Intracranial aneurysms: links among inflammation, hemodynamics and vascular remodeling

Abstract

Abnormal vascular remodeling mediated by inflammatory cells has been identified as a key pathologic component of various vascular diseases, including abdominal aortic aneurysms, brain arteriovenous malformations and atherosclerosis. Based on findings from observational studies that analysed human intracranial aneurysms and experimental studies that utilized animal models, an emerging concept suggests that a key component of the pathophysiology of intracranial aneurysms is sustained abnormal vascular remodeling coupled with inflammation. This concept may provide a new treatment strategy to utilize agents to inhibit inflammation or cytokines produced by inflammatory cells such as matrix metalloproteinases. Such an approach would aim to stabilize these vascular lesions and prevent future expansion or rupture.

Figure 1

Schematic representation of hypothetic events in the development of aneurysms leading to aneurysm formation. Hemodynamic forces cause activation of factors in vessel wall, for example, MMPs. This initiation leads to lesion growth. Rupture may follow or stabilization may occur. Potential medical therapies might be aimed at promoting stabilization. Different phases may not be mechanistically determined by the same class of signals

Figure 2

Flow impingement and the resulting ‘impact zone’ at the distal wall of an idealized saccular aneurysm on a curved vessel, obtained from computational fluid dynamics simulation: (A) Two-dimensional velocity field in the center plane. Vectors represent both magnitude and direction of velocity; (B) wall shear stress (WSS) distribution at the distal aneurysm wall. Color scale represents WSS values from below 15 (deep blue) to above 35 dynes/cm² (bright red). The maximum WSS value is 298 dynes/cm². Following Hoi et al., we define the impact zone as the area where WSS>20 dynes/cm² (a value considered as an upper limit for normal physiologic condition)

Figure 3

Flow velocity magnitude distribution on a cross-section of a patient's intracranial aneurysm. The lumen was reconstructed from CT images and the flow field was calculated using computational fluid dynamics simulation. The distal neck serves as a flow divider splitting the inflow into different directions, therefore creating a large spatial variation of wall shear stress, a hallmark of a ‘disturbed flow’

Figure 4

Schematic representation of normal outward vascular remodeling under laminar flow and pathologic vascular remodeling leading to aneurysm formation at a flow divider. Increased hemodynamic stresses activate endothelial cells, which cause recruitment and activation of inflammatory cells and secretion of MMPs to degrade the internal elastic lamina. These processes initiate outward vascular remodeling. In normal vascular remodeling, the luminal diameter increases. The vessel enlargement brings the shear stress down to baseline level; therefore, blood vessels will be adapted and stabilized. However, during aneurysm formation, outward vascular remodeling becomes asymmetric or focalized. Flow impingement creates a complex hemodynamic environment with spatially varying shear stress and increased invasion of inflammatory cells. As the micro-aneurysm grows, part of the wall will continue to experience high shear stress. Focalized vascular remodeling continues with increasing participation of inflammation, which could repair the wall, stabilize the aneurysm or further degrade it, leading to rupture