Growth Rate of Small Abdominal Aortic Aneurysms and Genetic Polymorphisms of Matrix MetalloProteases-1, -3, and -9.
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SUBMITTER: Adovasio R
PROVIDER: S-EPMC4870053 | biostudies-literature | 2016 Jun
REPOSITORIES: biostudies-literature
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Growth Rate of Small Abdominal Aortic Aneurysms and Genetic Polymorphisms of Matrix MetalloProteases-1, -3, and -9.
Adovasio Roberto R Calvagna Cristiano C Sgorlon Giada G Zamolo Francesca F Mearelli Filippo F Biolo Gianni G Grassi Gabriele G Fiotti Nicola N
The International journal of angiology : official publication of the International College of Angiology, Inc 20150904 2
Genetic variants of matrix metalloproteases (MMPs)-1, -3, and 9, together with clinical variables, might predict the growth rate (GR) of abdominal aortic aneurysm (AAA). Genotyping of MMP-1 (-1,607 G+/G-), MMP-3 (- 1,171 6A/5A), and MMP-9 microsatellite (13-26 cytosine-adenosine repeats around -90) from peripheral blood was performed in 137 AAA patients with two AAA diameter measurements (at least 3 months to 1 year apart). When the same technique (either ultrasound or computed tomography) was u ...[more]
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Project description:BACKGROUND:An abdominal aortic aneurysm (AAA) is an abnormal ballooning of the major abdominal artery. Some AAAs present as emergencies and require surgery; others remain asymptomatic. Treatment of asymptomatic AAAs depends on many factors but an important one is size of the aneurysm, as risk of rupture increases with aneurysm size. Large asymptomatic AAAs (> 5.5 cm in diameter) are usually operated on; very small AAAs (< 4.0 cm diameter) are monitored with ultrasonography. The optimal timing of surgery would benefit from further evidence. OBJECTIVES:This review compared long-term survival in patients with AAAs of diameter 4.0 to 5.5 cm who received immediate repair versus routine ultrasound surveillance. SEARCH METHODS:For this update the Cochrane Peripheral Vascular Diseases Group searched their Specialised Register (February 2012) and CENTRAL (2012, Issue 1). Reference lists of relevant articles were checked for additional studies and the searches were supplemented by handsearches of recent conference proceedings and information from experts in the field. SELECTION CRITERIA:Randomised controlled trials in which men and women with asymptomatic AAAs of diameter 4.0 to 5.5 cm were randomly allocated to immediate repair or imaging-based surveillance at least every six months. Outcomes had to include mortality or survival. DATA COLLECTION AND ANALYSIS:Two authors (GF, MAMM) abstracted the data, which were cross-checked by the other authors (DJB, JTP). Due to the small number of trials, formal tests of heterogeneity and sensitivity analyses were not conducted. MAIN RESULTS:Four trials with a combined total of 3314 patients, the UK Small Aneurysm Trial (UKSAT), the Aneurysm Detection and Management (ADAM) trial, the Comparison of Surveillance Versus Aortic Endografting for Small Aneurysm Repair (CAESAR), and the Positive Impact of Endovascular Options for treating Aneurysms Early (PIVOTAL) fulfilled the inclusion criteria. The four trials showed an early survival benefit in the surveillance group (due to 30-day operative mortality with surgery) but no significant differences in long-term survival (adjusted hazard ratio (HR) 0.88, 95% confidence interval (CI) 0.75 to 1.02, mean follow up 10 years (UKSAT); HR 1.21, 95% CI 0.95 to 1.54, mean follow up 4.9 years (ADAM); HR 0.76, 95% CI 0.30 to 1.93, median follow up 32.4 months (CAESAR); HR 1.01, 95% CI 0.49 to 2.07, mean follow up 20 months (PIVOTAL)). The meta analyses of mortality at one year (CAESAR and PIVOTAL only) and six years (UKSAT and ADAM only) revealed a non-significant association (Peto odds ratio at one year 1.15, 95% CI 0.59 to 2.25; Peto odds ratio at six years 1.11, 95% CI 0.91 to 1.34). AUTHORS' CONCLUSIONS:The results from the four trials to date demonstrate no advantage to early repair (via open or endovascular surgery) for small AAA (4.0 to 5.5 cm) and suggest that 'best care' for these patients favours surveillance. Furthermore, the more recent trials focused on the efficacy of endovascular aneurysm repair and still failed to show benefit. Thus, both open and endovascular repair of small AAAs are not supported by currently available evidence.
| S-EPMC4175535 | biostudies-other
Project description:BackgroundThe most relevant determinant in scheduling monitoring intervals for abdominal aortic aneurysms (AAAs) is maximum diameter. The aim of the study was to develop a statistical model that takes into account specific characteristics of AAA growth distributions such as between-patient variability as well as within-patient variability across time, and allows probabilistic statements to be made regarding expected AAA growth.MethodsCT angiography (CTA) data from patients monitored at 6-month intervals with maximum AAA diameters at baseline between 30 and 66 mm were used to develop the model. By extending the model of geometric Brownian motion with a log-normal random effect, a stochastic growth model was developed. An additional set of ultrasound-based growth data was used for external validation.ResultsThe study data included 363 CTAs from 87 patients, and the external validation set comprised 390 patients. Internal and external cross-validation showed that the stochastic growth model allowed accurate description of the distribution of aneurysm growth. Median relative growth within 1 year was 4.1 (5-95 per cent quantile 0.5-13.3) per cent. Model calculations further resulted in relative 1-year growth of 7.0 (1.0-16.4) per cent for patients with previously observed rapid 1-year growth of 10 per cent, and 2.6 (0.3-8.3) per cent for those with previously observed slow growth of 1 per cent. The probability of exceeding a threshold of 55 mm was calculated to be 1.78 per cent at most when adhering to the current RESCAN guidelines for rescreening intervals. An online calculator based on the fitted model was made available.ConclusionThe stochastic growth model was found to provide a reliable tool for predicting AAA growth.
| S-EPMC10364708 | biostudies-literature
Project description:Abdominal aortic aneurysms (AAA) are characterized by a progressive dilatation of the abdominal aorta, and are associated with a high risk of rupture once the dilatation exceeds 55 mm in diameter. A large proportion of AAA develops an intraluminal thrombus, which contributes to hypoxia, inflammation and tissue degradation. We have previously shown that patients with AAA produce clots with altered structure which is more resistant to fibrinolysis. The aim of this study was to investigate genetic polymorphisms of FXIII and fibrinogen in AAA to identify how changes to these proteins may play a role in the development of AAA.Subjects of Western/European descent, ?55 years of age (520 AAA patients and 449 controls) were genotyped for five polymorphisms (FXIII-A Val34Leu, FXIII-B His95Arg, FXIII-B Splice Variant (intron K nt29576C-G), Fib-A Thr312Ala and Fib-B Arg448Lys) by RT-PCR. Data were analysed by ?2 test and CubeX.The FXIII-B Arg95 allele associated with AAA (Relative risk - 1.240, CI 1.093-1.407, P = 0.006). There was no association between FXIII-A Val34Leu, FXIII-B Splice Variant, Fib-A Thr312Ala or Fib-B Arg448Lys and AAA. FXIII-B His95Arg and FXIII-B Splice variant (intron K nt29576C-G) were in negative linkage disequilibrium (D' = -0.609, p = 0.011).The FXIII-B Arg95 variant is associated with an increased risk of AAA. These data suggest a possible role for FXIII in AAA pathogenesis.
| S-EPMC4226572 | biostudies-literature
Project description:BACKGROUND:The natural history of abdominal aortic aneurysms (AAAs) suggests that some remain slow in growth rate whereas many develop a more accelerated growth rate and reach a threshold for intervention. We hypothesized that different mechanisms are responsible for AAAs that remain slow growing and never become actionable vs the aggressive AAAs that require intervention and may be reflected by distinct associations with genetic polymorphisms. METHODS:AAA growth rate was determined from serial imaging data in 168 control and 141 AAA patients with ultrasound or computed tomography imaging studies covering ?5 years. Genetic polymorphisms all previously reported as showing a significant correlation with AAA with functional effects on the expression or function were determined by analysis of the genomic DNA, including angiotensin 1 receptor (rs5186), interleukin-10 (IL-10; rs1800896), methyl-tetrahydrofolate reductase (rs1801133), low-density lipoprotein receptor-related protein 1 (LRP1; rs1466535), angiotensin-converting enzyme (rs1799752), and several matrix metalloproteinase 9 (MMP-9) single nucleotide polymorphisms. RESULTS:Of the AAA patients, 81 were classified as slow AAA growth rate (<3.25 mm/y) vs 60 with aggressive AAA growth rate (>3.25 mm/y, those presenting with a rupture, or those with maximal aortic diameter >5.5 cm [male] or >5.0 cm [female]). Discriminating confounds between the groups were identified by logistic regression. Analyses identified MMP-9 p-2502 single nucleotide polymorphism (odds ratio [OR], 0.54; 95% confidence interval [CI], 0.31-0.94; P = .029) as a significant confound discriminating between control vs slow-growth AAA, MMP-9 D165N (OR, 0.49; 95% CI, 0.26-0.95; P = .035) and LRP1 (OR, 4.99; 95% CI, 1.13-22.1; P = .034) between control vs aggressive-growth AAAs, and methyltetrahydrofolate reductase (OR, 2.99; 95% CI, 1.01-8.86; P = .048), MMP-9 p-2502 (OR, 2.19; 95% CI, 1.05-4.58; P = .037), and LRP1 (OR, 4.96; 95% CI, 1.03-23.9; P = .046) as the statistically significant confounds distinguishing slow-growth AAAs vs aggressive-growth AAAs. CONCLUSIONS:Logistic regression identified different genetic confounds for the slow-growth and aggressive-growth AAAs, indicating a potential for different genetic influences on AAAs of distinct aggressiveness. Future logistic regression studies investigating for potential genetic or clinical confounds for this disease should take into account the growth rate and size of the AAA to better identify confounds likely to be associated with aggressive AAAs likely to require intervention.
| S-EPMC4176942 | biostudies-literature
Project description:Abdominal aortic aneurysms (AAAs) are characterized by histologic signs of chronic inflammation, destructive remodeling of extracellular matrix, and depletion of vascular smooth muscle cells. We investigated the process of extracellular matrix remodeling by performing a genetic association study with polymorphisms in the genes for matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and structural extracellular matrix molecules in AAA. Our hypothesis was that genetic variations in one or more of these genes contribute to greater or lesser activity of these gene products, and thereby contribute to susceptibility for developing AAAs.DNA samples from 812 unrelated white subject (AAA, n = 387; controls, n = 425) were genotyped for 14 polymorphisms in 13 different candidate genes: MMP1(nt-1607), MMP2(nt-955), MMP3(nt-1612), MMP9(nt-1562), MMP10(nt+180), MMP12(nt-82), MMP13(nt-77), TIMP1(nt+434), TIMP1(rs2070584), TIMP2(rs2009196), TIMP3(nt-1296), TGFB1(nt-509), ELN(nt+422), and COL3A1(nt+581). Odds ratios and P values adjusted for gender and country of origin using logistic regression and stratified by family history of AAA were calculated to test for association between genotype and disease status. Haplotype analysis was carried out for the two TIMP1 polymorphisms in male subjects.Analyses with one polymorphism per test without interactions showed an association with the two TIMP1 gene polymorphisms (nt+434, P = .0047; rs2070584, P = .015) in male subjects without a family history of AAA. The association remained significant when analyzing TIMP1 haplotypes (chi 2 P = .014 and empirical P = .009). In addition, we found a significant interaction between the polymorphism and gender for MMP10 ( P = .037) in cases without a family history of AAA, as well as between the polymorphism and country of origin for ELN ( P = .0169) and TIMP3 ( P = .0023) in cases with a family history of AAA.These findings suggest that genetic variations in TIMP1, TIMP3, MMP10, and ELN genes may contribute to the pathogenesis of AAAs. Further work is needed to confirm the findings in an independent set of samples and to study the functional role of these variants in AAA. It is noteworthy that contrary to a previous study, we did not find an association between the MMP9 (nt-1562) polymorphism and AAA, suggesting genetic heterogeneity of the disease.Abdominal aortic aneurysms (AAAs) are an important cardiovascular disease, but the genetic and environmental risk factors, which contribute to individual's risk to develop an aneurysm, are poorly understood. Histologically, AAAs are characterized by signs of chronic inflammation, destructive remodeling of the extracellular matrix, and depletion of vascular smooth muscle cells. We hypothesized that genes involved in these events could harbor changes that make individuals more susceptible to developing aneurysms. This study identified significant genetic associations between DNA sequence changes in tissue inhibitor of metalloproteinase 1 (TIMP1), TIMP3, matrix metalloproteinase 10 (MMP10) and elastin (ELN) genes, and AAA. The results will require confirmation using an independent set of samples. After replication it is possible that these sequence changes in combination with other risk factors could be used in the future to identify individuals who are at increased risk for developing an AAA.
| S-EPMC1249499 | biostudies-literature
Project description:Background Intraluminal thrombus (ILT) within abdominal aortic aneurysms (AAAs) may be a potential marker for subsequent aneurysm growth. Purpose To investigate the role of ILT in AAA progression as assessed with CT and MRI. Materials and Methods This was a retrospective study, with patient data included from January 2004 to December 2018 at a Veteran Affairs medical center. Male patients with AAA who underwent contrast material-enhanced CT at baseline and CT or black-blood MRI at follow-up (minimal follow-up duration of 6 months) were included. The maximal AAA diameter was measured with multiplanar reconstruction, and the annual growth rate of aneurysms was calculated. Uni- and multivariable linear regression analyses were used to determine the relationship between demographic and imaging factors and aneurysm growth. Results A total of 225 patients (mean age, 72 years ± 9 [standard deviation]) were followed for a mean of 3.3 years ± 2.5. A total of 207 patients were followed up with CT, and 18 were followed up with MRI. At baseline, the median size of the AAA was 3.8 cm (interquartile range [IQR], 3.3-4.3 cm); 127 of 225 patients (54.7%) had ILT. When compared with AAAs without ILT, AAAs with ILT had larger baseline diameters (median, 4.1 cm [IQR, 3.6-4.8 cm] vs 3.4 cm [IQR, 3.2-3.9 cm]; P < .001) and faster growth rates (median, 2.0 mm/y [IQR, 1.3-3.2 mm/y] vs 1.0 mm/y [IQR, 0.4-1.8 mm/y]; P < .001). Small AAAs (size range, 3-4 cm) with ILT grew 1.9-fold faster than did those without ILT (median, 1.5 mm/y [IQR, 0.9-2.7 mm/y] vs 0.8 mm/y [IQR, 0.3-1.5 mm/y]; P < .001). Medium AAAs (size range, 4-5 cm) with ILT had 1.2-fold faster growth than did those without ILT (median growth, 2.1 mm/y [IQR, 1.4, 3.7 mm/y] vs 1.8 mm/y [IQR, 0.9, 2.0 mm/y]; P = .06). In multivariable analysis, baseline diameter and ILT were independently positively related to aneurysm growth rate (standardized regression coefficient, 0.43 [P < .001] and 0.15 [P = .02], respectively). Conclusion Both maximal cross-sectional aneurysm diameter and the presence of intraluminal thrombus are independent predictors of abdominal aortic aneurysm growth. © RSNA, 2020 Online supplemental material is available for this article.
| S-EPMC7051169 | biostudies-literature
Project description:ImportanceCurrently there is no drug therapy for abdominal aortic aneurysm (AAA).ObjectiveTo test the efficacy of the angiotensin receptor blocker telmisartan in slowing AAA growth in the Telmisartan in the Management of Abdominal Aortic Aneurysm (TEDY) trial.Design, setting, and participantsA randomized, double-blind, placebo-controlled trial recruited participants between September 6, 2011, and October 5, 2016, to evaluate the efficacy of telmisartan treatment in patients with AAA. Participants with 35- to 49-mm AAAs recruited from Australia, the Netherlands, and the US were randomized 1:1 to receive telmisartan, 40 mg, or identical placebo. Analyses were conducted according to intention-to-treat principles. Final follow-up was conducted on October 11, 2018, and data analysis was performed between June and November 2019.InterventionTelmisartan, 40 mg, or identical placebo.Main outcomes and measuresThe primary outcome of the difference in AAA growth, assessed on core imaging laboratory-read ultrasonographic scanning, was tested with linear mixed-effects models. Other outcomes included effects on blood pressure, computed tomographic (CT)-measured AAA diameter and volume, time to AAA-related events (AAA repair or mortality due to AAA rupture), and health-related quality of life.ResultsOf 300 intended participants, 210 were enrolled and randomized to receive telmisartan (n = 107) or placebo (n = 103). Of patients included in the intention-to-treat analysis (telmisartan: n = 106, placebo: n = 101), 183 were men (88%); mean (SD) age was 73.5 (7.9) years. At 1 year, participants receiving telmisartan had mean lower systolic (8.9; 95% CI, 4.1-13.8 mm Hg; P < .001) and diastolic (7.0; 4.3-9.8 mm Hg; P < .001) blood pressure levels compared with participants receiving placebo. A total of 188 participants (91%) received at least 2 ultrasonographic scans and 133 participants (64%) had at least 2 CT scans. There was no significant difference in ultrasonographic-assessed AAA growth rates among those assigned telmisartan (1.68 mm/y) or placebo (1.78 mm/y): mean difference, -0.11 mm/y (95% CI, -0.60 to 0.38 mm/y; P = .66). Telmisartan had no significant effects on AAA growth assessed by CT-measured AAA diameter (mean difference, -0.01 mm/y; 95% CI, -0.02 to 0.01 mm/y; P = .23) or volume (mean difference, -0.02 cm3/y; 95% CI, -0.04 to 0.00 cm3/y; P = .11), AAA-related events (relative risk, 1.35; 95% CI, 0.54-3.35; P = .52), or health-related quality of life (mean difference in physical component score at 24 months, 0.4; 95% CI, 0.4-0.4; P = .80). Hypotensive symptoms (eg, syncope) were twice as common among participants receiving telmisartan compared with placebo (28 [26%] vs 13 [13%]; P = .02), but overall adverse event rates were otherwise similar for both groups.Conclusions and relevanceThis underpowered study did not show a treatment effect for telmisartan on small AAA growth. Future trials will need to ensure adequate sample size and duration of follow-up.Trial registrationsanzctr.org.au Identifier: ACTRN12611000931976; ClinicalTrials.gov Identifier: NCT01683084.
| S-EPMC7450408 | biostudies-literature
Project description:Aneurysm hemodynamics is known for its crucial role in the natural history of abdominal aortic aneurysms (AAA). However, there is a lack of well-developed quantitative assessments for disturbed aneurysmal flow. Therefore, we aimed to develop innovative metrics for quantifying disturbed aneurysm hemodynamics and evaluate their effectiveness in predicting the growth status of AAAs, specifically distinguishing between fast-growing and slowly-growing aneurysms. The growth status of aneurysms was classified as fast (≥ 5 mm/year) or slow (< 5 mm/year) based on serial imaging over time. We conducted computational fluid dynamics (CFD) simulations on 70 patients with computed tomography (CT) angiography findings. By converting hemodynamics data (wall shear stress and velocity) located on unstructured meshes into image-like data, we enabled spatial pattern analysis using Radiomics methods, referred to as "Hemodynamics-informatics" (i.e., using informatics techniques to analyze hemodynamic data). Our best model achieved an AUROC of 0.93 and an accuracy of 87.83%, correctly identifying 82.00% of fast-growing and 90.75% of slowly-growing AAAs. Compared with six classification methods, the models incorporating hemodynamics-informatics exhibited an average improvement of 8.40% in AUROC and 7.95% in total accuracy. These preliminary results indicate that hemodynamics-informatics correlates with AAAs' growth status and aids in assessing their progression.
| S-EPMC10449842 | biostudies-literature
Project description:This study determined whether relaxin or matrix metalloproteinase (MMP)-9 influences angiotensin II (AngII)-induced abdominal aortic aneurysms (AAA).Methods?and?Results:Male C57BL/6 or apolipoprotein E-/-mice were infused with AngII with or without relaxin. Relaxin did not influence AngII-induced AAA in either mouse strain. Infusion of AngII reduced, but relaxin increased, MMP-9 mRNA in macrophages. We then determined the effects of MMP-9 deficiency on AAA in apolipoprotein E-/-mice. MMP-9 deficiency led to AAA formation in the absence of AngII, and augmented AngII-induced aortic rupture and AAA incidence.MMP-9 deficiency augmented AngII-induced AAA.
| S-EPMC5964022 | biostudies-literature
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