Role of Wall Shear Stress in an Intracranial Aneurysm Formation: A Systematic Review

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Results:
Wall shear stress showed to have a significant role in intracranial aneurysm inception. Other hemodynamic factors also played role in the inception of cerebral aneurysms. The geometry and optimality principle along with social factors like smoking is also responsible for the formation of cerebral aneurysms.

Conclusion:
Wall shear stress plays a major role in intracranial aneurysm formation. Gradient oscillatory number is the emerging hemodynamic factor for the inception of cerebral aneurysms. However, limited experiments in humans have resulted in inconclusive results.

Background
Aneurysm formation is a continuous remodelling process that involves the breakdown of the extracellular matrix and is described by the loss of the internal elastic lamina, media layer thinning, and bulge formation [1,2]. Cerebral aneurysms (CAs) are distinguished by a pathological wall structure characterized by rupture of the internal elastic lamina and media, resulting in focally weakened arterial wall pouches [3,4]. The incidence of unruptured CAs in the general population has been approximated to be 2% to 5% [5]. Hemodynamics has been found to play a significant role in the genesis, progression, and rupture of intracranial aneurysms (IA) [6][7][8]. Specific elements, such as site, blood pressure, boundary condition, and vascular shape, do, nevertheless, influence hemodynamic factors [9][10][11]. Recent fluid dynamics research has highlighted the close connections between hemodynamics and IAs [12]. Among numerous hemodynamic characteristics, high wall shear stress placed on artery

Results
Literature search and data extraction 2134 unique articles were identified, of which 32 were retrieved for more detailed evaluation. 17 articles met the inclusion criteria and were involved in the qualitative analysis. Figure 1 shows the results of our literature search and selection. Table 1 shows the summary of study data for the risk of aneurysm formation.

Study design
All eligible studies were observational studies measuring the influence of WSS in intracranial inception.

Risk of formation
In a study conducted by Castro et al, three individuals were chosen for Model A (without aneurysms) and Model B (with aneurysms). A comparison of the two models for Patient 1 reveals that the aneurysm began to develop in the high WSS region. The aneurysm impacted two unconnected high WSS areas in patient 2. In the case of patient 3, the aneurysm developed across an area with both high and moderate WSS values. In a study of Anterior Communicating Artery (AComA) aneurysms, Castro et al discovered a probable link between areas of high WSS prior to aneurysm development and aneurysm location [21].
Le et al performed a retrospective hemodynamic analysis before and after aneurysm development in a ruptured aneurysm of the posterior communicating artery and an unruptured aneurysm of the posterior communicating artery using a vessel surface repair approach [22]. The first patient was a 62-year-old male who had a ruptured aneurysm, and the second was a 48-year-old man who had an unruptured aneurysm. Their early findings revealed that the artery wall was exposed to higher WSS, WSSG, and blood-flow velocity before the formation of an aneurysm [22]. Utami et al. achieved consistent findings [23].
Sasaki and colleagues investigated twenty-one bifurcation models with varied in-branch angles and branch sizes. The highest WSS value was studied in all models using a steady-flow simulation using computational fluid dynamics. The amplitude of WSS was shown to be substantially linked with bifurcation geometry and aneurysm development [24].
The role of the optimality principle was discussed by Zhang et al [25]. They demonstrated that normal anterior cerebral artery bifurcations followed the optimality principle, but AComA bifurcations did not, Disobeying the optimality principle results in dramatically increased hemodynamic stress, which may damage the bifurcation wall and lead to aneurysm formation. IA developed in locations other than the bifurcation apex [25]. In support of this, Geers et al investigated the involvement of WSS in aneurysm formation at locations other than the bifurcation apex and the exterior wall of the arterial bed [26].
Sunderland et al created 3D computational vasculatures using angiographic pictures of 18 patients who had several closely spaced IAs in the internal carotid artery. Two models were created: one with all IAs computationally eliminated and one with one IA retained. They discovered that a combination of hemodynamic parameters was more important in the onset of an aneurysm than individual indices [27]. Kulcsar et al and Watanabe et al obtained similar findings [28,29].
Kono et al described a patient who had a freshly developed aneurysm with proximal stenosis, which was validated by serial imaging. They created two pre-aneurysm models, one with stenosis and one without, and ran computational fluid dynamics simulations on both. Because of the stenosis-induced jet flow, the maximal WSS and WSSG at the aneurysm start site were roughly doubled and tripled, respectively. As a result, they underlined the importance of proximal stenosis in aneurysm formation [30]. Lauric et al, on the other hand, investigated the curvature effects on hemodynamic circumstances [31]. Many additional elements had an important part in the development of IAs. Singh et al investigated the effects of smoking and hypertension on the establishment of aneurysms [32].
Shimogonya et al, on the other hand, discovered no significant correlation between WSS and aneurysm inception [33]. They also developed a novel hemodynamic measure termed Gradient Oscillatory Number (GON), which may impact aneurysm development. Chen et colleagues found that regionally higher WSS and GON were strongly linked with locations vulnerable to sidewall IA development in the hypothesized pre-diseased geometries of 22 clinical sidewalls IAs [34]. Ford et al discovered similar findings [35]. Tanaka et al discovered no obvious connections between hemodynamic parameters and aneurysm initiation, contradicting all of the preceding studies [36]. The magnitude of WSS in ruptured and unruptured aneurysms has been determined in certain studies. Nonetheless, the degree of WSS observed varies, and the threshold of high or low WSS has been documented very infrequently. WSS values ranging from 7.8 to 12.3 dyne/cm 2 were shown to independently describe aneurysm development by Zhang et al. There was a one-fold increase in the likelihood of AComA aneurysm development with each additional unit of WSS [37].

Discussion
The analysis of cerebral arteries from autopsies and IA animal models has been critical in understanding the early alterations in the emerging aneurysm. The aneurysm wall frequently has a disturbed internal elastic lamina (IEL), media thinning, and bulge development.
For the etiology of IAs, several theories have been proposed. The first theory claimed a congenital etiology, but the second theory proposed that IAs are acquired lesions that develop over time, with hemodynamic conditions having a role in their onset. Indeed, the preferred position of the aneurysm at artery bifurcations with a certain flow pattern suggested a role for hemodynamics in aneurysm development. Meng et al. investigated how "a hemodynamic insult" may result in maladaptive remodelling of the vessel wall. They identified three regions at arterial bifurcations with different blood patterns using CFD, the first one being the impingement zone, where blood from the parent artery hits the apex of the bifurcation and creates a stagnation point before accelerating into the branches (WSS ≤ 20 dynes/cm 2 ; velocity < 0.05 m/s; positive Wall Shear Stress gradient(WSSG);the second one being the acceleration region, where blood flow continues to accelerate until the maximum velocity (WSS > 20 dynes/cm 2 , high positive WSSG); and the third one being recovery region where the velocity of blood reaches the maximum and starts to decelerate until the physiological level of WSS ~20 dynes/cm 2 (negative WSSG). They discovered early alterations mimicking IA initiation in places subjected to SWSS and positive WSSG by mapping CFD with histological analysis of the arterial bifurcation. Further research found that aneurysmal remodeling occurs only when hemodynamic forces exceed a particular threshold (WSS > 1.22 x 103 dynes/cm 2 and WSSG > 530 Pa/mm) in their rabbit model.
Although these findings assist to clarify the function of hemodynamic pressures in the onset of IA, Meng et al investigations were conducted on an artificial extracranial bifurcation in a small number of animals and require additional validation in other, preferably intracranial, animal models. Furthermore, the stated hemodynamic threshold values are only for rabbits and may change in humans where vessel diameter is varied and several confounding variables, such as genetic risk factors and habits such as smoking, might impact IA development.
The idea of the WSS threshold, on the other hand, explains why IAs occur more frequently at particular bifurcations and individuals than others. Each arterial bifurcation has a unique flow pattern based on its location, bifurcation angle, and parent and daughter artery sizes, making some more likely to reach the threshold. Singh et al33 investigated the effects of smoking and hypertension on aneurysm development. As a result, a weaker wall caused by age, smoking, hypertension, and genetic disorders would be more susceptible to hemodynamic disturbances. A meta-analysis of patients' hemodynamic forces and the development of IAs supports the notion that IAs are caused by spatial WSS (SWSS) and positive WSSG [38,39].
There are some limitations to this study. Firstly, only CFDrelated studies are examined. The current IA CFD models produce poor results due to improper simplifications, reliance on physically meaningless parameters, and a sloppy computational representation of physiologic blood flow. As a result, new generation IA CFD models should be explored in order to understand the function of various hemodynamic variables in the onset of IA. Secondly, only items published in English were considered.

Conclusion
Intracranial aneurysm formation is thought to have a complex