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Introduction: Vascular surgery has been greatly evolved during the last decades and novel minimally invasive techniques have been introduced. Aim of this review is to briefly present all these advances and compare them with traditional repairs. Areas covered: The authors have extensively searched literature through the Pubmed and Embase databases. All articles published up to December 2021 referring to minimally invasive techniques used for treatment of peripheral artery disease, carotid disease, aortic aneurysms, and venous disease were evaluated. Minimally invasive techniques under investigation included endovascular and hybrid techniques, robot-assisted and laparoscopic approaches. Expert Opinion: Several minimally invasive techniques such as endovascular and hybrid approaches have been extensively used during the last two decades to treat vascular surgery patients offering them lower mortality and morbidity risks. Novel robot-assisted techniques have shown promising results in preclinical studies although further clinical evaluation is needed. © 2022 Informa UK Limited, trading as Taylor & Francis Group.

This report aims to present a rare case of a common carotid artery (CCA) pseudoaneurysm with a concomitant internal carotid artery (ICA) stenosis that were treated with a hybrid technique. This strategy included the retrograde placement of a CCA covered stent under ICA clamping followed by standardized carotid endarterectomy. The technique will be discussed and compared with other possible treatments. © The Author(s) 2021.

Despite increased public health awareness, atherosclerosis remains a leading cause of mortality worldwide. Significant variations in response to statin treatment have been noted among different populations suggesting that the efficacy of statins may be altered by both genetic and environmental factors. The existing literature suggests that certain long noncoding RNAs (lncRNAs) might be up-or downregulated among patients with atherosclerosis. LncRNA may act on multiple levels (cholesterol homeostasis, vascular inflammation, and plaque destabilization) and exert athero-protective or atherogenic effects. To date, only a few studies have investigated the interplay between statins and lncRNAs known to be implicated in atherosclerosis. The current review characterizes the role of lncRNAs in atherosclerosis and summarizes the available evidence related to the effect of statins in regulating lncRNAs. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Objective: Transcarotid/transcervical revascularisation (TCAR) is an alternative to carotid endarterectomy (CEA) and transfemoral carotid stenting (tfCAS). This review aimed to evaluate pooled data on patients undergoing TCAR. Data sources: Medline, Embase, Scopus, and Cochrane Library databases were used. Review methods: This systematic review was conducted under Systematic Reviews and Meta-Analysis guidelines. Eligible studies (published online up to September 2020) reported 30 day mortality and stroke/transient ischaemic attack (TIA) rates in patients undergoing TCAR. Data were pooled in a random effects model and weight of effect for each study was also reported. Quality of studies was evaluated according to Newcastle – Ottawa scale. Results: Eighteen studies (three low, seven medium, and eight high quality) included 4 852 patients (4 867 TCAR procedures). The pooled 30 day mortality rate was 0.7% (n = 32) (95% confidence interval [CI] 0.5 – 1.0), 30 day stroke rate 1.4% (n = 62) (95% CI 1.0 – 1.7), and 30 day stroke/TIA rate 2.0% (n = 92) (95% CI 1.4 – 2.7). Pooled technical success was 97.6% (95% CI 95.9 – 98.8). The cranial nerve injury rate was 1.2% (95% CI 0.7 – 1.9) (n = 14; data from 10 studies) while the early myocardial infarction (MI) rate was 0.4% (95% CI 0.2 – 0.6) (n = 16; data from 17 studies). The haematoma/bleeding rate was 3.4% (95% CI 1.7 – 5.8) (n = 135; data from 10 studies), with one third of these cases needing drainage or intervention. Within a follow up of 3 – 40 months the restenosis rate was 4% (95% CI 0.1 – 13.1) (data from nine studies; n = 64/530 patients) and death/stroke rate 4.5% (95% CI 1.8 – 8.4) (data from five studies; n = 184/3 742 patients). Symptomatic patients had a higher risk of early stroke/TIA than asymptomatic patients (2.5% vs. 1.2%; odds ratio 1.99; 95% CI 1.01 – 3.92); p =.046; data from eight studies). Conclusion: TCAR is associated with promising early and late outcomes, with symptomatic patients having a higher risk of early cerebrovascular events. More prospective comparative studies are needed in order to verify TCAR as an established alternative treatment technique. © 2021 European Society for Vascular Surgery

Background: The objective of the current study was to summarize and evaluate all published evidence regarding viscoelastic testing in the field of liver surgery. Methods: A systematic search of the literature was performed using Medline/PubMed, Scopus, Cochrane Library Central, Google Scholar, and clinicaltrials.gov databases. The following keywords were used:“Thromboelastography”, “Thromboelastometry”, “Viscoelastic tests OR testing”, “Sonoclot Devices”, “Point-of-care tests OR testing”, “Coagulation OR Haemostasis OR Hemostasis”, “Liver OR Hepatic Surgery”, “Cirrhosis.” Results: A total of 12 studies analyzing 348 patients who underwent viscoelastic testing of coagulation during liver surgery for benign or malignant diseases were included; 7 (58.3%) studies reported on the use of thromboelastography (TEG), and 5 (41.7%) reported on rotational thromboelastometry (ROTEM). Viscoelastic testing (TEG and ROTEM) identified normo-, hyper- and hypo-coagulable status in 77% (n = 268/348), 18.4% (n = 64/348), and 4.6% (n = 16/348) of patients, respectively. In contrast, conventional coagulation tests indicated normo-coagulability in 111 patients (34.2% out of 325) and hypo-coagulability in 214 (65.8% out of 325) patients following liver resection. No patient (0% out of 291) experienced postoperative hemorrhage, whereas 5.8% (n = 17/291) experienced postoperative thromboembolic events. Conclusions: Global viscoelastic testing may be a reasonable adjunct to conventional coagulation testing to provide a more robust assessment of the coagulation status of patients undergoing liver surgery. © 2020 International Hepato-Pancreato-Biliary Association Inc.

Background: In vascular endothelial cells, cysteine metabolism by the cystathionine γ lyase (CSE), generates hydrogen sulfide-related sulfane sulfur compounds (H2Sn), that exert their biological actions via cysteine S-sulfhydration of target proteins. This study set out to map the "S-sulfhydrome" (ie, the spectrum of proteins targeted by H2Sn) in human endothelial cells. Methods: Liquid chromatography with tandem mass spectrometry was used to identify S-sulfhydrated cysteines in endothelial cell proteins and β3 integrin intraprotein disulfide bond rearrangement. Functional studies included endothelial cell adhesion, shear stress-induced cell alignment, blood pressure measurements, and flow-induced vasodilatation in endothelial cell-specific CSE knockout mice and in a small collective of patients with endothelial dysfunction. Results: Three paired sample sets were compared: (1) native human endothelial cells isolated from plaque-free mesenteric arteries (CSE activity high) and plaque-containing carotid arteries (CSE activity low); (2) cultured human endothelial cells kept under static conditions or exposed to fluid shear stress to decrease CSE expression; and (3) cultured endothelial cells exposed to shear stress to decrease CSE expression and treated with solvent or the slow-releasing H2Sndonor, SG1002. The endothelial cell "S-sulfhydrome" consisted of 3446 individual cysteine residues in 1591 proteins. The most altered family of proteins were the integrins and focusing on β3 integrin in detail we found that S-sulfhydration affected intraprotein disulfide bond formation and was required for the maintenance of an extended-open conformation of the β leg. β3 integrin S-sulfhydration was required for endothelial cell mechanotransduction in vitro as well as flow-induced dilatation in murine mesenteric arteries. In cultured cells, the loss of S-sulfhydration impaired interactions between β3 integrin and Gα13 (guanine nucleotide-binding protein subunit α 13), resulting in the constitutive activation of RhoA (ras homolog family member A) and impaired flow-induced endothelial cell realignment. In humans with atherosclerosis, endothelial function correlated with low H2Sngeneration, impaired flow-induced dilatation, and failure to detect β3 integrin S-sulfhydration, all of which were rescued after the administration of an H2Snsupplement. Conclusions: Vascular disease is associated with marked changes in the S-sulfhydration of endothelial cell proteins involved in mediating responses to flow. Short-term H2Snsupplementation improved vascular reactivity in humans highlighting the potential of interfering with this pathway to treat vascular disease. © 2021 Lippincott Williams and Wilkins. All rights reserved.

The proper management of small abdominal aortic aneurysms (AAAs), namely those under the threshold of 5.5 cm in diameter, has been under investigation for years. Risk of rupture for this group of AAAs is higher than the general population, although it remains low enough not to require a repair. However, specific factors have been associated with increased expansion or rupture rate, and these factors could identify potential candidates for earlier intervention. This review aims to collect and present all available data on the development and progress of small AAAs. Moreover, recommendations on proper management are discussed as well. © 2019 Elsevier Inc.

Introduction: Asymptomatic carotid artery stenosis (ACAS) may cause future stroke and therefore patients with ACAS require best medical treatment. Patients at high risk for stroke may opt for additional revascularization (either surgery or stenting) but the future stroke risk should outweigh the risk for peri/post-operative stroke/death. Current risk stratification for patients with ACAS is largely based on outdated rand-omized-controlled trials that lack the integration of improved medical therapies and risk factor control. Furthermore, recent circulating and imaging biomarkers for stroke have never been included in a risk stratification model. The TAXINOMISIS Project aims to develop a new risk stratification model for cerebrovascular complications in patients with ACAS and this will be tested through a prospective observational multicentre clinical trial performed in six major European vascular surgery centres. Methods and analysis: The risk stratification model will compromise clinical, circulating, plaque and imaging biomarkers. The prospective multicentre observational study will include 300 patients with 50%-99% ACAS. The primary endpoint is the three-year incidence of cerebrovascular complications. Biomarkers will be re-trieved from plasma samples, brain MRI, carotid MRA and duplex ultrasound. The TAXINOMISIS Project will serve as a platform for the development of new computer tools that assess plaque progression based on radiology images and a lab-on-chip with genetic variants that could predict medication response in individual patients. Conclusion: Results from the TAXINOMISIS study could potentially improve future risk stratification in patients with ACAS to assist personalized evidence-based treatment decision-making. © 2020 The Authors.

Aims: Levosimendan (LEVO) a clinically-used inodilator, exerts multifaceted cardioprotective effects. Case-studies indicate protection against doxorubicin (DXR)-induced cardiotoxicity, but this effect remains obscure. We investigated the effect and mechanism of different regimens of levosimendan on sub-chronic and chronic doxorubicin cardiotoxicity. Methods and results: Based on preliminary in vivo experiments, rats serving as a sub-chronic model of doxorubicin-cardiotoxicity and were divided into: Control (N/S-0.9%), DXR (18 mg/kg-cumulative), DXR+LEVO (LEVO, 24 μg/kg-cumulative), and DXR+LEVO (acute) (LEVO, 24 μg/kg-bolus) for 14 days. Protein kinase-B (Akt), endothelial nitric oxide synthase (eNOS), and protein kinase-A and G (PKA/PKG) pathways emerged as contributors to the cardioprotection, converging onto phospholamban (PLN). To verify the contribution of PLN, phospholamban knockout (PLN-/-) mice were assigned to PLN-/-/Control (N/S-0.9%), PLN-/-/DXR (18 mg/kg), and PLN-/-/DXR+LEVO (ac) for 14 days. Furthermore, female breast cancer-bearing (BC) mice were divided into: Control (normal saline 0.9%, N/S 0.9%), DXR (18 mg/kg), LEVO, and DXR+LEVO (LEVO, 24 μg/kg-bolus) for 28 days. Echocardiography was performed in all protocols. To elucidate levosimendan's cardioprotective mechanism, primary cardiomyocytes were treated with doxorubicin or/and levosimendan and with N omega-nitro-L-arginine methyl ester (L-NAME), DT-2, and H-89 (eNOS, PKG, and PKA inhibitors, respectively); cardiomyocyte-toxicity was assessed. Single bolus administration of levosimendan abrogated DXR-induced cardiotoxicity and activated Akt/eNOS and cAMP-PKA/cGMP-PKG/PLN pathways but failed to exert cardioprotection in PLN-/- mice. Levosimendan's cardioprotection was also evident in the BC model. Finally, in vitro PKA inhibition abrogated levosimendan-mediated cardioprotection, indicating that its cardioprotection is cAMP-PKA dependent, while levosimendan preponderated over milrinone and dobutamine, by ameliorating calcium overload. Conclusion: Single dose levosimendan prevented doxorubicin cardiotoxicity through a cAMP-PKA-PLN pathway, highlighting the role of inotropy in doxorubicin cardiotoxicity. © 2019 Published on behalf of the European Society of Cardiology. All rights reserved.

Herein we report nine cases of carotid endarterectomy in which we used a cold atmospheric helium plasma device (J-Plasma; Apyx Medical Corporation, Clearwater, Fla). Although clinical reports are limited, experimental data indicate that this technology could be used for dissection and coagulation during surgery, yielding limited adjacent tissue damage. As a result, it could be extremely useful in procedures like carotid endarterectomy that necessitate careful dissection and coagulation with limited damage of adjacent neurovascular structures. © 2020 The Author(s)

Suprarenal aortic clamping during abdominal aortic aneurysm (AAA) repair results in ischemia-reperfusion injury (IRI) in local (i.e. kidney) and distant (i.e. heart) tissue. To investigate perioperative approaches that mitigate IRI-induced tissue damage, Wistar rats underwent suprarenal aortic clamping either alone or in combination with short cycles of ischemic conditioning before and/or after clamping. Serum analysis revealed significant reduction in key biochemical parameters reflecting decreased tissue damage at systemic level and improved renal function in conditioned groups compared to controls (p < 0.05), which was corroborated by histolopathological evaluation. Importantly, the levels of DNA damage, as reflected by the biomarkers 8-oxo-G, γH2AX and pATM were reduced in conditioned versus non-conditioned cases. In this setting, NADPH oxidase, a source of free radicals, decreased in the myocardium of conditioned cases. Of note, administration of 5-HD and 8-SPT blocking key protective signaling routes abrogated the salutary effect of conditioning. To further understand the non-targeted effect of IRI on the heart, it was noted that serum TGF-β1 levels decreased in conditioned groups, whereas this difference was eliminated after 5-HD and 8-SPT administration. Collectively, conditioning strategies reduced both renal and myocardial injury. Additionally, the present study highlights TGF-β1 as an attractive target for manipulation in this context. © 2020, The Author(s).

Cystathionine γ lyase (CSE) is the major source of hydrogen sulfide-derived species (H2Sn) in endothelial cells and plays an important role in protecting against atherosclerosis. Here we investigated the molecular mechanisms underlying the regulation of CSE expression in endothelial cells by fluid shear stress/flow. Fluid shear stress decreased CSE expression in human and murine endothelial cells and was negatively correlated with the transcription factor Krüppel-like factor (KLF) 2. CSE was identified as a direct target of the KLF2-regulated microRNA, miR-27b and high expression of CSE in native human plaque-derived endothelial cells, was also inversely correlated with KLF2 and miR-27b levels. One consequence of decreased CSE expression was the loss of Prx6 sulfhydration (on Cys47), which resulted in Prx6 hyperoxidation, decamerization and inhibition, as well as a concomitant increase in endothelial cell reactive oxygen species and lipid membrane peroxidation. H2Sn supplementation in vitro was able to reverse the redox state of Prx6. Statin therapy, which is known to activate KLF2, also decreased CSE expression but increased CSE activity by preventing its phosphorylation on Ser377. As a result, the sulfhydration of Prx6 was partially restored in samples from plaque containing arteries from statin-treated donors. Taken together, the regulation of CSE expression by shear stress/disturbed flow is dependent on KLF2 and miR-27b. Moreover, in murine and human arteries CSE acts to maintain endothelial redox balance at least partly by targeting Prx6 to prevent its decamerization and inhibition of its peroxidase activity. © 2019 The Authors

Background: There has been a dramatic increase in worldwide health care spending over the last several decades. Operative procedures and perioperative care in the USA represent some of the most expensive episodes per patient. In view of both the rising cost of health care in general and the rising cost of surgical care specifically, policymakers and stakeholders have sought to identify ways to increase the value—improving quality of care while controlling (or diminishing) costs. In this context, we reviewed data relative to achieving the “value proposition” in the delivery of gastrointestinal surgical care. Methods: The National Library of Medicine online repository (PubMed) was text searched for human studies including “cost,” “quality,” “outcomes,” “health care,” “surgery,” and “value.” Results from this literature framed by the Donabedian conceptual model (identifying structures, processes, and outcomes), and the resulting impact of efforts to improve quality on costs. Results: The relationship between quality and costs was nuanced. Better quality care, though associated with better outcomes, was not always reported as concomitant with low costs. Moreover, some centers reported higher costs of surgical care commensurate with higher quality. Conversely, higher costs in health care delivery were not always linked to improved outcomes. While higher quality surgical care can lead to lower costs, higher costs of care were not necessarily associated with better outcomes. Strategies to improve quality, reduce cost, or achieve both simultaneously included regionalization of complex operations to high-volume centers of excellence, overall reduction in complications, introducing evidence-based improvements in perioperative care pathways including as enhanced recovery after surgery (ERAS), and elimination of inefficient or low-value care. Conclusions: The relationship between quality and cost following gastrointestinal surgical procedure is complex. Data from the current study should serve to highlight the various means available to improve the value proposition related to surgery, as well as encourage surgeons to become more engaged in the national conversation around the Triple Aim of better health care quality, lower costs, and improved health care outcomes. © 2020, The Society for Surgery of the Alimentary Tract.

Introduction: This study compares the incidence of vascular complications and other major outcomes between patients undergoing transcatheter aortic valve implantation, with and without a standardized preoperative vascular surgeon consultation. Methods: This retrospective study evaluated all patients scheduled for transcatheter aortic valve implantation during a five-year period at a Hellenic University Hospital. Two main periods were evaluated: Group A (early period (2014–2015), without a standardized preoperative vascular surgeon consultation) and Group B (late period (2016–2018), with a standardized preoperative vascular surgeon consultation). All vascular complications as well as other major outcomes (early death, stroke, myocardial infarction, and treatment) were recorded. Univariate and multivariate analyses were also conducted. Results: Overall, 382 transcatheter aortic valve implantation procedures were conducted (Group A: n = 115; duration = 19 months; Group B: n = 267; duration = 41 months). Overall, 58 vascular complications were recorded (21 patients in Group A and 37 patients in Group B (18.3% versus 13.9%; P = 0.279)). However, vascular complications that necessitated a vascular surgeon’s interference were more frequent during the first period (13% versus 4.9%; P = 0.009). Among patients with a vascular complication, early mortality was higher during the first period (14.3% versus 0%; P = 0.034) although stroke and myocardial infarction rates were similar. Age >80 years (OR = 1.856 [1.134–3.452]; P = 0.03) and preoperative vascular surgeon consultation (OR = 0.345 [0.132–0.756]; P = 0.015) were the only independent predictors for vascular complications. Conclusions: A standardized preoperative evaluation by a vascular surgeon may decrease the risk for vascular complications that necessitate a repair as well as early mortality among patients undergoing transcatheter aortic valve implantation procedures. © The Author(s) 2020.

Background: The aim of this study is to present the experience of a Vascular Division at a Hellenic University hospital concerning the management of iatrogenic vascular injuries (IVIs) of the abdomen or pelvis. Patients and Methods: This is a retrospective study evaluating all IVIs reported during a 10-year period in our institution. Only injuries warranting a vascular surgeon consultation were included in the study. Non-iatrogenic injuries were not included. Mortality and major complications within 30 days were evaluated. Results: Overall, 70 cases were recorded, with 41% being venous and 59% being arterial injuries. Iliac arteries (51%) were the most common location and rupture/lacerations (73%) were the most common type of injury. General surgery (61.5%) and cardiology (30%) procedures were the most frequently involved procedures. A 30-day mortality was 5.7%, with 30% of cases treated conservatively. Synthetic bypass grafting (odds ratio [OR] = 65.0; 95% confidence interval [CI], 4.022-1050.358; P =.003) and male gender (OR = 83.77; 95% CI, 4.040-1736.738; P =.004) were associated with death. Conclusions: Iatrogenic vascular injuries of the abdomen or pelvis are usually associated with general surgery and endovascular procedures. When vascular consultation is requested early, mortality could remain low. However, a selected number of stable patients with retroperitoneal or pelvic hematomas could be treated conservatively, yielding satisfying results. © The Author(s) 2019.

Background: Hydrogen sulfide (H2S), generated by cystathionine γ lyase (CSE), is an important endogenous regulator of vascular function. The aim of the present study was to investigate the control and consequences of CSE activity in endothelial cells under physiological and proatherogenic conditions. Methods: Endothelial cell CSE knockout mice were generated, and lung endothelial cells were studied in vitro (gene expression, protein sulfhydration, and monocyte adhesion). Mice were crossed onto the apolipoprotein E-deficient background, and atherogenesis (partial carotid artery ligation) was monitored over 21 days. CSE expression, H2S bioavailability, and amino acid profiling were also performed with human material. Results: The endothelial cell-specific deletion of CSE selectively increased the expression of CD62E and elevated monocyte adherence in the absence of an inflammatory stimulus. Mechanistically, CD62E mRNA was more stable in endothelial cells from CSE-deficient mice, an effect attributed to the attenuated sulfhydration and dimerization of the RNA-binding protein human antigen R. CSE expression was upregulated in mice after partial carotid artery ligation and in atheromas from human subjects. Despite the increase in CSE protein, circulating and intraplaque H2S levels were reduced, a phenomenon that could be attributed to the serine phosphorylation (on Ser377) and inhibition of the enzyme, most likely resulting from increased interleukin-1β. Consistent with the loss of H2S, human antigen R sulfhydration was attenuated in atherosclerosis and resulted in the stabilization of human antigen R-target mRNAs, for example, CD62E and cathepsin S, both of which are linked to endothelial cell activation and atherosclerosis. The deletion of CSE from endothelial cells was associated with the accelerated development of endothelial dysfunction and atherosclerosis, effects that were reversed on treatment with a polysulfide donor. Finally, in mice and humans, plasma levels of the CSE substrate l-cystathionine negatively correlated with vascular reactivity and H2S levels, indicating its potential use as a biomarker for vascular disease. Conclusions: The constitutive S-sulfhydration of human antigen R (on Cys13) by CSE-derived H2S prevents its homodimerization and activity, which attenuates the expression of target proteins such as CD62E and cathepsin S. However, as a consequence of vascular inflammation, the beneficial actions of CSE-derived H2S are lost owing to the phosphorylation and inhibition of the enzyme. © 2019 American Heart Association, Inc.

Purpose: The use of platelet-rich plasma (PRP) for the treatment of nonhealing ulcers is a relatively new technique. Although it seems to result in a satisfying level of healing and low complication rates, data regarding its effectiveness remain sparse. This study aims to evaluate the potential therapeutic effects of PRP on chronic nonhealing ulcers. Materials and Methods: This was a prospectively designed study comparing outcomes between patients treated with PRP (Group A, n=15) and patients treated conventionally (Group B, n=12) for different types of nonhealing ulcers. In Group A, PRP was produced from the patients’ own peripheral blood samples and was applied on the ulcer once every week. In Group B, patients were treated conventionally, without applying PRP. The total treatment period was 5 weeks. Results: Both groups were similar regarding age, sex, comorbidities, and time of treatment. In Group A, patients showed a nonsignificant reduction of 4.5 mm2 in ulcer area (P=0.190) and a reduction of more than 1 mm in depth (P=0.0006), while Group B showed an increase of 108±80.5 mm2 in ulcer area after 5 weeks (P=0.016). The healing rate (HR) in Group A was stable and positive throughout the treatment period, while HR in Group B was initially negative but became positive after the 3rd week. Conclusion: PRP application once a week promotes the healing of chronic ulcers. It improves the ulcer’s depth and HR, although its effect on ulcer area seems to be nonsignificant. However, larger comparative series are still needed to confirm these findings. Copyright © 2019, The Korean Society for Vascular Surgery.

Peripheral artery disease (PAD) is the third most common manifestation of atherosclerosis after coronary artery (CAD) and cerebrovascular disease (CVD). People with PAD have plaque findings in other vascular territories as well and, thus, are at increased risk of major adverse cardiovascular or cerebrovascular events (MACCE), including myocardial infarction, and stroke. In that context, the COMPASS multicenter, randomized controlled trial showed that the risk of MACCE was significantly reduced by 24% in the rivaroxaban plus aspirin arm compared with aspirin alone (4.1% vs 5.4% respectively; HR: 0.76, 95% CI: 0.66 to 0.86). Interestingly, the rivaroxaban/aspirin arm also showed a reduction in cardiovascular death (HR: 0.78; 95% CI: 0.64-0.96]) and all-cause mortality (HR: 0.82; 95% CI: 0.71-0.96) by 22% and 18%, respectively. Recently, the FDA approved the use of the dual pathway approach, rivaroxaban 2.5 mg twice daily plus aspirin 75-100mg once daily, to reduce the risk of major cardiovascular (CV) events, such as CV death, myocardial infarction and stroke, in people with CAD as well as PAD. In comparing rivaroxaban plus aspirin versus aspirin alone, a preliminary economic analysis showed that saving per patient was USD 462 for events and USD 220 for procedures with a total reduction of USD 682 per participant in the US with the combination group (rivaroxaban plus aspirin). The data from COMPASS trial suggest that low dose rivaroxaban plus aspirin may be a preferred treatment strategy in PAD patients in whom the bleeding risk is deemed to be favourable. © 2018 Bentham Science Publishers.

Antithrombotic treatment including anticoagulants and antiplatelets has evolved during the last decades, and several recommendations have been included in the latest guidelines regarding the proper management of patients undergoing vascular surgery. However, there are significant differences compared to older recommendations, and indications vary among patients with peripheral artery disease, carotid disease, and abdominal aortic aneurysm. In this mini review, we critically evaluate all these data to produce useful conclusions for everyday clinical practice. © 2018 Hellenic Society of Cardiology

The repair of an abdominal aortic aneurysm (AAA) is a high-risk surgical procedure related to hormonal and metabolic stress-related response with an ensuing activation of the inflammatory cascade. In contrast to open repair (OR), endovascular aortic aneurysm repair (EVAR) seems to decrease the postoperative stress by offering less extensive incisions, dissection, and tissue manipulation. However, these beneficial effects may be offset by the release of cytokines and arachidonic acid metabolites during intra-luminal manipulation of the thrombus using catheters in endovascular repair, resulting in systemic inflammatory response (SIR), which is clinically called post-implantation syndrome. In this systematic review we compared OR with EVAR in terms of the post-interventional inflammatory response resulting from alterations in the circulating cytokine levels. We sought to summarize all the latest evidence regarding post-implantation syndrome after EVAR. We searched Medline (PubMed), ClinicalTrials.gov and the Cochrane library for clinical studies reporting on the release of cytokines as part of the inflammatory response after both open/conventional and endovascular repair of the AAA. We identified 17 studies examining the cytokine levels after OR versus EVAR. OR seemed to be associated with a greater SIR than EVAR, as evidenced by the increased cytokine levels, particularly IL-6 and IL-8, whereas IL-1β, IL-10 and TNF-α showed conflicting results or no difference between the two groups. Polyester endografts appear to be positively correlated with the incidence of post-implantation syndrome after EVAR. Future large prospective studies are warranted to delineate the underlying mechanisms of the cytokine interaction in the post-surgical inflammatory response setting. © 2018 CPS and SIMM.

Carotid and coronary artery disease are two major atherosclerotic conditions that have shown an increased prevalence in the last three decades that is associated with high morbidity and mortality. Recent data have revealed that the development of the atherosclerotic plaque — the basic entity in both diseases — may share similar characteristics and mechanisms irrespective of the location site. Even though the biology of atherosclerotic process is similar, there are differences in plaque morphology and characteristics. Indeed, plaque erosion, calcified nodules, fibrous cap thickness and macrophage accumulation may be different in the setting of coronary and carotid artery disease. The perivascular adipose tissue surrounding the coronary arteries (but not carotids) could also affect plaque biology. In this review we focus on comparative the characteristics of both types of atherosclerotic plaques and summarize existing knowledge to provide useful conclusions about current and future treatment strategies. © 2017 Elsevier Ltd

The molecular and cellular mechanisms underlying plaque destabilization remain obscure. We sought to elucidate the correlation between NO, H2S and CO-generating enzymes, nitro-oxidative stress and plaque stability in carotid arteries. Carotid atherosclerotic plaques were collected from 62 patients who had undergone endarterectomy due to internal artery stenosis. Following histological evaluation the plaques were divided into stable and unstable ones. To investigate the impact of simvastatin we divided patients with stable plaques, into those receiving and to those not receiving simvastatin. Expression and/or levels of p-eNOS/eNOS, pAkt/t-Akt, iNOS, cystathionine beta synthase (CBS), cystathionine gamma lyase (CSE), heme oxygenase-1(HO-1), soluble guanyl cyclase sGCα1, sGCβ1, NOX-4 and HIF-1α were evaluated. Oxidative stress biomarkers malondialdehyde (MDA) and nitrotyrosine (NT) were measured. NT levels were decreased in stable plaques with a concomitant increase of eNOS phosphorylation and expression and Akt activation compared to unstable lesions. An increase in HIF-1α, NOX-4, HO-1, iNOS, CBS and CSE expression was observed only in unstable plaques. 78% of patients under simvastatin were diagnosed with stable plaques whereas 23% of those not receiving simvastatin exhibited unstable plaques. Simvastatin decreased iNOS, HO-1, HIF-1α and CSE whilst it increased eNOS phosphorylation. In conclusion, enhanced eNOS and reduced iNOS and NOX-4 were observed in stable plaques; CBS and CSE positively correlated with plaque vulnerability. Simvastatin, besides its known effect on eNOS upregulation, reduced the HIF-1α and its downstream targets. The observed changes might be useful in developing biomarkers of plaque stability or could be targets for pharmacothepary against plaque vulnerability. © 2017

Adenosine-to-inosine (A-to-I) RNA editing, which is catalyzed by a family of adenosine deaminase acting on RNA (ADAR) enzymes, is important in the epitranscriptomic regulation of RNA metabolism. However, the role of A-to-I RNA editing in vascular disease is unknown. Here we show that cathepsin S mRNA (CTSS), which encodes a cysteine protease associated with angiogenesis and atherosclerosis, is highly edited in human endothelial cells. The 3′ untranslated region (3′ UTR) of the CTSS transcript contains two inverted repeats, the AluJo and AluSx + regions, which form a long stem-loop structure that is recognized by ADAR1 as a substrate for editing. RNA editing enables the recruitment of the stabilizing RNA-binding protein human antigen R (HuR; encoded by ELAVL1) to the 3′ UTR of the CTSS transcript, thereby controlling CTSS mRNA stability and expression. In endothelial cells, ADAR1 overexpression or treatment of cells with hypoxia or with the inflammatory-γ 3 and tumor-necrosis-factor-α induces CTSS RNA editing and consequently increases cathepsin S expression. ADAR1 levels and the extent of CTSS RNA editing are associated with changes in cathepsin S levels in patients with atherosclerotic vascular diseases, including subclinical atherosclerosis, coronary artery disease, aortic aneurysms and advanced carotid atherosclerotic disease. These results reveal a previously unrecognized role of RNA editing in gene expression in human atherosclerotic vascular diseases. © 2016 Nature America, Inc. All rights reserved.

Atherosclerotic plaque formation is associated with irregular distribution of wall shear stress (WSS) that modulates endothelial function and integrity. Polycystins (PC)-1/-2 constitute a flow-sensing protein complex in endothelial cells, able to respond to WSS and induce cell-proliferation changes leading to atherosclerosis. An endothelial cell-culture system of measurable WSS was established to detect alterations in PCs expression under conditions of low-and high-oscillatory shear stress in vitro. PCs expression and p53 activation as a regulator of cell proliferation were further evaluated in vivo and in 69 advanced human carotid atherosclerotic plaques (AAPs). Increased PC-1/PC-2 expression was observed at 30-60â ‰min of low shear stress (LSS) in endothelial cells. Elevated PC-1 expression at LSS was followed by p53 potentiation. PCs immunoreactivity localizes in areas with macrophage infiltration and neovascularization. PC-1 mRNA and protein levels were significantly higher than PC-2 in stable fibroatherotic (V) and unstable/complicated (VI) AAPs. Elevated PC-1 immunostaining was detected in AAPs from patients with diabetes mellitus, dyslipidemia, hypertension and carotid stenosis, at both arteries (50%) or in one artery (90%). PCs seem to participate in plaque formation and progression. Since PC-1 upregulation coincides with p38 and p53 activation, a potential interplay of these molecules in atherosclerosis induction is posed.

Background Atherosclerotic lesions at the origin of common carotid, subclavian, and innominate arteries are causes for brain and hand ischemic symptoms. Surgical reconstructions of symptomatic cases remain the golden standard treatment, although the endovascular approach has been promising as well. In this retrospective study, long-term results of open reconstructions from 2 University Hospitals are presented. Methods Through a 30-year period, prospective data of 107 patients, suffering from symptomatic atherosclerotic supra-aortic artery disease, were retrospectively reviewed and included in this study. Demographic data, arterial risk factors, presenting symptoms and signs, diagnostic evaluation, operative treatment and complications, resolution of symptoms, redo surgery, and overall mortality were analyzed. Results Eighty-one patients were operated on for subclavian, 14 for innominate, and 12 for common carotid severe lesions, through an extra-thoracic reconstruction (91 patients) or a transthoracic one (16 patients). Perioperative mortality was null although morbidity was 16.8%, and primary perioperative patency was 97.2% (secondary patency 100%). The cumulative primary patency was 95.3%, 90.7%, and 86.0% at 5, 10, and 15 years, respectively. The mean time of patency was 214.6 months (95% confidence interval = 198.5-230.6), with no difference between transthoracic and extrathoracic reconstructions (P = 0.278). Conclusions Open reconstructions remain a therapeutic strategy with a considerably low perioperative morbidity/mortality offering excellent long-term results regarding patency of the reconstructions and clinical resolution of the symptoms. However, in the modern era of the endovascular techniques, we need more studies for establishing anatomic and clinical criteria regarding patient selection for endovascular angioplasty/stenting or open repair. © 2015 Elsevier Inc.

Oleuropein, a natural phenolic compound, prevents acute doxorubicin (DXR)-induced cardiotoxicity but there is no evidence regarding its role in chronic DXR-induced cardiomyopathy (DXR-CM). In the present study, we investigated the role of oleuropein in DXR-CM by addressing cardiac geometry and function (transthoracic echocardiography), cardiac histopathology, nitro-oxidative stress (MDA, PCs, NT), inflammatory cytokines (IL-6, Big ET-1), NO homeostasis (iNOS and eNOS expressions), kinases involved in apoptosis and metabolism (Akt, AMPK) and myocardial metabonomics. Rats were randomly divided into 6 groups: Control, OLEU-1 and OLEU-2 [oleuropein at 1000 and 2000. mg/kg in total, respectively, intraperitoneally (i.p.) for 14. days], DXR (18. mg/kg, i.p. divided into 6 equal doses for 2. weeks), DXR-OLEU-1 and DXR-OLEU-2 (both oleuropein and DXR as previously described). Impaired left ventricular contractility and inflammatory and degenerative pathology lesions were encountered only in the DXR group. The DXR group also had higher MDA, PCs, NT, IL-6 and Big ET-1 levels, higher iNOS and lower eNOS, Akt and AMPK activation compared to controls and the oleuropein-treated groups. Metabonomics depicted significant metabolite alterations in the DXR group suggesting perturbed energy metabolism and protein biosynthesis. The effectiveness of DXR in inhibiting cell proliferation is not compromised when oleuropein is present. We documented an imbalance between iNOS and eNOS expressions and a disturbed protein biosynthesis and metabolism in DXR-CM; these newly recognized pathways in DXR cardiotoxicity may help identifying novel therapeutic targets. Activation of AMPK and suppression of iNOS by oleuropein seem to prevent the structural, functional and histopathological cardiac effects of chronic DXR toxicity. © 2014.

Interactions between TNF-like Cytokine 1A (TL1A) and its receptors, death receptor-3 (DR3) and decoy receptor-3 (DcR3) may be important in atherogenesis. We hypothesized that dysregulation of this system predicts formation of new atheromatic plaques in rheumatoid arthritis (RA). Forty-five patients were prospectively followed up for 40.5. ±. 3.6. months. Serum concentrations of TL1A and DcR3 were measured at baseline and carotid and femoral arteries examined by ultrasound at baseline and at the end of follow-up. Individual serum levels of TL1A correlated with the progression of carotid atheromatic plaque height (Spearman rho. =. 0.550, p. =. 0.003). Patients with low TL1A and undetectable DcR3 serum levels at baseline showed significantly fewer newly formed carotid plaques during the next 3.5. years than the remaining patients (P. =. 0.016). Univariate analysis showed that a "low TL1A/DcR3" immunophenotype predicted a preserved atherosclerosis profile in carotid (P. =. 0.026), or carotid and/or femoral arteries (P. =. 0.022). Dysregulated TL1A-induced signaling may be associated with risk for accelerated atherosclerosis in RA. © 2013 Elsevier Inc.

The administration of carbon tetrachloride (CCl4) has been established as a model of toxin-induced acute and chronic liver injury. In the present study, we investigate the progression of the biochemical response to acute CCl4-induced liver injury, capturing metabolic variations during both toxic insult and regeneration using NMR-based metabonomic analysis of liver tissue and plasma.A single dose of CCl4 (1mL/kg BW) was intraperitoneally administered to male Wister rats sacrificed every 12h up to 72h post treatment, while healthy animals served as controls. Acquired 1H NMR spectra of liver tissue extracts and plasma samples were explored with multivariate analysis and the resulted models were correlated with conventional biochemical and histopathological indices of toxicity for monitoring the progression of experimental injury. The metabonomic analysis resulted in discrimination between the subjects under toxic insult (up to 36. h) and those at the regenerative phase (peaked at 48. h). At 72. h normalization of liver's pathology similar to the controls group was apparent. Principal component analysis (PCA) trajectories highlighted the time points of the greater degree of toxic insult and the regenerative state.A number of metabolites such as glucose, lactate, choline, formate exhibited variations suggesting CCl4 induced impairment in essential biochemical pathways as energy metabolism, lipid biosynthesis and transmethylation reactions. The latter provides new evidence of B12 and folate pathways deficiency, indicative of new mechanistic implications possibly by direct inhibition of B12 dependent enzymes by the chlorinated radicals of CCl4 metabolism. © 2012 Elsevier Ireland Ltd.

AIM: To investigate melatonin's preventive action in oxidative stress in a rat model with high fat diet-induced non-alcoholic fatty liver disease (NAFLD). METHODS: NAFLD was induced by high fat diet (HFD) in adult, male, Wistar rats, weighing 180-230 g. After acclimatization for one week, they were randomly assigned to 6 experimental groups that comprised animals on regular diet plus 5 or 10 mg/kg melatonin, for 4 or 8 wk; animals on HFD, with or without 5 or 10 mg/kg melatonin, for 4 or 8 wk; and animals on HFD for 8 or 12 wk, with melatonin 10 mg/kg for the last 4 wk. Liver damage was assessed biochemically by the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and histologically. Lipid peroxidation and oxidative stress were assessed by malondialdehyde and glutathione levels in liver tissue. Lipidemic indices and portal vein pressure were also measured. RESULTS: Compared to rats not receiving melatonin, rats on 5 or 10 mg/kg of melatonin had lower mean liver weight (-5.0 g and -4.9 g) (P < 0.001) and lower liver weight to body weight ratio (-1.0%) (P < 0.001), for the two doses, respectively. All rats fed HFD without melatonin developed severe, grade III, steatosis. Rats on HFD with concurrent use of melatonin showed significantly less steatosis, with grade III steatosis observed in 1 of 29 (3.4%) rats on 10 mg/kg melatonin and in 3 of 27 (11.1%) rats on 5 mg/kg melatonin. Melatonin was ineffective in reversing established steatosis. Melatonin also had no effect on any of the common lipidemic serum markers, the levels of which did not differ significantly among the rats on HFD, irrespective of the use or not of melatonin. Liver cell necrosis was significantly less in rats on HFD receiving melatonin than in those not on melatonin, with the AST levels declining by a mean of 170 U/L (P = 0.01) and 224 U/L (P = 0.001), and the ALT levels declining by a mean of 62.9 U/L (P = 0.01) and 93.4 U/L (P < 0.001), for the 5 and 10 mg/kg melatonin dose, respectively. Melatonin mitigated liver damage due to peroxidation and oxidative stress in liver tissue as indicated by a significant decline in MDA production by 12.7 (P < 0.001) and 12.2 (P < 0.001) μmol/L /mg protein /mg tissue, and a significant increase in glutathione by 20.1 (P = 0.004) and 29.2 (P < 0.001) μmol/L /mg protein /mg tissue, for the 5 and 10 mg/kg melatonin dose, respectively. CONCLUSION: Melatonin can attenuate oxidative stress, lessen liver damage, and improve liver histology in rats with high fat diet-induced NAFLD, when given concurrently with the diet. © 2013 Baishideng.

Background: Toll-like receptors (TLRs) have long been considered to be major culprits in the development of atherosclerosis, contributing both to its progression and clinical complications. However, evidence for most TLRs beyond TLR2 and TLR4 is lacking. Methods and Results: We used experimental mouse models, human atheroma cultures, and well-established human biobanks to investigate the role of TLR7 in atherosclerosis. We report the unexpected finding that TLR7, a receptor recognizing self-nucleic acid complexes, is protective in atherosclerosis. In Apoe mice, functional inactivation of TLR7 resulted in accelerated lesion development, increased stenosis, and enhanced plaque vulnerability as revealed by Doppler ultrasound and/or histopathology. Mechanistically, TLR7 interfered with macrophage proinflammatory responses to TLR2 and TLR4 ligands, reduced monocyte chemoattractant protein-1 production, and prevented expansion of Ly6C inflammatory monocytes and accumulation of inflammatory M1 macrophages into developing atherosclerotic lesions. In human carotid endarterectomy specimens TLR7 levels were consistently associated with an M2 anti-inflammatory macrophage signature (interleukin [IL]-10, IL-1RA, CD163, scavenger and C-type lectin receptors) and collagen genes, whereas they were inversely related or unrelated to proinflammatory mediators (IL-12/IL-23, interferon beta, interferon gamma, CD40L) and platelet markers. Moreover, in human atheroma cultures, TLR7 activation selectively suppressed the production of key proatherogenic factors such as monocyte chemoattractant protein-1 and tumor necrosis factor without affecting IL-10. Conclusions: These findings provide evidence for a beneficial role of TLR7 in atherosclerosis by constraining inflammatory macrophage activation and cytokine production. This challenges the prevailing concept that all TLRs are pathogenic and supports the exploitation of the TLR7 pathway for therapy. [-] [-] [-] [-] [-] [-] [-] [-] [-] [-] [-] [-] [-] [-] [-] [-] [-] [-].

Background: We reviewed our experience to determine the effect of epidural versus intravenous analgesia on postoperative pulmonary function and pain control in patients with chronic obstructive pulmonary disease (COPD) undergoing open surgery for abdominal aortic aneurysm. Methods: A retrospective study with prospective collection of data of 30 COPD patients undergoing open abdominal aortic aneurysm repair, during a 5-year period. Group I (n = 16) was operated under combined general and epidural anesthesia and epidural analgesia; group II (n = 14), under general anesthesia and intravenous analgesia. All patients performed pulmonary function tests (PFTs) preoperatively and during postoperative days 1 and 4. Pain assessment was performed on all patients during rest and activity on postoperative days 1, 2, and 4 by using the visual analog scale. Data were recorded for PFTs, postoperative pain, length of hospital stay, length of ICU stay, and postoperative pulmonary morbidity, including atelectasis and pulmonary infections. Results: There was no in-hospital mortality. Hospital stay was similar between the two groups (group I: 7.1 ± 1.0, group II: 7.5 ± 1.1). Group I patients showed significantly increased postoperative PFT values compared with group II patients at all time points (postoperative day 1: FEV1(%): 32.3 ± 4.4 vs. 27.1 ± 1.6, p = 0.007, FVC(%): 35.4 ± 8,5 vs. 28.3 ± 2.3, p = 0.035; postoperative day 4: FEV1(%): 50.4 ± 6.8 vs. 41.9 ± 6.8, p = 0.017, FVC(%): 51.3 ± 8.3 vs. 43.0 ± 7.9, p = 0.046). However, postoperative clinical pulmonary morbidity was not different between groups. Group I patients showed significantly reduced postoperative pain at all time points compared with group II patients. These differences were more pronounced during postoperative days 1 and 2, both at rest (visual analog score: 1.1 ± 0.9 vs. 2.6 ± 1.6, p = 0.02 and 0.7 ± 0.8 vs. 1.9 ± 1.1, p = 0.021, respectively) and during activity (2.3 ± 0.8 vs. 4.0 ± 1.7, p = 0.013 and 1.6 ± 0.7 vs. 2.8 ± 1.2, p = 0.019, respectively). Conclusions: Epidural anesthesia and postoperative epidural analgesia improve the postoperative respiratory function, compared with general anesthesia and systemic analgesia, and reduce postoperative pain as well, in COPD patients undergoing elective infrarenal abdominal aortic aneurysm repair. © 2011 Annals of Vascular Surgery Inc.

Intercellular adhesion molecule-1 (ICAM-1), a cell adhesion molecule with a key role in inflammation and immunosurveillance, has been implicated in carcinogenesis by facilitating instability of the tumor environment. The K469E single nucleotide polymorphism (SNP) (G>A) affects the ICAM-1 mRNA splicing pattern; the alternatively spliced isoform (ICAM-1-S) lacks transmembrane and intracellular domain, which affects the structural and signal transduction properties. Moreover, the expression of ICAM-1 is transcriptionally regulated by p53, and this SNP has been shown to be related with apoptosis. PCR-RFLP analysis was used to assess the K469E SNP status comparatively in 203 non-small cell lung cancer patients and 175 healthy sex-matched controls. This SNP was examined in relation to tumor kinetic parameters (Ki-67 immunohistochemical evaluation and Tdt-mediated dUTP nick end labeling assay), p53 immunohistochemistry status, and clinicopathological data in patients with operable stages. Both the genotype and allele frequency did not differ significantly between patients and controls. However, patients with the AG/AA genotypes had worse survival (39 vs 45 months, p = 0.036) and tended to be present in advanced stages (p = 0.057). Moreover, the AG/AA genotypes exerted a synergistic effect with aberrant p53 on tumor progression, while the GG genotype retained a better apoptotic index. The AG/AA genotypes correlated with worse survival and advanced stages probably due to defective immunosurveillance and apoptosis. These genetic backgrounds may confer a selective advantage for dissemination of tumor cells with high metastatic potential compared to GG genotype. © 2012 International Society of Oncology and BioMarkers (ISOBM).

Aims The effectiveness of postconditioning (POC) in hypercholesterolaemia is in dispute. We investigated the effects of 3-day lipophilc (simvastatin) or hydrophilic (pravastatin) statin treatment, without or with POC in normocholesterolaemic (Norm) and hypercholesterolaemic (Chol) rabbits. Methods and resultsNorm or Chol rabbits were subjected to 30 min ischaemia and randomized in two series of 12 groups each: control, simvastatin (Sim), pravastatin (Prav), POC, Sim-POC, Prav-POC, Chol, Sim-Chol, Prav-Chol, POC-Chol, Sim-POC-Chol, Prav-POC-Chol. After ischaemia, rabbits of the first series underwent 3 h reperfusion, followed by infarct size, total cholesterol, and low density lipoprotein plasma level evaluation; animals of the second series underwent 10 min reperfusion followed by tissue sampling for nitrotyrosine (NT), malondialdehyde, endothelial nitric oxide synthase (eNOS), and Akt analyses. N-nitro-l-arginine methylester (L-NAME) was given in two additional groups (POC-L-NAME and Prav-Chol-L-NAME) for infarct size assessment. All interventions reduced infarction in Norm (24.3 ± 1.3, 25.9 ± 2.8, 27.9 ± 3.1, 23.3 ± 2.3, and 33.4 ± 2.5, in POC, Sim, Prav, Sim-POC, and Prav-POC groups, respectively, vs. 49.3 ± 1.9 in control, P < 0.05), but only Prav did so in Chol animals (25.7 ± 3.3 and 25.3 ± 3.9 in Prav-Chol and Prav-POC-Chol vs. 50.9 ± 1.7, 44.8 ± 4.3, 41.5 ± 3.5, and 49.3 ± 5.5 in Chol, Sim-Chol, POC-Chol, and Sim-POC-Chol, respectively, P < 0.05). L-NAME abolished the infarct size-limiting effect of POC and Prav-Chol. Prav induced the greatest reduction in NT, while it was the only intervention that increased myocardial eNOS and Akt in Chol rabbits (P < 0.05 vs. all others). Conclusion Prav, in contrast to same-dose Sim or POC, reduces infarction in Chol rabbits independently of lipid lowering, potentially through eNOS activation and nitro-oxidative stress attenuation. © 2012 The Author.

Objectives: The study aimed to evaluate a wide range of apoptotic markers in the vein wall of patients with superficial chronic venous disease (SCVD) compared with normal veins. Design: This was an observational study. Methods: Vein specimens were obtained from 19 patients suffering from SCVD. From each patient, a specimen of the proximal part of the great saphenous vein (GSV), a specimen of the distal part of the vein and a specimen of a varicose tributary were obtained. Immunohistochemical analysis was used to localise the expression of BAX, p53, Caspase 3, BCL-2, BCL-6, BCL-xs, BCL-xl and Ki-67. Vein specimens from 10 healthy GSVs were used as controls. Results: Saphenous vein specimens from patients with SCVD showed increased BAX, Caspase 3, BCL-xl and BCL-xs (p < 0.01 for all) and Ki-67 (p = 0.02) compared with healthy GSVs. In the venous disease group, GSV specimens from the distal ankle area showed increased BAX (p < 0.01) and BCL-xs (p = 0.031) compared with varicose tributaries specimens, which subsequently showed increased BAX (p = 0.044), Caspase 3 (p = 0.028) and BCL-xs (p = 0.037) compared with specimens from the proximal GSV. In addition, in the venous disease group, specimens from distal GSV showed increased BAX (p < 0.01), Caspase 3 (p = 0.019) and BCL-xs (p = 0.014) compared with the proximal GSV. Conclusion: Varicose veins exhibit increased apoptotic activity, by means of increased BAX, Caspase 3, BCL-xl and BCL-xs, compared with normal veins. Patients with varicose vein disease show increased apoptosis in the distal saphenous trunk compared with the proximal saphenous trunk, suggesting an association between chronic venous hypertension and apoptosis. (C) 2010 European Society for Vascular Surgery. Published by Elsevier, Ltd. All rights reserved.

Unstable atherosclerotic plaques of the carotid arteries are at great risk for the development of ischemic cerebrovascular events. The degradation of the extracellular matrix by matrix metalloproteinases (MMPs) and NO-induced apoptosis of vascular smooth muscle cells (VSMCs) contribute to the vulnerability of the atherosclerotic plaques. Basic fibroblast growth factor (bFGF) through its mitogenic and angiogenic properties has already been implicated in the pathogenesis of atherosclerosis. However, its role in plaque stability remains elusive. To address this issue, a panel of human carotid atherosclerotic plaques was analyzed for bFGF, FGF-receptors-1 and -2 (FGFR-1/-2), inducible nitric oxide synthase (iNOS) and MMP-9 expression. Our data revealed increased expression of bFGF and FGFR-1 in VSMCs of unstable plaques, implying the existence of an autocrine loop, which significantly correlated with high iNOS and MMP-9 levels. These results were recapitulated in vitro by treatment of VSMCs with bFGF. bFGF administration led to up-regulation of both iNOS and MMP-9 that was specifically mediated by nuclear factor-kappaB (NF-kappaB) activation. Collectively, our data demonstrate a novel NF-kappaB-mediated pathway linking bFGF with iNOS and MMP-9 expression that is associated with carotid plaque vulnerability. J Cell Mol Med

Unstable atherosclerotic plaques of the carotid arteries are at great risk for the development of ischemic cerebrovascular events. The degradation of the extracellular matrix by matrix metalloproteinases (MMPs) and nitric oxide induced apoptosis of vascular smooth muscle cells (VSMCs) contribute to the vulnerability of the atherosclerotic plaques. Basic fibroblast growth factor (bFGF) through its mitogenic and angiogenic properties has already been implicated in the pathogenesis of atherosclerosis. However, its role in plaque stability remains elusive. To address this issue, a panel of human carotid atherosclerotic plaques was analysed for bFGF, FGF-receptors-1 and -2 (FGFR-1/-2), inducible nitric oxide synthase (iNOS) and MMP-9 expression. Our data revealed increased expression of bFGF and FGFR-1 in VSMCs of unstable plaques, implying the existence of an autocrine loop, which significantly correlated with high iNOS and MMP-9 levels. These results were recapitulated in vitro by treatment of VSMCs with bFGF. bFGF administration led to up-regulation of both iNOS and MMP-9 that was specifically mediated by nuclear factor-κB (NF-κB) activation. Collectively, our data demonstrate a novel NF-κB-mediated pathway linking bFGF with iNOS and MMP-9 expression that is associated with carotid plaque vulnerability. © 2010 The Authors. Journal compilation © 2010 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

Background: Oxidative stress is an important determinant in atherosclerosis development. Various markers of oxidative stress, such as oxidation of low-density lipoprotein (LDL), nitrosative stress, lipid peroxidation, and protein oxidation, have been implicated in the initiation and/or progression of atherosclerosis, but their association with plaque erosion and symptomatic carotid disease has not been fully defined. In addition, certain oxidative markers have been shown in various models to promote plaque remodeling through matrix metalloproteinase (MMP) activation. Objective: To perform a global investigation of various oxidative stress markers and assess for potential relationships with destabilization and symptomatic development in human carotid plaques. Methods: Thirty-six patients undergoing endarterectomy were evaluated and compared with 20 control specimens obtained at the time of autopsy. Differences between stable and unstable plaques, symptomatic and asymptomatic patients, and

Doxorubicin (DXR) is a commonly used antineoplastic agent; however, its use is limited due to cardiotoxicity. Oxidative stress and consequent alterations of cardiac energetics are involved in the development of DXR toxicity. Oleuropein (Oleu) is a phenolic antioxidant, present in olive tree, reported to confer protection against DXR cardiotoxicity. In this study, NMR based-metabonomicswas applied to characterize the metabolic profile of the acute DXR cardiotoxicity in rats and to evaluate the metabolic alterations conferred by co-treatment with Oleu. Wistar rats were divided into six groups and treated as follows: control group with a single injection of 2mL normal saline intraperitoneally (i.p.), DXR group with a single dose of 20mg/kg, i.p and DXR plus Oleu groups with 20mg/kg DXR i.p., and 100 or 200mg/kg/BWofOleu i.p. for 5 or 3 consecutive days starting either 2 days before or on the day of DXR administration. Hearts were excised 72 h after DXR treatment and 1H-NMR spectra of aqueousmyocardiumextracts were recorded. Principal Component Analysis (PCA) and Partial Least Square Discriminant Analysis (PLS-DA) revealed differences in themetabolic profile between control and DXR attributed to severalmetabolites. A number of them were quantified by integration of the NMR spectra. Myocardial levels of acetate and succinate were increased in DXR compared to controls, while branched amino acids were decreased. These results correlate with nonenzymatic conversion of pyruvate to acetate and of a-ketoglutarate to succinate by DXR free radicals. Oleu completely restored the changes of metabolites to the normal levels. Acetate and succinate constitute novel biomarkers related to DXR, and Oleu treatment aids the compensation of distressed energy metabolic pathways. Copyright © 2009 John Wiley & Sons, Ltd.

Introduction: Double-steal syndrome represents a causative factor for blood flow compromise of the cerebral vascular bed with transient neurologic symptoms. We present the case of a patient with innominate artery atherosclerotic occlusion, manifested as blood flow reversal in the vertebral and common carotid arteries. Symptomatic atherosclerotic occlusive disease of the innominate artery is relatively rare and represents less than 2% of all extracranial causes of cerebrovascular insufficiency. Case presentation: We report on a 73-year-old male patient who presented at our hospital for the evaluation of dizziness and episodes of syncope. Angiography and color Doppler examinations documented the double syndrome as retrograde flow in the right vertebral artery and the right carotid artery. Conclusion: Constituting an indication for surgical correction, his condition was managed with the performance of carotid-carotid extra-anatomic bypass for the permanent reestablishment of antegrade blood flow in the vascular network supplying the brain. Carotid-carotid extra-anatomic bypass was a good option for our patient, since he remains symptom free after one year of follow up. © 2008 Filis et al; licensee BioMed Central Ltd.

Oleuropein (oleu) is a natural phenolic antioxidant, which is present in elevated concentration in olives, olive oil and olive tree leaves. Doxorubicin (DXR) induced cardiotoxicity is mainly induced by oxidative stress but the precise mechanism remains obscure. However, there is evidence that high concentration of nitric oxide (NO) occurring as a result of iNOS induction and peroxynitrite formation may be involved in DXR cardiotoxicity. The aim of the present study was to evaluate a possible protective role of oleu in DXR induced cardiotoxicity in vivo. Fifty rats were divided into 6 groups and treated as follows: control group with a single injection of 2 ml normal saline intraperitoneally (i.p.), DXR group with a single dose of 20 mg/kg i.p, and DXR plus oleu groups with 20 mg/kg DXR i.p. and 100 or 200 mg/kg/BW of oleu i.p. for 5 or 3 consecutive days starting either 2 days before or on the day of DXR administration. Seventy-two hours after DXR treatment blood samples were collected for creatine phosphokinase (CPK), creatine phosphokinase-MB (CPK-MB), lactate dehydrogenase (LDH), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) assessments and the rats were then sacrificed. Hearts were used for general histology, iNOS immunohistochemical and Western blot analysis, and for determination of tissue concentrations of lipid peroxidation products, protein carbonyls (PCs), and nitrotyrosine (NT). DXR treated animals demonstrated very extensive cytoplasmic vacuolisation whereas much less vacuolisation was found in oleu treated groups. They also revealed a significant elevation of cardiac enzymes release into systemic circulation (P < 0.05 vs saline). Both doses of Oleu tested and both treatment protocols reduced DXR elevated serum levels of CPK, CPK-MB, LDH, AST and ALT (P < 0.05). Furthermore, it reduced DXR induced lipid peroxidation, PCs content, NT concentration and iNOS induction in myocardial tissue (P < 0.05). Oleu exerts a protective effect by eliminating DXR induced cardiotoxicity expressed by the alteration of intracellular and peripheral markers. Combined oleu and DXR treatment improves the therapeutic outcome by preventing undesirable toxicity. © 2006 Elsevier Inc. All rights reserved.

Leg ulcers caused by chronic venous insufficiency remain a therapeutic dilemma. Their optimal clinical (conservative or surgical) management is still controversial if not problematic. We present our experience with a therapeutic modality including a paratibial fasciotomy and dissection of the posterior perforator veins (Hach procedure) for the treatment of patients with chronic venous ulcers. Patients, methods: Between January 2001 and May 2005 62 patients, (40 women and 22 men) with active venous ulcers in the legs (CEAP 6) were included in the study. Patients were submitted to a paratibial fasciotomy with subfascial dissection of the posterior perforator veins. Results: During a four years study period, we performed 67 fasciotomies in 62 patients with chronic venous ulcers. In 43 limbs besides a fasciotomy we performed a saphenofemoral junction ligation and stripping. In 28 ulcers we used a vacuum-assisted therapy (V.A.C) for median time eight days. Furthermore, 22 patients with ulcers larger than 3 x 3 cm received an autologous skin graft. The cumulative ulcer healing rate after fasciotomy was 29% in three months, 52% at six months and 97% in one year. Ulcers size was found to be significantly related to healing time (p < 0.001). Conclusion: Paratibial fasciotomy is an effective method for the treatment of patients with chronic venous ulcers. This therapeutic modality could be safely applied in cases when other more conservative therapeutical measures fail. © 2007 Schattauer GmbH.