血管痉挛综合征（CVS）（N=19），将患者分为两组。定量检测 CSF 中的精氨酸酶-1 以及 L-精氨酸和 L-鸟氨酸。通过改良 Rankin 量表（mRS）评估 3 个月后的迟发性脑缺血（DCI）和功能状态。结果评估包括：与对照组相比，SAH 患者的 CSF 中存在精氨酸酶-1，而对照组中未检测到该酶。与无 CVS 的患者相比，CVS 患者的精氨酸酶-1 水平在临床事件后第 14 天之前更高。精氨酸酶活性的公认替代参数，即 L-精氨酸与 L-鸟氨酸比值（Arg/Orn），与 CSF 精氨酸酶-1 水平相关。从发病开始（第 1-3 天，p=0.0009）到第 14 天，CVS 患者的 Arg/Orn 降低。早期 Arg/Orn 的逻辑回归分析预测 CVS（p=0.008）和 DCI（p=0.035），独立于年龄、Hunt 和 Hess 分级以及脑室内出血。发病时 Arg/Orn<2.71 预测 CVS 的灵敏度为 86.7%，特异性为 72.2%。Arg/Orn≥2.71 预测功能预后良好。我们提出了一种新的机制，该机制可能导致 SAH 期间一氧化氮（NO）的剥夺：精氨酸酶-1从红细胞中释放到 CSF 中，导致 L-精氨酸的消耗和 NO 生物利用度降低。此外，Arg/Orn 是预测 CVS、DCI 和 3 个月后动脉瘤性 SAH 功能结局的可靠指标。我们的数据提供了一种新的预后生物标志物，可能有助于制定 SAH 的新治疗策略。临床试验注册-URL：http://www.drks.de。唯一标识符：DRKS00015293，注册日期：2018 年 9 月 13 日。
