Very small intracranial aneurysms (VSIAs, ≤3 mm) represent ~13.2–15.1% of all intracranial aneurysms (1, 2). According to a report by the International Study of Unruptured Intracranial Aneurysms (3), the risk of rupture of small (<7 mm) anterior circulation aneurysms was 0.1%/year. However, it was not uncommon for VSIAs to be responsible for subarachnoid hemorrhage (2). With developments in imaging, diagnosis of asymptomatic VSIAs has increased. Ruptured aneurysms must be isolated from the cerebral circulation. However, treatment of unruptured VSIAs remains controversial. The decision to treat an unruptured VSIA must factor in the risk of treatment: both microsurgical clipping and endovascular coiling (4). Thus, characterizing the features of aneurysms associated with rupture status is clinically important.

Recent studies have demonstrated that morphological and hemodynamic factors, including aneurysm size, neck size, size ratio (SR), aspect ratio (AR), wall shear stress (WSS), and oscillatory shear index (OSI), are associated with the rupture status of intracranial aneurysms (5–8). However, no previous study has evaluated the morphological and hemodynamic characteristics associated with rupture status from a cohort of VSIAs. Additionally, hemodynamic results are conflicting as both low and high WSS were reported to be associated with rupture status. Evidence shows that combined samples, including different sizes of aneurysm, might influence hemodynamic results in the assessment of rupture status, with larger aneurysms usually being characterized with low WSS (9, 10). The confounding effect of size should be controlled in the analysis of rupture status of aneurysms.

The aim of the present study was to identify the morphological and hemodynamic parameters that independently characterize the rupture status of VSIAs, using patient-specific computational fluid dynamics (CFD).

The Ethics Committee of Beijing Tian Tan Hospital approved this study. Written informed consent was obtained from each study patient.

In this study, we showed that aneurysm type and LSA were significantly different between ruptured and unruptured VSIAs. Moreover, ruptured VSIAs were more likely to be located at bifurcation sites, with markedly low WSS. This finding may be clinically important for the evaluation of risk of VSIA rupture. In VSIAs that are equally suitable for observation or endovascular treatment, being located at bifurcation with markedly low WSS may guide management and more prompt intervention.

The mechanisms of intracranial aneurysm rupture have been studied with regard to morphologic and hemodynamic characteristics (8, 15–18), but aneurysms with different size, rather than relative uniform size, were investigated in these studies. This might explain previous conflicting findings. In an attempt to eliminate potential bias from size differences, we focused only on VSIAs in the present study.

A previous study reported low rupture risk for small aneurysms (3). However, VSIAs are often implicated in subarachnoid hemorrhage (1, 2). Treatment decisions for unruptured lesions are complicated because of the high risk of intra-operative complications (4). Therefore, clarification of the characteristics associated with rupture status of VSIAs is clinically important. In the current study, we found that ruptured VSIAs were more likely to be located at bifurcation sites with markedly low WSS. This finding may provide a simple method to predict bleeding risk in patients with unruptured VSIAs, and provide tailored treatment for such patients.

Many studies have demonstrated that bifurcation aneurysms are associated with aneurysm formation (19, 20), but few studies focus on correlations between aneurysm type (bifurcation or sidewall) and rupture. Baharoglu et al. (5) found that there was a dichotomy between sidewall and bifurcation aneurysms in identifying rupture status of intracranial aneurysms. Aneurysm type was included as an important morphologic parameter and evaluated in the current study, and our results showed that bifurcation type was independently associated with rupture status of VSIAs. A similar result was reported in Baharoglu et al. (5). The authors used CFD analysis in two generic aneurysm models (sidewall and bifurcation type), and found a fundamental difference in hemodynamics between sidewall and bifurcation aneurysms, which might be the reason why bifurcation type was more likely to rupture.

Rupture status of intracranial aneurysms can be successfully characterized by hemodynamic factors. However, results have been controversial for two theories explaining the mechanisms of intracranial aneurysm rupture, namely, high and low WSS. One reason for controversy might be that most studies simulated a full-range of aneurysm size in the sample studied. For example, it was reported that aneurysm size was a confounding factor in WSS rupture discrimination (2, 9). Thus, some studies eliminated the confounding effect of aneurysm size using size-match analysis. However, few such investigations have been published. To the best of our knowledge, the present study is the first and largest report of hemodynamic factors associated with rupture status of VSIAs.

This study also showed that LSA was independently associated with VSIA rupture status, which supports the low WSS theory. These data are consistent with our previous results showing that larger LSA might be associated with increasing risk of rupture (21). Pereira et al. (7) performed a case–control study in small aneurysms (mean, 3.7 mm) prone to rupture. Although no significant differences were found, all WSS-related parameters were lower in aneurysms that were prone to rupture. Ruptured aneurysms more frequently have larger LSA on the dome. Previous studies found that the thin-walled dome regions of unruptured aneurysms co-localized with low WSS, and bleeding points of ruptured aneurysms were often located at the dome with low WSS (22). Low WSS can cause dysfunction of flow-induced NO, increase endothelial permeability, and trigger atherosclerotic and inflammatory pathways (8, 13). Subsequently, degradation of the aneurysm wall occurs and ultimately leads to rupture. Hemodynamic factors may help us to identify ruptured aneurysms and offer insight into rupture mechanisms. Although results from the present study support the low WSS theory, the controversial result of WSS in stratifying the rupture status of intracranial aneurysms remains. The high WSS theory purports that high WSS initiates a different pathway to wall degradation, and should also be explored for association with rupture (8, 23).

The present study has some limitations that must be considered. First, although we focused on a subset of aneurysms (VSIAs) that removed the confounding effect of aneurysm size, all cases came from a single center and the number of cases was still smaller than optimal. Therefore, the findings may only be applicable to the specific size category studied, and may not be applicable to larger aneurysms. Second, this was a retrospective study, and the flow characteristics of pre-ruptured aneurysms may be different to post-ruptured aneurysms. Moreover, aneurysm geometry may have been affected by the rupture event. Such a theoretical possibility may have caused bias in the present results. A large-scale prospective randomized study should be performed to validate the morphological and hemodynamic findings in unruptured VSIAs that eventually rupture. Third, the mechanisms of aneurysm rupture cannot be explained wholly by hemodynamics or morphology. Other factors, such as genetic factors and clinical history, may also play an important role in the development of aneurysms. Fourth, similar to previous CFD studies (8), several assumptions, including rigid wall, laminar flow, Newtonian fluid, patient-specific inlet flow velocity, and traction-free outlet boundary conditions were made in our simulation, which may affect the generalizability of the hemodynamic results.

In the largest population of VSIAs studied to date, bifurcation type and larger LSA were independently associated with VSIA rupture status. Further studies are needed prospectively on patient-derived geometries prior to rupturing or leaking based on large multi-population data to confirm the utility of the present findings.

YsZ carried out the simulation study and drafted the manuscript. JL, ZT, and YZ performed data collection and data analysis. XY and JL participated in the design of this study and helped to check the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.