Disrupted Binding of Cystathionine γ-Lyase to p53 Promotes Endothelial Senescence.

BACKGROUND: Advanced age is unequivocally linked to the development of cardiovascular disease; however, the mechanisms resulting in reduced endothelial cell regeneration remain poorly understood. Here, we investigated novel mechanisms involved in endothelial cell senescence that impact endothelial cell transcription and vascular repair after injury. METHODS: Native endothelial cells were isolated from young (20±3.4 years) and aged (80±2.3 years) individuals and subjected to molecular analyses to assess global transcriptional and metabolic changes. In vitro studies were conducted using primary human and murine endothelial cells. A murine aortic re-endothelialization model was used to examine endothelial cell regenerative capacity in vivo. RESULTS: RNA sequencing of native endothelial cells revealed that aging resulted in p53-mediated reprogramming to express senescence-associated genes and suppress glycolysis. Reduced glucose uptake and ATP contributed to attenuated assembly of the telomerase complex, which was required for endothelial cell proliferation. Enhanced p53 activity in aging was linked to its acetylation on K120 due to enhanced activity of the acetyltransferase MOZ (monocytic leukemic zinc finger). Mechanistically, p53 acetylation and translocation were, at least partially, attributed to the loss of the vasoprotective enzyme, CSE (cystathionine γ-lyase). CSE physically anchored p53 in the cytosol to prevent its nuclear translocation and CSE absence inhibited AKT (Protein kinase B)-mediated MOZ phosphorylation, which in turn increased MOZ activity and subsequently p53 acetylation. In mice, the endothelial cell-specific deletion of CSE activated p53, induced premature endothelial senescence, and arrested vascular repair after injury. In contrast, the adeno-associated virus 9-mediated re-expression of an active CSE mutant retained p53 in the cytosol, maintained endothelial glucose metabolism and proliferation, and prevented endothelial cell senescence. Adenoviral overexpression of CSE in native endothelial cells from aged individuals maintained low p53 activity and reactivated telomerase to revert endothelial cell senescence. CONCLUSIONS: Aging-associated impairment of vascular repair is partly determined by the vasoprotective enzyme CSE.

Mapping the Endothelial Cell S-Sulfhydrome Highlights the Crucial Role of Integrin Sulfhydration in Vascular Function.

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 ß3 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 H2Sn donor, 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 ß3 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 ß leg. ß3 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 ß3 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 H2Sn generation, impaired flow-induced dilatation, and failure to detect ß3 integrin S-sulfhydration, all of which were rescued after the administration of an H2Sn supplement. CONCLUSIONS: Vascular disease is associated with marked changes in the S-sulfhydration of endothelial cell proteins involved in mediating responses to flow. Short-term H2Sn supplementation improved vascular reactivity in humans highlighting the potential of interfering with this pathway to treat vascular disease.

Adenosine-to-inosine Alu RNA editing controls the stability of the pro-inflammatory long noncoding RNA NEAT1 in atherosclerotic cardiovascular disease.

Long non-coding RNAs (lncRNAs) have emerged as critical regulators in human disease including atherosclerosis. However, the mechanisms involved in the post-transcriptional regulation of the expression of disease-associated lncRNAs are not fully understood. Gene expression studies revealed that Nuclear Paraspeckle Assembly Transcript 1 (NEAT1) lncRNA expression was increased by >2-fold in peripheral blood mononuclear cells (PBMCs) derived from patients with coronary artery disease (CAD) or in carotid artery atherosclerotic plaques. We observed a linear association between NEAT1 lncRNA expression and prevalence of CAD which was independent of age, sex, cardiovascular traditional risk factors and renal function. NEAT1 expression was induced by TNF-α, while silencing of NEAT1 profoundly attenuated the TNF-α-induced vascular endothelial cell pro-inflammatory response as defined by the expression of CXCL8, CCL2, VCAM1 and ICAM1. Overexpression of the RNA editing enzyme adenosine deaminase acting on RNA-1 (ADAR1), but not of its editing-deficient mutant, upregulated NEAT1 levels. Conversely, silencing of ADAR1 suppressed the basal levels and the TNF-α-induced increase of NEAT1. NEAT1 lncRNA expression was strongly associated with ADAR1 in CAD and peripheral arterial vascular disease. RNA editing mapping studies revealed the presence of several inosines in close proximity to AU-rich elements within the AluSx3+/AluJo- double-stranded RNA complex. Silencing of the stabilizing RNA-binding protein AUF1 reduced NEAT1 levels while silencing of ADAR1 profoundly affected the binding capacity of AUF1 to NEAT1. Together, our findings propose a mechanism by which ADAR1-catalyzed A-to-I RNA editing controls NEAT1 lncRNA stability in ASCVD.

Epithelioid hemangioendothelioma of the retroperitoneum - a rare vascular tumor.

Epithelioid hemangioendothelioma (EHE) is a rare vascular tumor, affecting the liver, the lungs and the bones most frequently. It has a heterogenous clinical presentation and there is no consensus on optimal treatment. This report aims to present a rare case of a retroperitoneal EHE and to discuss on proper management.

Utility of viscoelastic coagulation testing in liver surgery: a systematic review.

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.

Cystathionine γ Lyase Sulfhydrates the RNA Binding Protein Human Antigen R to Preserve Endothelial Cell Function and Delay Atherogenesis.

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-1ß. 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.

The TAXINOMISIS Project: A multidisciplinary approach for the development of a new risk stratification model for patients with asymptomatic carotid artery stenosis.

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 randomized-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 retrieved 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.

Vascular complications during transcatheter aortic valve implantation: The role of the vascular surgeon.

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.

Pleiotropic effects of laminar flow and statins depend on the Krüppel-like factor-induced lncRNA MANTIS.

AIMS: To assess the functional relevance and therapeutic potential of the pro-angiogenic long non-coding RNA MANTIS in vascular disease development. METHODS AND RESULTS: RNA sequencing, CRISPR activation, overexpression, and RNAi demonstrated that MANTIS, especially its Alu-element, limits endothelial ICAM-1 expression in different types of endothelial cells. Loss of MANTIS increased endothelial monocyte adhesion in an ICAM-1-dependent manner. MANTIS reduced the binding of the SWI/SNF chromatin remodelling factor BRG1 at the ICAM-1 promoter. The expression of MANTIS was induced by laminar flow and HMG-CoA-reductase inhibitors (statins) through mechanisms involving epigenetic rearrangements and the transcription factors KLF2 and KLF4. Mutation of the KLF binding motifs in the MANTIS promoter blocked the flow-induced MANTIS expression. Importantly, the expression of MANTIS in human carotid artery endarterectomy material was lower compared with healthy vessels and this effect was prevented by statin therapy. Interestingly, the protective effects of statins were mediated in part through MANTIS, which was required to facilitate the atorvastatin-induced changes in endothelial gene expression. Moreover, the beneficial endothelial effects of statins in culture models (spheroid outgrowth, proliferation, telomerase activity, and vascular organ culture) were lost upon knockdown of MANTIS. CONCLUSION: MANTIS is tightly regulated by the transcription factors KLF2 and KLF4 and limits the ICAM-1 mediated monocyte adhesion to endothelial cells and thus potentially atherosclerosis development in humans. The beneficial effects of statin treatment and laminar flow are dependent on MANTIS.

Weekend effect among patients undergoing elective vascular surgery.

OBJECTIVE: Several studies have described a higher mortality among patients admitted or operated during the weekend for various diseases. However, pooled data on patients undergoing elective vascular surgery procedures are sparse. METHODS: The PubMed, Embase, Scopus, and Cochrane Library databases were systematically searched to identify eligible studies. Studies comparing short-term mortality (≤30 days) between patients undergoing elective vascular surgery during the weekend and working days were included. When studies included patients undergoing mixed types of surgery, only the vascular surgery subgroups were evaluated. Urgent/emergency vascular procedures were excluded according to certain definitions provided by each study. Data were analyzed by using the StatsDirect Statistical software (Version 2.8.0, StatsDirect Ltd, Cambridge, UK). RESULTS: Overall, four retrospective studies including 131,201 patients undergoing elective vascular surgery (on working days, n = 130,163; on the weekend, n = 1038) were evaluated. The pooled short-term mortality risk was higher among patients operated during the weekend compared with working days (odds ratio [OR], 2.41; 95% confidence interval [CI], 1.58-3.67; P = .0004). This weekend effect was more evident among patients undergoing abdominal aortic aneurysm repair and carotid surgery (OR, 3.62 [95% CI, 1.49-8.82; P = .0046] and OR, 3.48 [95% CI, 1.15-10.54; P = .027], respectively). In the United States, the weekend effect was more evident among patients undergoing aortic aneurysm repair (OR, 3.61; 95% CI, 1.99-6.53; P < .0001). However, data from Canada originated from one study on patients undergoing carotid and peripheral arterial surgery only. CONCLUSIONS: Elective vascular surgery is associated with a higher short-term mortality risk when conducted over the weekend. Improvement of perioperative management during these days may be necessary to improve outcomes.

Cytokines as biomarkers of inflammatory response after open versus endovascular repair of abdominal aortic aneurysms: a systematic review.

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-1ß, 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.

Endovascular Repair of Blunt Thoracic Aortic Trauma: Is Postimplant Hypertension an Incidental Finding?

BACKGROUND: Blunt thoracic aortic injury (BTAI) is the second most common cause of death in trauma patients. Nowadays, thoracic endovascular aortic repair (TEVAR) has become the treatment of choice because of lower rates of mortality, paraplegia, and stroke. However, concerns have been raised whether graft implantation is related to the development of hypertension in the postoperative period. The aim of this study was to report short- and long-term outcomes of patients undergoing TEVAR for BTAIs at a tertiary hospital and to investigate postimplant hypertension. METHODS: Between January 2005 and January 2016, 23 patients with blunt thoracic aortic trauma underwent TEVAR. Median age was 44 years (range, 18-73). Among them, 14 (60.9%) patients were diagnosed with aortic rupture, whereas 9 (39.1%) with pseudoaneurysm. Α single thoracic stent graft was deployed in 21 patients, and the rest 2 patients received 2 stent grafts. RESULTS: Complete exclusion of the injury was feasible in all subjects (100% primary success). The left subclavian artery (SCA) was intentionally covered in 6 patients (26%). Intraoperative complications included one nonfatal stroke managed conservatively and one external iliac artery rupture treated with iliofemoral bypass. One patient (4.3%) died on the first postoperative day in the intensive care unit (ICU) because of hemorrhagic shock. The overall 30-day mortality and morbidity were 4.3% and 8.7%, respectively. New-onset postimplantation arterial hypertension was observed in 8 (34.8%) previously nonhypertensive patients. Younger age (P = 0.027) and SCA coverage (P = 0.01) were identified as potential risk factors for the development of postimplant hypertension, whereas the presence of concomitant injuries (P = 0.3) and intraoperative complications (P = 0.1) were not. After a median follow-up of 100 months (range, 18-120), 6 of them still remain on antihypertensive therapy, whereas the other 2 did not require permanent treatment. CONCLUSIONS: TEVAR is a safe approach in the treatment of BTAI associated with low short- and long-term morbidity and mortality rates. Lower age and SCA coverage may contribute to the development of postimplant hypertension. Further larger cohort studies are warranted to elucidate the underlying mechanisms of postimplant hypertension.

Risk factors for postoperative delirium in patients undergoing vascular surgery.

OBJECTIVE: Postoperative delirium (PODE) remains a common complication after vascular surgery procedures although the exact pathogenesis remains unclear, mainly because of its multifactorial character. The aim of this systematic review was to evaluate pooled data on potential risk factors for PODE in patients undergoing vascular surgery procedures. METHODS: A systematic literature review was conducted conforming to established criteria to identify eligible articles published from 1990 to 2016. Eligible studies evaluated potential risk factors for PODE after vascular surgery procedures, using both univariate and multivariate analysis. PODE was defined as a disturbance of consciousness with reduced ability to focus, sustain, or shift attention after vascular surgery procedures and was diagnosed in all studies using well-established criteria. Only risk factors reported in at least four studies were included in this review. Pooled results were calculated, and further multivariate regression analysis was conducted. RESULTS: Overall, nine studies (published from 2003 to 2015) including 2388 patients in total were evaluated (457 with and 1931 without PODE). Patients with PODE were older (73.27 vs 69.87 years; P < .0001) and showed a higher male sex rate (78.1% vs 73.5%; P = .043). Open aortic surgery was the most frequent procedure in this analysis, followed by lower limb revascularization. Patients with PODE also showed higher rates of diabetes mellitus, hypertension, cardiac disease, and neurologic disease; lower hemoglobin level; larger duration of surgery; longer hospital and intensive care unit stay; and higher blood loss. Mean age (odds ratio [OR], 3.44; 95% confidence interval [CI], 2.933-4.034; P < .0001), hypertension (OR, 1.94; 95% CI, 1.469-2.554; P < .0001), cardiac disease (OR, 3.16; 95% CI, 2.324-4.284; P < .0001), open aortic surgery (OR, 1.74; 95% CI, 1.421-2.143; P < .0001), blood loss (OR, 1.01; 95% CI, 1.007-1.010; P < .0001), hospital stay (OR, 2.26; 95% CI, 1.953-2.614; P <. 0001), and intensive care unit stay (OR, 6.12; 95% CI, 4.699-7.957; P < .0001) were identified as the strongest risk predictors for PODE, followed by male sex, diabetes mellitus, neurologic disease, and history of smoking. However, body mass index, renal failure, preoperative hemoglobin level, and general anesthesia were not found to be risk factors for PODE in such patients. CONCLUSIONS: This study has confirmed that PODE after vascular surgery procedures is a multifactorial disease, and several independent risk factors have been identified. However, pooled data regarding the effect of PODE on primary outcomes after vascular surgery procedures are still lacking. The results of this review could contribute to the designation of future prediction models and improve prevention of PODE in these patients.

The effect of body mass index on major outcomes after vascular surgery.

OBJECTIVE: Obesity has been associated with an increased risk for cardiovascular morbidity and mortality, although pooled evidence in patients undergoing vascular surgery are lacking. The aim of this systematic review was to evaluate the effect of body mass index (BMI) on major postoperative outcomes in patients undergoing vascular surgery. METHODS: A systematic literature review conforming to established criteria to identify eligible articles published before May 2016 was conducted. Eligible studies evaluated major postoperative outcomes in vascular surgery patients of different BMI groups according to the weight classification of the National Institutes of Health criteria: underweight (UW), BMI ≤18.5 kg/m2; normal weight (NW), BMI of 18.6 to 24.9 kg/m2; overweight (OW), BMI of 25 to 29.9 kg/m2; and obese (OB), BMI ≥30 kg/m2. Major outcomes included 30-day mortality, cardiac complications, and respiratory complications. Secondary outcomes included wound and cerebrovascular complications, renal complications, deep venous thrombosis/pulmonary embolism, and other complications. RESULTS: Overall, eight retrospective studies were eligible including a total of 92,525 vascular surgery patients (2223 UW patients, 29,727 NW patients, 34,517 OW patients, and 26,058 OB patients). Pooled data were as follows: mortality rate, 2.5%; cardiac events, 2.1%; respiratory events, 8.6%; wound complications, 6.4%; cerebrovascular events, 6.4%; renal complications, 3.9%; other infections, 5.3%; deep venous thrombosis/pulmonary embolism, 1.2%; and other complications, 3.7%. Meta-analysis showed that OB patients were associated with lower mortality (odds ratio [OR], 0.64; 95% confidence interval [CI], 0.541-0.757; P < .0001), cardiac morbidity (OR, 0.81; 95% CI, 0.708-0.938; P = .004), and respiratory morbidity (OR, 0.87; 95% CI, 0.802-0.941; P = .0006) after vascular surgery compared with NW patients. However, OB patients were associated with a higher wound complication rate (OR, 2.39; 95% CI, 1.777-3.211; P < .0001) compared with NW patients. In contrast, UW patients were associated with a higher mortality (OR, 1.71; 95% CI, 1.177-2.505; P = .005) and respiratory morbidity (OR, 1.84; 95% CI, 1.554-2.166; P < .0001) compared with NW patients. CONCLUSIONS: The "obesity paradox" does exist in patients undergoing vascular surgery. This paradox refers not only to 30-day overall mortality but also to 30-day cardiac and respiratory complications. However, obesity seems to be associated with more wound complications. Surprisingly, UW patients are associated with higher mortality as well as respiratory events postoperatively.

Assessment of the vulnerable carotid atherosclerotic plaque using contrast-enhanced ultrasonography.

Carotid atherosclerosis represents a primary cause for cerebrovascular ischemic events and its contemporary management includes surgical revascularization for moderate to severe symptomatic stenoses. However, the role of invasive therapy seems to be questioned lately for asymptomatic cases. Numerous reports have suggested that the presence of neovessels within the atherosclerotic plaque remains a significant vulnerability factor and over the last decade imaging modalities have been used to identify intraplaque neovascularization in an attempt to risk-stratify patients and offer management guidance. Contrast-enhanced ultrasonography of the carotid artery is a relatively novel diagnostic tool that exploits resonated ultrasound waves from circulating microbubbles. This property permits vascular visualization by producing superior angiography-like images, and allows the identification of vasa vasorum and intraplaque microvessels. Moreover, plaque neovascularization has been associated with plaque vulnerability and ischemic symptoms lately as well. At the same time, attempts have been made to quantify contrast-enhanced ultrasonography signal using sophisticated software packages and algorithms, and to correlate it with intraplaque microvascular density. The aim of this review was to collect all recent data on the characteristics, performance, and prognostic role of contrast-enhanced ultrasonography regarding carotid stenosis management, and to produce useful conclusions for clinical practice.

Meta-Analysis of Studies Evaluating the Effect of Cilostazol on Major Outcomes After Carotid Stenting.

PURPOSE: To evaluate the effect of cilostazol on major outcomes after carotid artery stenting (CAS). METHODS: A systematic literature review was conducted conforming to established criteria in order to identify articles published prior to May 2015 evaluating major post-CAS outcomes in patients treated with cilostazol vs patients not treated with cilostazol. Major outcomes included in-stent restenosis (ISR) within the observation period, the revascularization rate, major/minor bleeding, and the myocardial infarction/stroke/death rate (MI/stroke/death) at 30 days and within the observation period. Data were pooled for all studies containing adequate data for each outcome investigated; effect estimates are presented as the odds ratios (ORs) and 95 confidence intervals (CI). RESULTS: Overall, 7 studies pertaining to 1297 patients were eligible. Heterogeneity was low among studies so a fixed-effect analysis was conducted. Six studies (n=1233) were compared for the ISR endpoint, showing a significantly lower ISR rate with cilostazol treatment after a mean follow-up of 20 months (OR 0.158, 95% CI 0.072 to 0.349, p<0.001). Five studies (n=649) were compared regarding 30-day MI/stroke/death (OR 0.724, 95% CI 0.293 to 1.789, p=0.484) and 3 studies (n=1076) were analyzed regarding MI/stroke/death within the entire follow-up period (OR 0.768, 95% CI 0.477 to 1.236, p=0.276); no significant difference was found between the groups. Data on bleeding rates and revascularization rates post ISR were inadequate to conduct further analysis. CONCLUSION: Cilostazol seems to decrease total ISR rates in patients undergoing CAS without affecting MI/stroke/death events, both in the early and late settings.

The emerging role of microdialysis in diabetic patients undergoing amputation for limb ischemia.

Lower limb ischemia in diabetic patients is a result of macro- and microcirculation dysfunction. Diabetic patients undergoing limb amputation carry high mortality and morbidity rates, and decision making concerning the level of amputation is critical. Aim of this study is to evaluate a novel microdialysis technique to monitor tissue microcirculation preoperatively and predict the success of limb amputation in such patients. Overall, 165 patients with type 2 diabetes mellitus undergoing lower limb amputation were enrolled. A microdialysis catheter was placed preoperatively at the level of the intended flap for the stump reconstruction, and the levels of glucose, glycerol, lactate and pyruvate were measured for 24 consecutive hours. Patients were then amputated and monitored for 30 days regarding the outcome of amputation. Failure of amputation was defined as delayed healing or stump ischemia. Patients were divided into two groups based on the success of amputation. There was no difference between the two groups regarding gender, ASA score, body mass index, comorbidities, diagnostic modality used, level of amputation, as well as glucose, glycerol, and pyruvate levels. However, local concentrations of lactate were significantly different between the two groups and lactate/pyruvate (L/P) ratio was independently associated with failed amputation (threshold defined at 25.35). Elevated preoperative tissue L/P ratio is independently associated with worse outcomes in diabetic patients undergoing limb amputation. Therefore, preoperative tissue L/P ratio could be used as a predicting tool for limb amputation's outcome, although more clinical data are needed to provide safer conclusions.

Preoperative Cardiac Assessment before Carotid Surgery: Should Perhaps Things Change?

Carotid endarterectomy has been associated with perioperative symptomatic or asymptomatic myocardial ischemia and cardiac mortality although it has been classified as a procedure of intermediate cardiac risk. Recent data indicate that the Cardiac Risk Index score for preoperative assessment by the latest guidelines is not suitable for vascular surgery procedures in general and carotid procedures in particular. This review aims to present and analyze all these results, concluding that current recommendations for this specific procedure should perhaps be reevaluated.

Hybrid Treatment of an Abdominal Aortic Aneurysm with Severe Calcification of the Neck and Aortic Bifurcation.

BACKGROUND: Severe calcification of the aorta or iliac vessels remains a major concern when planning open or endovascular treatment of an abdominal aortic aneurysm (AAA). Therefore, we present a unique case of an AAA with concomitant severe calcification of the entire infrarenal aortoiliac region and discuss on proper management. CASE REPORT: A 70-year-old patient with a symptomatic AAA was scheduled for repair. The diagnostic investigation revealed a 70-mm-diameter AAA with severe calcification of the neck and the iliac and femoral arteries, raising major concerns regarding the proper repair strategy. Under careful consideration of all the risks and parameters, the patient underwent a hybrid treatment with endovascular balloon occlusion of the aortic neck and careful clamping just proximal to the bifurcation. Minimal mobilization of the aorta, careful transecting and drilling of the aortic wall, and careful suturing of a straight graft were part of the whole strategy. One-year follow-up of the patient is unremarkable. CONCLUSIONS: In cases of AAA with significantly calcified aorta and aortic bifurcation, careful preoperative planning is imperative, taking into consideration the individualized characteristics of each patient. Hybrid techniques including proximal endovascular occlusion, careful mobilizations, aortic wall drilling, and tight suturing of the graft could be a reasonable strategy for such patients. However, larger case series is needed to prove the efficacy of this method.

Beta-blockers in vascular surgery patients: is the debate still going on?

Patients undergoing vascular surgery are under increased risk for perioperative myocardial ischemia and cardiovascular complications, and optimal medical treatment is therefore imperative for these patients. Beta-blockade has been introduced as a cornerstone of optimal management, and standardized preoperative initiation has been recommended in the past. However, recent pooled data have questioned prior recommendations and have led to revision of international guidelines. This review aims to highlight the debate on perioperative beta-blockade for vascular surgery patients in order to produce useful conclusions for everyday clinical practice.