Systems immunology-based drug repurposing framework to target inflammation in atherosclerosis.

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 [18F] 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.

Self-gated, dynamic contrast-enhanced magnetic resonance imaging with compressed-sensing reconstruction for evaluating endothelial permeability in the aortic root of atherosclerotic mice.

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 (b1 and b2 ) were measured as surrogates of aortic root endothelial permeability and compared with macrophage density by immunohistochemistry. b2 , 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 b2 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.

Erratum: Publisher Correction: Systems immunology-based drug repurposing framework to target inflammation in atherosclerosis.

[This corrects the article DOI: 10.1038/s44161-023-00278-y.].

Prospective Multicentre Cohort Study of Fenestrated and Branched Endografts After Failed Endovascular Infrarenal Aortic Aneurysm Repair with Type Ia Endoleak.

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.

STABILISE Technique for a Non-A Non-B Acute Aortic Dissection in Marfan Syndrome.

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.

Editor's Choice - Durability of Open Repair of Juxtarenal Abdominal Aortic Aneurysms: A Multicentre Retrospective Study in Five French Academic Centres.

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 post-operative 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%) were men (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 m2. 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.

The Common Femoral Artery Bifurcation Lesions: Clinical Outcome of Simple Versus Complex Stenting Techniques - An Analysis Based on the TECCO Trial.

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.

Consecutive failing proximal landing zones.

We report the case of a 77-year-old man who presented with successive aortic aneurysms during a 12-year period. He was first treated in 2006 for an abdominal aortic aneurysm with a bifurcated endograft, then in 2016 for a tender type IV thoracoabdominal aortic aneurysm with a proximal aortic cuff with in situ laser fenestrations. He presented in 2018 with a 9-cm distal thoracic aorta aneurysm managed by an off-the-shelf t-Branch endograft (Cook Medical, Bloomington, Ind). The perioperative course was uneventful, and 6-month follow-up computed tomography scan has shown freedom from endoleaks and branch patency. This case illustrates that apparently "healthy" aortic necks can degenerate after endovascular aneurysm repair.

Fenestrated endovascular aneurysm repair and open surgical repair for the treatment of juxtarenal aortic aneurysms.

OBJECTIVE: The objective of this study was to compare surgical risk and early and late mortality of patients treated for anatomically classified juxtarenal aortic aneurysms (JRAs) by fenestrated endovascular aneurysm repair (F-EVAR) or open surgical repair (OSR) during a period when the two treatments were available and to validate an institutional algorithm for JRA repair. METHODS: We retrospectively included all patients treated electively in our center between January 2005 and December 2015 for JRAs classified into three anatomic categories, excluding suprarenal aneurysms. Lee score and American Society of Anesthesiologists (ASA) class evaluated preoperative surgical risk. We compared clinical and radiologic parameters between the patients treated by F-EVAR and those treated by OSR. The primary study end point was 30-day mortality. We also compared 5-year survival. RESULTS: From 2005 to 2015, there were 191 patients separated into two groups, one treated by OSR (n = 134; mean age, 69 years) and the other treated by F-EVAR (n = 57; mean age, 74 years). Patients of the F-EVAR group were significantly older (P = .001). Intensive care unit length of stay was significantly higher in the OSR group (3.4 days vs 1.5 days; P = .01). Surgical risk was significantly higher in the F-EVAR group as measured by Lee score ≥2 (OSR, 8.9 %; F-EVAR, 21%; P = .02) and ASA class 3 and class 4 (OSR, 32.8%; F-EVAR, 73.6%; P = .001), whereas 30-day postoperative mortality was not significantly different (OSR, 1.5%; F-EVAR, 0%; P = .394). The 5-year survival was not significantly different in the two groups (OSR, 82.1%; F-EVAR, 69.2%). CONCLUSIONS: In this study, despite a higher surgical risk by Lee score and higher ASA class in the group of patients treated by F-EVAR, postoperative mortality was not significantly different between these groups. In our opinion, F-EVAR and OSR of JRA are complementary.

Aortic treatment in connective tissue disease.

Connective tissue disease (CTD) represents a group of genetic conditions characterized by disruptive matrix remodeling. When this process involves aortic and vascular wall, patients with CTD have a high risk of developing arterial aneurysms, dissections and ruptures. Open surgical repair is still the gold standard therapy for patients with CTD with reasonable morbidity and mortality risk. The surgical treatment of CTD often requires multiple operations. In the endovascular era, fenestrated and branched stent grafts may play a role in reducing the complications of multiple open operations. Although the long-term results of endovascular treatment in the setting of CTD are unknown, it is generally accepted that endovascular treatment is restricted to selected patients with high surgical risk. In an emergency setting, endovascular intervention can serve as a lifesaving bridge to elective open aortic repair. Aortic centers performing a large volume of complex open and endovascular aortic repairs have started to combine these two techniques in a staged fashion. The goal is to reduce the morbidity and mortality associated with extensive aortic repairs in CTD patients. For this reason, recommend endovascular therapy when a "graft-to-graft" approach is possible. In this scenario, the surgeon who performs the open repair must take into consideration future interventions. Surgical repair in any aortic segment should allow creation of proximal and distal landing zones over 4 cm to secure the sealing of a future stent graft. Connective tissue disease should be treated with a multidisciplinary approach, in high volume centers. Endovascular treatment represents a potential option in patients at high risk for open repair. Staged hybrid procedures have emerged as a way to reduce spinal cord ischemia and avoid multiple open surgeries. The aim of this article is to discuss the management of aortic diseases in CTD, focusing on to the role of standard open surgery and emerging endovascular treatment, and to give an overview of the few series published regarding this topic with a small number of patients.

Optimizing imaging and reducing radiation exposure during complex aortic endovascular procedures.

Improvements in endovascular technologies and development of custom-made fenestrated and branched endografts currently allow clinicians to treat complex aortic lesions such as thoraco-abdominal and aortic arch aneurysms once treatable with open repair only. These advances are leading to an increase in the complexity of endovascular procedures which can cause long operation times and high levels of radiation exposure. This in turn places pressure on the vascular surgery community to display more superior interventional skills and radiological practices. Advanced imaging technology in this context represents a strong pillar in the treatment toolbox for delivering the best care at the lowest risk level. Delivering the best patient care while managing the radiation and iodine contrast media risks, especially in frail and renal impaired populations, is the challenge aortic surgeons are facing. Modern hybrid rooms are equipped with a wide range of new imaging applications such as fusion imaging and cone-beam computed tomography (CBCT). If these technologies contribute to reducing radiation, they can be complex and intimidating to master. The aim of this review is to discuss the fundamentals of good radiological practices and to describe the various imaging tools available to the aortic surgeon, both those available today and those we anticipate will be available in the near future, from equipment to software, to perform safe and efficient complex endovascular procedures.

Hybrid treatment of a giant thoracic aneurysm in a 38 year-old woman.

A 38-year-old woman, with no comorbidities, presented to an outside institution with a 10-cm aortic arch and descending thoracic aortic aneurysm. After an aborted attempt at hybrid repair, she underwent successful, staged repair with zone 1 thoracic endovascular aortic repair and open aneurysmal sac revision. The patient made an uneventful recovery with computed tomographic evidence of complete aneurysmal exclusion. This case demonstrates many of the techniques and issues in the evolving field of aortic arch repair.

A novel all-retrograde approach for t-Branch implantation in ruptured thoracoabdominal aneurysm.

The off-the-shelf t-Branch device (Cook Medical, Bloomington, Ind) significantly advanced the endovascular treatment of ruptured thoracoabdominal aortic aneurysms. Improved techniques for expeditious implantation of the t-Branch may improve clinical outcomes for this emergent procedure. Currently, implantation is described using axillary and femoral access. We describe the repair of a ruptured thoracoabdominal aortic aneurysm exclusively through femoral access aided by a steerable sheath and newer generation, low-profile bridging stents.

Development and Multiparametric Evaluation of Experimental Atherosclerosis in Rabbits.

Several animal models have been developed to study atherosclerosis. Here we present a rabbit atherosclerosis model generated by surgical denudation of the aortic endothelium in combination with a high-fat and cholesterol-enriched diet. This model is characterized by the formation of vascular lesions that exhibit several hallmarks of human atherosclerosis. Due to the rabbit's relative large size, as compared to rodents, this model is suited for the imaging-guided evaluation of novel therapeutic strategies using clinical scanners. In this chapter, we present an extensive outline of the procedures to induce aortic atherosclerotic lesions in rabbits as well as methods to evaluate the disease, including noninvasive in vivo multiparametric imaging and histopathology.

Frozen elephant trunk and arch endografts for chronic thoracoabdominal aortic dissections.

Chronic aortic dissecting aneurysms (TAAD) presenting after acute Stanford type A or B dissection includes both arch and/or thoracoabdominal aortic aneurysms (TAAA). Approximately 60% of patients who survive surgical treatment of acute type A aortic dissections will require another aortic procedure. Similarly, more than 70% of patients with chronic type B aortic dissections will experience false lumen dilation at 5-year follow-up, often requiring intervention. Open or hybrid aortic repairs of complex TAAD involving the arch and the TAAA are very demanding procedures for both patients and clinicians. Open surgery remains the first line therapy in fit patients. Recent development of branched arch devices has offered an alternative option for high-risk patients. Technical challenges associated with the endovascular management of these complex aneurysms include proximal sealing zone often located in the aortic arch or the ascending aorta, narrow true lumen working space, and aortic branch perfusion by either the true or false lumen, or both. Recent studies have reported encouraging results with endovascular treatment of these complex dissecting aneurysms, especially following open ascending aortic repair. The aim of this review was to describe the available strategies for arch repair in the setting of a chronic TAAD and to determine the subset of patients that can benefit from of a totally endovascular approach.

[Thoracoabdominal aneurysms]. / Du nouveau dans les anévrysmes thoraco-abdominaux.

Endovascular treatment of thoracoabdominal aneurysms: what's new? Thoracoabdominal aneurysms (T-AAA) are aortic aneurysms that involve both the thoracic and abdominal segments of the aorta and its associated visceral branches. Although the first successful open repair was reported over 50 years ago, the risks of treatment remain considerable. As the first generations of devices available for endovascular aneurysm repair (EVAR) were relatively simple tubes or bifurcated grafts, initial attempts to extend the benefits of EVAR to patients with T-AAA lead to "hybrid solution". Good results with hybrid repairs have not been universal and the approach does not exploit all of the potential advantages of a "pure" endovascular approach (lesser surgical insult). This unmet need, together with rapid technological advances, has encouraged the development of custom-made endografts with fenestrations and/or branches (F-BEVAR) for extension into the visceral vessel ostia. F-BEVAR requires considerably more complex device design and planning than conventional EVAR. Deployment is more technically demanding and takes longer to complete. Thus, patient, aneurysm anatomy and surgical team selection is paramount. Favorable outcomes have been widely reported following T-AAA repair with F-BEVAR in expert centers; more complex aortic lesions such as T-AAA in the context of chronic dissection or arch aneurysms are thus now also offered endovascular repair with F-BEVAR.