elastin and Intracranial-Aneurysm

The presence of an intracranial aneurysm (IA) is thought to have a genetic origin. The genetic association studies (GAS) that investigated the association between IA and elastin gene (ELN) variants have produced contradictory or inconclusive results.. In order to decrease the uncertainty of estimated genetic risk effects, a meta-analysis of published GAS-related variants in the ELN gene (ELN INT20 1315T > C, EX20 1264G > A, INT23 1501 + 24T > C and INT4 196 + 71G > A) with susceptibility to IA was conducted using a genetic model-free approach. The risk effects were estimated using the generalized odds ratio (ORG) metric.. The analysis showed significant association for the INT20 1315T > C variant [ORG = 0.66 (0.45-0.95)], indicating a protection effect. For the variants EX20 1264G > A, INT23 1501 + 24T > C and INT4 196 + 71G > A, no statistically significant association with IAs was found.. There is evidence that the ELN variant INT20 1315T > C is implicated in the development of IA; however, the results should be interpreted with caution since the number of published studies is limited.

Topics: Elastin; Genome-Wide Association Study; Humans; Intracranial Aneurysm

Intracranial aneurysms (IAs) are thought to have a multifactorial origin. The authors undertook a comprehensive meta-analysis on all genes investigated using a case-control model in ruptured (subarachnoid hemorrhage) and unruptured aneurysms.. Electronic databases were searched until and including July 2008 for any candidate gene studied in IA or subarachnoid hemorrhage using a case-control model. The ORs and 95% CIs were determined for each gene-disease association using fixed and random effect models.. Thirty studies of 8 genes and 13 polymorphisms were analyzed among 19,961 individuals (6622 cases and 13,339 controls). Two genes and 3 polymorphisms were associated with IA. The eNOS gene T786C polymorphism (OR 1.24, 95% CI 1.0-1.54; p = 0.05) and IL-6 gene G572C polymorphism (OR 7.08, 95% CI 2.85-17.57; p < 0.0001) both showed a significant association with ruptured/unruptured IA. The IL-6/G174C polymorphism exerted a significant protective effect against IA (OR 0.49, 95% CI 0.25-0.95; p = 0.04). The other candidate genes investigated (ACE, endoglin, APOE, elastin, MMP-3, and SERPINA3) showed no significant associations.. There is a likely genetic basis to sporadic IAs. However, the evidence base is small when compared against other complex disorders.

Topics: Aneurysm, Ruptured; Antigens, CD; Apolipoproteins E; Databases, Genetic; Elastin; Endoglin; Humans; Interleukin-6; Intracranial Aneurysm; Matrix Metalloproteinase 3; Nitric Oxide Synthase Type III; Peptidyl-Dipeptidase A; Polymorphism, Single Nucleotide; Receptors, Cell Surface; Serpins; Subarachnoid Hemorrhage

Genetic determinants probably play a role in the development of intracranial aneurysms. We review the present knowledge on this issue.. This work entailed a comprehensive search of the literature, a critical appraisal of the identified papers, and a personal view of limitations and future directions.. We identified 10 genome-wide linkage studies in families and sib pairs with intracranial aneurysms. These studies have identified several loci, but only 4 (1p34.3-p36.13, 7q11, 19q13.3, and Xp22) have been replicated in different populations. For the loci on 1p34.3-p36.13 and 7q11 association with positional candidate genes has also been demonstrated: for locus on 1p34.3-p36.13 association with the perlecan gene and for 7q11 association with the elastin and collagen type 1 A2 genes.. The progress in identifying genetic determinants for intracranial aneurysms is modest. Reasons for this modest progress include limitations of the present studies, limitations because of the nature of the disease, and limitations in our concept of aneurysms and aneurysm development. Future studies may benefit from strict definitions of familial aneurysms, reduced phenotypic heterogeneity (separating ruptured from unruptured aneurysms, and within these subsets probably also reduce morphological heterogeneity, eg, by grouping similar sites of aneurysms), taking into account age and other risk factors of the patients with aneurysms, and sufficiently large numbers of patients. In future studies we should not only look for genetic determinants of aneurysms, but also for genetic determinants of rupture of aneurysms. This would help in selecting patients for preventive treatment of aneurysms.

Topics: Chromosome Mapping; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 19; Chromosomes, Human, Pair 7; Chromosomes, Human, X; Collagen; Collagen Type I; Elastin; Heparan Sulfate Proteoglycans; Humans; Intracranial Aneurysm

Subarachnoid haemorrhage (SAH) results from leakage of blood into the subarachnoid space and carries high morbidity and mortality. However, there is limited understanding to date, of the risk factors, cellular, intermediate biochemical and genetic traits predisposing to SAH. Nevertheless, in conjunction with improved methods of diagnostic imaging and less invasive approaches to preventing aneurysmal rupture, there may be utility in gaining a better understanding of the pathogenesis and in identifying pre-disease markers. Additionally, it is not impossible that drugs of value (e.g. matrix or endothelial modifiers) could become available. Several different clinical subtypes can be recognised, distinguished by arterial or venous involvement, presence of unruptured arterial aneurysms, and apparently "sporadic" and "familial" occurrences. Epidemiological risk factors include alcohol consumption and smoking: hypertension is a risk factor for rupture. About 10% seem to reflect strong family history and this subset may be particularly illuminating with respect to the molecular pathogenesis. Haemodynamic stress and poor vascular structure may be the main mechanisms of pathogenesis. The epidemiological and statistical evidence for familial megaphenic genes and modifier genes is reviewed. This review focuses on the pathogenesis, as opposed to inflammatory response to SAH. It sets in context the roles of specific genes and their protein products, such as polycystin (PKD1), fibrillin (FBN1), collagen III (COL3A1), elastin (ELN), collagen IV, protease inhibitor or alpha1-antitrypsin (PI) and proteases. These considerations illustrate the shortfalls in current knowledge, the needs of future biochemical and cellular research and their potential implications for future prevention of this often fatal condition.

Topics: Animals; Collagen Type III; Collagen Type IV; Elastin; Fibrillin-1; Fibrillins; Humans; Intracranial Aneurysm; Mice; Microfilament Proteins; Proteins; Risk Factors; Subarachnoid Hemorrhage; TRPP Cation Channels

Intracranial aneurysms and systemic arterial hypertension coexist in a high percentage of patients. The relationship between intracranial aneurysms and hypertension is poorly defined.. Therefore, we reviewed the role of hypertension in the pathogenesis of saccular aneurysms as previously reported in clinical, experimental, and autopsy studies.. Among 24 relevant clinical and/or autopsy studies, the mean incidence of pre-existing hypertension was 43.5% in aneurysm patients compared to 24.4% in the normal population. Although definitive evidence is lacking, data from multiple types of investigations indicate that systemic arterial hypertension creates a greater risk for the development of intracranial aneurysms than previously believed. The underlying pathophysiological mechanism(s) are also poorly defined.. We propose a unifying hypothesis: Endothelial injury, occlusion of the vasa vasorum, and disruption of the synthesis of collagen and elastin are likely the most important factors in initiating the development of aneurysms. Chronic hypertension potentially affects all of these factors. Consequently, chronic hypertension may cause intimal thickening, necrosis of the tunica media, changes in the compositional matrix, and degeneration of the internal elastic lamina to develop in the arterial wall. These structural changes could cause a focal weakening in the arterial wall with resultant bulging. This theory accounts for the high incidence of intracranial aneurysms in the absence of any known associated hereditary or connective-tissue disease. Nor does it exclude the possibility of other etiological factors. From the perspective of prevention, however, it offers clear opportunities for prophylaxis.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Collagen; Elastin; Endothelium, Vascular; Humans; Hypertension; Intracranial Aneurysm; Middle Aged

Intracranial aneurysms (ICAs) are focal dilatations that imply a weakening of the brain artery. Incidental rupture of an ICA is increasingly responsible for significant mortality and morbidity in the American's aging population. Previous studies have quantified the pressure-volume characteristics, uniaxial mechanical properties, and morphological features of human aneurysms. In this pilot study, for the first time, we comprehensively quantified the mechanical, collagen fiber microstructural, and morphological properties of one resected human posterior inferior cerebellar artery aneurysm. The tissue from the dome of a right posterior inferior cerebral aneurysm was first mechanically characterized using biaxial tension and stress relaxation tests. Then, the load-dependent collagen fiber architecture of the aneurysm tissue was quantified using an in-house polarized spatial frequency domain imaging system. Finally, optical coherence tomography and histological procedures were used to quantify the tissue's microstructural morphology. Mechanically, the tissue was shown to exhibit hysteresis, a nonlinear stress-strain response, and material anisotropy. Moreover, the unloaded collagen fiber architecture of the tissue was predominantly aligned with the testing Y-direction and rotated towards the X-direction under increasing equibiaxial loading. Furthermore, our histological analysis showed a considerable damage to the morphological integrity of the tissue, including lack of elastin, intimal thickening, and calcium deposition. This new unified characterization framework can be extended to better understand the mechanics-microstructure interrelationship of aneurysm tissues at different time points of the formation or growth. Such specimen-specific information is anticipated to provide valuable insight that may improve our current understanding of aneurysm growth and rupture potential.

Topics: Anisotropy; Biomechanical Phenomena; Collagen; Elastin; Humans; Intracranial Aneurysm; Pilot Projects; Stress, Mechanical; Tensile Strength

Elastin encoded by elastin gene (ELN) is a crucial extracellular matrix protein responsible for arterial resilience. The objective of this study was to identify single nucleotide polymorphisms (SNPs) of ELN gene susceptible to intracranial aneurysm (IA) in Korean population. Two SNPs of ELN gene, rs2071307 (Gly422Ser) and rs2856728 (intron), were genotyped in 90 patients with IA and 90 age and frequency matched controls. Fisher's exact test was conducted to evaluate allelic association with IA. Of the two SNPs in ELN gene, T allele of rs2856728 (intron) showed statistically significant association with increased development of IA (odds ratio [OR]: 2.34, 95% confidence interval [CI]: 1.44-3.81, P = 7.6 × 10

Topics: Adult; Aged; Asian People; Elastin; Female; Genetic Predisposition to Disease; Genotype; Humans; Intracranial Aneurysm; Male; Middle Aged; Odds Ratio; Polymorphism, Single Nucleotide; Republic of Korea; Risk Assessment

Pathogenesis of intracranial aneurysm is complex and the precise biomechanical processes leading to their rupture are uncertain. The goal of our study was to characterize the aneurysmal wall histologically and to correlate histological characteristics with clinical and radiological factors used to estimate the risk of rupture. A new biobank of aneurysm domes resected at the Geneva University Hospitals (Switzerland) was used. Histological analysis revealed that unruptured aneurysms have a higher smooth muscle cell (SMC) content and a lower macrophage content than ruptured domes. These differences were associated with more collagen in unruptured samples, whereas the elastin content was not affected. Collagen content and type distribution were different between thick and thin walls of unruptured aneurysms. Classification of aneurysm domes based on histological characteristics showed that unruptured samples present organized wall rich in endothelial and SMCs compared with ruptured samples. Finally, aneurysm wall composition was altered in unruptured domes of patients presenting specific clinical factors used to predict rupture such as large dome diameter, dome irregularities, and smoking. Our study shows that the wall of aneurysm suspected to be at risk for rupture undergoes structural alterations relatively well associated with clinical and radiological factors currently used to predict this risk.

Topics: Adult; Aneurysm, Ruptured; Cerebral Angiography; Collagen; Elastin; Endothelial Cells; Female; Humans; Immunohistochemistry; Intracranial Aneurysm; Macrophages; Magnetic Resonance Angiography; Male; Middle Aged; Muscle, Smooth, Vascular; Risk Factors; Smoking

Background Fragmentation of the tunica media is a hallmark of intracranial aneurysm formation, often leading to aneurysmal progression and subsequent rupture. The objective of this study is to determine the plasma level of elastin fragments in the lumen of ruptured versus unruptured human intracranial aneurysms. Methods and Results One hundred consecutive patients with/without ruptured saccular intracranial aneurysms undergoing endovascular coiling or stent-assisted coiling were recruited. Blood samples were collected from the lumen of intracranial aneurysm using a microcatheter. The tip of the microcatheter was placed inside the aneurysm's sac in close proximity to the inner wall of the dome. Plasma levels of elastin fragments were measured using an ELISA -based method. Mean plasma level of soluble human elastin fragments was significantly greater in ruptured aneurysms when compared with nonruptured aneurysms (102.0±15.5 versus 39.3±9.6 ng/mL; P<0.001). Mean plasma level of soluble human elastin fragments did not have significant correlation with age, sex, size, or aneurysm location. Conclusions The present study revealed that a significantly higher concentration of soluble human elastin fragments in the lumen of ruptured intracranial aneurysms when compared with nonruptured ones.

Topics: Adult; Aged; Aged, 80 and over; Aneurysm, Ruptured; Biomarkers; Case-Control Studies; Elastin; Endovascular Procedures; Female; Humans; Intracranial Aneurysm; Male; Middle Aged; Peptide Fragments; Young Adult

Pathogenic germline mutations in ELN can be detected in patients with supravalvular aortic stenosis. The mutation might occur de novo or be inherited following an autosomal dominant pattern of inheritance. In this report we describe a three-generation family suffering from supravalvular aortic stenosis, various other arterial stenoses, sudden death, and intracranial aneurysms. A frameshift mutation in exon 12, not described before, was detected in the affected family members. This report emphasises the importance of family history, genetic counselling, and demonstrates the great variability in the phenotype within a single SVAS family.

Topics: Adult; Aortic Stenosis, Supravalvular; Elastin; Exons; Female; Frameshift Mutation; Genetic Counseling; Germ-Line Mutation; Humans; Intracranial Aneurysm; Male; Middle Aged; Pedigree; Phenotype

It has been suggested that the elastin gene is a candidate gene for the development of intracranial aneurysms (IAs). We investigated the association of single-nucleotide polymorphisms (SNPs) in the elastin gene in sporadic subarachnoid hemorrhage and in patients with unruptured aneurysms in China. We genotyped 446 (47.9%) IA patients (308 ruptured and 138 unruptured) and 485 (52.1%) control subjects for seven exonic and intronic SNPs in the elastin gene and then evaluated their allelic associations with sporadic ruptured and unruptured IAs. We found that IA is associated with two SNPs in the elastin gene: rs2071307 (odds ratio 2.87; 95% confidence interval, 2.26-3.64; p < 0.001) and rs2856728 (odds ratio 2.12; 95% confidence interval, 1.71-2.62; p < 0.001). Furthermore, the minor allele of rs2071307 (allele A) was also associated with IA rupture; 31.3% of patients with ruptured IAs were carriers of the minor allele, whereas only 23.2% of patients with unruptured IAs carried the minor allele (odds ratio 1.51; 95% confidence interval, 1.09-2.10; p = 0.013). In conclusion, our study indicates that the elastin gene may be associated with the formation of IAs, and importantly, that it may also be associated with the rupture of IAs.

Topics: Alleles; Aneurysm, Ruptured; Asian People; Case-Control Studies; China; Elastin; Exons; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Intracranial Aneurysm; Introns; Male; Middle Aged; Polymorphism, Single Nucleotide

A fluid-solid-growth (FSG) model of saccular cerebral aneurysm evolution is developed. It utilises a realistic two-layered structural model of the internal carotid artery and explicitly accounts for the degradation of the elastinous constituents and growth and remodelling (G&R) of the collagen fabric. Aneurysm inception is prescribed: a localised degradation of elastin results in a perturbation in the arterial geometry; the collagen fabric adapts, and the artery achieves a new homeostatic configuration. The perturbation to the geometry creates an altered haemodynamic environment. Subsequent degradation of elastin is explicitly linked to low wall shear stress (WSS) in a confined region of the arterial domain. A sidewall saccular aneurysm develops, the collagen fabric adapts and the aneurysm stabilises in size. A quasi-static analysis is performed to determine the geometry at diastolic pressure. This enables the cyclic stretching of the tissue to be quantified, and we propose a novel index to quantify the degree of biaxial stretching of the tissue. Whilst growth is linked to low WSS from a steady (systolic) flow analysis, a pulsatile flow analysis is performed to compare steady and pulsatile flow parameters during evolution. This model illustrates the evolving mechanical environment for an idealised saccular cerebral aneurysm developing on a cylindrical parent artery and provides the guidance to more sophisticated FSG models of aneurysm evolution which link G&R to the local mechanical stimuli of vascular cells.

Topics: Biomechanical Phenomena; Biomedical Engineering; Blood Flow Velocity; Cerebrovascular Circulation; Collagen; Computer Simulation; Elasticity; Elastin; Hemodynamics; Hemorheology; Humans; Intracranial Aneurysm; Models, Cardiovascular; Models, Neurological; Nonlinear Dynamics; Pulsatile Flow; Systole

Treatment of cerebral aneurysms by endovascular deployment of liquid embolic agents has been proposed as an alternative strategy to conventional coiling, and new materials are being developed for embolization. In this study, the authors used a single-injection, biocompatible, biodegradable and pH-responsive acrylated chitosan (aCHN) with conjugated vascular endothelial growth factor (rhVEGF) in a rat aneurysm model.. The efficacy of the aCHN formulation with rhVEGF was tested using a common carotid artery occlusion model in rats, and the extent of embolization was evaluated using quantitative, qualitative, and histopathological techniques after 14 days of implantation.. The mean occlusion was significantly greater for the rhVEGF/aCHN-treated group (96.8 +/- 3.0%) than for the group receiving aCHN (74.7 +/- 5.6%) (p < 0.01). Through qualitative evaluation, intimal and medial proliferation were significantly greater with rhVEGF/aCHN than with aCHN and controls (p < 0.001). Degradation of the aCHN filler was monitored in concert with the production of extracellular matrix components. Macrophages migrated in and proliferated inside the occluded carotid artery lumens were identified by histological and immunostainings. Results showed resorption of chitosan with concurrent development of collagen and elastin into the vessel lumen, suggesting clot maturation into fibrosis.. Chitosan with a bioactive agent such as rhVEGF showed excellent results in occluding aneurysms in a rat model.

Topics: Animals; Biocompatible Materials; Brain; Carotid Artery Diseases; Carotid Artery, Common; Chitosan; Collagen; Disease Models, Animal; Elastin; Embolization, Therapeutic; Extracellular Matrix; Fibrosis; Hydrogen-Ion Concentration; Intracranial Aneurysm; Macrophages; Mitogens; Rats; Rats, Sprague-Dawley; Vascular Endothelial Growth Factor A

Experimental and theoretical guidance is needed to understand how the collagen fabric evolves during the development of aneurysms. In this paper, we model the development of an aneurysm as a cylindrical/spherical membrane subject to 1D enlargement; these conceptual models reflect the development of fusiform and saccular cerebral aneurysms. The mechanical response is attributed to the elastin and collagen. We introduce variables which define the elastin and collagen fibre concentration; these evolve to simulate growth/atrophy of the constituents. A hypothetical aneurysm model is analysed: collagen stretch is constant, elastin degrades and collagen fibre concentration can adapt to maintain mechanical equilibrium. An analytic expression for the rate of evolution of the fibre concentration is derived. The functional form is dependent on (i) the current collagen fibre concentration, (ii) the deviations in the collagen fibre stretch from the attachment stretch, (iii) the rate of change of fibre stretch, (iv) the rate of loss of elastin and (v) the ratio of load borne by elastinous and collagenous constituents. Finally, numerical examples of aneurysm development are considered. Suitable candidates for the fibre concentration evolution equations are identified that yield stabilization of the aneurysm even when there is complete loss of elastin. This theoretical analysis provides the basis for the development of physiologically realistic models of aneurysm development.

Topics: Algorithms; Animals; Biomechanical Phenomena; Cerebral Arteries; Collagen; Computer Simulation; Elasticity; Elastin; Extracellular Matrix; Fibroblasts; Hemodynamics; Humans; Intracranial Aneurysm; Models, Cardiovascular; Stress, Mechanical; Time Factors; Weight-Bearing

The physiological mechanisms that give rise to the inception and development of a cerebral aneurysm are accepted to involve the interplay between the local mechanical forces acting on the arterial wall and the biological processes occurring at the cellular level. In fact, the wall shear stresses (WSSs) that act on the endothelial cells are thought to play a pivotal role. A computational framework is proposed to explore the link between the evolution of a cerebral aneurysm and the influence of hemodynamic stimuli that act on the endothelial cells. An aneurysm evolution model, which utilizes a realistic microstructural model of the arterial wall, is combined with detailed 3D hemodynamic solutions. The evolution of the blood flow within the developing aneurysm determines the distributions of the WSS and the spatial WSS gradient (WSSG) that act on the endothelial cell layer of the tissue. Two illustrative examples are considered: Degradation of the elastinous constituents is driven by deviations of WSS or the WSSG from normotensive values. This model provides the basis to further explore the etiology of aneurysmal disease.

Topics: Biomechanical Phenomena; Blood Flow Velocity; Blood Pressure; Collagen; Computational Biology; Computer Simulation; Elasticity; Elastin; Endothelial Cells; Hemodynamics; Hemorheology; Humans; Intracranial Aneurysm; Models, Cardiovascular

A cerebral aneurysm (CA) causes catastrophic subarachnoid hemorrhage. Degradation of extracellular matrix in arterial walls is a prominent feature of cerebral aneurysms. We investigated the expression and role of cysteine cathepsins, collagen- and elastin- degrading proteinases, in CA progression.. CAs were induced in Sprague-Dawley rats with or without cysteine cathepsin inhibitor, NC-2300. Expression of cathepsin B, K, S, and cystatin C, an endogenous inhibitor of cysteine cathepsins, in aneurysmal walls was examined in quantitative RT-PCR and immunohistochemistry. The activity of cysteine cathepsins and collagenase I and IV in aneurysmal walls was also assessed. Finally, expression of cysteine cathepsins and cystatin C in human CAs was examined.. Quantitative RT-PCR and immunohistochemistry revealed upregulated expression of cathepsin B, K, and S in the late stage of aneurysm progression. In contrast, cystatin C expression was reduced with aneurysm progression. Treatment with NC-2300 resulted in the decreased incidence of advanced CAs. The activity of cysteine cathepsins and collagenase I and IV in aneurysmal walls was reduced and elastin content was increased in the NC-2300-treated group. Finally, immunohistochemistry for cysteine cathepsins and cystatin C expression in human CAs showed the same expression pattern as in the rat study.. Data obtained by using NC-2300 revealed an important role of cysteine cathepsins in the progression of CAs. Our findings strongly suggest that an imbalance between cysteine cathepsins and their inhibitor may cause the excessive breakdown of extracellular matrix in the arterial walls leading to the progression and rupture of CAs.

Topics: Animals; Brain; Cathepsin B; Cathepsin K; Cathepsins; Cerebral Arteries; Collagenases; Cystatin C; Cystatins; Disease Models, Animal; Disease Progression; Elastin; Enzyme Inhibitors; Epoxy Compounds; Extracellular Matrix; Immunohistochemistry; Intracranial Aneurysm; Male; Rats; Rats, Sprague-Dawley; RNA, Messenger; Subarachnoid Hemorrhage

Previous studies have shown positive evidence of linkage of the intracranial aneurysm (IA) at chromosome 7q11, 17cen, 19q13, and Xp22. These regions contain elastin (ELN), nitric oxide synthetase 2A (NOS2A), apolipoprotein E (APOE), and angiotensin-I converting enzyme 2 (ACE2), which are considered to be promising candidate genes for IA. We aimed to examine the association of single-nucleotide polymorphisms (SNPs) with IA in these candidate genes.. To identify polymorphisms in NOS2A and ACE2, all exons and exon-intron boundaries were screened by direct sequencing in 30 randomly selected controls. The program tagSNPs was used to select an optimal set of haplotype-tagging SNPs. For ELN and APOE, SNPs were selected from previous reports. These selected SNPs were then genotyped in 362 cases with IA and 332 residential area matched controls. THESIAS software was used to investigate the association of alleles and haplotypes with IA by adjusting with covariates.. We genotyped 8 SNPs in ELN, 8 SNPs in NOS2A, 3 epsilon alleles in APOE and 1 SNP in ACE2. No alleles or haplotypes of 4 candidate genes revealed any significant association with IA.. Investigated polymorphisms in this study were not associated with IA.

Topics: Adult; Aged; Aged, 80 and over; Alleles; Angiotensin-Converting Enzyme 2; Apolipoproteins E; Elastin; Female; Genetic Predisposition to Disease; Humans; Intracranial Aneurysm; Japan; Linkage Disequilibrium; Male; Middle Aged; Nitric Oxide Synthase Type II; Peptidyl-Dipeptidase A; Polymorphism, Single Nucleotide

The rupture of an intracranial aneurysm (IA) results in subarachnoid hemorrhage, a catastrophic neurological condition with high morbidity and mortality. Following-up on our previous genome-wide linkage study in Japanese population, we extensively analyzed a 4.6 Mb linkage region around D7S2472 on 7q11 by genotyping 168 single nucleotide polymorphisms (SNPs). SNP association and window scan haplotype-based association studies revealed a susceptibility locus for IA on a single LD block covering the 3'-untranslated region (3'-UTR) of ELN and the entire region of LIMK1. An association study with 404 IA patients and 458 non-IA controls revealed that the ELN 3'-UTR G(+659)C SNP has the strongest association to IA (P=0.000002) and constitutes a tag-SNP for an at-risk haplotype, which contains two functional SNPs, the ELN 3'-UTR (+502) A insertion and the LIMK1 promoter C(-187)T SNP. These allelic and haplotype-based associations were confirmed in a Korean population. Ex vivo and in vitro analyses demonstrate that the functional impact of both SNPs is the decrease of transcript levels, either through accelerated ELN mRNA degradation or through decreased LIMK1 promoter activity. Elastin and LIMK1 protein are involved in the same actin depolymerization signaling pathway; therefore, these lines of evidence suggest a combined effect of the SNPs in the at-risk haplotype possibly by weakening the vascular wall and promoting the development of IA.

Topics: 3' Untranslated Regions; Adult; Aged; Asian People; Case-Control Studies; Cells, Cultured; Chromosomes, Human, Pair 7; Elastin; Female; Genetic Predisposition to Disease; Haplotypes; Humans; Intracranial Aneurysm; Japan; Korea; Lim Kinases; Male; Middle Aged; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Protein Kinases

A study of intracranial aneurysm (IA) sibpairs suggested association of an ELN haplotype with IA risk. Subsequent linkage analysis of the ELN region on chromosome 7q11 in high-risk Utah IA pedigrees significantly confirmed linkage between IA and the ELN region.. We have investigated the ELN gene as a potential candidate gene for IA in Utah pedigrees. One IA case from each pedigree, who shared an ELN region haplotype segregating in the pedigree, was screened for mutation. The promoter region, 34 exons, and the 3'UTR (UnTranslated Region) of the ELN gene were screened for variants using DHPLC.. Variants were observed in the promoter region, exons 4 and 6, and the 3'UTR. Variants in exon 6 and in one 3'UTR position were unique to Utah. The remaining variants were absent in the controls. There was no evidence for segregation of the ELN variants found in IA cases with the hypothesized chromosome 7 haplotypes segregating in pedigrees.. Our analysis does not support ELN as the gene responsible for familial IA in the linked Utah IA pedigrees.

Topics: 3' Untranslated Regions; Aneurysm; Elastin; Exons; Family Health; Female; Gene Frequency; Genetic Linkage; Genetic Predisposition to Disease; Genetic Variation; Haplotypes; Humans; Intracranial Aneurysm; Introns; Male; Mutation; Pedigree; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Risk; Sequence Analysis, DNA; Utah

There is growing evidence that genetic variants have an impact on the pathogenesis of intracranial aneurysm (IA). Recently, the genetic locus around the elastin gene (7q11) has been identified as linked to IA in a Japanese population. Our aim was to confirm these results in Caucasian populations.. We conducted a case-control study in 120 Caucasian patients with IA and 172 controls to investigate 8 single nucleotide polymorphisms (SNPs) and various haplotypes within the elastin gene, which were frequently found and associated with the phenotype in the Japanese populations. Real-time PCR and melting curve analysis were used for the detection of genotypes.. Allele frequencies and genotypes were equally distributed between Caucasian cases and controls. We failed to identify haplotypes that are associated with the phenotype in our population, which is in contrast to the Japanese study. However, allele frequencies in control populations differ between Caucasians and Japanese.. We found no association between SNPs and haplotypes of the elastin gene and the occurrence of IA in our Caucasian populations. However, our data provide strong evidence for racial/ethnic differences in the association of SNP and specific haplotypes of the elastin gene with the phenotype. There might be other genetic variants of the elastin gene associated with IA in Caucasians.

Topics: Adult; Aged; Aged, 80 and over; Asian People; Elastin; Female; Gene Frequency; Genetic Predisposition to Disease; Haplotypes; Humans; Intracranial Aneurysm; Japan; Male; Middle Aged; Polymorphism, Single Nucleotide; White People

A locus containing the elastin gene has been linked to familial intracranial aneurysms in 2 distinct populations. We investigated the association of single-nucleotide polymorphisms (SNPs) and haplotypes of SNPs in the elastin gene with the occurrence of subarachnoid hemorrhage (SAH) from sporadic aneurysms in the Netherlands.. We genotyped 167 SAH patients and 167 matching controls for 18 exonic and intronic SNPs in the elastin gene. A Bonferroni correction was applied for multiple comparisons with all novel associations, with a correction factor derived from the number of SNPs tested (P value after Bonferroni correction [P(corr)]).. SAH was statistically significant associated with an SNP in exon 22 of the elastin gene (minor allele frequency was 0.000 in patients and 0.028 in controls; odds ratio [OR], 0.0; 95% CI, 0.0 to 0.7; P=0.004; P(corr)=0.05) and possibly with an SNP in intron 5 (minor allele frequency was 0.062 in patients and 0.128 in controls; OR, 0.5; 95% CI, 0.2 to 0.8; P=0.007; P(corr)=0.08). Haplotypes of intron 5/exon 22 (P(corr)=0.002), intron 4/exon 22 (P(corr)=0.02), and intron 4/intron 5/exon 22 (P=9.0x10(-9)) were also associated with aneurysmal SAH.. Variants and haplotypes within the elastin gene are associated with the risk of sporadic SAH in Dutch patients. Gradual increase of statistical power with the inclusion of 2 or 3 SNPs in the studied haplotypes supports the validity of our conclusion that the elastin gene is a susceptibility locus for SAH.

Topics: Alleles; Cohort Studies; Elastin; Exons; Gene Frequency; Genetic Heterogeneity; Genetic Predisposition to Disease; Haplotypes; Humans; Intracranial Aneurysm; Introns; Linkage Disequilibrium; Netherlands; Polymorphism, Single Nucleotide; Protein Structure, Tertiary; Subarachnoid Hemorrhage

We sought to test the linkage of familial intracranial aneurysms (FIAs) to the ELN (elastin) locus in chromosome 7q11 reported previously.. Intracranial aneurysm (IA) probands were searched from patient records or neurosurgeons' recalls in collaborating hospitals. Members of the participating probands' families who had unknown affection status were screened by MR angiography and diagnosed by digital subtraction angiography. Inclusion criteria of families for genetic analyses were as follows: at least 3 alive affected members or 2 alive affected members with at least 1 unaffected member (>or=60 years). Linkage to the ELN locus was tested with the use of GENEHUNTER by parametric and nonparametric methods. To exclude false-negatives in the linkage analysis, the lowest 5% limits of logarithms of the odds (LOD) and nonparametric LOD (NPL) scores for individual families and for the total set of families were simulated on assumption that the ELN locus is linked to FIAs.. Questionnaires were sent to 885 patients, and 563 responded. Seventy-nine probands were positive for family history. One hundred thirty-four family members of unknown affection status were screened. A total of 14 families with 64 members met the criteria. Linkage to the ELN locus was discarded in 11 families and was inconclusive for 3 families. The total LOD and total NPL scores for 14 families were -8.04 and -0.643, respectively. Our conclusion did not change even when the values of penetrance were changed or only affected members were analyzed.. The majority of aggregated IA Japanese families may not have a genetic linkage to chromosome 7q11.

Topics: Adult; Chromosomes, Human, Pair 7; Elastin; Family Health; Female; Genetic Linkage; Genetic Predisposition to Disease; Humans; Intracranial Aneurysm; Japan; Male; Middle Aged; Pedigree

The occurrence of intracranial aneurysms and of aneurysmal subarachnoid hemorrhage are influenced by genetic factors. Recent genomic studies in Japan have defined 3 chromosomal loci and 1 haplotype of elastin polymorphisms as important risk factors, both for affected sib pairs and sporadic patients.. We have genotyped 2 single nucleotide polymorphisms in the elastin gene and evaluated their allelic association with intracranial aneurysm in a Central European sample of 30 familial and 175 sporadic patients and 235 population controls.. We found no allelic association between this elastin polymorphism haplotype and intracranial aneurysm.. Our data probably reflect increased genetic heterogeneity of intracranial aneurysm in Europe compared with Japan.

Topics: Adult; Age of Onset; Alleles; Aneurysm, Ruptured; Austria; Chromatography, High Pressure Liquid; DNA Mutational Analysis; Elastin; Female; Genetic Heterogeneity; Genetic Predisposition to Disease; Germany; Haplotypes; Humans; Intracranial Aneurysm; Japan; Male; Middle Aged; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Rupture, Spontaneous; Subarachnoid Hemorrhage

To establish the relationship between elastin degradation and aneurysm growth in New Zealand white rabbit model aneurysms, and to explore the potential for pharmacologic inhibition of elastinolysis and aneurysm growth with use of the matrix metalloproteinase (MMP) inhibitor doxycycline.. Elastase-induced, saccular aneurysms created in the right common carotid artery in 30 animals randomly divided into controls (n = 16) and doxycycline treated (n = 14) were studied. Aneurysm growth was determined by angiography and aneurysm specimens were collected at 7 and 14 days for histologic and immunohistochemical analysis.. Aneurysms were characterized by marked elastin degradation and thickening of the arterial wall media in the absence of inflammatory cell markers. There was no evidence for expression of MMPs in the aneurysm wall at any time point. Aneurysm formation and growth were not prevented by the systemic administration of doxycycline. Mean aneurysm width increased from 3.1 +/- 0.7 mm at 3 days to 3.7 +/- 0.8 mm at 7 days and 4.2 +/- 0.8 mm at 14 days (P =.012 and P =.017, respectively). There was no statistically significant difference in aneurysm size and elastin content at any time point between doxycycline treated and control animals.. Elastase-induced rabbit aneurysm formation is accompanied by total elastin destruction that was not inhibited by the administration of doxycycline. Aneurysms in this model may be caused by the initial infusion of elastase, rather than by ongoing degradation from endogenous proteases released by inflammatory cells.

Topics: Animals; Carotid Artery Diseases; Disease Models, Animal; Doxycycline; Elastin; Intracranial Aneurysm; Matrix Metalloproteinase Inhibitors; Pancreatic Elastase; Rabbits; Random Allocation

Topics: Elastin; Humans; Intracranial Aneurysm; Leukocyte Elastase; Temporal Arteries

Topics: Elastin; Humans; Intracranial Aneurysm; Pancreatic Elastase; Temporal Arteries

alpha 1-Antitrypsin (AAT) and alpha 2-macroglobulin (AMG) are elastase inhibitors that bind the enzyme and reduce measured levels of free elastase. It was recently demonstrated that some patients with intracranial aneurysms have significantly elevated plasma elastase (PE) levels. Although this elevation is unrelated to plasma AAT, it is unknown whether abnormal AAT phenotypes or reduced AMG levels play a role. Moreover, the pathological significance of this elevation is not understood.. Plasma from 24 patients with aneurysms (ruptured, n = 15; unruptured, n = 9) and 10 age-matched patients who comprised a control group was analyzed for PE and AMG levels by enzyme-linked immunosorbent assay and for AAT phenotype by isoelectric focusing. Sections of superficial temporal temporal artery obtained from these patients at the time of surgery were examined for evidence of elastin degradation by using a van Gieson stain, with scoring on a nine-point quantitative scale.. Patients with aneurysms showed significantly elevated PE levels (119 +/- 28 versus 17 +/- 7 micrograms/ml, P < 0.05), but AMG levels were not decreased. AAT phenotypic abnormalities were observed in 10% (2 of 20) of the patients with aneurysms, but this was not different from the expected population incidence (7%). Elastin degradation scores were significantly higher in patients with aneurysms than in patients control group (4.26 +/- 0.54 versus 1.21 +/- 0.43, P < 0.05). In addition, patients with higher elastase levels (> 80 micrograms/ml) demonstrated 55% higher degradation scores than did those with lower elastase levels (< 80 micrograms/ml).. These data suggest that high PE levels may play a role in systemic arterial elastin degradation seen in patients with intracranial aneurysms. These data also support the contention that elevated elastase levels are not the result of decreased protease inhibitor levels. Although PE levels were significantly higher for the entire group of patients with aneurysms, this assay has relatively low sensitivity for predicting the presence of unruptured aneurysms. Additional study is necessary to determine whether serum elastase levels greater than 80 micrograms/ml, in the setting of other risk factors, are useful in identifying asymptomatic patients for additional screening.

Topics: Adult; Aged; alpha 1-Antitrypsin; alpha-Macroglobulins; Aneurysm, Ruptured; Craniotomy; Elastic Tissue; Elastin; Enzyme-Linked Immunosorbent Assay; Female; Humans; Intracranial Aneurysm; Male; Middle Aged; Pancreatic Elastase; Predictive Value of Tests; Prospective Studies; Reference Values; Subarachnoid Hemorrhage; Temporal Arteries

Current predominant theories for the pathogenesis of intracranial saccular aneurysms have a congenital or a degenerative basis. Complementing these theories, the predilection of intracranial aneurysms for the human species has been attributed to a variety of human neurovascular morphological traits, which however, on closer scrutiny are not unique to the human species. Human evolution to a bipedal primate has required significant adaptation in several organ systems, with significant consequent biological costs. We hypothesize that susceptibility to intracranial aneurysms is part of this latter cost of adopting an upright stance with respect to the neurovascular systems. Evidence supporting the above hypothesis, is presented.

Topics: Animals; Aorta; Biological Evolution; Cardiovascular Physiological Phenomena; Cardiovascular System; Cerebral Arteries; Connective Tissue; Dogs; Elastin; Humans; Intracranial Aneurysm; Models, Cardiovascular; Models, Neurological; Posture

Laplace's law, which describes a linear relation between the tension and the radius, is often used to characterize the mechanical response of the aneurysm wall to distending pressures. However, histopathological studies have confirmed that the wall of the fully developed aneurysm consists primarily of collagen and is subject to large increases in tension for small increases in the radius, i.e., a nonlinear relationship exists between the tension within the aneurysm wall and the radius. Thus, a nonlinear version of Laplace's law is proposed to accurately describe the development and rupture of a fusiform saccular aneurysm. The fusiform aneurysm was modelled as a thin-walled ellipsoidal shell with a major axis radius, Ra, minor axis radius, Rb, circumferential tension, S0, and meridional tension, S phi, with phi defining the angle from the surface normal. Using both linear and nonlinear models, differential expressions of the volume distensibility evaluated at 90 degrees were used to determine the critical radius of the aneurysm along the minor axis from S0 and S phi in terms of the following geometric and biophysical variables; A, elastic modulus of collagen; E, elastic modulus of the aneurysm (elastin and collagen); t, wall thickness; P, systolic pressure; and Ra. For typical physiological values of A = 2.8 MPa, E = 1.0 MPa, T = 40 microns, P = 150 mmHg, and Ra = 4Rb, the linear model yielded critical radii of 4.0 mm from S phi and 2.2 mm from S0. The resultant critical radius was 4.56 mm. Using the same values, the critical radii from the tension components of the nonlinear model were 3.5 mm from S phi and 1.9 mm from S0.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aneurysm, Ruptured; Cerebral Arteries; Collagen; Elasticity; Elastin; Humans; Intracranial Aneurysm; Models, Theoretical

Elastin and reticular fibers were identified using standard histological strains in middle cerebral arteries taken from patients who had died from aneurysmal subarachnoid hemorrhage and control patients who did not have cerebral aneurysms. Examination of cerebral arteries from normal individuals revealed a dense network of fine reticular fibers in the arterial media that were uniformly distributed. Computerized morphometric analysis indicated that reticular fibers in the arterial media of cerebral arteries were significantly decreased in patients with aneurysms. In addition, these fibers were irregularly distributed and shortened when compared to those seen in control arteries. In both patients with aneurysms and control patients, elastin fibers were limited almost exclusively to the internal elastin lamina. No differences were observed in the appearance or content of elastin fibers in control patients and patients with aneurysm. Although other explanations cannot be excluded, these observations are consistent with the hypothesis that "intrinsic" abnormalities in the walls of cerebral arteries lead to conditions that favor the formation and rupture of cerebral aneurysms.

Topics: Aged; Cerebral Arteries; Elastin; Female; Humans; Image Processing, Computer-Assisted; Intracranial Aneurysm; Male; Middle Aged; Reticulin

The occluded canine tail artery, which comes off in the same plane as the aortoiliac junction, has been used as a flow model for cerebral aneurysms. These experiments were designed to determine if it is a realistic distensible model of human intracranial aneurysms. Distensibility studies were done on the aorta, and the iliac and tail arteries of four dogs. From these pressure-volume studies, tension-strain curves, elastances, and collagen slack were obtained. The tail artery is stiffer longitudinally and more distensible circumferentially than the other vessels. The iliac arteries and the aorta are not significantly different. The elastance of elastin and collagen is lower in the tail artery, and the collagen is more wavy circumferentially. Longitudinally, the collagen slack is least for the tail artery, and the elastance of elastin is not different in all three vessels. The number of elastin layers in the iliac and tail arteries seen in cross section is not significantly different, but the aorta is different from both these vessels. In another four dogs the aorta proximal to the trifurcation was cannulated and infused with saline to increase pressure. India ink marks were put on the surface to measure changes in length. Photographs were taken at intervals of 10 mmHg(1 mmHg = 133.3 Pa). This was done with the vessels tethered and untethered in the body and then taken out and studied with the same method in vitro. Arteries tethered in the body expanded circumferentially more than longitudinally. The tail artery becomes less distensible if untethered in the body and therefore acts more like an aneurysm.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Aorta; Arteries; Collagen; Disease Models, Animal; Dogs; Elasticity; Elastin; Iliac Artery; Intracranial Aneurysm; Microscopy, Electron, Scanning; Regional Blood Flow; Staining and Labeling; Tail

Topics: Adult; Animals; Arteries; Biomechanical Phenomena; Cerebral Arteries; Dogs; Elastin; Humans; Intracranial Aneurysm; Middle Aged; Pressure

Topics: Blood Pressure; Cell Wall; Circle of Willis; Elasticity; Elastin; Humans; In Vitro Techniques; Intracranial Aneurysm; Ligation; Pressure