Indoxyl sulphate-initiated activation of cardiac fibroblasts is modulated by aryl hydrocarbon receptor and nuclear factor-erythroid-2-related factor 2.

In the last decade, extensive attention has been paid to the uremic toxin indoxyl sulphate (IS) as an inducer of cardiac fibroblast (cFib) activation and cardiac fibrosis in chronic kidney disease. At cellular level, IS engages aryl hydrocarbon receptor (AhR) and regulates many biological functions. We analysed how AhR inhibition by CH-223191 (CH) and overexpression of non-functional (dominant negative, DN) nuclear factor-erythroid-2-related factor 2 (NRF2), a transcription factor recruited by AhR, modulate the response of neonatal mouse (nm) cFib to IS. We also evaluated nm-cardiomyocytes after incubation with the conditioned medium (CM) of IS±CH-treated nm-cFib. IS induced activation, collagen synthesis, TLR4 and-downstream-MCP-1, and the genes encoding angiotensinogen, angiotensin-converting enzyme, angiotensin type 1 receptor (AT1r) and neprilysin (Nepr) in nm-cFib. CH antagonized IS-initiated nm-cFib activation, but did not affect or even magnified the other features. IS promoted NRF2 nuclear translocation and expression the NRF2 target Nqo1. Both pre-incubation with CH and transfection of DN-NRF2 resulted in loss of NRF2 nuclear localization. Moreover, DN-NRF2 overexpression led to greater TLR4 and MCP-1 levels following exposure to IS. The CM of IS-primed nm-cFib and to a larger extent the CM of IS+CH-treated nm-cFib upregulated AT1r, Nepr and TNFα and myostatin genes in nm-cardiomyocytes. Hence, IS triggers pro-inflammatory activation of nm-cFib partly via AhR, and AhR-NRF2 counteract it. Strategies other than AhR inhibition are needed to target IS detrimental actions on cardiac cells.

Engineering of poly(caprolactone) and poly(glycerol sebacate) small-diameter vascular prosthesis with quercetin.

The fabrication of biodegradable, bioabsorbable, and biocompatible vascular scaffolds with enhanced mechanical and biological properties that are able to modulate local inflammation and induce endothelialization after surgical implant is still a challenge. In this work, a fibrous scaffold, made of poly(ε-caprolactone) and poly(glycerol sebacate), was fabricated to be potentially used as a small-diameter graft in vascular surgery. The novelty of this research is represented by the direct incorporation of quercetin, a well-known antioxidant compound with several biological properties, into a polymeric scaffold obtaining a vascular construct able to modulate two key factors involved in postsurgical inflammation, matrix metalloproteinase-9 and endothelial nitric oxide synthase. For its production, an electrospinning apparatus, a solution made of the two polymers (both 20% (w/v), mixed at the ratio 1:1 (v/v)), and free quercetin (0.05% (w/v)) were used. Scanning electron and atomic force microscopies were employed to investigate the morphological properties of the fabricated electrospun scaffolds. Furthermore, physicochemical properties, including Fourier-transform infrared spectroscopy, mass loss, fluid uptake, quercetin release, mechanical properties, and biological activity of the scaffolds were studied. The expression of matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, and of endothelial nitric oxide synthase was evaluated when the quercetin-functionalized scaffold was exposed to  human endothelial cells treated with tumor necrosis factor-α. The results of this study confirmed the feasibility of incorporating free quercetin during the electrospinning process to impart biological properties to small-diameter vascular prostheses.

Endovascular aortic repair impact on myocardial contractility: A prospective study.

BACKGROUND: This study aimed to estimate if the altered sphygmic wave transmission may affect the left ventricular (LV) contractile function in patients undergoing endovascular aortic repair (EVAR). METHODS: A prospective single-centre study was carried out on consecutive patients undergoing EVAR for abdominal aortic aneurysm. A preoperative and 6-month single photon emission computed tomography (SPECT) with arterial stiffness measurement were performed to evaluate variations in pressure wave curve and myocardial perfusion parameters. RESULTS: From 2018 to 2020 a total of 16 patients were included in the study. Among the parameters evaluated, we found a measurable reduction of the reflected wave transit time from pre- to postoperative period, for both stress (115.13 ± 7.2 ms-111.1 ± 7.0 ms, p = .08) and rest SPECT acquisitions (115.3 ± 6.2 ms-112.2 ± 5.6 ms, p = .1). Unidirectional increase of both LV end-systolic volume (34 ± 9 mL-39 ± 8 mL, p = .02) and end-diastolic volume (85 ± 34 mL-89 ± 29 mL, p = .6) was also observed. Lastly, the ratio between the end-systolic pressure and the end-systolic volume (maximal systolic myocardial stiffness) decreased from 3.6 ± 1.5 mmHg/mL to 2.66 ± .74 mmHg/mL (p = .03). CONCLUSIONS: Our data showed that EVAR induced an altered transmission of the sphygmic wave associated with an early LV contractile impairment.

Bevacizumab encapsulation into PLGA nanoparticles functionalized with immunouteroglobin-1 as an innovative delivery system for atherosclerosis.

Atherosclerosis represents one of the main causes of death in the Western world. It is a multifactorial pathology characterized by lesions that reduce the lumen of the vessels causing serious clinical events. The extra-domain B of fibronectin is overexpressed during angiogenesis and in tissues undergoing growth and extensive remodeling, i.e., atherosclerotic plaque. Bevacizumab is a recombinant humanized monoclonal antibody that can play a central role against angiogenesis reducing the risk associated with this process in atherosclerosis. In this work, an innovative nanosystem for the targeted delivery of bevacizumab to the atherosclerotic lesion is proposed. A production protocol for poly(lactic-co-glycolic acid)-polyethylene glycol nanoparticles loaded with bevacizumab and functionalized with immunouteroglobin-1 was designed. Once functionalized nanoparticles with immunouteroglobin-1 were produced, they were characterized in terms of morphology, mean diameter, ζ-potential, association and conjugation efficiencies, bevacizumab release profile, both in phosphate buffered saline and in serum, bevacizumab stability after release, cytocompatibility, and hemocompatibility. Nanoparticle mean diameter was in the range of 217-265 nm, their surface charge was between -22 and -8 mV, and the association and conjugation efficiencies of about 76 and 59 %, respectively. Fourier transform infrared spectroscopy analysis confirmed the functionalization of their surface with immunouteroglobin-1. In vitro assays showed that the studied nanoparticles were cytocompatible, once in contact with human endothelial and murine macrophage cell lines up to 72 h, and hemocompatible, once in contact with red blood cells, at different concentrations of encapsulated bevacizumab (0.1, 1, 10, and 100 µg/mL).

Bevacizumab-Controlled Delivery from Polymeric Microparticle Systems as Interesting Tools for Pathologic Angiogenesis Diseases.

This work is a comparative study among three different biocompatible and biodegradable polymers, poly(lactic-co-glycolic acid), poly(ε-caprolactone), and poly(lactic acid), used to produce microparticles for the encapsulation of bevacizumab for drug delivery purposes. All the formulations were produced using the double emulsion water-oil-water evaporation method and characterized in terms of particle mean diameter, particle size distribution, and bevacizumab entrapment efficiency. Bevacizumab cumulative release was taken into consideration to study the dissolution kinetics from the three different polymeric delivery platforms for a period of 50 days at 37 °C in phosphate buffered saline and mathematical models of the drug release kinetic were attempted in order to describe the release phenomena from the different types of the studied microparticles. Finally, cell viability on human endothelial cell line EA.hy926 was studied to define the maximum cytocompatible concentration for each microsystem, registering the mitochondrial functionality through MTS assay.

PCSK9 and Other Metabolic Targets to Counteract Ischemia/Reperfusion Injury in Acute Myocardial Infarction and Visceral Vascular Surgery.

Ischemia/reperfusion (I/R) injury complicates both unpredictable events (myocardial infarction and stroke) as well as surgically-induced ones when transient clampage of major vessels is needed. Although the main cause of damage is attributed to mitochondrial dysfunction and oxidative stress, the use of antioxidant compounds for protection gave poor results when challenged in clinics. More recently, there is an assumption that, in humans, profound metabolic changes may prevail in driving I/R injury. In the present work, we narrowed the field of search to I/R injury in the heart/brain/kidney axis in acute myocardial infarction, major vascular surgery, and to the current practice of protection in both settings; then, to help the definition of novel strategies to be translated clinically, the most promising metabolic targets with their modulatory compounds-when available-and new preclinical strategies against I/R injury are described. The consideration arisen from the broad range of studies we have reviewed will help to define novel therapeutic approaches to ensure mitochondrial protection, when I/R events are predictable, and to cope with I/R injury, when it occurs unexpectedly.

Ischemia-reperfusion damage is attenuated by GQ-11, a peroxisome proliferator-activated receptor (PPAR)-α/γ agonist, after aorta clamping in rats.

INTRODUCTION: Ischemia-Reperfusion (I/R) damage is one of the major challenges in cardiothoracic surgeries and in a pathological manner, is identified by exacerbated damage signals resulted from blood supply restriction and subsequent flow restoration and re­oxygenation. I/R damage includes cellular dysfunction and death, impairing tissue and organ function. Inflammation and oxidative stress are known to underlie either ischemia or reperfusion, leaded by HIF, TNF-α, NF-κB, IL-6 and ROS formation. However, the available approaches to prevent I/R damage has been unsuccessful so far. As agonists of peroxisome-proliferation activation receptor (PPAR) are described as transcription factors related to anti-inflammatory factors, we proposed to observe the effects of novel dual agonist, GQ-11, in I/R-related damage. METHODS: Male, Wistar rats, 60 days age and 305 g body weight average were treated with vehicle, pioglitazone or GQ-11 (20 mg/kg) for 7 consecutive days and were submitted to aorta clamping for 30 min followed by 3 h of reperfusion. 18F-fluorodeoxyglucose (18F-FDG), an analog of glucose associated with inflammation when accumulated, was observed in liver and bowel by positron emission tomography (PET). RESULTS: GQ-11 decreased 18F-FDG uptake in liver and bowel when compared to vehicle and pioglitazone. The treatment also modulated inflammatory markers IL-10, TGF-ß, IL-6, IL1-ß, TNFα, and CCL-2, besides antioxidant enzymes such as catalase, GPx and SOD. CONCLUSION: Inflammation and oxidative stress showed to be important processes to be regulated in I/R in order to prevent exacerbated responses that leads to cell/tissue dysfunction and death. PPAR agonists - including GQ-11 - might be promising agents in a strategy to avoid tissue dysfunction and death after cardiothoracic surgeries.

A Machine Learning Model for the Identification of High risk Carotid Atherosclerotic Plaques.

Carotid artery disease is an inflammatory condition involving the deposition and accumulation of lipid species and leucocytes from blood into the arterial wall, which causes the narrowing of the carotid arteries on either side of the neck. Different imaging modalities can by implemented to determine the presence and the location of carotid artery stenosis, such as carotid ultrasound, computed tomography angiography (CTA), magnetic resonance angiography (MRA), or cerebral angiography. However, except of the presence and the degree of stenosis of the carotid arteries, the vulnerability of the carotid atherosclerotic plaques constitutes a significant factor for the progression of the disease and the presence of disease symptoms. In this study, our aim is to develop and present a machine learning model for the identification of high risk plaques using non imaging based features and non-invasive imaging based features. Firstly, we implemented statistical analysis to identify the most statistical significant features according to the defined output, and subsequently, we implemented different feature selection techniques and classification schemes for the development of our machine learning model. The overall methodology has been trained and tested using 208 cases of 107 cases of low risk plaques and 101 cases of high risk plaques. The highest accuracy of 0.76 was achieved using the relief feature selection technique and the support vector machine classification scheme. The innovative aspect of the proposed machine learning model is both the different categories of the utilized input features and the definition of the problem to be solved.

Innovative nanotools for vascular drug delivery: the atherosclerosis case study.

Cardiovascular diseases are the leading cause of mortality in the Western world. Among them, atherosclerosis represents one of the most common diseases in the modern society due to a common sedentary lifestyle, high-fat diet, and smoking. In the near future, a new approach could potentially improve the therapy of vascular pathologies, where to date the non-specific treatments present several limitations, such as poor biodistribution, quick elimination from the body, and undesired side-effects. In this field, nanotechnology has a great potential for the therapy and diagnosis of atherosclerosis with more and more recent and innovative publications. This review is a critical analysis of the results reported in the literature regarding the different and possible new approaches for the therapy and diagnosis of atherosclerosis.

[Management of cardiogenic shock: a proposal for a shared protocol]. / Gestione dello shock cardiogeno: una proposta di percorso integrato.

Cardiogenic shock (CS) is a complex and relatively rare disease. Whilst its mortality remains unacceptably high, a multidisciplinary approach based on pre-established and shared protocols may improve prognosis and ensure appropriate resource allocation. Comprehensive hemodynamic assessment and monitoring as well as tailored, goal-directed medical therapy are part of an optimal management. Moreover, mechanical support devices may be helpful as they sustain hemodynamics to a greater extent as compared to inotropes and vasopressors, while lacking their cardiotoxic effects. Therefore, they are increasingly used in CS patients. In 2019, a new protocol for the management of patients with CS was adopted at the Ospedale Policlinico San Martino (HSM) in Genoa, Italy. Following in the footsteps of similar international experiences, the HSM protocol aims at streamlining the management of these high-risk patients improving the cooperation among healthcare specialists, and also addressing the key issues of mechanical support device implantation and appropriate referral for palliative care.

Renal Ischemia/Reperfusion Early Induces Myostatin and PCSK9 Expression in Rat Kidneys and HK-2 Cells.

During visceral interventions, the transient clampage of supraceliac aorta causes ischemia/reperfusion (I/R) in kidneys, sometime resulting in acute renal failure; preclinical studies identified redox imbalance as the main driver of I/R injury. However, in humans, the metabolic/inflammatory responses seem to prevail on oxidative stress. We investigated myostatin (Mstn) and proprotein convertase subtilisin/kexin type 9 (PCSK9), proatherogenic mediators, during renal I/R. Compared to sham-operated animals, the kidneys of rats who had experienced ischemia (30 min) had higher Mstn and PCSK9 expression after 4 h of reperfusion. After 24 h, they displayed tubular necrosis, increased nitrotyrosine positivity, and nuclear peroxisome proliferator-activated receptor gamma coactivator-1alpha relocation, markers of oxidative stress and mitochondria imbalance. Mstn immunopositivity was increased in tubuli, while PCSK9 immunosignal was depleted; systemically, PCSK9 was higher in plasma from I/R rats. In HK-2 cells, both ischemia and reperfusion enhanced reactive oxygen species production and mitochondrial dysfunction. H2O2 upregulated Mstn and PCSK9 mRNA after 1 and 3.5 h, respectively. Accordingly, ischemia early induced Mstn and PCSK9 mRNA; during reperfusion Mstn was augmented and PCSK9 decreased. Mstn treatment early increased PCSK9 expression (within 8 h), to diminish over time; finally, Mstn silencing restrained ischemia-induced PCSK9. Our study demonstrates that renal I/R enhances Mstn and PCSK9 expression and that Mstn induces PCSK9, suggesting them as therapeutic targets for vascular protection during visceral surgery.

1-Year Results From a Prospective Experience on CAS Using the CGuard Stent System: The IRONGUARD 2 Study.

OBJECTIVES: The aim of this study was to evaluate the 1-year safety and efficacy of a dual-layered stent (DLS) for carotid artery stenting (CAS) in a multicenter registry. BACKGROUND: DLS have been proved to be safe and efficient during short-term follow-up. Recent data have raised the concern that the benefit of CAS performed with using a DLS may be hampered by a higher restenosis rate at 1 year. METHODS: From January 2017 to June 2019, a physician-initiated, prospective, multispecialty registry enrolled 733 consecutive patients undergoing CAS using the CGuard embolic prevention system at 20 centers. The primary endpoint was the occurrence of death and stroke at 1 year. Secondary endpoints were 1-year rates of transient ischemic attack, acute myocardial infarction, internal carotid artery (ICA) restenosis, in-stent thrombosis, and external carotid artery occlusion. RESULTS: At 1 year, follow-up was available in 726 patients (99.04%). Beyond 30 days postprocedure, 1 minor stroke (0.13%), four transient ischemic attacks (0.55%), 2 fatal acute myocardial infarctions (0.27%), and 6 noncardiac deaths (1.10%) occurred. On duplex ultrasound examination, ICA restenosis was found in 6 patients (0.82%): 2 total occlusions and 4 in-stent restenoses. No predictors of target ICA restenosis and/or occlusion could be detected, and dual-antiplatelet therapy duration (90 days vs 30 days) was not found to be related to major adverse cardiovascular event or restenosis occurrence. CONCLUSIONS: This real-world registry suggests that DLS use in clinical practice is safe and associated with minimal occurrence of adverse neurologic events up to 12-month follow-up.

Initial Clinical Experience With a New Conformable Abdominal Aortic Endograft: Aortic Neck Coverage and Curvature Analysis in Challenging Aortic Necks.

OBJECTIVES: Aim of this work was to investigate precision of deployment and conformability of a new generation GORE EXCLUDER Conformable Endoprosthesis with active control system (CEXC Device, W.L. Gore and Associates, Flagstaff, AZ, USA) by analyzing aortic neck coverage and curvature. METHODS: All consecutive elective patients affected by abdominal aortic aneurysm or aortoiliac aneurysm treated at our institution between November 2018 and June 2019 with the new CEXC Device were enrolled. Validated software was adopted to determine the available apposition surface area into the aortic neck, apposition of the endograft to the aortic wall, shortest apposition length (SAL), shortest distance between the endograft fabric and the lowest renal arteries (SFD) and between the endograft fabric and the contralateral renal artery (CFD). Pointwise centerline curvature was also computed. RESULTS: Twelve patients (10 men, median age 78 years (71.75, 81.0)) with available pre- and postoperative computed tomography angiography (CTA) were included. Technical success was obtained in all the cases. Preoperative median length of the proximal aortic neck was 16.1 mm (10.7, 21.7) and suprarenal (α) and infrarenal (ß) neck angulation were, respectively, 28.9° (15.7°, 47.5°) and 75.0° (66.9°, 81.4°). Postoperative median apposition surface coverage was 79% (69.25%, 90.75%) of the available apposition surface. SFD and CFD were 1.5 mm (0.75, 5.25) and 7 mm (4.5, 21.5), respectively. Average curvature over the infrarenal aorta decreased from 25 m-1 (21.75, 29.0) to 22.5 m-1 (18.75, 24.5) postoperatively (p=0.02). Maximum curvature did not decrease significantly from 64.5 m-1 (54.25, 92.0) to 62 m-1 (41.75, 71.5) (p=0.1). CONCLUSIONS: Our early experience showed that deployment of the CEXC Device is safe and effective for patients with challenging proximal aortic necks. Absence of significant changes between pre- and postoperative proximal aortic neck angulations and curvature confirms the high conformability of this endograft.

Dextran/poly-L-arginine multi-layered CaCO3-based nanosystem for vascular drug delivery.

The development of heterogeneous drug delivery systems leads to innovative strategies for targeted therapy of common pathologies, such as cancer, immunological and neurological disorders. Nowadays, it is possible to choose among a great variety of nanoparticles on the basis of the needs they have to satisfy. However, a candidate for the treatment of cardiovascular pathologies is still missing. In this context, a targeted therapy implies the conceptualization of nanoparticles that take active part in the treatment of vascular pathologies. The aim of this work was to provide a method to produce multi-layered calcium carbonate (CaCO3) nanoparticles encapsulating a model protein, bovine serum albumin, with model antibodies on their surface. CaCO3 nanoparticles were produced by the combination of complex coacervation and mineralization and were engineered using layer-by-layer technique with a polysaccharide, dextran sulfate, and a homo-poly-amino acid, poly-L-arginine. Morphology, biocompatibility, cellular uptake, influence on cell expression of the inflammatory marker matrix metalloproteinase-9, and hemocompatibility of the nanoparticles were studied. The presence of the dextran/poly-L-arginine layers did not negatively affect the nanoparticle overall characteristics and they did not trigger proinflammatory response in vitro. Taking together all the obtained results, we consider the proposed CaCO3 nanoparticles as a promising tool in cardiovascular field.

Prediction model of isolated iliac and abdominal aneurysms.

OBJECTIVES: We analyse the cardiovascular risk factors in patients undergoing screening for Isolated Iliac Aneurysm (IIA) and Abdominal Aortic Aneurysm (AAA) and propose a logistic regression model to indicate patients at risk of IIA and/or AAA. METHODS: A screening programme was carried out to identify the presence of aneurysm based on Duplex scan examination. Cardiovascular risk factors information was collected from each subject. A descriptive analysis for the incidence of IIA and AAA stratified by age and sex was carried out to evaluate factors incidence. A logistic regression model was developed to predict the probability of developing an aneurysm based on the observed risk factor levels. A threshold probability of aneurysm risk for a datum patient was also identified to effectively direct screening protocols to patients most at risk. RESULTS: A cohort of 10 842 patients was evaluated: 1.52% affected by IIA, 2.69% by AAA and 3.90% by at least one. Risk factors analysis showed that: IIA was correlated with cardiological status, diabetes, cardiovascular disease family history, and dyslipidaemia; AAA was correlated with cardiological status, body mass index, hypertension, and dyslipidaemia; diabetes and dyslipidaemia were the most relevant factors with at least one aneurysm. The prediction tool based on the logistic regression and the threshold probability predict the presence of IIA and AAA in 69.7% and 83.8% of cases, under k-fold cross-validation. CONCLUSIONS: The proposed regression model can represent a valid aid to predict IIA and AAA presence and to select patients to be screened.

Geometric Analysis to Determine Kinking and Shortening of Bridging Stents After Branched Endovascular Aortic Repair.

PURPOSE: To evaluate bridging stent geometry in patients who underwent branched endovascular aortic repair (B-EVAR) and to correlate the outcomes with intrinsic bridging stent characteristics aiming to identify the stent(s) that guarantees the best performance. METHODS: Pre-operative and post-operative computed tomography images of all patients undergoing B-EVAR between September 2016 and April 2019 were retrospectively analyzed. Following geometrical features were measured: target vessel take-off angle (TOA); longitudinal stent shortening; shape index (SI), intended as ratio between minimum and maximum diameter of the lumen cross sections, averaged on three segments: zone 1 (proximal stented zone), zone 2 (intermediate), and zone 3 (distal). RESULTS: Thirty-eight branches (8 right (RRA) and 8 left renal arteries (LRA), 11 superior mesenteric arteries (SMA), 11 celiac trunks (CTR)) were treated. Fluency (Bard Peripheral Vascular), COVERA (Bard Peripheral Vascular), and VBX (WLGore&Assoc) stent-grafts were implanted in 10, 12, and 16 branches, respectively. Pre-operative TOA was more acute in RRA and LRA when compared to CTR and SMA, and straightened in post-operative configuration (109.86 ± 28.65° to 150.27 ± 21.0°; P < 0.001). Comparable values of SI among the stent types were found in zone 1 (P = 0.08), whereas higher SI in VBX group was detected in zones 2 (P < 0.001) and 3 (P < 0.001). The VBX group was also the most affected by stent shortening (11.12 ± 5.65%; P = 0.001). CONCLUSION: Our early experience showed that the VBX stent offers greater stent circularity than the other devices even if a greater shortening has been observed drawing attention with regards to the decision of the nominal stent length.

COVID-19 Impact on Vascular Surgery Practice: Experience From an Italian University Regional Hub Center for Vascular Pathology.

BACKGROUND: The aim of the study is to evaluate the impact of COVID-19 pandemic on vascular surgery practice in a regional hub center for complex vascular disease. METHODS: This is an observational single-center study in which we collected clinical and surgical data during (P1) and after (P2) the COVID-19 outbreak and the lockdown measures implemented in Northern Italy. We compared those data with the two-month period before the pandemic (P0). RESULTS: Compared to P0, ambulatory activities were severely reduced during P1 and limited to hospitalized patients and outpatients with urgent criteria. We performed 61 operations (18 urgent and 43 elective), with a decrease in both aortic (-17.8%), cerebrovascular (-53.3%), and peripheral artery (-42.6%) disease treatments. We also observed a greater drop in open procedures (-53.2%) than in endovascular ones (-22%). All the elective patients were treated for notdeferrable conditions and they were COVID-19 negative at the ward admission screening; despite this one of them developed COVID19 during the hospital stay. Four COVID-19 positive patients were treated in urgent setting for acute limb ischemia. Throughout P2 we gradually rescheduled elective ambulatory (+155.5%) and surgical (+18%) activities, while remaining substantially lower than during P0 (respectively -45.6% and -25.7%). CONCLUSIONS: Despite COVID-19 pandemic, our experience shows that with careful patient's selection, dedicated prehospitalization protocol and proper use of personal protective equipment it is possible to guarantee continuity of care.

Ficolin-2 serum levels predict the occurrence of acute coronary syndrome in patients with severe carotid artery stenosis.

BACKGROUND AND PURPOSE: erosion of vulnerable atherosclerotic plaques may cause life-threatening thromboembolic complications. There is indeed an urgent need to recognize a clear-cut biomarker able to identify vulnerable plaques. Here, we focused on circulating proteins belonging to the lectin pathway (LP) of complement activation. METHODS: we analyzed mannose-binding lectin (MBL), ficolin-1, -2 and -3 (LP initiators) levels by ELISA in sera from n = 240 of an already published cohort of patients undergoing endarterectomy for severe carotid stenosis and followed-up until 18 months after surgery. Immunofluorescence followed by confocal and polarized light microscopy was used to detect LP initiator intraplaque localization. Spearman's rank test was drawn to investigate correlation between serum LP levels and circulating inflammatory proteins or intraplaque components. Survival analyses were then performed to test the predictive role of LP on long-term adverse outcome. RESULTS: ficolins, but not MBL, correlated positively with 1) high circulating levels of inflammatory markers, including MPO, MMP-8, MMP-9, ICAM-1, osteopontin, neutrophil elastase, and; 2) immune cell intraplaque recruitment. Immunofluorescence showed ficolins in calcified plaques and ficolin-2 in cholesterol-enriched plaque regions in association with macrophages. In the multivariate survival analysis, ficolin-2 serum levels predicted a major adverse cardiovascular event during the follow-up, independently of symptomatic status and inflammatory markers (hazard ratio 38.6 [95 % CI 3.9-385.2]). CONCLUSIONS: ficolins support intraplaque immune cell recruitment and inflammatory processes ultimately leading to plaque vulnerability. Especially for ficolin-2 a strong predictive value toward adverse cardiovascular events was demonstrated. This evidence offers potentially new pharmacological target to dampen the inflammatory mechanisms leading to plaque vulnerability.

Evaluation of Clinical Outcomes After Revascularization in Patients With Chronic Limb-Threatening Ischemia: Results From a Prospective National Cohort Study (RIVALUTANDO).

We evaluated the outcomes of revascularization in patients with chronic limb-threatening ischemia (CLTI) treated in real-world settings. This is a prospective multicenter cohort study with 12-month follow-up enrolling patients (n = 287) with CLTI undergoing open, endovascular, or hybrid lower extremity revascularization. The primary end point was amputation-free survival (AFS) at 12 months. Cox proportional analysis was used to determine independent predictors of amputation and restenosis. At 30 days, major adverse cardiovascular and major adverse limb events (MALE) rates were 3.1% and 2.1%, respectively. At 1 year, the overall survival rate was 88.8%, the AFS was 86.6%, and the primary patency was 70.5%. Freedom from MALE was 62.5%. After multivariate analysis, smoking (hazard ratio [HR] = 2.2, P = 0.04), renal failure (HR = 2.3, P = 0.03), Rutherford class (≥5) (HR = 3.2, P = 0.01), and below-the-knee disease (HR = 2.0, P = 0.05) were significant predictors of amputation; iloprost infusion (>10 vials) (HR = 0.64, P = 0.05) was a significant protective factor. Cilostazol administration (HR = 0.77, P = 0.05) was a significant protective factor for restenosis. Results from this prospective multicenter registry offer a consistent overview of clinical outcomes of CLTI patients at 1 year when adequately revascularized. Medical treatment, including statins, cilostazol and iloprost, were associated with improved 1-year freedom from restenosis and amputation.

Patient-specific computational fluid dynamics of femoro-popliteal stent-graft thrombosis.

Intra-stent thrombosis is one of the major failure modes of popliteal aneurysm endovascular repair, especially when the diseased arterial segment is long and requires overlapping stent-grafts having different nominal diameters in order to accommodate the native arterial tapering. However, the interplay between stent sizing, post-operative arterial tortuosity, luminal diameter, local hemodynamics, and thrombosis onset is not elucidated, yet. In the present study, a popliteal aneurysm was treated with endovascular deployment of two overlapped stent-grafts, showing intra-stent thrombosis at one-year follow-up examination. Patient-specific computational fluid-dynamics analyses including straight- and bent-leg position were performed. The computational fluid-dynamics analysis showed that the overlapping of the stent-grafts induces a severe discontinuity of lumen, dividing the stented artery in two regions: the proximal part, affected by thrombosis, is characterized by larger diameter, low tortuosity, low flow velocity, low helicity, and low wall shear stress; the distal part presents higher tortuosity and smaller lumen diameter promoting higher flow velocity, higher helicity, and higher wall shear stress. Moreover, leg bending induces an overall increase of arterial tortuosity and reduces flow velocity promoting furtherly the luminal area exposed to low wall shear stress.