Rupture-related Mechanism Of Intracranial Aneurysm Based On Hemodynamics And Aneurysmal Wall Inflammation Analysis

Part Ⅰ Morphological and Hemodynamic Risk Factors for the Rupture of Small Intracranial AneurysmsObjective:Intracranial Aneurysms(IAs)are the main causes of subarachnoid hemorrhage in adults,which has a high mortality and disability rate.The clinical management of small(< 5mm)Unruptured Intracranial aneurysm(UIAs)remains controversial,and the quantitative assessment of its rupture risk is of great clinical significance.Morphological and hemodynamic parameters have been confirmed to be related to the rupture of the IAs,but the results of relevant studies are still inconsistent,which may be related to the fact that these studies do not stratified by aneurysm size and location.At present,there has been no study on risk factors of small IAs rupture specifically for a single site.This study aims to explore morphological and hemodynamic parameters related to small IAs rupture,and provide basis for clinical treatment decisions of small UIAs.Methods:Clinical data of patients with intracranial aneurysms continuously admitted to our center from January 2016 to December 2019 were collected to analyze the location distribution and rupture of each location of small IAs.A single site with the highest incidence of small IAs was selected and all continuous cases in this site were included.The clinical baseline data,morphological and hemodynamic parameters of IAs in the ruptured group and the unruptured group were compared.The parameters with statistical differences were included in Logistic regression analysis to determine the independent risk factors associated with small IAs rupture.Results:1.Among all IAs patients admitted during the study period,51.4%(712 cases)were small IAs,among which 44.1%(329 cases)were ruptured small IAs.The proximal anterior cerebral artery(A1 segment)had the highest incidence of small IAs,of which 46.9%(23 cases)was ruptured IAs.The median size of ruptured A1 segment aneurysms was only 3.51 mm.2.Since all A1 segment aneurysms admitted during this study were small aneurysms,49 cases of continuous A1 segment aneurysms were included for rupture risk factors analysis.There was no statistical difference in the clinical baseline data of A1 segment aneurysms between the ruptured group and the unruptured group.In morphology,the ruptured group had significantly higher aspect ratio(AR),size ratio(SR),dome-neck ratio(DR),bottleneck index(BI)and irregular morphology ratio.In terms of hemodynamics,the rupture group A1 segment aneurysms had significantly lower wall shear stress(WSS)and higher oscillatory shear index(OSI).3.Logistic regression analysis showed that size ratio(SR)(OR=0.0474;95% confidence interval:0.268-0.837;P=0.010),wall shear stress(WSS)(OR=3.672;95% confidence interval :1.578 to 8.540;P=0.003)were independent risk factors for rupture of A1 segment aneurysms.Conclusion:1.Small-sized IAs still has a high proportion of rupture,and the proximal anterior cerebral artery(A1 segment)has the highest incidence of small-sized IAs,and it is characterized by rupture that can occur even if the aneurysm is small.2.Morphological and hemodynamic parameters were correlated with the rupture of A1-segment aneurysm.Higher size ratio(SR)and lower wall shear stress(WSS)were the independent risk factors for the rupture of A1-segment aneurysm.Morphology combined with hemodynamic analysis is expected to become an effective means for risk stratification of rupture of small UIAs,which can provide the basis for reasonable clinical treatment decision of small UIAs.3.It has been verified in this study that the morphology and hemodynamics are also significantly correlated with the rupture of small intracranial aneurysms,but the specific mechanism needs further investigation.Part Ⅱ The Interaction Mechanism between Hemodynamics and Aneurysmal Wall Inflammation in the Rupture of Intracranial AneurysmsObjective:Abnormal hemodynamics is considered to play a key role in the formation and rupture of IAs.Cerebral blood flow analysis based on Computational Fluid Dynamics(CFD)technology is widely used to quantify the rupture risk of IAs.The first part of this study also confirmed the correlation between hemodynamics and small IAs rupture,but the mechanism of the correlation between hemodynamics and IAs rupture remains unclear.Degenerative remodeling of IAs wall caused by inflammation is considered to be an important cause of IAs rupture.The purpose of this study was to analyze the relationship between cerebral hemodynamic changes and aneurysmal wall inflammation,and to explore their interactional mechanism in the rupture of IAs.Methods:A total of 42 IAs patients(18 ruptured and 24 unruptured)recruited between January2019 and December 2020 were enrolled.All patients underwent microsurgical aneurysm clipping with craniotomy,and the distal aneurysmal wall tissues were removed for histopathological analysis(including CD31,CD68,MPO,α-SMA,PCNA immunohistochemical analysis and TUNEL apoptosis detection).The differences of inflammatory indicators between the two groups were compared,and the independent risk factors of inflammatory indexes related to rupture were screened.According to the positive rate of CD68(macrophage marker),the included aneurysms were divided into three groups with low,medium and high inflammatory response.Morphological and hemodynamic parameters among each group were analyzed to clarify the relationship between morphological and hemodynamic parameters and the degree of aneurysmal wall inflammation and their role in IAs rupture.Results :1.Compared with the unruptured group,the pathological analysis of ruptured aneurysms showed more severe endothelial cell damage,inflammatory cell infiltration and degenerative remodeling of extracellular matrix.In terms of inflammatory indicators,the rupture group had significantly increased CD68,MPO positive cell rate,mural cell apoptosis rate and significantly lower PCNA positive rate.The other indicators,CD31 and α-SMA,showed no significant difference.Logistic regression analysis showed that CD68 positive cell rate and mural cell apoptosis rate were independent risk factors for inflammation related to IAs rupture.2.The degree of inflammatory response of aneurysmal wall,morphology and hemodynamic characteristics were significantly correlated with IAs rupture,and the proportion of IAs rupture increased significantly with the aggravation of inflammatory response.The morphological characteristics of the group with high aneurysmal wall inflammation were larger diameter,higher aspect ratio(AR),size ratio(SR)and dome to neck ratio(SR),and higher proportion of irregular morphology.The blood flow characteristics were significantly lower wall shear stress(WSS),higher oscillatory shear index(OSI),and longer blood flow stagnation time(RRT).3.Conditional Logistic regression analysis showed that low WSS(P= 0.017,OR=0.235,95% confidence interval: 0.071-0.773)and high OSI(P=0.022,OR=4.832,95% confidence interval: 1.25--18.684)was an independent risk factor for aggravation of IAs tumor wall inflammation.There was no statistical significance in morphological indexes in Logistic regression analysis.Conclusion:1.Endothelial cell injury,inflammatory cell infiltration,degeneration of extracellular matrix and mural cell apoptosis all play important roles in IAs rupture,among which macrophage infiltration and mural cell apoptosis are most closely related to IAs rupture.2.With the aggravation of inflammatory reaction of tumor wall,the proportion of IAs rupture increased significantly.IAs with high degree of inflammation have large and irregular morphological characteristics and flow characteristics with lower wall shear stress and more diffuse direction.The blood flow characteristics are closely related to the degree of inflammatory reaction of aneurysmal wall.3.Low and variable shear stress blood flow may aggravate the damage of vascular endothelial cells and promote macrophage infiltration,thus aggravating the degenerative remodeling of the vascular wall and leading to IAs rupture.Cerebral blood flow analysis based on CFD technology can reflect the degree of tumor wall inflammation in IAs,and can be used as an effective clinical tool to predict the risk of IAs rupture.