20-HETE is Associated with Unfavorable Outcomes in Subarachnoid Hemorrhage Patients

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.

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Endothelin-1 and Endothelin Receptor Gene Variants and Their Association With Negative Outcomes Following Aneurysmal Subarachnoid Hemorrhage

Biological Research For Nursing ◽

10.1177/1099800412459674 ◽

2012 ◽

Vol 15 (4) ◽

pp. 390-397 ◽

Cited By ~ 9

Author(s):

Matthew Gallek ◽

Sheila Alexander ◽

Elizabeth Crago ◽

Paula Sherwood ◽

Michael Horowitz ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Receptor Gene ◽

Delayed Cerebral Ischemia ◽

The United States ◽

Endothelin 1 ◽

Potent Vasoconstrictor ◽

Poor Outcomes

Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating disease that affects approximately 30,000 people a year in the United States. Delayed cerebral ischemia (DCI) and cerebral vasospasm (CV) are common complications after aSAH. In addition, aSAH patients have a high risk of poor long-term outcomes. Endothelin-1 (ET-1), a potent vasoconstrictor, or its two types of receptors, ET receptor A (ETA) and ET receptor B (ETB), may play a role in the pathogenesis of DCI and CV. Genetic variations within the ET-1, ETA, or ETBgenes may also account for variance observed in the outcomes of aSAH patients. The purpose of this study was to describe the distribution of the Lys198Asn polymorphism, a known functional SNP in the ET-1 gene, and tagging SNPs of the ET-1, ETA, and ETBgenes in individuals recovering from aSAH. This study also investigated the relationships among the ET polymorphisms, DCI, and global functional outcomes measured at 3 and 6 months after aSAH. Participants included individuals aged 18–75 years with a diagnosis of aSAH. There was a trend found between the variant allele of an ET-1 SNP (rs6912834) and angiographic vasospasm. There were also associations found between two ETBSNPs (rs9574124 and rs3027111) and poor outcomes as measured by the Glasgow Outcome scale at 3 months. These findings support the role of ET-1 and ETBin recovery following aSAH.

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Clinical complications and outcomes of angiographically negative subarachnoid hemorrhage

Neurology ◽

10.1212/wnl.0000000000007501 ◽

2019 ◽

Vol 92 (20) ◽

pp. e2385-e2394 ◽

Cited By ~ 2

Author(s):

Cody L. Nesvick ◽

Soliman Oushy ◽

Lorenzo Rinaldo ◽

Eelco F. Wijdicks ◽

Giuseppe Lanzino ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Confidence Interval ◽

Ventriculoperitoneal Shunt ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Delayed Cerebral Ischemia ◽

Tertiary Referral Center ◽

Short And Long Term ◽

Csf Diversion

ObjectiveTo define the in-hospital course, complications, short- and long-term functional outcomes of patients with angiographically negative subarachnoid hemorrhage (anSAH), particularly those with aneurysmal-pattern anSAH (aanSAH).MethodsRetrospective cohort study of patients with aneurysmal subarachnoid hemorrhage (aSAH), aanSAH, and perimesencephalic-pattern anSAH (panSAH) treated at a single tertiary referral center between January 2006 and April 2018. Ninety-nine patients with anSAH (33 aanSAH and 66 panSAH) and 464 patients with aSAH were included in this study. Outcomes included symptomatic hydrocephalus requiring CSF drainage, need for ventriculoperitoneal shunt, radiographic vasospasm, delayed cerebral ischemia (DCI), radiographic infarction, disability level within 1 year of ictus, and at last clinical follow-up as defined by the modified Rankin Scale.ResultsPatients with aanSAH and panSAH had similar rates of DCI and radiologic infarction, and patients with aanSAH had significantly lower rates compared to aSAH (p ≤ 0.018). Patients with aanSAH were more likely than those with panSAH to require temporary CSF diversion and ventriculoperitoneal shunt (p ≤ 0.03), with similar rates to those seen in aSAH. Only one patient with anSAH died in the hospital. Compared to those with aSAH, patients with aanSAH were significantly less likely to have a poor functional outcome within 1 year of ictus (odds ratio 0.26, 95% confidence interval 0.090–0.75) and at last follow-up (hazard ratio 0.30, 95% confidence interval 0.19–0.49, p = 0.002).ConclusionsDCI is very uncommon in anSAH, but patients with aanSAH have a similar need for short- and long-term CSF diversion to patients with aSAH. Nevertheless, patients with aanSAH have significantly better short- and long-term outcomes.

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Long-term effects of nimodipine on cerebral infarcts and outcome after aneurysmal subarachnoid hemorrhage and surgery

Journal of Neurosurgery ◽

10.3171/jns.1991.74.1.0008 ◽

1991 ◽

Vol 74 (1) ◽

pp. 8-13 ◽

Cited By ~ 66

Author(s):

Juha Öhman ◽

Antti Servo ◽

Olli Heiskanen

Keyword(s):

Subarachnoid Hemorrhage ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Controlled Trial ◽

Delayed Cerebral Ischemia ◽

Ct Scanning ◽

Long Term Effects ◽

Cerebral Infarcts ◽

Double Blind ◽

Content Type

✓ A total of 213 patients with verified aneurysmal subarachnoid hemorrhage (SAH) of Grades I to III (Hunt and Hess classification) were enrolled in a double-blind placebo-controlled trial to determine the effect of intravenous nimodipine on delayed ischemic deterioration and computerized tomography (CT)-visualized infarcts after SAH and surgery. The administration of the drug or matching placebo was started immediately after the radiological diagnosis of a ruptured aneurysm had been made. Of the 213 patients enrolled in the study, 58 were operated on early (within 72 hours after the bleed: Days 0 to 3), 69 were operated on subacutely (between Days 4 and 7), and 74 had late surgery (on Day 8 or later). Eleven patients died before surgery was undertaken and one was not operated on. A follow-up examination with CT scanning, performed 1 to 3 years after the SAH (mean 1.4 years), revealed no significant differences in the overall outcome between the groups. However, nimodipine treatment was associated with a significantly lower incidence of deaths caused by delayed cerebral ischemia (p = 0.01) and significantly lower occurrence of cerebral infarcts visualized by CT scanning in the whole population (p = 0.05), especially in patients without an associated intracerebral hemorrhage on admission CT scan (p = 0.03).

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Detection of delayed cerebral ischemia using objective pupillometry in patients with aneurysmal subarachnoid hemorrhage

Journal of Neurosurgery ◽

10.3171/2018.9.jns181928 ◽

2020 ◽

Vol 132 (1) ◽

pp. 27-32 ◽

Cited By ~ 2

Author(s):

Salah G. Aoun ◽

Sonja E. Stutzman ◽

Phuong-Uyen N. Vo ◽

Tarek Y. El Ahmadieh ◽

Mohamed Osman ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Cerebral Ischemia ◽

Transcranial Doppler ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Medical Center ◽

Delayed Cerebral Ischemia ◽

Final Analysis ◽

Neurological Injury ◽

University Of Texas ◽

The University

OBJECTIVECerebral vasospasm causing delayed cerebral ischemia (DCI) is a source of significant morbidity after subarachnoid hemorrhage (SAH). Transcranial Doppler is used at most institutions to detect sonographic vasospasm but has poor positive predictive value for DCI. Automated assessment of the pupillary light reflex has been increasingly used as a reliable way of assessing pupillary reactivity, and the Neurological Pupil Index (NPi) has been shown to decrease hours prior to the clinical manifestation of ischemic injury or herniation syndromes. The aim of this study was to investigate the role of automated pupillometry in the setting of SAH, as a potential adjunct to TCD.METHODSOur analysis included patients that had been diagnosed with aneurysmal SAH and admitted to the neuro–intensive care unit of the University of Texas Southwestern Medical Center between November 2015 and June 2017. A dynamic infrared pupillometer was used for all pupillary measurements. An NPi value ranging from 3 to 5 was considered normal, and from 0 to 2.9 abnormal. Sonographic vasospasm was defined as middle cerebral artery velocities greater than 100 cm/sec with a Lindegaard ratio greater than 3 on either side on transcranial Doppler. Most patients had multiple NPi readings daily and we retained the lowest value for our analysis. We aimed to study the association between DCI and sonographic vasospasm, and DCI and NPi readings.RESULTSA total of 56 patients were included in the final analysis with 635 paired observations of daily TCD and NPi data. There was no statistically significant association between the NPi value and the presence of sonographic vasospasm. There was a significant association between DCI and sonographic vasospasm, χ2(1) = 6.4112, p = 0.0113, OR 1.6419 (95% CI 1.1163–2.4150), and between DCI and an abnormal decrease in NPi, χ2(1) = 38.4456, p < 0.001, OR 3.3930 (95% CI 2.2789–5.0517). Twelve patients experienced DCI, with 7 showing a decrease of their NPi to an abnormal range. This change occurred > 8 hours prior to the clinical decline 71.4% of the time. The NPi normalized in all patients after treatment of their vasospasm.CONCLUSIONSIsolated sonographic vasospasm does not seem to correlate with NPi changes, as the latter likely reflects an ischemic neurological injury. NPi changes are strongly associated with the advent of DCI and could be an early herald of clinical deterioration.

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New Mechanisms and Targets of Subarachnoid Hemorrhage: A Focus on Mitochondria

Current Neuropharmacology ◽

10.2174/1570159x19666211101103646 ◽

2021 ◽

Vol 19 ◽

Author(s):

Zeyu Zhang ◽

Anke Zhang ◽

Yibo Liu ◽

Xiaoming Hu ◽

Yuanjian Fang ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Mitochondrial Dynamics ◽

Delayed Cerebral Ischemia ◽

Early Brain Injury ◽

Adverse Outcomes ◽

Heavy Burden ◽

Poor Outcomes ◽

Spontaneous Subarachnoid Hemorrhage ◽

Membrane Organelle

: Spontaneous subarachnoid hemorrhage (SAH) accounts for 5-10% of all strokes, and is a subtype of hemorrhagic stroke that places a heavy burden on health care. Despite great progress in surgical clipping and endovascular treatment for ruptured aneurysms, cerebral vasospasm (CVS) and delayed cerebral ischemia (DCI) threaten the long-term outcomes of patients with SAH. Moreover, there are limited drugs available to reduce the risk of DCI and adverse outcomes in SAH patients. New insight suggests that early brain injury (EBI), which occurs within 72 h after the onset of SAH, may lay the foundation for further DCI development and poor outcomes. The mechanisms of EBI mainly include excitotoxicity, oxidative stress, neuroinflammation, blood-brain barrier (BBB) destruction, and cellular death. Mitochondria are a double-membrane organelle, and they play an important role in energy production, cell growth, differentiation, apoptosis, and survival. Mitochondrial dysfunction, which can lead to mitochondrial membrane potential (ΔΨm) collapse, overproduction of reactive oxygen species (ROS), release of apoptogenic proteins, disorders of mitochondrial dynamics, and activation of mitochondria-related inflammation, is considered a novel mechanism of EBI related to DCI as well as post-SAH outcomes. In addition, mitophagy is activated after SAH. In this review, we discuss the latest perspectives on the role of mitochondria in EBI and DCI after SAH. We emphasize the potential of mitochondria as therapeutic targets, and summarize the promising therapeutic strategies targeting mitochondria for SAH.

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

Stroke ◽

10.1161/strokeaha.110.605816 ◽

2011 ◽

Vol 42 (7) ◽

pp. 1872-1877 ◽

Cited By ~ 34

Author(s):

Elizabeth A. Crago ◽

Bhavani P. Thampatty ◽

Paula R. Sherwood ◽

Chie-Wen J. Kuo ◽

Catherine Bender ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Subarachnoid Hemorrhage ◽

Cerebral Ischemia ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Delayed Cerebral Ischemia ◽

Poor Outcomes

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Plasma Estrogen Levels Are Associated With Severity of Injury and Outcomes After Aneurysmal Subarachnoid Hemorrhage

Biological Research For Nursing ◽

10.1177/1099800414561632 ◽

2014 ◽

Vol 17 (5) ◽

pp. 558-566 ◽

Cited By ~ 8

Author(s):

Elizabeth A. Crago ◽

Paula R. Sherwood ◽

Catherine Bender ◽

Jeffrey Balzer ◽

Dianxu Ren ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Cerebral Perfusion ◽

Trajectory Analysis ◽

Clinical Evidence ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Delayed Cerebral Ischemia ◽

Chromatography Tandem Mass Spectrometry ◽

Severity Of Injury ◽

Liquid Chromatography Tandem Mass ◽

Poor Outcomes

Background:Biochemical mediators alter cerebral perfusion and have been implicated in delayed cerebral ischemia (DCI) and poor outcomes after aneurysmal subarachnoid hemorrhage (aSAH). Estrogens (estrone [E1] and estradiol [E2]) are mediators with neuroprotective properties that could play a role in DCI. This study explored associations between plasma estrogen levels and outcomes following aSAH.Methods:Plasma samples from 1–4, 4–6, and 7–10 days after hemorrhage from 99 adult aSAH patients were analyzed for estrogen levels using liquid chromatography tandem mass spectrometry. DCI was operationalized as radiographic/ultrasonic evidence of impaired cerebral blood flow accompanied by neurological deterioration. Outcomes were assessed using the Modified Rankin Scale at 3 and 12 months after hemorrhage. Statistical analysis included correlation, regression, and group-based trajectory.Results:Higher E1 and E2 levels were associated with higher Hunt and Hess grade (E1, p = .01; E2, p = .03), the presence of DCI (E1, p = .02; E2, p = .02), and poor 3-month outcomes (E1, p = .002; E2, p = .002). Trajectory analysis identified distinct populations over time for E1 (61% E1 high) and E2 (68% E2 high). Patients in higher trajectory groups had higher Fisher grades (E1, p = .008; E2, p = .01), more frequent DCI (E1, p = .04; E2, p = .08), and worse 3-month outcomes (E1, p = .01; E2, p = .004) than low groups.Conclusions:These results provide the first clinical evidence that plasma E1 and E2 concentrations are associated with severity of injury and outcomes after aSAH.

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Aneurysmal Subarachnoid Hemorrhage and Vasospasm

AACN Advanced Critical Care ◽

10.4037/aacnacc2018491 ◽

2018 ◽

Vol 29 (2) ◽

pp. 163-174 ◽

Cited By ~ 4

Author(s):

Shannon K. Burns ◽

Kacie J. Brewer ◽

Courtney Jenkins ◽

Sally Miller

Keyword(s):

Subarachnoid Hemorrhage ◽

Cerebral Ischemia ◽

Aneurysmal Subarachnoid Hemorrhage ◽

External Ventricular Drain ◽

Delayed Cerebral Ischemia ◽

Endovascular Coiling ◽

Ruptured Aneurysms ◽

The Past ◽

Endovascular Interventions ◽

Poor Outcomes

Aneurysmal subarachnoid hemorrhage is potentially fatal and is associated with poor outcomes in many patients. Advances in neurosurgical and medical management of ruptured aneurysms have improved mortality rates in patients with aneurysmal subarachnoid hemorrhage. Surgical and endovascular interventions, such as external ventricular drain placement, aneurysm clipping, and endovascular coiling, have been developed over the past few decades. Patients with aneurysmal subarachnoid hemorrhage are also at risk for cerebral vasospasm and delayed cerebral ischemia. This article describes the diagnosis and treatment of aneurysmal subarachnoid hemorrhage, vasospasm, and cerebral ischemia. Concurrent medical considerations and ideas for future neuroinflammatory vasospasm research are also discussed.

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Haptoglobin phenotype predicts the development of focal and global cerebral vasospasm and may influence outcomes after aneurysmal subarachnoid hemorrhage

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1412833112 ◽

2015 ◽

Vol 112 (4) ◽

pp. 1155-1160 ◽

Cited By ~ 33

Author(s):

Jenna L. Leclerc ◽

Spiros Blackburn ◽

Dan Neal ◽

Nicholas V. Mendez ◽

Jeffrey A. Wharton ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Cerebral Vasospasm ◽

Functional Outcomes ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Delayed Cerebral Ischemia ◽

Free Hemoglobin ◽

Disease States ◽

Critical Care Management ◽

Poor Outcomes ◽

Harmful Effects

Cerebral vasospasm (CV) and the resulting delayed cerebral ischemia (DCI) significantly contribute to poor outcomes following aneurysmal subarachnoid hemorrhage (aSAH). Free hemoglobin (Hb) within the subarachnoid space has been implicated in the pathogenesis of CV. Haptoglobin (Hp) binds free pro-oxidant Hb, thereby modulating its harmful effects. Humans can be of three Hp phenotypes: Hp1-1, Hp2-1, or Hp2-2. In several disease states, the Hp2-2 protein has been associated with reduced ability to protect against toxic free Hb. We hypothesized that individuals with the Hp2-2 phenotype would have more CV, DCI, mortality, and worse functional outcomes after aSAH. In a sample of 74 aSAH patients, Hp2-2 phenotype was significantly associated with increased focal moderate (P= 0.014) and severe (P= 0.008) CV and more global CV (P= 0.014) after controlling for covariates. Strong trends toward increased mortality (P= 0.079) and worse functional outcomes were seen for the Hp2-2 patients with modified Rankin scale at 6 wk (P= 0.076) and at 1 y (P= 0.051) and with Glasgow Outcome Scale Extended at discharge (P= 0.091) and at 1 y (P= 0.055). In conclusion, Hp2-2 phenotype is an independent risk factor for the development of both focal and global CV and also predicts poor functional outcomes and mortality after aSAH. Hp phenotyping may serve as a clinically useful tool in the critical care management of aSAH patients by allowing for early prediction of those patients who require increased vigilance due to their inherent genetic risk for the development of CV and resulting DCI and poor outcomes.

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

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2014.195 ◽

2014 ◽

Vol 35 (2) ◽

pp. 267-276 ◽

Cited By ~ 15

Author(s):

Mark K Donnelly ◽

Yvette P Conley ◽

Elizabeth A Crago ◽

Dianxu Ren ◽

Paula R Sherwood ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Cerebral Ischemia ◽

Metabolic Pathway ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Epoxyeicosatrienoic Acids ◽

Multiple Testing Correction ◽

Long Term Outcomes ◽

Fisher Grade ◽

Csf Levels

Preclinical studies show that epoxyeicosatrienoic acids (EETs) regulate cerebrovascular tone and protect against cerebral ischemia. We investigated the relationship between polymorphic genes involved in EET biosynthesis/metabolism, cytochrome P450 (CYP) eicosanoid levels, and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage (aSAH). Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid (DHET) cerebrospinal fluid (CSF) levels, as well as acute outcomes defined by delayed cerebral ischemia (DCI) or clinical neurologic deterioration (CND), were assessed over 14 days. Long-term outcomes were defined by Modified Rankin Scale (MRS) at 3 and 12 months. CYP2C8∗4 allele carriers had 44% and 36% lower mean EET and DHET CSF levels ( P=0.003 and P=0.007) and were 2.2- and 2.5-fold more likely to develop DCI and CND ( P=0.039 and P=0.041), respectively. EPHX2 55Arg, CYP2J2∗7, CYP2C8∗1B, and CYP2C8 g.36785A allele carriers had lower EET and DHET CSF levels. CYP2C8 g.25369T and CYP2C8 g.36755A allele carriers had higher EET levels. Patients with CYP2C8∗2C and EPHX2 404del variants had worse long-term outcomes while those with EPHX2 287Gln, CYP2J2∗7, and CYP2C9 g.816G variants had favorable outcomes. Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3-month outcomes. Dihydroxyeicosatetraenoic acids were not associated with outcomes. No associations passed Bonferroni multiple testing correction. These are the first clinical data demonstrating the association between the EET biosynthesis/metabolic pathway and the pathophysiology of aSAH.

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