Shear stress and aneurysms: a review.

Wall shear stress, the frictional force of blood flow tangential to an artery lumen, has been demonstrated in multiple studies to influence aneurysm formation and risk of rupture. In this article, the authors review the ways in which shear stress may influence aneurysm growth and rupture through changes in the vessel wall endothelial cells, smooth-muscle cells, and surrounding adventitia, and they discuss shear stress-induced pathways through which these changes occur.

Hemodynamic and morphological characteristics of a growing cerebral aneurysm.

The growth of cerebral aneurysms is linked to local hemodynamic conditions, but the driving mechanisms of the growth are poorly understood. The goal of this study was to examine the association between intraaneurysmal hemodynamic features and areas of aneurysm growth, to present the key hemodynamic parameters essential for an accurate prediction of the growth, and to gain a deeper understanding of the underlying mechanisms. Patient-specific images of a growing cerebral aneurysm in 3 different growth stages acquired over a period of 40 months were segmented and reconstructed. A unique aspect of this patient-specific case study was that while one side of the aneurysm stayed stable, the other side continued to grow. This unique case enabled the authors to examine their aims in the same patient with parent and daughter arteries under the same inlet flow conditions. Pulsatile flow in the aneurysm models was simulated using computational fluid dynamics and was validated with in vitro experiments using particle image velocimetry measurements. The authors' detailed analysis of intrasaccular hemodynamics linked the growing regions of aneurysms to flow instabilities and complex vortex structures. Extremely low velocities were observed at or around the center of the unstable vortex structure, which matched well with the growing regions of the studied cerebral aneurysm. Furthermore, the authors observed that the aneurysm wall regions with a growth greater than 0.5 mm coincided with wall regions of lower (< 0.5 Pa) time-averaged wall shear stress (TAWSS), lower instantaneous (< 0.5 Pa) wall shear stress (WSS), and high (> 0.1) oscillatory shear index (OSI). To determine which set of parameters can best identify growing and nongrowing aneurysms, the authors performed statistical analysis for consecutive stages of the growing CA. The results demonstrated that the combination of TAWSS and the distance from the center of the vortical structure has the highest sensitivity and positive predictive value, and relatively high specificity and negative predictive value. These findings suggest that an unstable, recirculating flow structure within the aneurysm sac created in the region adjacent to the aneurysm wall with low TAWSS may be introduced as an accurate criterion to explain the hemodynamic conditions predisposing the aneurysm to growth. The authors' findings are based on one patient's data set, but the study lays out the justification for future large-scale verification. The authors' findings can assist clinicians in differentiating stable and growing aneurysms during preinterventional planning.

Flow-induced, inflammation-mediated arterial wall remodeling in the formation and progression of intracranial aneurysms.

OBJECTIVE: Unruptured intracranial aneurysms (UIAs) are relatively common lesions that may cause devastating intracranial hemorrhage, thus producing considerable suffering and anxiety in those affected by the disease or an increased likelihood of developing it. Advances in the knowledge of the pathobiology behind intracranial aneurysm (IA) formation, progression, and rupture have led to preclinical testing of drug therapies that would prevent IA formation or progression. In parallel, novel biologically based diagnostic tools to estimate rupture risk are approaching clinical use. Arterial wall remodeling, triggered by flow and intramural stresses and mediated by inflammation, is relevant to both. METHODS: This review discusses the basis of flow-driven vessel remodeling and translates that knowledge to the observations made on the mechanisms of IA initiation and progression on studies using animal models of induced IA formation, study of human IA tissue samples, and study of patient-derived computational fluid dynamics models. RESULTS: Blood flow conditions leading to high wall shear stress (WSS) activate proinflammatory signaling in endothelial cells that recruits macrophages to the site exposed to high WSS, especially through macrophage chemoattractant protein 1 (MCP1). This macrophage infiltration leads to protease expression, which disrupts the internal elastic lamina and collagen matrix, leading to focal outward bulging of the wall and IA initiation. For the IA to grow, collagen remodeling and smooth muscle cell (SMC) proliferation are essential, because the fact that collagen does not distend much prevents the passive dilation of a focal weakness to a sizable IA. Chronic macrophage infiltration of the IA wall promotes this SMC-mediated growth and is a potential target for drug therapy. Once the IA wall grows, it is subjected to changes in wall tension and flow conditions as a result of the change in geometry and has to remodel accordingly to avoid rupture. Flow affects this remodeling process. CONCLUSIONS: Flow triggers an inflammatory reaction that predisposes the arterial wall to IA initiation and growth and affects the associated remodeling of the UIA wall. This chronic inflammation is a putative target for drug therapy that would stabilize UIAs or prevent UIA formation. Moreover, once this coupling between IA wall remodeling and flow is understood, data from patient-specific flow models can be gathered as part of the diagnostic workup and utilized to improve risk assessment for UIA initiation, progression, and eventual rupture.

Human herpesvirus DNA occurrence in intracranial aneurysmal wall: illustrative case.

BACKGROUND: Subarachnoid hemorrhages secondary to intracranial aneurysms (IAs) are events of high mortality. These neurological vascular diseases arise from local and systemic inflammation that culminates in vessel wall changes. They may also have a possible relationship with chronic viral infections, such as human herpesvirus (HHV), and especially Epstein-Barr virus (EBV), which causes several medical conditions. This is the first description of the presence of HHV deoxyribonucleic acid (DNA) in a patient with IA. OBSERVATIONS: A 61-year-old woman with a downgraded level of consciousness underwent radiological examinations that identified a 10-mm ruptured aneurysm in the anterior communicating artery. A microsurgery clip was performed to definitively treat the aneurysm and occurred without surgical complications. Molecular analysis of the material obtained revealed the presence of EBV DNA in the aneurysm wall. The patient died 21 days after admission due to clinical complications and brain swelling. LESSONS: This is the first description of the presence of herpesvirus DNA in a patient with IA, presented in 2.8% of our data. These findings highlight that viral infection may contribute to the pathophysiology and is an additional risk factor for IA formation, progression, and rupture by modulating vessel wall inflammation and structural changes in chronic infections.

Cerebral cavernomas in adults and children express relaxin.

OBJECTIVE: To shed light on the role of relaxin in cerebral cavernous malformations (CCMs) in adults and children, the authors investigated endothelial cell (EC) expression of relaxin 1, 2, and 3; vascular endothelial growth factor receptor-1 and -2 (VEGFR-1 and -2); Ki-67; vascular geometry; and hemorrhage, as well as the clinical presentation of 32 patients with surgically resected lesions. METHODS: Paraffin-embedded sections of 32 CCMs and 5 normal nonvascular lesion control (NVLC) brain tissue samples were immunohistochemically stained with antibodies to relaxin 1, 2, and 3; angiogenesis growth factor receptors Flt-1 (VEGFR-1) and Flk-1 (VEGFR-2); and proliferation marker Ki-67. For morphometric analysis, Elastica van Gieson stain was used, and for hemorrhage demonstration, Turnbull stain was used. Data from the pediatric and adult CCMs were compared with each other and with those obtained from the NVLCs. Statistical analyses were performed with Fisher's exact test, the chi-square test, the phi correlation coefficient, and the Student t-test. A p value < 0.05 was considered significant. RESULTS: Pediatric and adult cavernoma vessels did not significantly differ in diameter. Hemorrhage was observed in CCMs but not in NVLC samples (p < 0.05). There was no difference in expression of Ki-67, VEGFR-1 and -2, and relaxin 1, 2, and 3 in the ECs of pediatric and adult CCMs. The ECs of CCMs were largely negative for relaxin 3 compared to NVLCs (p < 0.05), whereas CCMs, compared to control brain tissue samples, more frequently expressed Flt-1 and relaxin 2 (p < 0.05). Ki-67 was not expressed in the NVLCs, but the difference was not statistically significant. Relaxin 1 and 2 expression and increased expression of VEGFR-1 were associated with a supra- versus infratentorial location (p < 0.05). CONCLUSIONS: Relaxin 1 and 2 and VEGFR-1 play a role in supratentorial cavernomas. Relaxin 3 may play a physiological role in normal brain vasculature. Relaxin 1 and 3 are also found in normal cerebral vasculature. Relaxin 1, 2, and 3 are associated with increased VEGFR-1 expression.

Sex-related differences in wall remodeling and intraluminal thrombus resolution in a rat saccular aneurysm model.

OBJECTIVE: Intracranial aneurysms (IAs) are more often diagnosed in women. Hormones and vessel geometry, which influences wall shear stress, may affect pathophysiological processes of the arterial wall. Here, the authors investigated sex-related differences in the remodeling of the aneurysm wall and in intraluminal thrombus resolution. METHODS: A well-characterized surgical side-wall aneurysm model was used in female, male, and ovariectomized rats. Decellularized grafts were used to model highly degenerated and decellularized IA walls and native grafts to model healthy IA walls. Aneurysm growth and thrombus composition were analyzed at 1, 7, 14, and 28 days. Sex-related differences in vessel wall remodeling were compared with human IA dome samples of men and pre- and postmenopausal women. RESULTS: At 28 days, more aneurysm growth was observed in ovariectomized rats than in males or non-ovariectomized female rats. The parent artery size was larger in male rats than in female or ovariectomized rats, as expected. Wall inflammation increased over time in all groups and was most severe in the decellularized female and ovariectomized groups at 28 days compared with the male group. Likewise, in these groups the most elastin fragmentation was seen at 28 days. In female rats, on days 1, 7, and 14, the intraluminal thrombus was mainly composed of red blood cells and fibrin. On days 14 and 28, macrophage and smooth muscle cell invasion inside the thrombus was shown, leading to the removal of red blood cells and deposition of collagen and elastin. On days 14 and 28, similar profiles of thrombus reorganization were observed in male and ovariectomized female rats. However, collagen content in thrombi and vessel wall macrophage content were higher in aneurysms of male rats at 28 days than in those of female rats. On day 28, thrombus coverage by endothelial cells was lower in ovariectomized than in female or male rats. Finally, analysis of human IA domes showed that endothelial cell coverage was lower in men and postmenopausal women than in younger women. CONCLUSIONS: Aneurysm growth and intraluminal thrombus resolution show sex-dependent differences. While certain processes (endothelial cell coverage and collagen deposition) point to a strong hormonal dependence, others (wall inflammation and aneurysm growth) seem to be influenced by both hormones and parent artery size.

Induction of aneurysmogenic high positive wall shear stress gradient by wide angle at cerebral bifurcations, independent of flow rate.

OBJECTIVE: Endothelium adapts to wall shear stress (WSS) and is functionally sensitive to positive (aneurysmogenic) and negative (protective) spatial WSS gradients (WSSG) in regions of accelerating and decelerating flow, respectively. Positive WSSG causes endothelial migration, apoptosis, and aneurysmal extracellular remodeling. Given the association of wide branching angles with aneurysm presence, the authors evaluated the effect of bifurcation geometry on local apical hemodynamics. METHODS: Computational fluid dynamics simulations were performed on parametric bifurcation models with increasing angles having: 1) symmetrical geometry (bifurcation angle 60°-180°), 2) asymmetrical geometry (daughter angles 30°/60° and 30°/90°), and 3) curved parent vessel (bifurcation angles 60°-120°), all at baseline and double flow rate. Time-dependent and time-averaged apical WSS and WSSG were analyzed. Results were validated on patient-derived models. RESULTS: Narrow symmetrical bifurcations are characterized by protective negative apical WSSG, with a switch to aneurysmogenic WSSG occurring at angles ≥ 85°. Asymmetrical bifurcations develop positive WSSG on the more obtuse daughter branch. A curved parent vessel leads to positive apical WSSG on the side corresponding to the outer curve. All simulations revealed wider apical area coverage by higher WSS and positive WSSG magnitudes, with increased bifurcation angle and higher flow rate. Flow rate did not affect the angle threshold of 85°, past which positive WSSG occurs. In curved models, high flow displaced the impingement area away from the apex, in a dynamic fashion and in an angle-dependent manner. CONCLUSIONS: Apical shear forces and spatial gradients are highly dependent on bifurcation and inflow vessel geometry. The development of aneurysmogenic positive WSSG as a function of angular geometry provides a mechanotransductive link for the association of wide bifurcations and aneurysm development. These results suggest therapeutic strategies aimed at altering underlying unfavorable geometry and deciphering the molecular endothelial response to shear gradients in a bid to disrupt the associated aneurysmal degeneration.

Tumor cell-specific chromosomal abnormality in the vascular endothelial cells of anaplastic oligodendroglioma.

OBJECTIVE 1p/19q co-deletion is a well-established tumor cell-specific chromosomal abnormality in oligodendroglial tumors. The endothelial cells (ECs) of oligodendroglial tumor vessels are considered to be normal cells that do not acquire mutations. METHODS A total of 30 samples from 16 male and 14 female patients (median age of 46.5 years) with a histological diagnosis of primary anaplastic oligodendroglioma (AO) were collected in the study. The immunofluorescence technique was used to identify vascular ECs, and the 1p/19q status was detected with fluorescence in situ hybridization. Kaplan-Meier plots were compared using the log-rank method. RESULTS The ECs in AO had a higher 1p36 (detected signal) deletion rate than 1q25 (reference signal) (p < 0.01) and a higher 19q13 (detected signal) deletion rate than 19p13 (reference signal) (p < 0.01). The survival analysis results showed that both the progression-free survival (PFS) and overall survival (OS) of the patients with 1p/19q-co-deleted ECs were significantly longer than those with 1p/19q-intact ECs (PFS, p < 0.001; OS, p < 0.001). This correlation was validated by an independent cohort. In addition, the Cox regression model revealed that 1p/19q co-deletion in ECs was an independent prognostic factor (HR 0.056 [95% CI 0.012-0.261], p < 0.001 for PFS; HR 0.061 [95% CI 0.013-0.280], p < 0.01 for OS). CONCLUSIONS 1p/19q co-deletion and polysomy can be also found in the ECs of AO, which suggests that the ECs are, in part, tumor related and reflect a novel aspect of tumor angiogenesis.