Familial Aneurysmal Formation

At least some role for congenital factors in the development of aneurysms is evidenced by studies that show a higher prevalence of cerebral aneurysms among family members of affected cohorts. Some studies suggest that the prevalence of familial cerebral aneurysms (defined as at least 2 affected first-degree relatives in the same family) ranges from 6% to 10% (73-78). One study found a 20% prevalence rate, and this was true for Caucasian, African American, and Hispanic patients (73). Another study found inheritance patterns suggestive of multiple modes of inheritance, with patterns suggestive of, but not definitive for, autosomal dominant, autosomal dominant with incomplete penetrance, and autosomal recessive inheritance (79).

Patients with familial intracranial aneurysms experience SAH at an earlier age, compared to those with nonfamilial aneurysms (76,77,80-83), although the severity of hemorrhage is no different between familial and nonfamilial aSAH (76,84). In some families with multiple affected generations, latter generations experience aSAH at a younger age, a pattern of genetic disease known as anticipation that can be associated with expanding triplet repeats (80,85). Definitive evidence that genetic anticipation plays a role in familial intracranial aneurysms remains to be demonstrated (83 ).

Genetics might play a role in aneurysmal formation, even in the absence of Mendelian inheritance. Recently, single nucleotide polymorphisms of collagen Type 1-alpha 2 (COL1A2) have been associated with familial as well as with nonfamilial cerebral aneurysms (86 ). Interestingly, one of these polymorphisms leads to an amino acid substitution at the location for keratin sulfate proteoglycan binding.


The apex of the intracerebral arterial bifurcation is the most common site for aneurysms, perhaps due to several factors, including the properties of fluid flow in an arterial bifurcation. Because blood flowing along the walls of a vessel is slowed by viscous drag, the actual flow occurs in several concentric layers of increasing velocity from the periphery to the center. Blood flowing in the center of the vessel and, thus, least hindered by viscous drag is called the axial stream. The axial stream is directed at the apex of the bifurcation, resulting in hemodynamic stress unique to this location. Increases in the angle of the bifurcation, blood flow, and blood pressure all increase the stress directed into the arterial apex. Thus, shear stress is much greater at the apex than it is at other areas of the bifurcation. Acute increases in shear stress at the apical blood-vascular interface might lead to endothelial damage and exposure of underlying basement membrane (87) and/or fragmentation of the IEL (30,88), perhaps the initial insult that leads to aneurysmal formation. Furthermore, the kinetic energy of the axial stream is converted to pressure energy (stagnation pressure) as it decelerates at the apex, thus adding another unique stressor to this area of the bifurcation (12 ).

Although the apex is the site of unique hemodynamic stress and, therefore, the site most susceptible to aneurysmal formation, the reason why certain individuals develop aneurysms and others do not remains elusive. A simple explanation would be that certain individuals are susceptible to aneurysmal formation due to a congenital weakness specific to the apex, such as a medial defect of Forbus. However, as discussed above, the historical view—that the arrangement of the medial layer at bifurcations is a congenital defect—is currently debated.

Alterations in the flow of blood through the intracranial vessels might lead to increased wall stress and subsequent aneurysmal formation. Aneurysmal formation after iatrogenic manipulation of vascular flow (i.e., extracranial-intracranial bypass) has been demonstrated (89). Alterations in blood flow that develop as a result of increased arterial flow to an arteriovenous malformation can lead to aneurysmal formation (90,91). Indeed, it is estimated that 10% of saccular aneurysms occur on the arterial vessels that feed arteriovenous malformations (92). Interestingly, it has been shown that removal of an arteriovenous malformation can lead to reduction in the size of an aneurysm on the afferent arterial vessel when the aneurysm is adjacent to the nidus (93).

Certain patterns of the cerebral vasculature lead to altered patterns of hemodynamic stress. For example, multiple case studies demonstrate anterior communicating artery aneu-rysms in the setting of a size imbalance of the proximal segments of the anterior cerebral arteries (33,94-97). Those in favor of the congenital theory argue that such anatomic variation is secondary to an unidentified congenital defect av8; therefore, aneurysms that are associated with these variations must also be secondary to congenital issues. However, no evidence suggests that variations in the Circle of Willis are actually congenital abnormalities. Furthermore, anatomic variations of the cerebral vasculature are no more likely to occur in patients with aneurysms ( 33 ).

Growth and Rupture

Multiple factors participate in aneurysmal initiation, growth, and eventual rupture, including mechanical factors. It is logical to assume that increases in aneurysmal wall stress increase the risk of aneurysmal rupture. Wall stress is defined by Laplace's law:

S=p-r/2t where S is the wall stress, p the intraluminal pressure, r the aneurysmal radius, and t the aneurysmal wall thickness. Because an aneurysmal wall is composed primarily of collagen, it has been hypothesized that it should rupture if stress exceeds 109 dynes/cm2 (the breaking strength of collagen) (98 ).

Increases in intraluminal pressure and/or increases in the size of an aneurysm increase wall stress and, therefore, the susceptibility to rupture. Intraluminal pressure is also caused by multiple factors, among them, systolic blood pressure (25). Thus, any increases in systemic blood pressure will be reflected in intraluminal pressure. Because of the decreased distensibil-ity of the aneurysmal wall relative to the normal cerebral vasculature due to the high collagen content, the wall experiences a greater degree of stress for a given pressure. Evidence suggests that an aneurysmal wall might experience 10 times the amount of stress seen by a normal cerebral artery at a given pressure (25), which is consistent with the idea that systemic hypertension has a role in aneurysmal growth and rupture. Further, aneurysms might be susceptible to rupture during times of increased systemic pressure, such as during a Valsalva maneuver, heavy lifting, coitus, and trauma (99). One computer model of a Valsalva maneuver suggests that enough pressure can be developed in such situations to lead to aneurysmal rupture (100). However, clinical series fail to demonstrate a preponderance of patients undertaking physical exertion at the time of rupture.

It is believed that turbulence of blood flow promotes the enlargement and rupture of cerebral aneurysms. Turbulent flow is characterized by the random and volatile fluctuation of pressure and velocity of fluid particles, in contrast to the stable pressure and velocity characterized by laminar flow. Turbulence in arterial vessels occurs when blood flow exceeds a critical velocity, described by the Reynold's number, as defined by the following equation:

Re = pVD/n where p is the fluid density, V is the average fluid velocity, D is the vessel radius, and n is the fluid viscosity. In a long straight tube using a Newtonian fluid, turbulence first appears at a Reynolds number of 2000.

Blood flow at a cerebral bifurcation has been modeled by Ferguson using glass tubes (101). He showed that the Reynold's number for bifurcations in the Circle of Willis without an aneurysm is between 600 and 750, while a value of approximately 400 was derived for models of bifurcations with aneurysms. His work led him to propose that, although the Reynolds number was low enough for turbulence to develop at a bifurcation with an aneurysm, it was unlikely that normal bifurcations would have significant turbulent blood flow. Thus, it is unlikely that turbulence is an initiating factor in aneurysmal formation but might have a causal role in the growth and eventual rupture of aneurysms. Using glass models of aneurysms, it was shown that turbulent flow occurs within the aneurysmal sac at low flow rates, which is in line with visualizing turbulence within the sacs of animal models (102) . Further evidence of turbulent flow is provided by intraoperative measurement of bruits emanating from the aneurys-mal sac (101). Despite intentional induction of hypotension during aneurysmal clipping, the investigators discovered evidence of bruits originating from the aneurysmal sac in 10 out of 17 cases, with an average frequency of 460 Hz. Using a thin-shell assumption applied to a hypothetical spherical model, Hung and Botwin argue that the frequency of these bruits falls within the natural frequency of many aneurysms (103). If the frequency of the bruit is the same as the natural frequency of an aneurysm, the resulting resonance could lead to structural weakness, aneurysm enlargement, and eventual rupture. However, Doppler recordings in patients undergoing craniotomy for aneurysmal clipping detected periodic flow fluctuations of only 7-16 Hz (104). These flow fluctuations are lower than the natural frequency of a fluid-filled aneurysmal sac, which is estimated to exceed 100 Hz. These lower frequency vibrations would not lead to aneurysmal propagation.

A computer simulation of pulsatile blood flow in and around saccular aneurysms has clarified our understanding of how hemodynamics might lead to aneurysmal wall stress (105 ). The model suggests that during the acceleration phase of systole, blood moves into the aneurysm along the proximal wall and exits at the distal wall. Interestingly, during both the deceleration phase of systole and the diastolic phase, blood flow through the aneurysm might actually reverse by entering along the distal wall of the aneurysm and leaving by the proximal wall. This pattern of flow oscillation leads to considerable amounts of wall shear stress, particularly at the distal wall of the aneurysm. It is hypothesized that the endothelial cells at the distal wall undergo continuous injury. Perhaps individuals who are capable of maintaining vascular homeostasis are able to heal these microinjuries and avoid aneurysmal growth, and those who are unable to respond adequately can develop dilation of the aneurysmal neck and aneurysmal growth. If this hypothesis is true, growth would likely originate from the distal wall, and not from the aneurysmal dome. This would explain the importance of obliterating the neck of the aneurysm during clipping or coiling procedures (106) , because any aneurysmal neck tissue from the distal wall would be subject to hemodynamic stress and future aneurysmal growth as a consequence.

It is unclear why some intracranial aneurysms rupture and others do not. Certain aneu-rysms develop significant amounts of thrombus within the sac, which might serve to dampen fluctuations in pressure and, therefore, decrease wall stress and damage to the endothelium. This thrombus might develop in situations of significant turbulence (107) or if flow stasis (98) is within the sac. Multiple computer simulations of blood flow within an aneurysm suggest that vortex formation occurs within aneurysms during the cardiac cycle, thereby creating a nidus for thrombus formation (105,108 ).

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