Surgical strategy for inflammatory thoracic aortic aneurysms in the endovascular surgery era.

OBJECTIVE: Inflammatory thoracic aortic aneurysms (TAAs) are very rare aortic conditions. Resection and replacement of the inflammatory aorta is the first-line treatment, and thoracic endovascular aortic repair (TEVAR) has recently been reported as a less invasive alternative even for this aortic cohort. In the present study, we reviewed our experience with inflammatory TAAs and assessed the preoperative management, surgical procedures, and outcomes. METHODS: From 2006 to 2019, 21 surgeries were performed for inflammatory TAAs in 17 of 2583 patients (0.7%) who had undergone cardiovascular surgery at our institution. The etiologies were Takayasu's arteritis in 13 patients, giant cell arteritis in 2, antineutrophil cytoplasmic antibody-associated vasculitis in 1, and unknown in 1. The mean follow-up period was 66.2 ± 50.2 months (range, 19-186 months). RESULTS: Three patients had undergone multiple surgeries. The aorta was replaced in 14 patients (ascending aorta in 9, aortic arch in 4, and thoracoabdominal aorta in 1). Three isolated TEVARs were performed in two patients and single-stage hybrid aortic repair (ascending aorta and partial arch replacement combined with zone 0 TEVAR) in four patients for extended arch and descending thoracic aortic aneurysms. Stent grafts were deployed on the native aorta in five of the seven TEVARs. The perioperative inflammation was well-controlled with prednisolone (mean dose, 7.4 ± 9.4 mg) in all patients except for one who had required two surgeries under inflammation-uncontrolled situations. No aorta-related complications, including anastomotic aneurysms and TEVAR-related aortic dissection, developed during the follow-up period, and the 5-year freedom from all-cause death was 92.9%. CONCLUSIONS: The mid-term outcomes of surgery for inflammatory TAAs were acceptable. Although replacement remains the standard procedure for inflammatory TAAs, TEVAR is a less invasive acceptable alternative when the inflammation is properly managed.

Inflammation in thoracic aortic aneurysms.

Mutations in extracellular matrix and smooth muscle cell contractile proteins predispose to thoracic aortic aneurysms in Marfan syndrome (MFS) and related disorders. These genetic alterations lead to a compromised extracellular matrix-smooth muscle cell contractile unit. The abnormal aortic tissue responds with defective mechanosensing under hemodynamic stress. Aberrant mechanosensing is associated with transforming growth factor-beta (TGF-ß) hyperactivity, enhanced angiotensin-II (Ang-II) signaling, and perturbation of other cellular signaling pathways. The downstream consequences include enhanced proteolytic activity, expression of inflammatory cytokines and chemokines, infiltration of inflammatory cells in the aortic wall, vascular smooth muscle cell apoptosis, and medial degeneration. Mouse models highlight aortic inflammation as a contributing factor in the development of aortic aneurysms. Anti-inflammatory drugs and antioxidants can reduce aortic oxidative stress that prevents aggravation of aortic disease in MFS mice. Targeting TGF-ß and Ang-II downstream signaling pathways such as ERK1/2, mTOR, PI3/Akt, P38/MAPK, and Rho kinase signaling attenuates disease pathogenesis. Aortic extracellular matrix degradation and medial degeneration were reduced upon inhibition of inflammatory cytokines and matrix metalloproteinases, but the latter lack specificity. Treating inflammation associated with aortic aneurysms in MFS and related disorders could prove to be beneficial in limiting disease pathogenesis.

The many faces of IgG4-related disease: report of a case with inaugural recurrent aortic aneurism ruptures and literature review.

Vascular involvement in IgG4-related disease (IgG4-RD), is a well-recognized feature and large vessel commitment, especially the aorta, can be the only manifestation of the disease. Being a newly recognized disease, its diagnosis and workup still represents a challenge in clinical practice. A 47-year-old-man with two aortic aneurysms ruptures, one at abdominal and the other at thoracic level, was referred to our rheumatology department. The initial analysis of the surgical specimen obtained 3 years earlier revealed a nonspecific aortitis. Re-evaluation of the biopsy with immunohistology now demonstrated the presence of IgG4 deposits. Evidence-based recommendations regarding diagnosis, treatment and follow-up of IgG4-related large-vessel involvement are lacking. In this particular case, histopathology were crucial. The authors review and discuss vascular involvement in IgG4-RD and respective treatment options.

Causal relationship between immune cells and aortic aneurysms: a Mendelian randomization study.

OBJECTIVES: The causal association between immune cell traits and aortic aneurysm remains unknown. METHODS: We performed a bidirectional two-sample Mendelian randomization analysis to explore the causality between 731 immune cell characteristics and the risk of abdominal aortic aneurysm and thoracic aortic aneurysms through publicly available genetic data, respectively. To examine heterogeneity and horizontal pleiotropy, Cochran's Q test and MR-Egger intercept were utilized. Additionally, multivariable Mendelian randomization analysis and meta-analysis were performed in further analysis. RESULTS: We found that 20 immune phenotypes had a suggestive causality on abdominal aortic aneurysm, and 15 immune phenotypes had a suggestive causal effect on thoracic aortic aneurysm. After further false discovery rate adjustment (q value <0.1), CD20 on IgD+ CD38- B cell (q = 0.053) and CD127 on CD28+ CD4+ T cell (q = 0.096) were associated with an increased risk of abdominal aortic aneurysm, respectively, indicating a significant causality between them. After adjusting for smoking, there is still statistical significance between CD127 on CD28+ CD4+ T cell and abdominal aortic aneurysm. However, after adjusting for lipids, no statistical significance can be observed between CD127 on CD28+ CD4+ T cells and abdominal aortic aneurysm. Furthermore, there is still statistical significance between CD20 on IgD+ CD38- B cells and abdominal aortic aneurysm after adjusting for lipids and smoking, which was further identified by meta-analysis. CONCLUSIONS: We found a causal association between immune cell traits and aortic aneurysm by genetic methods, thus providing new avenues for future mechanism studies.

Salmonella mycotic thoracoabdominal aortic aneurysm associated with chronic lymphocytic leukemia.

Non-typhoidal Salmonella infections typically cause self-limiting gastroenteritis. However, extraintestinal focal infections, including mycotic aneurysms of the aorta, can also occur. We present the case of a 71-year-old man with chronic lymphocytic leukemia (CLL) and a large type V thoracoabdominal mycotic aneurysm infected with Salmonella enteritidis, complicated by thoracolumbar spondylodiscitis, paravertebral collections, and epidural abscess. This is the first report of Salmonella aortitis in the setting of CLL, and the unusual extent of local infective invasion seen here with Salmonella enteritidis infection raises a suspicion of CLL-related immunosuppression as a direct predisposing factor. This case illustrates the need to consider the possibility of an immune defect, even in CLL patients with normal leukocyte counts. The underlying mechanisms are unclear, but are likely to involve defects in cell-mediated immunity, thought to be of particular importance in invasive infections with intracellular pathogens such as Salmonella spp.

Unraveling divergent gene expression profiles in bicuspid and tricuspid aortic valve patients with thoracic aortic dilatation: the ASAP study.

Thoracic aortic aneurysm (TAA) is a common complication in patients with a bicuspid aortic valve (BAV), the most frequent congenital heart disorder. For unknown reasons TAA occurs at a younger age, with a higher frequency in BAV patients than in patients with a tricuspid aortic valve (TAV), resulting in an increased risk for aortic dissection and rupture. To investigate the increased TAA incidence in BAV patients, we obtained tissue biopsy samples from nondilated and dilated aortas of 131 BAV and TAV patients. Global gene expression profiles were analyzed from controls and from aortic intima-media and adventitia of patients (in total 345 samples). Of the genes found to be differentially expressed with dilation, only a few (<4%) were differentially expressed in both BAV and TAV patients. With the use of gene set enrichment analysis, the cell adhesion and extracellular region gene ontology sets were identified as common features of TAA in both BAV and TAV patients. Immune response genes were observed to be particularly overexpressed in the aortic media of dilated TAV samples. The divergent gene expression profiles indicate that there are fundamental differences in TAA etiology in BAV and TAV patients. Immune response activation solely in the aortic media of TAV patients suggests that inflammation is involved in TAA formation in TAV but not in BAV patients. Conversely, genes were identified that were only differentially expressed with dilation in BAV patients. The result has bearing on future clinical studies in which separate analysis of BAV and TAV patients is recommended.

CD248+CD8+ T lymphocytes suppress pathological vascular remodeling in human thoracic aortic aneurysms.

Aortic aneurysms are characterized by vascular inflammation, neovascularization, and extracellular matrix destruction of the aortic wall. Although experimental studies indicate a potential role of CD248 in microvessel remodeling, the functions of CD248 in human vascular pathologies remain unexplored. Here we aimed to study how CD248 interferes with pathological vascular remodeling of human aortic aneurysms. Immunofluorescent staining showed that CD248 expression was mainly localized in the CD8+ T cells infiltrating in the adventitia and media of aortic walls of patients with ascending thoracic aortic aneurysms. qPCR and immunofluorescent staining analyses revealed increased aortic CD248 expression and infiltrating CD248+CD8+ T cells in aortic aneurysms than in nonaneurysmal aortas. Flow cytometry analysis of human peripheral blood further identified a fraction of circulating CD248+ cells which was confined in the CD8+ T-cell compartment. The increased infiltrating of CD248+CD8+ T cells was coincident with reduced circulating CD248+CD8+ T cells in patients with ascending TAA when compared with patients with coronary artery diseases and healthy donors. The CD248+CD8+ T cells were characterized by upregulated IL-10 and downregulated IL-1ß/INF-γ expression when compared with CD248-CD8+ T cells. Moreover, when co-cultured with human aortic endothelial cells, the CD248+CD8+ T cells not only downregulated endothelial expression of ICAM1/VCAM1 and MMP2/3 but also suppressed endothelial migration. This study shows that CD248 reduces pathological vascular remodeling via anti-inflammatory CD248+CD8+ T cells, revealing a CD248-mediated cellular mechanism against human aortic aneurysms.

A clinicopathologic study of immunoglobulin G4-related sclerosing disease of the thoracic aorta.

OBJECTIVE: Immunoglobulin G4-related sclerosing disease (IgG4-SD) has recently been reported to occur in the cardiovascular system and manifest as inflammatory abdominal aortic aneurysm. Thoracic aortic lesions are often associated with aortitis in several divergent etiologies. Thus, this study was performed to review thoracic aortic lesions from the aspect of IgG4-SD and to elucidate the clinicopathologic characteristics of this subgroup in the thoracic aorta. METHODS: The study comprised 125 patients, including 71 with thoracic aortic aneurysm (TAA), 44 with aortic dissection, 7 with Takayasu aortitis, and 3 with infectious aortitis. IgG4-SD was identified by diffuse infiltration of numerous IgG4-positive plasmacytes by immunohistochemical examinations. Clinicopathologic features were compared between IgG4-related and IgG4-unrelated lesions. RESULTS: Among the 125 patients, IgG4-SD was found in 5 patients with TAA but was not detected in the other subgroups of thoracic aortic lesion. IgG4-related TAA included one case of lymphoplasmacytic aortitis, 1 case of inflammatory aneurysm, and three cases of atherosclerotic aneurysms. Patients with IgG4-related TAA showed clinicopathologic features similar to patients with IgG4-SD: male gender, old age, history of bronchial asthma and allergies, elevation of white blood cell counts, C-reactive protein levels, and IgG4 and IgE concentrations (in one patient); eosinophilic infiltration, obliterative phlebitis, lymph follicle formation, and perineural inflammation. In addition, compared with IgG4-unrelated TAA, IgG4-related TAA was characterized by clinically more frequency of involvement of the aortic arch (P = .002), saccular formation (P = .003), and fibrous adhesion to surrounding tissue (P < .001), and histopathologically thicker entire aortic wall and adventitia (P < .001 each). CONCLUSIONS: IgG4-SD is involved in 4% of all thoracic aortic lesions and uniformly presents in the form of an aneurysm with distinct histologic and clinicopathologic features. IgG4-SD represents one, albeit rare, etiology of TAA, especially those originating in the aortic arch.

High fat diet containing cholesterol induce aortic aneurysm through recruitment and proliferation of circulating agranulocytes in apoE knock out mice model.

We studied and compared the efficiency of induction aneurysm in apo E mice by using high fat diet and Ang II. Aneurysm induced in 6 week old male apo E -/- mice by subcutaneous release of Ang II injection for 45 days. Also, aneurysm was induced in three month old male apo E by administration of high fat diet for a period of three months. No difference in body weight in Ang II treated mice. But, increase in body weight and mean arterial blood pressure observed in high fat diet group animals. Highly significant increase in total cholesterol, TG, LDL and significant decrease in HDL level were observed in Ang II treated animals. Significant increase in total cholesterol, but no changes in TG, LDL, HDL levels were observed in high fat diet group. Higher percentage of circulating monocytes was observed in ang II treated group but more number of circulating lymphocytes were observed in high fat diet group in FACS analysis. In histopathology, intimal layer of abdominal aorta was completely replaced by chronic inflammatory cells particularly macrophages (80%) which appeared as foam cells and lymphocytes (20%) in ang II treated animals. Degradation of elastin, infiltration of lymphocytes, chondrocytes and cellular migration towards media were observed in the abdominal aorta of high fat diet group. Real time analysis and immunofluorescence assay supports over expression of Vcam 1 Icam1, MCP 1and MMP2 genes were observed in Ang II treated animals. In immunofluorescence assay, over expression of Mac 3 protein specific for macrophages was observed in abdominal aorta of ang II treated animals, but over expression of CD45.1 & 45.2 proteins specific to lymphocytes were observed in high fat diet group. Based on our observations, Ang II induced aortic aneurysm by recruiting/ proliferating circulating monocytes by up regulating Icam-1, Vcam -1 and MCP-1. Also, ang II involved in degradation of elastin in the abdominal aorta by up regulation of MMP2 to promote agranulocytes migration in the intimal layers. Epithelial cell hyperplasia with accumulation of fatty fluids (cyst) was observed in seminal vesicle and ventral prostate of high fat treated animals. Fatty degeneration, germ cell apoptosis and infiltration giant cells were observed in the testes of high fat diet group. As per available literature these observations were not reported with high fat diet treatments with apo E models. High fat diet induced aneurysm prominently in abdominal, thoracic aorta and extensive plaque formation was observed in femoral and renal arteries. Administration of high fat diet containing cholesterol induced aneurysm in apo E mice model also efficient method to rule out the pathogenesis of aortic aneurysm when compared with angiotensin.

IgG4-related inflammatory aneurysm of the aortic arch.

IgG4-related sclerosing disease can occur in the cardiovascular system and some inflammatory abdominal aortic aneurysms have been shown to belong to IgG4-related sclerosing disease. Herein is reported a case of IgG4-related inflammatory aortic aneurysm of the aortic arch. A 71-year-old Japanese man was found to have an aneurysm of the aortic arch with maximum dimension of 5.5 cm. The surgically resected aneurysm wall had conspicuous fibrosclerotic changes, dense lymphoplasmacytic infiltration and occasional obliterative phlebitis in the adventitia; the thickness of the adventitia was 6.5 mm. Immunohistochemistry indicated numerous IgG4-positive plasma cell infiltrates; 84% of the IgG-bearing cells were IgG4 positive. The diagnosis of IgG4-related inflammatory aortic aneurysm of the aortic arch was made. Although previously reported IgG4-related inflammatory aortic aneurysms were confined to the abdominal aorta, the present case report demonstrates that IgG4-related inflammatory aortic aneurysm can occur in the aortic arch, thereby extending the spectrum of IgG4-related periaortitis. Further studies are needed to clarify the spectrum of IgG4-related sclerosing disease in the cardiovascular system.

Elastin-Specific Autoimmunity in Smokers With Thoracic Aortic Aneurysm and Dissection is Independent of Chronic Obstructive Pulmonary Disease.

Background Thoracic aortic aneurysm ( TAA ) and dissection ( TAD ) are characterized by progressive disorganization of the aortic wall matrix, including elastin, a highly immunogenic molecule. Whether acquired autoimmune responses can be detected in TAA / TAD patients who are smokers is unknown. The objectives of this study were to determine whether TAA / TAD smokers have increased T-cell responses to human elastin fragments, and to determine whether autoimmune responses in TAA / TAD smokers are dependent on chronic obstructive pulmonary disease. Methods and Results In a cross-sectional study (N=86), we examined peripheral blood CD 4+ T cell responses to elastin fragments in never-, former-, or current-smokers with or without TAA / TAD . CD 4+ T cells were co-cultured with irradiated autologous peripheral blood CD 1a+/ CD 14+ antigen presenting cells pulsed with or without elastin fragments to measure cytokine production. Baseline plasma concentration of anti-elastin antibodies and elastin-degrading enzymes (eg, matrix metalloproteinase-9, and -12, and neutrophil elastase) were measured in the same cohort. elastin fragment-specific CD 4+ T cell expression of interferon-γ, and anti-elastin antibodies were dependent on history of smoking in TAA / TAD patients but were independent of chronic obstructive pulmonary disease. Matrix metalloproteinase-9, and -12, and neutrophil elastase plasma concentrations were also significantly elevated in ever-smokers with TAA / TAD . Conclusions Cigarette smoke is associated with loss of self-tolerance and induction of elastin-specific autoreactive T- and B-cell responses in patients with TAA / TAD . Development of peripheral blood biomarkers to track immunity to self-antigens could be used to identify and potentially prognosticate susceptibility to TAA / TAD in smokers.

Double-locus lymphoplasmacytic aortitis.

Thoracic aortic aneurysm is an indication for major cardiovascular operative procedures. The etiology is usually hypertension and/or atherosclerotic disease; reaching a certain diameter often results in acute aortic syndrome. Immunoglobulin G4-related aortitis, characterized by lymphoplasmacytic vascular tunica media induration without well-defined underlying infectious or autoimmune systemic causes, is uncommon. Histological similarity to immunoglobulin G4 disease in other organs suggests that this aortitis might be a manifestation of systemic pathology. We describe a case of double-locus lymphoplasmacytic aortitis in a 72-year-old man who had the incidental finding of intramural hematoma on elective thoracic computed tomography as part of a respiratory work-up.

Immunoglobulin G Subclass 4-Related Lymphoplasmacytic Thoracic Aortitis in a Patient with Acute Type A Aortic Dissection.

Immunoglobulin G subclass 4-related disease (IgG4-RD) is a recently recognized systemic inflammatory disease characterized by an elevated serum IgG4 level and an IgG4-positive lymphocyte infiltrate mainly in exocrine tissues. Previous reports documented IgG4-RD in several cardiovascular disorders. We present a case of type A aortic dissection associated with IgG4-RD. A 52-year-old man diagnosed with a type A aortic dissection was referred for surgical treatment. He underwent emergency hemiarch reconstruction with a prosthetic graft. His postoperative recovery was uncomplicated. Histopathologic examination of his aortic tissue showed marked adventitial thickening with fibrosis and an IgG4-positive plasma cell infiltrate. He was diagnosed with type A aortic dissection incidentally complicated by IgG4-RD. The relationship between IgG4-RD and the pathogenesis of aortic dissection remains unknown and requires further investigation.

Antineutrophil Cytoplasmic Antibody-Associated Multiple Giant Saccular Aortic Aneurysms.

We describe a very rare case of a 67-year-old man with multiple saccular aortic aneurysms throughout the entire aorta due to antineutrophil cytoplasmic antibody-associated vasculitis (AAV). The patient underwent staged aortic surgical procedures, including stent-graft insertion for a left iliac artery aneurysm, thoracic endovascular aortic repair for a descending aortic aneurysm, and total replacement of the ascending aorta and aortic arch with the use of high-dose steroids to control inflammation. The histologic findings demonstrated that the damage to the vasa vasorum of the adventitia resulting from AAV caused ischemia of the media, resulting in the formation of saccular aneurysmal changes.

Transmural inflammation by interferon-gamma-producing T cells correlates with outward vascular remodeling and intimal expansion of ascending thoracic aortic aneurysms.

Arterial pathology manifests as aneurysmal or obstructive disease depending on changes in lumen size due to vascular remodeling (change in vessel external diameter) and/or intimal expansion. Recent clinical and experimental observations in abdominal aortic aneurysms have led to the emerging dogma that Th2-dominant immune responses result in expansive vascular remodeling and luminal ectasia, whereas Th1 immune responses cause intimal hyperplasia and luminal stenosis. We tested this hypothesis by descriptive analyses of 31 non-aneurysmal and 29 aneurysmal ascending thoracic aortic specimens. Approximately half the aneurysms were distinguished by transmural inflammation. The remaining aneurysms and all the non-aneurysmal aortas had a similar leukocytic infiltrate that spared the inner media. Aneurysm tissue had increased expression of the prototypical Th1 cytokine, interferon (IFN)-gamma, and undetectable Th2 cytokines. Specimens with inner media infiltration displayed robust production of IFN-gamma, induction of the IFN-gamma-inducible chemokines IP-10 and Mig, and recruitment of lymphocytes bearing their cognate receptor CXCR3. Transmural inflammation and IFN-gamma production were associated with increased aortic external diameter, intimal thickening, preserved vascular smooth muscle cell density, and decreased matrix proteins. Th1, but not Th2, immune responses have a positive correlation with both outward vascular remodeling and intimal expansion of ascending thoracic aortic aneurysms.

Pathogenesis of thoracic and abdominal aortic aneurysms.

The major disease processes affecting the aorta are aortic aneurysms and dissections. Aneurysms are usually described in terms of their anatomic location, with thoracic aortic aneurysms (TAAs) involving the ascending and descending aorta in the thoracic cavity and abdominal aortic aneurysms (AAAs) involving the infrarenal abdominal aorta. Both thoracic and abdominal aortas are elastic arteries, and share similarities in their physical structures and cellular components. However, thoracic and abdominal aortas differ in their biochemical properties and the origin of their vascular smooth muscle cells (VSMCs). These similarities and differences between thoracic and abdominal aortas provide the basis for the various pathologic mechanisms observed in this disease. This review focuses on the comparison of the pathologic mechanisms involved in TAA and AAA.

Mycotic aneurysm of the distal aortic arch caused by Aspergillus.

We describe an unusual case of a thoracic aortic aneurysm caused by Aspergillus. A 70-year-old man underwent prednisolone and Ara-C treatments for a myelodysplastic syndrome. Blood examination revealed pancytopenia. Under these treatments, an aneurysm presented at the distal aortic arch. He underwent resection of the aneurysm with a graft repair covered by a pedicled omentum flap, followed by prolonged administration of micafungin and itraconazole for a mycotic aneurysm. The postoperative course was favorable without complications. Serum C-reactive protein became negative and he was discharged 2 months after the surgery. However, 4 months after the surgery, he died from worsening of the myelodysplastic syndrome. The prognosis for patients with mycotic aneurysms is poor due to their immunocompetent condition arising from underlying diseases. Therefore, in addition to prompt treatment with antifungal agents combined with surgical debridement, control of the underlying disease is essential for improving the outcome.

Oxidative stress in the pathogenesis of thoracic aortic aneurysm: protective role of statin and angiotensin II type 1 receptor blocker.

OBJECTIVE: The pathogenesis of thoracic aortic aneurysms (TAA) is still unclear. A recent investigation indicated that angiotensin II, a potent activator of NADH/NADPH oxidase, plays an important role in aneurysmal formation. We investigated the potential role of p22phox-based NADH/NADPH oxidase in the pathogenesis of TAA. METHODS: Human thoracic aneurysmal (n=40) and non-aneurysmal (control, n=39) aortic sections were examined, and the localization of p22phox, an essential component of the oxidase, and its expressional differences were investigated by immunohistochemistry and Western blot. In situ reactive oxygen species (ROS) generation was examined by the dihydroethidium method, and the impact of medical treatment on p22phox expression was investigated by multiple regression analysis. RESULTS: In situ production of ROS and the expression of p22phox increased markedly in TAA throughout the wall, and Western blot confirmed the enhanced expression of p22phox. The expression was more intense in the regions where monocytes/macrophages accumulated. In these inflammatory regions, numerous chymase-positive mast cells and angiotensin converting enzyme-positive macrophages were present. Their localization closely overlapped the in situ activity of matrix metalloproteinase and the expression of p22phox. Multiple regression analysis revealed that medical treatment with statin and angiotensin II type 1 receptor blocker (ARB) suppressed p22phox expression in TAA. CONCLUSION: Our findings indicate the role of p22phox-based NADH/NADPH oxidase and the local renin-angiotensin system in the pathogenesis of TAA. Statin and ARB might have inhibitory effects on the formation of aneurysms via the suppression of NADH/NADPH oxidase.