Dataset Information

Homocysteine-Enhanced Proteolytic and Fibrinolytic Processes in Thin Intraluminal Thrombus and Adjacent Wall of Abdominal Aortic Aneurysm: Study In Vitro.

ABSTRACT: Homocysteine (Hcy) may affect the pathogenesis of abdominal aortic aneurysms (AAAs) through enhancement of proteolysis and an impaired coagulation/fibrinolysis system. Intensified haemostatic capacity may promote local proteolytic degradation of the aortic wall. This study aimed to examine the effects of Hcy on haemostatic and proteolytic processes in samples of thick and thin fragments of the ILT and underlying walls. Subjects and Methods. Thirty-six patients who underwent AAA surgery were enrolled. Aneurysm tissue sections were incubated with DL-Hcy (100 and 500 ?mol/L) in a series of experiments and analyzed for concentration/activity of proteolytic and haemostatic markers by enzyme-linked immunosorbent assay. Results. Incubation of wall underlying thin ILT segments (B) with DL-Hcy resulted in an increase of active MMP-2 levels compared to control tissue (9.54 ± 5.88 versus 7.44 ± 4.48, p=0.011). DL-Hcy also induced t-PA and plasminogen concentration increases in thin thrombus sections (B1) compared to control tissue (respectively: 1.39 ± 1.65 versus 0.84 ± 0.74, p=0.024; 11.64 ± 5.05 versus 10.34 ± 5.52, p=0.018). In contrast, wall adjacent to thick thrombus segments (A) showed decreases in MMP-2 and TF activities compared to control (respectively, 5.89 ± 3.39 versus 7.26 ± 5.49, p=0.046; 67.13 ± 72.59 versus 114.46 ± 106.29, p=0.007). In thick ILT sections (A1), DL-Hcy decreased MMP-2 activity and t-PA and plasminogen concentrations compared to control tissue (respectively, 2.53 ± 2.02 versus 3.28 ± 2.65, p=0.006; 0.67 ± 0.57 versus 0.96 ± 0.91, p=0.021; 9.25 ± 4.59 versus 12.63 ± 9.56, p=0.017). In addition, analysis revealed positive correlations at all sites between activities/concentrations of MMP-2, TF, and PAI-1 measured in control tissues and after incubation with DL-Hcy. Conclusions. These data indicate the potential for excess Hcy to enhance damage of arterial wall in thinner AAA segments as a result of the increased activity of MMP-2 and fibrinolytic factors.

SUBMITTER: Siennicka A

PROVIDER: S-EPMC6311307 | biostudies-other | 2018

REPOSITORIES: biostudies-other

ACCESS DATA

Publications

Homocysteine-Enhanced Proteolytic and Fibrinolytic Processes in Thin Intraluminal Thrombus and Adjacent Wall of Abdominal Aortic Aneurysm: Study In Vitro.

Siennicka Aldona A Zuchowski Marta M Chełstowski Kornel K Cnotliwy Miłosław M Clark Jeremy Simon JS Jastrzębska Maria M

BioMed research international 20181212

Homocysteine (Hcy) may affect the pathogenesis of abdominal aortic aneurysms (AAAs) through enhancement of proteolysis and an impaired coagulation/fibrinolysis system. Intensified haemostatic capacity may promote local proteolytic degradation of the aortic wall. This study aimed to examine the effects of Hcy on haemostatic and proteolytic processes in samples of thick and thin fragments of the ILT and underlying walls. <i>Subjects and Methods</i>. Thirty-six patients who underwent AAA surgery we ...[more]

PMID: 30643799

Similar Datasets

Project description:BackgroundAbdominal aortic aneurysms (AAAs) represent a complex multifactorial hemodynamic, thrombotic, and inflammatory process that can ultimately result in aortic rupture and death. Despite improved screening and surgical management of AAAs, the mortality rates have remained high after rupture, and little progress has occurred in the development of nonoperative treatments. Intraluminal thrombus (ILT) is present in most AAAs and might be involved in AAA pathogenesis. The present review examined the latest clinical and experimental evidence for possible involvement of the ILT in AAA growth and rupture.MethodsA literature review was performed after a search of the PubMed database from 2012 to June 2020 using the terms "abdominal aortic aneurysm" and "intraluminal thrombus."ResultsThe structure, composition, and hemodynamics of ILT formation and propagation were reviewed in relation to the hemostatic and proteolytic factors favoring ILT deposition. The potential effects of the ILT on AAA wall degeneration and rupture, including a review of the current controversies regarding the position, thickness, and composition of ILT, are presented. Although initially potentially protective against increased wall stress, increasing evidence has shown that an increased volume and greater age of the ILT have direct detrimental effects on aortic wall integrity, which might predispose to an increased rupture risk.ConclusionsILT does not appear to be an innocent bystander in AAA pathophysiology. However, its exact role remains elusive and controversial. Despite computational evidence of a possible protective role of the ILT in reducing wall stress, increasing evidence has shown that the ILT promotes AAA wall degeneration in humans and in animal models. Further research, with large animal models and with more chronic ILT is crucial for a better understanding of the role of the ILT in AAAs and for the potential development of targeted therapies to slow or halt AAA progression.

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.

Project description:BACKGROUND:Abdominal aortic aneurysm (AAA) wall inflammation and mechanical structural stress may influence AAA expansion and lead to rupture. We hypothesized a positive correlation between structural stress and fluorine-18-labeled 2-deoxy-2-fluoro-d-glucose (18F-FDG) positron emission tomography-defined inflammation. We also explored the influence of computed tomography-derived aneurysm morphology and composition, including intraluminal thrombus, on both variables. METHODS AND RESULTS:Twenty-one patients (19 males) with AAAs below surgical threshold (AAA size was 4.10±0.54 cm) underwent 18F-FDG positron emission tomography and contrast-enhanced computed tomography imaging. Structural stresses were calculated using finite element analysis. The relationship between maximum aneurysm 18F-FDG standardized uptake value within aortic wall and wall structural stress, patient clinical characteristics, aneurysm morphology, and compositions was explored using a hierarchical linear mixed-effects model. On univariate analysis, local aneurysm diameter, thrombus burden, extent of calcification, and structural stress were all associated with 18F-FDG uptake (P<0.05). AAA structural stress correlated with 18F-FDG maximum standardized uptake value (slope estimate, 0.552; P<0.0001). Multivariate linear mixed-effects analysis revealed an important interaction between structural stress and intraluminal thrombus in relation to maximum standardized uptake value (fixed effect coefficient, 1.68 [SE, 0.10]; P<0.0001). Compared with other factors, structural stress was the best predictor of inflammation (receiver-operating characteristic curve area under the curve =0.59), with higher accuracy seen in regions with high thrombus burden (area under the curve =0.80). Regions with both high thrombus burden and high structural stress had higher 18F-FDG maximum standardized uptake value compared with regions with high thrombus burdens but low stress (median [interquartile range], 1.93 [1.60-2.14] versus 1.14 [0.90-1.53]; P<0.0001). CONCLUSIONS:Increased aortic wall inflammation, demonstrated by 18F-FDG positron emission tomography, was observed in AAA regions with thick intraluminal thrombus subjected to high mechanical stress, suggesting a potential mechanistic link underlying aneurysm inflammation.

Project description:BACKGROUND:Intraluminal thrombus (ILT) signal intensity on MRI has been studied as a potential marker of abdominal aortic aneurysm (AAA) progression. PURPOSE:1) To characterize the relationship between ILT signal intensity and AAA diameter; 2) to evaluate ILT change over time; and 3) to assess the relationship between ILT features and AAA growth. STUDY TYPE:Prospective. SUBJECTS:Eighty AAA patients were imaged, and a subset (n?=?41) were followed with repeated MRI for 16?±?9?months. FIELD STRENGTH/SEQUENCE:3D black-blood fast-spin-echo sequence at 3?T. ASSESSMENT:ILT was designated as "bright" if the signal was greater than 1.2 times that of adjacent psoas muscle. AAAs were divided into three groups based on ILT: Type 1: bright ILT; Type 2: isointense ILT; Type 3: no ILT. During follow-up, an active ILT change was defined as new ILT formation or an increase in ILT signal intensity to bright; stable ILT was defined as no change in ILT type or ILT became isointense from bright previously. STATISTICAL TESTS:Shapiro-Wilk test; Mann-Whitney U-test; Fisher's exact test; Kruskal-Wallis test; Spearman's r; intraclass correlation coefficient (ICC), Cohen's kappa. RESULTS:AAAs with Type 1 ILT were larger than those with Types 2 and 3 ILT (5.1?±?1.1?cm, 4.4?±?0.9?cm, 4.2?±?0.8?cm, P?=?0.008). The growth rate of AAAs with Type 1 ILT was significantly greater than that of AAAs with Types 2 and 3 ILT (2.6?±?2.5, 0.6?±?1.3, 1.5?±?0.6?mm/year, P?=?0.01). During follow-up, AAAs with active ILT changes had a 3-fold increased growth rate compared with AAAs with stable ILT (3.6?±?3.0?mm/year vs. 1.2?±?1.5?mm/year, P?=?0.008). DATA CONCLUSION:AAAs with bright ILT are larger in diameter and grow faster. Active ILT change is associated with faster AAA growth. Black-blood MRI can characterize ILT features and monitor their change over time, which may provide new insights into AAA risk assessment. LEVEL OF EVIDENCE:2 Technical Efficacy Stage: 5 J. Magn. Reson. Imaging 2019;50:994-1001.

Project description:Abdominal aortic aneurysms (AAAs) involve chronic overexpression of proteases in the aortic wall that result in disruption of elastic fibers and consequent loss of vessel elasticity. Nearly 75% of AAAs contain flow-obstructing, fibrin-rich intraluminal thrombi (ILT), which act as a) a bioinert shield, protecting the underlying AAA wall from high hemodynamic stresses, and b) a reservoir of inflammatory cells and proteases that cause matrix breakdown. For these reasons, restoring flow through the aorta lumen and facilitating transmural diffusion of therapeutics from circulation to the AAA wall must be achieved by slow thrombolysis of the ILT to render it porous without rapid breakdown. Intravenously dosed tissue plasminogen activator (tPA) has been shown to rapidly lyse ILTs in acute stroke and myocardial infarctions. For future use in opening up AAA segments, in this study, we investigated the ability of tPA released from poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs) to slowly lyse fibrin clots without inducing proteolytic injury and matrix synthesis-inhibitory effects on cultured rat aneurysmal smooth muscle cells (EaRASMCs). Fibrin clot lysis time was greatly extended over that in presence of exogenous tPA. Surface functionalization of NPs with a cationic amphiphile allowed them to bind to anionic fibrin clot, release tPA at a slower rate and to lyse the clot as a front proceeding outwards in unlike the more rapid and homogenous lysis that occurred due to anionic PLGA NPs. Elastic matrix content was decreased in EaRASMC cultures exposed to byproducts of clot lysis with exogenous tPA, but not tPA-NPs, and was likely due to increased proteolytic activity (MMPs, plasmin) in EaRASMC cultures exposed to exogenous tPA-lysed clots. Our results suggest that gradual ILT lysis via slow release of tPA from NPs will be likely beneficial over exogenous tPA delivery in preserving elastic matrix content and attenuating matrilysis in the adjoining AAA wall, in vivo, while rendering the ILT porous to facilitate transmural delivery of endoluminally delivered AAA therapeutics.

Dataset Information

Homocysteine-Enhanced Proteolytic and Fibrinolytic Processes in Thin Intraluminal Thrombus and Adjacent Wall of Abdominal Aortic Aneurysm: Study In Vitro.

Publications

Homocysteine-Enhanced Proteolytic and Fibrinolytic Processes in Thin Intraluminal Thrombus and Adjacent Wall of Abdominal Aortic Aneurysm: Study In Vitro.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets