[Effects of Leptin and Leptin-associated Signaling Pathways on the Occurrence and Progression of Abdominal Aortic Aneurysms].

Abdominal aortic aneurysm(AAA) is a chronic dilated artery disease induced by atherosclerosis,infection,trauma and other related causes.The available studies about AAA mainly focus on the inflammatory response,senility,and microenvironmental changes,while the research on the metabolic changes such as glucose metabolism and lipid metabolism remains to be conducted.As a critical regulatory factor in endocrine,glucose,and lipid metabolisms,leptin is associated with a variety of signaling pathways such as adenosine monophosphate-activated protein kinase,Janus kinase/signal transducer and activator of transcription,and cytokine-cytokine receptor,as demonstrated by the KEGG pathway enrichment analysis.Moreover,these signaling pathways are generally involved in regulating the occurrence of AAA.In addition,leptin affects the occurrence of a variety of diseases such as obesity,diabetes,and hyperlipidemia,which contribute to the formation of AAA.Diabetes might be a protective factor for the formation of AAA,while the relationship of hyperlipidemia and obesity with the formation of AAA remains unclear.Therefore,leptin might play an essential role in the formation of AAA.Further studies about the effect of leptin on AAA may provide the potential research direction and facilitate the discovery of therapeutic targets.

[Differences of Gut Microbiota Diversity between Patients with Abdominal Aortic Aneurysm and Atherosclerosis].

Objective To investigate the differences of gut microbiota between patients with abdominal aortic aneurysm and atherosclerosis.Methods From December 2018 to June 2019,20 fresh stool samples were collected respectively from the patients with abdominal aortic aneurysm and atherosclerosis treated at the Department of Vascular Surgery,Peking Union Medical College Hospital.The 16S rDNA high-throughput sequencing was employed to compare the composition,abundance,and α and ß diversities of gut microbiota between the two disease groups,and further determine the significantly differential genera.Results The two groups had great similarities in the composition of gut microbiota.There was no statistical difference in α diversity.Although ß diversity did not have statistically significant difference,certain microbial taxa showed differences between the two groups.The LEfSe demonstrated that the abdominal aortic aneurysm group had higher relative abundance of Leuconostocaceae,Ruminococcaceae,Weissella,and Faecalibacterium while lower relative abundance of Firmicuteria,Selenomonadales,and Veillonellaceae.Conclusion The structure of gut microbiota has differences between patients with abdominal aortic aneurysm and atherosclerosis,and sample size should be enlarged to validate the results.

[Treatment of Concomitant Intra-abdominal Malignancy and Abdominal Aortic Aneurysm].

Objective To explore the outcomes in patients who receive the endovascular abdominal aortic aneurysm repair(EVAR)and have concomitant intra-abdominal malignancy.Methods Between January 2014 and December 2019,all the patients who underwent surgery for malignancy and/or EVAR were retrospectively reviewed.Results Twenty-eight abdominal aortic aneurysm(AAA)patients with concomitant intra-abdominal malignancy were included.The patients were treated by two-stage operation and the priority was given for EVAR in 21 patients.There was no perioperative death or major complications.In the follow-up,one patient developed graft thrombosis and one had type Ⅱ endoleak.There was no AAA-associated death.Conclusions It is preferred that EVAR should come first followed by operation for malignancy.Details of treatment strategy still need further investigation.

[Sleeve Shaping Technique for Two Cases of Peripheral Artery Aneurysms Involving Important Branches].

Peripheral artery aneurysms,with low incidence and complex anatomic structure,often involve important branches.This paper introduces a new surgical technique-sleeve shaping on the basis of two cases.The basic data,including characteristics,imaging,operation and follow-up data of the cases,were collected.The data were then combined with the previous literature for explaining in detail that this technique can be used as a supplementary method of reconstruction following resection or endovascular repair.

Ablation and Inhibition of the Immunoproteasome Catalytic Subunit LMP7 Attenuate Experimental Abdominal Aortic Aneurysm Formation in Mice.

Low-molecular mass protein 7 (LMP7) is a proteolytic subunit of the immunoproteasome that is involved in regulating inflammatory responses. However, the role of LMP7 in the pathogenesis of abdominal aortic aneurysm (AAA) remains unknown. In this study, ApoE knockout (KO) or LMP7/ApoE double KO (dKO) mice were infused with angiotensin II (Ang II, 1000 ng/kg per minute) for up to 28 d. We found that LMP7 expression was significantly upregulated in AAA tissues from ApoE KO mice and human patients. Moreover, Ang II infusion markedly increased the incidence and severity of AAA in ApoE KO mice, which was considerably reduced in LMP7/ApoE dKO mice. Histological alterations, including aortic wall thickening, collagen deposition, elastin fragmentation, and vascular smooth muscle cell apoptosis in AAA tissue of ApoE KO mice, were also significantly attenuated in LMP7/ApoE dKO mice. Interestingly, LMP7/ApoE dKO mice showed a marked reduction of infiltration of CD3+ T cells, especially CD4+ T cells in AAA tissues compared with ApoE KO mice. Moreover, ablation of LMP7 substantially inhibited the differentiation of CD4+ T cells into Th1 and Th17 cells by reducing the activation of multiple transcriptional factors. We also investigated the effects of an LMP7-specific inhibitor PR-957 (also known as ONX 0914) on AAA formation in ApoE KO mice. PR-957 treatment could reduce the AAA incidence and severity. In conclusion, our results provide, to our knowledge, novel evidence that ablation or pharmacological inhibition of LMP7 attenuates Ang II-induced AAA formation, and LMP7 might be a novel therapeutic target for treating AAA in humans.

Chemokine (C-X-C motif) receptor 2 blockade by SB265610 inhibited angiotensin II-induced abdominal aortic aneurysm in Apo E-/- mice.

Inflammation plays a critical role in the development of abdominal aortic aneurysm (AAA). Chemokine receptor CXCR2 mediates inflammatory cell chemotaxis in several diseases. However, the role of CXCR2 in AAA and the underlying mechanisms remain unknown. In this study, we found that the CXCR2 expressions in AAA tissues from human and angiotensin II (Ang II)-infused apolipoprotein E knockout (Apo E-/-) mice were significantly increased. The pharmacological inhibition of CXCR2 (SB265610) markedly reduced Ang II-induced AAA formation. Furthermore, SB265610 treatment significantly reduced collagen deposition, elastin degradation, the metal matrix metalloprotease expression and accumulation of macrophage cells. In conclusion, these results showed CXCR2 plays a pathogenic role in AAA formation. Inhibition of CXCR2 pathway may represent a novel therapeutic approach to treat AAA.

Orthotopic renal autotransplantation for young-onset and medical treatment-requiring complex renovascular hypertension.

OBJECTIVE: In this article, we aim to prove the safety and effectiveness of orthotopic renal autotransplantation using ex vivo repair for the treatment of complex renovascular hypertension (RVH). METHODS: We retrospectively reviewed five consecutive patients (three women, two men) with young-onset RVH from January 2009 to August 2014. Orthotopic renal autotransplantation using ex vivo repair was performed and perioperative data were collected for statistical analysis. RESULTS: The median age at diagnosis was 20 years (range, 11 to 27 years). Technique success was achieved in all the patients with no in-hospital or late deaths. During a median follow-up of 3.4 years (range, 1.5 to 6 years), the postoperative blood pressure was decreased compared with preoperative level (204 ± 8/133 ± 8 mm Hg vs 129 ± 3/78 ± 5 mm Hg; p < 0.0001). The postoperative anti-hypertensive medications number was reduced (3.4 ± 0.4 vs 0.2 ± 0.2; p < 0.0001). Early and late renal functions were both well preserved as measured by no changes in serum creatinine level ( p > 0.05). The primary patent rate was 100% (5/5) at one-year follow-up. CONCLUSION: In our small series, orthotopic renal autotransplantation using ex vivo repair was safe and effective for the resolution of complex young-onset RVH.

An association of spleen volume and aortic diameter in patients and in mice with abdominal aortic aneurysm.

BACKGROUND: To investigate the potential mechanism of splenic enlargement in Ang II/APOE model and the associations between the spleen volume and the indices of abdominal aortic aneurysm (AAA) in human. METHODS: To investigate the changes of spleen volume on AAA formation, apolipoprotein E knockout (Apo E-/-) mice were treated with Ang II (1000 ng/kg/min) up to 28 days to generate AAA. We used Magnetic Resonance Imaging (MRI), liquid measurement, H&E and immunohistochemistry to analyze the morphological or pathological changes of spleen. To investigate the changes of spleen volume in human, a retrospective case-control study involving 30 male AAA patients and 25 male controls were performed. Spleen volume was measured on computed tomography images. Univariate analysis and multivariable sequential logistic regression analyses were used to analyze the association between spleen volume and maximal diameter (Dmax). RESULTS: In Ang II/APOE model, we found splenic enlargement in mice with AAA compared with the sham group. Histopathological investigations revealed hypertrophies of splenic follicles and increased populations of CD3+ T cells. In clinic cohort study, univariate analysis revealed higher values in large AAA (Dmax > 5.5 cm,n = 15) compared with the small (Dmax < 5.5 cm,n = 15) for spleen volume (230.6 ± 64.5 cm3 vs. 170.0 ± 32.8 cm3; P = 0.0030). Regression analysis revealed a statistically significant positive linear correlation of spleen volume and Dmax of AAA (r = 0.3611;P = 0.0423). CONCLUSIONS: Mimicking the splenic pathology observed in murine AAA model, there is a strong positive correlation between spleen volume and the Dmax in male AAA patients. As Dmax is a valuable predictor of AAA rupture, the spleen enlargement may be another indicator.

Angiopoietin-related growth factor is independently associated with lower extremity peripheral arterial disease.

AIMS: The present study investigated the association of serum levels of angiopoietin-related growth factor (AGF) with lower extremity peripheral arterial disease (LEPAD). METHODS: The study group is comprised of 105 patients with lower extremity peripheral arterial disease. The control group consisted of 80 individuals without lower extremity peripheral arterial disease. Serum AGF concentrations were determined by enzyme-linked immunosorbent assay. The relationship between AGF and clinical and biochemical parameters was studied. Besides, this study analyzed AGF levels in LEPAD patients according to disease severity and evaluated the prognostic value of AGF for amputation and mortality in LEPAD patients after a follow-up period of 1.7years. RESULTS: Median serum AGF levels were significantly higher in LEPAD group (103.70±64.69ng/mL) as compared with control group (53.83±37.87ng/mL) (P<0.001). In addition, T2DM patients with LEPAD exhibited markedly higher serum AGF concentrations (118.7±60.90ng/mL) than those without LEPAD (60.23±32.62ng/mL) (P<0.0001). Moreover, LEPAD positively predicted AGF concentrations in multivariate linear regression analysis (P<0.0001). Serum AGF levels were independently associated with LEPAD in binary logistic regression analysis model. Among LEPAD patients, those with critical limb ischemia (n=43) showed higher AGF levels (124.9±73.9 vs. 88.98±53.26ng/mL, P=0.01) compared with those with intermittent claudication (n=62). Furthermore, patients with the highest AGF tertile had an increased all-cause mortality and cardiovascular mortality (P=0.033 and P=0.025, respectively). CONCLUSIONS: Our results suggested that lower extremity peripheral artery disease was positively associated with AGF serum levels. High serum AGF level was a potential risk factor for LEPAD and associates with disease severity and poor outcome in LEPAD patients.

Pre-reconstruction of cervical-to-petrous internal carotid artery: An improved technique for treatment of vascular lesions involving internal carotid artery at the lateral skull base.

BACKGROUND: Reconstruction of the internal carotid artery (ICA) is an operative challenge for lesions involving the lateral skull base because of excessive blood loss, intraoperative cranial nerve injury, and difficulties in cerebral protection. METHODS: Between January 2010 and October 2014, 9 patients with vascular lesions at the lateral skull base were treated with a "pre-reconstruction" technique, which means reconstruction of the ICA in advance of excising the lesions. RESULTS: All operations were technically successful with no mortality or strokes. The mean blood loss was 921 ± 210 mL. The mean total clamping time was 18 ± 5 minutes. Among the 5 patients without invasion of specific cranial nerves, no long-term sequelae occurred during the follow-up period ranging from 11 to 54 months. CONCLUSION: With less blood loss, slighter cranial nerve injuries, and shorter clamping time, the "pre-reconstruction" technique was safe and effective for the treatment of vascular lesions at the lateral skull base. © 2016 Wiley Periodicals, Inc. Head Neck 38: E1562-E1567, 2016.

Revascularization of a giant right renal artery aneurysm near the hilum.

This article describes a case of a giant right renal artery aneurysm near the hilum treated with surgical excision, ex vivo renal artery reconstruction, and orthotopic autotransplantation with successful outcome. The giant right renal artery aneurysm is rare, and the successful outcome in our case report proved the safety and effectiveness of the ex vivo reconstruction in treatment of complex renal artery lesions. A 57-year-old male smoker with a history of recurrent abdominal pain was diagnosed with a 5.1-cm right renal artery aneurysm near the hilum. We chose surgical excision, ex vivo reconstruction, and orthotopic renal autotransplantation to treat this patient according to the preoperative computed tomography angiography and glomerular filtration rate. The operation was successful and the patient recovered uneventfully.

Combining detection of Notch1 and tumor necrosis factor-α converting enzyme is a reliable biomarker for the diagnosis of abdominal aortic aneurysms.

AIMS: Although many markers were associated with abdominal aortic aneurysm (AAA), there is no clear consensus on which marker is of the most value. Studies have implicated the role of Notch signaling in the pathogenesis of AAA. We investigate the value of plasma Jagged1, Notch receptors and tumor necrosis factor-α converting enzyme (TACE) in identifying AAA. MAIN METHODS: 42 patients with AAA and 36 controls were enrolled in our study. The concentrations of plasma Jagged1, Notch receptors and TACE were measured by enzyme-linked immunosorbent assay (ELISA). The diagnostic value of plasma Notch1 and TACE was assessed by logistic regression and receiver operator characteristic (ROC) curve. Double immunofluorescence staining was used to investigate the distribution of Notch1 and TACE in AAA tissue specimens. KEY FINDINGS: The concentrations of plasma Notch1 and TACE were significantly higher in AAA than in the controls, respectively (Notch1: P < 0.001; TACE: P = 0.0001). The area under the curve (AUC) from ROC curve of plasma Notch1 and TACE in determining the presence of AAA was 0.878 and 0.804, respectively. Combining detection of plasma Notch1 and TACE could improve the accuracy in detecting AAA (AUC 0.984, P < 0.0001). The predicted probability cutoff of 0.70 gave a sensitivity of 90.5% and a specificity of 100% for combining detection of plasma Notch1 and TACE in predicting AAA. SIGNIFICANCE: This is the first report revealing that plasma Notch1 and TACE are highly expressed in AAA. Combining detection of plasma Notch1 and TACE may be reliable for identifying the presence of AAA.

Aortic bypass and orthotopic right renal autotransplantation for midaortic syndrome: a case report.

BACKGROUND: Midaortic syndrome (MAS) is a rare vascular anomaly characterized by segmental narrowing of the distal descending thoracic or abdominal aorta. Renal or visceral arteries may also be affected to varying degrees. MAS is often associated with renovascular hypertension, and requires early intervention. When medical therapy and percutaneous interventions fail to control hypertension, surgical treatment is required. We report a case of MAS that failed to respond to bilateral renal artery stenting, but treated with aortic bypass and orthotopic right renal autotransplantation with good outcome. CASE PRESENTATION: A 31-year-old woman presented with headache and poorly controlled hypertension due to severe MAS. She had severe ostial stenoses of renal and visceral arteries. Her hypertension failed to respond to medical therapy (four drugs) and bilateral renal artery stenting. The implanted stent in the right renal artery rendered revascularization of the artery difficult. A one-stage revascularization was performed, which consisted of an aortoaortic bypass (between the suprarenal and infrarenal abdominal aorta) with a prosthetic graft, an orthotopic right renal autotransplantation and an aorto-left renal arterial bypass with autogenous saphenous vein grafts. Her recovery was uneventful. At 1-year follow-up, the patient remained well. Her hypertension improved. A postoperative computed tomography angiography showed that all the grafts were patent with no abnormalities at the anastomosis. CONCLUSION: Multiple bypass surgery with reimplantation of autogenous vein graft onto the prosthetic graft is a feasible and effective procedure in renal artery revascularization for MAS. Orthotopic autotransplantation is the procedure of choice in complex renal artery reconstruction.

Notch γ-secretase inhibitor dibenzazepine attenuates angiotensin II-induced abdominal aortic aneurysm in ApoE knockout mice by multiple mechanisms.

Abdominal aortic aneurysm (AAA) is a life-threatening aortic disease in the elderly. Activation of Notch1 pathway plays a critical role in the development of AAA, but the underlying mechanisms remain poorly understood. In the present study, we explored the mechanisms by which Notch1 activation regulates angiotensin II (Ang II)-induced AAA formation and evaluated the therapeutic potential of a new Notch γ-secretase inhibitor, dibenzazepine (DBZ), for the treatment of AAA. Apolipoprotein E knockout (Apo E(-/-)) mice infused for 4 weeks with Ang II (1000 ng/kg/min, IP) using osmotic mini-pumps were received an intraperitoneal injection of either vehicle or 1 mg/kg/d DBZ. Notch1 signaling was activated in AAA tissue from both Ang II-infused Apo E(-/-) mice and human undergoing AAA repair in vivo, with increased expression of Notch intracellular domain (NICD) and its target gene Hes1, and this effect was effectively blocked by DBZ. Moreover, infusion of Ang II markedly increased the incidence and severity of AAA in Apo E(-/-) mice. In contrast, inhibition of Notch activation by DBZ prevented AAA formation in vivo. Furthermore, DBZ markedly prevented Ang II-stimulated accumulation of macrophages and CD4(+) T cells, and ERK-mediated angiogenesis, simultaneously reversed Th2 response, in vivo. In conclusion, these findings provide new insight into the multiple mechanisms of Notch signaling involved in AAA formation and suggest that γ-secretase inhibitor DBZ might be a novel therapeutic drug for treating AAAS.