An Anatomic Classification Scheme for Surgical Planning of Renal Artery Aneurysms.

PURPOSE: Renal artery aneurysm (RAA) is a rare disease. This study proposed and evaluated a new classification for RAA to assist in surgical decision-making. MATERIALS AND METHODS: Single-center data of 105 patients with RAAs from the vascular department of vascular surgery were collected retrospectively. A new classification scheme was proposed. Type I aneurysms arise from the main trunk, accessory branch, or first-order branches away from any bifurcation. Type II aneurysms arise from the first bifurcation with narrow necks (defined as dome-to-neck ratio >2) or from intralobular branches. Type III aneurysms with a wide neck arise from the first bifurcation and affect 2 or more branches that cannot be sacrificed without significant infarction of the kidney. RESULTS: There was 50 (47.62%) type I, 33 (31.43%) type II, and 22 (20.95%) type III aneurysms. The classification assigned endovascular repair as first-line treatment (for type I or II), while open techniques were conducted if anatomically suitable (for type III). A kappa level of 0.752 was achieved by the classification compared with a level of 0.579 from the classic Rundback classification. Technical primary success was achieved in 100% and 96.05%, and symptoms were completely resolved in 100% and 84.85%, while hypertension was relieved in 84.21% and 72.92% of patients receiving open surgery or endovascular repair, respectively. No significant difference was observed for perioperative or long-term complications among the 3 classification types. CONCLUSION: The new classification proved to be a convenient and effective method for facilitating choice of intervention for RAAs. CLINICAL IMPACT: This study proposed and evaluated a new classification scheme for renal artery aneurysms, which proved to be a convenient and effective method for facilitating surgical decision-making. Coil embolization was the first-line treatment if suitable, while aneurysm resection and reconstruction with vein graft were conducted for some complex lesions. The safety and efficacy of both open and endovascular methods were validated.

Theoretical Feasibility of Using Arch Branched Endograft Devices for Repair of Post Type A Aortic Dissection in Patients With Prior Ascending Aortic Replacement.

PURPOSE: Ascending aortic replacement is a common emergency procedure for treating acute type A aortic dissection. Secondary open or endovascular interventions for residual arch pathologies is difficult because of adhesions, short prosthetic grafts, and distorted anatomies. Aortic arch branched stent grafts have emerged as a potential solution for these patients if they have suitable anatomical conditions. This study aimed to evaluate the theoretical anatomical and technical feasibility of 2 currently used aortic arch branch endografts in patients who had prior replacement of the ascending aorta. MATERIALS AND METHODS: All patients who had a prosthetic ascending aortic or hemiarch replacement for acute type A dissection in a single institution between January 2013 and December 2018 were included. Contrast computed tomography images on the most recent follow-up were analyzed on a 3-dimensional workstation. Morphological parameters were measured individually for the ascending aorta, aortic arch, supra-aortic branches, and access iliac arteries. The computed tomography scan of each patient was individually evaluated for anatomical suitability for the arch branched and double-branch devices according to set selection criteria. RESULTS: Computed tomography images of 56 patients (median age of 57 years, 45 males) were reviewed. Based on our evaluation, 26 patients (46.4%) were good candidates for an endovascular arch branched device. It would be feasible for 13 patients (23.2%), but prudent preoperative planning was required due to complicated anatomy. The other 17 patients (30.4%) were unsuitable because they met at least 1 exclusion criterion. Short prosthetic grafts, extreme graft angulations, and extensive dissections in the supra-aortic branches were the main reasons for exclusion. CONCLUSION: Endovascular repair using arch branched endografts is feasible in patients with prior ascending aortic arch or hemiarch replacement for acute type A aortic dissection. The most common anatomical conditions that may influence the feasibility of the arch branched endograft procedure include insufficient proximal seal length, severe angulation of the graft, and extensive aortic dissection within the supra-aortic vessels.

Drug-coated balloon for treatment of non-atherosclerotic renal artery stenosis-a multi-center study.

INTRODUCTION: Renal artery stenosis (RAS) is a significant reason for secondary hypertension. Impaired renal function and subsequent cardiopulmonary dysfunction could also occur. Patients of non-atherosclerotic RAS has a relatively young age and long life expectancy. Revascularization with percutaneous transluminal angioplasty (PTA) is a viable treatment option. However, restenosis is unavoidable which limits its use. Drug-coated balloon (DCB) has been proven to be effective in restenosis prevention in femoropopliteal arterial diseases and in patients with renal artery stenosis. And PTA for Renal artery fibromuscular dysplasia is safe and clinically successful. Therefore, we could speculate that DCB might have potential efficacy in non-atherosclerotic RAS treatment. METHODS AND ANALYSIS: This will be a randomized multi-center-controlled trial. Eighty-four eligible participants will be assigned randomly in a 1:1 ratio to the control group (plain old balloon, POB) and the experimental group (DCB). Subjects in the former group will receive balloon dilatation alone, and in the latter group will undergo the DCB angioplasty. The DCB used in this study will be a paclitaxel-coated balloon (Orchid, Acotec Scientific Holdings Limited, Beijing, China). Follow-up visits will be scheduled 1, 3, 6, 9, and 12 months after the intervention. Primary outcomes will include controlled blood pressure and primary patency in the 9-month follow-up. Secondary outcomes will include technical success rate, complication rate, and bail-out stenting rate. TRIAL REGISTRATION: ClinicalTrials.gov (number NCT05858190). Protocol version V.4 (3 May 2023).

Ant-Neointimal Formation Effects of SLC6A6 in Preventing Vascular Smooth Muscle Cell Proliferation and Migration via Wnt/ß-Catenin Signaling.

Vascular smooth muscle cells (VSMCs) play an important role in the pathogenesis of vascular remolding, such as atherosclerosis and restenosis. Solute carrier family 6 member 6 (SLC6A6) is a transmembrane transporter that maintains a variety of physiological functions and is highly expressed in VSMCs. However, its role on VSMCs during neointimal formation remains unknown. In this study, mRNA and protein levels of SLC6A6 were examined using models of VSMC phenotype switching in vivo and in vitro and human artery samples with or without atherosclerosis. SLC6A6 gain- and loss-of-function approaches were performed by adenovirus infection or small interfering RNA (siRNA) transfection, respectively. Reactive oxygen species (ROS), proliferation, migration, and phenotype-related proteins of VSMCs were measured. Vascular stenosis rate and related genes were assessed in a rat vascular balloon injury model overexpressing SLC6A6. SLC6A6 was downregulated in dedifferentiated VSMCs, atherosclerotic vascular tissues, and injured vascular tissues. SLC6A6 suppressed VSMC proliferation and migration, while increasing contractile VSMC proteins. Mechanistically, SLC6A6 overexpression reduced ROS production and inhibited the Wnt/ß-catenin pathway. Furthermore, SLC6A6 overexpression suppressed neointimal formation in vivo. Collectively, overexpression of SLC6A6 suppresses neointimal formation by inhibiting VSMC proliferation and migration via Wnt/ß-catenin signaling and maintaining the VSMC contractile phenotype.

Rationale and design for the study of recombinant human hepatocyte growth factor plasmid in the treatment of patients with chronic limb-threatening ischemia (HOPE CLTI): Randomized, placebo-controlled, double-blind, phase III clinical trials.

BACKGROUND: Although patients with CLTI have benefited from the rapid development of endovascular techniques, many patients are considered unsuitable for revascularization procedures. A previous phase II clinical trial has suggested that recombinant human hepatocyte growth factor plasmid (NL003) can salvage limbs during the treatment of patients with CLTI. However, the safety and efficacy of this drug need to be evaluated in a larger cohort. STUDY DESIGN: HOPE CLTI is a multicenter, randomized, double-blind, placebo-controlled phase III clinical study to evaluate the efficacy and safety of intramuscular injection of NL003 in CLTI patients. This study consisted of 22 trials: HOPE CLTI-1, which includes patients with rest pain (Rutherford stage 4), and HOPE CLTI-2, which includes patients with limb ulcers (Rutherford stage 5). In both trials, patients are randomized with a 2:1 ratio of intramuscular injection of NL003 to placebo. The primary endpoint of HOPE CLTI-1 is the complete pain relief rate. The primary endpoint of HOPE CLTI-2 is the complete ulcer healing rate. The safety endpoint was assessed based on adverse events after injection of NL003. Enrollment began in July 2019. The HOPE CLTI-1 trial aims to complete the randomization of at least 300 patients, while the HOPE CLTI-2 trial aims to enroll at least 240 patients. Both trials are organized such that patients will be followed for 6 months after the first intramuscular injection. CONCLUSIONS: HITOP CLTI, which is comprised of 2 multicenter, double-blind, placebo-controlled phase III clinical trials, aims to evaluate the efficacy and safety of the intramuscular administration of NL003 in patients with CLTI.

Melatonin attenuates restenosis after vascular injury in diabetic rats through activation of the Nrf2 signaling pathway.

Diabetes is a major risk factor for the development of cardiovascular disease. Diabetic patients have a higher incidence of restenosis following endovascular therapy than non-diabetic patients. Melatonin is primarily synthesized and secreted by the pineal gland and plays an important protective anti-inflammatory and antioxidant role in a variety of cardiovascular diseases. However, no studies to date have evaluated the underlying effects and molecular mechanisms of melatonin on diabetes-related restenosis. Herein, we used an in vivo model of diabetes-related restenosis and an in vitro model of high glucose-cultured vascular smooth muscle cells to investigate the anti-restenosis effect and signaling mechanisms induced by melatonin treatment. The present study provides the first evidence that melatonin attenuates restenosis following vascular injury in diabetic rats. We further investigated the underlying molecular mechanisms both in vivo and in vitro. The data suggest that the Nrf2 signaling pathway is an important molecular target for melatonin-mediated inhibition of diabetes-related restenosis after vascular injury. These findings indicate that melatonin may represent a potential candidate for the prevention or treatment of vascular diseases and restenosis following endovascular therapy, especially in diabetic patients.

A systematic review and meta-analysis on the association between C-reactive protein levels and adverse limb events after revascularization in patients with peripheral arterial disease.

OBJECTIVE: Patients with peripheral arterial disease (PAD) are predisposed to postprocedure adverse limb events (ALE). Previous single-center studies investigating the relationship between baseline C-reactive protein (CRP) levels and postprocedure ALE have reported inconsistent results. Therefore, we performed a systematic review and meta-analysis of reported data to determine the association between CRP levels and the occurrence of postprocedure ALE in patients with PAD. METHODS: Studies investigating the association between the CRP levels and postprocedure ALE (ie, target vessel revascularization, amputation, restenosis, disease progression, composite endpoint of any of these ALE) were identified in the Medline, EMBASE, and Cochrane databases. Meta-analyses of the reported hazard ratios (HRs) were conducted using an inverse variance-weighted random effects model. Subgroup analyses were performed to determine the differences in outcomes between open surgery and endovascular treatment. Pooled estimates are reported as HRs to compare higher and lower CRP levels and odds ratio or relative risk per unit increase in logeCRP (natural logarithm C-reactive protein). RESULTS: A total of eight studies involving 1460 participants were included in our meta-analysis. Patients with higher baseline CRP levels had a greater risk of ALE (HR, 1.09; 95% confidence interval, 1.00-1.18; P = .04) compared with those with lower baseline CRP levels. The pooled estimate of odds ratio and relative risk for ALE was 2.25 (95% confidence interval, 1.49-3.41; P < .01) per unit increase in logeCRP. Subgroup analyses found no significant differences in the pooled estimates in studies of open surgery vs endovascular treatment. CONCLUSIONS: Our results have demonstrated that high baseline CRP levels are predictive of ALE in patients with PAD after lower limb revascularization.

An indirect comparison by Bayesian network meta-analysis of drug-coated devices versus saphenous vein graft bypass in femoropopliteal arterial occlusive disease.

OBJECTIVE: To compare the efficacy and safety between drug-coated devices (DCDs) and bypass surgery with saphenous vein graft (BSV) in femoropopliteal arterial occlusive disease. METHODS: A Bayesian network meta-analysis and indirect comparison were performed. Randomized controlled trials of BSV, bypass surgery with prosthetic graft, bare metal stents, endoluminal bypass (covered stent), percutaneous transluminal angioplasty, and DCDs treating femoropopliteal arterial occlusive disease were collected. The primary end point was target lesion revascularization/target vessel revascularization, and secondary end points were all-cause mortality, limb salvage, and early complications (PROSPERO registry number: CRD42019136530). RESULTS: Forty-two trials and 6867 patients were included. The comparison of DCDs and BSV revealed no significant difference in the 1-year target lesion revascularization/target vessel revascularization (DCDs vs BSV: odds ratio [OR], 0.60; 95% credible interval [CrI], 0.16-2.39). Total early complications from BSV were significantly higher than those from DCDs (DCDs vs BSV: OR, 0.14; 95% CrI, 0.05-0.45), and the main complications of BSV were not death related. There was also no significant difference in systemic early complications (DCDs vs BSV: OR, 0.19; 95% CrI, 0.00-7.82) and 1-year amputation rate (DCDs vs BSV: OR, 2.81; 95% CrI, 0.16-89.53). The 30-day (DCDs vs BSV: OR, 0.38; 95% CrI, 0.00-110.46), 1-year (DCDs vs BSV: OR, 0.96; 95% CrI, 0.24-3.29), 2-year (DCDs vs BSV: OR, 1.60; 95% CrI, 0.64-4.95), and 5-year all-cause mortality rates (DCDs vs BSV: OR, 2.05; 95% CrI, 0.92-4.39) showed no significant differences between DCDs and BSV, although there was a noticeable tendency toward significant results of a higher 5-year mortality rate. CONCLUSIONS: There is no significant difference between DCDs and BSV in short-term efficacy or short- and long-term mortality. Despite traditional BSV remaining the gold standard, DCDs provide a reasonable alternative therapy. In addition, the DCDs have a lower short-term morbidity associated with the procedure at the cost of the possible risk of higher long-term mortality. Clinical trials with more validity are required for a direct comparison between BSV and DCDs.

Potential Role of Melatonin as an Adjuvant for Atherosclerotic Carotid Arterial Stenosis.

Carotid artery stenosis (CAS) is an atherosclerotic disease characterized by a narrowing of the artery lumen and a high risk of ischemic stroke. Risk factors of atherosclerosis, including smoking, hypertension, hyperglycemia, hyperlipidemia, aging, and disrupted circadian rhythm, may potentiate atherosclerosis in the carotid artery and further reduce the arterial lumen. Ischemic stroke due to severe CAS and cerebral ischemic/reperfusion (I/R) injury after the revascularization of CAS also adversely affect clinical outcomes. Melatonin is a pluripotent agent with potent anti-inflammatory, anti-oxidative, and neuroprotective properties. Although there is a shortage of direct clinical evidence demonstrating the benefits of melatonin in CAS patients, previous studies have shown that melatonin may be beneficial for patients with CAS in terms of reducing endothelial damage, stabilizing arterial plaque, mitigating the harm from CAS-related ischemic stroke and cerebral I/R injury, and alleviating the adverse effects of the related risk factors. Additional pre-clinical and clinical are required to confirm this speculation.

Endovascular Aortic Repair Is a Viable Strategy for Treatment of Primary Infected Abdominal Aortic Aneurysm.

BACKGROUND: Infected abdominal aortic aneurysm (IAAA) is rare, and information is limited whether endovascular aortic repair (EVAR) can be considered a permanent treatment or is a temporary fix preceding open surgery. This retrospective study reviewed the short- and long-term outcomes of open surgery, emergent EVAR, and elective EVAR in the treatment of primary IAAA. METHODS: Between January 2008 and January 2017, 16 men and 3 women (aged 60.7 y; range 30-76 y) with IAAA were treated with emergent open repair, emergent EVAR, or elective EVAR, after adjunctive antibiotic therapy. Demographics, aneurysm anatomy, clinical presentations, laboratory tests, details of aneurysm repair, morbidity, mortality, and postoperative outcomes of these patients were reviewed. RESULTS: Positive microbial cultures were obtained in 12 patients. Six and 3 patients underwent emergent EVAR and open repair, respectively. Ten patients who completed the full antibiotic regimen received elective EVAR. The mean follow-up duration was 28.8 mo (range, 1.5-96 mo). The 30-day mortality rates of the emergent EVAR, open repair, and elective EVAR groups were 16.7% (1/6), 0%, and 0%, respectively; the 1-year survival rates were 16.7% (1/6), 100% (1/1), and 88.9% (8/9). Reduction in the blood erythrocyte sedimentation rate (ESR) during the first week of antibiotic treatment was inversely related to aneurysm rupture and correlated with patients' post-EVAR survival time. CONCLUSIONS: Elective EVAR for IAAA had acceptable short- and long-term outcomes. Patients' response to initial antibiotic treatment may help facilitate management. Less than 0.130 reduction in ESR during the first week of antibiotic treatment may indicate risk of aneurysm rupture.

Cigarette smoke exposure impairs lipid metabolism by decreasing low-density lipoprotein receptor expression in hepatocytes.

BACKGROUND: Cigarette smoke (CS) exposure impairs serum lipid profiles and the function of vascular endothelial cells, which accelerates the atherosclerosis. However, the precise mechanism and effect on the expression of low-density lipoprotein receptor (LDLR) in the liver by CS exposure is still unclear. METHODS: In this study, adult male C57BL/6 J mice were divided into three groups, with one group being exposed to CS for 6 weeks. HepG2 cells were treated with CS extract at concentrations of 1, 2.5, 5, and 10%. RESULTS: The serum levels of total cholesterol (TC), triglycerides (TGs), and low-density lipoprotein cholesterol (LDL-C) for the CS-exposure group were significantly higher than those in the control group (P < 0.05). Moreover, CS exposure decreased the LDLR expression in the hepatocytes and promoted inflammation in the blood vessel walls. Melatonin was intraperitoneally injected at 10 mg/kg/d for 6 weeks alongside CS exposure, and this significantly decreased the levels of TC, TGs, and LDL-C and decreased the expression of intercellular adhesion molecule-1 and the infiltration of cluster determinant 68-cells. In vitro, CS extract prepared by bubbling CS through phosphate-buffered saline decreased the LDLR expression in HepG2 cells in a time- and concentration-dependent manner, and this effect was prevented by pretreatment with 100 µM melatonin. CONCLUSIONS: In conclusion, CS exposure impaired lipid metabolism and decreased LDLR expression in hepatocytes, and these effects could be prevented by melatonin supplementation. These findings implied that melatonin has the potential therapeutic applicability in the prevention of lipid metabolic disorder in smokers.

Melatonin alleviates cigarette smoke-induced endothelial cell pyroptosis through inhibiting ROS/NLRP3 axis.

Endothelial dysfunction (ED) is a crucial and initial stage for the development of cardiovascular diseases. Accumulated evidence has demonstrated causative links between cigarette smoke (CS) and ED. However, the underlying mechanisms remain largely unknown. Pyroptosis is a unique form of inflammatory cell death. In this study, we found that cigarette smoke extract (CSE) increased pyroptosis in endothelial cells (ECs) as evidenced by increasing lactate dehydrogenase release and the number of propidium iodide (PI) positive cells. A specific NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inhibitor (MCC950) pretreatment dramatically reduced CSE-induced pyroptosis. Additionally, we also observed that N-Acetylcysteine (NAC, a ROS scavenger) pretreatment inhibited NLRP3 inflammasome activation as evidenced by suppressing the upregulation of NLRP3, ASC, cleaved-caspase-1, GSDMD-N, IL-1ß and IL-18 protein levels in CSE-treated ECs. Meanwhile, NAC pretreatment also remarkably inhibited CSE-induced EC pyroptosis. Melatonin is a hormone synthesized and secreted by mammalian pineal gland and plays a protective role in various cardiovascular diseases through its powerful anti-inflammatory and antioxidant properties. In this study, melatonin was observed to inhibit ROS production, NLRP3 inflammasome activation and pyroptosis in CSE-treated ECs. Moreover, oxidative stress and NLRP3 inflammasome activation in carotid arteries of smoking rats was also inhibited by melatonin. In conclusion, our study generated two novel findings, (i) CS activates ROS/NLRP3 axis and induces EC pyroptosis; (ii) melatonin attenuates CS-induced EC pyroptosis by inhibiting ROS/NLRP3 axis.

The long non-coding RNA MALAT1 activates Nrf2 signaling to protect human umbilical vein endothelial cells from hydrogen peroxide.

The potential effect of the long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) against hydrogen peroxide (H2O2)-induced oxidative injury in endothelial cells was tested. We show that forced-expression of MALAT1 using a lentiviral vector ("LV-MALAT1") significantly attenuated H2O2-induced death and apoptosis of human umbilical vein endothelial cells (HUVECs). Conversely, knocking down of MALAT1 by targeted siRNA exacerbated H2O2-induced HUVEC injury. For the mechanism study, we show that LV-MALAT1 induced Keap1 downregulation, leading to nuclear-factor-E2-related factor 2 (Nrf2) stabilization and activation. Critically, Nrf2 shRNA almost completely abolished LV-MALAT1-mediated HUVEC protection against H2O2. Significantly, H2O2-induced oxidative stress, lipid peroxidation and DNA damages in HUVECs were attenuated by LV-MALAT1, but were intensified with MALAT1 siRNA. In summary, we identified a novel signaling axis involving MALAT1, Keap1 and Nrf2, which in turn protects HUVECs from oxidative injury.

Open surgery versus endovascular approach in treatment of extracranial carotid artery aneurysms.

OBJECTIVE: The objective of this study was to investigate and to compare the early and long-term results of open surgery with endovascular intervention in the treatment of extracranial carotid artery aneurysms (ECCAs). METHODS: A retrospective review of patients diagnosed with ECCAs who underwent open surgical or endovascular treatment from 1997 to 2017 was performed. Clinical characteristics, aneurysm profile, and treatment outcomes were recorded. Early results (<30 days) were evaluated in terms of mortality, perioperative stroke or transient ischemic attack, and cranial nerve injury. Late results were analyzed in terms of both overall and stroke-free survival and freedom from reinterventions. RESULTS: A total of 48 patients with ECCAs including 34 (70.8%) true aneurysms and 14 (29.2%) pseudoaneurysms were treated. The median age was 51 years, and 19 patients (39.6%) were men; 41 patients (85.4%) had symptoms, whereas 7 (14.6%) were asymptomatic. Among 48 patients, 32 patients (66.7%) underwent open surgery; endovascular repair was performed on 16 patients (33.3%). The 30-day stroke or transient ischemic attack rate was not significantly different between the open group (6.3% [2/32]) and the endovascular group (0% [0/16]; P = .307). Cranial nerve injuries occurred in eight patients in the open group (25%) and in no patient in the endovascular group (0%; P = .029). Median length of stay was significantly longer in the open group than in the endovascular group (20 vs 14 days, respectively; P = .013). Median follow-up was 46 months (range, 0-20 years), and no aneurysm-related death occurred during this period. Overall survival rates at 5 years were 88.7% (standard error [SE], 0.08) in the open group and 91.7% (SE, 0.08) in the endovascular group (P = .319; log-rank, .992). For the same time interval, stroke-free survival rates were 85.2% (SE, 0.10) in the open group and 92.2% (SE, 0.07) in the endovascular group (P = .653; log-rank, .201). One patient (1/28 [3.6%]) in the open group and two patients (2/16 [12.5%]) in the endovascular group underwent endovascular reinterventions because of restenosis during the follow-up period. Reintervention-free survival rates were 90.9% in the open group (SE, 0.09) and 69.2% in the endovascular group (SE, 0.21; P = .082; log-rank, 3.016). CONCLUSIONS: In this single-institutional experience, both operative and endovascular interventions for ECCAs provided acceptable early and 5-year results. The endovascular approach had significantly less cranial nerve injury and shorter length of hospital stay.

The protective effect of melatonin on brain ischemia and reperfusion in rats and humans: In vivo assessment and a randomized controlled trial.

Carotid endarterectomy (CEA) is the treatment of choice for carotid stenosis. Some patients develop ischemia and reperfusion (I/R) injury after CEA. This study was designed to investigate the neuroprotective effects of melatonin on I/R injury in both rats and humans. To this end, 36 male rats were evaluated, and a double-blind randomized controlled trial (RCT) including 60 patients was performed. A rat model of middle cerebral artery occlusion was used to mimic cerebral I/R. After 2 hour of occlusion and 24 hour of reperfusion, blood samples and brain tissues were harvested for further assessments. Compared with the vehicle treatment, melatonin decreased the expression of nuclear factor κ light-chain-enhancer of activated B cells (NF-κB) and S100 calcium-binding protein ß (S100ß) (P < 0.05) and markedly increased the expression of nuclear erythroid 2-related factor 2 (Nrf2), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) (P < 0.05). The participants in the RCT took 6 mg/d melatonin orally from 3 days before surgery to 3 days after surgery. Blood samples were drawn at the following times: baseline; pre-anesthesia; carotid reconstruction completion; and 6, 24, and 72 hour after CEA. Compared with the oral placebo treatment, melatonin decreased the expression of NF-κB, tumor necrosis factor-α, interleukin-6 (IL-6), and S100ß (P < 0.05) and increased the expression of Nrf2, SOD, CAT, and GPx (P < 0.05) in patients after CEA. Our findings suggested that melatonin could ameliorate brain I/R injury after CEA and that this outcome was essentially due to the antioxidant and anti-inflammatory effects of melatonin.

Melatonin attenuates smoking-induced hyperglycemia via preserving insulin secretion and hepatic glycogen synthesis in rats.

Epidemiology survey indicated that cigarette smoking is a risk factor of diabetes. However, the precise mechanisms remain to be clarified. In this study, we found that smoking caused metabolic malfunctions on pancreas and liver in experimental animal model. These were indicated by hyperglycemia, increased serum hemoglobin A1c level and decreased insulin secretion, inhibition of liver glycogen synthase (LGS), and hepatic glycogen synthesis. Mechanistic studies revealed that all these alterations were caused by the inflammatory reaction and reactive oxygen species (ROS) induced by the smoking. Melatonin treatment significantly preserved the functions of both pancreas and liver by reducing ß cell apoptosis, CD68-cell infiltration, ROS production, and caspase-3 expression. The siRNA-knockdown model identified that the protective effects of melatonin were mediated by melatonin receptor-2 (MT2). This study uncovered potentially underlying mechanisms related to the association between smoking and diabetes. In addition, it is, for first time, to report that melatonin effectively protects against smoking-induced glucose metabolic alterations and the signal transduction pathway of melatonin is mainly mediated by its MT2 receptor. These observations provide solid evidence for the clinically use of melatonin to reduce smoking-related diabetes, and the therapeutic regimens are absent currently.

Intravascular Fibrolipoma of the Femoral Vein.

Lipoma of the lower leg vein is rare, and the histopathological variant, fibrolipoma, is even rarer. Here, we report an intravascular fibrolipoma located at the junction of the deep femoral vein and the femoral vein in a 50-year-old male patient. Tumor resection and venous reconstruction with a prosthetic graft were performed. Eight months later, the patient was asymptomatic and did not exhibit swelling. To our knowledge, this is the first case report of an intravascular fibrolipoma in the literature. Lower vein venography, computed tomography venography, ultrasonography, and histologic images are presented, along with a description of the procedures employed for tumor resection and venous reconstruction.

High glucose induces the expression of osteopontin in blood vessels in vitro and in vivo.

Osteopontin (OPN) is involved in mineral metabolism and the inflammatory response while diabetes mellitus is associated with severe and extensive vascular calcification. Therefore, we speculated that OPN could be a key factor in the calcification and dysfunction of blood vessels exposed to high glucose. To identify the relationship between high glucose and OPN, we used high glucose medium to stimulate smooth muscle cells (SMCs) and vascular endothelial cells (VECs) in vitro and diabetic rats for in vivo analyses. As assessed by flow cytometry and western blots, SMC and VEC apoptosis levels increased with high glucose. Potassium and calcium uptake by cells were also increased with high glucose. These findings demonstrated the relationship between mineral metabolism and high glucose. Western blot and quantitative real time polymerase chain reaction analyses demonstrated that OPN increased in vitro with high glucose stimulation. The inflammatory factor ICAM1 and the inhibitory phosphorylation of endothelial nitric-oxide synthase (eNOS) (Thr495) were also upregulated by high glucose. In contrast, the anti-inflammatory factor Nrf2 and the activating phosphorylation of eNOS (Ser1177) were downregulated. Similar to the change of OPN, phosphorylated P38 was increased with high glucose. SB203580, an inhibitor of P38 phosphorylation, downregulated the expression of OPN and related inflammatory factors. Additionally, OPN was increased in the aortas and plasma of diabetic rats. In conclusion, our findings demonstrate that high glucose can induce the expression of OPN, which may be a key factor in the calcification and dysfunction of the vascular wall in diabetes.

Perivascular adipose tissue alleviates inflammatory factors and stenosis in diabetic blood vessels.

Adipose tissue can modulate disease processes in a depot-specific manner. However, the functional properties of perivascular adipocytes, and their influence on the pathophysiology of blood vessel walls, remain to be determined. In this study, we aimed to investigate whether perivascular adipose tissue could have an ameliorative effect on blood vessels damaged in diabetes. Using in vitro coculture, and in vivo transplantation model simulating diabetic angioplasty-induced injury, we showed that perivascular adipose tissue has an important function in protecting blood vessels from high glucose impairment. Levels of inflammatory cytokines, including intercellular cell adhesion molecule-1 and osteopontin, were markedly reduced, whereas that of endothelial nitric-oxide synthase was markedly elevated in vascular walls. These depot-specific differences in blood vessels exposed to high levels of glucose were demonstrable both in vivo, with transplanted adipose tissues, and in vitro, when vascular endothelial cells were cocultured with adipocytes. In addition, intimal hyperplasia was also decreased by transplanted perivascular adipose tissue after balloon injury combined with hyperglycemia. We conclude that perivascular adipocytes can reduce inflammation in blood vessels and promote the normal function of endothelium, which could afford a new therapeutic strategy in vascular walls damaged by diabetes.

The protective effect of melatonin on smoke-induced vascular injury in rats and humans: a randomized controlled trial.

Smoking is one of the most harmful lifestyles in the world. Very few studies have investigated the effects of melatonin in smoke-induced vascular injury. This study was designed to investigate whether melatonin could protect rats and humans from smoke-induced vascular injury. 32 male rats and a double-blind randomized controlled trial (RCT) containing 63 participants formed the subjects of this study. In rats, 10 mg/kg of melatonin was intraperitoneally injected. Blood samples and abdominal artery were harvested two weeks later. Melatonin decreased the expression of platelet endothelial cell adhesion molecule-1 (CD31), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and endothelin-1 (ET-1) compared with the smoke exposed group (P < 0.05), whereas endothelial nitric oxide synthase (eNOS), nuclear erythroid 2-related factor 2 (Nrf2), NAD(P)H quinone oxidoreductase 1 (NQO-1), catalytic glutamate cysteine ligase (GCLC) and heme oxygenase-1 (HO-1) recovered markedly (P < 0.05). In humans, 3 mg/day of melatonin was taken orally by the participants. Blood samples were drawn at baseline and after two weeks of treatment. Compared with the oral placebo group, melatonin decreased the concentration of fibrinogen (Fbg) (P = 0.04) and free fatty acids (FFA) (P = 0.04) in smokers, along with the decreased expression of ICAM-1, VCAM-1 and ET-1 (P = 0.004, P = 0.001, P < 0.0001, respectively). In contrast, Nrf2 and HO-1 expression were markedly increased (P = 0.0001, P = 0.0049, respectively) after smokers took melatonin orally. In summary, our present data suggest that melatonin could ameliorate smoke-induced vascular injury.