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.

Tryptophan Catabolism and Inflammation: A Novel Therapeutic Target For Aortic Diseases.

Aortic diseases are the primary public health concern. As asymptomatic diseases, abdominal aortic aneurysm (AAA) and atherosclerosis are associated with high morbidity and mortality. The inflammatory process constitutes an essential part of a pathogenic cascade of aortic diseases, including atherosclerosis and aortic aneurysms. Inflammation on various vascular beds, including endothelium, smooth muscle cell proliferation and migration, and inflammatory cell infiltration (monocytes, macrophages, neutrophils, etc.), play critical roles in the initiation and progression of aortic diseases. The tryptophan (Trp) metabolism or kynurenine pathway (KP) is the primary way of degrading Trp in most mammalian cells, disturbed by cytokines under various stress. KP generates several bioactive catabolites, such as kynurenine (Kyn), kynurenic acid (KA), 3-hydroxykynurenine (3-HK), etc. Depends on the cell types, these metabolites can elicit both hyper- and anti-inflammatory effects. Accumulating evidence obtained from various animal disease models indicates that KP contributes to the inflammatory process during the development of vascular disease, notably atherosclerosis and aneurysm development. This review outlines current insights into how perturbed Trp metabolism instigates aortic inflammation and aortic disease phenotypes. We also briefly highlight how targeting Trp metabolic pathways should be considered for treating aortic diseases.

Immunoglobulin G4-Related Aortitis and Severe Aortic Valve Stenosis Treated With Transcatheter Aortic Valve Replacement and Immunosuppression.

IgG4-related disease is an immune-mediated fibro-inflammatory disorder with multisystemic involvement. Aortitis and peri-aortitis are the most common cardiovascular manifestations of the disease. We present the case of a 65-year-old man with symptomatic severe aortic stenosis and concomitant IgG4 aortitis. The diagnosis was confirmed by IgG4 serum levels, positive positron emission computed tomography (PET-CT) scans, and pathology from mediastinal dissection. Surgical aortic valve replacement (SAVR) was unfeasible owing to extensive mediastinal fibrosis, and transcatheter aortic valve replacement (TAVR) was successfully performed. As ascending aorta access for SAVR in IgG4 aortitis with long-run fibrosis entails a high risk of mortality, TAVR could be considered in certain suitable patients.

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.

MicroRNA-223 triggers inflammation in porcine aorta by activating NLRP3 inflammasome under selenium deficiency.

Selenium (Se) is an essential trace element in organism. Se deficiency can cause many diseases, including vascular disease. Studies have shown that inflammation is the main inducement of vascular disease, microRNA (miRNA) can influence inflammation in various ways, and Se deficiency can affect miRNAs expression. To study the mechanism of aorta damage caused by Se deficiency, we constructed a Se deficiency porcine aorta model and found that Se deficiency can significantly inhibit miR-223, which downregulates the expression of nucleotide-binding oligomerization domain-like receptor family 3 (NLRP3). Subsequently, we found that in Se deficiency group, NLRP3, and its downstream (caspase-1, apoptosis-related spot-like protein [ASC], IL-18, IL-1ß) expression was significantly increased. In vitro, we cultured pig iliac endothelium cell lines, and constructed miR-223 knockdown and overexpression models. NLRP3 messenger RNA and protein levels were significant increased in the knockdown group, and decreased in the overexpression group. The results of this study show that Se deficiency in porcine arteries can induce inflammation through miR-223/NLRP3.

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.

Saprochaete capitata aortitis in an immunocomopetent patient after myocardial revascularization.

Saprochaete species infection is a rare fungal disease reported so far only in immunocompromised patients. We describe the first case of aortitis caused by Saprochaete capitata, presenting as ascending aorta aneurysm, with secondary endophthalmitis in an immunocompetent patient. Infection by Saprochaete capitata is potentially fatal, with a mortality ranging from 50% to 90% of cases. In the present case aortic aneurysm caused by Saprochaete capitata aortitis was successfully treated by the combination of accurate diagnosis with surgical and specific antifungal therapy.

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.

The Protective Effect of Crataegus aronia Against High-Fat Diet-Induced Vascular Inflammation in Rats Entails Inhibition of the NLRP-3 Inflammasome Pathway.

This study investigated whether the whole-plant aqueous extract of Crataegus aronia (C. aronia) could protect against or alleviate high-fat diet (HFD)-induced aortic vascular inflammation in rats by inhibiting the NLRP-3 inflammasome pathway and examined some mechanisms of action with respect to its antioxidant and hypolipidemic effects. Adult male Wistar rats were divided into five groups (n = 6/each): standard diet (10% fat) fed to control rats, control + C. aronia (200 mg/kg), HFD (40% fat), HFD + C. aronia, and HFD post-treated with C. aronia. The HFD was fed for 8 weeks and C. aronia was administered orally for 4 weeks. In addition, isolated macrophages from control rats were pre-incubated with two doses of C. aronia (25 and 50 µg/mL) with or without lipopolysaccharide (LPS) stimulation. Only in HFD-fed rats, co- and post-C. aronia therapy lowered circulatory levels of LDL-C and ox-LDL-c and aortic protein levels of LOX-1 and CD36. C. aronia also inhibited the nuclear accumulation of NF-κB and lowered protein levels of NLRP-3, caspase-1, and mature IL-1ß. In vitro, in the absence of ox-LDL-c, C. aronia led to reduced nuclear levels of NF-κB, ROS generation, and protein NLRP-3 levels, in both LPS-stimulated and unstimulated macrophages, in a dose-dependent manner. However, protein levels of LOX-1 were not affected by C. aronia in unstimulated cells. In conclusion, C. aronia inhibits the NLRP-3 inflammasome pathway, induced by HFD feeding in the aorta of rats, mainly by its hypolipidemic effect and in vitro, in LPS-stimulated macrophages, by its antioxidant effect.

Immunoglobulin G4-related thoracic aortitis.

Patients with immunoglobulin G4-related thoracic aortitis often have nonspecific symptoms, but pain in the chest or back is common. The rate of misdiagnosis of immunoglobulin G4-related thoracic aortitis is high, which may lead to mistreatment in extreme cases. A correct diagnosis should be based on comprehensive medical imaging, pathology, and laboratory and immunohistochemical results. Most patients' condition can be significantly improved using conservative or surgical treatment.

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.

Clinical phenotypes of IgG4-related disease: an analysis of two international cross-sectional cohorts.

OBJECTIVE: IgG4-related disease (IgG4-RD) is a heterogeneous, multiorgan condition of unclear aetiology that can cause organ failure. Difficulty recognising IgG4-RD contributes to diagnostic delays. We sought to identify key IgG4-RD phenotypes. METHODS: We used two cross-sectional studies assembled by an international, multispecialty network of IgG4-RD specialists who submitted 765 cases to derive and replicate phenotypic groups. Phenotype groups of disease manifestations and key covariate distributions across the identified groups were measured using latent class analysis. RESULTS: In the derivation cohort (n=493), we identified four groups with distinct manifestations: Group 1 (31%), Pancreato-Hepato-Biliary disease; Group 2 (24%), Retroperitoneal Fibrosis and/or Aortitis; Group 3 (24%), Head and Neck-Limited disease and Group 4 (22%), classic Mikulicz syndrome with systemic involvement. We replicated the identification of four phenotype groups in the replication cohort. Compared with cases in Groups 1, 2 and 4, respectively, cases in Group 3 were more likely to be female (OR 11.60 (95% CI 5.39 to 24.98), 10.35 (95% CI 4.63 to 23.15) and 9.24 (95% CI 3.53 to 24.20)) and Asian (OR 6.68 (95% CI 2.82 to 15.79), 7.43 (95% CI 2.97 to 18.56) and 6.27 (95% CI 2.27 to 17.29)). Cases in Group 4 had a higher median serum IgG4 concentration (1170 mg/dL) compared with groups 1-3 (316, 178 and 445 mg/dL, respectively, p<0.001). CONCLUSION: We identified four distinctive IgG4-RD phenotypes according to organ involvement. Being Asian or female may predispose individuals to head and neck-limited disease. These phenotypes serve as a framework for identifying IgG4-RD and studying its aetiology and optimal treatment.

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.