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• W2746674564 abstract "ARREST: Aneurysm Rupture Reduction and Expansion Stabilization Trial Fe MRI: ferumoxytol-enhanced magnetic resonance imaging IAs: intracranial aneurysms IL: interleukin ISUIA: International Study of Unruptured Intracranial Aneurysms MCP-1: monocyte chemoattractant protein 1 MMPs: matrix metalloproteinases mPGES-1: microsomal prostaglandin E2 synthase-1 NF-κB: nuclear factor-κB SAH: subarachnoid hemorrhage TNF-α: tumor necrosis factor alpha VCAM-1: vascular cell adhesion molecule 1 VSMCs: vascular smooth muscle cells The biology of intracranial aneurysms (IA) has been under intense investigation over the past two decades.1-7 Despite recent advances in neurosurgery, morbidity and mortality rates associated with IA treatment remain significant. In addition, IA rupture is often a lethal and highly disabling event.8 In an attempt to develop safe and effective medical therapies, neurosurgeons have studied the biological processes leading to IA formation, progression, and rupture.5,9-14 Available data point to inflammation as a major player in the remodeling process of IAs and their progression to rupture.5 Preliminary understanding of these mechanisms can potentially be of therapeutic benefit as it allows for the emergence of therapies targeting the damaging inflammatory process in IA walls.7,15-17 Our group and others have been investigating a potential role for aspirin, a familiar antiplatelet and anti-inflammatory agent, in the prevention of IA rupture.7,15-17 In this paper, we review the role of inflammation in the pathogenesis of IAs as it pertains to aspirin. The effect of aspirin in decreasing inflammation in IA walls and the associated risk of subarachnoid hemorrhage (SAH) is reviewed. We also discuss the recent finding of a gender differential response in the effect of aspirin on IAs. INFLAMMATORY PROCESS ASSOCIATED WITH THE FORMATION AND RUPTURE OF IAs There is normally a balance of hemodynamic stress and arterial wall integrity that allows for adequate pressure and blood flow through the vasculature. However, imbalances in that equilibrium, as can be caused by mechanical stress, lead to damage to the arterial wall, initially to the endothelium and the internal elastic lamina. Disruption and dysfunction of the endothelium due to high wall sheer stress appears to be the initial step in IA formation, and the magnitude of sheer stress closely predicts the degree of endothelium dysfunction and inflammatory response.5,18 The endothelium plays a key role in regulating the inflammatory process by expressing antiatherogenic and anti-inflammatory molecules. When there is damage to the endothelium, as in IA walls, it disrupts this anti-inflammatory regulation. Furthermore, the mechanical stress to the endothelium activates mediating pathways of inflammation, leading to chronic inflammation.5 One such inflammatory mediator that is activated in response to stress to the endothelium is nuclear factor-κB (NF-κB). In fact, its activation is considered the first step of aneurysm formation.19 NF-κB directly upregulates monocyte chemoattractant protein 1 (MCP-1) and vascular cell adhesion molecule 1 (VCAM-1) gene, which results in macrophage recruitment into the arterial wall. Mohan et al20 demonstrated that a longer period of stress to the endothelial cells corresponds with significantly increased and prolonged NF-κB activation. This underlying process contributes to the chronic inflammatory state of this disease via macrophage recruitment into the aneurysm wall. NF-κB also potentially regulates apoptosis in the vascular smooth muscle cells (VSMCs) of the arterial wall.19 The inflammatory process underlying aneurysm formation, progression, and rupture is complex and multifactorial; however, recent studies have been able to identify major components and pathways involved. Two main inflammatory cells that have been found to significantly drive the pathogenesis of IAs are macrophages and VSMCs.18 Understanding these main constituents and pathways that lead to the progression of IAs is pivotal and beneficial for developing therapies to change the disease course and prevent the mortality and morbidity associated with IAs. Macrophages are a pivotal component of the inflammatory process underlying IA formation, progression, and rupture. In addition to inflammatory mediators like NF-kB that are activated to recruit macrophages, macrophage migration into the vessel wall is facilitated by the loss of tight junction proteins due to endothelial damage, which leads to opening of the tight junctions through which macrophages can migrate.21 Once in the damaged vessel wall, macrophages recruit other inflammatory cells by releasing proinflammatory cytokines, most importantly tumor necrosis factor alpha (TNF-α), interleukin-1 (IL-1), and IL-6.5,18,22 Along these lines, Chalouhi et al18 found high plasma concentrations of various chemokines and chemoattractant cytokines (IL-8 and IL-17) in the lumen of human IAs indicating an active process of inflammatory cells recruitment into arterial walls. Macrophages also release matrix metalloproteinases (MMPs) which are normally involved in vascular remodeling within the arterial walls.19 The MMPs digest the surrounding arterial extracellular matrix, thereby further damaging the integrity of arterial wall.18 The loss of the internal elastic lamina coupled with extracellular matrix remodeling by MMPs leads to weakening of the vessel wall, causing progression of the aneurysm (Figure 1).23 In fact, studies have shown that increasing macrophage infiltration and MMP activity are associated with increasing aneurysm progression.19Figure 1: Elevated wall sheer stress to the endothelium causes disruption of the layer and release of inflammatory mediators that recruit macrophages into the damaged vessel walls. Macrophages, via secretion of inflammatory cytokines and enzymes, recruit more inflammatory cells, induce smooth muscle cell to undergo phenotypic modulation and apoptosis and breakdown of the surrounding extracellular matrix. These events lead to weakening of the arterial wall and aneurysm formation. As the processes continue long-term due to the persistent hemodynamic stress and inflammatory response, the aneurysm can progress and eventually lead to rupture as the wall integrity is overcome by stress. NF-κB indicates nuclear factor-κB; MCP-1, monocyte chemoattractant protein 1; VCAM-1, vascular cell adhesion molecule 1; IL-1β, interleukin-1β; TNF-α, tumor necrosis factor α; MMP, matrix metalloproteinase; SMC, smooth muscle cell; ECM, extracellular matrix; M1, proinflammatory M1 macrophage; M2, anti-inflammatory M2 macrophage.Significant macrophage infiltration can be found in the walls of ruptured IAs.24 When Hasan et al25 looked at tissue from ruptured and unruptured aneurysms after patients underwent microsurgical clipping, they found the ratio of proinflammatory M1 cells to anti-inflammatory M2 cells to be elevated in ruptured aneurysms, compared to unruptured where the concentrations were equal. This suggests that the imbalance of macrophage subtypes and specifically the increased proportion of proinflammatory M1 macrophage plays a key role in inducing aneurysm rupture. The study also found increased levels of mast cells in ruptured aneurysms, suggesting the role of another key inflammatory cell in aneurysm formation, growth, and rupture.25 The infiltration of these inflammatory cells—macrophages, T lymphocytes, and mast cells—leads to tissue fibrosis, which is considered the end-phase of chronic inflammatory processes.22,26 Another major component in the inflammatory process is the VSMCs of the media layer of the arterial wall. The media is key in maintaining the structure of the artery and therefore disruption and degeneration of this layer significantly contribute to aneurysm formation and progression.5,18 In response to the initial damage, these medial VSMCs migrate into the intima where they proliferate leading to myointimal hyperplasia. They also undergo phenotypic changes to become proinflammatory and promatrix remodeling, causing an increased expression of inflammatory markers and MMPs with subsequent arterial wall weakening. Several key cytokines are involved in the pathogenesis of IAs, including TNF-α and IL-1β.18 These cytokines are released by inflammatory cells like macrophages, as mentioned earlier. TNF-α has proinflammatory and proapoptotic roles. It induces VSMCs to undergo phenotypic modulation, inhibiting the contractile phenotype and also promotes inflammation and matrix remodeling by activating genes like MMPs, MCP-1, VCAM-1, and IL-1β.5,18,22,27 Starke et al28 emphasized the role of TNF-α in aneurysm progression and rupture.29 They found the expression of TNF-α to be increased in unruptured IAs in mice and even further increased in ruptured aneurysms. In TNF-α knockout mice and mice pretreated with a TNF-α inhibitor, there was decreased incidence of IA formation and rupture, with the inhibitor resulting in aneurysm stabilization and decreased chances of rupture if an aneurysm formed. IL-1β induces VSMC apoptosis, inhibits extracellular matrix synthesis in the VSMCs, and suppresses the biosynthesis of collagen at the transcriptional and post-transcriptional levels, all of which contribute to weakening of the vessel wall and progression of the IA to rupture.18,30,31 THE ROLE OF ASPIRIN IN DECREASING ANEURYSM RUPTURE IN HUMANS AND MICE Inflammation plays a major role in the formation, growth, and rupture of IAs; as such, several anti-inflammatory drugs have been tested for their potential to decrease IA formation and rupture.16,17 Aspirin has emerged as the most promising medical therapy to prevent IA rupture.15,16 Aspirin has an inhibitory effect on COX-2 and microsomal prostaglandin E2 synthase-1 (mPGES-1). In a recent study, our group has shown that the levels of these 2 inflammatory molecules are higher in the walls of ruptured as opposed to unruptured human IAs.32 Furthermore, aspirin (81 mg daily) given for 3 mo resulted in the attenuation of the expression of COX-2, mPGES-1, and inflammatory cells in IA walls.33 Hasan et al,3 in a nested case-control study from the International Study of Unruptured Intracranial Aneurysms (ISUIA—published in Lancet in 2003), were the first to demonstrate that aspirin (325 mg ≥ 3 times weekly) significantly decreases the risk of IA rupture with a significant relationship between frequency of intake and response. Along similar lines, Garcia Rodriguez et al34 using data from the health improvement network reported a lower risk of SAH with long-term aspirin intake. In addition, the same analysis showed that aspirin was not associated with an increased risk of intracerebral hemorrhage when compared to no aspirin treatment. The authors concluded that chronic low-dose aspirin conferred protection against SAH. The role of aspirin in preventing IA rupture has also been noted elsewhere. In a retrospective study from the US, there was a higher rate of presentation with SAH in patients not on aspirin.35 We believe that the main mechanism underlying the protective effect of aspirin is the anti-inflammatory pathway. However, some attribute this effect to the antiplatelet action of aspirin with attenuation of mural thrombi in IAs and the resultant inflammatory cascade. In 747 patients with IAs, however, clopidogrel—a more potent antiplatelet agent than aspirin—did not reduce the risk of IA rupture which argues against this hypothesis. Our group has investigated the potential use of targeted imaging with ferumoxytol-enhanced magnetic resonance imaging (Fe MRI) to assess the effects of aspirin on inflammation in the walls of IAs.18,36-38 Ferumoxytol is an intravenously administered ultrasmall superparamagnetic iron oxide agent and is approved by the Food and Drug Administration as an iron replacement therapy for patients with anemia secondary to chronic renal failure. Because ferumoxytol is cleared by macrophages 24 to 72 h after injection, it has also been utilized as an MRI contrast agent. To study whether the effects of aspirin can be seen on Fe MRI, we enrolled 5 patients with IAs who underwent baseline imaging with Fe MRI prior to aspirin intake.36 Repeat imaging after 3 mo showed that the signal intensity in the walls of IAs that corresponds to ferumoxytol uptake by macrophages had decreased in all 5 patients. This indicated that aspirin attenuates the inflammatory process and that Fe MRI may detect these changes. In a follow-up study, we randomized 11 patients with unruptured IAs into 2 groups (aspirin vs no aspirin). Imaging with Fe MRI was undertaken at baseline and after 3 mo just before microsurgical clipping.33 We found a significant decrease in the signal intensity in IA walls in patients on aspirin. Furthermore, immunostaining of aneurysm samples following microsurgical clipping showed a decrease in the expression of various inflammatory cells and markers in IA walls. To further study the effects of aspirin on IAs, our group recently reviewed the results of the ISUIA to determine whether aspirin prevented IA rupture similarly in men and women.7 We found that the proportion of SAH cases in males on aspirin ≥3 times per week (6%) was significantly lower than in males taking aspirin less frequently (47%). In contrast to men, the proportion of SAH cases in women on aspirin ≥3 times per week (16%) did not statistically differ from the proportion of SAH cases in women who used aspirin less frequently (29%). As such, frequent aspirin use decreased the risk of IA rupture in men more than women in the IUSIA. We further investigated this gender differential response in a mouse model of IAs.7 In mice, like in humans, we found that aspirin or a COX-2 inhibitor decreases the risk of IA rupture (not formation) and improves asymptomatic survival compared with control mice not receiving aspirin. There was also decreased expression of inflammatory molecules in cerebral arteries of mice treated with aspirin or COX-2 inhibitor including MMP-9 and MCP-1, which are known to be implicated in cerebral aneurysm pathology.5,18 The mechanism responsible for the protective effects of aspirin appears to be the COX-2 pathway as shown by the similarity between the effects of aspirin and a COX-2 inhibitor on aneurysm formation (no change), rupture (decreased), asymptomatic survival (increased). Furthermore, aspirin and COX-2 inhibitor were associated with the same inflammatory profile in IA walls at the molecular level. As such, this study by Chalouhi et al7 brought evidence from both human and animal studies that aspirin protects against IA rupture and that this effect varies by gender. In an attempt to understand this gender differential response, we examined differences in expression of inflammatory molecules in female and male mice on aspirin.7 We found that female mice receiving aspirin had lower levels of 15-PGDH in cerebral arteries and higher levels of proinflammatory mediators, namely COX-2, CD-68, MMP-9, MCP-1, and NF-kB compared with male mice. However, with the addition of 15-PGDH activator in female mice, the levels of proinflammatory mediators in cerebral arteries as well as the risk of IA rupture decreased significantly in female mice to equal those in male mice. Similar changes were seen with the addition of 15-PGDH inhibitor in male mice. These findings appeared to indicate that females may have lower levels of 15-PGDH, which may mediate at least partly the protective effects of aspirin against IA rupture. Restoring 15-PGDH activity in females eliminates this gender difference. The differential action of aspirin may also be related to a difference in aspirin metabolism with reduced pharmacological effect in females.39,40 Aspirin resistance is also more common in women than men.41 Escolar et al40 and Gum et al41 documented the sex-related difference in the effects of aspirin on platelets in the subendothelium and showed a resistance or reduced benefit in women more than men. In sum, Chalouhi et al7 demonstrated both in humans and mice that aspirin decreases the risk of IA rupture, and that this effect is more pronounced in men than in women. The activation of 15-PGDH in females may reduce the risk of IA rupture and attenuate the gender differential response to aspirin. CONCLUSION Inflammation is a key mechanism responsible for IA formation, progression, and rupture. Aspirin holds promise as a potentially safe, effective, affordable, and widely available treatment to halt IA rupture. Aspirin could be a beneficial therapy for a large number of patients who do not meet the criteria for invasive treatment such as those harboring small aneurysms (<5-7 mm). The use of aspirin is also advantageous for its several other health benefits, including the prevention of myocardial infarction, ischemic stroke, and colorectal cancer.34 The work presented in this paper has paved the way for the Aneurysm Rupture Reduction and Expansion Stabilization Trial (ARREST). The ARREST is a randomized placebo-controlled clinical trial in which we primarily investigate whether aspirin therapy in patients with small unruptured aneurysms (3-7 mm) decreases the incidence of IA growth and rupture. Several other studies and trials in various countries are also underway to determine whether aspirin is an effective therapy in the prevention of SAH. Disclosure The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article." @default.
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• W2746674564 title "Aspirin for the Prevention of Intracranial Aneurysm Rupture" @default.
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