scholarly journals ANGPT1 methylation and delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage patients

2021 ◽  
Vol 1 (1) ◽  
Author(s):  
Dongjing Liu ◽  
Annie I. Arockiaraj ◽  
John R. Shaffer ◽  
Samuel M. Poloyac ◽  
Paula R. Sherwood ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Subarachnoid Hemorrhage ◽  
Cerebral Ischemia ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Delayed Cerebral Ischemia ◽  
Pooled Analysis ◽  
Aneurysm Rupture ◽  
Cpg Sites ◽  
Significance Threshold ◽  
Post Hoc

Abstract Background Delayed cerebral ischemia (DCI) is a common secondary complication and an important cause of disability and mortality among patients who survive aneurysmal subarachnoid hemorrhage (aSAH). Knowledge on DCI pathogenesis, risk factors, and biomarkers are essential for early detection and improved prognosis. To investigate the role of DNA methylation in DCI risk, we conducted an epigenome-wide association study (EWAS) in 68 patients followed up to 1 year after the initial aneurysm rupture. Blood samples were collected within 48 h post hemorrhage and used for DNA methylation profiling at ~ 450k CpG sites. A separate cohort of 175 patients was sequenced for the top CpG sites from the discovery analysis for a replication of the EWAS findings. Results EWAS did not identify any epigenome-wide significant CpGs. The top signal, cg18031596, was annotated to ANGPT1, a gene with critical functions in angiogenesis after vascular injury. Post hoc power calculations indicated a well-powered discovery analysis for cg18031596. Analysis of the replication cohort showed that four out of the five CpG sites sequenced at the ANGPT1 locus passed a Bonferroni-adjusted significance threshold. In a pooled analysis of the entire sample, three out of five yielded a significant p-value, and the top association signal (p-value = 0.004) was seen for a CpG that was not originally measured in the discovery EWAS. However, four ANGPT1 CpG sites had an opposite effect direction in the replication analysis compared to the discovery EWAS, marking a failure of replication. We carefully examined this observed flip in directions and propose several possible explanations in addition to that it was a random chance that ANGPT1 ranked at the top in the discovery EWAS. Conclusions We failed to demonstrate a significant and consistent effect of ANGPT1 methylation in DCI risk in two cohorts. Though the replication attempt to weaken the overall support of this gene, given its relevant function and top rank of significance in the EWAS, our results call for future studies of larger aSAH cohorts to determine its relevance for the occurrence of DCI.

scholarly journals Relationship of the vascular territory affected by delayed cerebral ischemia and the location of the ruptured aneurysm in patients with aneurysmal subarachnoid hemorrhage

2021 ◽  
Author(s):  
Helene Hurth ◽  
Jochen Steiner ◽  
Ulrich Birkenhauer ◽  
Constantin Roder ◽  
Till-Karsten Hauser ◽  
...  
Keyword(s):  
At Risk ◽  
Subarachnoid Hemorrhage ◽  
Cerebral Ischemia ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Delayed Cerebral Ischemia ◽  
Aneurysm Rupture ◽  
Ruptured Aneurysm ◽  
Vascular Territory ◽  
Monitoring Methods ◽  
Anterior Circulation

Abstract Objective To determine the area most at risk of delayed cerebral ischemia (DCI) in relation to the location of the ruptured aneurysm in patients with aneurysmal subarachnoid hemorrhage (aSAH) and, therefore, help to choose the site for focal multimodal neuromonitoring. Methods We retrospectively analyzed angiographic findings, CCT scans, and patient charts of patients who were admitted with aSAH to our neurosurgical intensive care unit between 2009 and 2017. DCI was defined as infarction on CCT 2–6 weeks after aSAH. Results DCI occurred in 17.9% out of 357 included patients. A DCI occurring in the vascular territory of the artery carrying the ruptured aneurysm was found in 81.0% of patients with anterior circulation aneurysms but only in 16.7% with posterior circulation aneurysms (Fisher’s exact, p=0.003). The vascular territory most frequently showing a DCI was the ipsilateral MCA territory (86.7%) in ICA aneurysms, the contra- (71.4%) and the ipsilateral (64.3%) ACA territory in ACA aneurysms, the right (93.8%) and the left (81.3%) ACA territory in AcomA aneurysms, and the ipsilateral MCA territory in MCA aneurysms (69.2%) as well as in VA/PICA/SCA aneurysms (100.0%). DCI after the rupture of a BA aneurysm occurred with 33.3% in 6 out of 8 vascular territories, respectively. DCI of multiple vascular territories occurred in 100.0% of BA aneurysms, 87.5% of AcomA aneurysms, 71.4% of ACA aneurysms, 40.0% of ICA aneurysms, 38.5% of MCA aneurysms, and 33.3% of VA/PICA/SCA aneurysms. Discussion Few studies exist that could determine the area most at risk of a DCI after an aSAH. Our data could identify the territory most at risk for DCI with a probability of > 60% except for BA aneurysms, which showed DCI in various areas and patients suffering from multiple DCIs. Either the ipsilateral ACA or MCA were affected by the DCI in about 80% of ACA and more than 90% of AcomA, ICA, MCA, and VA/PICA/SCA aneurysms. Therefore, local intraparenchymal neuromonitoring in the ACA/MCA watershed area might detect the vast majority of DCIs for all aneurysm locations, except for BA aneurysms. In ACA and AcomA aneurysms, bilateral DCI of the ACA territory was common, and bilateral probe positioning might be considered for monitoring high-risk patients. Non-focal monitoring methods might be preferably used after BA aneurysm rupture.

Role of platelets in the pathogenesis of delayed injury after subarachnoid hemorrhage

2021 ◽  
pp. 0271678X2110208
Author(s):  
Ari Dienel ◽  
Peeyush Kumar T ◽  
Spiros L Blackburn ◽  
Devin W McBride
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Cerebral Ischemia ◽  
Blood Vessel ◽  
Vascular Function ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Delayed Cerebral Ischemia ◽  
Aneurysm Rupture ◽  
Large Artery ◽  
Major Contributor

Aneurysmal subarachnoid hemorrhage (aSAH) patients develop delayed cerebral ischemia and delayed deficits (DCI) within 2 weeks of aneurysm rupture at a rate of approximately 30%. DCI is a major contributor to morbidity and mortality after SAH. The cause of DCI is multi-factorial with contributions from microthrombi, blood vessel constriction, inflammation, and cortical spreading depolarizations. Platelets play central roles in hemostasis, inflammation, and vascular function. Within this review, we examine the potential roles of platelets in microthrombi formation, large artery vasospasm, microvessel constriction, inflammation, and cortical spreading depolarization. Evidence from experimental and clinical studies is provided to support the role(s) of platelets in each pathophysiology which contributes to DCI. The review concludes with a suggestion for future therapeutic targets to prevent DCI after aSAH.

scholarly journals Sevoflurane and Desflurane Exposures Following Aneurysmal Subarachnoid Hemorrhage Confer Multifaceted Protection against Delayed Cerebral Ischemia

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 820
Author(s):  
Keshav Jayaraman ◽  
Meizi Liu ◽  
Gregory J. Zipfel ◽  
Umeshkumar Athiraman
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Cerebral Ischemia ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Delayed Cerebral Ischemia ◽  
Preclinical Studies ◽  
Large Artery ◽  
Sham Surgery ◽  
Neurological Patients ◽  
Neurologic Function ◽  
Preclinical And Clinical Studies

Numerous studies have demonstrated the ability of isoflurane conditioning to provide multifaceted protection against aneurysmal subarachnoid hemorrhage (SAH)-associated delayed cerebral ischemia (DCI); however, preclinical studies have not yet examined whether other commonly used inhalational anesthetics in neurological patients such as sevoflurane or desflurane are also protective against SAH-induced neurovascular deficits. We therefore sought to identify the potential for sevoflurane and desflurane conditioning to protect against DCI in an endovascular perforation mouse model of SAH. Neurological function was assessed daily via neuroscore. Large artery vasospasm and microvessel thrombosis were assessed three days after SAH or sham surgery. Four groups were examined: Sham, SAH + room air, SAH + 2% Sevoflurane, and SAH + 6% Desflurane. For the SAH groups, one hour after surgery, mice received 2% sevoflurane, 6% desflurane, or room air for one hour. We found that conditioning with sevoflurane or desflurane attenuated large artery vasospasm, reduced microvessel thrombosis, and improved neurologic function. Given their frequent clinical use and strong safety profile in patients (including those with SAH), these data strongly support further studies to validate these findings in preclinical and clinical studies and to elucidate the mechanisms by which these agents might be acting.

scholarly journals Effects of post-interventional antiplatelet therapy on angiographic vasospasm, delayed cerebral ischemia, and clinical outcome after aneurysmal subarachnoid hemorrhage: a single-center experience

2021 ◽  
Author(s):  
Claudia Ditz ◽  
Björn Machner ◽  
Hannes Schacht ◽  
Alexander Neumann ◽  
Peter Schramm ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Cerebral Ischemia ◽  
Functional Outcome ◽  
Antiplatelet Therapy ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Delayed Cerebral Ischemia ◽  
Control Group ◽  
Lesion Volume ◽  
Single Center ◽  
Single Center Experience

AbstractPlatelet activation has been postulated to be involved in the pathogenesis of delayed cerebral ischemia (DCI) and cerebral vasospasm (CVS) after aneurysmal subarachnoid hemorrhage (aSAH). The aim of this study was to investigate potentially beneficial effects of antiplatelet therapy (APT) on angiographic CVS, DCI-related infarction and functional outcome in endovascularly treated aSAH patients. Retrospective single-center analysis of aSAH patients treated by endovascular aneurysm obliteration. Based on the post-interventional medical regime, patients were assigned to either an APT group or a control group not receiving APT. A subgroup analysis separately investigated those APT patients with aspirin monotherapy (MAPT) and those receiving dual treatment (aspirin plus clopidogrel, DAPT). Clinical and radiological characteristics were compared between groups. Possible predictors for angiographic CVS, DCI-related infarction, and an unfavorable functional outcome (modified Rankin scale ≥ 3) were analyzed. Of 160 patients, 85 (53%) had received APT (n = 29 MAPT, n = 56 DAPT). APT was independently associated with a lower incidence of an unfavorable functional outcome (OR 0.40 [0.19–0.87], P = 0.021) after 3 months. APT did not reduce the incidence of angiographic CVS or DCI-related infarction. The pattern of angiographic CVS or DCI-related infarction as well as the rate of intracranial hemorrhage did not differ between groups. However, the lesion volume of DCI-related infarctions was significantly reduced in the DAPT subgroup (P = 0.011). Post-interventional APT in endovascularly treated aSAH patients is associated with better functional outcome at 3 months. The beneficial effect of APT might be mediated by reduction of the size of DCI-related infarctions.

scholarly journals Evaluating CT Perfusion Using Outcome Measures of Delayed Cerebral Ischemia in Aneurysmal Subarachnoid Hemorrhage

2012 ◽  
Vol 34 (2) ◽  
pp. 292-298 ◽  
Author(s):  
P.C. Sanelli ◽  
N. Anumula ◽  
C.E. Johnson ◽  
J.P. Comunale ◽  
A.J. Tsiouris ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Cerebral Ischemia ◽  
Outcome Measures ◽  
Ct Perfusion ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Delayed Cerebral Ischemia

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

2018 ◽  
Vol 128 (5) ◽  
pp. 1311-1317 ◽  
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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