Differences in Cerebral Aneurysm Rupture Rate According to Arterial Anatomies Depend on the Hemodynamic Environment

Discussion

Hemodynamics is likely involved in cerebral aneurysm ruptures, and some of the rupture predictors become significant risk factors due to the influence of hemodynamics.^1,5⇓–7 Several studies have quantitatively examined hemodynamic metrics in ruptured and unruptured cerebral aneurysms.^7,10 These reports examined the degree of association between hemodynamic metrics and aneurysm rupture and demonstrated that ruptured and unruptured aneurysms had significantly different hemodynamic characteristics.¹⁰ Therefore, it is presumed that some of the known rupture risks become significant by reflecting the influence of these hemodynamic environments. However, to our knowledge, no report has described the significance of the association between hemodynamic parameters as independent variables and the rupture risks, such as size and location, or conversely, how much the rupture risks as independent variables are related to hemodynamic environments, though several reports have examined the association between hemodynamic factors and rupture itself.^7,10 Therefore, we statistically examined the mutual relationship between hemodynamic parameters and representative risk factors such as age, sex, smoking history, and hypertension in addition to size and location. This is thus the first examination of this type. The results of our analyses indicate that arterial anatomic parameters (size and location of aneurysms) and hemodynamic metrics characterizing the WSS magnitude and disturbance were significantly associated; both the associations of the arterial anatomic parameters with the hemodynamic metrics and the associations of the hemodynamic metrics with the arterial anatomic parameters were statistically significant (On-line Table 1 and On-line Fig 3), suggesting that rupture risks based on arterial anatomic parameters are determined by the hemodynamic environment.

Larger and AcomA aneurysms have higher rupture rates than smaller and MCA aneurysms, respectively.² The present results show that the TAWSS on the aneurysmal surface was significantly negatively associated with size and location (On-line Table 1 and Figs 1 and 2 and On-line Figs 3–5). This finding is consistent with studies showing that a significant decrease in the magnitude of the WSS on the aneurysmal surface is closely associated with the aneurysm rupture status.^1,6,8,9

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Fig 1.

Comparisons of hemodynamic metrics between a representative small aneurysm (A) and a large aneurysm (B).

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Fig 2.

Comparisons of hemodynamic metrics between a representative anterior communicating artery aneurysm (A) and an MCA aneurysm (B).

This leads us to ask what mechanisms cause the WSS to become low or disturbed depending on the size and location. Are the mechanisms different between size and location? Based on the present data, we considered the mechanisms from the point of view of fluid mechanics. The finding that the TAWSS was significantly decreased on AcomA aneurysms compared with MCA aneurysms could be explained qualitatively. It is hemodynamically clear that the TAWSS on the aneurysmal surface is affected principally by the size of the aneurysm and the inflow rate into the aneurysm.¹¹ The larger the size of the aneurysm (ie, the larger the open space inside the aneurysm) and the lower the inflow rate, the lower the TAWSS will be.

Because it was difficult to measure the inflow rate into the aneurysm for all the cases, we use the flow rate in the parent vessel, the anterior cerebral artery or MCA, in the following discussion. In our results, the anterior cerebral artery flow rate was significantly lower than the MCA flow rate, whereas the aneurysmal size showed no significant difference between the AcomA and MCA aneurysm groups (On-line Table 3). Therefore, the significant difference in TAWSS between the 2 groups was due mainly to the difference in flow rates. In contrast, the decrease in the TAWSS with increasing aneurysm size may be explained simply by the effect of size because the flow rate in the parent vessel showed no difference between the 2 size groups (On-line Table 4).

A significant positive association was observed between each of the WSS disturbance–based metrics (the OSI, GON, and NtransWSS) and the size of the aneurysm (On-line Table 1, Fig 1, and On-line Fig 4). With respect to location, however, only NtransWSS differed significantly among the different locations (On-line Table 1, Fig 2, and On-line Fig 5). These findings suggest that aneurysm size and location both contribute significantly to the hemodynamic disturbance, but in qualitatively different ways. In the present study, we defined a new metric, the NtransWSS, by dividing the nodal transverse WSS¹² by the TAWSS at the same node because this normalization allowed us to compare the transverse WSS among multiple cases on the same basis. The OSI can distinguish between purely forward (low OSI) and reversing unidirectional (high OSI) flow, but the NtransWSS cannot (low NtransWSS in both cases). In contrast, the NtransWSS can distinguish between reversing unidirectional (low NtransWSS) and multidirectional (high NtransWSS) flow, but the OSI cannot (high OSI in both cases).¹²

It thus seems reasonable to infer that the hemodynamic environments of small and large aneurysms are characterized in part by purely forward and multidirectional WSS, respectively, because both the OSI and NtransWSS were significantly different. In contrast, the hemodynamic environment of the MCA and AcomA aneurysms may be characterized in part by reversing unidirectional and multidirectional WSS, respectively, because significant variations were observed in the NtransWSS, but not in the OSI. The more disturbed hemodynamic stress at AcomA aneurysms compared with MCA aneurysms may be because AcomA, but not MCA, aneurysms are positioned along the circle of Willis.

Among the hemodynamic metrics, the NtransWSS had the highest OR for both size and location (On-line Table 1). This suggests that rupture rates in aneurysms of different sizes and locations are most strongly influenced by the multidirectional disturbance in WSS. Several experimental studies have reported that low WSS or disturbed WSS without a clear direction, ie, multidirectional WSS, or both cause sustained molecular signaling of proinflammatory and proliferative pathways of vascular endothelial cells.^13,14 The inflammatory processes in vessel walls play a critical role in the pathogenesis of cerebral aneurysms.^15⇓–17 Therefore, the clinical evidence of higher rupture rates in AcomA aneurysms and larger aneurysms might be associated, in part, with the inflammation in the vessel walls enhanced by the low WSS and the multidirectionally disturbed WSS detected by the NtransWSS.^7,18

Several researchers have proposed various aneurysmal geometric parameters for predicting rupture risk.^19⇓–21 The use of surrogate geometric parameters of the hemodynamic environment with high rupture risk would be of great clinical value because geometric parameters can be measured more easily than hemodynamic metrics at clinical sites. We thus investigated which previously proposed geometric parameters of aneurysms best correlated with the TAWSS and NtransWSS. Our analyses revealed that the aspect ratio was most strongly correlated with both the TAWSS and NtransWSS, followed by the size ratio. The aspect ratio has been reported to play a greater role than the size in the rupture of AcomA and MCA aneurysms.^19,20 The size ratio has been reported to be a useful rupture risk predictor, particularly for small aneurysms of <5 mm.²¹

However, the correlation between some geometric parameters, including size ratio and aspect ratio, and aneurysm rupture is still controversial.²² This is presumably because these geometric parameters only partially reflect hemodynamic environments (On-line Table 2). Therefore, we defined a novel geometric parameter, the AAI, which serves as a special refined geometric marker for the nonsphericity of aneurysmal shapes. The AAI best reflected both the TAWSS and the NtransWSS among all of the geometric parameters examined (On-line Table 2). The AAI is thus a potentially useful geometric parameter for predicting the rupture risk of aneurysms. We will validate its usefulness on completion of the ABO study. Because CFD analyses currently take time and effort, it is clinically impractical to conduct them for all unruptured aneurysm cases. Thus, the use of arterial geometric parameters may be more convenient at the clinical level. Indeed, it might be reasonable to first perform a screening with useful arterial geometric parameters and then to examine the detailed hemodynamics using a CFD analysis for essential cases.

To better understand how the hemodynamic metrics change with increasing aneurysm size, we examined the threshold size at which the hemodynamic metrics changed notably. The difference in the WSS magnitude–based metrics between the 2 different size groups with a threshold of 5 mm was larger than that with a threshold of 7 mm, whereas the difference in the WSS disturbance–based metrics between the 2 different size groups with a threshold of 7 mm was larger than that when the threshold was 5 mm (On-line Table 6). In other words, as the aneurysm size increases, the magnitude of the WSS declines first, and then the WSS disturbance occurs. Cerebral aneurysms may have at least 2 different critical sizes at which the rupture risk is heightened.

In the CFD ABO study, individual flow rates and arterial geometries have been acquired from each registered patient to provide realistic patient-specific CFD models. In most hemodynamic cohort studies using CFD analyses, the inlet boundary conditions are based on a typical flow velocity or flow rate of healthy subjects.^7,18 Alternatively, in other studies, the inlet boundary conditions were set so that the mean WSS at the ICA was equal to 1.5 Pa.²³ However, we found that the mean flow rate and the WSS at the ICA of the large MCA cases (≥5 mm) were significantly higher than those of the small MCA cases (<5 mm; On-line Table 6). Thus, the mean WSS at the ICA is not constant but strongly depends on characteristics of the individual case. Because such substantial differences are thought to have a non-negligible impact on hemodynamic characteristics,¹⁰ it is essential to use patient-specific inflow boundary conditions in combination with patient-specific arterial geometry in these types of statistical analyses.

The present study has some limitations. First, we did not directly measure the rupture risk, but we measured recognized risk factors for rupture. Second, it remains unclear whether the NtransWSS can further help to stratify the rupture risk of aneurysms with similar sizes and locations, though the results suggest that an enhanced NtransWSS may be strongly associated with aneurysm rupture. Third, we cannot conclude that the NtransWSS is superior to other hemodynamic metrics in terms of the risk assessment of aneurysm rupture. Fourth, only AcomA and MCA aneurysms were examined. It is unclear how the present results would change if aneurysms at other locations were included. These limitations may be resolved by a statistical hemodynamic comparison between unruptured and ruptured/enlarged aneurysms at various locations, which will be made in our ongoing clinical study.