**1. Pathophysiology of aneurysms**

A cerebral aneurysm is defined as a local outpouching of an intracranial artery and can either be saccular or fusiform. The formation of aneurysms is an incompletely understood gradual process [1] involving genetics, epidemiology and pathobiology, in conjugation with the study of biophysics provides a more complete picture on how these factors interact [2]. The natural history of saccular intracranial aneurysms consists of three phases: initiation, growth, and either stabilization or rupture, and the application of scientific principles to biological processes has made it easier to understand the behavior of aneurysm formation and rupture.

#### **1.1 Genetic factors**

Various genome studies and subsequent replication case control studies suggest genetic components in the formation of intracranial aneurysms (IA), no specific genes strongly associated with formation have yet been identified. A meta-analysis [3], identified three single nucleotide polymorphisms (SNPs) located on chromosome 9 within the *CDKN2B-AS1* gene, on chromosome 8 near the *SOX17* transcription regulator gene, and on chromosome 4 near the endothelin receptor gene associated with the presence of sporadic IAs. A new IA susceptibility locus on 13q

was identified [4]. Subsequent genome-wide association studies [5, 6] have found additional loci on chromosome 7 near *HDAC9*, as well as in chromosomal regions 1p34.3–p36.13, 19q13.3, Xp22 and 7q11. The strongest evidence for linkage was with a locus on 7q11 near the perlecan gene that encodes elastin, a protein that is involved in the preservation of vessel wall integrity.

#### **1.2 Structural changes and hemodynamics**

Cerebral arteries are prone to aneurysm formation due to presence of cerebrospinal fluid, sparse tunica adventitia, lower proportion of elastic fibers and disruption of internal lamina at bifurcation [7–9]. Blood is an active participant in the formation of aneurysms, its flow provides the mechanical triggers for reactions in the vessels at the level of the endothelium, while it is also a biological participant in the inflammatory cascade [10, 11]. This dual function of blood contributes significantly to the degradation of the arterial wall in the formation of aneurysms [2].

Cohort studies on people with a familial preponderance to saccular aneurysm have shown that the geometry of bifurcations around the circle of Willis adds additional stress to the vessel walls, given the significant shifts in flow velocity, dynamic forces, and shear stress. Thus, high flow across a wall that is not "designed" for the exposed pressures results in tissue injury and remodeling. The biological result may be plaque or may be an aneurysm, depending on the presence (or absence) of an intact media [2]. Fluid-dynamic models calculate and visualize wall shear stress or wall shear gradients, intra-aneurysmal flow, impingement zones, and flow patterns or velocities. Wall shear stress constitutes the degree of friction in the intracranial aneurysm wall that results from blood inflow and impingement into the aneurysm. High and low wall shear stress can both be present during aneurysm formation but the relevance of these flow conditions to the pathogenesis, growth and rupture of an aneurysm remain unclear [12]. The role of shear stress is very controversial, responsible for damage at specific phases of aneurysmal development and rupture. Some studies suggest the direct effect of shear stress on the vessel wall resulting in injury and degeneration of the wall's media, leading to aneurysm formation. Others suggest that low shear stress in the aneurysm and the vessel wall may result in small thrombus formation, endothelial reactivity, and inflammation at the site, thus weakening the vessel.

Data generated from fluid-dynamic models could help improve our understanding of aneurysm formation patterns and potential structural deficiencies in aneurysms. The relevance of existing data derived from computational fluid modeling is limited, however, because the majority of studies compared ruptured with unruptured aneurysms. An ideal approach would be to compare the same aneurysm before and after rupture [13–16].

#### **1.3 Molecular changes**

In response to internal elastic lamina disruption and the subsequent mechanical overload and shift in tensile forces, vascular smooth muscle cells and fibroblasts synthesize collagen types I and V, which are the main molecular constituents of intracranial aneurysms [17].

Once the molecular mechanisms fail to compensate for the mechanical overload of the vessel wall and myo-intimal injury, cellular and humoral inflammatory responses become the main drivers of aneurysm formation [17–20]. These responses are mediated by inflammatory cytokines such as tumor necrosis factor (TNF), IL-1β and matrix metalloproteinases (MMPs), promote influx of macrophages and continuous degradation of collagen and elastin fibers. Wall shear stress might also contribute to cellular inflammatory responses during aneurysm formation.

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*Endovascular Treatment of Brain Aneurysms DOI: http://dx.doi.org/10.5772/intechopen.88964*

**1.4 Can aneurysm rupture be predicted?**

landscape of research for cerebral aneurysms [2].

**2. Prevalence and incidence of aneurysms**

quality of equipment and expert's judgment [27].

Aneurysm rupture has been suggested to occur as aneurysm expansion approaches and exceeds the physical limits of the tissue. It has also been suggested that the vibrations induced by pulsatile flow and the subsequent resonant frequency may promote aneurysmal rupture [21, 22]. Although not directly resulting in aneurysmal rupture, vibrational irregularities secondary to the presence of the aneurysm may accelerate the degeneration of the aneurysmal wall and subsequently lead to rupture. A shift to quantitative and not just qualitative analysis, and a focus on flow and flow dynamics as a force of influence in rupture have changed the

Although Unruptured Intracranial Aneurysms (UIA) are common [23, 24]. Their prevalence is subject to changes due to the improvements in invasive and noninvasive imaging techniques, the increasing knowledge about the related factors that determines screening in asymptomatic populations and the increase in the life expectancy. Historically, the methods used to address prevalence were retrospective or prospective autopsy studies in the decades from 1950's to the earliest 2000's [25] but non-invasive imaging studies have demonstrated higher prevalence and prevalence ratios compared to autopsy studies (PR 3•5, 95% CI 2•1–6•1)3. To study UIA, the Magnetic Resonance Angiography (MRA) is the most common method for detection in asymptomatic patients [26] and compared to Intra-Arterial Digital Subtraction Angiography (IA-DSA), systematic reviews have found no significant differences in the prevalence reported between these two imaging techniques (more details will be elucidated in the next section of this chapter). However, it's important to highlight that prevalence reported in non-invasive imaging studies can present limitations due to the interobserver agreement, training, experience,

The IA characteristics are also a major concern in prevalence studies; technical limitations in regard to location, size and morphology can decrease the sensitivity and specificity of the diagnostic methods. Both, large and relatively small [28] cohort's studies had shown that saccular morphology is the most common form of presentation and that among patients without history of subarachnoid hemorrhage (SAH) the distribution of IA in the internal carotid artery (ICA) and middle cerebral artery (MCA) are 24.8 and 22.7% [29] respectively, however in patients with previous history of SAH, the prevalence is higher in the MCA. In regard to the size, modern imaging techniques can easily detect aneurysms from 2 mm, which is extremely important to determine the risks of possible treatments or natural history, so far, the current evidence is that UIA > 5 mm, location in basilar artery apex and decrease in BMI over the follow-up period are related to speed up the 2.9% of aneurysm growth per year. However, irrespective of aneurysm size, the irregular shape and daughter sac are more likely to rupture [30, 31]. Although we know these are contributing factors, there is still a need to understand better the contribution of aneurysm related factors. The prevalence of UIA among the general population is 3–5% [32] but there are several differences between populations that increase the risk for having a IA or a SAH. The risk factors commonly associated to IA development and rupture whether there's a previous history of SAH or not, are age > 30, female sex, African-American race, smoking, alcoholism, hypercholesterolemia, high blood pressure, first and second-degree relatives with SAH history, and other comorbidities as polycystic kidney disease, connective tissue disorders and brain tumors [33–36]. However,

*New Insight into Cerebrovascular Diseases - An Updated Comprehensive Review*

in the preservation of vessel wall integrity.

**1.2 Structural changes and hemodynamics**

was identified [4]. Subsequent genome-wide association studies [5, 6] have found additional loci on chromosome 7 near *HDAC9*, as well as in chromosomal regions 1p34.3–p36.13, 19q13.3, Xp22 and 7q11. The strongest evidence for linkage was with a locus on 7q11 near the perlecan gene that encodes elastin, a protein that is involved

Cerebral arteries are prone to aneurysm formation due to presence of cerebrospinal fluid, sparse tunica adventitia, lower proportion of elastic fibers and disruption of internal lamina at bifurcation [7–9]. Blood is an active participant in the formation of aneurysms, its flow provides the mechanical triggers for reactions in the vessels at the level of the endothelium, while it is also a biological participant in the inflammatory cascade [10, 11]. This dual function of blood contributes significantly to the degradation of the arterial wall in the formation of aneurysms [2].

Cohort studies on people with a familial preponderance to saccular aneurysm have shown that the geometry of bifurcations around the circle of Willis adds additional stress to the vessel walls, given the significant shifts in flow velocity, dynamic forces, and shear stress. Thus, high flow across a wall that is not "designed" for the exposed pressures results in tissue injury and remodeling. The biological result may be plaque or may be an aneurysm, depending on the presence (or absence) of an intact media [2]. Fluid-dynamic models calculate and visualize wall shear stress or wall shear gradients, intra-aneurysmal flow, impingement zones, and flow patterns or velocities. Wall shear stress constitutes the degree of friction in the intracranial aneurysm wall that results from blood inflow and impingement into the aneurysm. High and low wall shear stress can both be present during aneurysm formation but the relevance of these flow conditions to the pathogenesis, growth and rupture of an aneurysm remain unclear [12]. The role of shear stress is very controversial, responsible for damage at specific phases of aneurysmal development and rupture. Some studies suggest the direct effect of shear stress on the vessel wall resulting in injury and degeneration of the wall's media, leading to aneurysm formation. Others suggest that low shear stress in the aneurysm and the vessel wall may result in small thrombus formation, endo-

thelial reactivity, and inflammation at the site, thus weakening the vessel.

before and after rupture [13–16].

**1.3 Molecular changes**

intracranial aneurysms [17].

Data generated from fluid-dynamic models could help improve our understanding of aneurysm formation patterns and potential structural deficiencies in aneurysms. The relevance of existing data derived from computational fluid modeling is limited, however, because the majority of studies compared ruptured with unruptured aneurysms. An ideal approach would be to compare the same aneurysm

In response to internal elastic lamina disruption and the subsequent mechanical overload and shift in tensile forces, vascular smooth muscle cells and fibroblasts synthesize collagen types I and V, which are the main molecular constituents of

Once the molecular mechanisms fail to compensate for the mechanical overload

of the vessel wall and myo-intimal injury, cellular and humoral inflammatory responses become the main drivers of aneurysm formation [17–20]. These responses are mediated by inflammatory cytokines such as tumor necrosis factor (TNF), IL-1β and matrix metalloproteinases (MMPs), promote influx of macrophages and continuous degradation of collagen and elastin fibers. Wall shear stress might also contribute to cellular inflammatory responses during aneurysm formation.

**182**
