Aortic Wall Destruction Research Articles

MRTF-A promotes angiotensin II-induced inflammatory response and aortic dissection in mice.

Aortic dissection (AD) is a major cause of acute aortic syndrome with high mortality due to the destruction of aortic walls. Although recent studies indicate the critical role of inflammation in the disease mechanism of AD, it is unclear how inflammatory response is initiated. Here, we demonstrate that myocardin-related transcription factor A (MRTF-A), a signal transducer of humoral and mechanical stress, plays an important role in pathogenesis of AD in a mouse model. A mouse model of AD was created by continuous infusion of angiotensin II (AngII) that induced MRTF-A expression and caused AD in 4 days. Systemic deletion of Mrtfa gene resulted in a marked suppression of AD development. Transcriptome and gene annotation enrichment analyses revealed that AngII infusion for 1 day caused pro-inflammatory and pro-apoptotic responses before AD development, which were suppressed by Mrtfa deletion. AngII infusion for 1 day induced pro-inflammatory response, as demonstrated by expressions of Il6, Tnf, and Ccl2, and apoptosis of aortic wall cells, as detected by TUNEL staining, in an MRTF-A-dependent manner. Pharmacological inhibition of MRTF-A by CCG-203971 during AngII infusion partially suppressed AD phenotype, indicating that acute suppression of MRTF-A is effective in preventing the aortic wall destruction. These results indicate that MRTF-A transduces the stress of AngII challenge to the pro-inflammatory and pro-apoptotic responses, ultimately leading to AD development. Intervening this pathway may represent a potential therapeutic strategy.

High Salt Intake Worsens Aortic Dissection in Mice: Involvement of IL (Interleukin)-17A-Dependent ECM (Extracellular Matrix) Metabolism.

Aortic dissection (AD) is a fatal disease that occurs suddenly without preceding clinical signs or symptoms. Although high salt intake is a proposed risk factor for cardiovascular diseases, the relationship between AD and high salt intake has not been clarified. We examined the effect of high-salt challenge on a mouse AD model. Approach and Results: AD was induced in male mice by continuous infusion of β-aminopropionitrile and Ang II (angiotensin II). High-salt challenge exacerbated aortic wall destruction in AD. Deletion of Il17a (IL-17KO [IL (interleukin)-17A knockout]) did not affect the AD phenotype at baseline, but it abolished the high salt-induced worsening of the aortic destruction. Unexpectedly, aortas of IL-17KO mice exhibited global changes in ECM (extracellular matrix)-related genes without alteration of proinflammatory genes, altered architecture of collagen fibers, and reduced stiffness before AD induction. The aortas of IL-17KO mice were less sensitive to AD-inducing stimuli, as shown by the induction of phenotypic modulation markers SMemb and vimentin, suggesting a reduced stress response. The aortas of IL-17KO mice had a higher population of smooth muscle cells with nuclear-localized phosphorylated Smad2, indicative of TGFβ (transforming growth factor-beta) signal activation. Consistently, pretreatment of smooth muscle cells in culture with IL-17A blunted the activation of Smad2 by TGFβ1. These findings indicate that high salt intake has a worsening effect on AD in the context of high aortic wall stiffness, which is under the control of IL-17A through ECM metabolism. Therefore, salt restriction may represent a low-cost and practical way to reduce AD risk.

Characterizing Possible Biomarkers in Ascending Aortic Aneurysms - MMP-2/9 Serum Levels in Patients and Healthy Controls

Objectives: The role of Matrix-Metalloproteinases 2 and 9 (MMP-2/9) in the pathogenesis of ascending aortic aneurysms and its potential as a wall-derived prognostic serum-bio-indicator have not been fully characterized yet. We examined blood serum samples of patients before surgical intervention for ascending and/or root aneurysm and healthy volunteers. Methods: MMP-2 and MMP-9 levels in the serum of n = 32 patients (aortic root/ascending aorta > = 45 mm, n = 26, [81%] aortic regurgitation, n = 12 [38%] aortic stenosis, n = 3 [9%] normally functioning valve, n = 13 [41%] bicuspid aortic valve) were compared with the levels of n = 19 healthy volunteers. For identification of differences between patients and controls a Wilcoxon rank sum test was used. For statistical analyses focusing on identifying factors impacting on MMP serum levels ANOVA one-way test was used. The influence of aortic diameter in patients suffering from ascending aortic aneurysm on the MMP-2 and MMP-9 levels was examined by Spearman´s rank correlation test in 31 patients. Results: Patients with aneurysm of the ascending aorta presented significantly lower MMP-2 serum levels when compared with controls, whereas no significant difference for MMP-9 levels was detected (MMP-2 p = 0,001, MMP-9 p = 0,505). Analysis of gender and age, comorbidities such as aortic insufficiency and stenosis, bicuspidity of the aortic valve, obesity, hypertension and hyperlipidemia revealed that only hyperlipidemia was significantly associated with altered MMP-9 level in patients with ascending aortic aneurysm (p = 0,042). In those patients Sartane medication was linked to a significant decrease of serum MMP-9 level (p = 0,01).The ascending aortic diameter was significantly correlated with MMP-2 level (correlation coefficient = 0.373, p = 0.039). Conclusions: Hyperlipidemia influences MMP-9 level in the serum of patients with ascending aortic aneurysm. The lower levels of MMP-2 in patients compared with healthy controls suggest a higher binding to matrix components as found in abdominal aortic aneurysm. The correlation between aortic diameter and the MMP- 2 level possibly alludes to higher aortic wall destruction in aneurysms with larger diameters. Thus this correlation of MMP-2 serum levels with larger diameters should put MMP-2 in the focus of further evaluation as a prognostic biomarker.

Chemokine (C-X-C motif) receptor 4 blockade by AMD3100 inhibits experimental abdominal aortic aneurysm expansion through anti-inflammatory effects.

Inflammation plays a critical role in the development of abdominal aortic aneurysms (AAAs). Because stromal cell-derived factor 1 (SDF-1) is known for its ability to attract inflammatory cells, we investigated whether SDF-1/chemokine (C-X-C motif) receptor 4 (CXCR4) axis is expressed in aneurysmal aortic wall and plays a role in AAA physiopathology and asked whether its blockade modulates AAA formation and expansion. Quantitative real-time polymerase chain reaction analysis showed that SDF-1α and CXCR4 mRNA levels are increased in both human and CaCl2-induced mouse AAA wall and are positively correlated to the aortic diameter in mice. ELISA quantification and immunostaining demonstrated that, in mice, aortic SDF-1α is rapidly induced during AAA formation, first by apoptotic vascular smooth muscle cells in the injured media and then by adventitial macrophages once AAA is fully established. Using green fluorescent protein-positive (GFP(+/-)) bone marrow transplantation experiments, we demonstrated that aortic SDF-1 overexpression is implicated in the recruitment of bone marrow-derived macrophages within the AAA wall. Furthermore, in mice, blockade of CXCR4 by AMD3100 decreases the infiltration of adventitial macrophages, inhibits AAA formation, and prevents aortic wall destruction. AMD3100 reduces the mRNA levels of MMP-12 and MMP-14 as well as that of inflammatory effectors MCP-1, MIP-1β, MIP-2α, RANTES, IL-1β, IL-6, TNF-α, and E-selectin. Finally, AMD3100 stabilizes the diameter of formed, expanding AAAs in 2 experimental models. SDF-1/CXCR4 axis is upregulated in human and mouse AAAs. Blockade of CXCR4 with AMD3100 suppresses AAA formation and progression in two rodent models. Blockade of SDF-1/CXCR4 axis may represent a new strategy to limit progression of small human AAAs.

Aortic wall destruction associated with a rare 11.5‐cm ascending aortic aneurysm

Aortic wall destruction associated with a rare 11.5‐cm ascending aortic aneurysm

AB0777 Computed tomodensitometric (CT) angiographic imaging characteristics of idiopathic aortitis: A case control study

BackgroundIdiopathic aortitis is a rare condition characterized by giant cell or lymphoplasmacytic inflammation of aorta in absence of a secondary cause. No information is available on pre-operative imaging findings in...

Bone Marrow Mesenchymal Stem Cells Stabilize Already-formed Aortic Aneurysms More Efficiently than Vascular Smooth Muscle Cells in a Rat Model

Abdominal aortic aneurysms (AAAs) expand because of aortic wall destruction. Enrichment in Vascular Smooth Muscle Cells (VSMCs) stabilizes expanding AAAs in rats. Mesenchymal Stem Cells (MSCs) can differentiate into VSMCs. We have tested the hypothesis that bone marrow-derived MSCs (BM-MSCs) stabilizes AAAs in a rat model. Rat Fischer 344 BM-MSCs were isolated by plastic adhesion and seeded endovascularly in experimental AAAs using xenograft obtained from guinea pig. Culture medium without cells was used as control group. The main criteria was the variation of the aortic diameter at one week and four weeks. We evaluated the impact of cells seeding on inflammatory response by immunohistochemistry combined with RT-PCR on MMP9 and TIMP1 at one week. We evaluated the healing process by immunohistochemistry at 4 weeks. The endovascular seeding of BM-MSCs decreased AAA diameter expansion more powerfully than VSMCs or culture medium infusion (6.5% ± 9.7, 25.5% ± 17.2 and 53.4% ± 14.4; p = .007, respectively). This result was sustained at 4 weeks. BM-MSCs decreased expression of MMP-9 and infiltration by macrophages (4.7 ± 2.3 vs. 14.6 ± 6.4 mm(2) respectively; p = .015), increased Tissue Inhibitor Metallo Proteinase-1 (TIMP-1), compared to culture medium infusion. BM-MSCs induced formation of a neo-aortic tissue rich in SM-alpha active positive cells (22.2 ± 2.7 vs. 115.6 ± 30.4 cells/surface units, p = .007) surrounded by a dense collagen and elastin network covered by luminal endothelial cells. We have shown in this rat model of AAA that BM-MSCs exert a specialized function in arterial regeneration that transcends that of mature mesenchymal cells. Our observation identifies a population of cells easy to isolate and to expand for therapeutic interventions based on catheter-driven cell therapy.

Reestablishment of the Endothelial Lining by Endothelial Cell Therapy Stabilizes Experimental Abdominal Aortic Aneurysms

Loss of the endothelium and its replacement by a thick thrombus are structural features of human abdominal aortic aneurysms (AAAs). In AAAs, the relationship between aortic diameter expansion, the presence of thrombus, and the lack of endothelial cells (ECs) remains unexplored. We hypothesized that reendothelialization by cell therapy would modulate aortic wall destruction and ultimately stabilize AAAs. We evaluated the impact of local seeding of rat aortic ECs or peripheral blood-derived outgrowth ECs on AAA evolution. Rat aortic ECs (n=30) or serum-free medium (controls; n=29) were seeded endovascularly immediately (day 0) or 14 days after surgery in the rat xenograft model. Rat aortic EC seeding prevented AAA formation and stabilized formed AAAs at 28 days (diameter increase at day 0+28, 51±6% versus 83±6%; day 14+28, -1±4% versus 22±6% in rat aortic ECs and controls, respectively; P<0.01). This stabilizing effect was associated with the reestablishment of the endothelial lining, the suspension of proteolysis, and the reconstitution of new aortic wall rich in smooth muscle cells and extracellular matrix. Transplanted rat aortic ECs did not participate directly in aortic wall repair but exerted their healing properties through paracrine mechanisms involving the upregulation of endothelium-derived stabilizing factors and the recruitment of resident vascular cells. In rats, the transplantation of outgrowth ECs (n=7) significantly reduced by 30% the progression of AAAs and restored the abluminal endothelium at 28 days compared with controls (n=9). Our study demonstrates the potential of restoring the endothelial lining to control AAA dynamics and designates ECs as an efficient therapy to stop AAA expansion.

Évaluation de la prescription du ionogramme sanguin aux urgences hospitalières pédiatriques.Étude prospective multicentrique

Abdominal aortic aneurysms (AAAs) expand because of aortic wall destruction. Enrichment in Vascular Smooth Muscle Cells (VSMCs) stabilizes expanding AAAs in rats. Mesenchymal Stem Cells (MSCs) can differentiate into VSMCs. We have tested the hypothesis that bone marrow-derived MSCs (BM-MSCs) stabilizes AAAs in a rat model.Rat Fischer 344 BM-MSCs were isolated by plastic adhesion and seeded endovascularly in experimental AAAs using xenograft obtained from guinea pig. Culture medium without cells was used as control group. The main criteria was the variation of the aortic diameter at one week and four weeks. We evaluated the impact of cells seeding on inflammatory response by immunohistochemistry combined with RT-PCR on MMP9 and TIMP1 at one week. We evaluated the healing process by immunohistochemistry at 4 weeks.The endovascular seeding of BM-MSCs decreased AAA diameter expansion more powerfully than VSMCs or culture medium infusion (6.5% ± 9.7, 25.5% ± 17.2 and 53.4% ± 14.4; p = .007, respectively). This result was sustained at 4 weeks. BM-MSCs decreased expression of MMP-9 and infiltration by macrophages (4.7 ± 2.3 vs. 14.6 ± 6.4 mm2 respectively; p = .015), increased Tissue Inhibitor Metallo Proteinase-1 (TIMP-1), compared to culture medium infusion. BM-MSCs induced formation of a neo-aortic tissue rich in SM-alpha active positive cells (22.2 ± 2.7 vs. 115.6 ± 30.4 cells/surface units, p = .007) surrounded by a dense collagen and elastin network covered by luminal endothelial cells.We have shown in this rat model of AAA that BM-MSCs exert a specialized function in arterial regeneration that transcends that of mature mesenchymal cells. Our observation identifies a population of cells easy to isolate and to expand for therapeutic interventions based on catheter-driven cell therapy.

Epstein-Barr virus-containing t-cell lymphoma and atherosclerotic abdominal aortic aneurysm in a young adult

Malignant lymphoma infiltrating the abdominal aorta and resulting in an aortic aneurysm has never been documented. We report here a case of angiocentric T-cell lymphoma in a 33-year-old man who for months presented intermittent fever, splenomegaly, and an abdominal pulsatile mass. Angiography revealed extensive aneurysmal dilatation of the infrarenal abdominal aorta, bilateral iliac artery, and right common femoral artery. Splenic abscess and infected abdominal aortic aneurysm were initially suspected. An urgent splenectomy and aneurysmectomy with an aortic bifemoral bypass were performed. Pathological examination of the aortic aneurysm showed extensive necrosis, severe atherosclerosis, and lymphoma cell infiltration of the aortic wall. The lymphoid cells in the aorta and spleen were stained positive for CD45RO, CD56, and CD8, but negative for CD4 and CD19. Double-labeling immunohistochemistry and in situ hybridization using EBER1 for Epstein-Barr virus (EBV) revealed positive nuclear staining in the atypical T-lymphoid cells. This is the first definitive proof of peripheral T-cell lymphoma involving the abdominal aorta. Our evidence also supports that the EBV infection of T cells could be responsible for the atherosclerosis and hypertriglyceridemia, and the angiocentricity of the tumor cells apparently results in the presenting atherosclerotic aortic wall destruction, providing an additional causative concept for abdominal aortic aneurysm.

Surgical treatment for acute native aortic valvular infective endocarditis: long-term follow-up

During the period 1970–1993, 116 patients (63 men, 53 women) with native aortic valvular infective endocarditis were treated surgically. The mean age was 37 years. The main causative organisms were streptococci and staphylococci. Indication for surgery was cardiac failure (70 cases), uncontrolled sepsis (30), peripheral emboli (11) and overwhelming destruction of the aortic valve (five). Hospital and late mortality rates were 8% and 11% respectively. Patients who died in hospital and those who presented a paravalvular leakage had a ring abscess associated with aortic wall destruction. Among 34 patients screened for cerebral septic emboli the condition was confirmed in 15, of whom six were symptom-free. Thus, it is believed that in the presence of root abscess, surgery should be undertaken promptly, regardless of the cardiac status. It is confirmed that cerebral septic emboli should be systematically screened for in the presence of any infective endocarditis.

Surgical Treatment for Acute Native Aortic Valvular Infective Endocarditis: Long-Term Follow-Up

During the period 1970-1993, 116 patients (63 men, 53 women) with native aortic valvular infective endocarditis were treated surgically. The mean age was 37 years. The main causative organisms were streptococci and staphylococci. Indication for surgery was cardiac failure (70 cases), uncontrolled sepsis (30), peripheral emboli (11) and overwhelming destruction of the aortic valve (five). Hospital and late mortality rates were 8% and 11 % respectively. Patients who died in hospital and those who presented a paravalvular leakage had a ring abscess associated with aortic wall destruction. Among 34 patients screened for cerebral septic emboli the condition was confirmed in 15, of whom six were symptom-free. Thus, it is believed that in the presence of root abscess, surgery should be undertaken promptly, regardless of the cardiac status. It is confirmed that cerebral septic emboli should be systematically screened for in the presence of any infective endocarditis.