Clinical Performance of the Low Profile Zenith Alpha Abdominal Endovascular Graft: 2 Year Results from the ZEPHYR Registry.

OBJECTIVE: The midterm outcomes of the low profile Zenith Alpha Abdominal Endovascular Graft from the ZEnith alPHa for aneurYsm Repair (ZEPHYR) registry are reported. METHODS: The ZEPHYR registry is a physician initiated, multicentre, non-randomised, core laboratory controlled, prospective registry. Inclusion criteria were patients with a non-ruptured abdominal aortic aneurysm with a maximum diameter ≥ 50 mm or enlargement > 5 mm within 6 months, with a site reported infrarenal neck length of ≥ 10 mm and with the intention to electively implant the Zenith Alpha abdominal endograft. Patients from 14 sites across Germany, Belgium, and the Netherlands were included. The primary endpoint was treatment success, defined as technical success and clinical success. Technical success was defined as successful delivery and deployment of the endograft in the planned position without unintentional coverage of internal iliac or renal arteries, with successful removal of the delivery system. Clinical success was defined as freedom from aneurysm sac expansion > 5 mm, type I or type III endoleaks, aneurysm rupture, stent graft migration > 10 mm, open conversion, and stent graft occlusion. RESULTS: Three hundred and forty-seven patients were included in the ZEPHYR registry. The median clinical follow up was 743 days (interquartile range [IQR] 657, 806) with a median imaging follow up of 725 days (IQR 408, 788). Treatment success at 6 months, 1, and 2 years was 92.5%, 90.4%, and 85.3%, respectively. Freedom from secondary intervention was 94.3%, 93.4%, and 86.9%, respectively. The predominant reason for secondary intervention was limb complications. Freedom from limb occlusion (per patient) at 6 months, 1, and 2 years was 97.2%, 95.8%, and 92.5%, respectively. Univariable and multivariable Cox regression analyses could not identify any independent predictor for limb complications. CONCLUSION: While treatment success is comparable with other commercially available grafts, the rate of limb complications at 2 years is of concern. The manufacturer's instructions for use should be followed closely. Further studies are necessary to investigate the root cause of the increased rate of limb complications with the Zenith Alpha Abdominal Endovascular Graft.

Catheter-Directed Thrombolysis Protocols for Deep Venous Thrombosis of the Lower Extremities-A Systematic Review and Meta-analysis.

OBJECTIVE: To summarize characteristics, complications, and success rates of different catheter-directed thrombolysis (CDT) protocols for the treatment of lower extremity deep venous thrombosis (LE-DVT). METHODS: A systematic review using electronic databases (MEDLINE, Scopus, and Web of Science) was performed to identify randomized controlled trials and observational studies related to LE-DVT treated with CDT. A random-effects model meta-analysis was performed to obtain the pooled proportions of early complications, postthrombotic syndrome (PTS), and venous patency. RESULTS: Forty-six studies met the inclusion criteria reporting 49 protocols (n = 3,028 participants). In studies that addressed the thrombus location (n = 37), LE-DVT had iliofemoral involvement in 90 ± 23% of the cases. Only four series described CDT as the sole intervention for LE-DVT, while 47% received additional thrombectomy (manual, surgical, aspiration, or pharmacomechanical), and 89% used stenting.Definition of venogram success was highly variable, being the Venous Registry Index the most used method (n = 19). Among those, the minimal thrombolysis rate (<50% lysed thrombus) was 0 to 53%, partial thrombolysis (50-90% lysis) was 10 to 71%, and complete thrombolysis (90-100%) was 0 to 88%. Pooled outcomes were 8.7% (95% confidence interval [CI]: 6.6-10.7) for minor bleeding, 1.2% (95% CI: 0.8-1.7%) for major bleeding, 1.1% (95% CI: 0.6-1.6) for pulmonary embolism, and 0.6% (95% CI: 0.3-0.9) for death. Pooled incidences of PTS and of venous patency at up to 1 year of follow-up were 17.6% (95% CI: 11.8-23.4) and 77.5% (95% CI: 68.1-86.9), respectively. CONCLUSION: Assessment of the evidence is hampered by the heterogeneity of protocols, which may be reflected in the variation of PTS rates. Despite this, CDT is a low-risk treatment for LE-DVT.

Perprocedural Heparinization in Non-cardiac Arterial Procedures: The Current Practice in the Netherlands.

PURPOSE: Heparin is the most widely-used anticoagulant to prevent thrombo-embolic complications during non-cardiac arterial procedures (NCAP). Unfortunately, there is a lack of evidence and consequently non-uniformity in guidelines on perprocedural heparin management. Detailed insight into the current practice of antithrombotic strategies during NCAP in the Netherlands is important, aiming to identify potential optimal protocols and local differences concerning perprocedural heparinization. MATERIALS AND METHODS: A comprehensive online survey was distributed electronically to vascular surgeons of every hospital in the Netherlands in which NCAP were performed. Data were collected from September 2020 to October 2021. RESULTS: The response rate was 90% (53/59 hospitals). During NCAP, all surgeons generally administered heparin before arterial clamping. In 74% (39/54) of hospitals, a single heparin dosing protocol was used for all types of patients and vascular procedures. In 40%, there was no uniformity in heparin dosing between vascular surgeons. Depending on the procedure, a fixed bolus heparin, predominantly 5000 IU, was administered in 73% to 93%. In the remaining hospitals (7%-27%), a bodyweight-based heparin protocol was used, with an initial dose of 70 or 100 IU/kg. A minority (28%) monitored the effect of heparin in patients using the activated clotting time add (ACT) after activated clotting time. Target values varied between 180 and 250 seconds or 2 times the baseline ACT. CONCLUSION: This survey demonstrates considerable variability in perprocedural heparinization during NCAP in the Netherlands. Future research on heparin dosing is needed to harmonize and optimize heparin dosage protocols and contemporary guidelines during NCAP, and thereby improve vascular surgical care and patient safety. CLINICAL IMPACT: This survey demonstrated persisting intra- and inter-hospital variability in perprocedural heparinization during non-cardiac arterial procedures (NCAP) in the Netherlands. The observed variability in heparinization strategies highlights the need for high quality evidence on perprocedural anticoagulation strategies. This is needed in order to harmonize and optimize heparin dosage protocols and contemporary guidelines and thereby improve vascular surgical patient care. Based on the current results, an international survey will be conducted by the authors to gain additional insight into the antithrombotic strategies used during NCAP, aiming to harmonize anticoagulation protocols worldwide.

Catheter Directed Thrombolysis for Not Immediately Threatening Acute Limb Ischaemia: Systematic Review and Meta-Analysis.

OBJECTIVE: This systematic review and meta-analysis reports the outcomes of catheter directed thrombolysis (CDT) in patients with not immediately threatening (Rutherford I) acute lower limb ischaemia (ALI). DATA SOURCES: PubMed, Embase, and the Cochrane Library. REVIEW METHODS: A systematic search of PubMed, Embase, and the Cochrane Library was performed to identify observational studies and trials published between 1990 and 2022 reporting on the results of CDT in patients with Rutherford I ALI. A meta-analysis was performed using a random effects model with 95% confidence intervals (CIs). The outcomes of interests were treatment duration, angiographic success, bleeding complications, amputation and mortality rates, primary and secondary patency, and functional outcome expressed as pain free walking distance. RESULTS: Thirty-nine studies were included, comprising 1 861 patients who received CDT for not immediately threatening ALI. Funnel plots showed an indication of publication bias, and heterogeneity was substantial. Data from 5 to 13 studies were included in the meta-analysis. The pooled treatment duration was 2 days (95% CI 1 - 2), with an angiographic success rate of 80% (95% CI 73 - 86) and a 30 day freedom of amputation rate of 98% (95% CI 92 - 100). The major bleeding rate was 5% (95% CI 2 - 14), with a 30 day mortality rate of 3% (95% CI 1 - 5). The amputation free survival rate was 71% (95% CI 62 - 80) at the one year and 63% (95% CI 51 - 73) at the three year follow up. Long term patency rates were retrieved from four studies: 48% at one year (95% CI 27 - 70). No data could be retrieved on patient walking distance. CONCLUSION: Although CDT in the treatment of not immediately threatening ALI showed high angiographic success, the long term outcomes were relatively poor, with low patency and a substantial risk of major amputation. Further research is required to interpret the outcome of CDT in the context of potential confounders such as age and comorbidities.

What we have learned from in-vitro studies of the chimney endovascular technique for treatment of complex abdominal aortic aneurysms: A systematic review.

BACKGROUND: A considerable number of patients with abdominal aortic aneurysms (AAA) is not eligible for standard endovascular repair. These complex cases require alternative surgical approaches including the readily available chimney graft endovascular aneurysm repair (Ch-EVAR) or sealing (Ch-EVAS). The optimal configuration for Ch-EVAR or Ch-EVAS is important for success but not yet known. OBJECTIVE: The aim of the present study was to analyze current data of the outcomes of in-vitro chimney graft treatment in complex AAA. METHODS: A systematic review following PRISMA guidelines was conducted including studies reporting on gutter size, main graft compression, and chimney graft compression in in-vitro configurations. RESULTS: The search resulted in 285 articles. 11 studies considering 219 individual tests could be included. Gutter size was comparable between Ch-EVAR and Ch-EVAS configurations. In Ch-EVAR set-ups, the deployed BECG were Advanta V12, VIABAHN®, and BeGraft. One type of SECG was used: VIABAHN®. The four types of main grafts (MG) deployed were: Endurant™ I/II; EXCLUDER Conformable AAA Endoprosthesis and AAA Endoprosthesis, and AFX™ Endovascular AAA Delivery System. In the EVAS-configurations, the Nellix® EVAS system was deployed. In general, SECG presented smaller gutters with higher chimney graft compression. 30% main grafts oversizing seems to give the smallest gutters without high risk of infolding of MG. Oversizing, EndoAnchors, and secondary endobag filling (in Ch-EVAS) reduced gutter sizes. CG ballooning during the entire polymer injection in Ch-EVAS prevented CG compression. CONCLUSION: In-vitro investigations provide insight in optimal Ch-EVAR and Ch-EVAS configurations for simulated complex AAA repair. The findings above might aid physicians in their planning to potential CG set-ups and can be used in future research to refine the most optimal configuration for chimney graft technique in complex AAA.

Major Bleeding During Thrombolytic Therapy for Acute Lower Limb Ischaemia: Value of Laboratory Tests for Clinical Decision Making, 17 Years of Experience.

OBJECTIVE: Regular measurement of fibrinogen as dose guidance in catheter directed thrombolysis (CDT) for acute limb ischaemia (ALI) has recently been dropped from European guidelines based on inconsistent literature. This study aimed to determine whether low fibrinogen levels and high activated partial thromboplastin time (APTT) are associated with an increased major bleeding risk during CDT. METHODS: All consecutive patients treated with CDT for ALI in two Dutch hospitals between January 2004 and April 2021 were analysed retrospectively. Patients were treated with two dosing regimens (low dose: 50 000 IU/hour; high dose: 100 000 IU/hour) of urokinase and, after 2018, with a single low dose regimen of alteplase (rtPA) due to urokinase manufacturing problems. The incidence of major bleeding and associated APTT and fibrinogen levels were reviewed from patient charts. RESULTS: Of the 443 included cases, 277 underwent CDT with urokinase and 166 with rtPA. The incidence of major bleeding in the whole cohort was 7%. Patients with a fibrinogen levels < 1.0 g/L developed more major bleeding than those in whom the fibrinogen level did not drop below 1.0 g/L (15% vs. 6%; p = .041). Systemic heparinisation during CDT or high (> 80 seconds) APTT were not significantly associated with major bleeding. Angiographic success (47% vs. 72%; p = .003) and 30 day amputation free survival (53% vs. 82%; p < .001) were lower for cases with major bleeding. Older age (odds ratio [OR] 1.06, 95% confidence interval [CI] 1.02 - 1.11), cardiac history (OR 3.35, 95% CI 1.39 - 8.06), high dose regimens (≥ 75 000 IU/hour urokinase; OR 2.67, 95% CI 1.18 - 6.04), and fibrinogen values < 1.0 g/L (OR 5.59, 95% CI 1.98 - 15.77) were independent predictors for major bleeding during CDT. CONCLUSION: High dose thrombolytic regimens and fibrinogen levels of ≤ 1.0 g/L are associated with more major bleeding during thrombolytic therapy. Major bleeding significantly worsened the clinical outcome. A prospective comparative study is needed to assess the benefit of monitoring fibrinogen levels.

Feasibility of Microbubble-Accelerated Low-Dose Thrombolysis of Peripheral Arterial Occlusions Using an Ultrasound Catheter.

PURPOSE: Intra-arterial administration of microbubbles (MBs) through an ultrasound (US) catheter increases the local concentration of MBs into the thrombus and may further enhance outcomes of contrast-enhanced sonothrombolysis (CEST). The objective of this study was to evaluate the feasibility and lytic efficacy of intra-arterial infusion of MBs during US-enhanced thrombolysis in both in vitro and in vivo peripheral arterial occluded models. MATERIALS AND METHODS: SonoVue and Luminity MBs were infused at a flow rate of 20 mL/h through either the drug delivery lumen of the US catheter (DDC, n=20) or through the tube lumen of the vascular phantom (systematic infusion, n=20) during thrombolysis with a low-dose urokinase (UK) protocol (50 000 IU/h) with(out) US application to assess MB survivability and size by pre-treatment and post-treatment measurements. A human thrombus was placed into a vascular phantom of the flow system to examine the lytic effects of CEST by post-treatment D-dimer concentrations measurements of 5 treatment conditions (saline, UK, UK+US, UK+US+SonoVue, and UK+US+Luminity). Thrombolytic efficacy of localized MBs and US delivery was then investigated in vivo in 5 porcine models by arterial blood flow, microcirculation, and postmortem determined thrombus weight and remaining length. RESULTS: US exposure significantly decreased SonoVue (p=0.000) and Luminity (p=0.000) survivability by 37% and 62%, respectively. In vitro CEST treatment resulted in higher median D-dimer concentrations for the SonoVue (0.94 [0.07-7.59] mg/mL, p=0.025) and Luminity (0.83 [0.09-2.53] mg/mL, p=0.048) subgroups when compared with thrombolysis alone (0.36 [0.02-1.00] mg/mL). The lytic efficacy of CEST examined in the porcine model showed an improved median arterial blood flow of 21% (7%-79%), and a median thrombus weight and length of 1.02 (0.96-1.43) g and 2.25 (1.5-4.0) cm, respectively. One allergic reaction and 2 arrhythmias were observed due to the known allergic reaction on lipids in the porcine model. CONCLUSION: SonoVue and Luminity can be combined with an US catheter and could potentially accelerate thrombolytic treatment of peripheral arterial occlusions. CLINICAL IMPACT: Catheter-directed thrombolysis showed to be an effective alternative to surgery for acute peripheral arterial occlusions, but this technique is still associated with several limb and life-threatening complications. The effects of thrombolysis on clot dissolution may be further enhanced by intra-arterial administration of microbubbles through an ultrasound catheter. This study demonstrates the feasibility and lytic efficacy of intra-arterial infusion of microbubbles during US-enhanced thrombolysis in both in vitro and in vivo peripheral arterial occluded models.

Identifying high risk for proximal endograft failure after endovascular aneurysm repair in patients suitable for both open and endovascular elective aneurysm repair.

OBJECTIVE: Proximal endograft failure (type Ia endoleak or migration) after endovascular aneurysm repair (EVAR) is associated with hostile aneurysm neck morphology. Neck scoring systems were developed to predict proximal endograft failure but were studied in retrospective studies, which, due to selection bias, may have led to an overestimation of bad outcomes after EVAR. To predict patients who benefit from open repair, preoperative neck morphology and occurrence of long-term proximal endograft failure were investigated in patients enrolled in the endovascular arm of the Dutch Randomized Endovascular Aneurysm Management (DREAM) trial who were suitable for open repair by definition and have long-term follow-up. METHODS: A post-hoc on-treatment analysis of patients after EVAR was performed in 171 patients. Aneurysm neck morphology was quantified using the aneurysm severity grading (ASG) neck score calculated on preoperative computed tomography angiography images. The ASG neck score was used to predict proximal endograft failure. Receiver operating characteristic analysis was performed to calculate a threshold to divide favorable and unfavorable aneurysm necks (low and high risk); positive and negative likelihood-ratios were calculated accordingly. Freedom from proximal endograft failure was compared between groups using Kaplan-Meier analysis. RESULTS: During a median follow-up of 7.6 years, 20 patients suffered proximal endograft failure. Receiver operating characteristic analysis showed an area under the curve of 0.77 (95% confidence interval [CI], 0.65-0.90; P < .001), indicating acceptable prediction. The threshold was determined at ASG neck score ≥5; 30 patients had unfavorable neck morphology, of whom 11 developed proximal endograft failure. The positive likelihood-ratio was 4.4 (95% CI, 2.5-7.8), and the negative likelihood-ratio was 0.51 (95% CI, 0.3-0.8). Twelve years postoperatively, freedom from proximal endograft failure was 91.7% in the favorable group and 53.2% in the unfavorable group, a difference of 38.5% (95% CI, 13.9-63.1; P < .001). CONCLUSIONS: In this study, the ASG neck score predicted proximal endograft failure during the entire follow-up. This exhibits the persistent risk for proximal endograft failure long after EVAR and calls for ongoing surveillance especially in patients with unfavorable aneurysm necks.

Nationwide Experience with EVAS Relining of Previous Open or Endovascular AAA Treatment in The Netherlands.

OBJECTIVE: Relining of a previously placed surgical graft or endograft for an abdominal aortic aneurysm (AAA) is a reintervention to treat progression of disease or failure of the primary (endo)graft. Endovascular Aneurysm Sealing (EVAS) relining is a technique with potential advantages due to the absence of a bifurcation, the possibility for a unilateral approach, and sealing concept of the endobags. The purpose of this study was to describe the nationwide experience with EVAS relining of previous AAA repair in the Netherlands. METHODS: A retrospective analysis of all patients who underwent EVAS relining in 7 high volume vascular centres in the Netherlands between 2014 and 2019 was performed. Primary outcomes were technical and clinical success. Secondary outcomes were perioperative outcomes, complications and survival. RESULTS: Thirty-three patients underwent EVAS relining of open (n = 10) or endovascular (n = 23) repair. 26 were elective cases, 5 were urgent and 2 were acute (ruptured). Mean time between primary treatment and EVAS relining was 99 ± 74 months. Indications after open repair were proximal progression of disease (n = 7) and graft defect (n = 3). Indications after EVAR were type IA (n = 10), type IB (n = 3), type IIIA (n = 4), type IIIB (n = 3) endoleak, and endotension (n = 3). 18 patients underwent regular EVAS, 4 unilateral EVAS and 11 chimney-EVAS. In-hospital mortality was 6% (both patients with rAAA). Technical success was achieved in 97%. Median follow-up after EVAS relining was 20 months (range 0-43). Freedom from reintervention at 1-year and 2-year were 83% and 61% and the estimated survival 79% and 71%, respectively. EVAS relining after open repair had a clinical success of 90% at 1-year and of 70% at latest follow-up, while after EVAR clinical success rates were 70% and 52%, respectively. CONCLUSION: EVAS relining of previous AAA repair is associated with high technical success, however with limited clinical success at median follow-up of 20 months. Clinical success was higher in patients with EVAS relining after open repair than after EVAR. In patients with failed AAA repair, EVAS relining should only be considered, when established techniques such as fenestrated repair or open conversion are not available or indicated.

Robot-assisted transthoracic first rib resection for venous thoracic outlet syndrome.

BACKGROUND: Venous thoracic outlet syndrome (vTOS) is caused by external compression of the subclavian vein at the costoclavicular junction. It can be subdivided in McCleery Syndrome and Paget-Schroetter Syndrome (PSS). To improve the venous outflow of the arm and to prevent recurrent thrombosis, first rib resection with venolysis of the subclavian vein can be performed. Open transaxillary, supraclavicular, infraclavicular or combined paraclavicular approaches are well known, but more recent robot-assisted techniques are introduced. We report our short- and long-term results of a minimal invasive transthoracic approach for resection of the anteromedial part of the first rib using the DaVinci surgical robot, performed through three trocars. METHODS: We analyzed all patients with vTOS who were scheduled to undergo robot-assisted transthoracic first rib resection in the period July 2012 to May 2016. Outcomes were: technical success, operation time, blood loss, hospital stay, 30-day complications and patency. Functional outcomes were assessed using the "Disability of the Arm, Shoulder and Hand" (DASH) questionnaire. RESULTS: Fifteen patients (8 male, 7 female; mean age 32.9 years, range 20-54 years) underwent robot-assisted transthoracic first rib resection. Conversion to transaxillary resection was necessary in three patients. Average operation time was 147.9 min (range 88-320 min) with a mean blood loss of 79.5 cc (range 10-550 cc). Mean hospital stay was 3.5 days (range 2-9). In three patients, complications were reported (Clavien-Dindo grade 2-3a). Patency was 91% at 15.5 months' follow-up. DASH scores at one and three years showed excellent functional outcomes (7.1 (SD= 6.9, range 0-20.8) and 6.0 (SD= 6.4, range 0-25)) and are comparable to the scores of the normative general population. CONCLUSION: Robot-assisted transthoracic first rib resection with only three trocars is a feasible minimal invasive approach for first rib resection in the management of vTOS. This technique enables the surgeon to perform venolysis under direct 3D vision with good patency and long-term functional outcome. Studies with larger cohort size are needed to compare the outcomes of this robot-assisted technique with other more established approaches.

Thirty-day Results from the ZEPHYR Registry: Outcomes of EVAR Using the Zenith Alpha™ Abdominal Endovascular Graft for the Treatment of AAA in 347 Patients.

BACKGROUND: To report technical and clinical 30-day results following treatment with the Zenith Alpha™ abdominal stent graft from the ZEnith alPHa for aneurYsm Repair Registry (ZEPHYR). METHODS: Multicenter, nonrandomized, single arm, core laboratory-controlled, prospective registry collecting data on the Zenith Alpha Abdominal Endovascular Graft being used in subjects with abdominal aortic aneurysms (AAA) from sites in Germany, Belgium, and The Netherlands between December 2016 and December 2019. Inclusion criteria were non-ruptured AAAs with a maximum diameter ≥50 mm or enlargement >5 mm over 6 months with an AAA neck length ≥10 mm (site reported). Primary outcome measure was treatment success at 30 days. Treatment success was defined as a combined endpoint consisting of technical and clinical success. Technical success was defined as successful stent graft delivery and deployment as well as successful removal of the delivery system. Clinical success at 30 days was defined as freedom from type I and III endoleak, aneurysm rupture, conversion to open surgery and stent graft occlusion. RESULTS: Three hundred forty-seven subjects were included from 14 sites with a median age of 73.0 years (IQR 68.0-79.0). Thirty-four patients were female (9.8%). The median AAA diameter was 58.3 mm (IQR 55.0-63.5). The median proximal neck diameter was 23.6 mm (IQR 22.0-25.2) with a median proximal neck length of 24.4 mm (IQR 15.0-34.8) and a median infrarenal neck angulation of 24.5° (IQR 15.0-35.0). The right and left common iliac diameter were 16.1 mm (IQR 14.1-19.4) and 16.2 mm (IQR 14.1-19.1), respectively. The treatment success rate at 30 days was 94.8% (N = 329). Technical success was achieved in 333 patients (96.0%). The clinical success rate at 30 days was 98.8% (N = 343). Three patients had limb occlusions at 30 day follow up (0.9%). One patient had a type Ib endoleak (0.3%). Seventy percent of vascular access approaches were percutaneous. The reintervention rate was 1.7% (N = 6) within 30 days. Indications for reinterventions were a false aneurysm at puncture site (N = 1), limb complications (N = 2), stentgraft-associated renal artery occlusions (N = 2), and an external iliac artery thrombosis (N = 1). CONCLUSIONS: Endovascular aneurysm repair using the Zenith Alpha Abdominal Endovascular Graft is effective in the short term. Long term results will be reported in the future.

Therapeutic Use of Microbubbles and Ultrasound in Acute Peripheral Arterial Thrombosis: A Systematic Review.

Catheter-directed thrombolysis (CDT) for acute peripheral arterial occlusion is time consuming and carries a risk of major hemorrhage. Contrast-enhanced sonothrombolysis (CEST) might enhance outcomes compared with standard CDT. In the study described here, we systematically reviewed all in vivo studies on contrast-enhanced sonothrombolysis in a setting of arterial thrombosis. A systematic search of the PubMed, Embase, Cochrane Library and Web of Science databases was conducted. Two reviewers independently performed the study selection, quality assessment and data extraction. Primary outcomes were recanalization rate and thrombus weight. Secondary outcome was any possible adverse event. The 35 studies included in this review were conducted in four different (pre)clinical settings: ischemic stroke, myocardial infarction, (peripheral) arterial thrombosis and arteriovenous graft occlusion. Because of the high heterogeneity among the studies, it was not possible to conduct a meta-analysis. In almost all studies, recanalization rates were higher in the group that underwent a form of CEST. One study was terminated early because of a higher incidence of intracranial hemorrhage. Studies on CEST suggest that adding microbubbles and ultrasound to standard intra-arterial CDT is safe and might improve outcomes in acute peripheral arterial thrombosis. Further research is needed before CEST can be implemented in daily practice.

Molecular phenotyping and functional assessment of smooth muscle-like cells with pathogenic variants in aneurysm genes ACTA2, MYH11, SMAD3 and FBN1.

Aortic aneurysms (AAs) are pathological dilatations of the aorta. Pathogenic variants in genes encoding for proteins of the contractile machinery of vascular smooth muscle cells (VSMCs), genes encoding proteins of the transforming growth factor beta signaling pathway and extracellular matrix (ECM) homeostasis play a role in the weakening of the aortic wall. These variants affect the functioning of VSMC, the predominant cell type in the aorta. Many variants have unknown clinical significance, with unknown consequences on VSMC function and AA development. Our goal was to develop functional assays that show the effects of pathogenic variants in aneurysm-related genes. We used a previously developed fibroblast transdifferentiation protocol to induce VSMC-like cells, which are used for all assays. We compared transdifferentiated VSMC-like cells of patients with a pathogenic variant in genes encoding for components of VSMC contraction (ACTA2, MYH11), transforming growth factor beta (TGFß) signaling (SMAD3) and a dominant negative (DN) and two haploinsufficient variants in the ECM elastic laminae (FBN1) to those of healthy controls. The transdifferentiation efficiency, structural integrity of the cytoskeleton, TGFß signaling profile, migration velocity and maximum contraction were measured. Transdifferentiation efficiency was strongly reduced in SMAD3 and FBN1 DN patients. ACTA2 and FBN1 DN cells showed a decrease in SMAD2 phosphorylation. Migration velocity was impaired for ACTA2 and MYH11 cells. ACTA2 cells showed reduced contractility. In conclusion, these assays for showing effects of pathogenic variants may be promising tools to help reclassification of variants of unknown clinical significance in AA-related genes.

Microbubbles and Ultrasound Accelerated Thrombolysis for Peripheral Arterial Occlusions: The Outcomes of a Single Arm Phase II Trial.

OBJECTIVE: Acute peripheral arterial occlusions can be treated by catheter directed thrombolysis (CDT). However, CDT is time consuming and accompanied by the risk of bleeding complications. The addition of contrast enhanced ultrasound and microbubbles could improve thrombus susceptibility to thrombolytic agents and potentially shorten treatment time with a lowered risk of bleeding complications. This article reports the outcomes of the safety and feasibility of this novel technique. METHODS: In this single arm phase II trial, 20 patients with acute lower limb ischaemia received CDT combined with an intravenous infusion of microbubbles and locally applied ultrasound during the first hour of standard intra-arterial thrombolytic therapy. The primary endpoint was safety, i.e., occurrence of serious adverse events (haemorrhagic complications and/or amputation) and death within one year. Secondary endpoints included angiographic and clinical success, thrombolysis duration, additional interventions, conversion, and quality of life. RESULTS: The study included 20 patients (16 men; median age 68.0 years; range, 50.0 - 83.0; and 40% native artery and 60% bypass graft). In all patients, the use of microbubble contrast enhanced sonothrombolysis could be applied successfully. There were no serious adverse events related to the experimental treatment. Duplex examination showed flow distal from the occlusion after 23.1 hours (range 3.1 - 46.5) with a median thrombolysis time of 47.5 hours (range 6.0 - 81.0). The short term ABI and pain scores significantly improved; however, no changes were observed before or after thrombolysis in the microcirculation. Overall mortality and amputation rates were both 2% within one year. The one year patency rate was 55%. CONCLUSION: Treatment of patients with acute peripheral arterial occlusions with contrast enhanced sonothrombolysis is feasible and safe to perform in patients. Further research is necessary to investigate the superiority of this new treatment over standard treatment.

Systematic review of embolization of type I endoleaks using liquid embolic agents.

OBJECTIVE: The long-term success of endovascular aneurysm repair (EVAR) is limited by complications, most importantly endoleaks. In case of (persistent) type I endoleak (T1EL), secondary intervention is indicated to prevent secondary aneurysm rupture. Different treatment options are suggested for T1ELs, such as endo anchors, (fenestrated) cuffs, embolization, or open conversion. Currently, the treatment of T1EL with liquid embolic agents is available; however, results are not yet addressed. This review presents the safety and efficacy of embolization with liquid embolic agents for treatment of T1ELs after EVAR. METHODS: A systematic literature search was performed for all studies reporting the use of liquid embolic agents as monotherapy for treatment of T1ELs after EVAR. Patient numbers, technical success (successful delivery of liquid embolics in the T1EL) and clinical success (absence of aneurysm related death, endoleak recurrence or additional interventions during follow-up) were examined. RESULTS: Of 1604 articles, 10 studies met the selection criteria, including 194 patients treated with liquid embolics; 73.2% of the patients were male with a median age of 71 years. The overall technical success was 97.9%. Clinical success was 87.6%. Because the median follow-up was only 13.0 months (range, 1-89 months), data on long-term success are almost absent. Four cases (2.1%) of secondary aneurysm rupture after embolization owing to endoleak recurrence were reported. All ruptures occurred in aneurysms exceeding initial treatment diameter of 70 mm. CONCLUSIONS: Initial technical success after liquid embolization for T1EL is high, although long-term clinical success rates are lacking. Within this review, the risk of secondary rupture is comparable with untreated T1EL at 2% with a median follow-up of 13 months, regardless of the initial success of embolization. In general, no decrease in secondary aneurysm rupture after embolization of T1EL after EVAR is demonstrated, although the results of late embolization are debated.

Inflammatory Gene Expression of Human Perivascular Adipose Tissue in Abdominal Aortic Aneurysms.

OBJECTIVE: Perivascular adipose tissue (PVAT) contributes to vascular homeostasis and is increasingly linked to vascular pathology. PVAT density and volume were associated with abdominal aortic aneurysm (AAA) presence and dimensions on imaging. However, mechanisms underlying the role of PVAT in AAA have not been clarified. This study aimed to explore differences in PVAT from AAA using gene expression and functional tests. METHODS: Human aortic PVAT and control subcutaneous adipose tissue were collected during open AAA surgery. Gene analyses and functional tests were performed. The control group consisted of healthy aorta from non-living renal transplant donors. Gene expression tests were performed to study genes potentially involved in various inflammatory processes and AAA related genes. Live PVAT and subcutaneous adipose tissue (SAT) from AAA were used for ex vivo co-culture with smooth muscle cells (SMCs) retrieved from non-pathological aortas. RESULTS: Adipose tissue was harvested from 27 AAA patients (n [gene expression] = 22, n [functional tests] = 5) and five control patients. An increased inflammatory gene expression of PTPRC (p = .008), CXCL8 (p = .033), LCK (p = .003), CCL5 (p = .004) and an increase in extracellular matrix breakdown marker MMP9 (p = .016) were found in AAA compared with controls. Also, there was a decreased anti-inflammatory gene expression of PPARG in AAA compared with controls (p = .040). SMC co-cultures from non-pathological aortas with PVAT from AAA showed increased MMP9 (p = .033) and SMTN (p = .008) expression and SAT increased SMTN expression in these SMC. CONCLUSION: The data revealed that PVAT from AAA shows an increased pro-inflammatory and matrix metallopeptidase gene expression and decreased anti-inflammatory gene expression. Furthermore, increased expression of genes involved in aneurysm formation was found in healthy SMC co-culture with PVAT of AAA patients. Therefore, PVAT from AAA might contribute to inflammation of the adjacent aortic wall and thereby plays a possible role in AAA pathophysiology. These proposed pathways of inflammatory induction could reveal new therapeutic targets in AAA treatment.

Patient-Specific 3-Dimensional Model of Smooth Muscle Cell and Extracellular Matrix Dysfunction for the Study of Aortic Aneurysms.

INTRODUCTION: Abdominal aortic aneurysms (AAAs) are associated with overall high mortality in case of rupture. Since the pathophysiology is unclear, no adequate pharmacological therapy exists. Smooth muscle cells (SMCs) dysfunction and extracellular matrix (ECM) degradation have been proposed as underlying causes. We investigated SMC spatial organization and SMC-ECM interactions in our novel 3-dimensional (3D) vascular model. We validated our model for future use by comparing it to existing 2-dimensional (2D) cell culture. Our model can be used for translational studies of SMC and their role in AAA pathophysiology. MATERIALS AND METHODS: SMC isolated from the medial layer of were the aortic wall of controls and AAA patients seeded on electrospun poly-lactide-co-glycolide scaffolds and cultured for 5 weeks, after which endothelial cells (EC) are added. Cell morphology, orientation, mechanical properties and ECM production were quantified for validation and comparison between controls and patients. RESULTS: We show that cultured SMC proliferate into multiple layers after 5 weeks in culture and produce ECM proteins, mimicking their behavior in the medial aortic layer. EC attach to multilayered SMC, mimicking layer interactions. The novel SMC model exhibits viscoelastic properties comparable to biological vessels; cytoskeletal organization increases during the 5 weeks in culture; increased cytoskeletal alignment and decreased ECM production indicate different organization of AAA patients' cells compared with control. CONCLUSION: We present a valuable preclinical model of AAA constructed with patient specific cells with applications in both translational research and therapeutic developments. We observed SMC spatial reorganization in a time course of 5 weeks in our robust, patient-specific model of SMC-EC organization and ECM production.

Survival and Living Situation After Ruptured Abdominal Aneurysm Repair in Octogenarians.

OBJECTIVE: To determine the 30 day and one year mortality and post-operative living situation in octogenarians treated for ruptured abdominal aortic aneurysm (rAAA). METHODS: A retrospective study was performed at four centres in the Netherlands. All consecutive patients aged ≥80 years, presenting with a rAAA between January 2013 and October 2018, were included. The primary outcomes were post-operative living situation and one year mortality. RESULTS: In total, 157 patients were included. Forty-seven received palliative care and 110 patients had surgery. After endovascular or open repair, the one year mortality rate was 50.0%. The 30 day mortality rate was 40.8% (95% confidence interval [CI] 27-55) and 31.7% (95% CI 20-44), for endovascular and open repair, respectively (p = .32). Sixty-five per cent of survivors were discharged home, while 34.8% went to a nursing home for rehabilitation. Of the surviving patients, 82.6% went back to living in their pre-rupture home situation. Of the investigated variables, only a high body mass index proved a significant predictor of death at 30 days and one year. Compared with operated patients, patients turned down for surgery were older (mean age 87.5 ± 3.8 vs. 84.0 ± 3.5; p < .001), lived significantly more often in a nursing home (odds ratio 1.02, 95% CI 1.00-1.03; p < .001), were more often dependent (odds ratio 3.69, 95% CI 2.31-5.88; p < .001) and had a lower Glasgow Coma Scale score on arrival (odds ratio 0.42, 95% CI 0.25-0.69; p = .002). All palliative patients died within three days. CONCLUSION: Overall treatment outcomes showed that octogenarians should not be denied surgery based on age alone, as half of the octogenarians that undergo surgical treatment are still alive one year after rAAA repair. In addition, > 80% returned to their own home after rehabilitation.