Distinct defects in collagen microarchitecture underlie vessel-wall failure in advanced abdominal aneurysms and aneurysms in Marfan syndrome.
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ABSTRACT:
SUBMITTER: Lindeman JH
PROVIDER: S-EPMC2818895 | biostudies-other | 2010 Jan
REPOSITORIES: biostudies-other
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Project description:Abdominal wall defects are common congenital anomalies with the most frequent being gastroschisis and omphalocele. Though both are the result of errors during embryologic development of the fetal abdominal wall, gastroschisis and omphalocele represent unique disorders that have different clinical sequelae. Gastroschisis is generally a solitary anomaly with postnatal outcomes related to the underlying integrity of the prolapsed bowel. In contrast, omphalocele is frequently associated with other structural anomalies or genetic syndromes that contribute more to postnatal outcomes than the omphalocele defect itself. Despite their embryological differences, both gastroschisis and omphalocele represent anomalies of fetal development that benefit from multidisciplinary and translational approaches to care, both pre- and postnatally. While definitive management of abdominal wall defects currently remains in the postnatal realm, advancements in prenatal diagnostics and therapies may one day change that. This review focuses on recent advancements, novel techniques, and current controversies related to the prenatal diagnosis and management of gastroschisis and omphalocele.
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Project description:Abdominal aortic aneurysm (AAA) is a vascular disease characterized by the enlargement of the infrarenal segment of the aorta. A ruptured AAA can cause internal bleeding and carries a high mortality rate, which is why the clinical management of the disease is focused on preventing aneurysm rupture. AAA rupture risk is estimated by the change in maximum diameter over time (i.e., growth rate) or if the diameter reaches a prescribed threshold. The latter is typically 5.5 cm in most clinical centers, at which time surgical intervention is recommended. While a size-based criterion is suitable for most patients who are diagnosed at an early stage of the disease, it is well known that some small AAA rupture or patients become symptomatic prior to a maximum diameter of 5.5 cm. Consequently, the mechanical stress in the aortic wall can also be used as an integral component of a biomechanics-based rupture risk assessment strategy. In this work, we seek to identify geometric characteristics that correlate strongly with wall stress using a sample space of 100 asymptomatic, unruptured, electively repaired AAA models. The segmentation of the clinical images, volume meshing, and quantification of up to 45 geometric measures of each AAA were done using in-house Matlab scripts. Finite element analysis was performed to compute the first principal stress distributions from which three global biomechanical parameters were calculated: peak wall stress, 99th percentile wall stress and spatially averaged wall stress. Following a feature reduction approach consisting of Pearson's correlation matrices with Bonferroni correction and linear regressions, a multivariate stepwise regression analysis was conducted to find the geometric measures most highly correlated with each of the biomechanical parameters. Our findings indicate that wall stress can be predicted by geometric indices with an accuracy of up to 94% when AAA models are generated with uniform wall thickness and up to 67% for patient specific, non-uniform wall thickness AAA. These geometric predictors of wall stress could be used in lieu of complex finite element models as part of a geometry-based protocol for rupture risk assessment.
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Project description:TGF-? signaling plays critical roles in the pathogenesis of aneurysms; however, it is still unclear whether its role is protective or destructive. In this study, we investigate the role of SMAD3 in the pathogenesis of calcium chloride (CaCl2)-induced abdominal aortic aneurysms (AAA) in Smad3(-/-), Smad3(+/-) and Smad3(+/+) mice. We find that loss of SMAD3 drastically increases wall thickening of the abdominal aorta. Histological analyses show significant vessel wall remodeling with elastic fiber fragmentation. Remarkably, under polarized light, collagen fibers in the hyperplastic adventitia of Smad3(-/-) mice show extensive reorganization accompanied by loosely packed thin and radial collagen fibers. The expressions of matrix metalloproteinases including MMP2, MMP9, and MMP12 and infiltration of macrophage/T cells are drastically enhanced in the vascular wall of Smad3(-/-) mice. We also observe marked increase of NF-?B and ERK1/2 signaling as well as the expression of nuclear Smad2, Smad4 and TGF-?1 in the vessel wall of Smad3(-/-) mice. In addition, we find that SMAD3 expression is reduced in the dedifferentiated medial smooth muscle-like cells of human AAA patients. These findings provide direct in vivo evidence to support the essential roles of SMAD3 in protecting vessel wall integrity and suppressing inflammation in the pathogenesis of AAAs.
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Project description:ObjectiveThe objective of this study was to better understand the pathophysiology and underlying genetic mechanisms behind two abdominal aortic aneurysm (AAA) subtypes using computed tomographic imaging in combination with whole genome sequencing.MethodsPatients with a known AAA and European ancestry were included in this investigation and underwent genetic and image analysis. Patients with AAAs and indications of descending thoracic aortic pathology (aortic dissection, penetrating aortic ulcers, intramural hematoma, atheromas, ulcerative plaque, and intramural ulceration, and intimal flaps/tears) were classified as having thoracic aortic disease, grouped together, and compared with patients with an AAA and a normal descending thoracic aorta. Whole genome sequencing was then performed on the 93 patients who had imaging features consistent with thoracic aortic disease and the 126 patients with a normal descending thoracic aorta.ResultsThe results of this study suggest one variant-level, four gene-level, and one gene set-level associations in patients with thoracic aortic disease who also had an AAA. The variant rs79508780 located in TSEN54 achieved study-wide significance (P = 1.71E-06). BATF3 and SMLR1 were significantly associated and EFCAB3 and TAF4 were reached suggestive assocation with a diseased descending thoracic aorta (P = 5.23E-26, P = 1.86E-25, P = 1.54E-05, and P = 8.31E-05, respectively). Gene sets were also compiled using MSigDB and trait-based index single nucleotide variation from major genome-wide association studies. GO_DNA_DOUBLE_STRAND_BREAK_PROCESSING, a gene set related to double-stranded DNA break repair, was significantly associated with thoracic aortic disease in AAA patients (P = 1.80E-06).ConclusionsThis pilot study provides further evidence that an AAA may be the end result of multiple degenerative pathways. Genetic variations in vitamin D signaling, cholesterol metabolism, extracellular matrix breakdown, and double-stranded DNA break repair pathways were associated with European patients who had an AAA and thoracic aortic disease. Additionally, this study provides support for the application of a radiogenomic approach for the investigation of other potential pathologies that could lead to the development of an AAA or influence future management decisions. (JVS-Vascular Science.).Clinical relevanceIn this study, we provide evidence that abdominal aortic aneurysms (AAAs) may be a result of multiple pathophysiologies rather than a single disease. We have identified genetic variants involved in vitamin D signaling, cholesterol metabolism, extracellular matrix breakdown, and double-stranded DNA break repair associated with structural defects in the aortic wall in patients with AAAs who are of European descent. Patients with AAAs and structural defects in the thoracic aorta have been previously linked to differential behavior after endovascular aneurysm repair. These patients with wall defects exhibited greater sac regression, a marker of surgical success, after endovascular aneurysm repair. Our study demonstrates the usefulness of a radiogenomic approach for elucidating mechanisms behind the formation and future behavior of AAAs that could aid surgeons in making future procedural and management decisions.
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Project description:Abdominal aortic aneurysm (AAA) rupture risk is currently determined based on size and symptoms. This approach does not address the rupture risk associated with small aneurysms. Given the role of matrix metalloproteinases (MMPs) in AAA weakening and rupture, we investigated the potential of MMP-targeted imaging for detection of aneurysm biology and prediction of outcome in a mouse model of AAA with spontaneous rupture.Fifteen-week-old mice (n=66) were infused with angiotensin II for 4 weeks to induce AAA. Saline-infused mice (n=16) served as control. The surviving animals underwent in vivo MMP-targeted micro-single photon emission computed tomographic/computed tomographic imaging, using RP805, a technetium-99m-labeled MMP-specific tracer, followed by ex vivo planar imaging, morphometry, and gene expression analysis. RP805 uptake in suprarenal aorta on micro-single photon emission computed tomographic images was significantly higher in animals with AAA when compared with angiotensin II-infused animals without AAA or control animals. CD68 expression and MMP activity were increased in AAA, and significant correlations were noted between RP805 uptake and CD68 expression or MMP activity but not aortic diameter. A group of angiotensin II-infused animals (n=24) were imaged at 1 week and were followed up for additional 3 weeks. RP805 uptake in suprarenal aorta at 1 week was significantly higher in mice that later developed rupture or AAA. Furthermore, tracer uptake at 1 week correlated with aortic diameter at 4 weeks.MMP-targeted imaging reflects vessel wall inflammation and can predict future aortic expansion or rupture in murine AAA. If confirmed in humans, this may provide a new paradigm for AAA risk stratification.
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Project description:Abdominal aortic aneurysm (AAA) is a prevalent cardiovascular disease characterized by the focal dilation of the aorta, which supplies blood to all the organs and tissues in the systemic circulation. With the AAA increasing in diameter over time, the risk of aneurysm rupture is generally associated with the size of the aneurysm. If diagnosed on time, intervention is recommended to prevent AAA rupture. The criterion to decide on surgical intervention is determined by measuring the maximum diameter of the aneurysm relative to the critical value of 5.5 cm. However, a more reliable approach could be based on understanding the biomechanical behavior of the aneurysmal wall. In addition, geometric features that are proven to be significant predictors of the AAA wall mechanics could be used as surrogates of the AAA biomechanical behavior and, subsequently, of the aneurysm's risk of rupture. The aim of this work is to identify those geometric indices that have a high correlation with AAA wall stress in the population of patients who received an emergent repair of their aneurysm. In-house segmentation and meshing algorithms were used to model 75 AAAs followed by estimation of the spatially distributed wall stress by performing finite element analysis. Fifty-two shape and size geometric indices were calculated for the same models using MATLAB scripting. Hypotheses testing were carried out to identify the indices significantly correlated with wall stress by constructing a Pearson's correlation coefficient matrix. The analyses revealed that 12 indices displayed high correlation with the wall stress, amongst which wall thickness and curvature-based indices exhibited the highest correlations. Stepwise regression analysis of these correlated indices indicated that wall stress can be predicted by the following four indices with an accuracy of 76%: maximum aneurysm diameter, aneurysm sac length, average wall thickness at the maximum diameter cross-section, and the median of the wall thickness variance. The primary outcome of this work emphasizes the use of global measures of size and wall thickness as geometric surrogates of wall stress for emergently repaired AAAs.
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Project description:Background/objectivesIn this report, the National Birth Defects Prevention Network (NBDPN) examines and compares gastroschisis and omphalocele for a recent 5-year birth cohort using data from 30 population-based birth defect surveillance programs in the United States.MethodsAs a special call for data for the 2019 NBDPN Annual Report, state programs reported expanded data on gastroschisis and omphalocele for birth years 2012-2016. We estimated the overall prevalence (per 10,000 live births) and 95% confidence intervals (CI) for each defect as well as by maternal race/ethnicity, maternal age, infant sex, and case ascertainment methodology utilized by the program (active vs. passive). We also compared distribution of cases by maternal and infant factors and presence/absence of other birth defects.ResultsThe overall prevalence estimates (per 10,000 live births) were 4.3 (95% CI: 4.1-4.4) for gastroschisis and 2.1 (95% CI: 2.0-2.2) for omphalocele. Gastroschisis was more frequent among young mothers (<25 years) and omphalocele more common among older mothers (>40 years). Mothers of infants with gastroschisis were more likely to be underweight/normal weight prior to pregnancy and mothers of infants with omphalocele more likely to be overweight/obese. Omphalocele was twice as likely as gastroschisis to co-occur with other birth defects.ConclusionsThis report highlights important differences between gastroschisis and omphalocele. These differences indicate the importance of distinguishing between these defects in epidemiologic assessments. The report also provides additional data on co-occurrence of gastroschisis and omphalocele with other birth defects. This information can provide a basis for future research to better understand these defects.
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Project description:Current clinical practice for the assessment of abdominal aortic aneurysms (AAA) is based on vessel diameter and does not account for the multifactorial, heterogeneous remodeling that results in the regional weakening of the aortic wall leading to aortic growth and rupture. This study was conducted to determine correlation between a novel non-invasive surrogate measure of regional aortic weakening and the results from invasive analyses performed on corresponding ex vivo aortic samples. Tissue samples were evaluated to classify local wall weakening and likelihood of further degeneration based on non-invasive indices. A combined, image-based fluid dynamic and in-vivo strain analysis approach was used to estimate the Regional Aortic Weakness (RAW) index and assess individual aortas of AAA patients prior to elective surgery. Nine patients were treated with complete aortic resection allowing the systematic collection of tissue samples that were used to determine regional aortic mechanics, microstructure and gene expression by means of mechanical testing, microscopy and transcriptomic analyses. The RAW index was significantly higher for samples exhibiting lower mechanical strength (p = 0.035) and samples classified with low elastin content (p = 0.020). Samples with higher RAW index had the greatest number of genes differentially expressed compared to any constitutive metric. High RAW samples showed a decrease in gene expression for elastin and a down-regulation of pathways responsible for cell movement, reorganization of cytoskeleton, and angiogenesis. Please note that the sample 'characteristisc: strain' represents the in-vivo strain corresponding to each section of aorta, which is measured from dynamic CT images of patient AAA using a proprietary software.
2021-01-26 | GSE165470 | GEO
Project description:ObjectiveHigh-resolution vessel wall imaging (HR-VWI) has emerged as a valuable tool in assessing unruptured intracranial aneurysms (UIAs). There is no standardized method to quantify contrast enhancement of the aneurysm wall. Contrast enhancement can be objectively measured as signal intensity (SI) or subjectively adjudicated. In this study, the authors compared the different methods to quantify wall enhancement of UIAs and determined the sensitivity and specificity of each method as a surrogate of aneurysm instability. They also compared SI quantification between scanners from different manufacturers.MethodsThe University of Iowa HR-VWI Project database was analyzed. This database compiles patients with UIAs who prospectively underwent HR-VWI using a 3T MRI scanner. The mean and maximal SI values of the aneurysm wall, pituitary stalk, and genu of the corpus callosum were used to compare 3 different measurement methods: 1) aneurysm enhancement ratio AER = (SIwall post - SIwall pre)/SIwall pre; 2) aneurysm-to-pituitary stalk contrast ratio CRstalk = SIwall post/SIstalk post; and 3) aneurysm enhancement index AEI = ([SIwall post/SIbrain post] - [SIwall pre/SIbrain pre])/(SIwall pre/SIbrain pre) (where "pre" indicates precontrast images and "post" indicates postcontrast images). Size ≥ 7 mm was used as a surrogate of aneurysm instability for receiver operating characteristic (ROC) curve analysis. To determine if the objective quantification of SI varies among scanners from different manufacturers, 9 UIAs underwent the same HR-VWI protocol using a 3T General Electric (GE) scanner and a 3T Siemens scanner. Three UIAs also underwent a third scanning procedure on a unit with a different magnet strength (7T GE).ResultsEighty patients with 102 UIAs were included in the study. The mean age was 64.5 ± 12.2 years, and 64 (80%) patients were women. UIAs ≥ 7 mm had significantly higher SIs than smaller UIAs (< 7 mm): AER = 0.82 vs 0.49, p < 0.001; CRstalk = 0.84 vs 0.61, p < 0.001; and AEI = 0.81 vs 0.48, p < 0.001. ROC curves demonstrated optimal sensitivity of 81.5% for CRstalk ≥ 0.60, 75.9% for AEI ≥ 0.50, and 74.1% for AER ≥ 0.49. Intermanufacturer correlation between 3T GE and 3T Siemens MRI scanners for CRstalk using mean and maximal SI values was excellent (Pearson coefficients > 0.80, p < 0.001). A similar correlation was identified among the 3 UIAs that underwent 7T imaging.ConclusionsCRstalk using maximal SI values was the most reliable objective method to quantify enhancement of UIAs on HR-VWI. The same ratios were obtained between different manufacturers and on scans obtained using magnets of different strengths.
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