Development Of Cerebral Vasospasm Research Articles

Correlation of Inflammatory Parameters with the Development of Cerebral Vasospasm, Takotsubo Cardiomyopathy, and Functional Outcome after Spontaneous Subarachnoid Hemorrhage.

Background: The present work aimed to determine whether a relationship exists between inflammatory parameters and the development of vasospasm (VS) and Takotsubo cardiomyopathy (TTC), as well as clinical outcome, in patients suffering from spontaneous subarachnoid hemorrhage (SAH). Methods: In this study, the authors processed the prospectively collected laboratory and clinical data of spontaneous SAH patients admitted to the neurointensive care unit between March 2015 and October 2023. The highest values of neutrophils (NEUpeak), monocytes (MONOpeak), neutrophil-to-lymphocyte ratio (NLRpeak), and CRP (CRPpeak) during the initial 7 days were correlated with the occurrence of VS and TTC, and with the outcome measures at day 30 after onset. Results: Data were collected from 175 SAH patients. Based on ROC analysis, for the development of VS, MONOpeak was the most accurate indicator (AUC: 0.619, optimal cut-off: 1.45 G/L). TTC with severe left ventricular dysfunction (ejection fraction < 40%) was indicated most sensitively by NEUpeak (ROC: 0.763, optimal cut-off: 12.34 G/L). Both for GOS and Barthel Index at day 30, CRPpeak was the best predictor for the outcome (GOS: ROC: 0.846, optimal cut-off: 78.33 mg/L and Barthel Index: ROC: 0.819, optimal cut-off: 78.33 mg/L). Conclusions: Laboratory parameters referring to inflammation during the initial 7 days after SAH correlate with the development of VS and TTC, and thus may predict functional outcome.

MicroRNA-130b May Induce Cerebral Vasospasm after Subarachnoid Hemorrhage via Modulating Kruppel-like Factor 4.

Recently, the diverse functions of microRNAs (miRNAs) in brain diseases have been demonstrated. We intended to uncover the functional role of microRNA-130b (miR-130b) in cerebral vasospasm (CVS) following subarachnoid hemorrhage (SAH). SAH was induced by injecting the autologous blood into the cisterna magna of Sprague Dawley rats. The cerebral vascular smooth muscle cells (cVSMCs) were extracted for invitro experimentation. In vitro and invivo assays were implemented with transfection of miR-130b mimic/inhibitor, sh-Kruppel-like factor 4 (KLF4), oe-KLF4 plasmids or p38/MAPK signaling pathway agonist (anisomycin), respectively, to elaborate the role of miR-130b in CVS following SAH. Elevated miR-130b and reduced KLF4 were found in SAH patients and rat models of SAH. KLF4 was the target gene of miR-130b. miR-130b promoted the proliferation and migration of cVSMCs through the Inhibition of KLF4. Besides, KLF4 inhibited the proliferation and migration of cVSMCs through blockage of the p38/MAPK pathway. Furthermore, invivo assay confirmed the inhibitory effect of decreased miR-130b in CVS following SAH. In conclusion, miR-130b may activate the p38/MAPK signaling pathway through targeted inhibition of KLF4, thereby contributing to some extent to the development of cerebral vasospasm after SAH.

110 Macrophage Cross Talk following Subarachnoid Hemorrhage: Contribution of Peripheral Immune Activation in the Development of Cerebral Vasospasm

INTRODUCTION: Microglia respond to the initial insult of aneurysm rupture, but become overwhelmed by ferritin toxicity. These microglia release inflammatory cytokines that cause vasospasm to facilitate peripheral macrophage diapedesis. This process is dependent on the p-STAT3 pathway. METHODS: The autologous SAH pre-clinical model was utilized and compared to blood and CSF from human patients. Mouse blood was injected along the skull base to c57/bl6 and CCR2/Cx3CR1 mice. Microglia depletion was done with pexidartinib. Ferritin within microglia, TLR4, and NFKb were measured via immunohistochemistry. Vasospasm was measured via India Ink gelatin assay. The Modified Garcia Scale and right turn test was utilized. Clarity assay was utilized to determine association between macrophages and brain microglia. Cerebral doppler was used to measure spreading cortical depressions. p-STAT3 was measured via western blot. For all experiments, saline sham, subarachnoid hemorrhage, and subarachnoid hemorrhage with p-STAT3 inhibitor were utilized. RESULTS: Microglia recruitment occured within parenchyma along the skull base adjacent to subarachnoid blood. Ferritin toxicity was noted by day 5 (r-0.95, p &lt; 0.05) and persisted to day 9 (r-0.98, p &lt; 0.01). A shift in microglia occured following SAH with Cox-2 and INOS predominance (k1 0.76, k2 1.21). Blockade of p-STAT3 resulted in decreased vasospasm (p&lt;0.01), improved modified Garcia scores (p &lt; 0.05), and improved right turn test (p &lt; 0.05) following SAH. Peripheral macrophage diapedesis occured in regions of microglia activation. P-STAT3 blockade improved cerebral blood flow and prevented spreading cortical depressions (p &lt; 0.01). NFKb and TLR4 activation was markedly reduced by p-Stat3 inhibition (p &lt; 0.05). Results correlated closely to human aneurysmal blood and CSF data. CONCLUSIONS: Microglia ferritin toxicity contributes to vasospasm to facilitate peripheral macrophage diapedesis. Targeting the p-STAT3 pathway leads to reduced vasospasm and improved behavioral outcomes.

Correlation between tomographic scales and vasospasm and delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage.

To determine the prevalence of sonographic vasospasm and delayed ischemic deficit in patients with aneurysmal subarachnoid hemorrhage, to evaluate the correlation between different tomographic scales and these complications, and to study prognostic factors in this group of patients. This was a prospective study of patients admitted to the intensive care unit with a diagnosis of aneurysmal subarachnoid hemorrhage. The prevalence of sonographic vasospasm and radiological delayed cerebral ischemia was analyzed, as was the correlation between different tomographic scales and these complications. A total of 57 patients were studied. Sixty percent of the patients developed sonographic vasospasm, which was significantly associated with delayed cerebral ischemia and mortality. The Claassen and Hijdra scales were better correlated with the development of cerebral vasospasm (areas under the curve of 0.78 and 0.68) than was Fisher's scale (0.62). Thirty-two patients (56.1%) developed cerebral infarction on CT; the significantly associated factors were poor clinical grade at admission (p = 0.04), sonographic vasospasm (p = 0.008) and severity of vasospasm (p = 0.015). Only the semiquantitative Hijdra scale was significantly correlated with the development of radiological delayed cerebral ischemia (p = 0.009). The patients who presented cerebral infarction had worse neurological evolution and higher mortality. This is the first study in our environment on the subject. The Claassen and Hijdra tomographic scales showed better prognostic performance than the Fisher scale for the development of cerebral vasospasm. The finding of sonographic vasospasm could be a noninvasive criterion for the early detection of delayed cerebral ischemia and neurological deterioration in patients with aneurysmal subarachnoid hemorrhage.

The Benefits and Feasibility of External Lumbar Cerebrospinal Fluid Drainage for Cerebral Vasospasm in Patients with Aneurysmal Subarachnoid Hemorrhage: Meta-Analysis and Trial Sequential Analysis.

Cerebral vasospasm after aneurysmal subarachnoid hemorrhage is a main cause contributing to poor outcomes. Removal of blood from the subarachnoid may decrease development of cerebral vasospasm. The purpose of this study is to determine the effect of lumbar cerebrospinal fluid (CSF) drainage on cerebral vasospasm and related complications through meta-analysis and trial sequential analysis (TSA). A systematic search of the literature was performed. Case-control studies of the effects of external lumbar drainage in patients with subarachnoid hemorrhage were included. The association between lumbar drain and vasospasm, cerebral infarction, subsequent treatment, and mortality were evaluated. Eleven of 122 articles were included in the meta-analysis. Lumbar CSF drainage reduces occurrence of vasospasm and related complications. In meta-analysis, the pooled odds ratio for symptomatic vasospasm, cerebral infarct, endovascular treatment for vasospasm, and mortality was 0.40 (95% confidence interval [CI], 0.31-0.51; P= 0.00001), 0.47 (95% CI, 0.35-0.62; P < 0.0001), 0.29 (95% CI, 0.18-0.46; P < 0.0001), and 0.41, (95% CI, 0.23-0.74; P= 0.003), respectively, compared with the non-lumbar drainage group. In TSA, the cumulative Z line crossed α-spending boundaries and reached the required sample size in analysis of symptomatic vasospasm and endovascular treatment for vasospasm. Lumbar CSF drainage can decrease symptomatic vasospasm, cerebral infarction, subsequent endovascular treatment, and mortality. Through TSA, the accuracy and reliability of the effect of lumbar CSF drainage-related cerebral vasospasm and endovascular treatment are increased. Further studies of the association between lumbar drain and cerebral infarction and mortality are required to confirm the generalization of the results.

Exploration of cerebral vasospasm from the perspective of microparticles.

Cerebral vasospasm is a frequently encountered clinical problem, especially in patients with traumatic brain injury and subarachnoid hemorrhage. Continued cerebral vasospasm can cause cerebral ischemia, even infarction and delayed ischemic neurologic deficits. It significantly affects the course of the disease and the outcome of the patient. However, the underlying mechanism of cerebral vasospasm is still unclear. Recently, increasing studies focus on the pathogenic mechanism of microparticles. It has been found that microparticles have a non-negligible role in promoting vasospasm. This research aims to summarize the dynamics of microparticles in vivo and identify a causal role of microparticles in the occurrence and development of cerebral vasospasm. We found that these various microparticles showed dynamic characteristics in body fluids and directly or indirectly affect the cerebral vasospasm or prompt it. Due to the different materials carried by microparticles from different cells, there are also differences in the mechanisms that lead to abnormal vasomotor. We suggest that microparticle scavengers might be a promising therapeutic target against microparticles associated complications.

Risk Factors for Cerebral Vasospasm in Patients with Aneurysmal Subarachnoid Hemorrhage: A Tertiary Care Center Experience

Objectives Cerebral vasospasm in subarachnoid hemorrhage (SAH) is associated with high morbidity and mortality. There is a lack of consensus on the risk factors leading to cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage (aSAH). In this retrospective study, our objective was to determine the association of risk factors for cerebral vasospasm aSAH. Methods A total of 259 charts of aSAH patients consecutively admitted to the surgical intensive care unit of Hamad General Hospital from January 2007 to December 2016 were reviewed and included. The patient's demographic data, including comorbidities like hypertension (HTN), was recorded. Variables of interest included measurements of the neurological deficit on admission, the severity of SAH, treatment modality, and the initial computerized tomography scan of the head for intraventricular hemorrhage, intracerebral hemorrhage, or hydrocephalus. Multivariate analysis and multiple logistic regression analyzed the relationship to identify the association of independent variables. Results Out of the 259 patients, 34% ( n = 87) suffered from cerebral vasospasm. The severity of SAH was associated with the development of cerebral vasospasm ( p < 0.05). The presence of HTN and neurological deficits on admission were associated with an increased risk of cerebral vasospasm ( p < 0.05, p < 0.01, respectively). Hydrocephalus requiring treatment using external ventricular drains decreased the risk of cerebral vasospasm ( p < 0.05). Intraventricular and intracerebral hemorrhage were not associated with cerebral vasospasm ( p = 0.25, p = 0.16). The endovascular treatment of cerebral aneurysms was associated with an increased risk of cerebral vasospasm ( p < 0.05). Conclusion Cerebral vasospasm is common among patients admitted with aSAH. It is significantly associated with the history of HTN, the neurological deficit on admission that corelates more strongly to the motor deficit on admission, the severity of hemorrhage (modified Fischer score), and endovascular treatment. External ventricular drainage was associated with a decrease in cerebral vasospasm. The present study's findings shed light on cerebral vasospasm's risk factors in the country and the region.

276 Bilirubin Oxidative Products as Predictive Biomarkers of Cerebral Vasospasm: A Pilot Study

OBJECTIVES/GOALS: Our aim is to understand the role bilirubin oxidation products play in the development of cerebral vasospasm in patients with subarachnoid hemorrhage. We aim to evaluate the time course of bilirubin, HO-1, and SOD1 in relation to the subsequent development of vasospasm in to establish predictors of vasospasm development. METHODS/STUDY POPULATION: Prospective cohort observational study involving collection of CSF samples of pts admitted to KU NeuroICU with SAH and placement of EVD. CSF will be extracted from the EVD of patients on the day of placement of the EVD, and then each subsequent day for a total of 10 days. Bilirubin concentration will be determined by means of spectrophotometry. HO-1 will be measured using a commercially available ELISA kit. Cu/Zn-Superoxide Dismutase will be measured using a commercially available ELISA kit. A review of patients chart will then be performed following discharge from hospital to determine if a diagnosis of vasospasm was made, details of the vasospasm (i.e. symptoms, severity), as well as to obtain demographic data and events occurring during patients admission that could confound statistical analysis. RESULTS/ANTICIPATED RESULTS: First: we will investigate the feasibility of collecting serial CSF samples and processing them for target analyte quantification. We predict that the protocol will yield quality data that will result in insight on the pathophysiology of cerebral vasospasm. Second: we will characterize the changes in target CSF bilirubin breakdown analytes over 10 days. From this we hypothesize that as bilirubin oxidation increases, the propensity for cerebral vasospasm will also increase. DISCUSSION/SIGNIFICANCE: If there is a clear correlation between formation of bilirubin and increase in HO-1, and SOD1, with the clinical signs of vasospasm, this could be used as a biomarker for not only identifying patients at risk for developing these complications but also a means to follow the effectiveness of potential therapies.

Development of cerebral vasospasm following traumatic intracranial hemorrhage: incidence, risk factors, and clinical outcomes.

Limited evidence exists characterizing the incidence, risk factors, and clinical associations of cerebral vasospasm following traumatic intracranial hemorrhage (tICH) on a large scale. Therefore, the authors sought to use data from a national inpatient registry to investigate these aspects of posttraumatic vasospasm (PTV) to further elucidate potential causes of neurological morbidity and mortality subsequent to the initial insult. Weighted discharge data from the National (Nationwide) Inpatient Sample from 2015 to 2018 were queried to identify patients with tICH who underwent diagnostic angiography in the same admission and, subsequently, those who developed angiographically confirmed cerebral vasospasm. Multivariable logistic regression analysis was performed to identify significant associations between clinical covariates and the development of vasospasm, and a tICH vasospasm predictive model (tICH-VPM) was generated based on the effect sizes of these parameters. Among 5880 identified patients with tICH, 375 developed PTV corresponding to an incidence of 6.4%. Multivariable adjusted modeling determined that the following clinical covariates were independently associated with the development of PTV, among others: age (adjusted odds ratio [aOR] 0.98, 95% CI 0.97-0.99; p < 0.001), admission Glasgow Coma Scale score < 9 (aOR 1.80, 95% CI 1.12-2.90; p = 0.015), intraventricular hemorrhage (aOR 6.27, 95% CI 3.49-11.26; p < 0.001), tobacco smoking (aOR 1.36, 95% CI 1.02-1.80; p = 0.035), cocaine use (aOR 3.62, 95% CI 1.97-6.63; p < 0.001), fever (aOR 2.09, 95% CI 1.34-3.27; p = 0.001), and hypokalemia (aOR 1.62, 95% CI 1.26-2.08; p < 0.001). The tICH-VPM achieved moderately high discrimination, with an area under the curve of 0.75 (sensitivity = 0.61 and specificity = 0.81). Development of vasospasm was independently associated with a lower likelihood of routine discharge (aOR 0.60, 95% CI 0.45-0.78; p < 0.001) and an extended hospital length of stay (aOR 3.53, 95% CI 2.78-4.48; p < 0.001), but not with mortality. This population-based analysis of vasospasm in tICH has identified common clinical risk factors for its development, and has established an independent association between the development of vasospasm and poorer neurological outcomes.

Contemporary view on subarachnoidal hemorrhage: literature review

Subarachnoid hemorrhage is a severe, life-threatening variant of hemorrhagic stroke. It happens due to the blood release into the subarachnoid space and requires emergency medical care. This review contains data on modern epidemiology, morphology and pathophysiology, clinical presentation and peculiarities of diagnostics and treatment of subarachnoid hemorrhage. It covers key studies of Russian and foreign scientific groups on the causes and risk factors of subarachnoid hemorrhage and mechanisms of cerebral vasospasm development. Main professional scales used in daily clinical practice are mentioned. The sensitivity and specificity of the existing methods of unruptured aneurysms neuroimaging and subarachnoid hemorrhage are analyzed. Also, the article includes summarized information on existing and prospective options for nonsurgical and surgical treatment.

Sodium Variability and Probability of Vasospasm in Patients with Aneurysmal Subarachnoid Hemorrhage

ObjectivesVasospasm is a well-known complication of aneurysmal subarachnoid hemorrhage (aSAH) that generally occurs 4–14 days post-hemorrhage. Based on American Heart Association guidelines, the current understanding is that hyponatremic episodes may lead to vasospasm. Therefore, we sought to determine the association between repeated serum sodium levels of aSAH patients and its relationship to radiographic vasospasm. Materials and methodsA single-center retrospective analysis from 2007–2016 was conducted of aSAH patients. Daily serum sodium levels were recorded up to day 14 post-admission. Hyponatremia was defined as a serum sodium value of < 135 mEq/L. We evaluated the relationship to radiologic vasospasm, neurologic deterioration, functional status at discharge, and mortality. A repeated measures analysis using a mixed-effect regression model was performed to assess the interindividual relationship between serum sodium trends and outcomes. ResultsA total of 271 aSAH patients were included. There were no significant differences in interindividual serum sodium values over time and occurrence of radiographic vasospasm, neurologic deterioration, functional, or mortality outcomes (p = .59, p = .42, p = .94, p = .99, respectively) using the mixed-effect regression model. However, overall mean serum sodium levels were significantly higher in patients who had neurologic deterioration, poor functional outcome (mRS 3-6), and mortality. ConclusionsSerum sodium level variations are not associated with subsequent development of cerebral vasospasm in aSAH patients. These findings indicate that serum sodium may not have an impact on vasospasm, and avoiding hypernatremia may provide a neurologic, functional and survival benefit.

Analysis of risk factors correlated with angiographic vasospasm in patients with aneurysmal subarachnoid hemorrhage using explainable predictive modeling

Cerebral vasospasm (CAV) is a major complication of aneurysmal subarachnoid hemorrhage (aSAH) in patients with ruptured intracranial aneurysm. Explainable artificial intelligence (XAI) was used to analyze the contribution of risk factors on the development of CAV. We obtained data about patients (n = 343) treated for aSAH in our hospital. Predictive factors including age, aneurysm size, Hunt and Hess grade, and modified Fisher grade were used as input to analyze the contribution and correlation of factors correlated with CAV using a random forest regressor. An analysis conducted using an XAI model showed that aneurysm size (27.6%) was most significantly associated with the development of CAV, followed by age (20.7%) and Glasgow coma scale score (7.1%). In some patients with an estimated artificial intelligence-selected CAV value of 51%, the important risk factors were aneurysm size (9.1 mm) and location, and hypertension is also considered a major influencing factor. We could predict that Fisher grade 3 contributed to 20.3%, and the group using Antiplatelet contributed to 12.2% which is expected to lower cerebral CAV compared to the Control group (16.9%). The accuracy rate of the XAI system was 85.5% (area under the curve = 0.88). Using the modeling, aneurysm size and age were quantitatively analyzed and were found to be significantly associated with CAV in patients with aSAH. Hence, XAI modeling techniques can be used to analyze factors correlated with CAV by schematizing prediction results in some patients. Moreover, poor Fisher grade and use of postoperative antiplatelet agent are important factors for prediction of CAV.

Temporal Relationship Between Onset of Fever and Development of Cerebral Vasospasm and Poor Functional Outcome in Aneurysmal Subarachnoid Haemorrhage

Online date: November 16, 2020 This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Hyperoxemia and Cerebral Vasospasm in Aneurysmal Subarachnoid Hemorrhage.

Cerebral vasospasm is a major contributor to disability and mortality after aneurysmal subarachnoid hemorrhage. Oxidation of cell-free hemoglobin plays an integral role in neuroinflammation and is a suggested source of tissue injury after aneurysm rupture. This study sought to determine whether patients with subarachnoid hemorrhage and cerebral vasospasm were more likely to have been exposed to early hyperoxemia than those without vasospasm. This single-center retrospective cohort study included adult patients presenting with aneurysmal subarachnoid hemorrhage to Vanderbilt University Medical Center between January 2007 and December 2017. Patients with an ICD-9/10 diagnosis of aneurysmal subarachnoid hemorrhage were initially identified (N = 441) and subsequently excluded if they did not have intracranial imaging, arterial PaO2 values or died within 96h post-rupture (N = 96). The final cohort was 345 subjects. The degree of hyperoxemia was defined by the highest PaO2 measured within 72h after aneurysmal rupture. The primary outcome was development of cerebral vasospasm, which included asymptomatic vasospasm and delayed cerebral ischemia (DCI). Secondary outcomes were mortality and modified Rankin Scale. Three hundred and forty five patients met inclusion criteria; 218 patients (63%) developed vasospasm. Of those that developed vasospasm, 85 were diagnosed with delayed cerebral ischemia (DCI, 39%). The average patient age of the cohort was 55 ± 13years, and 68% were female. Ninety percent presented with Fisher grade 3 or 4 hemorrhage (N = 310), while 42% presented as Hunt-Hess grade 4 or 5 (N = 146). In univariable analysis, patients exposed to higher levels of PaO2 by quintile of exposure had a higher mortality rate and were more likely to develop vasospasm in a dose-dependent fashion (P = 0.015 and P = 0.019, respectively). There were no statistically significant predictors that differentiated asymptomatic vasospasm from DCI and no significant difference in maximum PaO2 between these two groups. In multivariable analysis, early hyperoxemia was independently associated with vasospasm (OR = 1.15 per 50mmHg increase in PaO2 [1.03, 1.28]; P = 0.013), but not mortality (OR = 1.10 [0.97, 1.25]; P = 0.147) following subarachnoid hemorrhage. Hyperoxemia within 72h post-aneurysmal rupture is an independent predictor of cerebral vasospasm, but not mortality in subarachnoid hemorrhage. Hyperoxemia is a variable that can be readily controlled by adjusting the delivered FiO2 and may represent a modifiable risk factor for vasospasm.

Intracranial Aneurysm Biomarker Candidates Identified by a Proteome-Wide Study.

The scientific basis of intracranial aneurysm (IA) formation, its rupture and further development of cerebral vasospasm is incompletely understood. Aberrant protein expression may drive structural alterations of vasculature found in IA. Deciphering the molecular mechanisms underlying these events will lead to identification of early detection biomarkers and in turn, improved treatment outcomes. To unravel differential protein expression in three clinical subgroups of IA patients: (1) unruptured aneurysm, (2) ruptured aneurysm without vasospasm, (3) ruptured aneurysm who developed vasospasm, we performed untargeted quantitative proteomic analysis of aneurysm tissue and serum samples from three subgroups of IA patients and control subjects. Candidate molecules were then validated in a larger cohort of patients using enzyme-linked immunosorbent assay. A total of 937 and 294 proteins were identified from aneurysm tissue and serum samples, respectively. Several proteins that are known to maintain structural integrity of vasculature were found to be dysregulated in the context of aneurysm. ORM1, a glycoprotein, was significantly upregulated in both tissue and serum samples of unruptured aneurysm patients. We employed a larger cohort of subjects (n = 26) and validated ORM1 as a potential biomarker for screening of unruptured aneurysms. Samples from ruptured aneurysms with vasospasm showed significant upregulation of MMP9, a protease, compared with ruptured aneurysms without vasospasm. We validated MMP9 as a potential biomarker for vasospasm in a larger cohort (n = 52). This study reports the first global proteomic analysis of the entire clinical spectrum of IA. Furthermore, this study suggests ORM1 and MMP9 as potential biomarkers for unruptured aneurysm and cerebral vasospasm, respectively.

Can admission lipoprotein-associated phospholipase A2 predict the symptomatic cerebral vasospasm following aneurysmal subarachnoid hemorrhage?

BackgroundInflammation has been believed to be related to the development of cerebral vasospasm following aneurysmal subarachnoid hemorrhage (aSAH). A potential biomarker for vascular inflammation that is well recognized is the lipoprotein-associated phospholipase A2 (Lp-PLA2). However, whether Lp-PLA2 can predict the occurrence of symptomatic cerebral vasospasm (SCV) in aSAH patients is still unknown. Thus, this study aimed to assess the value of Lp-PLA2 for predicting SCV in patients with aSAH.MethodsBetween March 2017 and April 2018, we evaluated 128 consecutive aSAH patients who were admitted in the First Affiliated Hospital of Fujian Medical University. Their Lp-PLA2 level was obtained within 24 h of the initial bleeding. Factors might be related to SCV were analyzed.ResultsCompared to patients without SCV, those with SCV (9.4%, 12/128) had significantly higher Lp-PLA2 level. Multivariate logistic analysis revealed that worse modified Fisher grade (OR = 10.08, 95% CI = 2.04–49.86, P = 0.005) and higher Lp-PLA2 level (OR = 6.66, 95% CI = 1.33–3.30, P = 0.021) were significantly associated with SCV, even after adjustment for confounders. Based on the best threshold, Lp-PLA2 had a sensitivity of 83.3% and a specificity of 51.7% for predicting SCV, as shown by the receiver operating characteristic curve analysis. In the poor World Federation of Neurosurgical Societies grade patient sub-group, patients with Lp-PLA2 > 200 μg/L had significantly higher SCV rate than that of patients having Lp-PLA2 ≤ 200 μg/L.ConclusionThe admission Lp-PLA2 level might be a helpful predictor for SCV in aSAH.

Genetic Variability in the Iron Homeostasis Pathway and Patient Outcomes After Aneurysmal Subarachnoid Hemorrhage.

Iron can be detrimental to most tissues both in excess and in deficiency. The brain in particular is highly susceptible to the consequences of excessive iron, especially during blood brain barrier disruption after injury. Preliminary evidence suggests that iron homeostasis is important during recovery after neurologic injury; therefore, the exploration of genetic variability in genes involved in iron homeostasis is an important area of patient outcomes research. The purpose of this study was to examine the relationship between tagging single nucleotide polymorphisms (SNPs) in candidate genes related to iron homeostasis and acute and long-term patient outcomes after aneurysmal subarachnoid hemorrhage (aSAH). This study was a longitudinal, observational, candidate gene association study of participants with aSAH that used a two-tier design including tier 1 (discovery, n = 197) and tier 2 (replication, n = 277). Participants were followed during the acute outcome phase for development of cerebral vasospasm and delayed cerebral ischemia (DCI) and during the long-term outcome phase for death and gross functional outcome using the Glasgow Outcome Scale (GOS; poor = 1-3). Genetic association analyses were performed using a logistic regression model adjusted for age, sex, and Fisher grade. Approximate Bayes factors (ABF) and Bayesian false discovery probabilities (BFDP) were used to prioritize and interpret results. In tier 1, 235 tagging SNPs in 28 candidate genes were available for analysis and 26 associations (20 unique SNPs in 12 genes) were nominated for replication in tier 2. In tier 2, we observed an increase in evidence of association for three associations in the ceruloplasmin (CP) and cubilin (CUBN) genes. We observed an association of rs17838831 (CP) with GOS at 3months (tier 2 results, odds ratio [OR] = 2.10, 95% confidence interval [CI] = 1.14-3.86, p = 0.018, ABF = 0.52, and BFDP = 70.8%) and GOS at 12months (tier 2 results, OR = 1.86, 95% CI 0.98-3.52, p = 0.058, ABF = 0.72, and BFDP = 77.3%) as well as rs10904850 (CUBN) with DCI (tier 2 results, OR = 0.70, 95% CI 0.48-1.02, p = 0.064, ABF = 0.59, and BFDP = 71.8%). Among the genes examined, our findings support a role for CP and CUBN in patient outcomes after aSAH. In an effort to translate these findings into clinical utility and improve outcomes after aSAH, additional research is needed to examine the functional roles of these genes after aSAH.

Temporal Relationship between Hyponatremia and Development of Cerebral Vasospasm in Aneurysmal Subarachnoid Hemorrhage Patients: A Retrospective Observational Study

Background: Hyponatremia is a common complication after aneurysmal subarachnoid hemorrhage (aSAH). Previous studies have reported an association between hyponatremia and vasospasm, however whether hyponatremia directly contributes to the pathogenesis of cerebral vasospasm (CVS), or is a by-product is still unclear. The aim of this study was to explore an association between hyponatremia and CVS after aSAH, and evaluating the temporality of these 2 events. Methods: A retrospective study of consecutive patients with aSAH admitted to the Baylor St. Luke's Medical center between January 2008 and December 2012 was conducted. Demographics, baseline characteristics, serum sodium levels, and evidence of vasospasm detected by transcranial Doppler, CT Angiogram, MR angiogram, and digital subtracted angiography were collected. Patients were dichotomized into a hyponatremic and a normonatremic group. CVS incidence and clinical outcome was compared between groups. Timing of CVS after initial hyponatremia episodes was recorded Results: One hundred and sixty 4 patients with aSAH were included. Hyponatremia was identified in 66 patients (40.2%) and CVS occurred in 71 subjects (43.2%). The incidence of CVS was higher in the hyponatremic group compared to the normonatremic group, 65.1 % versus 28.5%, respectively (P < .001). Hyponatremia preceded CVS by median 1.5 days suggesting a temporal trend. Conclusions: Our study shows a significant association between hyponatremia and CVS, with hyponatremia preceding CVS events. This retrospective finding denotes the need for larger prospective studies, aiming to clarify the temporal relationship of serum sodium levels and CVS.

The important role of connexin 43 in subarachnoid hemorrhage-induced cerebral vasospasm

BackgroundGap junctions are involved in the development of cerebral vasospasm (CVS) after subarachnoid hemorrhage (SAH). However, the specific roles and regulatory functions of related connexin isoforms remain unknown. The aim of this study was to investigate the importance of connexin 43 (Cx43) in CVS and determine whether Cx43 alterations are modulated via the protein kinase C (PKC) signaling transduction pathway.MethodsOxyhemoglobin (OxyHb)-induced smooth muscle cells of basilar arterial and second-injection model in rat were used as CVS models in vitro and in vivo. In addition, dye transfer assays were used for gap junction-mediated intercellular communication (GJIC) observation in vitro and delayed cerebral ischemia (DCI) was observed in vivo by perfusion-weighted imaging (PWI) and intravital fluorescence microscopy.ResultsIncrease in Cx43 mediated the development of SAH-induced CVS was found in both in vitro and in vivo CVS models. Enhanced GJIC was observed in vitro CVS model, this effect and increased Cx43 were reversed by preincubation with specific PKC inhibitors (chelerythrine or GF 109203X). DCI was observed in vivo on day 7 after SAH. However, DCI was attenuated by pretreatment with Cx43 siRNA or PKC inhibitors, and the increased Cx43 expression in vivo was also reversed by Cx43 siRNA or PKC inhibitors.ConclusionsThese data provide strong evidence that Cx43 plays an important role in CVS and indicate that changes in Cx43 expression may be mediated by the PKC pathway. The current findings suggest that Cx43 and the PKC pathway are novel targets for developing treatments for SAH-induced CVS.

Anti-vasospastic Effects of Epidermal Growth Factor Receptor Inhibitors After Subarachnoid Hemorrhage in Mice.

Subarachnoid hemorrhage (SAH) is a devastating disease. Cerebral vasospasm is still an important cause of post-SAH poor outcomes, but its mechanisms remain unveiled. Activation of epidermal growth factor receptor (EGFR) is suggested to cause vasoconstriction in vitro, but no report has demonstrated the involvement of EGFR in vasospasm development after SAH in vivo. Cross-talk of EGFR and vascular endothelial growth factor (VEGF) receptor, which may affect post-SAH vasospasm, was also reported in cancer cells, but has not been demonstrated in post-SAH vasospasm. The aim of this study was to investigate whether EGFR as well as EGFR-VEGF receptor cross-talk engage in the development of cerebral vasospasm in a mouse SAH model. C57BL6 mice underwent endovascular perforation SAH or sham modeling. At 30min post-modeling, mice were randomly administrated vehicle or 2 doses of selective EGFR inhibitors intracerebroventricularly. A higher dose of the inhibitor significantly prevented post-SAH neurological impairments at 72h and vasospasm at 24h associated with suppression of post-SAH activation of EGFR and extracellular signal-regulated kinase (ERK) 1/2 in the cerebral artery wall, especially in the smooth muscle cell layers. Anti-EGFR neutralizing antibody also showed similar effects. However, neither expression levels of VEGF nor activation levels of a major receptor of VEGF, VEGF receptor-2, were affected by SAH and two kinds of EGFR inactivation. Thus, this study first showed that EGFR-ERK1/2 pathways may be involved in post-SAH vasospasm development, and that EGFR-VEGF receptor cross-talk may not play a significant role in the development of vasospasm in mice.