Introduction: Aneurysmal subarachnoid hemorrhage (aSAH) is associated with a high degree of secondary brain injury, often due to delayed ischemia. Growing evidence suggests that dysfunction of the microvasculature may be a key factor. P450 metabolites are important regulators of microvascular tone. Studies have shown that CSF levels of the vasoconstrictive metabolite, 20-hydroxyeicosatetraenoic acid (20-HETE) rise over the first two weeks after aSAH. A different group of metabolites the eicosatrienoic acids (EETs) have been shown in animal models to be vasodilatory. The purpose of this study is to determine if levels of p450 metabolites change over time in the CSF of patients with aSAH and secondarily if functional genetic polymorphisms in the gene (EPHX2) that controls the metabolic degradation of EETs correlates with clinical outcome.
Methods: Patients 18 to 80 years old with aSAH were enrolled in the study. Clinical and radiological presentation, development of vasospasm and clinical outcomes were recorded. Serial samples of CSF were collected over 14 days in patients with ventricular access devices. Levels of P450 metabolites in the CSF were quantified using liquid chromatography tandem mass spectrometry. Genotyping was conducted on DNA extracted from whole blood samples and allelic discrimination of EPHX2 polymorphisms was performed using Taqman amplification.
Results: CSF levels of 20-HETE declined during the acute phase of hemorrhage. Inversely, CSF levels of 14,15-EET rose. EPHX2 polymorphism analysis showed a trend of poorer Glasgow Outcome Score in the K55R population at time of discharge, compared to other genotypes. No difference was noted between patients with the R287Q EPHX2 polymorphism compared to Wild Type.
Conclusions: P450 metabolites may be important in aSAH. CSF levels of the vasodilatory 14,15 EETs gradually increased over a 14 day recovery period whereas the vasoconstrictive 20-HETEs declined over this same time. Polymorphisms that speed degradation of EETs (theoretically leading to lower circulating levels) may be associated with poorer clinical outcomes suggesting an important role of p450 metabolites in regulating microvascular tone after aSAH.
Patient Care: If P450 metabolites regulate microvascular tone after aSAH pharmaceuticals can be developed to regulate their levels thereby improving CBF at the time of greatest ischemic risk
Learning Objectives: Describe the potential role of the P450 metabolites in subarachnoid hemorrhage