Cerebrospinal Fluid 20-HETE Is Associated With Delayed Cerebral Ischemia and Poor Outcomes After Aneurysmal Subarachnoid Hemorrhage

Abstract

Background and Purpose Delayed cerebral ischemia (DCI) is a major complication after aneurysmal subarachnoid hemorrhage (aSAH) that is manifested by changes in cerebral blood flow (CBF) accompanied by neurological decline and results in long-term functional and neuropsychological (NP) impairment. Preclinical evidence has demonstrated that the arachidonic acid metabolite, 20-hydroxyeicosatetraenoic acid (20-HETE), affects cerebral microvascular tone and CBF after aSAH. The purpose of this study was to determine if CSF 20-HETE levels were associated with DCI and long term NP outcomes in aSAH patients. Methods CSF samples collected twice daily through 14 days after hemorrhage on 108 acute, adult aSAH patients. Samples were analyzed for 20-HETE via HPLC MSQ single quadrupole mass spectrometry. DCI was defined as the presence of impaired CBF (angiographic vasospasm, elevated transcranial Dopplers, abnormal CT or MR perfusion scans) accompanied by neurological deterioration. Outcomes including death and neuropsychological testing were completed at 3 months after hemorrhage. Results and Conclusions Detectible 20-HETE levels were observed in 31% of patient samples and were associated with severity of hemorrhage (Hunt&Hess p=0.04; Fisher p=0.05). Detection of 20-HETE was not associated with angiographic vasospasm (p=0.34), however, detectible 20-HETE was significantly associated with DCI (p=0.016). Our data also suggests that detectable 20-HETE was associated with decreased performance in 5 NP domains. These results provide the first clinical evidence that CSF 20-HETE concentrations are associated with DCI and poor outcomes and provide impetus for future studies to elucidate the clinical utility of inhibiting 20-HETE formation as a novel therapeutic intervention in patients with aSAH.

A role of the sodium pump in spreading ischemia in rats

“…67 Correspondingly, 20-HETE was shown to increase during SD in animals. 68 Also, 20-HETE is interesting in relationship with aSAH and the inverse hemodynamic response, because it was associated with delayed cerebral ischemia (DCI) in aSAH patients, 69 clusters of recurrent SDs with prolonged depression of spontaneous activity indicated the occurrence of DCI in human electrocorticographic recordings, 70 and such clusters displayed the inverse hemodynamic response to SD more often than isolated SDs. 5,7,71 Ouabain and endothelial-derived hyperpolarizing factor (EDHF).…”

Spreading Depression, Spreading Depolarizations, and the Cerebral Vasculature

“…More recently, lipoxygenase products have been investigated, because of their vasoactive properties, and because their CSF levels appear to be linked to delayed cerebral ischemia and poor outcomes after aneurysmal SAH (67,222) where injury depolarizations akin to SD occur spontaneously (93). Within the neurovascular unit, arachidonic acid released from astrocytes by Ca 2ϩ -activated phospholipase A 2 is converted to its main vasoconstrictor metabolite 20-HETE by a cytochrome P-450 enzyme (CYP4A) in vascular smooth muscle (328).…”

Genetic Markers in the EET Metabolic Pathway Are Associated with Outcomes in Patients with Aneurysmal Subarachnoid Hemorrhage

“…19 Outcomes Assessment Acute outcomes included the presence or absence of CND and DCI during the inpatient stay (up to 14 days). 20 Clinical neurologic deterioration was determined by a decline in neurologic exam for 41 hour evidenced by a documented global or focal deficit, an increase (two or more points) in NIH Stroke Scale or a decrease (two or more points) in Glasgow Coma Scale score in the absence of medication administration, fever, seizure, rebleed, increased intracranial pressure, or hydrocephalus. Delayed cerebral ischemia was defined as the presence of CND accompanied by evidence of impaired CBF (simultaneously or within 12 hours predetermination or postdetermination of CND).…”