STAT3 Activation Correlates with Adventitial Neutrophil Infiltration in Human Aortic Dissection.

Objective: Aortic dissection (AD) is a fatal disease that is caused by the rapid destruction of the aortic wall. Although recent studies in animal models indicate an important relationship between inflammation and tissue destruction, activation status of inflammatory signaling and its relation to the inflammatory cell infiltration are poorly characterized in human AD. Materials and Methods: We examined the activation of inflammatory signaling molecules NFκB and STAT3, and neutrophil infiltration in AD tissue samples that were obtained during the surgical repair within 24 h after AD onset. Results: Activation of NFκB was observed mainly in the intima both in AD samples and in aortic samples without AD. Activation of STAT3 was observed in AD samples, but not in the aortic sample without AD. Neutrophil infiltration was observed predominantly in the adventitial layer of AD samples. Histological analysis revealed that STAT3 was activated in cells other than neutrophils. Notably, STAT3 activation and neutrophil infiltration showed positive correlation in adventitial layer of AD tissue. Conclusion: These findings demonstrated that adventitial STAT3 activation was associated with neutrophil infiltration, suggesting their importance in AD pathogenesis.

[A Case of Subphrenic Lymph Node Metastasis from Gastric Cancer in Which FDG-PET/CT Was Useful for Diagnosis].

A 70-year-old man was admitted for lymph node metastasis detected by FDG-PET/CT showing a mass 10mm in diameter. He had a history of a distal gastrectomy for advanced gastric cancer and was administered postoperative adjuvant chemotherapy consisting of 2 courses of TS-1 with CDDP and TS-1 only for 1 year. Lymph node recurrence was diagnosed and resected 4 years after the initial surgery. Histological examination revealed lymph node metastasis of the gastric cancer. He was administered adjuvant chemotherapy using TS-1 and has been followed-up without recurrences for 17 months after the second operation. We reported a case in which FDG-PET/CT was potentially beneficial for the diagnosis of the postoperative small lymph node metastasis.

Abdominal Aortic Aneurysm Caused by Aortic Fibromuscular Dysplasia: A Case Report.

Fibromuscular dysplasia (FMD) mainly develops in medium-sized arteries, including renal, extracranial, and extremity arteries, but it rarely causes abdominal aortic aneurysm (AAA). A 69-year-old woman with AAA diagnosed on ultrasonography by a home doctor visited our hospital. Contrast-enhanced computed tomography revealed a saccular aneurysm of terminal abdominal aorta. We performed abdominal aortic replacement and resected the section with aneurysm. Pathological examination of the wall tissue of the resected aneurysm revealed findings that are consistent with FMD. We report this case of AAA caused by aortic FMD because of its rarity.

Cytokine Profile of Human Abdominal Aortic Aneurysm: Involvement of JAK/STAT Pathway.

Objective: Abdominal aortic aneurysm (AAA) is characterized by inflammation and destruction of normal tissue architecture. The present study aimed to evaluate the inflammatory signaling cascade by analyzing the cytokines of AAA tissue. Materials and Methods: We analyzed the comprehensive cytokine secretion profiles of 52 cytokines from human AAA in four patients with AAA using fluorescent beads-based multiplex assay. Further, the effect of janus kinase (JAK) inhibition by pyridone 6 on cytokine profiles was also evaluated. Results: Cytokine secretion profiles were found to be similar among the four patients. A high level of JAK/signal transducers and activator of transcription (STAT) pathway activity in AAA tissue in culture was maintained, which may be attributed to the secretion of endogenous JAK-activating cytokines. Inhibition of JAK by pyridone 6 resulted in the suppression of STAT3 phosphorylation and secretion of a subset of chemokines and JAK-activating cytokines. However, the inhibition of JAK had no effect on the secretion of matrix metalloproteinase (MMP)-2, MMP-9, or TGF-ß family that is responsible for the metabolism of extracellular matrix. Conclusion: The findings of the present study suggested that AAA tissue exhibits a stereotypical profile of cytokine secretion, where JAK/STAT pathway may play a role in regulating a subset of cytokines. Identification of such a cytokine profile may reveal potential diagnostic markers and therapeutic targets for AAA.

Characterization of SMAD2 Activation in Human Thoracic Aortic Aneurysm.

Objective: Thoracic aortic aneurysm (TAA) reflects the local expansion of the thoracic aorta; the underlying causal molecular mechanism of TAA is not well understood. Recent studies have shown the importance of transforming growth factor beta (TGFß) signaling in Marfan and Loeys-Dietz syndromes; however, its role in non-familial, non-syndromic TAA remains unclear. Materials and Methods: We performed histochemical and immunohistochemical analyses for activated (phosphorylated) SMAD2 (P-SMAD2) as an indicator of TGFß signaling activities in the ascending TAA tissue as well as in the ascending aortic tissue with a normal diameter obtained from 7 patients without any clinical findings suggesting familial or syndromic TAA. Results: TAA samples showed a higher P-SMAD2-positive area than samples with a normal diameter. P-SMAD2 signal was higher in the outer zone of the aortic and TAA walls. Within the TAA tissue, P-SMAD2 staining showed the following two distinct patterns: layer-like staining at the border of the medial layer and the thickened intima and a spot-like staining within the medial layer surrounding the microvessels. Conclusion: These findings suggested that TGFß signaling is activated in several distinct histopathological contexts in TAA, suggesting a complex role of TGFß.

Involvement of B Cells, Immunoglobulins, and Syk in the Pathogenesis of Abdominal Aortic Aneurysm.

BACKGROUND: Abdominal aortic aneurysm (AAA) is a potentially life-threatening disease that is common in older individuals. Currently, therapeutic options are limited to surgical interventions. Although it has long been known that AAA tissue is enriched in B cells and immunoglobulins, their involvement in AAA pathogenesis remains controversial. METHODS AND RESULTS: We investigated the role of B cells and immunoglobulins in a murine model of AAA, induced with a periaortic application of CaCl2, and in human AAA. Both human and mouse AAA tissue showed B-cell infiltration. Mouse AAA tissue showed deposition of IgG and activation of Syk, a key molecule in B-cell activation and immunoglobulin function, which were localized to infiltrating cells including B cells and macrophages. B-cell-deficient muMT mice showed suppression of AAA development that was associated with reduced activation of Syk and less expression of matrix metalloproteinase-9. Administration of exogenous immunoglobulins restored the blunted Syk activation and AAA development in muMT mice. Additionally, exogenous immunoglobulins induced interleukin-6 and metalloproteinase-9 secretions in human AAA tissue cultures. Furthermore, administration of R788, a specific Syk inhibitor, suppressed AAA expansion, reduced inflammatory response, and reduced immunoglobulin deposition in AAA tissue. CONCLUSIONS: From these results, we concluded that B cells and immunoglobulins participated in AAA pathogenesis by promoting inflammatory and tissue-destructive activities. Finally, we identified Syk as a potential therapeutic target.

Role of Macrophage Socs3 in the Pathogenesis of Aortic Dissection.

BACKGROUND: Aortic dissection (AD) is a life-threatening medical emergency caused by the abrupt destruction of the intimomedial layer of the aortic walls. Given that previous studies have reported the involvement of proinflammatory cytokine interleukin-6 in AD pathogenesis, we investigated the role of signal transduction and activator of transcription 3 signaling, a downstream pathway of interleukin-6 in macrophages in pathogenesis of AD. METHODS AND RESULTS: We characterized the pathological and molecular events triggered by aortic stress, which can lead to AD. Aortic stress on the suprarenal aorta because of infrarenal aorta stiffening and angiotensin II infusion for 1 week caused focal medial rupture at the branching point of the celiac trunk and superior mesenteric artery. This focal medial rupture healed in 6 weeks in wild-type (WT) mice, but progressed to AD in mice with macrophage-specific deletion of Socs3 gene (mSocs3-KO). mSocs3-KO mice showed premature activation of cell proliferation, an inflammatory response, and skewed differentiation of macrophages toward the tissue-destructive phenotype. Concomitantly, they showed aberrant phenotypic modulation of smooth muscle cells and transforming growth factor beta signaling, which are likely to participate in tissue repair. Human AD samples revealed signal transduction and activator of transcription 3 activation in adventitial macrophages adjacent to the site of tissue destruction. CONCLUSIONS: These findings suggest that AD development is preceded by focal medial rupture, in which macrophage Socs3 maintains proper inflammatory response and differentiation of SMCs, thus promoting fibrotic healing to prevent tissue destruction and AD development. Understanding the sequence of the pathological and molecular events preceding AD development will help predict and prevent AD development and progression.

The impact of preoperative identification of the Adamkiewicz artery on descending and thoracoabdominal aortic repair.

OBJECTIVE: To investigate the impact of preoperative identification of the Adamkiewicz artery (AKA) on prevention of spinal cord injury (SCI) through the multicenter Japanese Study of Spinal Cord Protection in Descending and Thoracoabdominal Aortic Repair (JASPAR) registry. METHODS: Between January 2000 and October 2011, 2435 descending/thoracoabdominal aortic repairs were performed, including 1998 elective repairs and 437 urgent repairs, in 14 major centers in Japan. The mean patient age was 67 ± 13 years, and 74.2% were males. There were 1471 open repairs (ORs), including 748 descending and 137 thoracoabdominal extent [Ex] I, 136 Ex II, 194 Ex III, 115 Ex IV, and 138 Ex V, and 964 endovascular repairs (EVRs). Of the 2435 patients, 1252 (51%) underwent preoperative magnetic resonance or computed tomography angiography to identify the AKA. RESULTS: The AKA was identified in 1096 of the 1252 patients who underwent preoperative imaging (87.6%). Hospital mortality was 9.2% (n = 136) in those who underwent OR and 6.4% (n = 62) in those who underwent EVR. The incidence of SCI was 7.3% in the OR group (descending, 4.2%; Ex I, 9.4%; Ex II, 14.0%; Ex III, 14.4%; Ex IV, 4.2 %; Ex V, 7.2%) and 2.9% in the EVR group. The risk factors for SCI in ORs were advanced age, extended repair, emergency, and occluded bilateral hypogastric arteries. In ORs of the aortic segment involving the AKA, having no AKA reconstruction was a significant risk factor for SCI (odds ratio, 2.79, 95% confidence interval, 1.14-6.79; P = .024). CONCLUSIONS: In descending/thoracoabdominal aortic repairs, preoperative AKA identification with its adequate reconstruction or preservation, especially, in ORs of aortic pathologies involving the AKA, would be a useful adjunct for more secure spinal cord protection.

Prosthetic vascular graft infection through a median sternotomy: a multicentre review †.

OBJECTIVES: The aim of this study is to analyse the treatment outcomes of thoracic prosthetic graft infection. METHODS: A retrospective chart review was conducted at six hospitals and included the records of 68 patients treated for postoperative prosthetic vascular graft infection (mean age: 62.3 ± 15.1, male 51) from January 2000 to December 2013. The number of patients and the locations of the treated infections were as follows: 13 for aortic root, 16 for ascending aorta, 35 for aortic arch and 4 for aortic root to arch. In-hospital infection occurred in 43 patients and after discharge in 25. RESULTS: The mean follow-up time was 2.0 ± 2.3 years. The follow-up rate was 94.1%. The most commonly isolated micro-organism was Staphylococcus aureus (72.1%). Rereplacement of infectious graft was performed in 18 patients (Dacron graft in 12, homograft in 4 and rifampicin-bonded Dacron graft in 2). The overall hospital mortality rate was 35.3% (24/68). The mortality rate among the patients with graft rereplacement was 33.3% (6/18), with pedicled muscle flaps or pedicled omental flaps to cover the graft 25.9% (7/27), with irrigation 55.0% (11/20) and on antibiotic therapy only 0% (0/3). Our multivariate analysis demonstrated that the risk factors of hospital death increased in the absence of pedicled flaps (muscle or omentum) to cover the graft (P = 0.001), age over 55 (P = 0.003), time from onset of initial operation <1 week (P = 0.031) and period before 2008 (P = 0.001). The overall 1-year survival rate was 58.6%. CONCLUSIONS: The treatment outcomes of thoracic prosthetic vascular graft infection have not been satisfactory. However, the use of pedicled muscle or omental flaps to cover the graft could improve the outcomes.

Sonic Hedgehog signaling regulates vascular differentiation and function in human CD34 positive cells: vasculogenic CD34(+) cells with Sonic Hedgehog.

Identification of pivotal factors potentially present in the in situ environment and capable of influencing the function of CD34(+) cells, which can be used for autologous cell therapy, is of paramount interest. SHh is one of the morphogens essential for embryonic vascular development as well as postnatal neovascularization, and the activation of SHh signaling with angiogenic and vascular differentiation responses in CD34(+) cells by SHh treatment differed depending on the G-CSF treatment or the background disease. SHh enhanced the migration, proliferation, adhesion, and EPC colony forming capacities of G-CSF mobilized CD34(+) cells, increasing the vasculogenic/angiogenic potential for neovascularization. An increase in the differentiation potential of CD34(+) cells toward vascular lineages was demonstrated with SHh treatment involving TGFß signaling pathway. The SHh-activated G-CSF mobilized CD34(+) cells directly contributed to vascular regeneration while non-activated CD34(+) cells showed a lower regenerative capacity in a mouse ischemic hindlimb model. SHh signaling regulates human CD34(+) cell fate and function, and may potentiate the therapeutic effect of G-CSF mobilized CD34(+) cells on ischemic diseases.

Therapeutic strategy for treating aortoesophageal fistulas.

PURPOSE: The development fistulas between the thoracic aorta and the esophagus are highly fatal conditions. We aimed to identify a therapeutic strategy for treating aortoesophageal fistula (AEF) in this study, by investigating all AEF cases presented in this special symposium at the 65th Annual Scientific Meeting of the Japanese Association for Thoracic Surgery. METHODS: Forty-seven AEF patients were included in this study. The survivors and nonsurvivors at six and 18 months after diagnosis of AEF were classified into "Group A6", "Group D6", "Group A18", and "Group D18", respectively. Comparisons between Group A6 and Group D6 and between Group A18 and Group D18 were made with regard to therapeutic strategy. RESULTS: Twenty-two (46.8 %) and 33 (70.3 %) of the 47 patients died within 6 and 18 months, respectively. The patients treated with omentum wrapping (p = 0.0052), esophagectomy (p = 0.0269) and a graft replacement strategy for the aorta (p = 0.002) were more frequently included in Group A6. The patients with the omentum wrapping (p = 0.0174) and esophagectomy (p = 0.0203) and graft replacement were more significantly included in Group A18. The results of the multivariate analysis indicated that the mortality rate at 6 and 18 months after diagnosis was significantly correlated with graft replacement (p = 0.0188) and esophagectomy (p = 0.0257), respectively. There were significant differences in the actuarial survival curves in patients who had omentum wrapping, graft replacement, and esophagectomy compared to patients who did not have these 3 therapeutic procedures. CONCLUSION: The use of thoracic endovascular aortic repair alone for AEF should not be considered a definitive surgery. In contrast, esophagectomy, open surgery with aortic replacement using prostheses and homografts and greater omentum wrapping significantly improve the mid-term survival of AEF.

Results of intra-wound continuous negative pressure irrigation treatment for mediastinitis.

Intra-wound continuous negative pressure irrigation treatment (IW-CONPIT) was administered to cases of mediastinitis as the therapy of choice, with satisfactory results being obtained in terms of improved survival rates and quick healing of wounds. Accordingly, these treatment results and efficacy were evaluated. After debridement, a sponge was trimmed to conform to the shape of the wound and then it was attached to the surface of the wound. Two tubes with several side holes were placed within the sponge. In cases in which the blood vessels and/or the heart are exposed, an artificial dermis was attached to cover the blood vessels and/or the heart in order to not come in direct contact with the sponge. Next, the top of the wound was covered with polyethylene film to create an air-tight wound seal. A bottle of saline solution was connected to one of the tubes and a continuous aspirator to the other, and continuous negative pressure irrigation of the wound was thus carried out. After performing this treatment for 2-3 weeks, and when wound granulation improved, either skin grafts or the transplantation of muscle flaps was performed as necessary to achieve wound healing. A combination of the continuous negative pressure method and the continuous irrigation method resulted in improved healing rates and lower mortality rates for mediastinitis. It also significantly reduced the number of dressings, as well as the degree of labour and medical materials required; therefore, a reduced hospital stay and shorter treatment period was thus achieved using this treatment method.

D-dimer value more than 3.6 µg/ml is highly possible existence deep vein thrombosis.

OBJECTIVE: The present study aimed to establish whether a more optimal cutoff value for D-dimer testing could definitively rule out acute deep vein thrombosis (DVT). METHODS: Between April 2009 and March 2010, 190 referral patients suspected to have DVT were assessed by the D-dimer assay. Additionally, ultrasonography (US) and computed tomography (CT) imaging were performed to detect thrombosis. RESULTS: DVT was identified in 47 patients (24%). The average D-dimer level in patients with DVT was 17.6±22.4 µg/ml, and was significantly lower (p=0.035),] at 2.7±4.2 µg/ml, in those without DVT. On the basis of receiver operating curve analysis, the specificity of the D-dimer for diagnosing DVT increased from 40% to 78.3%, and its sensitivity reached 93.8%, when the cutoff value for the assay was set at 3.6 µg/ml. CONCLUSIONS: D-dimer value over 3.6 µg/ml was highly prognostic for DVT.

Left atrial intramural hematoma after resection of myxoma: report of a case.

A 73-year-old woman was referred for treatment of left atrial (LA) myxoma. At surgery, a myxoma was attached to the left atrial side of the fossa ovalis in the atrial septum by a stalk and was transmurally excised with a margin of the atrial septum. The atrial septum was closed without any prosthetic materials under mild to moderate tension. Although she was asymptomatic, postoperative transesophageal echocardiography (TEE) revealed an abnormal cavity, containing heterogeneous echogenesity without blood flow, in the posterior LA wall. Magnetic resonance imaging (MRI) demonstrated a mass without significant enhancement. It was considered to be an intramural hematoma, and the diagnosis of LA dissection was made. Follow-up echocardiography showed disappearance of the dissected lumen without surgical intervention. Both TEE and MRI are useful for the correct diagnosis of an LA dissection; and surgical intervention, entry closure or internal drainage, may not always be necessary in the absence of a hemodynamic compromise with an LA dissection.

Thoracic endovascular aortic repair with homemade stent grafts: early and mid-term outcomes.

PURPOSE: We reviewed our experience with homemade stent grafts in the repair of a variety of thoracic aortic lesions. The objective of this study was to assess the early and mid-term outcomes of this therapy. METHODS: From 1999 to 2007, homemade stent grafts were inserted in 88 patients with an atherosclerotic aneurysm, dissection, pseudoaneurysm, trauma, or rupture in the thoracic aorta. The endoprostheses were stainless steel Z-stents covered by a polyester graft, and were custom-designed for each patient. RESULTS: Placement of stent grafts was technically successful in 81 of the 88 patients (92%). Within 30 days after treatment, 3 patients died, 3 had a cerebral infarction, and 3 had onset of paraplegia or paraparesis. Primary endoleaks were observed in 8 patients (9%). During the mean follow-up period of 32 ± 26 months, 7 patients had persistent endoleaks and 7 had stent-graft migration. The aneurysm-related mortality rate was 7%. The rate of freedom from open-surgery conversion at 32 months was 89.0%. CONCLUSIONS: Our early experience with elective and emergency thoracic endovascular aortic repair using homemade stent grafts provided therapeutic benefits to high-risk patients. Endoleaks and stent-graft migrations were the factors most commonly responsible for secondary intervention in the mid-term period. Careful follow-up of patients treated with this approach is needed to avoid major complications in the long term.

Hepatocyte growth factor promotes an anti-inflammatory cytokine profile in human abdominal aortic aneurysm tissue.

Abdominal aortic aneurysm (AAA) is characterized by the destruction of tissue architecture due to chronic inflammation of unknown etiology. Recent studies have indicated that control of inflammation is a promising therapeutic strategy; however, no established pharmacological intervention is currently available for AAA. We found that hepatocyte growth factor (HGF) was expressed in aneurysmal tissue, and colocalized with von Willebrand factor, the endothelial cell marker, in the most damaged part of the aneurysmal walls. In ex vivo cultures of human AAA tissue, exogenously added HGF in the presence of tumor necrosis factor-alpha (TNF-α) enhanced the secretion of anti-inflammatory cytokine interleukin-10 (IL-10) and suppressed the secretion of proinflammatory monocyte/macrophage chemotactic protein-1 (MCP-1). The angiotensin converting enzyme (ACE) inhibitors, imidaprilat and perindoprilat, enhanced the secretion of endogenous HGF, augmented the TNF-α-induced IL-10 secretion and suppressed MCP-1 secretion from AAA tissue. The ACE inhibitors also augmented the expression of HGF in the presence of bradykinin in human aortic endothelial cells in culture (HAECs). In contrast, HGF secretion was not affected by either an angiotensin II type 1 receptor (AT1) antagonist or angiotensin II in AAA tissue or in HAECs. These results suggested that angiotensin converting enzyme inhibitors may be useful in controlling chronic inflammation in AAA, partly due to their enhancement of HGF secretion.

[Long-term outcomes of thoracic endovascular aortic repair with homemade stent-grafts].

We reviewed our experience with homemade stent-grafts in the repair of thoracic aortic lesions. The objective of this study was to assess the long-term outcomes of this therapy. From 1999 to 2008, homemade stent-grafts were inserted in 94 patients with various thoracic diseases. The endoprostheses were stainless steel Z-stents covered with polyester graft and were custom designed for each patient. Placement of the stent-grafts was technically successful in 85 of the 94 patients (90%). Within 30 days after the treatment, 4 patients died, 3 had cerebral infarction, and 3 had the onset of paraplegia or paraparesis. Primary endoleaks were observed in 10 patients (11%). During the mean follow-up period of 43 +/- 29 months, 10 patients had endoleaks and 8 had stent-graft migration. The aneurysm-related mortality rate was 12%. Our early outcomes of elective and emergency thoracic endovascular aortic repair with homemade stent-grafts demonstrated their therapeutic effectiveness in high-risk patients with various thoracic diseases. Endoleaks and migration were, however, the factors most responsible for secondary intervention in the mid-term period. Careful follow-up of the treated patients is needed to avoid the major complication in the long-term period.