Role of ferroptosis-related genes in Stanford type a aortic dissection and identification of key genes: new insights from bioinformatic analysis.

Stanford type A aortic dissection (TAAD) is one of the most dangerous vascular diseases worldwide, and the mechanisms of its development remain unclear. Further molecular pathology studies may contribute to a comprehensive understanding of TAAD and provide new insights into diagnostic markers and potential therapeutic targets. Recent studies have identified that ferroptosis, a form of cell death, may play a previously unrecognized role in influencing the development of TAAD. In this study, we explored the pathological role of ferroptosis in TAAD by performing bioinformatics analyses. Gene set enrichment analysis (GSEA) showed that the ferroptosis-related gene (FRG) set was significantly different between normal and TAAD aortic samples at an overall level (p < 0.001). Further Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses explored the potential functions and pathways of FRG in TAAD. We further identified six key genes (CA9, HMOX1, IL6, CDKN1A, HIF1A, MYC) from differentially expressed FRGs in TAAD by constructing a protein-protein interaction (PPI) network, all key genes were upregulated in TAAD. Four of the key genes (CA9, IL6, CDKN1A, and HIF1A) were demonstrated to be correlated with cigarette smoke extract-induced ferroptosis in aortic vascular smooth muscle cells. These results suggest that ferroptosis is one of the essential pathological processes in the development of TAAD, and some FRGs affect TAAD development by mediating cellular ferroptosis, which provides deepening insights into the molecular mechanisms and potential therapeutic targets of TAAD.

Identification of Molecular Regulatory Features and Markers for Acute Type A Aortic Dissection.

BACKGROUND: Acute type A aortic dissection (ATAAD) is one of the most lethal cardiovascular diseases, and its molecular mechanism remains unclear. METHODS: Differentially expressed genes (DEGs) between ATAAD and control were detected by limma R package in GSE52093, GSE153434, GSE98770, and GSE84827, respectively. The coexpression network of DEGs was identified by the WGCNA package. Enrichment analysis was performed for module genes that were positively correlated with ATAAD using clusterProfiler R package. In addition, differentially methylated markers between aortic dissection and control were identified by ChAMP package. After comparing with ATAAD-related genes, a protein-protein interaction (PPI) network was established based on the STRING database. The genes with the highest connectivity were identified as hub genes. Finally, differential immune cell infiltration between ATAAD and control was identified by ssGSEA. RESULTS: From GSE52093 and GSE153434, 268 module genes were obtained with consistent direction of differential expression and high correlation with ATAAD. They were significantly enriched in T cell activation, HIF-1 signaling pathway, and cell cycle. In addition, 2060 differentially methylated markers were obtained from GSE84827. Among them, 77 methylation markers were ATAAD-related DEGs. Using the PPI network, we identified MYC, ITGA2, RND3, BCL2, and PHLPP2 as hub genes. Finally, we identified significantly differentially infiltrated immune cells in ATAAD. CONCLUSION: The hub genes we identified may be regulated by methylation and participate in the development of ATAAD through immune inflammation and oxidative stress response. The findings may provide new insights into the molecular mechanisms and therapeutic targets for ATAAD.

Immunological therapeutics in acute aortic syndrome.

Acute aortic syndrome is a group of interlinked conditions with common presenting symptoms, including aortic dissection, penetrating atherosclerotic ulcer, and intramural hematoma. Pharmacological management of acute aortic syndrome is a growing area, with key themes to address the underlying inflammatory pathways believed to be the cause. Research into interleukins, matrix metalloproteinases, and granulocyte macrophage colony-stimulating factor are just some of the many immunological properties being investigated and translated into medical therapies. Stem cell experiments may indicate further advances in the pathologies of acute aortic syndrome. The study of pharmacogenomics to improve treatment across different genomes is also a novel area outlined in this paper.

Characterization and Significance of Monocytes in Acute Stanford Type B Aortic Dissection.

Acute aortic dissection (AAD) is one of the most common fatal diseases noted in vascular surgery. Human monocytes circulate in dynamic equilibrium and display a considerable heterogeneity. However, the role of monocytes in AAD remains elusive. In our recent study, we firstly obtained blood samples from 22 patients with Stanford type B AAD and 44 age-, sex-, and comorbidity-matched control subjects. And the monocyte proportions were evaluated by flow cytometry. Results showed that the percentage of total CD14+ monocytes in the blood samples of Stanford AAD patients was increased significantly compared with that of normal volunteers (P < 0.0005), and the absolute numbers of CD14brightCD16+ and CD14brightCD16- monocytes both increased significantly regardless of the percentage of PBMC or CD14+ cells, while CD14dimCD16+ monocytes displayed the opposite tendency. However, the percentage of CD14+ cells and its three subsets demonstrated no correlation with D-dimer (DD) and C-reactive protein (CRP). Then, blood mononuclear cell (PBMC) samples were collected by Ficoll density gradient centrifugation, followed with CD14+ magnetic bead sorting. After the purity of CD14+ cells was validated over 90%, AAD-related genes were concentrated in CD14+ monocytes. There were no significant differences observed with regard to the mRNA expression levels of MMP1 (P = 0.0946), MMP2 (P = 0.3941), MMP9 (P = 0.2919), IL-6 (P = 0.4223), and IL-10 (P = 0.3375) of the CD14+ monocytes in Stanford type B AAD patients compared with those of normal volunteers. The expression levels of IL-17 (P < 0.05) was higher in Stanford type B AAD patients, while the expression levels of TIMP1(P<0.05), TIMP2(P<0.01), TGF-ß1 (P < 0.01), SMAD3 (P < 0.01), ACTA2 (P < 0.001), and ADAMTS-1 (P < 0.001) decreased. The data suggested that monocytes might play an important role in the development of Stanford type B AAD. Understanding of the production, differentiation, and function of monocyte subsets might dictate future therapeutic avenues for Stanford type B AAD treatment and can aid the identification of novel biomarkers or potential therapeutic targets for decreasing inflammation in AAD.

Activation of Bone Marrow-Derived Cells and Resident Aortic Cells During Aortic Injury.

BACKGROUND: The process of aortic injury, repair, and remodeling during aortic aneurysm and dissection is poorly understood. We examined the activation of bone marrow (BM)-derived and resident aortic cells in response to aortic injury in a mouse model of sporadic aortic aneurysm and dissection. MATERIALS AND METHODS: Wild-type C57BL/6 mice were transplanted with green fluorescent protein (GFP)+ BM cells. For 4 wk, these mice were either unchallenged with chow diet and saline infusion or challenged with high-fat diet and angiotensin II infusion. We then examined the aortic recruitment of GFP+ BM-derived cells, growth factor production, and the differentiation potential of GFP+ BM-derived and GFP- resident aortic cells. RESULTS: Aortic challenge induced recruitment of GFP+ BM cells and activation of GFP- resident aortic cells, both of which produced growth factors. Although BM cells and resident aortic cells equally contributed to the fibroblast populations, we did not detect the differentiation of BM cells into smooth muscle cells. Interestingly, aortic macrophages were both of BM-derived (45%) and of non-BM-derived (55%) origin. We also observed a significant increase in stem cell antigen-1 (Sca-1)+ stem/progenitor cells and neural/glial antigen 2 (NG2+) cells in the aortic wall of challenged mice. Although some of the Sca-1+ cells and NG2+ cells were BM derived, most of these cells were resident aortic cells. Sca-1+ cells produced growth factors and differentiated into fibroblasts and NG2+ cells. CONCLUSIONS: BM-derived and resident aortic cells are activated in response to aortic injury and contribute to aortic inflammation, repair, and remodeling by producing growth factors and differentiating into fibroblasts and inflammatory cells.

Association of lymphocyte to monocyte ratio and risk of in-hospital mortality in patients with acute type A aortic dissection.

Aim: The aim of the study was to evaluate the relationship between lymphocyte to monocyte ratio (LMR) at admission and in-hospital mortality of patients with acute type A aortic dissection (AAAD). Patients & methods: We enrolled 536 patients with AAAD between June 2013 and December 2017. Patients were divided into two groups: the deceased group and the survival group. Results: In multivariable analysis, the association between LMR and in-hospital mortality was still significant. When the Q4 was set as the reference value, the odds ratios values of Q1, Q2 and Q3 were 4.4 (95% CI: 2.2-8.9; p < 0.001), 1.4 (95% CI: 1.1-3.4; p = 0.03) and 1.7 (95% CI: 0.8-2.9; p = 0.158). Conclusion: Lower LMR may be independently associated with in-hospital mortality in AAAD.

Monocyte Subsets, Stanford-A Acute Aortic Dissection, and Carotid Artery Stenosis: New Evidences.

Monocytes are a heterogeneous cell population distinguished into three subsets with distinctive phenotypic and functional properties: "classical" (CD14++CD16-), "intermediate" (CD14++CD16+), and "nonclassical" (CD14+CD16++). Monocyte subsets play a pivotal role in many inflammatory systemic diseases including atherosclerosis (ATS). Only a low number of studies evaluated monocyte behavior in patients affected by cardiovascular diseases, and data about their role in acute aortic dissection (AAD) are lacking. Thus, the aim of this study was to investigate CD14++CD16-, CD14++CD16+, and CD14+CD16++ cells in patients with Stanford-A AAD and in patients with carotid artery stenosis (CAS). Methods. 20 patients with carotid artery stenosis (CAS group), 17 patients with Stanford-A AAD (AAD group), and 17 subjects with traditional cardiovascular risk factors (RF group) were enrolled. Monocyte subset frequency was determined by flow cytometry. Results. Classical monocytes were significantly increased in the AAD group versus CAS and RF groups, whereas intermediate monocytes were significantly decreased in the AAD group versus CAS and RF groups. Conclusions. Results of this study identify in AAD patients a peculiar monocyte array that can partly explain depletion of T CD4+ lymphocyte subpopulations observed in patients affected by AAD.

Lag3+ regulatory T lymphocytes in critical carotid artery stenosis.

The aim of this study was to evaluate CD25+ and Lag3+ T regulatory subpopulations in patients with critical carotid artery stenosis (CAS) and Stanford-A acute aortic dissection (AAD). CD25+ and Lag3+ were measured in 36 patients affected by CAS and 24 patients with Stanford type A AAD. Based on neurological symptoms, patients affected by CAS were further divided in 25 asymptomatic (CAS-A) and 11 symptomatic (CAS-S) subjects. Twenty-five patients with traditional cardiovascular risk factors (RF), matched for age and sex, were used as control group. Interleukin (IL)-10, IL-6 and transforming growth factor-ß-levels were also measured. CD25+ T cells were significantly increased in CAS-S versus CAS-A (p > 0.05), AAD (p > 0.05) and RF (p > 0.05). Moreover, a significant increase in Lag3+ Tregs was observed in CAS e CAS-S versus AAD (p < 0.05) and RF (p < 0.05), whereas no significant difference was observed between CAS-S and CAS-A. IL-6 was higher in AAD compared to the other groups. Patients with neurological symptoms display a peculiar expansion of CD25+ T cells, strongly confirming a relationship between ischemic brain damage and this regulatory subpopulation, whereas Lag3+ Tregs early distinguish CAS from AAD and probably exert protective actions against aortic wall rupture throughout their anti-inflammatory functions.

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.

Macrophage CD31 Signaling in Dissecting Aortic Aneurysm.

BACKGROUND: The authors recently found that a CD31 agonist peptide reaches macrophages in injured aortas and exerts beneficial effects on apolipoprotein E-knockout (Apo E-/-) mice subjected to angiotensin (Ang) II infusion, a model of experimental acute aortic dissection and intramural hematoma (ADIM). OBJECTIVES: The purpose of this study was to evaluate the therapeutic potential of a drug-suitable agonist peptide in experimental ADIM. METHODS: P8RI, a retro-inverso sequence of the best candidate identified by functional in vitro screening of a peptide library, passed an absorption, distribution, metabolism, excretion and toxicology analysis. Apo E-/- mice (male, 28-week-old) implanted with Ang II-releasing pumps received P8RI (2.5 mg/kg/day) or vehicle from day 14 (n = 10/group). Leukocytes were analyzed by flow cytometry. Healing features of human and mouse dissected aortic segments were assessed by histology and immunofluorescence. The effect of CD31 on macrophages was evaluated using cells from CD31-/- mice and P8RI, in vitro. RESULTS: Human and experimental ADIM were characterized by the infiltration of proinflammatory macrophages. The absence of CD31 enhanced the proinflammatory polarization of macrophages, whereas the CD31 agonist P8RI favored reparative macrophages both in vitro and in vivo. The administration of P8RI after the occurrence of ADIM prevented aneurysmal transformation by promoting the resolution of intramural hematoma and the production of collagen in dissected aortas in vivo, associated with enrichment of M2 macrophages at the site of injury. CONCLUSIONS: CD31 signaling promotes the switching of proinflammatory macrophages to the reparative phenotype and favors the healing of experimental dissected aortas. Treatment with a drug-suitable CD31 agonist may facilitate the clinical management of ADIM.

Immunophenotypic analysis of the chronological events of tissue repair in aortic medial dissections.

Acute medial dissection of aorta can occur in the context of a sudden and unexpected death. For medico-legal reasons it is important to estimate as accurately the histological age of dissections. We evaluated the additional value of a systematic application of immunohistochemistry, compared with conventional histology only, in determining chronological steps of injury and repair. Thirty two paraffin embedded specimens of aortic dissection were retrospectively allocated to one of four defined stages: acute (I), subacute (II), early organizing (III) and scarring (IV) using Hematoxylin and Eosin and Elastica van Gieson stained sections. Subsequent immunohistochemically staining was performed with the following markers: (myeloperoxidase (neutrophils), citrullinated-Histone 3 (neutrophil extracellular traps), CD68 (macrophages), CD3 (T-cells), CD31 and CD34 (endothelial cells), and smooth muscle actin. Immune stained sections were scored semi-quantitatively. Histologically, five cases were identified as stage I, 16 as II, 7 as III and 4 as IV. Additional immunostaining for smooth muscle cells and endothelial cells altered the classification in 25% of cases (all in groups II and III). Immunostaining and semi-quantitative grading of involvement of neutrophils, macrophages and NETs also provided specific distribution patterns over the 4 age categories, including unexpected involvement of the peri adventitial fat tissue. In conclusion, it appears that semi-quantitative immunohistochemistry of resident vascular wall cells, inflammatory cells and NETS represents a useful adjunct in detailed histopathological grading of the chronological age of aortic dissections.

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.

IgG4 Aortitis: A Case Report.

IgG4 aortitis is one of the entities seen in the spectrum of IgG4-related disease (IgG4-RD). It is characterized by serologic (elevated serum IgG4) and histologic features including a lymphoplasmacytic infiltrate with increased numbers of IgG4-positive plasma cells, storiform fibrosis and obliterative phlebitis. Some studies have described a correlation between infections and IgG4 aortitis. We describe a patient with an aneurysm of the infrarenal descending abdominal aorta with features of IgG4-RD, as well as culture evidence of Streptococcus sanguis. [Full article available at http://rimed.org/rimedicaljournal-2017-04.asp].

Potential Mechanism of Post-Acute Aortic Dissection Inflammatory Responses: The Role of mtDNA from Activated Platelets.

BACKGROUND: Acute aortic dissection (AD) is a lethal cardiovascular disease with severe inflammatory complications. Considering the proinflammatory properties of plasma mitochondrial DNA (mtDNA), we postulate that plasma mtDNA from activated platelets may be responsible for post-acute AD inflammatory responses. METHODS: We consecutively enrolled 68 patients with acute AD as well as matched hypertensive and healthy participants. Blood samples were collected on admission for blood routine tests, mtDNA assay, and inflammatory cytokine analysis. A computed tomography scan was used to evaluate the extent of dissections. RESULTS: Our results demonstrate that plasma mtDNA, platelet activation, and inflammatory levels were remarkably higher in acute AD patients than in hypertensive or healthy participants. These parameters were also higher in the Stanford A group than in the Stanford B group (p < 0.05). Bivariate correlation analysis demonstrated positive associations between mtDNA and inflammatory levels (tumor necrosis factor-α: r = 0.577; interleukin-6: r = 0.632), mtDNA and platelet activation (r = 0.642), and platelet activation and the extent of dissection (r = 0.635). CONCLUSION: Our study suggests that acute AD-induced tunica media exposure causes platelet activation, which leads to the initiation of inflammatory responses via the release of mtDNA into the circulation. Our study provides a novel fundamental basis and a potential therapeutic target for the prevention and treatment of post-AD inflammatory responses.

[THE ROLE OF TRANSFORMING GROWTH FACTOR-B IN IMMUNOPATHOGENESIS OF DISEASES OF CONNECTIVE TISSUE].

The recent studies of molecular physiology of fibrillin and pathophysiology of inherent disorders of structure and function of connective tissue such as dissection and aneurysm of aorta, myxomatously altered cusps and prolapses of mitral valve, syndrome of hyper-mobility of joints, demonstrated that important role in development of these malformations play alterations of transfer of signals by growth factors and matrix cellular interaction. These conditions under manifesting Marfan's syndrome can be a consequence of anomalies of fibrillin-1 which deficiency unbrakes process of activation of transforming growth factor-ß (TGFß). The involvement of TGFß in pathogenesis of Marfan's syndrome permits consider antagonists of angiotensin-transforming enzymes as potential pharmaceuticals in therapy of this disease. The article presents analysis of publications' data related to this problem.

Carotid aneurism with acute dissection: an unusual case of IgG4-related diseases.

AIM: IgG4-related disease is a systemic disease that involves organs and vascular structures, in particular, the aorta. This is the first case that showed the carotid artery involvement with dissection evolution. METHODS AND RESULTS: In a 67-year-old man with speech impairment and right-hand clumsiness, a brain computed tomography revealed signs of acute ischemia in the left frontal lobe while an echo-color Doppler sonography of the cervical vessels showed a tight stenosis of left internal carotid artery with a large pseudoaneurysm. Histological findings performed on the surgical specimen disclosed IgG4-related disease. CONCLUSIONS: To the best of our knowledge, this is the first manifestation of IgG4-related disease with carotid artery dissection complicated by pseudoaneurysm. Even though unsuccessful since the patients died within 48 h, this case highlights the diverse facets of the IgG4-related disease representing a new complication with important clinical implications of such a diagnosis targeting immunosuppressive therapy particularly B-cell depletion.

Intestinal Barrier Dysfunction: A Novel Therapeutic Target for Inflammatory Response in Acute Stanford Type A Aortic Dissection.

BACKGROUND: Intestinal barrier dysfunction would lead to a rigorous inflammatory reaction due to the translocation of intestinal lumen-derived bacteria and endotoxins. The aim of the present study was to investigate whether intestinal barrier dysfunction occurs in patients with acute Stanford type A aortic dissection (ATAAD) and to determine its potential relationship with the plasma levels of several inflammatory biomarkers in the progression of ATAAD. DESIGN AND METHODS: Serum samples from a total of 46 patients with ATAAD and 36 healthy volunteers were prospectively collected and analyzed. The serum levels of diamine oxidase (DAO), lactate dehydrogenase (LDH), interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), and C-reactive protein (CRP) were measured using colorimetric assay, enzyme-linked immunosorbent assay, and immunoturbidimetric assay. RESULTS: Serum levels of DAO, LDH, IL-6, TNF-α, and CRP in patients with ATAAD were significantly higher than those in healthy participants. A significantly positive correlation between DAO activity and IL-6 (r = .56, P < .001), TNF-α (r = .63, P < .001), and CRP (r = .53, P < .001) was observed. Moreover, the activity of DAO correlated negatively with the Pao 2/fraction of inspired oxygen (Fio 2) ratio (r = -.39, P = .007). CONCLUSIONS: Intestinal barrier dysfunction, reflected by an increased level of serum DAO, may play an important role in the development of systemic inflammatory responses in patients with ATAAD. Therefore, strategies of preserving a normal intestinal barrier function may open new horizons in the treatment of inflammation-related adverse events in the setting of ATAAD.

Frequency of immunoglobulin G4-related aortitis in cases with aortic resection and their clinical characteristics compared to other aortitises.

AIMS: To identify the frequency of immunoglobulin G4 (IgG4)-related aortitis in patients who undergo aorta surgery and are diagnosed by pathology as having chronic aortic inflammation and to compare IgG4-related aortitis with other non-infectious aortitises in terms of clinical characteristics. METHODS: The aorta specimen pathological reports of 1418 patients who underwent aortic aneurysm or dissection surgery were reviewed. In total, 41 had chronic aortic inflammation without atherosclerosis, cancer or infection. Their aorta biopsy specimens were subjected to IgG4 immunostaining. IgG4-related aortitis was diagnosed if the IgG4-positive plasma cell count exceeded 50 per high power field (HPF), the ratio of IgG4-positive to IgG-positive plasma cells exceeded 50% and dense lymphoplasmacytic infiltration, fibrosis and/or obliterative phlebitis were observed. RESULTS: Of the 41 non-infectious aortitis cases, 29, six and six had idiopathic aortitis, Takayasu's arteritis and Behcet's aortitis, respectively. Of the 29 idiopathic aortitis cases, three had IgG4-related aortitis. All were male and > 65 years of age. Two had thoracic aortic aneurysms and one had an abdominal aortic aneurysm. Their IgG4-positive plasma cell counts were 60/HPF or higher; lymphoplasmacytic infiltration and/or fibrosis, but not obliterative phlebitis, were observed. The IgG4-related aortitis cases were older (67 [range, 65-69] years) than the Takayasu's arteritis (47.5 [38-58] years) or Behcet's aortitis (47 [31-56] years) cases and more likely to be male than the Takayasu's arteritis cases (100% vs. 17%). CONCLUSION: In patients with chronic aortic inflammation, 7% had IgG4-related aortitis. This disease may be more common in older male patients than in other demographic groups.

Inflammatory thoracic aortic aneurysm (lymphoplasmacytic thoracic aortitis): a 13-year-experience at a German Heart Center with emphasis on possible role of IgG4.

BACKGROUND & AIM: Aortic aneurysms represent one of the major causes of cardiovascular surgery. Their etiology varies greatly based on patient's age and other clinicopathologic determinants. In addition to common atherosclerotic vascular diseases, an inflammatory etiology, in particular IgG4-related disease (IgG4-RD) has increasingly emerged as a cause of dissecting inflammatory aortic aneurysms (IAA). METHODS: To assess the frequency and types of IAA, we reviewed all cases of aortic aneurysms resected at our Erlangen Heart Center during 2000-2013. RESULTS: 376 patients underwent resection of aortic aneurysms in the study period. These are further categorized as ascending aortic aneurysms (45%), aortic arch aneurysm (2%), descending aortic aneurysm (3%), type A dissection (46%) and type B dissection (4%). Fifteen cases (4%) showed variable lymphoplasmacytic inflammation thus qualifying as IAA. Affected were 9 females and 6 males (female to male ratio = 1.5:1; age range: 52-80 yrs; mean: 70 yrs; median: 72 yrs). None was known to have IgG4-RD and serum IgG4 and/or IgG levels (known in 6 cases) were normal. Variable sclerosing lymphoplasmacytic inflammation was seen either confined to the adventitia (periaortitis; mainly in males) or extending through all layers (mainly in females). A wide range of IgG4 plasma cells (range: 3-182/HPF; mean: 51/HPF) and IgG4: IgG ratios (range: 0.02 to 0.91; mean: 0.37) were detected. All but one of the cases with at least focally transmural inflammation showed a higher IgG4: IgG ratios in excess of 0.3 (range, 0.32-0.91; median, 0.62). Lymphoid follicle and variable fibrosis were common but obliterative phlebitis was not seen. CONCLUSION: IgG4-rich sclerosing lymphoplasmacytic thoracic aortitis is a constant histological feature of thoracic IAA. Normal serum IgG4 in most patients, predilection for women and absence of other features of IgG4-RD all suggest a tissue-specific localized autoimmunological process and argue against a systemic disorder. The relationship (if any) of IgG4-rich lymphoplasmacytic thoracic aortitis in those patients with IAA lacking other organ manifestations or an elevated serum IgG4 level to systemic IgG4-RD remains unclear and merit further studies.