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

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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Associations between endothelin polymorphisms and aneurysmal subarachnoid hemorrhage, clinical vasospasm, delayed cerebral ischemia, and functional outcome

Journal of Neurosurgery ◽

10.3171/2016.12.jns162594 ◽

2018 ◽

Vol 128 (5) ◽

pp. 1311-1317 ◽

Cited By ~ 6

Author(s):

Christoph J. Griessenauer ◽

Robert M. Starke ◽

Paul M. Foreman ◽

Philipp Hendrix ◽

Mark R. Harrigan ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Cerebral Ischemia ◽

Functional Outcome ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Delayed Cerebral Ischemia ◽

Multivariate Logistic Regression Analysis ◽

Renin Angiotensin System ◽

Nucleotide Polymorphisms ◽

Endothelin 1 ◽

Potent Vasoconstrictor

OBJECTIVEEndothelin-1, a potent vasoconstrictor, and its receptors may be involved in the pathogenesis of aneurysmal subarachnoid hemorrhage (aSAH), clinical vasospasm, delayed cerebral ischemia (DCI), and functional outcome following aSAH. In the present study, common endothelin single nucleotide polymorphisms (SNPs) and their relation to aSAH were evaluated.METHODSBlood samples from all patients enrolled in the Cerebral Aneurysm Renin Angiotensin System (CARAS) study were used for genetic evaluation. The CARAS study prospectively enrolled patients with aSAH at 2 academic institutions in the US from 2012 to 2015. Common endothelin SNPs were detected using 5′ exonnuclease (TaqMan) genotyping assays. Analysis of associations between endothelin SNPs and aSAH and its clinical sequelae was performed.RESULTSSamples from 149 patients with aSAH and 50 controls were available for analysis. In multivariate logistic regression analysis, the TG (odds ratio [OR] 2.102, 95% confidence interval [CI] 1.048–4.218, p = 0.036) and TT genotypes (OR 7.884, 95% CI 1.003–61.995, p = 0.05) of the endothelin-1 T/G SNP (rs1800541) were significantly associated with aSAH. There was a dominant effect of the G allele (CG/GG genotypes; OR 4.617, 95% CI 1.311–16.262, p = 0.017) of the endothelin receptor A G/C SNP (rs5335) on clinical vasospasm. Endothelin SNPs were not associated with DCI or functional outcome.CONCLUSIONSCommon endothelin SNPs were found to be associated with presentation with aSAH and clinical vasospasm. Further studies are required to elucidate the relevant pathophysiology and its potential implications in the treatment of patients with aSAH.

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Role of Endothelin-1 in Human Aneurysmal Subarachnoid Hemorrhage: Associations with Vasospasm and Delayed Cerebral Ischemia

Neurocritical Care ◽

10.1007/s12028-011-9508-9 ◽

2011 ◽

Vol 15 (1) ◽

pp. 19-27 ◽

Cited By ~ 30

Author(s):

Bhavani P. Thampatty ◽

Paula R. Sherwood ◽

Matthew J. Gallek ◽

Elizabeth A. Crago ◽

Dianxu Ren ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Cerebral Ischemia ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Delayed Cerebral Ischemia ◽

Endothelin 1

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

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2015.75 ◽

2015 ◽

Vol 35 (9) ◽

pp. 1515-1522 ◽

Cited By ~ 19

Author(s):

Mark K Donnelly ◽

Elizabeth A Crago ◽

Yvette P Conley ◽

Jeffery R Balzer ◽

Dianxu Ren ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Medical Center ◽

Delayed Cerebral Ischemia ◽

University Of Pittsburgh ◽

Potential Contributor ◽

Csf Levels ◽

Novel Target ◽

Poor Outcomes

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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Faculty Opinions recommendation of Role of endothelin-1 in human aneurysmal subarachnoid hemorrhage: associations with vasospasm and delayed cerebral ischemia.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.721969829.793510591 ◽

2015 ◽

Author(s):

Peter Andrews

Keyword(s):

Subarachnoid Hemorrhage ◽

Cerebral Ischemia ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Delayed Cerebral Ischemia ◽

Endothelin 1

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Preventing Microthrombi Formation Improves Function After Subarachnoid Hemorrhage in Mice

Neurosurgery ◽

10.1093/neuros/nyz310_803 ◽

2019 ◽

Vol 66 (Supplement_1) ◽

Author(s):

Hussein Zeineddine ◽

Spiros L Blackburn ◽

Remya Veettil ◽

Kanako Matsumura ◽

Devin McBride

Keyword(s):

Subarachnoid Hemorrhage ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Behavioral Assessment ◽

Delayed Cerebral Ischemia ◽

The United States ◽

Neurological Deficits ◽

Major Contributor ◽

Platelet Activity ◽

Functional Deficits

Abstract INTRODUCTION Aneurysmal subarachnoid hemorrhage (aSAH) is a debilitating disease affecting around 30 000 people per year in the United States, with a mortality estimated as high as 67%. Morbidity resulting from SAH is also extensive and includes delayed cerebral ischemia (DCI). However, the mechanism by which delayed neurological deficits develop is still poorly understood. To date, the importance of microthrombosis in SAH has been underappreciated, with few studies reporting on its occurrence and no studies probing the mechanism of microthrombi formation. We hypothesize that platelet activity results in microthrombi formation and contributes to delayed neurological deficits. We aim to address the knowledge gap in regard to the role of platelet activity and microthrombosis in DCI. METHODS For all experiments, adult male mice 4 mo old were utilized. SAH was induced using the endovascular perforation model. Behavioral assessment was performed on days 1, 3, 5, and 7 post-SAH. Animals were euthanized at 2 and 7 d post-SAH. To investigate the role of platelets in microthrombi formation after SAH, we used prototypic inhibitors of platelet activation (PAF, P2Y1,12, TP?/??R, PAR-1, −4) and platelet aggregation (GP aIIb/IIIa). RESULTS Mice with SAH had a higher microthrombi count compared to shams. Treatment with platelet inhibitors significantly reduced the number of microthrombi compared to placebo and provided protection against functional deficits. CONCLUSION SAH induces microthrombi formation, which may be a major contributor to delayed neurological deficits. Inhibition of platelet function reduces the number of microthrombi formed and confers protection against delayed functional deficits in mice models of SAH.

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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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The Role of the Blood Neutrophil-to-Lymphocyte Ratio in Aneurysmal Subarachnoid Hemorrhage

Frontiers in Neurology ◽

10.3389/fneur.2021.671098 ◽

2021 ◽

Vol 12 ◽

Author(s):

Lingxin Cai ◽

Hanhai Zeng ◽

Xiaoxiao Tan ◽

Xinyan Wu ◽

Cong Qian ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Critical Role ◽

Delayed Cerebral Ischemia ◽

Early Brain Injury ◽

Neutrophil To Lymphocyte Ratio ◽

Lymphocyte Ratio ◽

Novel Therapeutic Strategies ◽

Improved Accuracy

Aneurysmal subarachnoid hemorrhage (aSAH) is an important type of stroke with the highest rates of mortality and disability. Recent evidence indicates that neuroinflammation plays a critical role in both early brain injury and delayed neural deterioration after aSAH, contributing to unfavorable outcomes. The neutrophil-to-lymphocyte ratio (NLR) is a peripheral biomarker that conveys information about the inflammatory burden in terms of both innate and adaptive immunity. This review summarizes relevant studies that associate the NLR with aSAH to evaluate whether the NLR can predict outcomes and serve as an effective biomarker for clinical management. We found that increased NLR is valuable in predicting the clinical outcome of aSAH patients and is related to the risk of complications such as delayed cerebral ischemia (DCI) or rebleeding. Combined with other indicators, the NLR provides improved accuracy for predicting prognosis to stratify patients into different risk categories. The underlying pathophysiology is highlighted to identify new potential targets for neuroprotection and to develop novel therapeutic strategies.

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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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