Interleukin-38 suppresses abdominal aortic aneurysm formation in mice by regulating macrophages in an IL1RL2-p38 pathway-dependent manner.

Macrophages play crucial roles in abdominal aortic aneurysm (AAA) formation through the inflammatory response and extracellular matrix degradation; therefore, regulating macrophages may suppress AAA formation. Interleukin-38 (IL-38) is a member of the IL-1 family, which binds to IL-36 receptor (IL1RL2) and has an anti-inflammation effect. Because macrophages express IL1RL2, we hypothesized that IL-38 suppresses AAA formation by controlling macrophages. We assessed a C57BL6/J mouse angiotensin II-induced AAA model with or without IL-38 treatment. RAW 264.7 cells were cultured with tumor necrosis factor-α and treated with or without IL-38. Because p38 has important roles in inflammation, we assessed p38 phosphorylation in vitro and in vivo. To clarify whether the IL-38 effect depends on the p38 pathway, we used SB203580 to inhibit p38 phosphorylation. IL1RL2+ macrophage accumulation along with matrix metalloproteinase (MMP)-2 and -9 expression was observed in mouse AAA. IL-38 reduced the incidence of AAA formation along with reduced M1 macrophage accumulation and MMP-2 and -9 expression in the AAA wall. Macrophage activities including inducible nitric oxide, MMP-2, and MMP-9 production and spindle-shaped changes were significantly suppressed by IL-38. Furthermore, we revealed that inhibition of p38 phosphorylation diminished the effects of IL-38 on regulating macrophages to reduce AAA incidence, indicating the protective effects of IL-38 depend on the p38 pathway. IL-38 plays protective roles against AAA formation through regulation of macrophage accumulation in the aortic wall and modulating the inflammatory phenotype. Using IL-38 may be a novel therapy for AAA patients.

Thigh sarcopenia and hypoalbuminemia predict impaired overall survival after infrainguinal revascularization in patients with critical limb ischemia.

OBJECTIVE: This study was performed to determine whether thigh sarcopenia can serve as a clinically relevant predictor of postoperative complications and overall survival after revascularization in patients with critical limb ischemia. METHODS: Patients who underwent preoperative computed tomography followed by infrainguinal revascularization from 2006 to 2015 were retrospectively analyzed. An axial computed tomography image was obtained at the midpoint of a line extending from the superior border of the patella to the greater trochanter of the femur. The thigh muscle area and bone area were measured. Thigh sarcopenia was defined as thigh muscle area/thigh bone area of <9. RESULTS: We included 117 patients with critical limb ischemia who underwent infrainguinal revascularization. The overall survival rates at two years were 86.5% and 55.1% in the thigh sarcopenia (-) and (+) groups, respectively (p < 0.01). The multivariate analysis showed that thigh sarcopenia (hazard ratio, 2.64; 95% confidence interval, 1.11-6.70; p = 0.03), cerebrovascular disease (hazard ratio, 3.18; 95% confidence interval, 1.31-7.36; p = 0.01), and serum albumin level (1 g/dL per increments) (hazard ratio, 0.41; 95% confidence interval, 0.21-0.81; p = 0.01) were the risk factors for overall survival two years after revascularization. CONCLUSION: Thigh sarcopenia is a risk factor for two-year overall survival in patients with critical limb ischemia after infrainguinal revascularization.

The Controlling Nutritional Status Score is Significantly Associated with Complete Ulcer Healing in Patients with Critical Limb Ischemia.

BACKGROUND: It has been reported that the Controlling Nutritional Status (CONUT) score, calculated using the serum albumin concentration, total peripheral lymphocyte count, and total cholesterol concentration, is a valuable nutritional status index. In the present study, we assessed whether the CONUT score was a significant predictor of complete ulcer healing in patients with critical limb ischemia (CLI). METHODS: In this retrospective, single center, cohort study, conducted from January 2013 to June 2018, we treated 112 limbs of 89 patients with Fontaine 4 CLI at the Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Japan. The primary endpoint of the study was complete ulcer healing after revascularization, and the secondary endpoint was amputation-free survival (AFS). RESULTS: The mean follow-up time was 17.8 months. Complete ulcer healing was achieved during the follow-up period in 91 (81.2%) limbs. The median ulcer healing time was 104 days (range, 16-574 days). In multivariate analysis, improvement of lower skin perfusion pressure ratio of <1, end-stage renal disease, and high CONUT score (>4) were predictive of incomplete ulcer healing in patients with Fontaine 4 CLI. In addition, the AFS rate was significantly better in patients with a CONUT score ≤4 than in those with a CONUT score >4. CONCLUSIONS: The CONUT score was associated with postprocedure ulcer healing and long-term limb retention in patients who underwent revascularization. The management of CLI involving ischemic foot ulcers may require ongoing consideration of nutritional status.

Frailty in patients with abdominal aortic aneurysm predicts prognosis after elective endovascular aneurysm repair.

OBJECTIVE: The diagnostic criteria for frailty in patients with abdominal aortic aneurysm (AAA) are undefined. Our purpose was to examine the influence of new diagnostic criteria for frailty on overall survival after endovascular aneurysm repair (EVAR). METHODS: We retrospectively analyzed data for patients undergoing EVAR between 2007 and 2015. Isolated common iliac artery aneurysm and ruptured AAA were excluded. Patients were defined as having frailty when they had at least two of low Geriatric Nutritional Risk Index, sarcopenia, or nonambulatory status. We examined whether frailty affected overall survival, postoperative complications, and reintervention. RESULTS: Over the study period, 349 patients underwent EVAR. Thirty-three patients were excluded. The 5-year overall survival after EVAR was 76.7% for the frailty-negative group vs 43.1% for the frailty-positive group (P < .01). Age, frailty-positive status, and current cancer therapy were risk factors for overall survival. Positive frailty was the only risk factor for postoperative complications. Forty-two patients underwent reintervention. Outside instructions for use was a risk factor for reintervention after EVAR. CONCLUSIONS: Assessing frailty in patients with AAA is useful for determining risk factors for 5-year overall survival and postoperative complications.

Successful Bridge Therapy with Initial Endovascular Repair for Arterioenteric Fistula Resulting from Pseudoaneurysm Rupture with Massive Gastrointestinal Hemorrhage after Pancreas Transplantation.

Pseudoaneurysm after pancreas transplantation has a reported incidence of 1.4 to 8.0% and may be caused by perioperative infection. Subsequent pseudoaneurysm rupture is a rare cause of arterioenteric fistula. Only 28 cases of arterioenteric fistula after pancreas transplantation have been reported in the past 20 years. We experienced a rare case of arterioenteric fistula resulting from pseudoaneurysm rupture after pancreas transplantation. We successfully treated the arterioenteric fistula with multistaged bridge therapy composed of initial endovascular aneurysm repair, secondary isolation of the fistula, and definitive open repair with extraanatomic bypass. No complications occurred in 1 year of follow-up; this staged therapy seems feasible for patients with arterioenteric fistula.

Budding Uninhibited by Benzimidazole-1 Insufficiency Prevents Acute Renal Failure in Severe Sepsis by Maintaining Anticoagulant Functions of Vascular Endothelial Cells.

Severe sepsis is critical to health and can result in acute renal failure (ARF). Tissue factor (TF) and thrombomodulin (TM) play key roles in vascular endothelial functions by helping maintain microcirculation in the kidney. Budding uninhibited by benzimidazole-1 (Bub1) plays a role in Akt and JNK signaling, which control TF and TM, respectively. We hypothesized that Bub1 could control vascular endothelial function in sepsis. The aim of this study was to determine the role of Bub1 in septic ARF. We used Mouse cecum ligation and puncture (CLP) using low Bub1 expressing (Bub1) and wild-type (Bub1) mice in vivo and lipopolysaccharide (LPS) stimulation of human aortic endothelial cell (HAEC) in vitro. Bub1 mice had a higher survival rate after CLP than Bub1. Bub1 mice had more severe ARF after CLP than Bub1 with blood biochemical and pathological analyses. TF expression in Bub1 mice and control HAEC (control) significantly increased in the septic model compared with Bub1 and Bub1 silenced HAEC (siBub1). TM expression in the control significantly decreased after LPS stimulation compared with siBub1. Akt and JNK phosphorylation of siBub1 were attenuated after LPS stimulation. Associations of Bub1 with Akt or JNK after LPS stimulation of HAEC were detected using immunoprecipitation, suggesting that Bub1 is involved in the phosphorylation of Akt and JNK after LPS stimulation. Bub1 insufficiency attenuates TF expression and reduces TM suppression by blocking Akt and JNK phosphorylation, respectively, thus leading to the prevention of ARF and death caused by sepsis.

Functional prognosis of critical limb ischemia and efficacy of restoration of direct flow below the ankle.

OBJECTIVE: Patients with critical limb ischemia have serious systemic comorbidities and are at high risk of impairment of limb function. In this study, we assessed the prognostic factors of limbs after revascularization. METHODS: In this retrospective single-center cohort study, from April 2008 to December 2012, we treated 154 limbs of 121 patients with critical limb ischemia by the endovascular therapy-first approach based on the patients' characteristics. The primary end point was amputation-free survival. Secondary end points were patency of a revascularized artery, major adverse limb events, or death. Furthermore, we investigated the ambulatory status one year after revascularization as prognosis of limb function. RESULTS: Endovascular therapy was performed in 85 limbs in 65 patients as the initial therapy (endovascular therapy group) and surgical reconstructive procedures (bypass group) were performed in 69 limbs in 56 patients. Early mortality within 30 days was not observed in either group. The primary patency rate was significantly better in the bypass group than in the endovascular therapy group ( p < 0.0001). Furthermore, the secondary patency rate was similar between the two groups ( p = 0.0096). There were no significant differences in amputation-free survival and major adverse limb event between the two groups. Univariate analysis showed that ulcer healing ( p < 0.0001), no hypoalbuminemia ( p = 0.0019), restoration of direct flow below the ankle ( p = 0.0219), no previous cerebrovascular disease ( p = 0.0389), and Rutherford 4 ( p = 0.0469) were predictive factors for preservation of ambulatory status one year after revascularization. In multivariate analysis, ulcer healing ( p < 0.0001) and restoration of direct flow below the ankle ( p = 0.0060) were significant predictors. CONCLUSIONS: Ulcer healing and restoration of direct flow below the ankle are independently associated with prognosis of limb functions in patients who undergo infrainguinal arterial reconstruction.

Cystic Arterial Disease Located Only in the Media of the Popliteal Artery: A Case Report.

Adventitial cystic disease of the popliteal artery is a rare non-atheromatous peripheral artery disease. In most cases, the cystic lesion is located in the adventitia of the popliteal artery. Herein, we present a rare case of cystic arterial disease in which the cyst was located only in the media of the popliteal artery. We successfully treated the cyst with resection of the affected popliteal artery and reconstruction with an autogenous vein graft.

BUBR1 Insufficiency Is Correlated with eNOS Reduction Experimentally In Vitro and In Vivo, and in Gastric Cancer Tissue.

BACKGROUND/AIM: Budding uninhibited by benzimidazole-related 1 (BUBR1) and endothelial nitric oxide synthase (eNOS) are related to aging and angiogenesis. This study examined the effect of low BUBR1 expression on eNOS expression in vivo, in vitro, and human gastric cancer tissues. MATERIALS AND METHODS: Human umbilical vein endothelial cells (HUVECs) were passaged to investigate the effect of aging on BUBR1 and eNOS expression; expression of eNOS and phospho-eNOS protein was assessed in BUBR1 siRNA-transfected HUVECs. Additionally, guanosine 3',5' cyclic monophosphate (cGMP) and eNOS protein levels were measured in BUBR1-insufficient mice (Bubr1L/-). BUBR1 and eNOS expression levels were also evaluated in human gastric cancer tissues. RESULTS: BUBR1 and eNOS, but not p-eNOS, levels were reduced significantly in aged and BUBR1 siRNA-transfected HUVECs. Additionally, cGMP production and the eNOS protein level were reduced in Bubr1L/- mice. Human gastric cancer tissues with low BUBR1 expression showed no eNOS expression. CONCLUSION: A decrease in BUBR1 reduced eNOS bioavailability through a pathway other than eNOS phosphorylation.

High intramuscular adipose tissue content as a precondition of sarcopenia in patients with aortic aneurysm.

PURPOSE: Sarcopenia is a major problem of the elderly. Although little is known about the cause of sarcopenia, the intramuscular adipose tissue content (IMAC) is known to be a cause of sarcopenia. The aim of this study was to investigate the significance of IMAC as a cause of sarcopenia. METHODS: We evaluated patients who underwent aneurysm repair and were monitored preoperatively and 3 years postoperatively by computed tomography (CT). The skeletal muscle area and IMAC were measured on preoperative L3 CT images. The clinical characteristics and risk factors for skeletal muscle wasting were assessed. RESULTS: Among the 155 patients, 38 (24.5%) had > 10% skeletal muscle wasting 3 years after the operation. Patients with > 10% skeletal muscle wasting had higher IMACs of the iliopsoas (- 0.31 ± 0.01 vs. -0.45 ± 0.01, P < 0.001) muscles and higher rates of cerebrovascular infarctions (7.7 vs. 23.7%, P = 0.0068), lung cancer (0 vs. 10.5%, P < 0.001), and urgent operations (0.9 vs. 10.5%, P = 0.029) and a longer postoperative fasting period (1.3 ± 0.1 vs. 3.1 ± 0.9 days, P < 0.001) than those without > 10% skeletal muscle wasting. The IMAC of the iliopsoas muscle correlated strongly with skeletal muscle wasting (P < 0.05, r = 0.70). CONCLUSIONS: A high IMAC of the iliopsoas muscle may cause sarcopenia and thus be a clinical target in disease prevention.

Prognostic factors of ulcer healing and amputation-free survival in patients with critical limb ischemia.

OBJECTIVE: A multidisciplinary approach is required to treat critical limb ischemia. We determined the poor prognostic factors of ischemic ulcer healing after optimal arterial revascularization, and assessed the efficacy of the medication therapy using cilostazol, which is a selective inhibitor of phosphodiesterase 3. METHODS: In this retrospective, single-center, cohort study, 129 limbs that underwent infrainguinal arterial revascularization for Rutherford class 5 critical limb ischemia were reviewed. The primary end point was the ulcer healing time after arterial revascularization. The secondary end point was the amputation-free survival rate. RESULTS: Of the 129 limbs, endovascular therapy was performed in 69 limbs, and surgical reconstructive procedures were performed in 60 limbs for initial therapy. Complete ulcer healing was achieved in 95 limbs (74%). The median ulcer healing time was 90 days. In multivariate analysis, no cilostazol use significantly inhibited ulcer healing ( p = 0.0114). A white blood cell count >10,000 ( p = 0.0185), a major defect after debridement ( p = 0.0215), and endovascular therapy ( p = 0.0308) were significant poor prognostic factors for ulcer healing. Additionally, ischemic heart disease ( p < 0.0001), albumin levels <3 g/dl ( p = 0.0016), no cilostazol use ( p = 0.0078), and a major defect after debridement ( p = 0.0208) were significant poor prognostic factors for amputation-free survival rate. CONCLUSIONS: Ulcer healing within 90 days after arterial revascularization is impaired by no cilostazol use, a white blood cell count >10,000, a major defect after debridement, and endovascular therapy. Furthermore, cilostazol improves amputation-free survival rate in patients with critical limb ischemia.

BubR1 insufficiency impairs angiogenesis in aging and in experimental critical limb ischemic mice.

OBJECTIVES: Budding uninhibited by benzimidazole-related 1 (BubR1), a cell cycle-related protein, is an essential component of the spindle checkpoint that regulates cell division. Mice in which BubR1 expression is reduced to 10% of the normal level display the phenotypic features of progeria. However, the role of BubR1 in vascular diseases and angiogenesis remains unknown. To investigate the influence of BubR1 on angiogenesis, we generated a low-null-BubR1-expressing (BubR1L/-) mouse strain with reduced BubR1 expression as low as 15% of the normal level without any abnormalities in appearance. METHODS: To elucidate the role of BubR1 in angiogenesis, we used a hind limb ischemia model induced in BubR1L/- mice and age-matched wild-type (WT) littermates. To evaluate the pathologic influence of BubR1 on angiogenesis, we measured the blood flow before and after hind limb ischemia surgery, and the expression of typical angiogenic factors in vivo and in vitro. RESULTS: In WT mice, blood flow in the ischemic left limb gradually recovered to approximately 80%, 14 days after surgery. Conversely, in the BubR1L/- group, blood flow in the left ischemic limb recovered to at most 30% (14 days after surgery, P < .01; immediately after the operation, and 5 and 9 days after surgery, P < .05). In adductor and calf muscles from BubR1L/- mice, regenerated muscle bundles, granulation tissue, and inflammatory cell invasion were more evident than in calf muscles from WT mice at 14 days after surgery. All WT mice at 14 days after surgery had complete limb salvage, but loss of limbs was observed in approximately 70% of BubR1L/- mice (P < .05). The vascular endothelial growth factor protein increase in ischemic hind limb muscles was lower in BubR1L/- mice compared with WT mice (P < .05), and vascular endothelial growth factor levels in human aortic smooth muscle cells treated with BubR1 knockdown siRNA were lower compared with scramble siRNA under hypoxic conditions (P < .01). HIF1α protein levels in the muscles after hind limb ischemia surgery were also significantly lower in BubR1L/- mice compared with WT mice (P < .05). CONCLUSIONS: BubR1 insufficiency impairs angiogenesis and results in limb loss in ischemic hind limbs. BubR1 may be a crucial angiogenic factor and might be beneficial for the treatment of limb ischemia.

Successful surgical intervention for rectal perforation due to polyarteritis nodosa: report of a case.

BACKGROUND: Polyarteritis nodosa (PAN) is a primary systemic necrotizing vasculitis with diffuse organ involvements, resulting in a high mortality rate due to multiple organ failure. Although the small bowel is the frequently targeted organ of PAN-associated vasculitis, rectal involvement is very rare, and only one case of rectal bleeding has been previously reported. The mortality rate of PAN with gastrointestinal (GI) perforation is reportedly much higher than that of without severe GI involvement. We herein report the first case of rectal perforation due to PAN, successfully managed with an adequate surgical intervention. CASE PRESENTATION: A 66-year-old woman with PAN had abdominal pain and melena with guarding. Computed tomography scan showed abdominal free air and bubbles in the rectal hematoma. We diagnosed it acute peritonitis, and emergency surgery was performed. After removing rectal hematoma and necrotic tissue, a huge lack of rectal wall spreading to the pelvirectal space was observed. In order to totally remove the necrotic tissue, abdominoperineal resection was needed. Together with histopathological examinations which showed neutrophils and fibrinous necrosis, we finally diagnosed rectal perforation due to PAN. At 19-month follow-up after surgery, she was still healthy with a stable disease of PAN. CONCLUSIONS: We herein reported the first case of successfully managed rectal perforation due to PAN. Early adequate surgical resection may be important for the case with rectal perforation.

Radial forces of stents used in thoracic endovascular aortic repair and bare self-expanding nitinol stents measured ex vivo - Rapid rescue for obstruction of the innominate artery using bare self-expanding nitinol stents.

Purpose Our objective was to compare the radial forces of several stents ex vivo to identify stents suitable for rescue of the unexpected coverage of aortic arch branches in thoracic endovascular aortic repair. Methods We measured the radial forces of two types of self-expanding bare nitinol stents (E-luminexx and Epic) used singly or as double-walled pairs, and of three endoprostheses used in thoracic endovascular aortic repair (TEVAR, Gore c-TAG, Relay, and Valiant) by compressing the stent using an MTS Instron universal testing machine (model #5582). We also examined the compressive effects of the TEVAR endoprostheses and the bare nitinol stents on each other. Results The radial force was greater in the center than at the edge of each stent. In all stents tested, the radial force decreased incrementally with increasing stent diameter. The radial force at the center was two times greater when using two stents than with a single stent. In the compression test, only E-luminexx used as a pair was not compressed after compressing a Relay endoprosthesis by 12 mm. Conclusion Two E-luminexx stents are appropriate to restore the blood flow if a TEVAR endoprosthesis covers the innominate artery following innominate-carotid-left subclavian arterial bypass.

Sarcopenia is a risk factor for cardiovascular events experienced by patients with critical limb ischemia.

BACKGROUND: Prognosis is poor for patients with critical limb ischemia (CLI), and the most frequent cause of death is cardiovascular disease. Low grip strength is a risk factor for cardiovascular events, and sarcopenia may be associated as well. Thus, we hypothesized that sarcopenia is a risk factor for cardiovascular events experienced by patients with CLI. If this is true and appropriate therapy becomes available, the prognosis of patients with CLI will improve with appropriate risk management strategies to prevent cardiovascular events. Therefore, the aim of this study was to verify this hypothesis. METHODS: We studied 114 patients who underwent revascularization and computed tomography between January 2002 and December 2012 in the Department of Surgery and Sciences at Kyushu University in Japan. Sarcopenia was defined as skeletal muscle area measured by L3-level computed tomography scan <114.0 cm2 and <89.8 cm2 for men and women, respectively. Clinical characteristics, cardiovascular event-free survival, <2-year death, causes of death, and effective treatments for sarcopenia were investigated. RESULTS: We identified 53 (46.5%) patients with sarcopenia. Three-year cardiovascular event-free survival rates were 43.1% and 91.2% for patients with and without sarcopenia, respectively (P < .01). During follow-up, cardiovascular disease caused the deaths of 4 and 15 patients without and with sarcopenia (P < .01), respectively, and in particular, ischemic heart disease caused the deaths of 0 and 5 patients without or with sarcopenia (P < .05), respectively. Single antiplatelet therapy (SAPT; hazard ratio, 0.46; 95% confidence interval, 0.24-0.82; P < .01) and statin therapy (hazard ratio, 0.38; 95% confidence interval, 0.16-0.78; P < .01) were independent factors associated with improved cardiovascular event-free survival. Three-year cardiovascular event-free survival rates for patients with sarcopenia who received SAPT, dual antiplatelet therapies, and no antiplatelet therapy were 75.3%, 21.1%, and 29.5%, respectively (P < .01). CONCLUSIONS: Sarcopenia is a risk factor for worse cardiovascular event-free survival, and SAPT and statin therapy reduced this risk for patients with CLI. Furthermore, SAPT but not dual antiplatelet therapy increased cardiovascular event-free survival in patients with sarcopenia.

Improved quality of life in patients with no-option critical limb ischemia undergoing gene therapy with DVC1-0101.

Critical limb ischemia (CLI) has a poor prognosis and adversely affects patients' quality of life (QOL). Therapeutic angiogenesis may improve mobility, mortality, and QOL in CLI patients. However, the effectiveness of gene therapy on such patients' QOL is unknown. DVC1-0101, a non-transmissible recombinant Sendai virus vector expressing human fibroblast growth factor-2 gene, demonstrated safety and efficacy in a phase I/II study of CLI patients. We investigated the effects of DVC1-0101 on QOL in this cohort. QOL was assessed using the Short Form-36 health survey version 2 (SF-36) in 12 patients at pre-administration, 28 days, and 3, 6, and 12 months post-treatment. We examined differences between pre and post-administration QOL scores and correlations between QOL scores and vascular parameters. Patients demonstrated low baselines scores on every SF-36 dimension. Post-treatment scores showed significant improvements in physical functioning at 3 and 6 months (P < 0.05), role-physical at 3, 6, and 12 months (P < 0.05), bodily pain at 1, 3, 6, and 12 months (P < 0.05), vitality at 1, 6, and 12 months (P < 0.05), and physical component summary at 6 and 12 months (P < 0.05). DVC1-0101-based gene therapy may improve QOL in CLI patients over a 6-month period.

A theoretical model to predict tensile deformation behavior of balloon catheter.

In this technical note, a simple theoretical model was proposed to express the tensile deformation and fracture of balloon catheter tested by the ISO standard using piece-wise linear force-displacement relations. The model was then validated by comparing with the tensile force-displacement behaviors of two types of typical balloon catheters clinically used worldwide. It was shown that the proposed model can effectively be used to express the tensile deformation behavior and easily be handled by physicians who are not familiar with mechanics of materials.