The PPAR-γ Agonist Pioglitazone Modulates Proliferation and Migration in HUVEC, HAOSMC and Human Arteriovenous Fistula-Derived Cells.

The failure of arteriovenous fistulas (AVFs) following intimal hyperplasia (IH) increases morbidity and mortality rates in patients undergoing hemodialysis for chronic kidney disease. The peroxisome-proliferator associated receptor (PPAR-γ) may be a therapeutic target in IH regulation. In the present study, we investigated PPAR-γ expression and tested the effect of pioglitazone, a PPAR-γ agonist, in different cell types involved in IH. As cell models, we used Human Endothelial Umbilical Vein Cells (HUVEC), Human Aortic Smooth Muscle Cells (HAOSMC), and AVF cells (AVFCs) isolated from (i) normal veins collected at the first AVF establishment (T0), and (ii) failed AVF with IH (T1). PPAR-γ was downregulated in AVF T1 tissues and cells, in comparison to T0 group. HUVEC, HAOSMC, and AVFC (T0 and T1) proliferation and migration were analyzed after pioglitazone administration, alone or in combination with the PPAR-γ inhibitor, GW9662. Pioglitazone negatively regulated HUVEC and HAOSMC proliferation and migration. The effect was antagonized by GW9662. These data were confirmed in AVFCs T1, where pioglitazone induced PPAR-γ expression and downregulated the invasive genes SLUG, MMP-9, and VIMENTIN. In summary, PPAR-γ modulation may represent a promising strategy to reduce the AVF failure risk by modulating cell proliferation and migration.

Tissue Ki67 proliferative index expression and pathological changes in hemodialysis arteriovenous fistulae: Preliminary single-center results.

BACKGROUND: Arteriovenous fistula (AVF) for hemodialysis integrates outward remodeling with vessel wall thickening in response to drastic hemodynamic changes. Aim of this study is to determine the role of Ki67, a well-established proliferative marker, related to AVF, and its relationship with time-dependent histological morphologic changes. MATERIALS AND METHODS: All patients were enrolled in 1 year and stratified in two groups: (A) pre-dialysis patients submitted to first AVF and (B) patients submitted to revision of AVF. Morphological changes: neo-angiogenesis (NAG), myointimal thickening (MIT), inflammatory infiltrate (IT), and aneurysmatic fistula degeneration (AD). The time of AVF creation was recorded. A biopsy of native vein in Group A and of arterialized vein in Group B was submitted to histological and immunohistochemical (IHC) analysis. IHC for Ki67 was automatically performed in all specimens. Ki67 immunoreactivity was assessed as the mean number of positive cells on several high-power fields, counted in the hot spots. RESULTS: A total of 138 patients were enrolled, 69 (50.0%) Group A and 69 (50.0%) Group B. No NAG or MIT were found in Group A. Seven (10.1%) Group A veins showed a mild MIT. Analyzing the Group B, a moderate-to-severe MIT was present in 35 (50.7%), IT in 19 (27.5%), NAG in 37 (53.6%); AD was present in 10 (14.5%). All AVF of Group B with the exception of one (1.4%) showed a positivity for Ki67, with a mean of 12.31 ± 13.79 positive cells/hot spot (range 0-65). Ki67-immunoreactive cells had a subendothelial localization in 23 (33.3%) cases, a myointimal localization in SMC in 35 (50.7%) cases. The number of positive cells was significantly correlated with subendothelial localization of Ki67 (p = 0.001) and with NA (p = 0.001). CONCLUSIONS: Native veins do not contain cycling cells. In contrast, vascular cell proliferation starts immediately after AVF creation and persists independently of the time the fistula is set up. The amount of proliferating cells is significantly associated with MIT and subendothelial localization of Ki67-immunoreactive cells, thus suggesting a role of Ki-67 index in predicting AVF failure.

Outcomes of radiocephalic arteriovenous fistula in octogenarians.

BACKGROUND: Current guidelines recommend radiocephalic arteriovenous fistula (RCAVF) as a first choice access for hemodialysis, without specific indication for octogenarians .This study was undertaken to assess the efficacy of RCAVF in octogenarians compared with younger patients. MATERIAL AND METHODS: All patients treated by RCAVF from January 2013 to December 2017 were included in a prospective database for a retrospective analysis. Patient demographics, comorbidities, and dialytic treatment data were collected prospectively and compared in patients <80 year-old and ⩾80 years-old. Clinical surveillance was performed during each dialysis session. The main endpoints were primary (PP) and assisted patency (AP). RESULTS: Within the study period, a total of 294 RCAVF were analyzed: 245 (83.3%) RCAVF were performed in <80 year-old and 49 (16.7%) ⩾80 years old. The overall PP and AP at 2-year was 69% ± 2% and 73% ± 3%, respectively. Patients ⩾ 80 years-old had a significantly reduced 2-year PP, AP of RCAVF compared with the younger patients: 50% ± 8% and 62% ± 7% versus 73% ± 3% and 75% ± 3%, p = 0.01 and p = 0.03, respectively.The analysis for possible risk factors for reduction of PP in patients ⩾80 years identified in the central venous catheter(CVC) a predictor of earlier RCAVF failure: HR 3.03(95% CI 1.29-7.13), p = 0.01.Kaplan-Meier curve confirms the reduction of PP in ⩾80 years old patients at 2-year follow-up with previous CVC compared patients without history of CVC: 59% ± 10% versus 24% ± 11%, p = 0.01. A comparison between the two groups was made in order to evaluate the impact of previous history of CVC .In absence of a history of CVC use older patients had a similar 2-year PP compared with younger patients: 59% ± 10% versus 72% ± 4%, p = 0.46. Otherwise, the history of a previous CVC reduced significantly the 2-year PP in ⩾80 years old patients compared the younger: 24% ± 12% versus 75% ± 5%, p = 0.0001. CONCLUSIONS: Despite lower overall primary and primary assisted patency, RCAVF are associated with satisfactory results also in octogenarians if performed in absence of history of CVC. Under these circumstances RCAVF can be considered a first choice treatment.

Roles of PI3K/AKT/mTOR Axis in Arteriovenous Fistula.

Renal failure is a worldwide disease with a continuously increasing prevalence and involving a rising need for long-term treatment, mainly by haemodialysis. Arteriovenous fistula (AVF) is the favourite type of vascular access for haemodialysis; however, the lasting success of this therapy depends on its maturation, which is directly influenced by many concomitant processes such as vein wall thickening or inflammation. Understanding the molecular mechanisms that drive AVF maturation and failure can highlight new or combinatorial drugs for more personalized therapy. In this review we analysed the relevance of critical enzymes such as PI3K, AKT and mTOR in processes such as wall thickening remodelling, immune system activation and inflammation reduction. We focused on these enzymes due to their involvement in the modulation of numerous cellular activities such as proliferation, differentiation and motility, and their impairment is related to many diseases such as cancer, metabolic syndrome and neurodegenerative disorders. In addition, these enzymes are highly druggable targets, with several inhibitors already being used in patient treatment for cancer and with encouraging results for AVF. Finally, we delineate how these enzymes may be targeted to control specific aspects of AVF in an effort to propose a more specialized therapy with fewer side effects.

Assessment and Management of Transplant Renal Artery Stenosis. A Literature Review.

BACKGROUND: Transplant renal artery stenosis (TRAS) following kidney transplantation is a possible cause of graft failure. This review aimed to summarize the evidence about physiopathology, diagnosis and early and late effectiveness of the endovascular treatment (EVT), including angioplasty and stenting procedures. METHODS: A literature research was performed using Pubmed, Scopus and the Cochrane Library databases (January 2000-September 2020) according to PRISMA guidelines. Studies were included if they describe EVT, percutaneous transluminal angioplasty or stent placement of TRAS, published in English and with a minimum of ten patients. RESULTS: Fifty-six studies were included. TRAS incidence ranges from 1% up to 12% in transplanted kidneys. The TRAS risk factors were: elderly donor and recipient, cytomegalovirus match status, Class II Donor Specific Antibodies (DSA), expanded donor criteria, delayed graft functioning and other anatomical and technical factors. The highest frequency of TRAS presentation is after 3-6 months after kidney transplantation. The most frequent localization of stenosis was para-anastomotic (ranging from 25% to 78%). In 9 studies, all patients were treated by percutaneous transluminal angioplasty (PTA), in 16 studies all patients received percutaneous transluminal stenting (PTS) and in 21 series patients received either PTA or PTS. The twelve months patency rates after EVT ranged from 72% to 94%. The overall complication rate was 9%, with pseudoaneurysms and hematomas as most frequent complications. CONCLUSIONS: TRAS can be successfully and safely treated through an endovascular approach. Stent delivery seems to guarantee a higher patency rate compared to simple angioplasty, however further studies are needed to confirm these results.

A prognostic score for clinical success after revascularization of critical limb ischemia in hemodialysis patients.

OBJECTIVE: The revascularization of critical limb ischemia (CLI) in hemodialysis (HD) patients features poor results in terms of patient survival and limb salvage. Recent predictive models in CLI revascularization did not specifically address HD patients. The aim of this study was to define risk factors for clinical success (CS) after revascularization of CLI in HD patients and to transform findings in a prognostic score. METHODS: A retrospective study was conducted of prospectively gathered data, including consecutive HD patients treated for CLI from January 2004 to December 2012. Patients' demographics, comorbidities, CLI stage (Rutherford classification), tissue loss (Texas University Wound classification [TUWC]), and type of revascularization were assessed. End points were CS after revascularization (amputation-free and reintervention-free survival) and a prognostic score for CS based on significant risk factors (multivariable analysis). RESULTS: In the study period, 131 patients (mean age, 70.2 ± 9.9 years; male, 76.3%) with a total of 180 limbs were treated. Endovascular (52.8%), surgical (28.9%), or hybrid (10.6%) revascularization was performed in 163 (90.6%) limbs in 117 patients. The mean (± standard deviation) follow-up was 20.8 ± 21.1 months. Considering revascularized patients, CS was 47.9%, 30.8%, and 17.8% at 6, 12, and 24 months, respectively. On multivariable analysis, age (hazard ratio [HR], 1.03; 95% confidence interval [CI], 1.01-1.05; P = .005), coronary artery disease (CAD; HR, 1.55; 95% CI, 1.04-2.32; P = .032), and TUWC stage D (HR, 1.80; 95% CI, 1.22-2.67; P = .003) were independent negative factors. Type of revascularization had no influence on CS. The score for predicting CS was 0.026 × age (years) + 0.441 × CAD + 0.59 × TUWC stage D. CAD and TUWC stage D were 1 in the presence of disease and 0 in the absence of disease. The score has a significant discrimination power of 75.5% (P = .036), with a best cutoff value of 2.07. Patients with a CS score <2.07 would have a low risk of clinical failure, whereas patients with a CS score >2.07 would have a high risk. There were 31 (26.5%) cases of low-risk score and 86 (73.5%) cases of high-risk score. Cases with low-risk score had a CS at 1 year of 51.6% compared with 23.3% in cases with high-risk score. CONCLUSIONS: CS after revascularization in HD patients remains poor independent of the type of revascularization. A prognostic model based on age, history of CAD, and severity of CLI (TUWC stage D lesion) can estimate an individual's chances of CS and may help in the decision-making process.

A Comparison of Two Surgical Techniques for the Second Stage of Brachiobasilic Arteriovenous Fistula Creation.

Two-stage transposed brachiobasilic arteriovenous fistula is a common procedure after brachiobasilic fistula (BBF) creation. Different techniques can be used for basilic vein transposition but few comparative literature reports are available. The aim of our study was to compare two different techniques for basilic vein transposition. The first maintains the BBF anastomosis and the basilic vein is placed in a subcutaneous pocket (BBAVF). The second transects the basilic vein at the BBF anastomosis and tunnels it superficially, with a new BBF in the brachial artery (BBAVFTn). From 2009 to 2014, all patients who underwent basilic vein superficialization were treated by one of the two techniques, recorded in a dedicated database and retrospectively reviewed. The surgeon chose the technique on the basis of personal preference. The two techniques were compared in terms of perioperative complications, length of hospital stay, time of cannulation, ease of cannulation, and long-term patency. Eighty patients were included in the study: 40 (50%) BBAVF and 40 (50%) BBAVFTn. Length of hospital stay was similar in the two groups (median [interquartile range-IQR] 3(2) [BBAVF] vs. 2(1) [BBAVFTn], P = 0.52, respectively). BBAVFTn was associated with a lower hematoma incidence (1/40 [2.5%] vs. 15/40 [37.5%], P = 0.01), shorter first cannulation time (median IQR: 11(10) vs. 23(8) days, P = 0.01) and easier cannulation compared with BBAVF (32/40 [80%] vs. 15/40 [37.5%], P < 0.001). Median (IQR) follow-up was 16(7) months. No statistical differences in terms of primary and assisted primary patency were found in BBAVFTn vs. BBAVF (at 24 months 91(5) vs. 71(7), P = 0.21 and 93(6) vs. 78(8), P = 0.33, respectively). Patients who underwent BBAVFTn surgery showed fewer surgical complications, better dialytic performance, and easier cannulation compared with those submitted to BBAVF.

Plication for the treatment of a radio-cephalic fistula with ulnar artery steal.

PURPOSE: Generally the steal syndrome occurs in proximal arterial-venous fistulas and only exceptionally with distal vascular access because of the high number of arteries supplying the hand. We describe a rare case of steal syndrome of a proximalized distal radio-cephalic fistula stealing from both the radial and ulnar artery through the palmar arch. METHODS: An 86 year old man was admitted because of a cyanotic, swollen left hand with trophic lesions at the third finger. He had a latero-terminal radio-cephalic fistula performed in 2006 with subsequent proximalization performed four years later after failure of the first one. Duplex ultrasound examination showed a high flow within the fistula (2080 mL/min) and a retrograde perfusion of the radial artery from the ulnar artery through the palmar arch and an angiography excluded stenosis along the radial artery. RESULTS: We treated the steal syndrome through a plication technique that was performed with careful flow variations measurement, under duplex evaluation, during the surgical procedure. That procedure was effective to maintain the fistula flow and obtain the symptoms relief. The patient was evaluated the day after the intervention and after 10 weeks. The clinical examination highlighted the resolution of hand ischemia. The Duplex Ultrasound examination showed a lower flow within the fistula (1060 mL/min) and a retrograde perfusion of the radial artery from the ulnar artery through the palmar arch with a three-phase flow. dialysis access from the fistula was never interrupted from immediately after surgery to the present date. CONCLUSIONS: Plication is an effective technique for treatment of steal syndrome requiring a short operative time and it is related to satisfying post-operative results.

High sensitivity C-reactive protein and vascular endothelial growth factor as indicators of carotid plaque vulnerability.

BACKGROUND: Carotid atherosclerotic plaques are one of the causes of cerebral stroke. The risk is higher for the vulnerable plaques but there are no specific markers to identify them. The aim of our study was to identify vulnerable carotid plaques by the mean of atherosclerotic serological markers in patients undergoing carotid revascularization by endarterectomy (CEA) or stenting (CAS). METHODS: High sensitivity C-reactive protein (hsCRP) and vascular-endothelial-growth-factor (VEGF) levels were assessed preoperatively in patients undergoing carotid revascularization. Carotid plaques vulnerability were investigated in two different methods: the "biological vulnerability" with the histological evaluation of the plaques from CEA, scoring five parameters (microvessel density, fibrous-cap-thickness, calcification, inflammatory infiltrate and lipid core), and the "structural vulnerability" with the evaluation of the plaques debris detached during CAS and captured by the cerebral protection filter, in terms of percentage of filter pores occlusion (OP). Results were correlated using χ2, Fisher's, Mann-Whitney, Student's t-tests and regression analysis. RESULTS: The histological analysis was performed in 40 specimens, vulnerable plaques (30%) were correlated with higher hsCRP levels (>5mg/l; OR, 2.5; CI 95%, 1.1-5.5; P=0.01) and VEGF levels (VEGF>500 pg/l; OR 3.0, CI 95%, 1.1-7.7; P=0.01). All the filters (N.40) contained microscopic debris (mean OP 26.6%±9.9); higher hsCRP levels (>5mg/l) were correlated with greater than 25% OP (OR, 2.6; CI 95%, 1.2-5.7). An increase in the percentage of OP was also observed in patients with VEGF>500 pg/l (OR, 2.9; CI, 95% 1.3-6.3). CONCLUSIONS: This study suggests that serological determinants are useful in recognizing the structural and biological vulnerability of carotid plaques.

Impact of duplex ultrasound surveillance program on patency of prosthetic arteriovenous graft for hemodialysis: a single-center experience.

BACKGROUND: Arteriovenous prosthetic graft (AVG) is an alternative hemodialysis vascular access choice; however, its performance is limited by a high rate of thrombosis. The aim of the study was to compare the long-term secondary patency of AVG in patients undergoing a surveillance program and the long-term secondary patency of AVG in patients with clinical assessment of AVG malfunction. METHODS: From 2009 to 2012, all patients with AVG entered in a duplex ultrasound (DUS) surveillance program (at 3 months and then every 6 months postoperatively) to assess AVG malfunction and/or stenosis (stenosis >50% and blood flow decrease [<600 mL/min]) and eventually treated by endovascular revascularization. AVG long-term patency in the surveillance group was compared with that obtained in a historical control group in which the malfunction was clinically detected. As secondary end point, the central vein catheter (CVC) placement after AVG thrombosis was compared in the 2 groups. RESULTS: Sixty patients were included in the study, 33 (55%) in the surveillance program and 27 (45%) in the historical group. The 2 groups had similar clinical characteristics and follow-up (59, interquartile range [IQR]: 45 vs. 56 [IQR, 40 months], P = 0.32). Fifteen (45%) AVG malfunctions were detected in the surveillance group and successfully treated (10 [66.6%] angioplasty and 5 [33.4%] angioplasty stenting). No malfunction was detected in the historical control group. By Kaplan-Meier analysis, the 5-year secondary patency was significantly higher in the surveillance group compared with the historical group: 42 ± 13% vs. 9 ± 7%, P = 0.03. By Cox analysis, the DUS surveillance was a significantly protective factor for AVG thrombosis, otherwise the use of CVC before the AVG and diabetes mellitus were AVG thrombosis risk factors. The CVC placement was significantly lower in the surveillance group compared with the historical group (14.0% vs. 42.2%, P = 0.02). CONCLUSIONS: The DUS surveillance allows a greater secondary patency compared with a clinical evaluation and reduces CVC placement rate.

Diffuse calcifications protect carotid plaques regardless of the amount of neoangiogenesis and related histological complications.

BACKGROUND: Neoangiogenesis is crucial in plaque progression and instability. Previous data from our group showed that Nestin-positive intraplaque neovessels correlated with histological complications. The aim of the present work is to evaluate the relationship between neoangiogenesis, plaque morphology, and clinical instability of the plaque. MATERIALS AND METHODS: Seventy-three patients (53 males and 20 females, mean age 71 years) were consecutively enrolled. Clinical data and 14 histological variables, including intraplaque hemorrhage and calcifications, were collected. Immunohistochemistry for CD34 and Nestin was performed. RT-PCR was performed to evaluate Nestin mRNA (including 5 healthy arteries as controls). RESULTS: Diffusely calcified plaques (13/73) were found predominantly in females (P = 0.017), with a significantly lower incidence of symptoms (TIA/stroke (P = 0.019) than noncalcified plaques but with the same incidence of histological complications (P = 0.156)). Accordingly, calcified and noncalcified plaques showed similar mean densities of positivity for CD34 and Nestin. Nestin density, but not CD34, correlated with the occurrence of intraplaque hemorrhage. CONCLUSIONS: Plaques with massive calcifications show the same incidence of histological complications but without influencing symptomatology, especially in female patients, and regardless of the amount of neoangiogenesis. These results can be applied in a future presurgical identification of patients at major risk of developing symptoms.

PTFE grafts versus tunneled cuffed catheters for hemodialysis: which is the second choice when arteriovenous fistula is not feasible?

Vascular access-related complications are still one of the leading causes of morbidity in hemodialysis patients. The aim of this study was to compare polytetrafluoroethylene (PTFE) grafts versus tunneled cuffed permanent catheters (TCCs) in terms of vascular access and patients' survival. An observational study was carried out with a 2-year follow-up. Eighty-seven chronic hemodialysis patients were enrolled: 31 with a PTFE graft as vascular access for hemodialysis versus 56 with a TCC. Patients' mean age was 63.8 ± 14.6 (grafts) versus 73.5 ± 11.3 years (TCCs), P = 0.001. Significantly more patients with TCC had atrial fibrillation than patients with grafts (30.3% versus 6.5%, P = 0.01). In an unadjusted Kaplan-Meier analysis, median TCC survival at 24 months was 5.4 months longer than that of PTFE grafts but not significantly (log-rank test = 1.3, P = ns). In a Cox regression analysis adjusted for age, gender, number of previous vascular accesses, diabetes, atrial fibrillation, smoking, and any complication, this lack of significant difference in survival of the vascular access between TCC and PTFE groups was confirmed and diabetes proved to be an independent risk factor for the survival of both vascular accesses considered (P = 0.02). In an unadjusted Kaplan-Meier analysis, a higher mortality was found in the TCC group than in the PTFE group at 24 months (log-rank test = 10.07, P < 0.01). The adjusted Cox regression analysis showed that patients with TCC had a 3.2 times higher risk of death than patients with PTFE grafts. When an arteriovenous fistula (AVF) is not possible, PTFE grafts can be considered the vascular access of second choice, whereas TCCs can be used when an AVF or PTFE graft are not feasible or as a bridge to AVF or PTFE graft creation.

Endovascular treatment of late coronary-subclavian steal syndrome.

OBJECTIVE: Coronary-subclavian steal syndrome (CSSS) is a rare cause of myocardial ischemia subsequent to stenosis or occlusion of the subclavian artery (SA) proximal to internal thoracic artery (ITA) coronary bypass. Only single cases have been reported in published studies to date. We report a significant series of patients with late CSSS treated through an endovascular approach. METHODS: We reviewed a series of consecutive patients treated for CSSS. The clinical, anatomic, and technical characteristics of the procedures were considered. Follow-up was performed through clinical and laboratory (electrocardiography, echocardiography, duplex ultrasonography) evaluations. RESULTS: From January 2005 to March 2013, 10 patients with CSSS were treated; 7 had stable and 3 unstable angina. Of the 10 patients, 8 had left SA stenosis (6 ostial to the origin and 2 in the middle segment), 1 had proximal occlusion of the left SA, and 1 had stenosis in the innominate artery (proximally to a right internal thoracic artery). Arterial access was at the brachial artery through surgical exposure (n=6), or radial artery percutaneously (n=3). In 1 case of proximal occlusion of the left SA, simultaneous femoral and percutaneous radial access was necessary. Predilatation of the stenotic lesion was performed in 6. Balloon expandable stents were used in 7 patients with proximal ostial stenosis or occlusion and self-expandable stents in 2 with nonostial lesions. In 1 other patient with proximal heavy calcified stenosis, cutting-balloon predilatation was performed, resulting in dissection of the SA and occlusion of the ITA graft; blood flow was restored in the left upper arm and myocardium by adjunctive dilatation of the SA and endovascular coronary revascularization. No patients developed angina during the follow-up period (15±7 months). CONCLUSIONS: A tailored endovascular approach can be used to treat CSSS. However, the occurrence of potentially lethal complications is possible and needs prompt correction.

Nestin and WT1 expression in atheromathous plaque neovessels: association with vulnerability.

INTRODUCTION: Neoangiogenesis is crucial for the progression and vulnerability of atheromasic lesions. Since adult vasa vasorum, which represent the neoangiogenetic burden of healthy arteries, constitutively express Nestin and Wilms Tumor (WT1), the aims of the present study are: i) to describe and quantify Nestin and WT1 in plaque neovessels; ii) to investigate the relationship between neovessel phenotype and plaque instability. METHODS: We prospectively evaluated 49 consecutive carotid endarterectomy specimens. Histopathological characteristics were separately collected, particularly the intraplaque histological complications. Immunohistochemistry was carried out for CD34, Nestin and WT1; the density of positivity was evaluated for each marker. RT-PCR was performed to assess Nestin and WT1 mRNA levels on the first 10 plaques and on 10 control arteries. RESULTS: Six (12.2%) plaques showed no neoangiogenesis. In the others, the mean immunohistochemical densities of CD34, Nestin, and WT1-positive structures were 41.88, 28.84 and 17.68/mm2. Among the CD34+ neovessels, 68% and 42% expressed Nestin and WT1 respectively, i.e., nearly 36% of the neovessels resulted to be Nestin+/WT1-. Furthermore, complicated plaques (n=30) showed significantly more CD34 and Nestin-positive vessels than uncomplicated plaques (n=13; P=0.045 and P=0.009), while WT1 was not increased (P=0.139). RT-PCR confirmed that WT1 gene expression was 3-fold lower than Nestin gene in plaques (p=0.001). CONCLUSIONS: Plaque neoangiogenesis shows both a Nestin+/WT1- and a Nestin+/WT1+ phenotype. The Nestin+/WT1- neovessels are significantly more abundant in complicated (vulnerable) plaques. The identification of new transcription factors in plaque neoangiogenesis, and their possible regulation, can open new perspectives in the therapy of vulnerable plaques.

The influence of study design on the evaluation of ruptured abdominal aortic aneurysm treatment.

BACKGROUND: The best strategy in the treatment for ruptured abdominal aortic aneurysm (RAAA) is an ongoing matter of debate. Differently from several retrospective studies, recent randomized controlled trials (RCTs) failed to demonstrate the superiority of endovascular repair (EVAR) over open repair (OPEN). The aim of the present study was to compare 30-day mortality of EVAR and OPEN in RAAA according to different study designs through a systematic review and meta-analysis. METHODS: A systematic literature search of all series comparing the outcome of EVAR and OPEN in RAAA was performed. Studies on symptomatic aneurysms without frank ruptures were excluded. The analyses evaluated the effect of the study design on EVAR versus OPEN 30-day mortality. The pooled mortality risk was expressed as odds ratio (OR) with a 95% confidence interval (CI) by random effect model. RESULTS: Four different study designs were evaluated. 1) Patients allocation in EVAR or OPEN was "unbiased" (3 studies, 2 RCTs): there was no superiority treatment in EVAR versus OPEN (OR, 1.58; 95% CI, 0.82-3.06; P = 0.17). 2) Patients submitted to EVAR were compared with a historical OPEN group (2 studies): no difference between EVAR and OPEN (OR, 3.55; 95% CI, 0.47-26.62; P = 0.22). 3) EVAR was the preferential treatment and OPEN was confined to patients with unsuitable anatomy for endovascular procedures (18 studies): in this type of study OPEN had a higher risk of 30-day mortality (OR, 2.18; 95% CI, 1.61-2.96; P < 0.00001). 4) The 30-day mortality after EVAR introduction in centers using both EVAR and OPEN was compared with the only OPEN treatment (7 studies): the latter had higher mortality compared with the protocol with both EVAR and OPEN options (OR, 2.26; 95% CI, 1.41-3.63; P = 0.0007). CONCLUSIONS: Only few studies are available to compare EVAR and OPEN in an "unbiased" cohort, with no significant differences between the 2 treatments. However, after the introduction of EVAR and OPEN protocols, the overall mortality for RAAA was reduced compared with the only OPEN option, suggesting a beneficial effect of EVAR in selected cases.

Impact of postoperative transient ischemic attack on survival after carotid revascularization.

OBJECTIVE: Major postoperative complications such as stroke and myocardial infarction are usually carefully evaluated in the analysis of carotid revascularization performance. Although transient ischemic attacks (TIAs) are often left unreported, they also may influence long-term outcome. The aim of our study was to evaluate the influence of postoperative TIA in the long-term survival of patients submitted to carotid revascularization. METHODS: All consecutive patients submitted to either carotid artery stenting or carotid endarterectomy for symptomatic or asymptomatic carotid stenosis from 2005 to 2012 were retrospectively analyzed. Patients were stratified according to their postoperative (30-day) neurologic course (no symptoms, TIA, or stroke). Kaplan-Maier with log-rank analysis was performed to compare the 5-year survival of patients with postoperative TIA, stroke, or neither; factors affecting the 5-year mortality were evaluated by multivariable Cox proportional hazards models. RESULTS: Over a total of 1390 carotid revascularizations (carotid endarterectomy, n = 868 [62.4%]; carotid artery stenting, n = 522 [37.6%]), neurological perioperative complications occurred in 67 (4.7%) cases (38, 2.7% TIA; 29, 2.0% stroke). At 5-year follow-up, overall survival was significantly lower in patients with postoperative TIA (78.4 ± 8.0% vs 97.4 ± 0.6%; P < .001) and postoperative stroke (68.2 ± 14.4% vs 97.4 ± 0.6%; P = .03) compared with patients without neurological complications. By means of multivariate Cox analysis, postoperative TIA and stroke were independent predictors of decreased survival (hazard ratio [HR], 3.10; 95% confidence interval [CI], 1.01-9.72; P = .04, and HR, 3.87; 95% CI, 1.13-13.19; P = .03, respectively), other than age >80 years, postoperative myocardial infarction, and chronic renal failure (HR, 2.07; 95% CI, 1.41-4.90; P = .01; HR, 4.33; 95% CI, 2.74-23.79; P = .04; HR, 2.54; 95% CI, 1.04-6.19; P = .04, respectively). CONCLUSIONS: TIAs are significant events, possibly determined by a wider extent of atherosclerotic disease, with important effects on long-term mortality similar to that in strokes. Different from most trials evaluating the outcomes of revascularization techniques, the incidence of perioperative TIA should be accurately considered in the analysis.

Inflammatory mediators and cerebral embolism in carotid stenting: new markers of risk.

PURPOSE: To investigate serological predictors of risk for cerebral embolism after carotid artery stenting (CAS). METHODS: Twenty consecutive symptomatic and asymptomatic patients (13 men; mean age 74 years) with carotid artery stenosis undergoing standardized filter-protected CAS (Wallstent) were preoperatively evaluated to identify unstable plaque (duplex ultrasound), complicated aortic plaque (transesophageal echocardiography), and inflammatory status [high-sensitivity C-reactive protein (hs-CRP) and serum amyloid-A protein (SAA) serum levels]. Aortic arch type, carotid tortuosity, and complexity of the procedure were considered. Cerebral embolism was evaluated by comparing the number, volume, and side (ipsilateral and non-ipsilateral) of preoperative and postoperative cerebral lesions detected on diffusion-weighted resonance magnetic imaging (DW-MRI) and through light and scanning electron microscopy analysis of cerebral protection filters obtained from CAS. RESULTS: All CAS procedures were completed with no complications. All patients had a negative preoperative DW-MRI, but at least 1 asymptomatic cerebral lesion appeared on DW-MRI after the procedure in 18 (90%) patients. Female gender was associated with a higher number of cerebral lesions (18.2±10.9 vs. 8.3±8.8 for men, p=0.03). Carotid plaque morphology, supra-aortic vessel anatomy, and procedure complexity did not correlate with number or volume of new cerebral lesions. Complicated aortic plaque was associated with a higher volume of non-ipsilateral cerebral lesions than uncomplicated plaque (235.0±259.3 vs. 63.6±63.2 mm(3), respectively; p=0.02). Hs-CRP ≥5 mg/L and SAA ≥10 mg/L were significantly associated with a higher number of new cerebral lesions [16.2±10.7 vs. 4.3±3.4 for hs-CRP <5 mg/L (p=0.02) and 14.8±10.3 vs. 2.8±3.4 for SAA <10 mg/L (p=0.006), respectively]. Hs-CRP ≥5 mg/L and SAA ≥10 mg/L also correlated with greater surface involvement by embolic materials in the protection filters at microscopic analysis [37.0% (5.1%) vs. 26.9% (2.5%) for hs-CRP <5 mg/L, p=0.004; 35.9% (13.5%) vs. 22.2% (6.9%) for SAA <10 mg/L, p=0.02]. CONCLUSION: In addition to female gender and the presence of complicated aortic plaque, inflammatory status can be a predictor of cerebral embolism in CAS.

Perioperative outcome of carotid endarterectomy according to type and timing of neurologic symptoms and computed tomography findings.

BACKGROUND: Carotid endarterectomy (CEA) in the early period after the onset of cerebral neurologic symptoms seems to be useful in the prevention of recurrent stroke while safety is still under debate. Asymptomatic carotid artery stenosis could be associated with silent cerebral ischemic events (CIEs) detectable on cerebral computed tomographic (CT) scans, but is not clear if (or how) silent cerebral lesions could influence the outcome of CEA. The aim of our work was to analyze the outcome of CEA according to the timing and type of neurologic symptoms and to evaluate the outcome of CEA in asymptomatic patients with silent cerebral events detected with preoperative cerebral CT scans. METHODS: Consecutive patients who underwent CEA between January 2006 and December 2010 were collected in a dedicated database and divided into a symptomatic group (with CEA performed within 2 weeks, 2-4 weeks, and 4-24 weeks after occurrence of the symptoms) and an asymptomatic group (with either positive-according to the classification of Stevens et al.-or negative preoperative cerebral CT scan) to evaluate the perioperative outcome in terms of CIEs, myocardial infarction (MI), and death. Results were compared using the chi-squared test, analysis of variance, and multivariate analysis. RESULTS: During the study period, 610 CEAs were performed, resulting in 16 (2.6%) CIEs (10 [1.6%] strokes and 6 [1.0%] transient CIEs), 6 (1.0%) MIs, and 3 (0.5%) deaths. Symptomatic patients (n = 162; 22.6%) were independently associated with a higher incidence of stroke and MI compared with asymptomatic patients (7 [5.1%] vs. 3 [0.7%]; P < 0.002; 2 [1.4%] vs. 4 [0.9%]; P < 0.02; respectively). The analysis of CEA outcome according to the timing of revascularization found no differences among groups within 2 weeks (5 [7.9%]), 2-4 weeks (no events), and after 4 weeks (6 [7.4%]); in the same manner, the type of preoperative symptom was not associated with significant differences in outcome. Preoperative positive cerebral CT scans were present in 88 (19.6%) asymptomatic patients and were associated with a higher incidence of perioperative CIEs (7 [7.9%] vs. 2 [0.5%]; P = 0.001), transient CIEs (4 [4.5%] vs. 2 [0.5%]; P = 0.004), and stroke (3 [3.0%] vs. 0 [0.0%]; P = 0.001). CONCLUSIONS: Although symptomatic patients have a higher risk of perioperative complications compared with asymptomatic patients, early CEA after symptom onset does not influence the results. Asymptomatic patients with positive CT scans who undergo CEA have a higher rate of neurologic complications.

Carotid revascularization in patients with ongoing oral anticoagulant therapy: the advantages of stent placement.

PURPOSE: To assess the influence of oral anticoagulant therapy conversion to heparin (OAT-CH) on carotid endarterectomy (CEA) outcomes and the influence of unmodified oral anticoagulant therapy (OAT) on carotid artery stenting (CAS) and to compare the outcomes of CEA in OAT-CH with CAS in ongoing OAT. MATERIALS AND METHODS: The 30-day results from all patients who underwent CEA and CAS in a 6-year period were analyzed for stroke, death, myocardial infarction (MI), and hematoma of the access site requiring surgical evacuation. We evaluated the influence of OAT-CH in CEA and the influence of OAT in CAS and compared CEA and CAS outcomes in patients receiving OAT-CH and OAT. RESULTS: Among 1,222 carotid revascularizations, there were 711 CEAs (58.1%) and 511 CAS procedures (41.9%). In the CEA group, 31 (4.4%) patients were treated with OAT-CH, and these patients had a significantly higher complication rate compared with patients not receiving OAT, including death (1 [3.2%] vs 4 [0.6%]; P = .04), stroke (4 [12.9%] vs 10 [1.4%]; P = .001), and hematoma (3 [9.6%] vs 11 [1.6%]; P = .02). In CAS, the results were similar in patients receiving OAT (30 [5.8%]) and patients not receiving OAT. Patients receiving OAT who underwent CAS had better outcomes than patients receiving OAT-CH who underwent CEA, including stroke, death, MI, and hematoma combined (0 [0.0%] vs 7 [22.5%]; P =.01). CONCLUSIONS: OAT management significantly influences the results of carotid revascularization. Because CAS with unmodified OAT had a significantly better outcome than CEA with OAT-CH, carotid revascularization strategies should favor CAS rather than CEA in this setting.