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Objective: Abdominal aortic aneurysm (AAA) is a chronic inflammatory disease. Studies of human aneurysm tissue demonstrate dense inflammatory cell infiltrates with CD4 + T cells predominating. Regulatory T cells (Tregs) play an important role in inhibiting pro-inflammatory T cell proliferation, therefore, limiting collateral tissue destruction. The aim of this study was to investigate whether ex vivo augmentation of human Tregs attenuates aneurysm formation in humanized murine model of AAA., Methods: Circulating Treg population in AAA patients and age- and gender-matched controls were determined by real-time polymerase chain reaction and flow cytometry. To create humanized murine model of AAA, irradiated Rag1-deficient (Rag1 -/- ) mice, without mature T lymphocytes, at 7 weeks of age were given 5 × 10 6 of human CD4 + T cells intraperitoneally. Then the mice underwent CaCl 2 aneurysm induction. Aortic diameters were measured before and at 6 weeks after aneurysm induction. Aortic tissue was collected for histology and protein extraction. Verhoeff-Van Gieson stain was used for staining elastic fiber. CD4 + T cells in the aortic tissue were detected by immunohistochemical staining., Results: In human peripheral blood mononuclear cells, the proportion of Tregs are decreased in AAA patients compared with matched control patients with significant vascular disease. We first validated the role of Tregs in the CaCl 2 model of AAA. To determine the role of human T cells in AAA formation, Rag1 -/- mice, resistant to CaCl 2 -aneurysm induction, were transplanted with human CD4 + T cells. Human CD4 + T cells were able to drive aneurysm formation in Rag1 -/- mice. We show that ex vivo augmentation of human Tregs by interleukin-2 resulted in decreased aneurysm progression., Conclusions: These data suggest that the ex vivo expansion of human Tregs may be a potential therapeutic strategy for inhibiting progression of AAA., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Macrophages play a critical role in the initiation and progression of abdominal aortic aneurysm (AAA) and are classically distinguished into M1 "proinflammatory" and M2 "anti-inflammatory" macrophages. Topical application of elastase associated with transforming growth factor β (TGF-β) systemic neutralization reproduces the main pathologic features of human AAA, offering a new model to investigate their role. The aim of this study was to investigate whether macrophages contribute to the expression of canonical M1/M2 markers in the aorta in the AAA model induced by elastase and systemic blockade of TGF-β and whether blocking of TGF-β activity affects macrophage phenotype and the expression of the M2 marker arginase 1 (ARG1)., Methods: C57Bl/6J male mice (6-8 weeks old) were randomly assigned to three experimental groups: mice that had local application of heat-inactivated elastase or elastase and mice that had elastase application and received injection of anti-TGF-β (elastase + anti-TGF-β group). Monocyte-macrophage depletion was achieved in the elastase + anti-TGF-β group using liposome clodronate. Macrophage phenotype was characterized by quantitative polymerase chain reaction, flow cytometry, and immunohistochemistry. Human infrarenal AAA tissues (n = 10) were obtained to analyze ARG1 expression., Results: Analysis of gene expression in the infrarenal aortic wall revealed that after 14 days, no significant difference for the expression of CCL2, NOS2, and Ym1/2 was observed in the elastase group compared with the elastase + anti-TGF-β group, whereas the expression of ARG1, interleukin (IL) 1β, and IL-6 was significantly increased. Macrophage depletion in the elastase + anti-TGF-β group led to a significant decrease of IL-1β, IL-6, ARG1, and Ym1/2 gene expression. Immunofluorescent staining confirmed that TGF-β neutralization significantly enhanced ARG1 protein expression in the aneurysmal tissue. Flow cytometry analysis revealed an increase of macrophages expressing ARG1 in the aorta of mice treated with elastase + anti-TGF-β compared with the elastase group, and their proportion increased with aneurysmal dilation. In humans, ARG1 protein expression was increased in aneurysmal tissues compared with controls, and positive cells were mainly found in the adventitia., Conclusions: TGF-β neutralization finely tunes macrophage phenotype in elastase-induced AAA and leads to an increase in ARG1 gene and protein expression in the aortic wall. Even if further studies are required to elucidate its role in AAA development, ARG1 could represent a new prognostic or therapeutic target in aneurysmal disease., (Copyright © 2018 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Recent evidence suggests that adaptive immunity develops during abdominal aortic aneurysm evolution. Uncertainties remain about the antigens implicated and their role in inducing rupture. Because antigens from the extracellular matrix (ECM) have been suspected, the aim of this experimental study was to characterize the role of adaptive immunity directed against antigens from the aortic ECM., Methods: In a first step, an experimental model of abdominal aortic aneurysm rupture based on adaptive immunity against the ECM was developed and characterized. Forty 4-week-old male Lewis rats were divided into two groups. In the ECM group (n = 20), rats were presensitized against the guinea pig aortic ECM before implantation of a decellularized aortic xenograft (DAX). In the control group (n = 20), rats were not presensitized before DAX implantation. In each group, half the rats were sacrificed at day 3 to analyze early mechanisms involved after DAX implantation. In a second step, we aimed to assess which ECM component was most efficient in inducing rupture. For this purpose, the nonfibrillar and fibrillar ECM components were sequentially extracted from the guinea pig aortic wall. Forty Lewis rats were then divided into four groups. Each group was presensitized against one ECM component (structural glycoproteins and proteoglycans, collagen, elastin alone, and elastin-associated glycoproteins) before DAX implantation. Apart from those that experienced rupture, rats were sacrificed at day 21. Xenografts were harvested for histologic, immunofluorescence, and conditioned medium analyses., Results: In total, early aortic rupture occurred in 80% of the ECM group vs 0% of the control group (P < .001). In the ECM group, major circumferential immunoglobulin deposits were observed in combination with the C3 complement fraction, without cell infiltration. Conditioned medium analysis revealed that matrix metalloproteinase 9 and myeloperoxidase levels and elastase activities were significantly increased in this group. Immunofluorescence analysis demonstrated that myeloperoxidase co-localized with tissue-free DNA and histone H4, highlighting local neutrophil activation and formation of neutrophil extracellular traps. Following differential presensitization, it appeared that rats presensitized against structural glycoproteins and proteoglycans were significantly more susceptible to rupture after DAX implantation., Conclusions: Stimulating adaptive immunity against the aortic ECM, especially structural glycoproteins and proteoglycans, triggers rupture after DAX implantation. Further studies are needed to assess the precise proteins involved., (Copyright © 2018 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: Previous in vitro and animal studies have suggested that osteopontin (OPN), an inflammatory extracellular matrix protein, is involved in the formation and growth of abdominal aortic aneurysms (AAAs). However, the mechanism by which this occurs continues to be nebulous. The relationship between OPN and inflammation-suppressing lymphocytes present in the human AAA condition was investigated and presented herein., Methods: Serum OPN concentrations were measured in healthy, risk factor-matched non-AAA and AAA patients by enzyme-linked immunosorbent assay (ELISA). Immunohistochemistry was used to determine the source of OPN secretion using aortic tissue collected from multiorgan donors and AAA patients undergoing open surgical repair. Vascular smooth muscle cells (VSMCs) were exposed to various inflammatory mediators, and OPN expression was evaluated by quantitative reverse transcriptase-polymerase chain reaction and ELISA. The inflammatory nature of OPN and the aortic wall was determined using a TR1 suppressor cell induction assay as a surrogate and characterized by ELISA and fluorescence-activated cell sorting., Results: OPN was found to be elevated in both the plasma and aortic homogenate of AAA patients compared with controls. On immunohistochemistry, OPN localized to the tunica media of the diseased aorta but was minimally expressed in healthy aorta. In vitro, cigarette smoke extract was the most potent stimulator of OPN secretion by VSMCs and increased both messenger RNA and supernatant concentrations. OPN demonstrated an ability to inhibit the induction of interleukin 10-secreting TR1 lymphocytes, a depleted population in the AAA patient, from naive precursors. Last, neutralizing receptor targets of OPN in the setting of AAA homogenate coincubation abrogated the inhibition of TR1 induction., Conclusions: OPN, secreted by the VSMCs of the tunica media, is elevated in the circulating plasma and aortic wall of patients with AAA. It can inhibit the induction of the TR1 suppressor cell, leading to an overall proinflammatory state contributing to progressive aortic wall breakdown and dilation., (Copyright © 2017 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: Abdominal aortic aneurysm (AAA) is a vascular disease relatively common in the elderly population. Although some events that contribute to the development and progression of AAA are known, there are limited data examining the association of Toll-like receptor 3 (TLR3) and RIG-I-like receptor expression with the pathogenesis of AAAs. In this study, we investigated the gene and protein expression of TLR3 and RIG-I-like receptors (RIG-I and MDA5) in aortic wall and blood of AAA patients and examined the relationship between their expression and immune response., Methods: Total RNA was extracted from aortic wall tissues and blood samples collected from 20 patients with AAA and blood samples of 17 healthy volunteers without aortic aneurysm. To evaluate the DDX58 (RIG-I), IFIH1 (MDA5), and TLR3 gene expression level, quantitative real-time polymerase chain reaction was used. Extracellular cytokine and pattern recognition receptor levels were quantified by enzyme-linked immunosorbent assays., Results: TLR3, RIG-I, and MDA5 were constitutively expressed in both aortic tissues and blood samples from AAA patients and healthy volunteers. In patients with AAA, higher TLR3 expression in aortic tissues than in blood was found (P = .004). The DDX58 messenger RNA expression was higher in blood of patients with AAA compared with healthy subjects (P = .021). A significantly higher level of plasma interleukin 4 was noticed in patients with AAA than in healthy individuals (P = .008)., Conclusions: This study suggests that RIG-I and TLR3 seem to be important factors in the pathogenesis of AAA., (Copyright © 2017 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: Immunoglobulin (Ig) G4-related aortic aneurysms (IgG4-AAs) are a special aortic aneurysm among IgG4-related diseases (IgG4-RDs), which are inflammatory and fibrous conditions characterized by tumorous swelling of affected organs and high serum IgG4 concentrations. Recently, IgG4-RD pathogenesis was shown to be associated with T-helper-2 (Th2) and regulatory T (Treg) dominant cytokine production, such as interleukin (IL)-4, IL-10, and IL-13. IL-6 is a key proinflammatory cytokine contributing to lymphocyte and plasmacyte maturation and to atherosclerosis and aneurysm development. We serologically and histopathologically evaluated the cytokine profile in IgG4-AA patients., Methods: Patients with IgG4-AAs (n = 10), non-IgG4-related inflammatory abdominal aortic aneurysms (non-IgG4-AAAs; n = 5), atherosclerotic AAAs (aAAAs; n = 10), and normal aortas without dilatation (n = 10) were examined for serum IL-10, IL-13, and IL-6 levels. Resected aortic tissues were evaluated for cluster of differentiation (CD) 34 (in the endothelial cells and mesenchymal cells) and CD163 (by macrophages) expression using immunohistochemistry and in situ hybridization., Results: Serum IL-10 levels were rather higher in IgG4-AA patients (median, 1.3 pg/mL) than in non-IgG4-AAA and aAAA patients and in patients with normal aortas. Elevated serum IL-13 levels relative to standard values were detected in two IgG4-AA patients but not in the other groups. Cells immunopositive for IL-10 and IL-13 were more frequent in IgG4-AAs and significantly correlated with serum IgG4 levels. Serum IL-6 levels (median, 78.5 pg/mL) were also significantly higher in IgG4-AA patients than in non-IgG4-AAA and aAAA patients and control patients with normal aortas (P = .01, P = .001, and P = .004, respectively). They positively correlated with serum IgG4 levels and adventitial thickness, but other cytokines did not. The number of IL-6-immunopositive cells in the adventitia was significantly higher in IgG4-AA patients (median, 17.8/high-power field) than in aAAA patients or patients with normal aortas (P =.001 and P = .002, respectively). In situ hybridization confirmed frequent IL-6 messenger (m)RNA expression in the endothelium, mesenchymal cells, and histiocytes in IgG4-AA adventitia. In the same cells of IgG4-AAs, coexpression of IL-6 and CD34 mRNA or CD163 mRNA was detected., Conclusions: The cytokine profiles of IgG4-AA patients had two characteristics: local IL-10 and IL-13 upregulation in IgG4-AAs was related to Th2 and Treg-predominant cytokine balance, similar to other IgG4-RDs, and IL-6 upregulation in the adventitia was characterized by activated immune reactions in IgG4-AA patients. IL-6 synthesis, through contributions of mesenchymal cells and macrophages in the adventitia, is strongly involved in IgG4-AA pathogenesis or progression, or both., (Copyright © 2017 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: It is known that T lymphocytes are activated in human abdominal aortic aneurysms (AAAs). γδT cells, as a subset of T cells, play a role in many inflammation-related diseases. However, whether γδT cells participate in the formation of AAA remains unknown. In this study, we explored the role of γδT cells in AAA lesions., Methods and Results: Using the porcine pancreatic elastase-induced AAA model, we found that knock out of γδT cells significantly attenuated AAA formation. To elucidate how γδT cells contribute to AAA, microarray analysis was performed, which found that the phosphoinositide 3-kinase/AKT signaling pathway was activated in elastase-perfused γδT knockout (γδT KO) mice. By studying differentially expressed genes involved in phosphoinositide 3-kinase signaling, we found that proliferation-related genes (Sos1, Mtor, Myc) were upregulated whereas apoptosis-related genes (Pten, Bcl1, Bad) were downregulated in elastase-perfused γδT KO mice. Furthermore, histopathologic analysis showed increased PCNA + and decreased TUNEL + cells in elastase-perfused γδT KO mice compared with wild-type mice. In addition, inflammatory cytokines including interleukin-1β, Mcp-1, and tumor necrosis factor-α were downregulated in the aneurysm tissues of elastase-perfused γδT KO mice., Conclusions: These data reveal a pathogenic role of γδT cells in the experimental AAA model, likely through mechanisms regulating cell proliferation and mediating inflammatory response. Thus, targeting of γδT cells may offer a potential therapeutic method for aortic aneurysms., (Copyright © 2016. Published by Elsevier Inc.)

Background: Abdominal aortic aneurysm (AAA) is a deadly irreversible weakening and distension of the abdominal aortic wall. The pathogenesis of AAA remains poorly understood. Investigation into the physical and molecular characteristics of perivascular adipose tissue (PVAT) adjacent to AAA has not been done before and is the purpose of this study., Methods and Results: Human aortae, periaortic PVAT, and fat surrounding peripheral arteries were collected from patients undergoing elective surgical repair of AAA. Control aortas were obtained from recently deceased healthy organ donors with no known arterial disease. Aorta and PVAT was found in AAA to larger extent compared with control aortas. Immunohistochemistry revealed neutrophils, macrophages, mast cells, and T-cells surrounding necrotic adipocytes. Gene expression analysis showed that neutrophils, mast cells, and T-cells were found to be increased in PVAT compared with AAA as well as cathepsin K and S. The concentration of ceramides in PVAT was determined using mass spectrometry and correlated with content of T-cells in the PVAT., Conclusions: Our results suggest a role for abnormal necrotic, inflamed, proteolytic adipose tissue to the adjacent aneurysmal aortic wall in ongoing vascular damage., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Abdominal aortic aneurysm (AAA) is a pathologic dilation of the aorta. Inflammation of the aortic wall has been shown to be involved in AAA formation. Malondialdehyde-acetaldehyde (MAA) adducts are MAA/protein hybrids with immunogenic, proinflammatory, and profibrotic properties. Levels of MAA adducts are elevated in patients with coronary artery disease; however, the role of MAA adducts in AAA is unclear. We hypothesize that levels of circulating antibodies against MAA adducts are increased in patients with AAA., Methods: Plasma samples were collected from mice and patients with AAA and control patients with atherosclerosis but not AAA. AAA was induced in mice by a standard CaCl2 protocol, with matching sham mice. Plasma levels of anti-MAA antibodies were quantified by enzyme-linked immunosorbent assay., Results: Patients with AAA exhibited higher levels of immunoglobulin G and immunoglobulin A anti-MAA antibody subtypes (P = .049 and .026, respectively) compared with control patients. Conversely, immunoglobulin M anti-MAA antibodies in AAA patients were lower compared with control patients (P = .018). In CaCl2-treated mice, immunoglobulin G anti-MAA antibodies were elevated after AAA formation (P = .006)., Conclusions: The pattern of anti-MAA antibodies is able to distinguish between patients with AAA and patients with atherosclerosis but no AAA. These results demonstrate that MAA adducts are associated with AAA and suggest that they may play a role in either initiating or propagating chronic inflammation in AAA., (Copyright © 2016. Published by Elsevier Inc.)

Immunoglobulin G4-related disease, a newly emerging systemic autoimmune disorder, can potentially involve the cardiovascular system. The standard treatment for immunoglobulin G4-related cardiovascular disease has not been established. We encountered a very rare case of an immunoglobulin G4-related inflammatory abdominal aortic aneurysm coexisting with a coronary artery aneurysm and periarteritis. The patient underwent surgical resection for the abdominal aortic aneurysm, followed by successful corticosteroid therapy for the coronary artery lesions. This is the first report of steroid-sensitive immunoglobulin G4-related coronary artery disease. A carefully planned treatment strategy for the multiple cardiovascular lesions was invaluable in the present case., (Copyright © 2015 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: Popliteal artery aneurysms (PAAs) and abdominal aortic aneurysms (AAAs) frequently coincide; however, symptoms differ. We systematically assessed aneurysm cellular wall composition and inflammatory markers to compare both anatomic locations., Methods: Aneurysmal walls of 38 PAAs and 198 AAAs were harvested from patients undergoing elective open surgical repair. Elastin, collagen, smooth muscle cells, iron, and inflammatory cells were quantified by immunohistochemistry. In addition, protease and cytokine levels were measured., Results: Aneurysmal degradation resulted in similarly degraded media. The location of inflammation differed: the focus for T and B lymphocytes and plasma cells was the intima in PAAs (all P < .001) and the adventitia for AAAs (all P < .001). Iron was more often observed in PAAs than in AAAs (68% vs 1%; P < .001), indicating more previous intramural hemorrhages. Matrix metalloproteinase 2 activity was higher in PAAs than in AAAs (median [interquartile range], 0.363 [0.174-0.556] vs 0.187 [0.100-0.391]; P = .008), whereas matrix metalloproteinase 9 showed no difference. Walls of AAAs were richer in tested cytokine levels than were walls of PAAs., Conclusions: PAAs showed more signs of previous intramural hemorrhages compared with AAAs. In addition, inflammation in PAAs is mainly located in the intima, whereas its focus in AAAs is the adventitia. These results suggest important differences in the pathophysiologic mechanism of aneurysm formation between these locations and might explain the differences in presentation on diagnosis., (Copyright © 2014 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Purpose: Neutrophils have been shown to be involved in all stages of human and experimental abdominal aortic aneurysm (AAA) development. The initial processes of neutrophil rolling and trapping in the intraluminal thrombus (ILT) are mediated mainly by P-selectin expressed by activated platelets. In the present study, we propose to evaluate the beneficial effect of fucoidan, a competitive binding agent of P-selectin, on aneurysmal growth in a rat model of aortic aneurysm with neutrophil enrichment of the ILT induced by repeated episodes of weak bacteremia., Methods: Sixty Lewis rats with experimental AAAs, developed from decellularized aortic xenografts, were divided into four groups. Two groups were used as controls: group fucoidan control (FC) was treated with 200 mg of fucoidan (F) delivered by 2 mL, 4-week osmotic pumps placed intraperitoneally before closing the abdomen, and group C received saline instead of fucoidan. Two more groups were injected weekly with Porphyromonas gingivalis (P. gingivalis [Pg]): group F+Pg received 200 mg of intraperitoneal fucoidan and group Pg received saline. AAAs were harvested after 4 weeks and peripheral blood was sampled at that time. Cell-free DNA (cf-DNA) and myeloperoxydase (MPO) antigen concentrations were determined in plasma and in AAA-conditioned media. Histology and P-selectin immunostaining were performed on AAA tissue samples., Results: Comparing rats injected with Pg, those receiving fucoidan presented reduced aneurysmal diameter. Histologic analysis of AAAs showed that fucoidan reduced the ILT thickness in Pg-injected rats, with fewer trapped neutrophils, and with signs of a healing process, as observed in control group C. Immunohistological analysis revealed a substantial decrease in P-selectin immunostaining at the luminal surface of aneurysms in fucoidan-treated rats compared to the other groups, suggesting an interaction between fucoidan and P-selectin. A significant decrease in MPO concentrations in both plasma and conditioned medium was induced by fucoidan treatment in Pg-injected rats, reflecting a pacification of the ILT biological activity. This effect was associated with a reduction in neutrophil activation and apoptosis, reflected by a significant decrease in cf-DNA concentration in both plasma and conditioned medium of fucoidan-treated rats., Conclusions: Our results suggest that fucoidan has a beneficial effect on experimental aneurysmal degeneration by decreasing neutrophil activation in the ILT enhanced by weak pathogen contamination. This effect seems to be related to its interaction with P-selectin, which may decrease the trapping of neutrophils into the ILT. Fucoidan could represent a therapeutic option in AAAs to decrease the neutrophil activation involved in the degenerative process of aneurysmal expansion and rupture., (Copyright © 2013 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.)

Objective: We hypothesized that the general inflammation observed in the wall of large, asymptomatic abdominal aortic aneurysms (AAAs) could be detected in vivo by 18-fluorodeoxglucose (FDG) positron-emission tomography (PET) and, if so, that this method could be used to study if active inflammation is an early pathogenetic finding in small AAAs detected by screening., Methods: In this prospective clinical study, 12 men were examined with FDG-PET computed tomography. Seven had large asymptomatic AAAs (range, 52-66 mm) that required surgery, and five had small AAAs (range, 34-40 mm) under surveillance. In the surgery group, biopsy specimens were taken from the aneurysm wall for histologic examinations., Results: Compared with normal segments of the aorta, liver, and blood and compared with healthy controls matched for age and sex, no increased FDG uptake, measured as standardized uptake value, was detected in any of the large or small AAAs. The SUV(mean) difference between infrarenal aorta and blood was -0.3 for cases and -0.1 for controls (P = .06). The corresponding differences between the infrarenal aorta and liver was -0.8 and -0.8 (P = .91) and between infrarenal aorta and suprarenal aorta was -0.2 and -0.1 for cases and controls, respectively (P = .20). The histologic examination of the aneurysm walls showed high inflammatory cell infiltration with T lymphocytes, B lymphocytes, and macrophages., Conclusions: The chronic inflammation observed in the wall of asymptomatic AAAs was not sufficiently metabolically active to result in an increased glucose metabolism detectable by FDG-PET by means of this standard protocol. To study the importance of inflammation in the pathogenesis of AAAs in vivo, PET tracers other than FDG need to be developed., (Crown Copyright © 2012. Published by Mosby, Inc. All rights reserved.)

Objective: Abdominal aortic aneurysm (AAA) is a frequent form of atherothrombotic disease, whose natural history is to enlarge and rupture. Indicators other than AAA diameter would be useful for preventive surgery decision-making, including positron-emission tomography (PET) methods permitting visualization of aortic wall leukocyte activation relevant to prognostic AAA evaluation. In this study, we compare three PET tracers of activated leukocytes, 18F-fluoro-deoxy-glucose (FDG), 18F-fluoro-methyl-choline (FCH), and 18F-DPA714 (a peripheral benzodiazepine receptor antagonist) for in vivo PET quantification of aortic wall inflammation in rat experimental AAAs, in correlation with histopathological studies of lesions., Methods: AAAs were induced by orthotopic implantation of decellularized guinea pig abdominal aorta in 46 Lewis rats. FDG-PET (n = 20), FCH-PET (n = 8), or both (n = 12) were performed 2 weeks to 4 months after the graft, 1 hour after tracer injection (30 MBq). Six rats (one of which had FDG-PET) underwent 18F-DPA714-PET. Rats were sacrificed after imaging; AAAs and normal thoracic aortas were cut into axial sections for quantitative autoradiography and histologic studies, including ED1 (macrophages) and CD8 T lymphocyte immunostaining. Ex vivo staining of AAAs and thoracic aortas with 18F-DPA714 and unlabeled competitors was performed., Results: AAAs developed in 35 out of 46 cases. FCH uptake in AAAs was lower than that of FDG in all cases on imaging, with lower AAA-to-background maximal standardized uptake value (SUV(max)) ratios (1.78 ± 0.40 vs 2.71 ± 0.54; P < .01 for SUV(max) ratios), and lower AAA-to-normal aorta activity ratios on autoradiography (3.52 ± 1.26 vs 8.55 ± 4.23; P < .005). FDG AAA-to-background SUV(max) ratios correlated with the intensity of CD8 + ED1 staining (r = .76; P < .03). FCH AAA-to-background SUV(max) ratios correlated with the intensity of ED1 staining (r = .80; P < .03). 18F-DPA714 uptake was similar in AAAs and in normal aortas, both in vivo and ex vivo., Conclusions: In rat experimental AAA, characterized by an important aortic wall leukocytes activity, FDG-PET showed higher sensitivity than FCH-PET and 18F-DPA714-PET to detect activated leukocytes. This enhances potential interest of this tracer for prognostic evaluation of AAA in patients., (Copyright © 2012 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.)

Background: Abdominal aortic aneurysm (AAA) is a chronic inflammatory condition associated with a prothrombotic, hypofibrinolytic diathesis that may increase the risk of cardiovascular events. The effect of endovascular aneurysm repair (EVAR) on this prothrombotic diathesis is not fully understood, especially over the medium and long term. A better understanding of these postintervention changes may improve the risk of cardiovascular complications in the long term. The purpose of this study was to examine thrombin generation, fibrinolysis, platelet and endothelial activation, and the inflammatory response during the 12 months following EVAR., Methods: Twenty-nine patients (mean age, 76.9 years) undergoing EVAR for AAA (mean diameter 6.9 cm) had prothrombin fragment (PF) 1 + 2, thrombin-antithrombin complex (TAT), plasminogen activator inhibitor (PAI) activity, tissue plasminogen activator (t-PA) activity and antigen, soluble P- and E-selectin, and highly sensitive C-reactive protein (hsCRP) measured before and at 24 hours, and 1, 6, and 12 months after surgery., Results: PF1 + 2 were markedly elevated prior to EVAR and remained so at 24 hours and 1 month, but had decreased significantly at 6 and 12 months. TAT was also elevated prior to EVAR and increased still further by 24 hours, but fell to below baseline levels thereafter. PAI activity and t-PA antigen were normal prior to EVAR, increased significantly at 24 hours, and then fell to baseline levels. t-PA activity was only detectable at 1 and 6 months; there was a significant rise in soluble P- and E-selectin after EVAR, which was sustained for 12 months. hsCRP increased transiently in response to EVAR but returned to preoperative levels by 1 month., Conclusions: The prothrombotic, hypofibrinolytic diathesis associated with AAA is normalized 12 months after EVAR. This beneficial systemic effect of EVAR for AAA disease may help protect patients against future thromboembolic cardiovascular events., (Copyright © 2012 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.)

Objective: The purpose of this study was to identify local differences in inflammation and tissue degradation within the circumference of the abdominal aortic aneurysm (AAA)., Background: AAAs have the potential to rupture, and it is unknown why this predominantly occurs at the posterolateral wall. Blood flow dynamics likely influence rupture location but do not explain the whole picture, suggesting that other factors inside the AAA wall have a prominent role., Methods: As part of the Aneurysm-Express study, full thickness circular biopsy specimens of AAAs from 25 patients were obtained during surgery according to a standardized protocol. Tissue from the dorsal, ventral, and lateral sides was processed for histology and protein extraction. Levels of matrix metalloproteinase (MMP)-2 and MMP-9 and various cytokines were measured., Results: Lateral AAA sites, when compared with the ventral and dorsal segments, showed more microvessels (median [interquartile range] per mm(2), 91.8 [72.6-124.6] vs 73.9 [63.0-108.0] and 73.6 [52.7-109.5]; P = .013 and P = .005, respectively) and more adventitial inflammation (16.1% [13.5%-24.7%] vs 5.8% [2.8%-18.6%] and 6.3% [4.3%-13.5%]; P = .001 and P < .001, respectively). We observed a higher active MMP-9 (0.139 [0.059-0.339] ng/mL vs 0.060 [0.000-0.157] ng/mL and 0.045 [0.000-0.147] ng/mL; P = .001 and P = .014, respectively) and higher interleukin-8 (28.644 [11.921-62.587] pg/mL vs 16.442 [4.300-34.130] pg/mL and 18.258 [8.273-44.989] pg/mL; P < .001 and P = .010, respectively)., Conclusion: Biopsy specimens of the ventral AAA wall do not optimally reflect the magnitude of inflammatory processes in the AAA. The lateral sides of the AAA contain more microvessels, more inflammatory cells, more active proteases, and higher cytokine levels. These results suggest that the lateral aortic regions are more rupture-prone and may better reflect the inflammatory status in histopathologic examinations., (Copyright © 2012 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.)

Objective: To examine serum cytokine/chemokine profiles before and 6 months after endovascular repair (EVAR) of abdominal aortic aneurysm (AAA) and to determine whether they correlate with serum inflammatory activity using an in vitro model of leukocyte recruitment., Methods: Serum IL-1-α, IL-1β, IL-4, IL-6, IL-8, IL-10, IFN-γ, IP-10, MCP-1, TNF-α, and TNF-β were measured using a cytometry-based immunoassay. To test patient serum for direct inflammatory activity, human endothelial cells (EC) were stimulated with 30% patient serum for 24 hours. To test patient serum for the ability to prime EC for inflammatory responses, EC were incubated with 30% patient serum for 24 hours, followed by stimulation with low-dose (5 U/mL) TNF for 4 hours. Under both regimens of stimulation, the degree of EC activation was assessed by assaying neutrophil recruitment in a flow-based model., Results: Only IL-1α (67.9 ± 10.4 pg/mL vs 41.9 ± 7.4 pg/mL) and IL-8 (51.5 ± 5.1 vs 32.6 ± 4.7 pg/mL) changed significantly after surgery. Patient serum alone was unable to activate EC. However, serum from both time points could prime EC responses to low-dose TNF. Thus, after priming with preoperative serum, EC stimulated with TNF could recruit 76.7 ± 12.0 neutrophils/mm(2) into the subendothelial cell space. Post-EVAR serum was significantly less effective (44.4 ± 10.2 neutrophils/mm(2)). This reduction in neutrophil recruitment correlated with reduced IL-1α in post-EVAR serum. The addition of a neutralizing antibody against IL-1α to pre-EVAR serum inhibited EC priming and neutrophil recruitment, strongly implying that this cytokine was the priming agent., Conclusion: EVAR reduces serum IL-1α and its inflammatory activity in patient serum. IL-1α is, therefore, implicated in the molecular pathology of AAAs and may have potential as a clinically useful biomarker., (Copyright © 2011 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.)

Objective: Inflammation is associated with the disruption of the aortic media and appears to play a fundamental role in the progression and development of abdominal aortic aneurysm (AAA). Haptoglobin (Hp) is a genetically determined acute phase protein, the synthesis of which is increased during inflammation. This study was designed to investigate both phenotype and plasma levels of Hp in patients with AAA., Methods: Patients with documented AAA who were admitted for elective open repair operation or endograft stent implantation, and non-AAA subjects admitted for coronary arteriography, but found to have normal or insignificant coronary artery disease, were included in the study. Plasma Hp levels were determined using a standard specific enzyme-linked immunosorbent assay, while Hp phenotype was determined by native polyacrylamide gel electrophoresis. Total cholesterol, high density lipoprotein, low density lipoprotein, and triglyceride levels were analyzed enzymatically, and C-reactive protein was analyzed by immunochemistry., Results: Forty-five patients with AAA and 49 non-AAA subjects were included. The Hp 2-2 phenotype was more predominant in AAA patients compared with non-AAA subjects, but this difference was not significant (67% vs 47%; P = .141), while plasma Hp concentrations were significantly higher in AAA patients (237 ± 144 vs 163 ± 86 ng/mL; P = .024). Further analysis revealed that plasma Hp concentrations were significantly higher in AAA patients with the 2-2 phenotype compared with corresponding non-AAA subjects (238 ± 144 vs 163 ± 86 ng/mL;P = .024)., Conclusions: Our findings suggest that plasma Hp concentrations are elevated in patients with AAA, particularly those with the Hp 2-2 phenotype., (Copyright © 2011 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.)

Background: Haptoglobin (Hp) polymorphism is associated with the prevalence and clinical evolution of many inflammatory diseases and atherosclerosis. Circulating neutrophils and neutrophil-associated proteases are an important initial component of experimental abdominal aortic aneurysm (AAA) formation. Elastase and C-reactive protein (CRP) levels are elevated in patients with AAAs. This study assessed the relationship between AAA expansion and Hp phenotypes, neutrophil count, elastase, and CRP levels., Methods: Eighty-three consecutive AAA patients underwent annual ultrasound scans. Three major Hp phenotypes (1-1, 2-1, and 2-2) were determined, and the neutrophil count, serum elastase, and high-sensitivity (hs) CRP levels were measured at the initial examination. After initial screening, patients were rescanned at 6- to 12-month intervals up to a period of 2 to 7 years. The mean yearly growth of the AAA largest transverse diameter was estimated for each group of Hp patients. The results are presented as median (interquartile range)., Results: Hp 2-1 patients had a significantly higher growth rate (3.69 [2.40] mm/y) of AAA compared with patients with Hp 2-2 (1.24 [0.79], P < .00001) and Hp 1-1 (1.45 [0.68], P = .00004). This association remained significant in the multivariate analysis. Elevated elastase serum activity was also evident in AAA patients with Hp 2-1 (0.119 [0.084] arbitrary units) in contrast to Hp 2-2 (0.064 [0.041], P < .00001) and Hp 1-1 (0.071 [0.040], P = .0006) patients. CRP serum levels (mg/L) were significantly higher in patients with Hp 2-1 (7.2 [7.1]) than in Hp 2-2 (3.4 [3.1], P = .0058) and Hp 1-1 (2.8 [4.1], P = .044). The neutrophil count was not significantly different among Hp groups., Conclusions: The Hp 2-1 phenotype showed a strong association with increased rates of the expansion of AAAs and may be a useful independent predictor of growth rate. Further large follow-up studies will be needed to investigate the pathomechanisms of association and the role of elastase and inflammation in the progression of AAA.

Background: Markers of inflammation and fibrin turnover are elevated in individuals with a large (>55 mm) abdominal aortic aneurysm (AAA). Fibrin degradation generates D-dimer, known to possess multiple proinflammatory effects, and levels are elevated during early AAA development. This study characterized the plasma inflammatory response during early AAA pathogenesis to determine the effect of D-dimer levels., Methods: The study compared 75 men with a small AAA (range, 30-54 mm) with 90 age-, sex-, and race-matched controls. Plasma interleukin-6 (IL-6), complement C3, high-sensitivity C-reactive protein (hsCRP), fibrinogen, and D-dimer levels were measured., Results: Mean levels of fibrinogen (2.92 vs 2.59 g/L; P = .003), hsCRP (2.07 vs 1.29 ng/mL; P = .005), and D-dimer (346.7 vs 120.2 ng/mL; P < .001) were higher in men with a small AAA. These markers correlated with maximum aortic diameter determined by ultrasound imaging. On multivariate analysis, D-dimer levels were elevated in AAA individuals independent of smoking, cardiovascular disease (CVD), atherosclerotic risk factors, and inflammatory parameters. Fibrinogen and hsCRP levels remained elevated after adjustment for these covariates but lost significance when D-dimer was added to the model., Conclusion: C-reactive protein and D-dimer levels are elevated during early AAA development. D-dimer levels are most tightly associated with AAA status, however, and may mediate the observed elevation in acute-phase reactants., (Copyright (c) 2010 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.)

Objective: Recently, the relationship between immunoglobulin (Ig)G4 and idiopathic sclerosing lesions has attracted much attention. IgG4-related disease was first described with regard to the pancreas (autoimmune pancreatitis), and has been expanded to various organ systems. We previously reported that inflammatory abdominal aortic aneurysm (IAAA) could be one of the manifestations of IgG4-related disease. In this study, we tried to elucidate the clinical characteristics of IgG4-related IAAA., Methods: This study consisted of 23 cases of IAAA and 40 cases of atherosclerotic abdominal aortic aneurysm (AAA). Clinical presentation, laboratory findings, and pathological features were examined. Aneurysms of 13 cases histologically corresponded to IgG4-related IAAA., Results: Those cases accounted for 5% of all surgical AAAs, and 57% of IAAAs. Compared to non-IgG4-related IAAA, IgG4-related cases were characterized by less frequent association with abdominal or back pain. Serum IgG4 concentrations were significantly elevated in IgG4-related cases. Interestingly, patients with IgG4-related IAAA frequently showed an allergic constitution, such as drug allergy, autoimmune diseases, high serum IgE concentrations, and a high titer of antinuclear antibody. Pathologically, IgG4-related cases were characterized by more significant thickening of the adventitia and more numerous IgG4-positive plasma cell infiltrations. Three non-IgG4-related cases showed aneurysmal rupture at the time of first presentation, whereas no IgG4-related cases showed rupture., Conclusion: Recognizing a new disease entity of IgG4-related IAAA seems important because this was clinically and pathologically different from conventional aAAA and non-IgG4-related IAAA.

Background: Matrix metalloproteinase-9 (MMP-9) is thought to play a central role in abdominal aortic aneurysm (AAA) initiation. Doxycycline, a tetracycline analogue, has direct MMP-9-inhibiting properties in vitro, and it effectively suppresses AAA development in rodents. Observed inhibition of AAA progression, and contradictory findings in human studies evaluating the effect of doxycycline therapy on aortic wall MMP-9, suggest that the effects of doxycycline extend beyond MMP-9 inhibition and that the effect may be dose-dependent., Methods: This clinical trial evaluated the effect of 2 weeks of low- (50 mg/d), medium- (100 mg/d), or high-dose (300 mg/d) doxycycline vs no medication in four groups of 15 patients undergoing elective AAA repair. The effect of doxycycline treatment on MMP and cysteine proteases, and their respective inhibitors, was evaluated by quantitative polymerase chain reaction, Western blot analysis, immunocapture protease activity assays, and immunohistochemistry., Results: Doxycycline was well tolerated and no participants dropped out. Doxycycline treatment reduced aortic wall MMP-3 and MMP-25 messenger RNA expression (P < .045 and P < .014, respectively), selectively suppressed neutrophil collagenase and gelatinase (MMP-8 and MMP-9) protein levels (P < .013 and <.004, respectively), and increased protein levels of the protease inhibitors tissue inhibitor of metalloproteinase 1 and cystatin C (P < .029). As for the apparent selective effect on neutrophil-associated proteases, we sought for a reducing effect on aortic wall neutrophil content that was indeed confirmed by immunohistochemical analysis that revealed a 75% reduction in aneurysm wall neutrophil content (P < .001)., Conclusions: Independent of its dose, short-term preoperative doxycycline therapy improves the proteolytic balance in AAA, presumably through an effect on aortic wall neutrophil content. This study provides a rationale for doxycycline treatment in patients with an AAA as well as in other (vascular) conditions involving neutrophil influx such as Kawasaki disease and Behçet disease.

Objective: C-reactive protein (CRP) is a marker of cardiovascular disease. The objective was to determine if abdominal aortic aneurysm (AAA) and CRP serum concentration and its CRP gene are associated., Methods and Results: AAA patients and AAA negative controls were recruited. CRP concentration was measured and the single nucleotide polymorphism (SNP), rs3091244, assessed. AAA cases were divided into those measuring 30-55 mm and >55 mm in diameter, to assess correlation of CRP with AAA size. A total of 248 (227 male) cases and 400 (388 male) controls were included. CRP concentration was higher in cases (385.0 microl/dL [310.4-442.8] vs 180.3 microl/dL [168.1-196.9]; P < .0001). It was higher in large aneurysms (685.7 microl/dL [511.8-1083.0] vs 291.0 microl/dL [223.6-349.6]; P < .0001), with significant correlation observed to size (r = 0.37, P < .0001). CC was the most common SNP genotype with no difference in distribution (P = .43) between cases and controls. No difference existed in CRP for each genotype in the overall cohort (P = .17), cases (P = .18) and controls (P = .19)., Conclusion: The results demonstrate that CRP production may be related to the presence of AAA, especially in advanced disease. The serum concentration of CRP does not appear to be influenced by the functional SNP of the CRP gene, which also appears to have no association with AAA formation.

Objective: Homeostasis of the immune system is maintained by apoptotic elimination of potentially pathogenic autoreactive lymphocytes. Emerging evidence shows that Fas-mediated apoptosis is impaired in activated lymphocytes from patients with autoimmune disease. The aim of this work was to assess apoptosis mediated by the cell death receptor Fas in peripheral T lymphocytes from patients with abdominal aortic aneurysms (AAA)., Methods: The apoptotic pathway was triggered by anti-Fas monoclonal antibodies in cultured and activated peripheral T-cell lines from 20 AAA patients with control groups of 15 patients with aortic atherosclerotic occlusive disease (AOD) and 25 healthy individuals. Cell survival and death (apoptosis) rate were assessed., Results: Cross-linkage of Fas receptor exerted a strong apoptotic response on T cells from AOD patients and healthy controls, but a much less pronounced effect on T cells from AAA patients. The evaluation of cell survival rate showed a significantly higher percentage in AAA group (98.9% +/- 10.3%) than in the AOD subjects (58.9% +/- 15.2%) or the healthy group (59.4% +/- 12.9%; P < .001). Apoptosis assessment by annexin V and propidium iodide staining and flow cytometry showed similar results. The defect in AAA group was not due to decreased Fas expression, since Fas was expressed at normal levels. Moreover, it specifically involved the Fas system because cell death was induced in the normal way by methylprednisolone. Complementary DNA sequencing identified no causal Fas gene mutation, but two silent single nucleotide polymorphisms with higher frequency were found in the AAA group., Conclusions: Fas-induced apoptosis in activated T cells from AAA patients is impaired. This may disturb the normal down-regulation of the immune response and thus provide a new insight into possible mechanisms and routes in the pathogenesis of AAA.

Objective: Inflammatory modulators are important in the pathogenesis of aneurysmal disease. Gene expression profiling of experimental abdominal aortic aneurysm (AAA) tissue demonstrated upregulation of the FK506BP12 (rapamycin binding protein) gene product. Rapamycin is a potent immunosuppressor that prevents recurrent stenosis. However, its effect on aneurysm formation has not been studied. We therefore examined the effect of rapamycin in an experimental rat AAA model., Methods: Adult male Wistar rats underwent elastase infusion into isolated infrarenal aortas to create experimental aneurysms. Rats were randomized to receive either rapamycin or placebo via gastric lavage daily starting on the day of surgery. On postoperative day 7 the aneurysm was measured, the infrarenal aorta was harvested, and the rats were euthanized. NF kappa B was measured with Western blotting as a marker of inflammation. Matrix metalloproteinase (MMP)-9 protein levels were measured. Hematoxylin-eosin and elastin staining were used to examine tissue inflammation and elastin preservation., Results: Aneurysms were significantly smaller in diameter in the rapamycin-treated group (3.3 +/- 0.7 mm vs 4.5 +/- 0.5 mm; P <.0001). NF kappa B levels were significantly reduced by 64% +/- 14% in rapamycin-treated aortas (P =.023). MMP-9 was reduced in rapamycin-treated aortas by 54% +/- 22% (P =.043). Hematoxylin-eosin and elastin staining showed no changes in inflammatory infiltrate or degradation of elastin fibers in elastase-infused aortic segments in rapamycin-treated rats., Conclusion: Rapamycin significantly reduces the rate of aneurysm expansion in the experimental AAA rat model by 40%. Biochemical evidence suggests that this is related to suppression of inflammatory signaling and decreased MMP-9 levels. Rapamycin could provide a new treatment for small aneurysms., Clinical Relevance: Human aortic aneurysms are characterized histologically by an inflammatory infiltrate with severe proteolytic destruction. Rapamycin is an immunosuppressive agent commonly used to control transplant rejection and intimal hyperplasia by modulating the inflammatory cascade. In this experimental model rapamycin suppressed aneurysm expansion, decreased NF kappa B activation (a marker of inflammation), and decreased matrix metalloproteinase-9 levels. It is hoped that rapamycin or other similar anti-inflammatory drugs will one day be able to control aneurysm expansion in patients

Objective: Aortic inflammation and the genes that regulate the immune response play an important role in abdominal aortic aneurysm pathogenesis. However, the modulating effects of such genetic and other environmental factors on the severity on aneurysm inflammation is not known. The objective of this study was to determine the influence of the human leukocyte antigen (HLA) class II genes, gender, and environmental factors on degree of abdominal aortic aneurysm tissue inflammation., Methods: Aneurysm specimens were obtained at the time of operation from 96 consecutive patients who underwent abdominal aortic aneurysm repair and were graded for degree of histologic inflammation. Multivariate analysis was used to determine the association of genetic and environmental factors with degree of inflammation and to determine the HLA-associated disease risk for aneurysm., Results: Active cigarette smoking and female gender were independently associated with high-grade tissue inflammation identified histologically (odds ratio [OR], confidence interval [CI]: 5.6, 1.6 to 19.3; and 6.0, 1.4 to 26.2, respectively), and a specific HLA allele (DR B1(*)01) was inversely associated with inflammation (OR, CI: 0.2, 0.04 to 0.7). Overall, the HLA-DR B1(*)02 and B1(*)04 alleles were significantly associated with disease risk, more than doubling risk for abdominal aortic aneurysm (OR, CI: 2.5, 1.4 to 4.3; and 2.1, 1.2 to 3.7, respectively)., Conclusion: Active cigarette smoking and female gender are significant disease-modulating factors associated with increased abdominal aortic aneurysm inflammation. In addition, the HLA class II immune response genes possess both disease modulating and disease risk properties, which may be useful in early aneurysm detection and surveillance.

Background: Chronic inflammation is a characteristic feature of abdominal aortic aneurysms (AAAs), but the molecular signals responsible for recruiting monocytes into the outer aortic wall are unresolved. The purpose of this study was to examine whether AAA tissues elaborate chemotactic activity for mononuclear phagocytes and to determine whether this activity is attributable to interactions between elastin degradation peptides (EDPs) and their cell surface receptor, the 67-kD elastin binding protein (EBP)., Material and Methods: Soluble proteins were extracted from human AAA tissues, and chemotactic activity for differentiated U937 mononuclear phagocytes was measured by use of a modified Boyden chamber. Chemotactic activity induced by N -formyl-Met-Leu-Phe was used as a positive control and checkerboard analysis was used to distinguish chemotaxis from chemokinesis. Inhibition of chemotaxis was tested by peptide competition, blocking antibodies and galactosugar-mediated dissociation of the 67-kD EBP., Results: AAA extracts stimulated a concentration-dependent increase in monocyte migration that reached up to 24% of the maximal effect induced by N -formyl-Met-Leu-Phe. Checkerboard analysis demonstrated that AAA extracts stimulated chemotaxis without a chemokinetic effect. AAA-derived chemotactic activity was eliminated by competition with Val-Gly-Val-Arg-Pro-Gly (VGVAPG), a repetitive peptide found in human elastin that binds to cellular elastin receptors, and decreased nearly 40% in the presence of BA-4, an antielastin monoclonal antibody that can block EDP-mediated chemotactic activity. Monocyte chemotaxis in response to both VGVAPG and AAA extracts was abolished in the presence of lactose, a galactosugar that specifically dissociates the 67-kD EBP, but it was unaffected by either glucose, fructose, or mannose., Conclusions: These findings indicate that soluble EDPs released within human AAA tissue can subsequently attract mononuclear phagocytes through ligand-receptor interactions with the 67-kD EBP, thereby providing a plausible molecular mechanism to explain the inflammatory response that accompanies aneurysmal degeneration. Better understanding of factors regulating inflammatory cell recruitment may lead to novel forms of therapy for early stages of aneurysmal degeneration.

Objective: To determine the nature of and to compare the inflammatory responses induced by (1) endovascular and (2) conventional abdominal aortic aneurysm (AAA) repair., Material and Methods: Twelve consecutive patients undergoing elective infrarenal AAA repair were prospectively studied. Seven patients were selected for endovascular procedures (the EAAA group); five patients underwent open surgery (the OAAA group). Three control patients undergoing carotid thromboendarterectomy were also included. Serial peripheral venous blood samples were collected preoperatively, immediately after declamping or placement of the endograft, and at hours 1, 3, 6, 12, 24, 48, and 72. Acute phase response expression of peripheral T lymphocyte and monocyte activation markers and adhesion molecules (flow cytometry), soluble levels of cell adhesion molecules (enzyme-linked immunosorbent assay), cytokine (tumor necrosis factor alpha, interleukin-6, and interleukin-8) release (enzyme-linked immunosorbent assay), and liberation of complement products (nephelometry) were measured., Results: Regarding acute phase response, the EAAA and OAAA groups showed significant increases in C-reactive protein (P <.001 and P =.001), body temperature (P =.035 and P =.048), and leukocyte count (P <.001 and P <.001). Similar time course patterns were observed with respect to body temperature (P =.372). Statistically significant different patterns were demonstrated for C-reactive protein (P =.032) and leukocyte count (P =.002). Regarding leukocyte activation, a significant upregulation of peripheral T lymphocyte CD38 expression was observed in the OAAA group only (P =.001). Analysis of markers such as CD69, CD40L, CD25, and CD54 revealed no perioperative fluctuations in any group. Regarding circulating cell adhesion molecules, the EAAA and OAAA groups displayed significant increases in soluble intercellular adhesion molecule-1 (P =.003 and P =.001); there was no intergroup difference (P =.193). All groups demonstrated high soluble von Willebrand factor levels (P =.018, P =. 007, and P =.027), there being no differences in the patterns (P =. 772). Otherwise, soluble vascular cell adhesion molecule-1, soluble E-selectin, and soluble P-selectin did not appear to vary in any group. Regarding cytokine release, although a tendency toward high tumor necrosis factor alpha and interleukin-8 levels was noticed in the EAAA group, global time course effects failed to reach statistical significance (P =.543 and P =.080). In contrast, interleukin-6 showed elevations in all groups (P =.058, P <.001, and P =.004). Time course patterns did not differ between the EAAA and OAAA groups (P =.840). Regarding complement activation, the C3d/C3 ratio disclosed significant postoperative elevations in the EAAA and OAAA groups (P =.013 and P =.009). This complement product release was reduced in the EAAA group (P <.001)., Conclusions: The current study indicated that both endovascular and coventional AAA repair induced significant inflammatory responses. Our findings showed that there were no large differences between the procedures with respect to circulating cell adhesion molecule and cytokine release. Moreover, the endoluminal approach produced a limited response in terms of acute phase reaction, T lymphocyte activation, and complement product liberation. This might support the concept that endovascular AAA repair represents an attractive alternative to open surgery. Given the relatively small sample size, further larger studies are required for confirmation of our observations.

Purpose: Inflammation has been implicated as a contributing factor in the expansion of abdominal aortic aneurysms (AAA). To test this hypothesis, we examined the effects of a monoclonal antibody (MAB) to the leukocyte CD18 adhesion molecule on the expansion of experimental AAA., Methods: Aneurysms were induced by perfusion of an isolated segment of the infrarenal aorta with elastase in 22 normotensive (WKY) and 17 genetically hypertensive (WKHT) rats. Animals of both strains were randomly allocated to control or MAB-treated groups (MAB, 5 microgram/100 gm body weight intraperitoneally, daily, beginning on the operative day for a total of four doses). The activity of the MAB against rat leukocytes had first been determined by in vitro immunofluorescence flow cytometry. Aortic size was directly measured initially and on day 14. At that time, a segment of aorta was stained with hematoxylin and eosin and mononuclear leukocytes and neutrophils were counted in each of 10 microscopic fields (400X)., Results: The initial aortic size in all animals was 1.11+/-0.15 mm. All groups developed aneurysms significantly larger than the initial aortic size (p<0.01). However, the MAB-treated animals had significantly smaller aneurysms than the untreated controls (mm): WKY: 3.63+/-1.26, WKY-MAB: 2.08+/-0.30, WKHT: 4.54+/-1.86, WKHT-MAB: 2.37+/-0.40, p<0.0001. There also were significantly fewer monocytes in the MAB-treated normotensive rats: WKY:35.5+/-29.9, WKHT:40.6+/-28.8, WKY-MAB: 8.9+/-8.5, WKHT-MAB: 32.3+/-25.7, p=0.03. Neutrophil counts did not differ significantly between the groups., Conclusions: Treatment with anti-CD18 monoclonal antibody slows the expansion of AAA in this experimental model. The associated inflammatory process at day 14, as indicated by monocyte infiltration, is reduced, but this effect may be opposed by the presence of hypertension. Further evaluation of the role of leukocytes and adhesion molecules in the expansion of AAA is warranted.

Purpose: Mechanical and immunologic factors may play a role in the development of native arterial and biologic graft aneurysms. We developed an experimental rat aortic allograft aneurysm model in which segments of infrarenal aorta were transplanted between hypertensive and normotensive rats to study these factors in this model., Methods: Aortic allografts and autografts were inserted into spontaneously hypertensive (SHR) and normotensive Wistar Kyoto (WKY) rats. Effects of immunologic and antihypertensive therapy were evaluated. Graft diameters were followed up with magnetic resonance imaging and at harvest. Direct-pressure measurements were taken and dp/dtmax (force of ventricular contractions) was calculated before harvest., Results: Autografts remained isodiametric and maintained their histologic architecture. Aneurysmal dilation of transplanted segments occurred in SHR host allografts but not in WKY host allografts. Histologic examination of all allograft specimens noted a rejection reaction characterized by inflammatory cell infiltration and medial smooth muscle cell loss. Antigenic enhancement accelerated aneurysm development in SHR hosts but had no significant effect on WKY hosts. Rates of allograft enlargement and final allograft diameters were similar in antihypertensive treated and untreated SHR hosts. The dp/dtmax in untreated SHR hosts was greatest and differed significantly from that in the WKY rats but only marginally from that in treated SHR hosts., Conclusions: Immunologic rejection but not abnormal hemodynamics is necessary for development of allograft aneurysm in this model.