Pathogenesis of abdominal aortic aneurysms: microRNAs, proteases, genetic associations.

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Pathogenesis of Abdominal Aortic Aneurysms: MicroRNAs, Proteases, Genetic Associations Lars Maegdefessel,1 Ronald L. Dalman,2 and Philip S. Tsao3,4 1 Department of Medicine, Karolinska Institute, Stockholm, Sweden; email: [email protected] 2 Division of Vascular Surgery, Stanford University School of Medicine, Stanford, California 94305; email: [email protected] 3 Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California 94305; email: [email protected] 4

VA Palo Alto Health Care System, Palo Alto, California 94304

Annu. Rev. Med. 2014. 65:49–62

Keywords

First published online as a Review in Advance on November 21, 2013

antagomiRs, metalloproteases, serine proteases, cysteine proteases, heritability, genome-wide association studies

The Annual Review of Medicine is online at med.annualreviews.org This article’s doi: 10.1146/annurev-med-101712-174206 c 2014 by Annual Reviews. Copyright All rights reserved

Abstract Abdominal aortic aneurysm (AAA) disease is a common, morbid, and highly lethal pathology. Extraordinary efforts have been launched to determine the molecular and pathophysiological characteristics of AAAs. Although surgery is highly effective in preventing death by rupture for larger AAAs, no guidance or preventive therapy is currently available for the >90% of patients whose aneurysms are below the surgical threshold. Predictive animal models of AAA as well as human pathological samples have revealed a complex circuit of AAA formation and progression. The proteolytic destruction of matrix components of the aorta by different proteases has been extensively studied over many years. Recently, a novel class of small noncoding RNAs, called microRNAs, was identified as “fine-tuners” of the translational output of target genes; they act by promoting mRNA degradation. Their therapeutic potential in limiting AAA development appears very intriguing. Further, current studies assessing genetic and heritable associations for AAA disease have provided great insight into its pathogenesis, potentially enabling us to better clinically manage affected patients.

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ABDOMINAL AORTIC ANEURYSM DISEASE


SMC: smooth muscle cell

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Abdominal aortic aneurysms (AAAs) are permanent dilations of the abdominal aorta that predispose to the fatal consequence of aortic rupture. The diagnosis of AAAs is commonly an accidental finding, although there is an increasing number of screening programs targeting high-risk populations (1). A number of screens demonstrate that the disease prevalence is approximately 5% in men and 1% in women over 60 years old (2, 3). The most feared clinical consequence of AAA progression is acute rupture, which carries a mortality of 80% (1). The number of deaths attributed to AAA rupture is nearly 15,000 annually in the United States (4). The dramatic burden caused by AAAs is partly due to the fact that aortic aneurysms prior to rupture rarely cause any symptoms. Symptoms may only begin to occur if the AAA rapidly increases its size, applying pressure on the surrounding organs, or after embolization of thrombi into the distal arterial system. The most common symptoms of AAAs include nonspecific, inconsistent abdominal pain/discomfort, which may also affect the thorax, the back, and the lower extremities. Other symptoms include a pulsating sensation in the abdomen, as well as lower leg ischemia due to thrombosis-related emboli. Currently, the only available treatment option remains surgical repair (5). The classic surgical approach is the insertion of an intraluminal graft via open access to the aneurysmal aorta. Recently, however, this highly morbid procedure has largely been replaced by endovascular stenting, which accounts for ∼70% of all interventions in Europe and North America. Besides being inappropriate to treat the early stages of the disease, both interventional procedures do carry a potential operative risk and thus appear only effective in preventing aortic rupture (1). No conservative pharmacological approach has been identified to effectively limit progression or the risk of rupture in humans with AAA. This lack is most likely due to the paucity of defined mechanisms of AAA initiation and expansion.

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The most important modifiable risk factor for AAA in those with screen-detected AAA appears to be cigarette smoking. Population studies have shown that smoking is associated with a five-fold increased risk for the presence of AAA (6). Thus, smoking cessation is considered the only presently available strategy to decrease the risk for expansion and rupture of small AAAs (7).

Pathologic Mechanism Behind AAA Development Aneurysm formation is a complex process involving all vascular cell subtypes. Important histological features include chronic adventitial and medial inflammatory cell infiltration, elastin fragmentation and degeneration, and medial attenuation (8), constituted by transmural vascular inflammatory processes, extracellular matrix degradation, and an imbalance of smooth muscle cell (SMC) homeostasis. The infrarenal part of the abdominal aorta is highly susceptible to AAA development. This can be at least partly attributed to differences in the embryonic origin of SMCs from the abdominal aorta, which originate from paraxial mesoderm-derived progenitors in somites, whereas SMCs of the ascending aorta arise from neural ectoderm-derived progenitors of the cardiac neural crest. Other contributing factors are related to variations in elastin and collagen content in different parts of the aorta (9) and the unique hemodynamic forces impacting particularly the infrarenal area (10). Lessons learned from animal as well as human pathology studies have indicated that aneurysm initiation involves a local inflammatory response with subsequent infiltration of monocyte/macrophages, polymorphonuclear leukocytes, and T and B lymphocytes. These processes are succeeded by enhanced production of reactive oxygen species, which is mediated through NADPH oxidases (11). The inflammatory response is further accelerated by various cytokines, leukotrienes, and immunoglobulins, enforced by upregulation of local adhesion molecules, which in combination


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contribute to SMC apoptosis, extracellular matrix (ECM) degeneration, and medial neovascularization (12–14). During AAA progression, increased activity of matrix metalloproteases (MMPs), as well as serine and cysteine proteases, augments degradation of ECM contents, such as different collagen isoforms (e.g., type I and III collagen) and elastin (8, 15). An initial compensatory increase in collagen synthesis (16) is therefore overturned by matrix filament cleavage (collagen turnover). Apart from impaired ECM remodeling, medial SMCs undergo changes toward a proliferative, secretory, and less differentiated phenotype. However, subsequently, SMC apoptosis becomes the main feature associated with AAA expansion and ultimately rupture (17, 18). Recent discoveries have attributed different genetic aspects to AAA disease. Genetic associations had already been described for thoracic aneurysm formation. The fact that inherited syndromes are causal for thoracic aortic aneurysm (TAA) formation hints that disrupted SMC and ECM homeostasis are important in aortic dilation (19). The role of TGF-β signaling dysregulation in this process is complex. Marfan syndrome and Loeys-Dietz syndrome, caused respectively by mutations in fibrillin-1 and TGF-β receptors I and II, predispose to ascending TAAs but are much less often associated with AAAs (20). The same is true of familial SMAD3 and ACTA2 mutations (21–23). A more detailed discussion of genetic associations in AAAs can be found below.

MICRORNAS MicroRNAs (miRNAs, miRs) are a class of well-conserved, short, noncoding RNAs that have emerged as key post-transcriptional regulators of gene expression in animals and plants. miRNAs play major roles in most, if not all, biological processes by influencing stability and translation of mRNAs (24). For cardiovascular disease in particular, several miRNAs have been identified in recent years as crucial regulators during myocardial infarction,

heart failure, peripheral artery disease, stroke, and AAA disease (25). miRNA genes are transcribed by RNA polymerase II as capped and polyadenylated primary miRNA transcripts (pri-miRNA) (26). Pri-miRNA is then processed in two independent steps by the enzymes Drosha and Dicer, in cooperation with a dsRNA binding protein, “DiGeorge syndrome critical region gene 8” (DGCR8) (27), into a ∼70-nucleotide precursor hairpin (pre-miRNA), which is then exported to the cytoplasm. In the cytoplasm, Dicer matures pre-miRNA into an imperfect RNA duplex. The strand with the weakest base pairing at the 5 terminus is loaded into the miRNA-induced silencing complex (miRISC) and is therefore considered biologically active (28). Initially, the non-miRISC strand was assumed to be an inactive passenger designated the ∗ (star)-strand. However, systemic computational analysis has demonstrated that starstrands may contain well-conserved targetrecognition sites, indicating their functional relevance (29). After the selected strand is loaded into the miRISC, the miRNA guides the miRISC to bind to the 3 untranslated region of its target sequence. The seed sequence (the first two to eight nucleotides) is considered the most important for target recognition and silencing of the mRNA (30, 31). Translation of the mRNA is inhibited after association of the miRISC with its target sequence. Efficient mRNA targeting requires continuous base pairing of the seed region to the target mRNA. The exact mechanisms of translational arrest by the miRNA:mRNA complex are still a matter of debate, although both initiation and elongation steps of translation are thought to be affected (25, 32).

ECM: extracellular matrix MMP: matrix metalloprotease TAA: thoracic aortic aneurysm

Therapeutic Approaches Using MicroRNA Modulators Based on the observation that modulation of miRNA expression in vivo can effectively modulate various disease pathologies in numerous preclinical models, miRNAs are a promising www.annualreviews.org • Abdominal Aortic Aneurysms

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therapeutic target (33). Inhibition or overexpression of a single miRNA can induce or attenuate pathological responses in the cardiovascular system as a result of the regulated coordination of numerous target genes involved in complex physiological and disease phenotypes. The most important difference between modulating miRNAs and the traditional therapeutic approach is that standard drugs typically interact with specific cellular targets, whereas miRNAs have the capability of modulating entire functional networks (34). miRNA modulation is performed by supplying antagomiRs (inhibitors of miRNA expression; synthetic reverse complements of oligonucleotides) that bind to a target miRNA and silence it, or by using premiRNAs/miRNA-mimics that act similar to mature and endogenous miRNAs (33). Recent animal and even human efficacy data indicate that antagomiRs have the potential to become a whole new class of drugs. These inhibitors of miRNA expression have several significant advantages that make them very attractive from a drug-development standpoint, including small size as well as frequent conservation of their target miRNAs across species. Using lessons learned from antisense technologies (e.g., siRNA), potent oligonucleotide chemistries to inhibit miRNAs are currently being investigated (35). These efforts have given rise to candidates that bind to their putative miRNA targets with remarkable affinity and specificity and have desirable drug-like qualities, including increased stability and favorable pharmacokinetics. No immunogenic or toxicological safety issues have been associated with the use of antagomiRs in humans to date. In contrast, the prospect of delivery of injectable, naked miRNA-mimics and/or premiRNAs has remained problematic. For now, lenti- as well as adeno-associated viruses represent an efficacious delivery platform for miRNAs, but these carry the risks common to most gene therapies. Lentiviral vectors, for example, are derived from HIV-1, and thus the production of wild-type HIV-1 through homologous recombination of the virus remains a


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major safety concern. However, recent lentiviral vector developments could possibly resolve this issue, making them a promising vector for future applications (36). The development of miRNA mimics, which do not require a viral vector, represents an important therapeutic goal. Some studies from the cancer field have achieved it in murine models by packaging synthetic miRNA duplexes within lipid nanoparticles (37, 38). For now, the ability to modulate miRNA activity through systemic delivery of miRNA inhibitors or mimics without toxicity provides unprecedented opportunities for intervening in disease processes. Despite remaining challenges, such as potential off-target effects and the urgent need for local or cell type–specific delivery mechanisms, the pace of discovery in this field portends new, clinically feasible therapeutic approaches. In recent years, several miRNAs have been found to regulate vascular pathologies in general and aortic aneurysm (thoracic and abdominal) disease in particular (Figure 1). The two miRNAs discussed in the following sections, miR-21 and miR-29b, have been described in the context of AAA disease (miR-29b also in TAA). Modulation of these two miRNAs with antagomiRs and pre-miRNAs successfully altered the disease phenotype in two independent murine models of AAA development. Furthermore, their contribution to the human pathology has been indicated in tissue samples from human patients undergoing surgical repair of their enlarged abdominal aorta (Figure 1).

MiR-21 and Vascular Smooth Muscle Cell Homeostasis miR-21 was initially considered as an oncomiRNA. Its expression is increased in many solid tumors and promotes cell survival, cell proliferation, and migration (39). Subsequent studies indicated that miR-21 is highly expressed in vascular SMCs, implicating its regulation of SMC phenotype in vascular disorders, such as postinjury neointimal lesion formation (40, 41). In this regard, it has been

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Elastic fibers Adventitia


miR-21

miR-29b

Internal elastic lamina Endothelium Smooth muscle layer Smooth muscle cell Adventitial fibroblast

Figure 1 Proposed beneficial effect of microRNA modulation in abdominal aortic aneurysm disease. Induction of miR-21 increases smooth muscle cell proliferation, whereas downregulation of miR-29b augments a profibrotic response in adventitial fibroblasts.

shown that miR-21 can induce upregulation of SMC-restricted contractile proteins through silencing of the expression of “programmed cell death protein” (PDCD)-4, which is also a known tumor suppressor protein. These data indicate that miR-21 is regulating both SMC contractile function (42) and proliferation (43). On the same matter, miR-21 has been identified to regulate growth and survival of SMCs by decreasing expression of “phosphatase and tensin homolog” (PTEN) and inducing expression of Bcl-2, which also exhibits proproliferative and antiapoptotic effects in a carotid injury model in rats (43). Regarding homeostasis, miR-21 promotes SMC differentiation in response to TGF-β1 and BMP-4 (42). Both factors were shown to stimulate the processing of miR-21 in human

pulmonary artery SMCs from the primary transcript to the mature miRNA via SMAD proteins. Additionally, miR-21 has been shown to regulate hypoxia-induced pulmonary SMC proliferation and migration by regulating PDCD4, Sprouty 2 (SPRY2), and peroxisome proliferator-activated receptor-α (PPARα), all of which have been previously identified to exert antiproliferative and antimigratory effects on SMCs (44). Another important factor in maintaining arterial wall homeostasis and structure is moderate stretch (45). However, exacerbated stretch (e.g., in arterial hypertension) potentially promotes pathological vascular remodeling through stimulation of SMC proliferation, apoptosis, and migration, as well as abnormal ECM deposition (46, 47). Interestingly, cyclic www.annualreviews.org • Abdominal Aortic Aneurysms

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stretch has been shown to modulate miR-21 expression at the transcription level via “FBJ murine osteosarcoma viral oncogene homolog” (c-fos/AP-1) in cultured human aortic SMCs (48). We detected significant upregulation of miR-21 in two established murine models of AAA disease, the porcine pancreatic elastase (PPE)-infusion model in C57B/L6 mice and the angiotensin II (AngII)-infusion model in ApoE−/− mice (49). Among the aforementioned SMC-specific miR-21 target genes influencing proliferation and apoptosis, PTEN was the only target gene to be substantially downregulated at three different time points (days 7, 14, and 28) during aneurysm initiation and propagation. PTEN is a lipid and protein phosphatase and (as mentioned above) an important tumor suppressor, and it acts as a key negative regulator of the PI3K pathway. Systemic injection of an antagomiR against miR-21 diminished the proproliferative impact of downregulated PTEN, leading to a significant increase in progression of AAAs. Further downregulation of PTEN with a lentiviral overexpression vector carrying pre-miR-21 (pre-miRNA) significantly limited aneurysm expansion by inducing SMC proliferation in the aortic wall in both murine models (49). As mentioned above, smoking is the major modifiable risk factor for AAA disease. In our study, nicotine (a major constituent of tobacco smoke) accelerated AAA growth in both murine aneurysm models and further increased miR21 levels, which may have been a protective response to limit further aneurysm expansion and ultimately rupture. In vitro studies utilizing human aortic SMCs and endothelial cells, as well as adventitial fibroblasts, showed aortic SMCs to be the most responsive to miR-21 modulation. Our group also showed that miR-21 induction in SMCs pretreated with nicotine, as well as those pretreated with AngII and interleukin-6 (IL-6), is dependent on NF-κB signaling (49). In support of these findings, the results from our animal studies regarding increased expression of miR-21 and downregulated PTEN were reproducible


PPE: porcine pancreatic elastase

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in samples obtained from human AAA patients undergoing surgical repair of their enlarged infrarenal aorta, but these changes were not seen in control abdominal aorta from organ donors. Notably, miR-21 was even further upregulated (and PTEN further decreased) in smokers with AAA disease compared to nonsmokers (49).

MiR-29b and Extracellular Matrix Remodeling The miR-29 family of miRNAs contains three members (miR-29a, miR-29b, and miR-29c) that are encoded by two separate loci, giving rise to two bi-cistronic precursor miRNAs (miR29a/b1 and miR-29b2/c). This family targets numerous gene transcripts that encode ECM proteins involved in fibrotic responses, including several collagen isoforms (e.g., type I and III collagen), fibrillin-1, and elastin (50). On the basis of these observations, miR29 seems to be a crucial regulator of aortic aneurysm disease. Through modulating expression of several genes that impact cellular pathways, miR-29 can alter ECM composition and dynamics. We found that miR-29b was the only member of the miR-29 family to be significantly downregulated at three different time points during murine AAA development and progression (50). Further decreasing miR-29b expression with an antagomiR targeting miR29b led to increased expression of the genes encoding type I, III, and V collagen (Col1a1, Col2a1, Col3a1, Col5a1), as well as the gene for elastin (Eln). In addition, MMP2 and MMP9 were downregulated in antimiR-29b-injected mice. These results were again reproducible in both murine AAA models (PPE and AngII infusion) and led to a significant decrease in aneurysm expansion compared to a scrambledcontrol-miRNA-injected group. Human AAA tissue samples displayed a similar pattern of reduced miR-29b expression with increased collagen gene expression in comparison to nonaneurysmal organ donor controls. These results suggest that the weakening of the aortic wall, caused by the progressive increase in the aortic diameter, induces the expression


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of collagens associated with repressed miR-29b levels, providing additional tensile support to the aortic wall in an attempt to limit expansion and rupture. Boon et al. (51) were able to connect miRNA regulation to aortic dilatation and aging. They determined that the miR-29 family expression was increased in the aging mouse aorta. Epidemiologically, aging is considered the most important risk factor for aneurysm development (51). Rather than utilizing the typical ApoE−/− or low-density lipoprotein (LDL) receptor−/− mice, Boon and colleagues utilized AngII infusion in 18-month-old C57BL/6 (wildtype) mice. In these aged mice, AngII infusion increased miR-29b expression in the entire aorta, which was expected to diminish the protective role of miR-29b during AAA development. In accordance with our aforementioned results, Boon et al. found that systemic treatment with an antimiR-29b significantly increased the expression of genes for type I and III collagen (Col1a1, Col3a1) as well as elastin (Eln), and decreased suprarenal aortic dilation in aged AngII-induced AAAs. In addition to miR-21 and miR-29b, other miRNAs have been described as differentially expressed in human as well as animal models of AAA disease (e.g., miR-26a, miR-145). However, no functional miRNA modulation studies have been performed to prove their contribution to aortic dilation.

PROTEASES AND THEIR ROLE IN AAA DEVELOPMENT As mentioned above, increased activity by proteases, mostly MMPs but also serine and cysteine proteases, causes an augmented degradation of ECM contents such as different collagen isoforms (e.g., type I and III collagen) and elastin (8, 15). Thus, proteases are crucial components of AAA progression.

Matrix Metalloproteases MMPs have been extensively studied in human and animal models of AAAs, with MMP9 being the best-established MMP in human

pathology. A recent meta-analysis included eight case-control studies that compared serum or plasma MMP-9 concentration between patients with AAAs and subjects without AAAs (52). Although pooled analyses demonstrated significantly higher circulating MMP-9 concentration in AAA patients than in subjects without AAAs, heterogeneity of circulating MMP-9 concentration was also evident, with value ranges of 30–750 ng/L in patients with AAAs and 9–680 ng/L in subjects without AAAs (52). The role of MMP-9 in AAA formation has also been studied using MMP-9-deficient mice. MMP-9 deficiency attenuated elastase-induced AAAs (53). MMP-9 deficiency also reduced calcium chloride–induced AAAs in mice (54). Infusion of macrophages not deficient in MMP9 from wildtype mice reversed the protection effects of MMP-9 deficiency on AAA formation, indicating macrophage-derived MMP-9 is required in the development of AAAs (54). The validation of MMP-9 as a critical component of human AAAs is compromised by lack of a specific pharmacological MMP-9 inhibitor. Several studies showed that doxycycline, a broad inhibitor of multiple MMPs, ameliorated elastase-induced AAAs in rats (55, 56) and mice (53), as well as AngII-induced AAAs in mice (15, 57). Additionally, several other MMPs (MMP-2, MMP-8, MMP-12) were studied in genetic deficient mice, but the effects on AAA development were not as prominent as those of MMP-9 (58).

Cysteine and Serine Proteases Cysteine and serine proteases are also present in AAAs. Dipeptidyl peptidase is a lysosomal cysteine protease critical for activation of neutrophil elastase and some other proteases. Deficiency of dipeptidyl peptidase attenuates elastase-induced AAAs in mice, but AAA progression is restored when neutrophils from wildtype mice are transferred to these mutant mice (59). Cathepsin K, L, and S are also detected in human AAAs (8, 60); however, their role in murine AAA expansion seems to be model specific, since cathepsin L and K www.annualreviews.org • Abdominal Aortic Aneurysms

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deficiency (61) markedly reduce PPE-induced AAAs, whereas cathepsin K deficiency does not affect AngII-induced AAAs. Cystatin C, a cysteine protease inhibitor, is diminished in human AAAs, and aortic diameters of human AAAs are inversely correlated with serum cystatin C levels (60). Deficiency of cystatin C has also been shown to augment murine AngII-induced AAAs. Furthermore, the inhibition of calpain, which is a calcium-dependent cysteine protease, has been identified to limit AngII-induced AAA formation (62). Among serine proteases, chymase and urokinase-type plasminogen activator (uPA) were studied in AAAs. Deficiency of mast cell chymase prevents elastase-induced AAAs in mice (61), and pharmacological inhibition of chymase reduces AngII-induced AAAs in ApoE−/− mice. Plasminogen degrades multiple ECM proteins through conversion of plasmin. Deficiency of plasminogen attenuates calcium chloride–induced AAAs in mice and this attenuation of aneurysm formation is reversed by administration of active MMP-9 (63). Plasminogen activator inhibitor-1 (PAI-1) is a natural inhibitor of uPA. Inhibition of PAI-1 via administration of recombinant adenovirus containing the human PAI-1 gene prevents AngII-induced AAAs in ApoE−/− mice only through a local delivery (intra-adventitial injection), but not through systemic delivery (tail-vein injection) (64). Studies addressing the role of uPA on AAAs have yielded conflicting results. It was previously reported that uPA deficiency attenuated AngII-induced AAAs in both ApoE−/− mice and C57BL/6 mice (65), but our recent study was unable to demonstrate a protective effect of uPA on AngII-induced AAAs in both LDL receptor−/− mice and C57BL/6 mice. In contrast, aortic rupture rates were increased in LDL receptor−/− mice with uPA deficiency (66). The basis for these conflicting results is unclear. Overall, many proteases have demonstrated roles in experimental AAAs. An intriguing aspect of this body of work is that although multiple proteases have been implicated, deficiency of a single protease frequently ablates AAA de-


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velopment. As noted above for leukocytes, this may imply a complex cooperation between proteases in some modes that have yet to be determined. Two large randomized clinical trials are currently examining the efficacy of doxycycline in patients with small AAAs. Further trials utilizing other protease inhibitors are also expected to start in the near future (1).

GENETIC ASSOCIATIONS IN AAA DISEASE An increasing body of strong evidence demonstrates that genetic factors are important in the development of AAA. The heterogeneity of the patient population, as well as the assortment of environmental risk factors and genetic predisposition exposed at an advanced age, is a major challenge in defining the potential genetic attribution. Some genetic findings, however, are quite intriguing and are discussed in the following sections.

Heritable Risk for AAA Disease Characterization of the genetic component of AAA is complicated by factors including the late age of onset of the disease, incorrect attribution of sudden death to cardiac events instead of AAA rupture, and the low rate of post mortems in most countries (67). It is well established that a patient’s risk for AAA approximately doubles with a positive family history of AAA. One strategy to define the genetic component for a disease is to study twins with the disease (68). A recently published study examined the inpatient treatment of 265 twins with AAA disease (69). Interestingly, the investigators found that concordances and correlations for AAA were higher in monozygotic twins than in dizygotic twins, indicating a strong genetic contribution to the disease. A number of studies have highlighted the relatively high incidence of AAA in siblings of AAA patients, reporting rates of up to 29% in brothers (67). One of these studies, using genome-wide DNA linkage analyses in samples from families in which at least two members suffered from an AAA, could identify


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two genomic regions on chromosomes, 4q31 and 19q13, linked to the disease (70). Whether the identified genetic loci are capable of detecting genetic risk alleles for aneurysms requires further investigation. The chromosome 19q13 locus contains a large number of interesting genes in relation to AAA, one of which is a serine protease called kallikrein 1 (KLK1) (71, 72). Kallikreins are a subgroup of serine proteases having diverse physiological functions. Growing evidence suggests that many kallikreins are implicated in carcinogenesis and some have potential as novel biomarkers of cancer and other disease states. KLK1 is functionally conserved in its capacity to release the vasoactive peptide Lys-bradykinin from low-molecularweight kininogen. Kinins act through two different receptors, B1 and B2. A recent report shows that B1 deficiency increases risk for AAA expansion in experimental mouse models (73). In another study that involved 1,629 patients with AAA, a single-nucleotide polymorphism (SNP), rs5516 in KLK1, was determined to be enriched in the AAA patients compared with controls (74). This SNP is known to alter the expression of splicing variants of KLK1, and indeed the expression of the short splice variant of KLK1 was upregulated in tissue samples taken from large AAAs compared to samples from small AAAs. Other possible candidate genes within the chromosome 19q13 locus were elucidated in 394 cases and 419 controls (75). Potential associations between SNPs and the risk for AAA were found for the enhancer binding protein (CEBPG), peptidase D (PEPD), and CD22. Other studies have examined genetic risk alleles for AAA by investigating SNPs in candidate genes within groups of cases without family history of AAA and controls. This approach is made feasible by the fact that most patients with AAA are not aware of any family history of the condition. A large number of genetic variations associated with AAA have been reported by these studies (67, 68), but most of these findings could not be replicated in other patient cohorts and study populations.

Genome-Wide Association Studies and AAA Development For common complex diseases, such as AAA, genome-wide association studies (GWAS) have been suggested as the most robust and efficient method to identify risk alleles. For adequately powered GWAS, a large number of cases and controls are needed to adjust for multiple testing and identify risk alleles. Thus, multiple collaborations between several research groups with well-characterized patient cohorts are necessary for these studies. Such collaborations entail obstacles and challenges, mostly related to the reproducibility of different methods and techniques to define risk factors and patient criteria. Despite these hurdles, GWAS have led to some interesting discoveries of risk alleles. The most consistent finding is the association of AAA with SNPs at the 9p21.3 locus (76). Initially, this genetic locus was described in GWAS for coronary heart disease but has continuously been associated with other cardiovascular diseases (77). Interestingly, the identified SNPs are in a region of the genome that does not contain genes. The best candidate gene in the chromosome 9 region associated with AAA is the noncoding RNA gene CDKN2BAS, also known as ANRIL. The genetic alteration responsible for the association of SNPs at 9p21 to AAA and other vascular disease has not been firmly established, but several animal and in vitro studies have implicated CDKN2BAS, as well as the two closest protein-encoding genes, CDKN2A and CDKN2B (78). Probably the most conclusive study on this important topic was performed by Leeper and colleagues (79). They showed that Cdkn2b−/− mice subjected to PPE infusion develop larger aortic aneurysms than wildtype mice. The difference could be explained by the fact that Cdkn2b−/− mice had fewer SMCs and increased apoptosis in the aortic wall. Immunohistochemical analysis of human aortic tissue samples revealed that CDKN2B expression was mainly detectable in SMCs, and there was a substantial reduction in protein levels in AAA aortic tissues compared to controls. www.annualreviews.org • Abdominal Aortic Aneurysms

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The first published GWAS (80) utilized a DNA pooling strategy to detect a genetic locus upstream of the gene encoding contactin3 (CNTN3), which is a lipid-anchored celladhesion molecule highly expressed in human aorta. Interestingly, the strongest association for AAA and CNTN3 was observed in smokers, who are (as mentioned) at high risk for AAA development. A second GWAS project (81) identified three already-known SNPs located in the chromosome 9p21 susceptibility region. It also identified the DAB2 interacting protein (DAB2IP) as being highly associated with AAA. DAB2IP negatively regulates cell survival and proliferation in the vessel wall and therefore could contribute to AAA expansion. The main finding of the most recent GWAS analyses is that the SNP rs1466535 located intronically on the LDL receptor–related protein 1 (LRP1) gene on chromosome 12q13.3 could potentially be associated with AAA disease (82). The possible importance of LRP1 in aneurysm formation is suggested by a murine experiment in which inactivation of Lrp1 in SMCs led to aneurysm formation in a hyperlipidemic mouse model (83).


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SUMMARY AND PERSPECTIVES Abdominal aortic aneurysms (AAAs) have emerged as a major health burden in our aging society. Contributions from multiple

research groups have uncovered a complex transcriptional and post-transcriptional regulatory milieu, which is believed to be essential for maintaining aortic vascular homeostasis. These discoveries have spurred extraordinary efforts to develop novel diagnostic and therapeutic strategies to identify AAAs early and limit their expansion. Targeting the disruptive effects of disease-related proteases has become a popular strategy to limit aneurysm initiation and propagation. However, no treatment option has been identified yet that can attenuate the disease in humans. The demonstration that miRNAs can easily be modulated by antagomiRs and premiRNAs/miRNA-mimics has tremendously accelerated miRNA research while nourishing hopes that miRNA therapeutics could be employed in humans with AAA disease in the future. For vascular diseases such as AAA in particular, local (coated stents and/or balloons) or cell type–specific delivery mechanisms seem necessary to avoid off-target effects on other organ systems. Such mechanisms would significantly increase the value of miRNA strategies in clinical practice. It is hoped that large studies examining the chromosome 4q31 and 19q13 loci will confirm recent findings and identify more precisely the genetic loci involved. The power of using GWAS to identify novel and functionally relevant mechanisms important for AAA pathogenesis will potentially help us to identify additional genetic risk factors for AAA.

DISCLOSURE STATEMENT The authors are not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this review.

ACKNOWLEDGMENTS We thank all past and current members of our laboratories at Stanford and Stockholm for their determination to generate the data for parts of the research presented in this review. Our own research projects are supported by grants from the National Institutes of Health (1P50HL083800-06 to P.S.T. and R.L.D.), the American Heart Association (0840172N to P.S.T.), the Karolinska Institute Cardiovascular Program Career Development Grant and the Swedish Heart-Lung-Foundation (20120615 both to L.M.). 58

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53. Pyo R, Lee JK, Shipley JM, et al. 2000. Targeted gene disruption of matrix metalloproteinase-9 (gelatinase B) suppresses development of experimental abdominal aortic aneurysms. J. Clin. Invest. 105:1641–49 54. Longo GM, Xiong W, Greiner TC, et al. 2002. Matrix metalloproteinases 2 and 9 work in concert to produce aortic aneurysms. J. Clin. Invest. 110:625–32 55. Curci JA, Petrinec D, Liao S, et al. 1998. Pharmacologic suppression of experimental abdominal aortic aneurysms: a comparison of doxycycline and four chemically modified tetracyclines. J. Vasc. Surg. 28:1082– 93 56. Petrinec D, Liao S, Holmes DR, et al. 1996. Doxycycline inhibition of aneurysmal degeneration in an elastase-induced rat model of abdominal aortic aneurysm: preservation of aortic elastin associated with suppressed production of 92 kD gelatinase. J. Vasc. Surg. 23:336–46 57. Turner GH, Olzinski AR, Bernard RE, et al. 2008. In vivo serial assessment of aortic aneurysm formation in apolipoprotein E-deficient mice via MRI. Circ. Cardiovasc. Imaging 1:220–26 58. Lu H, Rateri DL, Bruemmer D, et al. 2012. Novel mechanisms of abdominal aortic aneurysms. Curr. Atheroscler. Rep. 14:402–12 59. Pagano MB, Bartoli MA, Ennis TL, et al. 2007. Critical role of dipeptidyl peptidase I in neutrophil recruitment during the development of experimental abdominal aortic aneurysms. Proc. Natl. Acad. Sci. USA 104:2855–60 60. Shi GP, Sukhova GK, Grubb A, et al. 1999. Cystatin C deficiency in human atherosclerosis and aortic aneurysms. J. Clin. Invest. 104:1191–97 61. Sun J, Zhang J, Lindholt JS, et al. 2009. Critical role of mast cell chymase in mouse abdominal aortic aneurysm formation. Circulation 120:973–82 62. Subramanian V, Uchida HA, Ijaz T, et al. 2012. Calpain inhibition attenuates angiotensin II-induced abdominal aortic aneurysms and atherosclerosis in low-density lipoprotein receptor–deficient mice. J. Cardiovasc. Pharmacol. 59:66–76 63. Gong Y, Hart E, Shchurin A, et al. 2008. Inflammatory macrophage migration requires MMP-9 activation by plasminogen in mice. J. Clin. Invest. 118:3012–24 64. Qian HS, Gu JM, Liu P, et al. 2008. Overexpression of PAI-1 prevents the development of abdominal aortic aneurysm in mice. Gene Ther. 15:224–32 65. Deng GG, Martin-McNulty B, Sukovich DA, et al. 2003. Urokinase-type plasminogen activator plays a critical role in angiotensin II–induced abdominal aortic aneurysm. Circ. Res. 92:510–17 66. Uchida HA, Poduri A, Subramanian V, et al. 2011. Urokinase-type plasminogen activator deficiency in bone marrow–derived cells augments rupture of angiotensin II–induced abdominal aortic aneurysms. Arterioscler. Thromb. Vasc. Biol. 31:2845–52 67. Hinterseher I, Tromp G, Kuivaniemi H. 2011. Genes and abdominal aortic aneurysm. Ann. Vasc. Surg. 25:388–412 68. Golledge J, Kuivaniemi H. 2013. Genetics of abdominal aortic aneurysm. Curr. Opin. Cardiol. 28:290–96 69. Wahlgren CM, Larsson E, Magnusson PK, et al. 2010. Genetic and environmental contributions to abdominal aortic aneurysm development in a twin population. J. Vasc. Surg. 51:3–7; discussion 7 70. Linne A, Lindstrom D, Hultgren R. 2012. High prevalence of abdominal aortic aneurysms in brothers and sisters of patients despite a low prevalence in the population. J. Vasc. Surg. 56:305–10 71. Shibamura H, Olson JM, van Vlijmen-Van Keulen C, et al. 2004. Genome scan for familial abdominal aortic aneurysm using sex and family history as covariates suggests genetic heterogeneity and identifies linkage to chromosome 19q13. Circulation 109:2103–8 72. van Vlijmen–Van Keulen CJ, Rauwerda JA, Pals G. 2005. Genome-wide linkage in three Dutch families maps a locus for abdominal aortic aneurysms to chromosome 19q13.3. Eur. J. Vasc. Endovasc. Surg. 30:29– 35 73. Merino VF, Todiras M, Mori MA, et al. 2009. Predisposition to atherosclerosis and aortic aneurysms in mice deficient in kinin B1 receptor and apolipoprotein E. J. Mol. Med. (Berlin) 87:953–63 74. Biros E, Norman PE, Walker PJ, et al. 2011. A single nucleotide polymorphism in exon 3 of the kallikrein 1 gene is associated with large but not small abdominal aortic aneurysm. Atherosclerosis 217:452–57 75. Lillvis JH, Kyo Y, Tromp G, et al. 2011. Analysis of positional candidate genes in the AAA1 susceptibility locus for abdominal aortic aneurysms on chromosome 19. BMC Med. Genet. 12:14 www.annualreviews.org • Abdominal Aortic Aneurysms

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76. Helgadottir A, Thorleifsson G, Magnusson KP, et al. 2008. The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm. Nat. Genet. 40:217–24 77. Visel A, Zhu Y, May D, et al. 2010. Targeted deletion of the 9p21 non-coding coronary artery disease risk interval in mice. Nature 464:409–12 78. Biros E, Cooper M, Palmer LJ, et al. 2010. Association of an allele on chromosome 9 and abdominal aortic aneurysm. Atherosclerosis 212:539–42 79. Leeper NJ, Raiesdana A, Kojima Y, et al. 2013. Loss of CDKN2B promotes p53-dependent smooth muscle cell apoptosis and aneurysm formation. Arterioscler. Thromb. Vasc. Biol. 33:e1–10 80. Elmore JR, Obmann MA, Kuivaniemi H, et al. 2009. Identification of a genetic variant associated with abdominal aortic aneurysms on chromosome 3p12.3 by genome wide association. J. Vasc. Surg. 49:1525–31 81. Gretarsdottir S, Baas AF, Thorleifsson G, et al. 2010. Genome-wide association study identifies a sequence variant within the DAB2IP gene conferring susceptibility to abdominal aortic aneurysm. Nat. Genet. 42:692–97 82. Bown MJ, Jones GT, Harrison SC, et al. 2011. Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor–related protein 1. Am. J. Hum. Genet. 89:619–27 83. Boucher P, Gotthardt M, Li WP, et al. 2003. LRP: role in vascular wall integrity and protection from atherosclerosis. Science 300:329–32


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Contents

Annual Review of Medicine Volume 65, 2014


Adult Genetic Risk Screening C. Thomas Caskey, Manuel L. Gonzalez-Garay, Stacey Pereira, and Amy L. McGuire p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1 Identification of Genes for Childhood Heritable Diseases Kym M. Boycott, David A. Dyment, Sarah L. Sawyer, Megan R. Vanstone, and Chandree L. Beaulieu p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p19 Genomic Sequencing for Cancer Diagnosis and Therapy Linghua Wang and David A. Wheeler p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p33 Pathogenesis of Abdominal Aortic Aneurysms: MicroRNAs, Proteases, Genetic Associations Lars Maegdefessel, Ronald L. Dalman, and Philip S. Tsao p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p49 DNA Sequencing of Cancer: What Have We Learned? Juliann Chmielecki and Matthew Meyerson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p63 Applied Pharmacogenomics in Cardiovascular Medicine Peter Weeke and Dan M. Roden p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p81 Molecular Testing in Breast Cancer Costanza Paoletti and Daniel F. Hayes p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p95 Chemoprevention of Prostate Cancer Goutham Vemana, Robert J. Hamilton, Gerald L. Andriole, and Stephen J. Freedland p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 111 Thyroid Cancer Tobias Carling and Robert Udelsman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 125 Targeting Apoptosis Pathways for New Cancer Therapeutics Longchuan Bai and Shaomeng Wang p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 139 Targeting Metabolic Changes in Cancer: Novel Therapeutic Approaches Ekaterina Bobrovnikova-Marjon and Jonathan B. Hurov p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 157 Retinoblastoma: Saving Life with Vision David H. Abramson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 171 v

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Immune Modulation in Cancer with Antibodies David B. Page, Michael A. Postow, Margaret K. Callahan, James P. Allison, and Jedd D. Wolchok p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 185 Depression as a Risk Factor for Cancer: From Pathophysiological Advances to Treatment Implications M. Beatriz Currier and Charles B. Nemeroff p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 203 IL-1 Blockade in Autoinflammatory Syndromes Adriana A. Jesus and Raphaela Goldbach-Mansky p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 223 α7-Nicotinic Acetylcholine Receptor Agonists for Cognitive Enhancement in Schizophrenia Robert Freedman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 245 Annu. Rev. Med. 2014.65:49-62. Downloaded from www.annualreviews.org by Lomonosov Moscow State University on 01/26/14. For personal use only.

Anti–B Cell Antibody Therapies for Inflammatory Rheumatic Diseases Mikkel Faurschou and David R.W. Jayne p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 263 Nuclear Receptor Coactivators: Master Regulators of Human Health and Disease Subhamoy Dasgupta, David M. Lonard, and Bert W. O’Malley p p p p p p p p p p p p p p p p p p p p p p p 279 Male Circumcision: A Globally Relevant but Under-Utilized Method for the Prevention of HIV and Other Sexually Transmitted Infections Aaron A.R. Tobian, Seema Kacker, and Thomas C. Quinn p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 293 New Frontiers in Patient-Reported Outcomes: Adverse Event Reporting, Comparative Effectiveness, and Quality Assessment Ethan Basch p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 307 Evidence-Based Treatment of Post-Traumatic Stress Disorder JoAnn Difede, Megan Olden, and Judith Cukor p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 319 Chimeric Antigen Receptor Therapy for Cancer David M. Barrett, Nathan Singh, David L. Porter, Stephan A. Grupp, and Carl H. June p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 333 Renal Sympathetic Denervation for the Treatment of Refractory Hypertension Kui Toh Gerard Leong, Antony Walton, and Henry Krum p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 349 Transcatheter Aortic Valve Replacement: Game-Changing Innovation for Patients with Aortic Stenosis Kishore J. Harjai, Jean-Michel Paradis, and Susheel Kodali p p p p p p p p p p p p p p p p p p p p p p p p p p p p 367 Future of Cholesteryl Ester Transfer Protein Inhibitors Daniel J. Rader and Emil M. deGoma p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 385 Adaptive Clinical Trial Design Shein-Chung Chow p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 405

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Reduction of Low-Density Lipoprotein Cholesterol by Monoclonal Antibody Inhibition of PCSK9 Evan A. Stein and Frederick Raal p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 417 The Antithrombotic Effects of Statins A. Phillip Owens III and Nigel Mackman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 433 Delivering Value: Provider Efforts to Improve the Quality and Reduce the Cost of Health Care Jonathan E. Gordon, Joan M. Leiman, Emme Levin Deland, and Herbert Pardes p p p p 447


New Cost-Effective Treatment Strategies for Acute Emergency Situations Subani Chandra and David H. Chong p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 459 Reducing Hospital Readmission Rates: Current Strategies and Future Directions Sunil Kripalani, Cecelia N. Theobald, Beth Anctil, and Eduard E. Vasilevskis p p p p p p p p p 471 Indexes Cumulative Index of Contributing Authors, Volumes 61–65 p p p p p p p p p p p p p p p p p p p p p p p p p p p 487 Cumulative Index of Article Titles, Volumes 61–65 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 491 Errata An online log of corrections to Annual Review of Medicine articles may be found at http://www.annualreviews.org/errata/med

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Understanding the pathogenesis of abdominal aortic aneurysms.

Exploring autoimmunity in the pathogenesis of abdominal aortic aneurysms.

Quantitative expression and localization of cysteine and aspartic proteases in human abdominal aortic aneurysms.

Screening for abdominal aortic aneurysms.

Screening for abdominal aortic aneurysms.

Clinical practice. Abdominal aortic aneurysms.

Screening for abdominal aortic aneurysms.

Screening for abdominal aortic aneurysms.

Identification of microRNAs associated with abdominal aortic aneurysms and peripheral arterial disease.

Unusual problems of abdominal aortic aneurysms.

Misdiagnosis of ruptured abdominal aortic aneurysms.

Sealed rupture of abdominal aortic aneurysms.

Osteoprotegerin Prevents Development of Abdominal Aortic Aneurysms.

Computed tomography of abdominal aortic aneurysms.

Associations of ApoAI and ApoB-containing lipoproteins with AngII-induced abdominal aortic aneurysms in mice.

MicroRNAs and Current Concepts on the Pathogenesis of Abdominal Aortic Aneurysm.

Coronary artery aneurysms associated with ascending aortic aneurysms and abdominal aortic aneurysms: pathophysiologic implications.

Ruptured abdominal aortic aneurysms: a new perspective.

B2 cells suppress experimental abdominal aortic aneurysms.

Mortality from ruptured abdominal aortic aneurysms.

Ruptured abdominal aortic aneurysms. Surgical treatment.

Expanding Horizons for Abdominal Aortic Aneurysms.

Surgery for small asymptomatic abdominal aortic aneurysms.

A primer on infrarenal abdominal aortic aneurysms.