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20-HETE is associated with unfavorable outcomes in subarachnoid hemorrhage patients.

ABSTRACT: Emerging evidence has suggested that patients experiencing aneurysmal subarachnoid hemorrhage (aSAH) develop vascular dysregulation as a potential contributor to poor outcomes. Preclinical studies have implicated the novel microvascular constrictor, 20-hydroxyeicosatetraenoic acid (20-HETE) in aSAH pathogenesis, yet the translational relevance of 20-HETE in patients with aSAH is largely unknown. The goal of this research was to determine the relationship between 20-HETE cerebrospinal fluid (CSF) levels, gene variants in 20-HETE synthesis, and acute/long-term aSAH outcomes. In all, 363 adult patients (age 18 to 75) with aSAH were prospectively recruited from the University of Pittsburgh Medical Center neurovascular Intensive Care Unit. Patients were genotyped for polymorphic variants and cytochrome P450 (CYP)-eicosanoid CSF levels were measured over 14 days. Outcomes included delayed cerebral ischemia (DCI), clinical neurologic deterioration (CND), and modified Rankin Scores (MRS) at 3 and 12 months. Patients with CND and unfavorable 3-month MRS had 2.2- and 2.7-fold higher mean 20-HETE CSF levels, respectively. Patients in high/moderate 20-HETE trajectory groups (35.7%) were 2.5-, 2.1-, 3.1-, 3.3-, and 2.1-fold more likely to have unfavorable MRS at 3 months, unfavorable MRS at 12 months, mortality at 3 months, mortality at 12 months, and CND, respectively. These results showed that 20-HETE is associated with acute and long-term outcomes and suggest that 20-HETE may be a novel target in aSAH.

SUBMITTER: Donnelly MK

PROVIDER: S-EPMC4640341 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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20-HETE is associated with unfavorable outcomes in subarachnoid hemorrhage patients.

Donnelly Mark K MK Crago Elizabeth A EA Conley Yvette P YP Balzer Jeffery R JR Ren Dianxu D Ducruet Andrew F AF Kochanek Patrick M PM Sherwood Paula R PR Poloyac Samuel M SM

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20150429 9

Emerging evidence has suggested that patients experiencing aneurysmal subarachnoid hemorrhage (aSAH) develop vascular dysregulation as a potential contributor to poor outcomes. Preclinical studies have implicated the novel microvascular constrictor, 20-hydroxyeicosatetraenoic acid (20-HETE) in aSAH pathogenesis, yet the translational relevance of 20-HETE in patients with aSAH is largely unknown. The goal of this research was to determine the relationship between 20-HETE cerebrospinal fluid (CSF) ...[more]

PMID: 25920956

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Project description:BackgroundAdequate oxygenation in patients with aneurysmal subarachnoid hemorrhage (SAH) is imperative. However, hyperoxia increases formation of reactive oxygen species and may be associated with a dose-dependent toxicity. We postulated a threshold for arterial partial pressure of oxygen (paO2) above which toxicity effects precipitate and sought to study the effects on 30-day mortality, favorable outcome at discharge and at 3 months, and delayed cerebral ischemia.MethodsIn this retrospective single-center cohort study, patients with SAH and mechanical ventilation > 72 h were included. Oxygen integrals were calculated above the following thresholds: 80, 100, 120, and 150 mm Hg and time-weighted mean paO2. All calculations were done from admission to end of day 1, day 3, and day 14. We conducted multivariable logistic regression analyses adjusted for age, sex, duration of ventilation, and Hunt and Hess grade. Time-weighted mean paO2 was categorized by quartiles. Favorable outcome was defined as Glasgow Outcome Scale scores of 4 and 5.ResultsFrom November 2010 to February 2021, 282 of 549 patients fulfilled the inclusion criteria. Odds ratios for 30-day mortality increased dose dependently and were as follows: 1.07 (95% confidence interval [CI] 1.03-1.11; p = 0.001) for each 1 mm Hg per day above 80 mm Hg; 1.16 (95% CI 1.07-1.27), above 100 mm Hg; 1.36 (95% CI 1.15-1.61), above 120 mm Hg; and 1.59 (95% CI 1.22-2.08), above 150 mm Hg (all p < 0.001) at day 14. For favorable outcome at 3 months, odds ratios were 0.96 (95% CI 0.92-0.99) for each 1 mm Hg per day above 80 mm Hg; 0.90 (95% CI 0.84-0.98), above 100 mm Hg; 0.83 (95% CI 0.72-0.97), above 120 mm Hg; and 0.77 (95% CI 0.61-0.97), above 150 mm Hg (all p < 0.05). For time-weighted mean paO2, lowest 30-day mortality and highest favorable outcome at 3 months were found in the second quartile (78-85 mm Hg). Thirty-day mortality increased above 93 mm Hg (fourth quartile), with an odds ratio of 3.4 (95% CI 1.4-8.4, p = 0.007). Odds ratios for favorable outcome at 3 months were 0.28 (95% CI 0.12-0.69), 0.27 (95% CI 0.11-0.67), and 0.24 (95% CI 0.10-0.59) for the first, third, and fourth quartiles, respectively (all p < 0.01). No significant association was found at day 1 and day 3, for favorable outcome at discharge, or for delayed cerebral ischemia.ConclusionsIntegrals above the defined paO2 thresholds were dose-dependently associated with an increase in mortality in ventilated patients with SAH. When we considered time-weighted mean paO2, unfavorable outcomes and 30-day mortality were more frequent both below and above a certain range. Unfavorable outcomes increased in paO2 ranges usually defined as normoxia. This emphasizes the necessity to further characterize oxygenation thresholds in ventilated patients with SAH in prospective clinical studies.

Project description:The diagnosis of cerebral vasospasm after Subarachnoid-Hemorrhage is currently very difficult, additional tools such as blood biomarkers are necessary. We tested the ability of gene expression profiles of blood cells to predict vasospasm. 32 patients suffering subarachnoid-hemorrhage were included in this prospective monocentre study. They were grouped according to have a complicated cerebral vasospasm (Vasospasm) or not (Control) and Paired according to age (+/- 10 years), sex, Fisher grade (+/- 1), location, smoking (at least 3 first parameters). Gene expression profiles of blood cells were determined using 25,000~gene microarray. Blood sample: 2.5 mL harvested in PAXgene® Blood RNA tubes (PreAnalytix) RNA extraction: PAXgene® Blood RNA kit (Qiagen). We used a Universel Reference RNA (Stratagene). RNA amplification and labelling: kit Amino Allyl MessageAmp II (Ambion). We hybridized 4 microarrays per patient using pangenomic microarrays from the "Réseau National des Génopôles" (Illkirch, France). 2 slides were hybridized with reference RNA labelled Cy3 and patient RNA labelled Cy5, and 2 slides were hybridized with reference RNA labelled Cy5 and patient RNA labelled Cy3. Hybridation : Agilent protocol with few modifications : 750 ng of each labelled RNA were hubriddized at 60°C during 17 hours in an Aglient hybridization oven. After washings, Slides were scanned with a GenePix 4000B scanner (Molecular Devices). Image intensity data were extracted with GenePix Pro 6.0 analysis software. Quantification of Cy3 and Cy5 and selection of good spots were performed using the MAIA software (Novikov E and Barillot E. Software package for automatic microarray image analysis (MAIA). The ACUITY software was then used to normalize log ratios Cy3/Cy5 with Lowess non linear normalization, to filter out genes not present in at least 3 slides out of 4, to evaluate the reproducibility of the 4 microarrays of each patient (hierarchical clustering, Self Organizing Maps). Statistical analyses to insure reproducibility was performed using Excel (correlation coefficients, ANOVA). Only slides that passed all reprocubility tests were validated.

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20-HETE is associated with unfavorable outcomes in subarachnoid hemorrhage patients.

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20-HETE is associated with unfavorable outcomes in subarachnoid hemorrhage patients.

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