Expression And Clinical Significance Of HMGB1 And SRAGE In Cerebrospinal Fluid In Aneurysmal Subarachnoid Hemorrhage

Objective:Accumulating studies indicate that early brain injury(EBI)is the primary cause of poor prognosis of aneurysmal subarachnoid hemorrhage(aSAH),which is closely associated with neuroinflammation.High mobility group box 1(HMGB1)contributes to inflammation through binding to receptors for advanced glycation end products(RAGE)in various diseases.We aimed to determine the production of these two factors after aSAH and their relationship with clinical features.Methods:A total of 58 patients with aSAH at the Second Hospital Affiliated with Shanxi Medical University and Yuncheng Central Hospital Affiliated with Shanxi Medical University from January to December 2022.Meanwhile,patients with non-inflammatory diseases admitted to the Second Hospital of Shanxi Medical University during the same period were used as the controls.All aSAH patients were treated with endovascular coiling.According to the time of collecting samples,samples were divided into four groups: 1-3 days,4-6 days,7-9 days,and 10-12 days after aSAH.HMGB1 and soluble RAGE(sRAGE)levels in cerebrospinal fluid(CSF)of aSAH patients and controls were measured,and their temporal courses were observed.The correlation between early concentrations(1-3 days after aSAH)and clinical symptoms assessed by the modified Fisher grading,Subarachnoid Hemorrhage Early Brain Edema Score(SEBES)grading and Hunt-Hess grading,CSF IL-6 levels and peripheral blood white blood cell(WBC)count were estimated to neuroinflammation.Outcome 3 months was represented as the modified Rankin Scale(m RS),and poor outcome was defined as m RS scores of 3-6.The multivariate logistic regression model was built to investigate independent factors associated with 3-month poor outcome after aSAH.The receiver operating characteristic(ROC)curves and area under the curve were constructed to examine the ability of HMGB1 and sRAGE to predict the prognosis of aSAH patients..Finally,combination of CSF HMGB1 and sRAGE(bioscore)during EBI for predicting outcome.Results:1.58 aSAH patients and 12 controls were enrolled in this study.There were no significant differences in gender,age,smoking,hypertension,and diabetes between the aSAH group and the control group(P > 0.05).The levels of HMGB1(ng/m L)in CSF 1-3 days,4-6 days,7-9 days,and 10-12 days after aSAH were 9.00(95%CI:8.15-9.64),7.84(95%CI: 6.87-8.28),6.30(95%CI: 5.48-6.77)and 5.73(95%CI:5.08-6.37)respectively.The levels of sRAGE(pg/m L)in CSF 1-3 days,4-6 days,7-9days,and 10-12 days after aSAH were 718.20(95%CI: 685.30-821.93),671.69(95%CI: 636.71-778.48),651.37(95%CI: 602.95-738.65)and 594.78(95%CI:554.32-694.29)respectively.CSF HMGB1 and sRAGE concentrations were highest on days 1-3 after the onset of aSAH and decreased slightly thereafter.Moreover,both of them increased remarkably at various time points post aSAH when compared with the control groups(P < 0.05).2.Early CSF HMGB1 and sRAGE concentrations(1-3 days after aSAH)were positively associated with Hunt-Hess grading(r=0.446 and r=0.325,P < 0.05),SEBES grading(r=0.343 and r=0.321,P < 0.05),modified Fisher grading(r=0.347 and r=0.411,P < 0.05),CSF IL-6 levels(r=0.545 and r=0.572,P < 0.05),and WBC count(r=0.502 and r=0.577,P < 0.05).3.Early CSF HMGB1 levels(OR=1.568,95%CI: 1.101-2.231)and sRAGE levels(OR=1.004,95%CI: 1.001-1.007)emerged as independent predictors for3-month prognostic.ROC analysis showed that HMGB1 levels and sRAGE levels at early stage predicted 3-month unfavorable outcomes with AUC of 0.827(95%CI:0.712-0.94)and 0.820(95%CI:0.701-0.939),the best cutoff value was 9.17 ng/m L and 727.75 pg/m L respectively.4.The combined analysis of CSF HMGB1 and sRAGE levels during EBI could be a useful method to predict the prognosis in aSAH patients(OR=12.522,95%CI:3.219-48.713),which the AUC of 0.827.The rate of the accident of poor outcome ranged from 7.4% for a bioscore of 0 to 90.0%for a bioscore of 2.Conclusion:CSF HMGB1 and sRAGE levels of aSAH patients were increased early and then varied dynamically,which might act as potential monitoring biomarkers for poor outcome,especially when co-analyzed.HMGB1 and RAGE may participate in neuroinflammation in development of EBI.