Kengo Kawakami

Inflammatory abdominal aortic aneurysm: close relationship to IgG4-related periaortitis.

Inflammatory abdominal aortic aneurysm (AAA) is a member of a family of disorders referred to as “chronic periaortitis” together with retroperitoneal fibrosis. Retroperitoneal fibrosis is included in IgG4-related disease, which is characterized by numerous infiltrating IgG4-positive plasma cells and high serum IgG4 concentrations. However, the relationship between IgG4-related disease and inflammatory AAA has not been documented. In this study, we examined the clinicopathologic characteristics of inflammatory (10 cases) and atherosclerotic (22 cases) AAAs, based on the hypothesis that inflammatory AAA might be related to IgG4-related disease. Cases of inflammatory AAA could be classified into 2 groups based on immunostaining of IgG4. Four patients showed diffuse infiltration of abundant IgG4-positive plasma cells (IgG4-related cases), whereas the remaining 6 cases of inflammatory AAA and all cases of atherosclerotic AAA had only a few IgG4-positive plasma cells (non–IgG4-related cases). IgG4-related inflammatory AAA was pathologically characterized by the frequent infiltration of eosinophils, lymph follicle formation, perineural inflammatory extension, and inconspicuous infiltration of neutrophils compared with non–IgG4-related inflammatory AAA. Obliterative phlebitis, which is venous occlusion with inflammatory cell infiltration, is observed in all IgG4-related cases. In addition, serum IgG4 concentrations were significantly higher in IgG4-related inflammatory AAA (109 to 559 mg/dL, normal range: 4 to 110 mg/dL) than non–IgG4-related inflammatory AAA (32 to 59 mg/dL) and all atherosclerotic AAA (12 to 83 mg/dL). In conclusion, inflammatory AAAs might be classified into 2 groups: IgG4-related or nonrelated. The former might be one of the IgG4-related diseases, and could be included in IgG4-related periaortitis together with retroperitoneal fibrosis.

A case of multiple immunoglobulin G4–related periarteritis: a tumorous lesion of the coronary artery and abdominal aortic aneurysm

Immunoglobulin G4 (IgG4)-related disease can occur in various organs, most of which are glandular or ductal tissues. Here, we report a case of multiple IgG4-related vascular lesions. A 63-year-old patient was found to have an abdominal aortic aneurysm and a tumorous lesion around the right coronary artery. The surgically resected aneurysmal wall and a tumorous lesion of the right coronary artery showed similar histologic features including diffuse lymphoplasmacytic infiltration, occasional eosinophils, and obliterative phlebitis. Immunohistochemically, numerous IgG4-positive plasma cells were evident within the lesions. The serum concentrations of IgG4 in the preoperative period was 456 mg/dL (reference range, <135), which decreased to 242 mg/dL 2 weeks after surgery. We made a diagnosis of multiple IgG4-related periarteritis manifesting as an abdominal aortic aneurysm and a tumorous nodule of the coronary artery. This case report suggested that IgG4-related disease can occur in the vascular system and manifest as an aneurysm or a periarterial mass lesion.

Immunoglobulin G4-Related Periaortitis Complicated by Aortic Rupture and Aortoduodenal Fistula after Endovascular AAA Repair

Purpose: To report a rare and complicated case of immunoglobulin (Ig) G4-related periaortitis involving both the aortic wall and the retroperitoneum without aneurysmal formation. Case Report: A 79-year-old man with IgG4-related periaortitis suffered aortic rupture despite a normal caliber aorta after 6 months of steroid therapy (20 mg/d). Endovascular repair with an aortic cuff sealed the rupture. Steroid therapy was halted 2 weeks later due to infection. Four months later, a biopsy during esophagogastroduodenoscopy to investigate gastrointestinal bleeding suggested a relapse of IgG4-RD in the duodenum. Subsequent aortoduodenal fistula formation proved fatal. Generally, IgG4-related periaortitis does not result in such complications due to the absence of aneurysm formation and a thick aortic wall. Conclusions: Our report highlights a rare case of IgG4-related periaortitis where complications resulted following steroid therapy and surgical intervention, emphasizing the difficulties in dealing with IgG4-related cardiovascular lesions.

Upregulated interleukins (IL-6, IL-10, and IL-13) in immunoglobulin G4-related aortic aneurysm patients

Objective: Immunoglobulin (Ig) G4‐related aortic aneurysms (IgG4‐AAs) are a special aortic aneurysm among IgG4‐related diseases (IgG4‐RDs), which are inflammatory and fibrous conditions characterized by tumorous swelling of affected organs and high serum IgG4 concentrations. Recently, IgG4‐RD pathogenesis was shown to be associated with T‐helper‐2 (Th2) and regulatory T (Treg) dominant cytokine production, such as interleukin (IL)‐4, IL‐10, and IL‐13. IL‐6 is a key proinflammatory cytokine contributing to lymphocyte and plasmacyte maturation and to atherosclerosis and aneurysm development. We serologically and histopathologically evaluated the cytokine profile in IgG4‐AA patients. Methods: Patients with IgG4‐AAs (n = 10), non‐IgG4‐related inflammatory abdominal aortic aneurysms (non‐IgG4‐AAAs; n = 5), atherosclerotic AAAs (aAAAs; n = 10), and normal aortas without dilatation (n = 10) were examined for serum IL‐10, IL‐13, and IL‐6 levels. Resected aortic tissues were evaluated for cluster of differentiation (CD) 34 (in the endothelial cells and mesenchymal cells) and CD163 (by macrophages) expression using immunohistochemistry and in situ hybridization. Results: Serum IL‐10 levels were rather higher in IgG4‐AA patients (median, 1.3 pg/mL) than in non‐IgG4‐AAA and aAAA patients and in patients with normal aortas. Elevated serum IL‐13 levels relative to standard values were detected in two IgG4‐AA patients but not in the other groups. Cells immunopositive for IL‐10 and IL‐13 were more frequent in IgG4‐AAs and significantly correlated with serum IgG4 levels. Serum IL‐6 levels (median, 78.5 pg/mL) were also significantly higher in IgG4‐AA patients than in non‐IgG4‐AAA and aAAA patients and control patients with normal aortas (P = .01, P = .001, and P = .004, respectively). They positively correlated with serum IgG4 levels and adventitial thickness, but other cytokines did not. The number of IL‐6‐immunopositive cells in the adventitia was significantly higher in IgG4‐AA patients (median, 17.8/high‐power field) than in aAAA patients or patients with normal aortas (P =.001 and P = .002, respectively). In situ hybridization confirmed frequent IL‐6 messenger (m)RNA expression in the endothelium, mesenchymal cells, and histiocytes in IgG4‐AA adventitia. In the same cells of IgG4‐AAs, coexpression of IL‐6 and CD34 mRNA or CD163 mRNA was detected. Conclusions: The cytokine profiles of IgG4‐AA patients had two characteristics: local IL‐10 and IL‐13 upregulation in IgG4‐AAs was related to Th2 and Treg‐predominant cytokine balance, similar to other IgG4‐RDs, and IL‐6 upregulation in the adventitia was characterized by activated immune reactions in IgG4‐AA patients. IL‐6 synthesis, through contributions of mesenchymal cells and macrophages in the adventitia, is strongly involved in IgG4‐AA pathogenesis or progression, or both. Clinical Relevance: Interleukin (IL) 10 and IL‐13 upregulation in the aortic adventitia reflected T‐helper‐2 and regulatory T immune reactions in immunoglobulin (Ig) G4‐related aortic aneurysms (IgG4‐AAs) similar to other IgG4‐related diseases. Furthermore, IgG4‐AA was characterized by IL‐6 upregulation. In IgG4‐AA, serum IL‐6 correlated with serum IgG4 and adventitial thickness. Multiple cell populations, including the endothelium, mesenchymal cells, and macrophages in the adventitia, additionally contributed to the hyper‐IL‐6 syndrome in IgG4‐AA. Local IL‐6 synthesis in IgG4‐AA adventitia may play a role in disease pathogenesis and progression. Serum IL‐6 would be a useful biomarker for disease activity, and an IL‐6 inhibitor may serve as a new effective therapy for IgG4‐AA.

Surgical Treatment of a Left Ventricular Neurofibroma

Abstract  Primary cardiac neurofibroma is a rare occurrence. We describe a case of left ventricular neurofibroma in a 56‐year‐old woman with Von Recklinghausen disease. Resection of the tumor with concomitant mitral valve replacement yielded a satisfactory clinical result, and histological examination of the resected tissue confirmed benign neurofibroma. The anatomic distribution of the vagus nerve plexus, which penetrates the epicardium and myocardium and courses over the left ventricular subendocardial surface, provides a tissue source from which this neurogenic tumor may arise.

Clinical Outcomes After Endovascular Repair and Open Surgery to Treat Immunoglobulin G4–Related and Nonrelated Inflammatory Abdominal Aortic Aneurysms:

Purpose: To compare the follow-up results of endovascular aneurysm repair (EVAR) vs open surgery (OS) for inflammatory abdominal aortic aneurysms (IAAAs) with regard to immunoglobulin G4–related diseases (IgG4-RD), which are fibrous inflammatory conditions characterized by elevated serum IgG4 concentrations and numerous infiltrations of IgG4+ plasmacytes. Methods: Between January 2005 and December 2015, 91 patients were treated with EVAR (begun in 2008) and 166 patients underwent OS for AAA. Forty of these 257 patients had IAAAs identified by a >2-mm thickness of periaortic fibrosis (PAF). Of these 40, 21 had pathologically confirmed IgG4-RD and/or serum IgG4 concentrations ≥135 mg/dL (classified IgG4+); 8 (mean age 76 years; 8 men) were treated with EVAR and 13 (mean age 71 years; 11 men) underwent OS. Of the 19 IgG4– patients with IAAA, 9 (mean age 71 years; 8 men) had EVAR and 10 (mean age 75 years; 9 men) had OS. The 4 subgroups were compared in terms of symptoms, complications, inflammation markers, PAF, and aneurysm diameter using the latest midterm follow-up data (12–24 months). Results: Preoperative aneurysm diameter, PAF, gender, median age, symptoms, and median follow-up period were similar in all groups. Preoperative serum IgG4 was equal in EVAR and OS IgG4+ groups. Compared with the OS IgG4+ group, EVAR IgG4+ patients more frequently had postoperative IgG4 increase (5/8; p=0.006) and PAF progression (5/8; p=0.027), higher postoperative serum IgG4 levels (median 141 mg/dL; p=0.034), a thicker postoperative PAF (median 5.1 mm; p=0.016), and persistent clinical symptoms (p=0.006). Compared with EVAR IgG4– patients, the EVAR IgG4+ patients showed significantly thicker postoperative PAF (p=0.024) and larger increases in postoperative sac diameter (median +13.1 mm; p=0.030). Postoperative PAF and sac diameter frequently and synchronously became worse in the EVAR IgG4+ subgroup with increased IgG4 during follow-up. The rate of change in IgG4 significantly positively correlated with the rates of change in PAF (R=0.555, p=0.03) and sac diameter (R=0.902, p=0.003). Conclusion: Though sample sizes were rather small, this pilot study suggested that EVAR-treated IgG4+ IAAA patients have a higher risk of persistent symptoms and increases in PAF, sac diameter, and IgG4 levels. Therefore, OS should be preferred for complete recovery. Frequent monitoring of the postoperative serum IgG4 is necessary following EVAR in IgG4+ patients to detect these complications.

Inflammatory features, including symptoms, increased serum interleukin-6, and C-reactive protein, in IgG4-related vascular diseases

Immunoglobulin (IgG) 4-related diseases (IgG4-RDs) are fibro-inflammatory conditions characterized by tumorous swelling and serum IgG4 levels. Intrapelvic IgG4-RD has been subclassified according to the localization site and aortic shape as IgG4-related aortic aneurysms (IgG4-AAs), periaortitis (IgG4-PA), and retroperitoneal fibrosis (IgG4-RF). The IgG4-AA pathogenesis would involve interleukin (IL)-6 upregulation, and Th2-predominant and Treg-activated immune conditions. We characterized the features of intrapelvic IgG4-RD lesions, including presence of vascular lesions. The clinical, serological, and pathological features, including cytokines concerning Th1/2 and Treg (IL-4, IL-6, IL-10, IL-13, and interferon-gamma) of patients with IgG4-AAs (n = 24), IgG4-PA (n = 8), and IgG4-RF (n = 10) were retrospectively compared. Clinical symptoms, such as low-grade fever, abdominal/lumber pain, and anemia, were frequently detected in IgG4-AAs but rarely in IgG4-RF. Serum IL-6 and C-reactive protein (CRP) were significantly higher in IgG4-AAs and IgG4-PA than in IgG4-RF. Pathologically, IL-6+ cells were more frequently detected in IgG4-PA and IgG4-AAs than in IgG4-RF. There were no noteworthy differences in the clinical complications, white blood cell counts, serum IgE, and serum and immunopositive cells of other cytokines between the subgroups. Among IgG4-AAs and IgG4-PA, serum IL-6 and IL-6+ cells correlated with CRP, aortic diameter, and periaortic fibrosis. IgG4-AA and IgG4-PA, but not IgG4-RF, were characterized by “inflammatory” features, such as increased CRP and serum/pathological IL-6, and clinical inflammatory symptoms; thus, IgG4-AA and IgG4-PA belong to the same group as IgG4-related vascular disease. High levels of CRP and IL-6 would be hallmarks of IgG4-related vascular disease.

IgG4-Related Arterial Disease

Immunoglobulin G4-related diseases (IgG4-RD) are systemic inflammatory conditions, characterized by high serum IgG4 concentrations, and pathologically IgG4-positive plasmacytes infiltrations and storiform fibrosis. We described IgG4-related inflammatory abdominal aortic aneurysm in 2008, and revealed the existence of vascular lesions. IgG4-related vascular lesions frequently occur in the aorta and branching medium-sized arteries with or without aneurysmal change. The inflammatory lesion mainly involves in the adventitia, indicating remarkable adventitial fibrous thickening with infiltration of inflammatory cells. Clinical symptoms associated with IgG4-related vascular lesions might be fever, abdominal pain, hydronephrosis, or few subjective symptoms. Comprehensive diagnostic criteria is applied according to image findings of thickening lesions, high serum IgG4 levels, and histopathological findings. As a treatment, open surgical repair or endovascular aneurysm repair is performed for the aneurysmal cases, and steroid administration is used for the cases with strong inflammation. This disease can lead to a lethal situation due to the rupture following aneurysmal formation, thus special attention is needed unlike IgG4-RD occupying in the other organs. (This is a translation of Jpn J Vasc Surg 2017; 26: 129–134.)

Bailout Endovascular Stent Grafting for an Ascending Aortic Pseudoaneurysm Using an Infrarenal Aortic Extension Cuff

We report successful thoracic endovascular repair of a pseudoaneurysm rupture in the ascending aorta using infrarenal endovascular devices after an aortic valve replacement. Complete exclusion of the pseudoaneurysm was achieved with no endoleak or postoperative complications. Despite limitations of the current technology, this endovascular technique was a relatively less invasive, feasible lifesaving surgical option for the repair of a pseudoaneurysm of the ascending aorta with a diameter ≤32 mm.