Dapagliflozin Ameliorates the Formation and Progression of Experimental Abdominal Aortic Aneurysms by Reducing Aortic Inflammation in Mice.

BACKGROUND: Dapagliflozin, a sodium glucose transporter protein-2 (SGLT-2) inhibitor, reduces the risk for cardiovascular diseases. However, the influence of dapagliflozin on nondissecting abdominal aortic aneurysms (AAAs) remains unclear. METHODS: AAAs were created in male C57BL/6 mice via intra-aortic porcine pancreatic elastase (PPE) infusion. Mice were daily treated with dapagliflozin (1 or 5 mg/kg body weight) or an equal volume of vehicle through oral gavage beginning one day prior to PPE infusion for 14 days. To investigate its translational value, dapagliflozin or vehicle was also administered to mice with existing AAAs in another cohort. Aortic diameters were measured prior to (day 0 for baseline) and 14 days after PPE infusion. After sacrifice, mice aortae were collected, and following histological analyses were performed. RESULTS: Dapagliflozin treatment significantly reduced aneurysmal aortic expansion following PPE infusion as compared to vehicle treatment especially at 5 mg/kg body weight (approximately 21% and 33% decreases in 1 and 5 mg/kg treatment groups, respectively). The dose-dependent attenuation of AAAs by dapagliflozin was also confirmed on histological analyses. Dapagliflozin remarkably reduced aortic accumulation of macrophages, CD4+ T cells, and B cells particularly following dapagliflozin treatment at 5 mg/kg. Dapagliflozin treatment also markedly attenuated medial SMC loss. Though the difference was not significant, dapagliflozin treatment tended to attenuate CD8+ T cells and elastin degradation. Dapagliflozin treatment at 5 mg/kg caused a 53% reduction in neovessel density. Furthermore, dapagliflozin treatment mitigated further progress of existing AAAs. CONCLUSION: Dapagliflozin treatment ameliorated PPE-induced AAAs by inhibiting aortic leukocytes infiltration and angiogenesis.

Positive disease-specific autoantibodies have limited clinical significance in diagnosing IgG4-related disease in daily clinical practice.

OBJECTIVES: The 2019 ACR/EULAR classification criteria for IgG4-related disease (IgG4-RD) have exclusion criteria including positive disease-specific autoantibodies, and these have been documented to have a high specificity. This study aimed to further validate these criteria as well as identify characteristics of patients showing false-negative results. METHODS: We retrospectively analysed 162 IgG4-RD patients and 130 mimickers. The sensitivity, specificity and fulfilment rates for each criterion were calculated, and intergroup comparisons were performed to characterize the false-negative cases. RESULTS: Both the IgG4-RD patients and mimickers were aged ≥65 years with male predominance. The final diagnoses of mimickers were mainly malignancy, vasculitis, sarcoidosis and aneurysm. The classification criteria had a sensitivity of 72.8% and specificity of 100%. Of the 44 false-negative cases, one did not fulfil the entry criteria, 20 fulfilled one exclusion criterion and 27 did not achieve sufficient inclusion criteria scores. The false-negative cases had fewer affected organs, lower serum IgG4 levels, and were less likely to have received biopsies than the true-positive cases. Notably, positive disease-specific autoantibodies were the most common exclusion criterion fulfilled in 18 patients, only two of whom were diagnosed with a specific autoimmune disease complicated by IgG4-RD. In addition, compared with the true-positive cases, the 18 had comparable serum IgG4 levels, number of affected organs, and histopathology and immunostaining scores despite higher serum IgG and CRP levels. CONCLUSIONS: The ACR/EULAR classification criteria for IgG4-RD have an excellent diagnostic specificity in daily clinical practice. Positive disease-specific autoantibodies may have limited clinical significance for the diagnosis of IgG4-RD.

The pathology of Kawasaki disease aortitis: a study of 37 cases.

BACKGROUND: Kawasaki disease (KD) is a systemic vasculitis syndrome that occurs most frequently in children. Most clinical and pathological studies have focused on its coronary artery lesions. To date, no detailed studies of the aorta have been conducted. We studied KD autopsy cases with the aims of clarifying the time-course of changes in aortic lesions, the differences in the inflammatory cells and degree of inflammation at various aortic sites, and the progression of the inflammation. MATERIALS AND METHODS: The study materials were aortic specimens taken from 37 KD autopsy cases (acute phase: 19; remote phase: 18). Twenty-seven of the cases also had coronary aneurysms. We chose 3 aortic sites, i.e., the thoracic aorta, aortic root and aortic bifurcation, and we histologically observed and compared those sites in regard to the changes with time, the kinds of infiltrating cells and the number of inflammatory cells. We also observed the relationship between the vasa vasorum and inflammatory cell localization in the tunica media, and examined the progression of inflammation in the tunica media. RESULTS: Destruction of the vascular architecture was not seen in any of the 37 cases, but inflammatory cell infiltration was observed in 90% of the acute-phase cases. The inflammatory cell infiltration involved the tunica intima and tunica adventitia of the aorta on the 6th disease-day, and all layers of the aorta on the 13th disease-day; the infiltration peaked on the 18th disease-day. The infiltration gradually disappeared thereafter, and no significant infiltration was seen in the remote phase. The infiltrating inflammatory cells consisted mainly of CD163-positive macrophages. Comparison of the 3 sites of the aorta showed that the inflammatory cell infiltration was more severe in the aortic root and aortic bifurcation than in the thoracic aorta. The progression of inflammation to the aortic tunica media from the adventitia showed 2 patterns: 1 in which macrophages were aggregated around the vasa vasorum; and a second in which there was no such aggregation around the vasa vasorum, but there was diffuse inflammatory cell infiltration of the tunica media. In addition to this, there were findings of direct infiltration of cells from the tunica intima into the tunica media. CONCLUSION: Inflammation in KD occurs in the aorta. The changes with time and the kinds of infiltrating cells were the same as reported to date for coronary arteries in KD. There were differences in the degree of inflammation among the 3 aortic sites. It can be thought that the inflammation from the adventitia to the media progresses via the vas vasorum, and also, there is a possibility of spreading directly. From the intima to the media, inflammation spreads directly. However, formation of aneurysms and destruction of the vascular architecture of the aorta were absent in this study, unlike in coronary arteries.

Two Immunocompromised Patients With Diffuse Alveolar Hemorrhage as a Complication of Severe Coronavirus Disease 2019.

Diffuse alveolar hemorrhage (DAH) is a severe and potentially life-threatening disease manifestation. In addition to autoimmune diseases such as antineutrophil cytoplasmic antibody-associated vasculitis and anti-glomerular basement membrane syndrome, pulmonary viral infections are known to be culprits of DAH. Health-care providers worldwide in the coronavirus disease 2019 pandemic have been confronted with an unprecedented number of viral lung infections, with great variance in symptoms and severity. Hemoptysis, the key symptom of DAH, is a rare complication. We present two cases of immunocompromised patients with rapidly developing hypoxemic respiratory failure and evidence of DAH in the context of severe acute respiratory syndrome coronavirus 2 infection.

Coronary Arteritis and Periaortitis in IgG4-Related Disease.

We report an interesting case of coronary arteritis and periaortitis in a 62-year-old man with a history of biopsy-proven IgG4-related pulmonary disease. After 2 years of immune-suppressive therapy, the perivascular tissue surrounding all coronary arteries and the abdominal aorta was significantly attenuated, except that the luminal stenosis was aggravated to 70% in the left anterior descending coronary artery. Treatment with aspirin, atorvastatin, and ezetimibe was added. The patient was discharged under strict lesion surveillance at follow-up.

IgG4-related dacryocystitis and aortitis: A new association.

A 73-year-old woman with a history of muscular weakness and dyspnoea of unknown etiology was referred to our Ophthalmology Department for dacryocystitis. Lacrimal sac biopsy revealed IgG4 plasma cell infiltration and systemic diagnosis was done based on this, allowing an appropriate treatment to be established. To our knowledge, this is the first reported case of IgG4-related dacryocystitis associated to aortitis.

IL-25 exacerbates autoimmune aortitis in IL-1 receptor antagonist-deficient mice.

IL-25, a member of the IL-17 family of cytokines, is known to enhance type 2 immune responses, but suppress type 3 (IL-17A)-mediated immune responses. Mice deficient in IL-1 receptor antagonist (Il1rn-/- mice) have excessive IL-1 signaling, resulting in spontaneous development of IL-1-, TNF- and IL-17A-dependent aortitis. We found that expression of II25 mRNA was increased in the aortae of Il1rn-/- mice, suggesting that IL-25 may suppress development of IL-1-, TNF- and IL-17A-dependent aortitis in Il1rn-/- mice by inhibiting type 3-mediated immune responses. However, we unexpectedly found that Il25-/-Il1rn-/- mice showed attenuated development of aortitis, accompanied by reduced accumulation of inflammatory cells such as dendritic cells, macrophages and neutrophils and reduced mRNA expression of Il17a and Tnfa-but not Il4 or Il13-in local lesions compared with Il1rn-/- mice. Tissue-, but not immune cell-, derived IL-25 was crucial for development of aortitis. IL-25 enhanced IL-1ß and TNF production by IL-25 receptor-expressing dendritic cells and macrophages, respectively, at inflammatory sites of aortae of Il1rn-/- mice, contributing to exacerbation of development of IL-1-, TNF- and IL-17A-dependent aortitis in those mice. Our findings suggest that neutralization of IL-25 may be a potential therapeutic target for aortitis.

Aortitis caused by antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis: a case-based review.

Antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) is a systemic necrotizing small vessel vasculitis primarily affecting elderly patients. Neutrophil apoptosis and release of pro-inflammatory mediators promote small vessel inflammation and hence multi-organ disease. It rarely affects larger vessels with extremely rare aortic involvement. Diagnosis is made based on clinical presentation, tissue biopsy of affected organ, as well as immunofluorescence and ELISA assays for ANCA. Management includes immunosuppression (e.g., glucocorticoids, cyclophosphamide and rituximab) and supportive therapy. We present a rare case of a younger patient with AAV involving the aorta. The patient's diagnosis was supported by clinical presentation, systemic organ involvement, strongly positive c-ANCA, and skin as well as aortic tissue biopsy results. After failing multiple immunosuppressants, he responded well to rituximab with improved symptoms, inflammatory markers, and imaging findings. Based on our literature review, we were only able to find ten cases of ANCA-related vasculitis involving the aorta. This is the first reported case of successful treatment of AAV-related aortitis using rituximab. Our case report and literature review provide insight into treatment of severe cases of AAV with aortic involvement.

IgG4-aortitis among thoracic aortic aneurysms.

OBJECTIVE: The incidence of aortitis in patients with thoracic aortic diseases is not well established. The aim of this study was to analyse the frequency and clinical course of patients with aortitis in a surgical series. METHODS: 320 consecutive patients with ascending aorta/aortic arch aneurysm or acute aortic syndrome who underwent surgery from 2012 to 2017 in a single tertiary referral hospital were retrospectively reviewed. Epidemiological data, clinical course and variables related to diagnosis, treatment and follow-up were collected from patients with histologically proven aortitis. RESULTS: From 320 examined aortic samples, 279 (87.2%) thoracic aneurysms and 41 acute aortic syndromes (12.8%), 9 (2.8%) were aortitis: 3 cases of Takayasu's arteritis, 3 of IgG4-related aortitis, 2 of giant cell, and 1 classified as idiopathic. Median age at surgery was 53.4 (51-69.2) years and six cases were female. Seven patients presented with non-specific symptoms and the diagnosis was made at pathology. Surgery was elective in eight patients and emergent in one case of IgG4-related aortitis. 18F-fluorodeoxyglucose positron emission tomography/CT (18F-FDG PET/CT) was performed for disease extension study and as a monitoring technique during the follow-up of five patients, with just one case performed presurgically. All the patients with IgG4-related disease showed extrathoracic aortic involvement. There were no deaths, neither in-hospital nor during the 1.7 years of median follow-up. CONCLUSIONS: In surgically treated thoracic aorta pathology, the frequency of aortitis is low; IgG4-related disease is among the most common aetiologies with a frequency similar to other types of aortitis, such as Takayasu's and giant cell arteritis, and clinical manifestations are non-specific making presurgical diagnosis difficult. 18F-FDG PET/CT allows a better assessment of disease extension and therapeutic response. Surgery can be successfully performed and corticosteroid therapy ensures a good mid-term follow-up.

A Case of IgG4-Related Aortitis and Pericarditis: Diagnostic Challenges and Natural History.

BACKGROUND IgG4-related disease (IgG4-RD) is a systemic inflammatory condition with a myriad of presentations related to the pattern of organ involvement. Diagnostic workup for IgG4-RD requires a high index of suspicion, and further workup often includes the results of serological testing for elevated levels of IgG4. Correlation of presentation, past medical history, and histopathologic analysis are required to make a diagnosis. CASE REPORT In this case, incidental discovery of non-infectious aortitis and pulmonary mass lesions were the specific signs that led to the consideration of IgG4-RD. It was only after careful consideration of the patient's past medical history and examination of previously stored surgical specimens (pericardial tissue) that a conclusive, retrospective diagnosis of IgG4-related disease was reached. CONCLUSIONS This case demonstrates that the natural history of IgG4-related disease can be indolent and variable in presentation. Appropriate diagnosis requires consideration of all manifestations of the disease, sometimes with surveillance over several years.

Analysis of In Vivo Serpin Functions in Models of Inflammatory Vascular Disease.

Serpins have a wide range of functions in regulation of serine proteases in the thrombotic cascade and in immune responses, representing up to 2-10% of circulating proteins in the blood. Selected serpins also have cross-class inhibitory actions for cysteine proteases in inflammasome and apoptosis pathways. The arterial and venous systems transport blood throughout the mammalian body representing a central site for interactions between coagulation proteases and circulating blood cells (immune cells) and target tissues, a very extensive and complex interaction. While analysis of serpin functions in vitro in kinetics or gel shift assays or in tissue culture provides very necessary information on molecular mechanisms, the penultimate assessment of biological or physiological functions and efficacy for serpins as therapeutics requires study in vivo in whole animal models (some also consider cell culture to be an in vivo approach).Mouse models of arterial transplant with immune rejection as well as models of inflammatory vasculitis induced by infection have been used to study the interplay between the coagulation and immune response pathways. We describe here three in vivo vasculitis models that are used to study the roles of serpins in disease and as therapeutics. The models described include (1) mouse aortic allograft transplantation, (2) human temporal artery (TA) xenograft into immunodeficient mouse aorta, and (3) mouse herpes virus (MHV68)-induced inflammatory vasculitis in interferon-gamma receptor (IFNγR) knockout mice.

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.

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.

Bromodomain-containing protein 7 deficiency augments atherosclerotic lesions in ApoE-/- mice.

Atherosclerotic plaque formation is characterized by the persistence of lipid-laden macrophages on the inner walls of arteries. Chronic inflammation and imbalanced macrophage function are likely to play a critical role. Herein, we investigated whether bromodomain-containing protein 7 (Brd7), a member of the bromodomain-containing protein family, regulates atherosclerosis, and if so, which mechanisms are responsible for the process. We found that Brd7 is expressed in mouse atherosclerotic plaques, and mostly in macrophages. Inhibition of Brd7 accelerates atherosclerotic lesion formation in ApoE-/- mice by promoting NF-κB-mediated inflammation. Furthermore, Brd7 inhibition alters the phenotype of macrophages and promotes plaque instability, at least partly via STAT6 signaling. Our data define a previously undescribed role of Brd7 in the development of atherosclerosis.

Large-vessel vasculitis in human immunodeficiency virus-infected patients.

OBJECTIVE: The objective of this study was to describe large-vessel vasculitis (LVV) in patients with human immunodeficiency virus (HIV) infection. It is a retrospective single-center study conducted between 2000 and 2015 through a university hospital of 11 HIV-infected patients with LVV. METHODS: The characteristics and outcome of 11 HIV-infected patients with LVV (7 patients fulfilled international criteria for Takayasu arteritis, 5 patients had histologic findings of vasculitis, and 5 patients had imaging features of aortitis) were analyzed and compared with those of 82 patients with LVV but without HIV infection. RESULTS: Concerning the HIV-infected patients with LVV (n = 11), the mean age was 40 years (range, 36-56 years), and 55% of patients were female. At diagnosis of LLV, the mean initial CD4 cell count was 455 cells/mm3 (range, 166-837 cells/mm3), and the median HIV viral load was 9241 copies. Vascular lesions were located in the aorta (n = 7), in supra-aortic trunks (n = 7), and in digestive arteries (n = 3). Inflammatory aorta infiltrates showed a strong expression of interferon-γ and interleukin 6. In HIV-negative LVV patients (n = 82), the median age was 42 years, and 88% of the patients were women. Thirty patients had an inflammatory syndrome. Seventy patients had been treated with glucocorticosteroids and 57 with immunosuppressive treatments. Compared with their negative counterparts, HIV-positive patients with LVV were more frequently male (P = .014), had more vascular complications (ie, Ishikawa score; P = .017), and had more frequent revascularization (P = .047). After a mean follow-up of 96 months, four relapses of vasculitis were reported, and one patient died. Regardless of the HIV virologic response, antiretroviral therapy improved LVV in only one case. CONCLUSIONS: LVV in HIV-infected patients is a rare and severe entity.

Plasmacytic Aortitis with Occlusion of the Right Coronary Artery.

BACKGROUND Inflammation of the aortic wall, known as aortitis, is a rare clinical entity which is frequently asymptomatic, or identified when the patient presents with an aortic aneurysm or dissection. It is most often caused by infection or autoimmune vasculitides such as giant cell or Takayasu's arteritis. CASE REPORT The case presented is that of a 55-year-old man with symptomatic occlusion of the right coronary artery caused by a plasmacytic aortitis suggestive of IgG4 disease, which was successfully treated with coronary artery bypass grafting and an ascending aortic graft. CONCLUSIONS A review of the current literature emphasizes how poorly the etiology and natural history of plasmacytic aortitis is understood.

Differential effects of NOX4 and NOX1 on immune cell-mediated inflammation in the aortic sinus of diabetic ApoE-/- mice.

Oxidative stress and inflammation are central mediators of atherosclerosis particularly in the context of diabetes. The potential interactions between the major producers of vascular reactive oxygen species (ROS), NADPH oxidase (NOX) enzymes and immune-inflammatory processes remain to be fully elucidated. In the present study we investigated the roles of the NADPH oxidase subunit isoforms, NOX4 and NOX1, in immune cell activation and recruitment to the aortic sinus atherosclerotic plaque in diabetic ApoE(-/-) mice. Plaque area analysis showed that NOX4- and NOX1-derived ROS contribute to atherosclerosis in the aortic sinus following 10 weeks of diabetes. Immunohistochemical staining of the plaques revealed that NOX4-derived ROS regulate T-cell recruitment. In addition, NOX4-deficient mice showed a reduction in activated CD4(+) T-cells in the draining lymph nodes of the aortic sinus coupled with reduced pro-inflammatory gene expression in the aortic sinus. Conversely, NOX1-derived ROS appeared to play a more important role in macrophage accumulation. These findings demonstrate distinct roles for NOX4 and NOX1 in immune-inflammatory responses that drive atherosclerosis in the aortic sinus of diabetic mice.

Atypical chemokine receptor 1 deficiency reduces atherogenesis in ApoE-knockout mice.

AIMS: Atypical chemokine receptor 1 (Ackr1; previously known as the Duffy antigen receptor for chemokines or Darc) is thought to regulate acute inflammatory responses in part by scavenging inflammatory CC and CXC chemokines; however, evidence for a role in chronic inflammation has been lacking. Here we investigated the role of Ackr1 in chronic inflammation, in particular in the setting of atherogenesis, using the apolipoprotein E-deficient (ApoE(-/-)) mouse model. METHODS AND RESULTS: Ackr1(-/-)ApoE(-/-) and Ackr1(+/+)ApoE(-/-) littermates were obtained by crossing ApoE(-/-) mice and Ackr1(-/-) mice on a C57BL/6J background. Ackr1 (+/+)ApoE(-/-)mice fed a Western diet up-regulated Ackr1 expression in the aorta and had markedly increased atherosclerotic lesion size compared with Ackr1(-/-)ApoE(-/-) mice. This difference was observed in both the whole aorta and the aortic root in both early and late stages of the model. Ackr1 deficiency did not affect serum cholesterol levels or macrophage, collagen or smooth muscle cell content in atherosclerotic plaques, but significantly reduced the expression of Ccl2 and Cxcl1 in the whole aorta of ApoE(-/-) mice. In addition, Ackr1 deficiency resulted in a modest decrease in T cell subset frequency and inflammatory mononuclear phagocyte content in aorta and blood in the model. CONCLUSIONS: Ackr1 deficiency appears to be protective in the ApoE knockout model of atherogenesis, but it is associated with only modest changes in cytokine and chemokine expression as well as T-cell subset frequency and inflammatory macrophage content.