Reconstruction of Chest Wall Defects Using a Technique Involving Mesh, Titanium Plates, and a Pedunculated Muscle Flap.

We herein present a new surgical reconstruction technique for large chest wall defects after resection of advanced chest wall tumors.

CXCL8 hyper-signaling in the aortic abdominal aneurysm.

There are indications for elevated CXCL8 levels in abdominal aortic aneurysm disease (AAA). CXCL8 is concurrently involved in neutrophil-mediated inflammation and angiogenesis, two prominent and distinctive characteristics of AAA. As such we considered an evaluation of a role for CXCL8 in AAA progression relevant. ELISA's, real time PCR and array analysis were used to explore CXCL8 signaling in AAA wall samples. A role for CXCL8 in AAA disease was tested through the oral CXCR1/2 antagonist DF2156A in the elastase model of AAA disease. There is an extreme disparity in aortic wall CXCL8 content between AAA and aortic atherosclerotic disease (median [IQR] aortic wall CXCL8 content: 425 [141-1261] (AAA) vs. 23 [2.8-89] (atherosclerotic aorta) µg/g protein (P < 1 ·â€¯10-14)), and abundant expression of the CXCR1 and 2 receptors in AAA. Array analysis followed by pathway analysis showed that CXCL8 hyper-expression in AAA is followed increased by IL-8 signaling (Z-score for AAA vs. atherosclerotic control: 2.97, p < 0.0001). Interference with CXCL8 signaling through DF2156A fully abrogated AAA formation and prevented matrix degradation in the murine elastase model of AAA disease (p < 0.001). CXCL8-signaling is a prominent and distinctive feature of AAA, interference with the pathway constitutes a promising target for medical stabilization of AAA.

A potential role for glycated cross-links in abdominal aortic aneurysm disease.

BACKGROUND: Diabetes is a risk factor for atherosclerotic disease but negatively associated with the development and progression of abdominal aortic aneurysm (AAA). Advanced glycation end products (AGEs) are increased in diabetes and renders the vascular matrix more resistant to proteolysis. We assessed the concentration of AGEs in AAA biopsies obtained from diabetic and nondiabetic patients and hypothesized that (nonenzymatic) glycation of AAA tissue protects against proteolytic breakdown of collagen. METHODS: AAA biopsies were collected from 30 diabetic and 30 matched nondiabetic AAA patients at the time of open repair. Aortic control samples from 10 nondiabetic and 16 diabetic patients were collected, and concentrations of the AGE cross-link pentosidine was measured. Furthermore, noncross-linking AGEs (adducts), as well as proteolytic enzymes known to play a role in aneurysm development (matrix metalloproteinase [MMP]-2, MMP-9, cathepsin B and S) were quantified. Ex vivo, nondiabetic AAA biopsies were glycated and measured subsequently for collagen type I release. RESULTS: Pentosidine concentrations in AAA wall biopsies were increased in patients with diabetes compared with nondiabetics 9.4 (5.0-13.5) vs 6.0 (2.5-9.6) pmol/µmol lysine (P = .02). Increased pentosidine concentrations were also observed in nonaneurysmatic aortic wall biopsies from diabetic patients. In diabetic AAA vascular wall tissue, pentosidine concentration was negatively correlated with aortic diameter (r = -0.43; P = .02). Ex vivo glycated AAA biopsies were resistant against MMP-induced collagen type I degradation as compared with controls (7.0 vs 10.4 µg/L; P = .02). No differences were observed for AGEs that are not forming cross-links. CONCLUSIONS: These findings suggest that cross-linking AGEs like pentosidine play a protective role in AAA progression in diabetic patients.

IL-6: A Janus-like factor in abdominal aortic aneurysm disease.

BACKGROUND AND AIMS: An abdominal aortic aneurysm (AAA) is part of the atherosclerotic spectrum of diseases. The disease is hallmarked by a comprehensive localized inflammatory response with striking IL-6 hyperexpression. IL-6 is a multifaceted cytokine that, depending on the context, acts as a pro- or anti-inflammatory factor. In this study, we explore a putative role for IL-6 in AAA disease. METHODS: ELISA's, Western blot analysis, real time PCR and array analysis were used to investigate IL-6 expression and signaling in aneurysm wall samples from patients undergoing elective AAA repair. A role for IL-6 in AAA disease was tested through IL-6 neutralization experiments (neutralizing antibody) in the elastase model of AAA disease. RESULTS: We confirmed an extreme disparity in aortic wall IL-6 content between AAA and atherosclerotic disease (median [5th-95th percentile] aortic wall IL-6 content: 281.6 [0.0-1820.8] (AAA) vs. 1.9 [0.0-37.8] µg/g protein (atherosclerotic aorta), (p < 0.001). Array analysis followed by pathway analysis showed that IL-6 hyper-expression is followed by increased IL-6 signaling (p < 0.000039), an observation confirmed by higher aneurysm wall pSTAT3 levels, and SOCS1 and SOCS3 mRNA expression, (p < 0.018). Remarkably, preventive IL-6 neutralization i.e. treatment started one day prior to the elastase-induction resulted in >40% 7-day mortality due to aortic rupture. In contrast, delayed IL-6 neutralization (i.e. neutralization started at day 4 after elastase induction) did not result in ruptures, and quenched AAA growth (p < 0.021). CONCLUSIONS: AAA disease is characterized by increased IL-6 signaling. In the context of the elastase model of AAA disease, IL-6 appears a multi-faceted factor, protective upon acute injury, but negatively involved in the perpetuation of the disease process.

Histological analysis of extracranial carotid artery aneurysms.

INTRODUCTION: Extracranial carotid artery aneurysms (ECAA) are rare but may be accompanied with significant morbidity. Previous studies mostly focused on diagnostic imaging and treatment. In contrast, the pathophysiological mechanisms and natural course of ECAA are largely unknown. Understanding the pathophysiological background may add to prediction of risk for adverse outcome and need for surgical exclusion. The aim of this study was to investigate the histopathological characteristics of ECAA in patients who underwent complete surgical ECAA resection. MATERIAL AND METHODS: From March 2004 till June 2013, 13 patients were treated with open ECAA repair. During surgery the aneurysm sac was resected and processed for standardized histological analysis. Sections were stained with routine hematoxylin and eosin and special stains to detect elastin, collagen, different types of inflammatory cells, vascular smooth muscle cells and endothelial cells. RESULTS: Histopathological characterization revealed two distinct categories: dissection (abrupt interruption of the media; n = 3) and degeneration (general loss of elastin fibers in the media; n = 10). In the degenerative samples the elastin fibers in the media were fragmented and were partly absent. Inflammatory cells were observed in the vessel wall of the aneurysms. CONCLUSION: Histological analysis in this small sample size revealed dissection and degeneration as the two distinct underlying mechanisms in ECAA formation.

Leukotriene B4 levels in human atherosclerotic plaques and abdominal aortic aneurysms.

BACKGROUND: Leukotriene B4 (LTB4) has been associated with the initiation and progression of atherosclerosis and abdominal aortic aneurysm (AAA) formation. However, associations of LTB4 levels with tissue characteristics and adverse clinical outcome of advanced atherosclerosis and AAA are scarcely studied. We hypothesized that LTB4 levels are associated with a vulnerable plaque phenotype and adverse clinical outcome. Furthermore, that LTB4 levels are associated with inflammatory AAA and adverse clinical outcome. METHODS: Atherosclerotic plaques and AAA specimens were selected from two independent databases for LTB4 measurements. Plaques were isolated during carotid endarterectomy from asymptomatic (n = 58) or symptomatic (n = 317) patients, classified prior to surgery. LTB4 levels were measured without prior lipid extraction and levels were corrected for protein content. LTB4 levels were related to plaque phenotype, baseline patient characteristics and clinical outcome within three years following surgery. Seven non-diseased mammary artery specimens served as controls. AAA specimens were isolated during open repair, classified as elective (n = 189), symptomatic (n = 29) or ruptured (n = 23). LTB4 levels were measured similar to the plaque measurements and were related to tissue characteristics, baseline patient characteristics and clinical outcome. Twenty-six non-diseased aortic specimens served as controls. RESULTS: LTB4 levels corrected for protein content were not significantly associated with histological characteristics specific for vulnerable plaques or inflammatory AAA as well as clinical presentation. Moreover, it could not predict secondary manifestations independently investigated in both databases. However, LTB4 levels were significantly lower in controls compared to plaque (p = 0.025) or AAA (p = 0.017). CONCLUSIONS: LTB4 levels were not associated with a vulnerable plaque phenotype or inflammatory AAA or clinical presentation. This study does not provide supportive evidence for a role of LTB4 in atherosclerotic plaque destabilization or AAA expansion. However, these data should be interpreted with care, since LTB4 measurements were performed without prior lipid extractions.

Intraluminal abdominal aortic aneurysm thrombus is associated with disruption of wall integrity.

OBJECTIVE: An association of intraluminal thrombus (ILT) with abdominal aortic aneurysm (AAA) growth has been suggested. Previous in vitro experiments have demonstrated that aneurysm-associated thrombus may secrete proteolytic enzymes and may develop local hypoxia that might lead to the formation of tissue-damaging reactive oxygen species. In this study, we assessed the hypothesis that ventral ILT thickness is associated with markers of proteolysis and with lipid oxidation in the underlying AAA vessel wall. METHODS: Ventral AAA tissue was collected from asymptomatic patients at the site of maximal diameter during open aneurysm repair. Segments were divided, one part for biochemical measurements and one for histologic analyses. We measured total cathepsin B, cathepsin S levels, and matrix metalloproteinase (MMP)-2 and MMP-9 activity. Myeloperoxidase and thiobarbituric acid reactive substances were determined as measures of lipid oxidation. Histologic segments were analyzed semiquantitatively for the presence of collagen, elastin, vascular smooth muscle cells (VSMCs), and inflammatory cells. Preoperative computed tomography angiography scans of 83 consecutive patients were analyzed. A three-dimensional reconstruction was obtained, and a center lumen line of the aorta was constructed. Ventral ILT thickness was measured in the anteroposterior direction at the level of maximal aneurysm diameter on the orthogonal slices. RESULTS: Ventral ILT thickness was positively correlated with aortic diameter (r=0.25; P=.02) and with MMP-2 levels (r=0.27; P=.02). No biochemical correlations were observed with MMP-9 activity or cathepsin B and S expression. No correlation between ventral ILT thickness and myeloperoxidase or thiobarbituric acid reactive substances was observed. Ventral ILT thickness was negatively correlated with VSMCs (no staining, 18.5 [interquartile range, 12.0-25.5] mm; minor, 17.6 [10.7-22.1] mm; moderate, 14.5 [4.6-21.7] mm; and heavy, 8.0 [0.0-12.3] mm, respectively; P=.01) and the amount of elastin (no staining, 18.6 [12.2-30.0] mm; minor, 16.5 [9.0-22.1] mm; moderate, 11.7 [2.5-15.3] mm; and heavy 7.7 [0.0-7.7] mm, respectively; P=.01) in the medial aortic layer. CONCLUSIONS: ILT thickness appeared to be associated with VSMCs apoptosis and elastin degradation and was positively associated with MMP-2 concentrations in the underlying wall. This suggests that ILT thickness affects AAA wall stability and might contribute to AAA growth and rupture. ILT thickness was not correlated with markers of lipid oxidation.

Intraplaque neovascularization and hemorrhage: markers for cardiovascular risk stratification and therapeutic monitoring.

Atherosclerotic disease results in major clinical events and remains a leading cause of morbidity and mortality in the western World. Atherosclerotic plaques have a heterogeneous presentation. Atherosclerotic plaques with a vulnerable phenotype have been associated with an increased risk for cardiovascular complications. Intraplaque neovascularization and hemorrhage are histopathological features that have been linked with the vulnerable plaque. The role of intraplaque neovascularization and hemorrhage in plaque destabilization and lesion progression has gained serious interest. Intraplaque neovascularization and hemorrhage have been correlated with the occurrence of prior cardiovascular events and have predictive value for the occurrence of future cardiovascular events. Pharmacological interventions showed an inhibiting effect of lipid-lowering drugs on plaque neovascularization. Imaging modalities such as contrast-enhanced ultrasound or MRI are able to visualize intraplaque neovascularization and hemorrhage noninvasively. Consequently, detection of intraplaque neovascularization and hemorrhage visualized with noninvasive imaging might improve the stratification of 'high-risk' patients.

Osteoprotegerin is associated with aneurysm diameter and proteolysis in abdominal aortic aneurysm disease.

OBJECTIVE: Serum osteoprotegerin (OPG) concentrations have previously been associated with growth of abdominal aortic aneurysms (AAAs). In vitro experiments showed that OPG promotes matrix metalloprotease (MMP) release from monocytes and vascular smooth muscle cells. We hypothesized that OPG expression is increased in human AAAs and is associated with proteolysis. METHODS AND RESULTS: AAA biopsies were collected from 329 patients. We assessed the concentrations of OPG, cathepsins A, B, and S as well as the activity of MMP-2 and MMP-9. The AAA wall infiltration by macrophages, lymphocytes, and plasma cells was estimated by immunohistochemistry. The concentration of OPG correlated positively with aortic diameter (<55 mm: 16.1 [5.8-28.7], 55-70 mm: 21.9 [10.2-36.0], >70 mm: 24.0 [13.5-52.9] ng OPG/mg total amount of protein, P=0.020), cathepsin A (r=0.221, P=0.005), B (r=0.384, P<0.001), and S (r=0.467, P<0.001), MMP-2 (r=0.180, P<0.001), MMP-9 (r=0.178, P<0.001), and the number of lymphocytes (P<0.001) and plasma cells (P=0.001). OPG immunostaining was predominantly demonstrated in plasma cells. CONCLUSIONS: The concentration of aortic wall OPG is positively associated with established markers of AAA severity and pathogenesis. OPG appeared to be associated with lymphocytes and plasma cells. These human data support previous experimental data suggesting a role for OPG in AAA pathogenesis.

The influence of smoking on endovascular abdominal aortic aneurysm repair.

OBJECTIVE: The main purpose of this study was to evaluate the influence of smoking on perioperative outcomes of endovascular aneurysm repair (EVAR), aneurysm sac behavior, abdominal aortic aneurysm (AAA) neck growth after EVAR, and its effect on stent graft migration during follow-up. METHODS: Baseline characteristics and follow-up data were collected prospectively by patient record forms. Follow-up visits were scheduled at 1, 3, 6, 12, 18, and 24 months, and annually thereafter and included a clinical examination and imaging studies. Patients were stratified in three groups according to their smoking status as nonsmokers, former smokers, and smokers. RESULTS: This study analyzed the data for 4176 nonsmokers, 2406 former smokers, and 2056 smokers who were enrolled prospectively in the European Collaborators on Stent-Graft Techniques for Aortic Aneurysm Repair (EUROSTAR) database. Compared with nonsmokers, smokers required more percutaneous transluminal angioplasty and stent placements during EVAR (P < .001), and stent graft migration occurred more often (hazard ratio, 1.45; 95% confidence interval, 1.03-2.05; P = .033). Nonsmokers had more late type II endoleaks than former smokers and smokers (58.5%, 55.9%, and 35.5%, respectively; P < .001). Smoking had no effect on aneurysm sac behavior or AAA neck growth after EVAR. CONCLUSIONS: Smokers need more percutaneous transluminal angioplasty procedures and stents during EVAR. They have fewer late type II endoleaks during follow-up; however, smokers should be closely monitored because they have an increased risk of stent graft migration.

Annual rupture risk of abdominal aortic aneurysm enlargement without detectable endoleak after endovascular abdominal aortic repair.

OBJECTIVES: Whether abdominal aortic aneurysm (AAA) enlargement after endovascular aneurysm repair (EVAR), without an identifiable endoleak, is a risk factor for AAA rupture remains controversial. To our knowledge, studies including large patient numbers investigating this topic have not been done. Therefore, a considerable number of conversions to open AAA repair have been performed in this patient group. This study evaluated AAA rupture risk in patients without detectable endoleaks but with AAA enlargement after EVAR treatment. METHODS: Baseline characteristics and follow-up data were collected prospectively by case record forms. Follow-up visits were scheduled at 1, 3, 6, 12, 18, and 24 months, and annually thereafter. The follow-up assessment included clinical examination and imaging studies. Patients were divided into three groups according to the degree of shrinkage or enlargement of the aneurysm. Group A included patients with >8 mm aneurysm shrinkage, group B consisted of patients with ≤ 8 mm shrinkage to ≤ 8 mm enlargement, and group C patients had an aneurysm enlargement of >8 mm. RESULTS: The basis for this analysis was 6337 patients who were enrolled prospectively in the European Collaborators on Stent-Graft Techniques for Aortic Aneurysm Repair (EUROSTAR) database between 1996 and 2006. Group A included 691 patients; group B, 5307 patients; and group C, 339 patients. Ruptures occurred in 3 patients in group A, in 14 patients in group B, and in 9 patients in group C. The annual rate of rupture in group C was <1% in the first 4 years but accelerated to 7.5% up to 13.6% in the years thereafter. The mortality rate of elective conversion to open AAA repair was 6.0%. CONCLUSIONS: The risk of rupture in patients with an AAA enlargement of 8 mm after EVAR, without detectable endoleaks, is <1% in the first 4 years. No ruptures were seen in patients with AAA enlargement without detectable endoleaks who were not treated with Vanguard stent grafts (Boston Scientific Corp, Natick, Mass) and had AAA diameters <70 mm. For this group, conversion to open repair might not be mandatory, and regular follow-up can be advised instead. After 4 years of follow-up, this study observed an increased annual rupture risk, which might indicate the need for conversion; however, groups are small, and follow-up bias could play a role.