Eicosanoid ratios are associated with hemorrhage severity and predict development of delayed cerebral ischemia following subarachnoid hemorrhage

Abstract

Delayed cerebral ischemia (DCI) is a life-threatening complication of aneurysmal subarachnoid hemorrhage (aSAH). The vasoactive P450 eicosanoids 20-hydroxyeicosatretraenoate (20-HETE) and 14,15-epoxyeicosatrenoate (14,15-EET) are associated with the development of DCI and may play opposing roles in DCI risk. We hypothesized that the ratio of these opposing eicosanoids in cerebrospinal fluid (CSF) is associated with hemorrhage severity and the risk of developing DCI after aSAH. In a preclinical model, rats received intracisternal blood injections to approximate aSAH. Hemorrhage severity, cerebral blood flow (CBF), cortical spreading depolarizations were recorded, and CSF eicosanoid levels were quantified using mass spectrometry. In a parallel clinical study, CSF samples were collected and analyzed prospectively from subjects with aSAH and outcomes were tracked. Preclinically, rats with greater hemorrhage severity had impaired CBF and lower median 14,15-EET/20-HETE ratios compared to those with lesser or no hemorrhage. In aSAH patients, the CSF 14,15-EET/20-HETE ratio was negatively correlated with hemorrhage grade on imaging. Patients who developed DCI had lower median 14,15-EET/20-HETE ratios compared to those without DCI. The CSF 14,15-EET/20-HETE ratio correlates with hemorrhage severity and may reflect a mechanistic underpinning of microvascular dysfunction that contributes to DCI. These results suggest that vasoactive eicosanoids may be a therapeutic target in aSAH.