Gene-regulatory networks (GRNs) offer a mechanistic framework for dissecting the complex molecular and genetic architecture of coronary artery disease and for identifying new therapeutic opportunities. Here, we present a GRN-driven drug-repurposing strategy that integrates transcriptional signatures induced by silencing key drivers of the human arterial wall foam cell regulator GRN 42 with drug-induced gene expression profiles from the NIH LINCS program. In vitro screening of top candidate compounds validates the computational predictions, identifying candidate foam cell modulators and showing that auranofin, an FDA-approved gold salt used to treat rheumatoid arthritis, effectively reduces foam cell formation. In vivo, auranofin attenuates atherosclerosis and inflammation in both male mice and rabbits. Clinically, auranofin was associated with reduced cardiovascular risk in a retrospective cohort of patients with rheumatoid arthritis. Together, these findings show that a GRN-based drug-repurposing framework, coupled with preclinical and clinical validation, can uncover new therapeutic applications for existing drugs, including auranofin, in coronary artery disease. Gene regulatory networks (GRNs) are powerful platforms to unravel the genetic complexity of coronary artery disease (CAD). Here, the authors show that a GRN-based drug repurposing coupled with pre-clinical and clinical validation uncovers auranofin as a new potential CAD therapy.

Background: Fenestrated endografts have been a safe and effective solution in our institution for patients with juxtarenal abdominal aortic aneurysms (AAAs) that were not candidates for conventional repair and had suitable anatomy. The objective of our study was to evaluate the longterm outcomes of these interventions. Methods: Between September 2005 and December 2021, this study included all the patients bearing juxtarenal aneurysm electively treated with a fenestrated endograft. We conducted a retrospective analysis of prospectively collected monocentric data. Preoperative, perioperative, and postoperative data were processed. Postoperative follow-up included at least a systematic computed tomography scan at 6, 12, 18, and 24 months then every year. Secondary procedure was defined as any additional procedure performed to treat aneurysm or endograft-related complications after index procedure. Demographic and perioperative data were analyzed descriptively. Overall survival and freedom from secondary procedures were determined using the Results: A total of 169 patients (92% male) were treated by fenestrated endograft with a mean 55 +/- 37 months follow-up. The median aneurysm diameter was 59 mm. In 39 patients (23.1%), we performed a secondary procedure, by endovascular means in 57% of cases, mostly after the first year of follow-up (53.8%). The most frequent cause for secondary procedure was type 1b endoleak due to the evolution of aneurysmal disease of the iliac arteries (25.6%), followed by endograft limb thrombosis (20.5%), local complications related to index procedure (17.9%) and procedures performed to insure target vessel patency over time (18%). On the last CT scan of the follow-up, patients without secondary procedure were significantly more likely to present a shrinkage of the aneurysmal sac (P - 0.001), defined as a modification of the maximum diameter > 5 mm. Overall survival was not significantly different between patients that had secondary procedures compared to those that had not (80 months vs. 62 months, P - 0.3). Freedom from secondary procedures was 87% at 24 months and 63% at 60 months. Excluding secondary procedures within 30 days, freedom from secondary procedures was 76% at 50 months. Conclusions: Fenestrated endografts constitute a sustainable therapeutic solution in the treatment of juxtarenal AAAs. The occurrence of late complications justifies a rigorous follow-up of treated patients.

Current planning of aortic and peripheral endovascular procedures is largely based on manual measurements performed from 3D reconstructions of preoperative CT-scan. Assessment of device behavior inside patient anatomy is often difficult and available tools, such as 3D-printed models, have several limitations.Digital twin (DT) technology has been used successfully in automotive and aerospace industries and applied recently to endovascular aortic aneurysm repair. Artificial intelligence (AI) allows the treatment of large amounts of data and its use in medicine is increasing rapidly. The aim of the present review is to present the current status of DT combined with AI for planning endovascular procedures.Patient-specific DTs of aorta are generated from preoperative CT-scan and integrate aorta mechanical properties using finite element analysis. Same methodology is used to generate 3D models of aortic stent-grafts (SG) and simulate their deployment. Post-processing of DT models is then performed to generate multiple parameters related to SG oversizing and apposition. Machine learning algorithms allow to compute parameters into a synthetic index to predict type 1A endoleak risk. Other planning and sizing applications include custom-made fenestrated and branched stent-grafts for complex aneurysms.DT technology is also being investigated for planning peripheral endovascular procedures such as carotid artery stenting.DT provides detailed information on endovascular device behavior. Analysis of DT derived parameters with machine learning algorithms may improve accuracy in predicting complications such as type 1A endoleaks.

The development of new immunotherapies to treat the inflammatory mechanisms that sustain atherosclerotic cardiovascular disease (ASCVD) is urgently needed. Herein, we present a path to drug repurposing to identify immunotherapies for ASCVD. The integration of time-of-flight mass cytometry and RNA sequencing identified unique inflammatory signatures in peripheral blood mononuclear cells stimulated with ASCVD plasma. By comparing these inflammatory signatures to large-scale gene expression data from the LINCS L1000 dataset, we identified drugs that could reverse this inflammatory response. Ex vivo screens, using human samples, showed that saracatinib—a phase 2a-ready SRC and ABL inhibitor—reversed the inflammatory responses induced by ASCVD plasma. In Apoe −/− mice, saracatinib reduced atherosclerosis progression by reprogramming reparative macrophages. In a rabbit model of advanced atherosclerosis, saracatinib reduced plaque inflammation measured by [ 18 F]fluorodeoxyglucose positron emission tomography–magnetic resonance imaging. Here we show a systems immunology-driven drug repurposing with a preclinical validation strategy to aid the development of cardiovascular immunotherapies.

Visceral artery aneurysms (VAAs) are rare vascular lesions that can be life-threatening. Despite their severity, they are underestimated and underdiagnosed because they are often asymptomatic. Artificial Intelligence (AI) has brought new techniques in medical imaging, including segmentation of the vascular system, thus offering new opportunities to better diagnose VAAs. The aim of this pilot study was to develop a deep learning method for fully automatic VAA detection from angio-CTs.

To evaluate the short and mid-term consequences on the renal function and the mortality of the coverage of polar renal arteries during the endovascular treatment of juxtarenal renal aneurysms (JRA) with fenestrated stentgrafts.

Introduction: The identification of new treatments for atherosclerosis (ACVD), a common complex disease, is a daunting task because sets of genes, rather than individual genes, control cell functions. Using systems genetics, our team identified gene regulatory network (GRN42) that is active in the human atherosclerotic arterial wall and is involved in the regulation of foam cell formation. Hypothesis: A network-driven drug repurposing approach combined with rigorous preclinical validation will identify new uses for existing drugs to treat ACVD. Methods: We developed a GRN42-based computational drug repurposing pipeline to infer new uses for existing drugs. Selected compounds were screened by measuring their ability to inhibit foam cell formation in vitro using THP-1-derived macrophages. The in vivo efficacy was validated in ApoE-/- mice fed a western diet by histology and in atherosclerotic rabbits using histology and non-invasive 18 F-FDG PET-MR imaging. Results: 30 candidate compounds were predicted to influence the function of GRN42 and 5 were selected for in vitro screening based on their prediction scores (Figure 1A). As expected, vitamin D reduced cholesteryl esters accumulation in foam cells. Auranofin, and FDA-approved drug for rheumatoid arthritis reduced foam cell formation. As predicted methyl-fasudil had no effect, while nicardipine and flutamide increased foam cell formation (Figure 1B). Auranofin reduced plaque burden in ApoE-/- mice (Figure 1C) and in rabbits reduced lipid accumulation (Figure 1D) and inflammation shown as reduced 18 F-FDG uptake in the arterial wall (Figure 1E). Conclusions: Our results provide robust evidence that a GRN-based computational drug repurposing approach, when combined with robust preclinical validation using translational molecular imaging, can successfully identify new uses of existing drugs for the treatment of ACVD.

The mortality of IMHs is related with aortic complications (AC). The objective of this study was to analyze the mid-term results of the treatment of the IMHs and to determine the predictive factors of the occurrence of ACs

High‐risk atherosclerotic plaques are characterized by active inflammation and abundant leaky microvessels. We present a self‐gated, dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) acquisition with compressed sensing reconstruction and apply it to assess longitudinal changes in endothelial permeability in the aortic root of Apoe −/− atherosclerotic mice during natural disease progression. Twenty‐four, 8‐week‐old, female Apoe −/− mice were divided into four groups (n = 6 each) and imaged with self‐gated DCE‐MRI at 4, 8, 12, and 16 weeks after high‐fat diet initiation, and then euthanized for CD68 immunohistochemistry for macrophages. Eight additional mice were kept on a high‐fat diet and imaged longitudinally at the same time points. Aortic‐root pseudo‐concentration curves were analyzed using a validated piecewise linear model. Contrast agent wash‐in and washout slopes ( b 1 and b 2 ) were measured as surrogates of aortic root endothelial permeability and compared with macrophage density by immunohistochemistry. b 2 , indicating contrast agent washout, was significantly higher in mice kept on an high‐fat diet for longer periods of time ( p = 0.03). Group comparison revealed significant differences between mice on a high‐fat diet for 4 versus 16 weeks ( p = 0.03). Macrophage density also significantly increased with diet duration ( p = 0.009). Spearman correlation between b 2 from DCE‐MRI and macrophage density indicated a weak relationship between the two parameters (r = 0.28, p = 0.20). Validated piecewise linear modeling of the DCE‐MRI data showed that the aortic root contrast agent washout rate is significantly different during disease progression. Further development of this technique from a single‐slice to a 3D acquisition may enable better investigation of the relationship between in vivo imaging of endothelial permeability and atherosclerotic plaques' genetic, molecular, and cellular makeup in this important model of disease.

A 35-year-old man, with a deep pectus excavatum due to a Marfan syndrome treated 9 years before for an acute type A dissection involving only the aortic arch, by a Bentall surgery, was admitted for acute chest pain. Computed tomography (CT) scan showed an acute type non-A non-B dissection extending to the iliac. After 5 days with strict arterial blood pressure management, the patient had recurrent refractory chest pain and a hybrid technique associating full supra-aortic vessels debranching and STABILISE technique during the same procedure was performed. The patient had an uneventful recovery with CT scan showing complete aortic arch aneurysm exclusion.

INTRODUCTION:Patients exposed to nilotinib for chronic myeloid leukemia (CML) appear to be at risk of arterial complication. The prevalence and aspect of ultrasound asymptomatic arterial lesions are unknown.OBJECTIVE:To describe prevalence and characteristics of ultrasound arterial anomalies in patients treated with nilotinib for CML.METHODS:Patients treated with nilotinib from 2006 to 2015 in the department of the Paoli-Calmettes Institute, Marseille, were included retrospectively. A vascular ultrasound screening was carried out from 2010. The arterial lesions at the first examination were described: plaque and its echogenicity, stenosis or occlusion. A vascular arterial anomaly (VAA) was defined by the presence of a clinical and/or ultrasound anomaly. Patients with or without VAA at initial vascular examination were compared using bivariate and multivariate analysis.RESULTS:74 patients were included (51.4% men, mean age 54.5 years); 25 patients had ultrasound arterial anomalies (33.8%). Carotid bulb was the most involved territory (44%). Arterial anomalies were: 88% plaques, 44%>50% stenosis and 12% occlusion. 72.7% plaques were echolucent or hypoechogenic. A VAA was present in 25 patients with initial vascular evaluation (33.8%). Patients with VAA at baseline were significantly older (64.9 vs 49.3, P<0.001), older at nilotinib initiation (60.8 vs 46.5, P<0.001), with more arterial hypertension (40% vs 12.2%, P=0.01), with more cardiovascular risk factors (P=0.03). In patient with no cardiovascular risk factor 12.5% had VAA (n=24).CONCLUSION:Nilotinib seems to be associated to arterial lesions of unstable lipid-like appearance. The most involved arterial territory was the carotid bulb and the most common lesion was echolucent or hypoechogenic plaque. VAA can occur in patients without cardiovascular risk factors. This result encourages us to systematically screen and follow all patients exposed to nilotinib even those without cardiovascular risk factors.

Initially reported in 2014,1 the STABILISE technique has recently gained popularity due to excellent post-operative results and the possible positive aortic remodelling during follow up.2–4 However, this technique which requires fenestration of the intimal flap, creating false lumen aortic wall systemic blood pressure pressurisation, may be associated with aneurysmal evolution. Based on recent reports of the technique, including a series of seven patients with connective tissue disorder (CTD) suggesting that STABILISE is feasible and safe in this particular subset of patients,3 complicated acute type B aortic dissections (c-ATBAD) were treated by STABILISE in all the patients with suitable anatomy.

Introduction: Inflammation is a key driver of atherosclerosis. The identification of new treatments and strategies targeting the specific inflammatory signaling that persists in optimally treated atherosclerotic patients remain an unmet clinical need. Hypothesis: The integration of time-of-flight mass cytometry (CyTOF), gene expression analysis, and drug repositioning computational approaches applied to pre-clinical validation in models of the disease using non-invasive imaging will help to identify drugs tailored to residual inflammatory signaling in patients with atherosclerosis. Methods: We developed a new systems biology pipeline to identify new therapeutic/indication pair that combines CyTOF and RNA sequencing (RNA-seq) data analysis of clinical samples from patients with carotid and coronary artery disease (CVD) ( Fig. 1A ). This approach allowed the identification of new uses for existing compounds. The predicted anti-atherosclerotic effect was validated in ApoE-/- mice and in a rabbit model of atherosclerosis using 18 F-Fluorodeoxyglucose (FDG) PET-MRI. Results: We found a specific inflammatory signature in CD14 + monocytes stimulated with CVD plasma that was used to identify 50 small molecules predicted to reverse this signature. CyTOF screening of the top eight candidate compounds showed that Saracatinib—a phase 2a-ready Src/Abl inhibitor—blunted the inflammatory response found in CD14 + monocytes ( Fig. 1B ). The anti-atherosclerotic efficacy of Saracatinib was confirmed in ApoE-/- mice fed a high fat diet ( Fig.1C ). In the atherosclerotic rabbit model, Saracatinib reduced plaque inflammation measured as reduction of 18 F-FDG uptake by PET-MRI ( Fig. 1D ). Conclusions: These data support the use of our integrated systems biology pipeline as a powerful approach to identify new immune signature specific to patients with atherosclerosis that can be leveraged to identify new indications for existing drugs to treat cardiovascular disease.

OBJECTIVE:Failed endovascular infrarenal aortic aneurysm repair (EVAR) due to development of late type Ia endoleak exposes patients to the risk of rupture and should be treated. The purpose of this study was to evaluate the results of fenestrated/branched EVAR (F/BEVAR) for treatment of failed EVAR with type Ia endoleak. METHODS:From January 2010 to December 2019, a prospective multicentre study was conducted (ClinicalTrials.gov identifier: NCT04532450) that included 85 consecutive patients who had undergone F/BEVAR to treat a type Ia endoleak following EVAR. The primary outcome was overall freedom from any re-intervention or death related to the F/BEVAR procedure. RESULTS:In 30 cases (35%) EVAR was associated with a short < 10 mm or angulated (> 60°) infrarenal aortic neck, poor placement of the initial stent graft (n = 3, 4%), sizing error (n = 2, 2%), and/or stent graft migration (n = 7, 8%). Type Ia endoleak was observed after a period of 59 ± 25 months following EVAR. The authors performed 82 FEVAR (96%) and three BEVAR (4%) procedures with revascularisation of 305 target arteries. Overall technical success was 94%, with three failures including one persistent Type Ia endoleak and two unsuccessful stent graft implantations. Intra-operative target artery revascularisation was successful in 303 of 305 attempts. The in hospital mortality rate was 5%. Cardiac, renal and pulmonary complications occurred in 6%, 14%, and 7% of patients, respectively. Post-operative spinal cord ischaemia occurred in four patients (4.7%). At three years, the survival rate was 64% with overall freedom from any re-intervention or aneurysm related death of 40%, and freedom from specific F/BEVAR re-intervention of 73%. At three years, the secondary patency rate of the target visceral arteries was 96%. During follow up, 27 patients (33%) required a revision procedure of the fenestrated (n = 11) or index EVAR stent graft (n = 16), including six open conversions. CONCLUSION:While manufactured F/BEVAR was effective in treating type Ia endoleak in patients with failed EVAR, it was at the cost of a number of secondary endovascular and open surgical procedures.

Background: Common femoral artery (CFA) stenting appears as a promising alternative treatment to the open surgery for de novo CFA stenosis. The stenting of lesions just located at the CFA is simple, whereas stenting of CFA bifurcation lesions is more complex, and outcomes are still matter of debate. The aim of this study was to describe and to compare clinical outcomes of techniques used to treat simple over complex lesions for the stenting of CFA lesions. Materials/Methods: From the French randomized controlled trial, TECCO, a total of 54 patients underwent stenting intervention and were enrolled in this study. Patients were excluded if they had CFA thrombosis, restenosis, and nonatheromatous lesions. Patients were classified by simple and complex lesions based on the type of lesion. The primary end point was the primary sustained clinical improvement. Results: Eighteen patients were included in the simple lesion group, and 36 patients, in the complex lesion group. Baseline characteristics of patients were comparable between the 2 groups.The technical success was 100% in the simple lesion group and 91.7% in the complex lesion group. There was no significant difference between the 2 groups, regarding the primary sustained clinical improvement. The primary patency rates at 24 months for simple and complex lesion groups were 86.3% and 79%, respectively (P = 0.66). Freedom from target lesion revascularization was of 93.3% and 82% in the simple and complex lesion group, respectively (P = 0.34). Conclusions: The stenting technique for CFA bifurcation lesions is a safe and effective technique. More trials with a large number of patients are needed to define the optimal stenting technique.

Arterio-ureteral fistulas (AUF) are rare but their management is complex. Their non-specific clinical presentation frequently leads to a diagnostic and therapeutic delay. There are few data in the current literature which allow proposing a univocal attitude. The objective of this study was to describe the risk factors of occurrence, the diagnostic course, the treatment and its results.

OBJECTIVE:To evaluate the short and long-term results of in situ prosthetic graft treatment using rifampicin-soaked silver polyester graft in patients with aortic infection. MATERIAL AND METHOD:All the patients surgically managed in our center for an aortic infection were retrospectively analyzed. The primary endpoint was the intra-hospital mortality, secondary outcomes were limb salvage, persistent or recurrent infection, prosthetic graft patency, and long-term survival. RESULTS:From January 2004 to December 2015, 18 consecutive patients (12 men and 6 women) were operated on for aortic infection. Six mycotic aneurysms and 12 prosthetic infections, including 8 para-entero-prosthetic fistulas, were treated. In 5 cases, surgery was performed in emergency. During the early postoperative period, we performed one major amputation and two aortic infections were persistent. Intra-hospital mortality was 27.7%. The median follow-up among the 13 surviving patients was 26 months. During follow-up, none of the 13 patients presented reinfection or bypass thrombosis. CONCLUSION:This series shows that in situ revascularization with rifampicin-soaked silver polyester graft for aortic infection have results in agreement with the literature in terms of intra-hospital mortality with a low reinfection rate.

To evaluate the Zilver PTX stent for the treatment of the above-the-knee femoro-popliteal lesions in real conditions of use in France.

Objectives: With a focus on renal function, the goal of this multicentre study was to assess peri-operative complications and late mortality of open surgical repair (OSR) of juxtarenal abdominal aortic aneurysms (JRAAA). Methods: From February 2005 to December 2015, 315 consecutive patients undergoing elective OSR of a JRAAA in five French academic centres were evaluated retrospectively. The definition of JRAAA was an aortic aneurysm extending up to but not involving the renal arteries, i.e., a short neck <10 mm. End points included postoperative death; acute kidney injury (AKI) defined by the RIFLE (Risk, Injury, Failure, Loss of function, End stage renal disease) criteria; and long term follow-up with freedom from chronic renal decline (CRD) and any graft related complications. Factors predictive of renal insufficiency were determined by multivariable analysis. Results: Of 315 patients, 292 (92.6%) weremen (mean age 68 +/- 8 years), and 73 (23.2%) had baseline chronic kidney disease (CKD) with an estimated glomerular filtration rate of <60 mL/min/1.73 m(2). The level of aortic clamping was supracoeliac (n = 11), suprarenal (n = 235), or inter-renal above one renal artery (n = 69). The mean duration of renal artery clamping was 24 +/- 7 min (range 10-55 min). Eleven patients (3.5%) presented with a renal artery stenosis that was treated conservatively. Perfusion of the renal arteries with a chilled Ringer's solution was used selectively in seven patients (2.2%). The overall 30 day mortality was 0.9% (three patients). AKI occurred in 53 patients (16.8%). Nine patients (2.9%) required temporary dialysis and one patient required chronic dialysis. Predictors of AKI were pre-existing CKD (odds ratio [OR] 2.25, 95% confidence interval [CI] 1.13-4.48; p = .021], diabetes (OR 3.15, 95% CI 1.48-6.71; p = .003), hypertension (OR 3.38, 95% CI 1.33-8.57; p = .01), and age (OR 1.05, 95% CI 1.01-1.10; p = .014). The level of aortic clamping and duration of renal artery clamping were not associated with an increased risk of AKI. The Kaplan-Meier survival estimate was 71% +/- 5% at five years. Predictors of CRD during follow up were AKI (hazard ratio [HR] 15.81, 95% CI 5.26-47.54; p = .001), diabetes (HR 4.56, 95% CI 1.57-13.17; p = .005), and pre-existing CKD (HR 2.93, 95% CI 1.19-7.20; p = .019), with freedom from CRD of 89% +/- 3% at five years. Surveillance imaging was obtained by computed tomography angiography in 290 patients (92.6%) at a mean follow up of 4.3 +/- 2.4 years. Renal artery occlusion occurred in two patients (0.7% of imaged renal arteries). One patient (1.9%) had an aneurysm of the visceral aorta and eight patients had a descending thoracic aneurysm. Conclusions: This multicentre study suggests that in fit patients, open JRAAA repair can be performed with acceptable operative risk with durable results in terms of both graft integrity and preservation of renal function.