Proteolytically active ADAM10 and ADAM17 carried on membrane microvesicles in human abdominal aortic aneurysms.

The intraluminal thrombus (ILT) of human abdominal aortic aneurysm (AAA) has been suggested to damage the underlying aortic wall, but previous work found scant activity of soluble proteases in the abluminal layer of the ILT, adjacent to the aneurysm. We hypothesised that transmembrane proteases carried by membrane microvesicles (MV) from dying cells remain active in the abluminal ILT. ILTs and AAA segments collected from 21 patients during surgical repair were assayed for two major transmembrane proteases, ADAM10 (a disintegrin and metalloprotease-10) and ADAM17. We also exposed cultured cells to tobacco smoke and assessed ADAM10 and ADAM17 expression and release on MVs. Immunohistochemistry showed abundant ADAM10 and ADAM17 protein in the ILT and underlying aneurysmal aorta. Domain-specific antibodies indicated both transmembrane and shed ADAM17. Importantly, ADAM10 and ADAM 17 in the abluminal ILT were enzymatically active. Electron microscopy of abluminal ILT and aortic wall showed MVs with ADAM10 and ADAM17. By flow cytometry, ADAM-positive microvesicles from abluminal ILT carried the neutrophil marker CD66, but not the platelet marker CD61. Cultured HL60 neutrophils exposed to tobacco smoke extract showed increased ADAM10 and ADAM17 content, cleavage of these molecules into active forms, and release of MVs carrying mature ADAM10 and detectable ADAM17. In conclusion, our results implicate persistent, enzymatically active ADAMs on MVs in the abluminal ILT, adjacent to the aneurysmal wall. The production of ADAM10- and ADAM17-positive MVs from smoke-exposed neutrophils provides a novel molecular mechanism for the vastly accelerated risk of AAA in smokers.

The receptor for advanced glycation end products and risk of peripheral arterial disease, amputation or death in type 2 diabetes: a population-based cohort study.

BACKGROUND: Patients with type 2 diabetes have a high risk for early and extensive development of peripheral arterial disease (PAD) and this excess risk is not explained by increased burden of traditional atherosclerotic risk factors. Activation of the receptor for advanced glycation end products (RAGE) could be one additional mechanism for accelerated PAD and increased risk for amputation and death. We investigated the association between RAGE plasma components and the risk for PAD, amputation and death in patients with type 2 diabetes. We also estimated the rate of amputation-free survival and survival without PAD. METHODS: We investigated if plasma levels of carboxymethyl-lysine, S100A12 and endosecretory RAGE (esRAGE) were associated with two endpoints: survival without development of PAD and survival without amputation in a 12 years prospective population-based cohort of 146 patients with type 2 diabetes, free from PAD at inclusion. Influence of baseline plasma levels of RAGE ligands (individually and combined by a RAGE-score) were evaluated for both endpoints in the Cox-regression analysis. RESULTS: 106 patients survived without amputation and 93 survived without signs of PAD during follow up. Higher levels of S100A12 and RAGE-score were associated with increased risk for amputation or death, hazard ratios (HR) 1.29; 95% confidence interval (CI) [1.04, 1.59] and 1.79; 95% CI [1.07, 2.99] and with increased risk for PAD or death, HR 1.22; 95% CI [1.00, 1.49] and 1.56; [1.00, 2.44] after adjustment for age and sex. The effect was decreased after adjustment for Framingham cardiovascular disease score: risk for amputation or death, HR 1.17; 95% CI [0.94, 1.46] and 1.54; [0.95, 2.49], and risk for PAD or death, HR 1.12; 95% CI [0.91, 1.38] and 1.38; [0.91, 2.11] for S100A12 and RAGE-score respectively. The incidence for amputation or death was 2.8 per 100 person-years; 95% CI [2.0, 3.7] and the incidence rate for PAD or death was 3.6 per 100 person-years; 95% CI [2.7, 4.8]. CONCLUSION: Higher plasma levels of S100A12 and the combined effect (RAGE-score) of esRAGE, carboxymethyl-lysine and S100A12 seem to be associated with shorter PAD- and amputation-free survival in patients with type 2 diabetes. This may indicate a role for S100A12 in PAD by activation of the RAGE system.

Differences in Elastin and Elastolytic Enzymes between Men and Women with Abdominal Aortic Aneurysm.

BACKGROUND: Abdominal aortic aneurysms (AAAs) in women differ in some important aspects from those in men. The lower prevalence rate, higher rupture rate and potentially increased growth rate in women with AAA suggest gender to be of importance for aneurysm development and progression. The aim of the study was to analyze wall properties with respect to synthesis and destruction of elastin in men and women with AAA, with and without an intraluminal thrombus. METHODS: Patient characteristics and aneurysm wall biopsies were collected from all women (n = 14) treated with open repair for AAA, 2008-2012, and men with similar aneurysm diameter and similar age (n = 23) treated during the same time period. The expressions of elastin, matrix metalloproteinase (MMP)-2 and -9, and cathepsin K were quantified by immunohistochemistry, Western blot, and gene expression analysis on the aneurysm wall. RESULTS: The protein expression of elastin was less in women than in men in the non-thrombus-covered aneurysm wall. In addition, the protein and mRNA expressions of MMP-9 were higher in women (-0.83 versus 0.09, P = 0.041). There was no difference in elastin and elastolytic enzymes between men and women in the thrombus-covered aneurysm wall. CONCLUSION: Less elastin in the non-thrombus-covered aneurysm wall in women than that in men, and the simultaneous higher level of MMP-9, suggest differences in the elastolytic process in AAA between the sexes.

Multidimensional growth measurements of abdominal aortic aneurysms.

BACKGROUND: Monitoring the expansion of abdominal aortic aneurysms (AAAs) is critical to avoid aneurysm rupture in surveillance programs, for instance. However, measuring the change of the maximum diameter over time can only provide limited information about AAA expansion. Specifically, regions of fast diameter growth may be missed, axial growth cannot be quantified, and shape changes of potential interest for decisions related to endovascular aneurysm repair cannot be captured. METHODS: This study used multiple centerline-based diameter measurements between the renal arteries and the aortic bifurcation to quantify AAA growth in 51 patients from computed tomography angiography (CTA) data. Criteria for inclusion were at least 1 year of patient follow-up and the availability of at least two sufficiently high-resolution CTA scans that allowed an accurate three-dimensional reconstruction. Consequently, 124 CTA scans were systematically analyzed by using A4clinics diagnostic software (VASCOPS GmbH, Graz, Austria), and aneurysm growth was monitored at 100 cross-sections perpendicular to the centerline. RESULTS: Monitoring diameter development over the entire aneurysm revealed the sites of the fastest diameter growth, quantified the axial growth, and showed the evolution of the neck morphology over time. Monitoring the development of an aneurysm's maximum diameter or its volume over time can assess the mean diameter growth (r = 0.69, r = 0.77) but not the maximum diameter growth (r = 0.43, r = 0.34). The diameter growth measured at the site of maximum expansion was ~16%/y, almost four times larger than the mean diameter expansion of 4.4%/y. The sites at which the maximum diameter growth was recorded did not coincide with the position of the maximum baseline diameter (ρ = 0 .12; P = .31). The overall aneurysm sac length increased from 84 to 89 mm during the follow-up (P < .001), which relates to the median longitudinal growth of 3.5%/y. The neck length shortened, on average, by 6.2% per year and was accompanied by a slight increase in neck angulation. CONCLUSIONS: Neither maximum diameter nor volume measurements over time are able to measure the fastest diameter growth of the aneurysm sac. Consequently, expansion-related wall weakening might be inappropriately reflected by this type of surveillance data. In contrast, localized spots of fast diameter growth can be detected through multiple centerline-based diameter measurements over the entire aneurysm sac. This information might further reinforce the quality of aneurysm surveillance programs.

The quasi-static failure properties of the abdominal aortic aneurysm wall estimated by a mixed experimental-numerical approach.

Assessing the risk for abdominal aortic aneurysm (AAA) rupture is critical in the management of aneurysm patients and an individual assessment is possible with the biomechanical rupture risk assessment. Such an assessment could potentially be improved by a constitutive AAA wall model that accounts for irreversible damage-related deformations. Because of that the present study estimated the elastic and inelastic properties of the AAA wall through a mixed experimental-numerical approach. Specifically, finite element (FE) models of bone-shaped tensile specimens were used to merge data from failure testing of the AAA wall with their measured collagen orientation distribution. A histo-mechanical constitutive model for collagen fibers was employed, where plastic fibril sliding determined not only remaining deformations but also weakening of the fiber. The developed FE models were able to replicate the experimentally recorded load-displacement property of all 16 AAA wall specimens that were investigated in the study. Tensile testing in longitudinal direction of the AAA defined a Cauchy strength of 569(SD 411) kPa that was reached at a stretch of 1.436(SD 0.118). The stiffness and strength of specimens decreased with the wall thickness and were elevated (p = 0.018; p = 0.030) in patients with chronic obstructive pulmonary disease (COPD). Smoking affected the tissue parameters that were related to the irreversible deformation response, and no correlation with gender and age was found. The observed effects on the biomechanical properties of the AAA wall could have long-term consequences for the management of aneurysm patients, i.e., specifically they might influence future AAA rupture risk assessments. However, in order to design appropriate clinical validation studies our findings should firstly be verified in a larger patient cohort.

Female and elderly abdominal aortic aneurysm patients more commonly have concurrent thoracic aortic aneurysm.

BACKGROUND: A recent report unexpectedly revealed that one-fourth of abdominal aortic aneurysm (AAA) patients also have an aneurysm in the thoracic aorta (TAA). It remains to be investigated which AAA patients have a higher risk of also developing TAAs. The aim of this study was to identify possible differences in the risk factor profile in AAA patients with or without a TAA. METHODS: All AAA patients attending an outpatient clinic and investigated using an abdominal and thoracic computed tomography scan were included (n = 354). Image analysis and hospital chart review were conducted. The association between comorbidity and TAA was estimated by logistic regression and odds ratios (ORs) with 95% confidence intervals (CIs). Gender-specific and neutral criteria were used. Validation of excluded patients was performed. RESULTS: Ninety-four (27%) of 354 AAA patients had a concurrent descending TAA (AAA/TAA). AAA/TAA patients were older than AAA patients (76 vs. 73 years). More women were identified in the AAA/TAA group (39% vs. 16%, P < 0.001). In the univariate logistic regression model, female gender (OR: 3.3, 95% CI: 1.9-5.6), hypertension (OR: 1.8, 95% CI: 1.1-3.0), and age (70-79 years-OR: 2.4, 95% CI: 1.3-4.6; 80-89 years-OR: 3.0, 95% CI: 1.5-6.0) were associated with concurrent TAA. In the multivariate model, only female gender and age were associated with TAA. CONCLUSIONS: AAA patients, in general, should be offered examination of the thoracic aorta, and special attention needs to be paid to female AAA patients and AAA patients at high age, if the AAA patient is considered operable. Surveillance of AAA patients must improve to enhance identification of the large group of patients who have developed, or will develop, TAAs. Future strategies will, of course, address pathophysiological aspects of aneurysmal development in the thoracic and infrarenal aorta.

An integrated fluid-chemical model toward modeling the formation of intra-luminal thrombus in abdominal aortic aneurysms.

Abdominal Aortic Aneurysms (AAAs) are frequently characterized by the presence of an Intra-Luminal Thrombus (ILT) known to influence their evolution biochemically and biomechanically. The ILT progression mechanism is still unclear and little is known regarding the impact of the chemical species transported by blood flow on this mechanism. Chemical agonists and antagonists of platelets activation, aggregation, and adhesion and the proteins involved in the coagulation cascade (CC) may play an important role in ILT development. Starting from this assumption, the evolution of chemical species involved in the CC, their relation to coherent vortical structures (VSs) and their possible effect on ILT evolution have been studied. To this end a fluid-chemical model that simulates the CC through a series of convection-diffusion-reaction (CDR) equations has been developed. The model involves plasma-phase and surface-bound enzymes and zymogens, and includes both plasma-phase and membrane-phase reactions. Blood is modeled as a non-Newtonian incompressible fluid. VSs convect thrombin in the domain and lead to the high concentration observed in the distal portion of the AAA. This finding is in line with the clinical observations showing that the thickest ILT is usually seen in the distal AAA region. The proposed model, due to its ability to couple the fluid and chemical domains, provides an integrated mechanochemical picture that potentially could help unveil mechanisms of ILT formation and development.

Biomarkers for abdominal aortic aneurysms from a sex perspective.

BACKGROUND: Abdominal aortic aneurysms (AAAs) differ in men and women. Women are older at diagnosis, have a higher risk of rupture, and worse outcome after surgery compared with men. The higher occurrence of AAAs in men accounts for the dominance of men in biomarker analyses. OBJECTIVE: The primary aim of this study was to investigate levels of established biomarkers for AAA in men and women, and the secondary aim was to compare biomarker levels in women with and without AAAs. METHODS: In this prospective case-control study, blood samples were collected from 16 women and 18 men with AAAs ≥5.5 cm, from 20 women with AAAs <5.5 cm, and from 18 women with peripheral artery disease (PAD). Plasma concentrations of matrix metalloproteinase (MMP) -2, -9, and -13; tissue inhibitor of MMP-1 (TIMP-1); plasminogen activator inhibitor 1 (PAI-1); high-sensitivity C-reactive protein (hsCRP); and estradiol levels were analyzed by ELISA. An ultrasound examination was performed in women with PAD to exclude an AAA. RESULTS: Age and other comorbid conditions were similar between men and women with AAAs. Women with AAAs had higher levels of MMP-9 compared with men with equally large AAAs (42.8 ng/mL vs 36.2 ng/mL, P = 0.036) and lower levels of estradiol (30.0 pmoL vs 86.5 pmol/L, P < 0.001). Women with AAAs had lower levels of MMP-9 compared with women without (59.5 ng/mL vs 132.6 ng/mL, P = 0.010). There was no significant difference in the plasma levels of MMP-2, MMP-13, hsCRP, PAI-1, TIMP-1, and estradiol between women with and without AAAs. CONCLUSION: The higher levels of MMP-9 in women compared with men with equally large AAAs could suggest that MMP-9 is a biomarker related to the sex differences in aneurysm development. The lower levels of estradiol in women with AAAs compared with men suggest that the possible protective effect of endogenous estrogen cannot be explained by a difference in circulating levels of estradiol.

Serine protease inhibitor A3 in atherosclerosis and aneurysm disease.

Remodeling of extracellular matrix (ECM) plays an important role in both atherosclerosis and aneurysm disease. Serine protease inhibitor A3 (serpinA3) is an inhibitor of several proteases such as elastase, cathepsin G and chymase derived from mast cells and neutrophils. In this study, we investigated the putative role of serpinA3 in atherosclerosis and aneurysm formation. SerpinA3 was expressed in endothelial cells and medial smooth muscle cells in human atherosclerotic lesions and a 14-fold increased expression of serpinA3n mRNA was found in lesions from Apoe-/- mice compared to lesion-free vessels. In contrast, decreased mRNA expression (-80%) of serpinA3 was found in biopsies of human abdominal aortic aneurysm (AAA) compared to non-dilated aortas. Overexpression of serpinA3n in transgenic mice did not influence the development of atherosclerosis or CaCl2-induced aneurysm formation. In situ zymography analysis showed that the transgenic mice had lower cathepsin G and elastase activity, and more elastin in the aortas compared to wild-type mice, which could indicate a more stable aortic phenotype. Differential vascular expression of serpinA3 is clearly associated with human atherosclerosis and AAA but serpinA3 had no major effect on experimentally induced atherosclerosis or AAA development in mouse. However, serpinA3 may be involved in a phenotypic stabilization of the aorta.

Spatial orientation of collagen fibers in the abdominal aortic aneurysm's wall and its relation to wall mechanics.

Collagen is the most abundant protein in mammals and provides the abdominal aortic aneurysm (AAA) wall with mechanical strength, stiffness and toughness. Specifically, the spatial orientation of collagen fibers in the wall has a major impact on its mechanical properties. Apart from valuable microhistological information, this data can be integrated by histomechanical constitutive models thought to improve biomechanical simulations, i.e. to improve the biomechanical rupture risk assessment of AAAs. Tissue samples (n = 24) from the AAA wall were harvested during elective AAA repair, fixated, embedded, sectioned and investigated by polarized light microscopy. The birefringent properties of collagen were reinforced by picrosirius red staining and the three-dimensional collagen fiber orientations were identified with a universal rotary stage. Two constitutive models for collagen fibers were used to integrate the identified structural information in a macroscopic AAA wall model. The collagen fiber orientation in the AAA wall was widely dispersed and could be captured by a Bingham distribution function (κ(1) = 11.6, κ(2) = 9.7). The dispersion was much larger in the tangential plane than in the cross-sectional plane, and no significant difference between the medial and adventitial layers could be identified. The layered directional organization of collagen in normal aortas was not evident in the AAA. The collagen organization identified, combined with constitutive descriptions of collagen fibers that depend on its orientation, explain the anisotropic (orthotropic) mechanical properties of the AAA wall. The mechanical properties of collagen fibers depend largely on their undulation, which is an important structural parameter that requires further experimental investigation.

Protease activity in the multi-layered intra-luminal thrombus of abdominal aortic aneurysms.

INTRODUCTION: Rupture of an abdominal aortic aneurysm (AAA) is the cause of death in approximately 2% of men above 65 years. Most AAAs contain an intra-luminal thrombus (ILT), which is a potential source of proteases capable of degrading the underlying aneurysm wall. The AAA wall covered by a thick ILT shows more signs of matrix degradation compared to the wall free from ILT. The purpose of the present study was to evaluate the presence of protease activity in the ILT. MATERIALS AND METHODS: ILT and peripheral blood from 32 patients undergoing elective surgery were collected. The ILT was divided into abluminal, luminal, and a middle layer in between. Collagenases, gelatinases, elastase, and their inhibitors were measured using ELISA in protein extracts from these layers. Immunohistochemistry was used for identification of cells. RESULTS: Neutrophil leukocytes and platelets were mostly detected in the luminal layer of the ILT. MMP-9 and neutrophil elastase were also abundant in this layer but with low activity. High concentrations of TIMP-1 and PAI-1 were detected in the abluminal layer, while alpha 1 antitrypsin was mostly found in the luminal layer of the ILT. CONCLUSIONS: In AAA thick ILTs with multiple layers contain substantial amounts of proteases, but their activity is limited to the luminal layer. Proteases in the abluminal layer are mostly inactive, probably due to excess amounts of inhibitors and are consequently unable to directly participate in the pathogenesis of AAA.

Reproductive history in women with abdominal aortic aneurysms.

BACKGROUND: The prevalence of abdominal aortic aneurysms (AAAs) differs considerably between the sexes, illustrated by the male/female ratio 4-6:1. Women are also reported to have a higher risk of rupture, and a poorer outcome compared with men. The primary aim of this study was to investigate if women with AAA have a different reproductive history compared with other women. The secondary aim was to study if women with a larger AAA differ in their reproductive history from women with a smaller AAA. METHOD: This case-control study was performed in October 2009 and included 140 consecutively monitored women with AAA and 140 with peripheral arterial disease (PAD) at the Department of Vascular Surgery at Karolinska University Hospital, Stockholm. AAA was defined as AAA diameter >3 cm, and women with AAA were subdivided into groups with AAA diameter ≥5 cm and diameter <5 cm. A validated questionnaire was used to obtain information about participants' reproductive history and general health. The response rate was 70% (n = 196). RESULTS: Women with AAA were smokers to a greater extent than women with PAD (previous, 52% vs 46%; current, 46% vs 34%, P = .001). Diabetes mellitus was more prevalent in women with PAD (28%) than in women with AAA (15%, P = .034). Angina pectoris occurred more often in women with AAA (26%) than in women with PAD (11%, P = .026). No significant difference was found between PAD and AAA women regarding statin use, treatment for hypertension, prior myocardial infarction, and body mass index (BMI). The 54 women with AAA ≥5 cm and the 44 women with AAA <5 cm were similar in age (76 vs 76 years, P = .908) and BMI (25.7 vs 24.0 kg/m(2), P = .66). No difference was noted in the occurrence of other risk factors between women with AAA ≥5 cm and women with AAA <5 cm. Mean age at menopause was lower in women with AAA ≥5 cm than in women with AAA <5 cm and in women with PAD (47.7 vs 49.9 vs 49.7 years, P = .011). Apart from menopausal age, the groups had a similar reproductive history, including hormone replacement therapy, parity, use of contraceptives, prior gynecological surgery, and breast cancer. CONCLUSION: These findings suggest that women with larger AAA reach menopausal age earlier, and this could influence an earlier onset of aneurysmatic disease or an increase in aneurysm growth. The true role of endogenous estrogen in aneurysm development and expansion is yet to be investigated.

Imaging the intraluminal thrombus of abdominal aortic aneurysms: techniques, findings, and clinical implications.

Intraluminal thrombus (ILT) is known to influence the natural history of abdominal aortic aneurysms, and its effect on the arterial wall may predict the risks of rupture. The main features of ILT believed to be associated with aneurysm growth and increased rupture risk are size; presence of fissures, dissections, or calcifications in the ILT; and inhomogeneity in its internal structure. Modern imaging allows for detailed depiction of the ILT. This review describes the techniques, findings, clinical implications, advantages, and disadvantages of imaging the ILT by ultrasound, contrast-enhanced computed tomography, and magnetic resonance imaging.

Analysis of aortic wall stress and rupture risk in patients with abdominal aortic aneurysm with a gender perspective.

OBJECTIVE: The most commonly used predictor of rupture of an abdominal aortic aneurysm (AAA) is the diameter; however, this does not estimate the true risk for each patient. Why women with AAAs have an increased growth rate, weaker aortic wall, and increased risk for rupture is yet unclear. It is likely that geometrical and biomechanical properties contribute to found gender differences. Several studies have shown that peak wall stress (PWS) and peak wall rupture risk (PWRR), predicted by a finite element (FE) analysis of AAAs derived from computed tomography (CT), is a better predictor of rupture than maximum diameter. The purpose of this study was to investigate if women with AAAs have an increased PWS and PWRR using an FE model compared to men. METHOD: Fifteen men and 15 women (AAAs 4-6 cm) were included. AAA geometry was derived from CT scans, and PWS and PWRR were estimated using the FE method. Comparisons were made by t test and Mann-Whitney test. RESULTS: Mean age (women 73 years old vs men 71 years old) and mean AAA diameter was similar (49.7 mm vs 50.1 mm) for women and men. PWS did not differ for women 184 and men 198 kPa. PWRR was 0.54 (0.28-0.85) for women and 0.43 (0.24-0.66) for men, P = .06. CONCLUSION: This is the first analysis of stress and strength of the aneurysm wall with a gender perspective. The reported higher rupture risk for women has previously not been tested with geometrical and biomechanical properties. PWS did not differ, but the PWRR was slightly higher in women. However, the difference did not reach statistical significance, probably due to the small sample size. In summary, the results in the present study suggest that differences in biomechanical properties could be a contributing explanation for the higher rupture risk reported for female patients with AAAs.

12- and 15-lipoxygenases in human carotid atherosclerotic lesions: associations with cerebrovascular symptoms.

Lipoxygenase (ALOX) enzymes are implicated in both pro- and anti-atherogenic processes. The aim of this study was to investigate mRNA expression of 12- and 15-lipoxygenases (ALOX12, ALOX12B, ALOX15, ALOX15B) and the atypical ALOXE3 in human carotid atherosclerotic lesions, in relation to cerebrovascular symptoms and risk factors. The Biobank of Karolinska Endarterectomies (BiKE) collection of human carotid plaque tissue and associated clinical data was utilized (n=132). Lesion mRNA levels were analyzed by TaqMan qPCR (n=132) and microarray hybridization (n=77). Of the investigated mRNAs, only ALOX15B (15-LOX-2; epidermis-type 15-LOX) was readily detected in all plaque samples by qPCR, and thus suitable for quantitative statistical evaluation. ALOX12, ALOX12B, ALOX15 and ALOXE3 were detected with lower frequency and at lower levels, or virtually undetected. Microarray analysis confirmed ALOX15B as the most abundant 12- or 15-lipoxygenase mRNA in carotid lesions. Comparing plaques with or without attributable cerebrovascular symptoms (amaurosis fugax, transient ischemic attack, or stroke), ALOX15B mRNA levels were higher in symptomatic than asymptomatic plaques (1.31 [1.11-1.56], n=102; and 0.79 [0.55-1.15], n=30, respectively; p=0.008; mean [95% CI], arbitrary units). Multiple regression analysis confirmed symptomatic/asymptomatic status as a significant determinant of ALOX15B mRNA levels, independently of potentially confounding factors. Immunohistochemical analyses showed abundant ALOX15B expression in macrophage-rich areas of carotid lesions, and lipidomic analyses demonstrated the presence of typical ALOX15B products in plaque tissue. In summary, we observed associations between high ALOX15B expression in carotid lesions and a history of cerebrovascular symptoms. These findings suggest a link between ALOX15B and atherothrombotic events that merits further investigation.

Mast cells: important players in the orchestrated pathogenesis of abdominal aortic aneurysms.

Mast cells (MCs) regulate inflammation and immunity. Their granular content includes heparin, histamine, and several enzymes (tryptase, chymase, carboxypeptidase, and cathepsin G). In addition, activated MCs synthesize and release eicosanoids and a large number of cytokines and chemokines. Recent findings suggest a role of MCs in abdominal aortic aneurysms (AAAs) in humans, where they are found in the media and adventitia. Experimentally induced AAA in MC-deficient animals and animals treated with MC inhibitors demonstrate that MCs are involved in the pathogenesis of AAA via several different mechanisms. MC-dependent activation of metalloproteinases and the renin-angiotensin system, contribution to smooth muscle cell apoptosis, and release of proteolytic enzymes are some key examples. Human studies indicate that MCs are the main source of cathepsin G in AAAs and contribute to activation of the renin-angiotensin system via chymase and cathepsin G. Activated MCs also contribute to neovascularization, inflammation, and atherosclerosis, all hallmarks of AAA. Thus, we may envision that MC stabilizing agents, as well as leukotriene receptor antagonists and histamine receptor blockers already in clinical use for treatment of other diseases, could also be tested for their efficacy in preventing development and growth of AAA.

High frequency of thoracic aneurysms in patients with abdominal aortic aneurysms.

OBJECTIVE: To investigate the prevalence of thoracic aortic aneurysms (TAA) in patients with abdominal aortic aneurysms (AAA). BACKGROUND: Different disease profiles between men and women treated for AAA have been reported. Reports regarding causes of death for treated AAA patients have shown an increased risk of death because of other aneurysms for women, possibly TAA. The prevalence of TAA in AAA patients is not well known. METHODS: Data for AAA patients attending the outpatient clinic at a university hospital were analyzed (N = 1055). Patients who had undergone abdominal and thoracic computed tomography were included (n = 354). The diameter of the aorta was measured in the ascending, descending, and infrerenal aorta. Comorbid conditions were analyzed. RESULTS: Mean age was 74 years, 23% were women. The presence of comorbid conditions did not differ between men and women except for a higher proportion of female smokers (P = 0.003). When sex-specific criteria were used, 100 patients (28%) had a TAA, 38 (48%) of the women compared with 62 (23%) of the men (P < 0.0001). Odds ratio for women compared with those of men to have a concurrent TAA was 3.09 (95% confidence interval, 1.84-5.22). CONCLUSIONS: More than one fourth of patients with AAA attending a regular outpatient clinic have a concomitant TAA, and women are particularly affected. During the last decades, the therapeutic options for TAA patients have changed considerably. Physicians need to increase the efforts to investigate also the thoracic aorta in AAA patients.

Novel aspects of the pathogenesis of aneurysms of the abdominal aorta in humans.

Aneurysm of the abdominal aorta (AAA) is a particular, specifically localized form of atherothrombosis, providing a unique human model of this disease. The pathogenesis of AAA is characterized by a breakdown of the extracellular matrix due to an excessive proteolytic activity, leading to potential arterial wall rupture. The roles of matrix metalloproteinases and plasmin generation in progression of AAA have been demonstrated both in animal models and in clinical studies. In the present review, we highlight recent studies addressing the role of the haemoglobin-rich, intraluminal thrombus and the adventitial response in the development of human AAA. The intraluminal thrombus exerts its pathogenic effect through platelet activation, fibrin formation, binding of plasminogen and its activators, and trapping of erythrocytes and neutrophils, leading to oxidative and proteolytic injury of the arterial wall. These events occur mainly at the intraluminal thrombus-circulating blood interface, and pathological mediators are conveyed outwards, where they promote matrix degradation of the arterial wall. In response, neo-angiogenesis, phagocytosis by mononuclear cells, and a shift from innate to adaptive immunity in the adventitia are observed. Abdominal aortic aneurysm thus represents an accessible spatiotemporal model of human atherothrombotic progression towards clinical events, the study of which should allow further understanding of its pathogenesis and the translation of pathogenic biological activities into diagnostic and therapeutic applications.

Increased expression of leukotriene C4 synthase and predominant formation of cysteinyl-leukotrienes in human abdominal aortic aneurysm.

Leukotrienes (LTs) are arachidonic acid-derived lipid mediators involved in the pathogenesis and progression of diverse inflammatory disorders. The cysteinyl-leukotrienes LTC(4), LTD(4), and LTE(4) are important mediators of asthma, and LTB(4) has recently been implicated in atherosclerosis. Here we report that mRNA levels for the three key enzymes/proteins in the biosynthesis of cysteinyl-leukotrienes, 5-lipoxygenase (5-LO), 5-LO-activating protein (FLAP), and LTC(4) synthase (LTC(4)S), are significantly increased in the wall of human abdominal aortic aneurysms (AAAs). In contrast, mRNA levels of LTA(4) hydrolase, the enzyme responsible for the biosynthesis of LTB(4), are not increased. Immunohistochemical staining of AAA wall revealed focal expression of 5-LO, FLAP, and LTC(4)S proteins in the media and adventitia, localized in areas rich in inflammatory cells, including macrophages, neutrophils, and mast cells. Human AAA wall tissue converts arachidonic acid and the unstable epoxide LTA(4) into significant amounts of cysteinyl-leukotrienes and to a lesser extent LTB(4). Furthermore, challenge of AAA wall tissue with exogenous LTD(4) increases the release of matrix metalloproteinase (MMP) 2 and 9, and selective inhibition of the CysLT1 receptor by montelukast blocks this effect. The increased expression of LTC(4)S, together with the predominant formation of cysteinyl-leukotrienes and effects on MMPs production, suggests a mechanism by which LTs may promote matrix degradation in the AAA wall and identify the components of the cysteinyl-leukotriene pathway as potential targets for prevention and treatment of AAA.