scholarly journals Sirtuin 1 Mediates Protection Against Delayed Cerebral Ischemia in Subarachnoid Hemorrhage in Response to Hypoxic Postconditioning

2021 ◽  
Author(s):  
Deepti Diwan ◽  
Ananth K. Vellimana ◽  
Diane J. Aum ◽  
Julian Clarke ◽  
James W. Nelson ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Cerebral Ischemia ◽  
Cerebral Vasospasm ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Delayed Cerebral Ischemia ◽  
Sirtuin 1 ◽  
Neurological Deficits ◽  
Multifactorial Disease ◽  
Time Points ◽  
Hypoxic Postconditioning

Background Many therapies designed to prevent delayed cerebral ischemia (DCI) and improve neurological outcome in aneurysmal subarachnoid hemorrhage (SAH) have failed, likely because of targeting only one element of what has proven to be a multifactorial disease. We previously demonstrated that initiating hypoxic conditioning before SAH (hypoxic preconditioning) provides powerful protection against DCI. Here, we expanded upon these findings to determine whether hypoxic conditioning delivered at clinically relevant time points after SAH (hypoxic postconditioning) provides similarly robust DCI protection. Methods and Results In this study, we found that hypoxic postconditioning (8% O 2 for 2 hours) initiated 3 hours after SAH provides strong protection against cerebral vasospasm, microvessel thrombi, and neurological deficits. By pharmacologic and genetic inhibition of SIRT1 (sirtuin 1) using EX527 and global Sirt1 −/− mice, respectively, we demonstrated that this multifaceted DCI protection is SIRT1 mediated. Moreover, genetic overexpression of SIRT1 using Sirt1‐Tg mice, mimicked the DCI protection afforded by hypoxic postconditioning. Finally, we found that post‐SAH administration of resveratrol attenuated cerebral vasospasm, microvessel thrombi, and neurological deficits, and did so in a SIRT1‐dependent fashion. Conclusions The present study indicates that hypoxic postconditioning provides powerful DCI protection when initiated at clinically relevant time points, and that pharmacologic augmentation of SIRT1 activity after SAH can mimic this beneficial effect. We conclude that conditioning‐based therapies administered after SAH hold translational promise for patients with SAH and warrant further investigation.

Cerebrospinal fluid macrophage migration inhibitory factor: a potential predictor of cerebral vasospasm and clinical outcome after aneurysmal subarachnoid hemorrhage

2020 ◽  
Vol 133 (6) ◽  
pp. 1786-1791 ◽  
Author(s):  
Kevin Kwan ◽  
Orseola Arapi ◽  
Katherine E. Wagner ◽  
Julia Schneider ◽  
Heustein L. Sy ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Cerebral Ischemia ◽  
Cerebral Vasospasm ◽  
Migration Inhibitory Factor ◽  
Macrophage Migration Inhibitory Factor ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Delayed Cerebral Ischemia ◽  
Inhibitory Factor ◽  
Macrophage Migration ◽  
Significant Difference

OBJECTIVEIn patients with aneurysmal subarachnoid hemorrhage (aSAH), poor outcomes have been shown to be correlated with subsequent cerebral vasospasm (CV) and delayed cerebral ischemia (DCI). The identification of novel biomarkers may aid in the prediction of which patients are vulnerable to developing vasospasm, cerebral ischemia, and neurological deterioration.METHODSIn this prospective clinical study at North Shore University Hospital, patients with aSAH or normal pressure hydrocephalus (NPH) with external ventricular drains were enrolled. The concentration of macrophage migration inhibitory factor (MIF) in CSF was assessed for correlation with CV or DCI, the primary outcome measures.RESULTSTwenty-five patients were enrolled in the aSAH group and 9 were enrolled in the NPH group. There was a significant increase in aggregate CSF MIF concentration in patients with aSAH versus those with NPH (24.4 ± 19.2 vs 2.3 ± 1.1 ng/ml, p < 0.0002). Incidence of the day of peak MIF concentration significantly correlated with the onset of clinical vasospasm (rho = 0.778, p < 0.0010). MIF concentrations were significantly elevated in patients with versus those without evidence of DCI (18.7 ± 4.93 vs 8.86 ± 1.28 ng/ml, respectively, p < 0.0025). There was a significant difference in MIF concentrations between patients with infection versus those without infection (16.43 ± 4.21 vs 8.5 ± 1.22 ng/ml, respectively, p < 0.0119).CONCLUSIONSPreliminary evidence from this study suggests that CSF concentrations of MIF are correlated with CV and DCI. These results, however, could be confounded in the presence of clinical infection. A study with a larger patient sample size is necessary to corroborate these findings.

scholarly journals Long-acting statin for aneurysmal subarachnoid hemorrhage: A randomized, double-blind, placebo-controlled trial

2017 ◽  
Vol 38 (7) ◽  
pp. 1190-1198 ◽  
Author(s):  
Masato Naraoka ◽  
Naoya Matsuda ◽  
Norihito Shimamura ◽  
Kenichiro Asano ◽  
Kenichi Akasaka ◽  
...  
Keyword(s):  
Placebo Group ◽  
Subarachnoid Hemorrhage ◽  
Cerebral Vasospasm ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Controlled Trial ◽  
Delayed Cerebral Ischemia ◽  
Pleiotropic Effects ◽  
Neurological Deficits ◽  
Double Blind ◽  
Long Acting

Statins have pleiotropic effects that are considered beneficial in preventing cerebral vasospasm and delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage (aSAH). Many studies using statins have been performed but failed to show remarkable effects. We hypothesized that a long-acting statin would be more effective, due to a longer half-life and stronger pleiotropic effects. Patients with aSAH were randomly assigned to a pitavastatin group (4 mg daily; n = 54) and a placebo group ( n = 54) after repair of a ruptured aneurysm. The primary efficacy end point was vasospasm-related delayed ischemic neurological deficits (DIND), and the secondary end points were cerebral vasospasm evaluated by digital subtraction angiography (DSA), vasospasm-related new cerebral infarctions, and outcome at three months. Severe cerebral vasospasms on DSA were statistically fewer in the pitavastatin group than in the placebo group (14.8% vs. 33.3%; odds ratio, 0.32; 95% confidence interval, 0.11–0.87, p = 0.042); however, the occurrence of DIND and new infarctions and outcome showed no statistically significant differences between the groups. The present study is the first to prove the definite, statin-induced amelioration of cerebral vasospasm on DSA. However, administration of any type of statin at the acute phase of aSAH is not recommended.

scholarly journals Delayed Cerebral Ischemia After Subarachnoid Hemorrhage: Is There a Relevant Experimental Model? A Systematic Review of Preclinical Literature

2021 ◽  
Vol 8 ◽  
Author(s):  
Suzanne Goursaud ◽  
Sara Martinez de Lizarrondo ◽  
François Grolleau ◽  
Audrey Chagnot ◽  
Véronique Agin ◽  
...  
Keyword(s):  
Systematic Review ◽  
Subarachnoid Hemorrhage ◽  
Cerebral Ischemia ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Delayed Cerebral Ischemia ◽  
Neurological Deficits ◽  
Related Complication ◽  
Pubmed Database ◽  
Blood Injection ◽  
Definition Of

Delayed cerebral ischemia (DCI) is one of the main prognosis factors for disability after aneurysmal subarachnoid hemorrhage (SAH). The lack of a consensual definition for DCI had limited investigation and care in human until 2010, when a multidisciplinary research expert group proposed to define DCI as the occurrence of cerebral infarction (identified on imaging or histology) associated with clinical deterioration. We performed a systematic review to assess whether preclinical models of SAH meet this definition, focusing on the combination of noninvasive imaging and neurological deficits. To this aim, we searched in PUBMED database and included all rodent SAH models that considered cerebral ischemia and/or neurological outcome and/or vasospasm. Seventy-eight publications were included. Eight different methods were performed to induce SAH, with blood injection in the cisterna magna being the most widely used (n = 39, 50%). Vasospasm was the most investigated SAH-related complication (n = 52, 67%) compared to cerebral ischemia (n = 30, 38%), which was never investigated with imaging. Neurological deficits were also explored (n = 19, 24%). This systematic review shows that no preclinical SAH model meets the 2010 clinical definition of DCI, highlighting the inconsistencies between preclinical and clinical standards. In order to enhance research and favor translation to humans, pertinent SAH animal models reproducing DCI are urgently needed.

scholarly journals Genetic Determinants of Cerebral Vasospasm, Delayed Cerebral Ischemia, and Outcome after Aneurysmal Subarachnoid Hemorrhage

2010 ◽  
Vol 30 (4) ◽  
pp. 676-688 ◽  
Author(s):  
Andrew F Ducruet ◽  
Paul R Gigante ◽  
Zachary L Hickman ◽  
Brad E Zacharia ◽  
Eric J Arias ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Cerebral Ischemia ◽  
Cerebral Vasospasm ◽  
Vascular Reactivity ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Association Studies ◽  
Genetic Research ◽  
Delayed Cerebral Ischemia ◽  
Cerebral Injury ◽  
Genetic Determinants

Despite extensive effort to elucidate the cellular and molecular bases for delayed cerebral injury after aneurysmal subarachnoid hemorrhage (aSAH), the pathophysiology of these events remains poorly understood. Recently, much work has focused on evaluating the genetic underpinnings of various diseases in an effort to delineate the contribution of specific molecular pathways as well as to uncover novel mechanisms. The majority of subarachnoid hemorrhage genetic research has focused on gene expression and linkage studies of these markers as they relate to the development of intracranial aneurysms and their subsequent rupture. Far less work has centered on the genetic determinants of cerebral vasospasm, the predisposition to delayed cerebral injury, and the determinants of ensuing functional outcome after aSAH. The suspected genes are diverse and encompass multiple functional systems including fibrinolysis, inflammation, vascular reactivity, and neuronal repair. To this end, we present a systematic review of 21 studies suggesting a genetic basis for clinical outcome after aSAH, with a special emphasis on the pathogenesis of cerebral vasospasm and delayed cerebral ischemia. In addition, we highlight potential pitfalls in the interpretation of genetic association studies, and call for uniformity of design of larger multicenter studies in the future.

scholarly journals Management of cerebral vasospasm following aneurysmal subarachnoid hemorrhage

2017 ◽  
Vol 5 (20) ◽  
pp. 33
Author(s):  
Mohamed Shehabeldin ◽  
Yazan Alderazi
Keyword(s):  
Critical Care ◽  
Subarachnoid Hemorrhage ◽  
Cerebral Ischemia ◽  
Cerebral Vasospasm ◽  
Endovascular Therapy ◽  
Clinical Presentation ◽  
Inflammatory Responses ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Delayed Cerebral Ischemia ◽  
Common Cause

Cerebral vasospasm is a serious complication following aneurysmal subarachnoidhemorrhage (SAH); it causes delayed cerebral ischemia (DCI) or infarction. Arterial vasospasmis considered the most common cause of disability and mortality among survivors of aneurysmalSAH. Monitoring for vasospasm is extremely important starting from the first day following ahemorrhage. The mechanism of vasospasm is not completely understood, but most data andstudies link the incidence of vasospasm to inflammatory responses secondary to extravasationof blood into the subarachnoid space. It is essential for critical care teams and health careproviders caring for patients with aneurysmal SAH to understand the clinical presentation andmanagement of cerebral vasospasm. In our review, we focus on the guidelines for monitoringand basic management of vasospasm and DCI which include monitoring options, hemodynamicand endovascular therapy, triggers for intervention, and triggers for treatment de-escalation.

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