Endovascular aortic repair with sac embolization for the prevention of type II endoleaks (the EVAR-SE study): study protocol for a randomized controlled multicentre study in Germany

Background Beyond a certain threshold diameter, abdominal aortic aneurysms (AAA) are to be treated by open surgical or endovascular aortic aneurysm repair (EVAR). In a quarter of patients who undergo EVAR, inversion of blood flow in the inferior mesenteric artery or lumbar arteries may lead to type II endoleak (T2EL), which is associated with complications (e.g. AAA growth, secondary type I endoleak, rupture). As secondary interventions to treat T2EL often fail and may be highly invasive, prevention of T2EL is desirable. The present study aims to assess the efficacy of sac embolization (SE) with metal coils during EVAR to prevent T2EL in patients at high risk. Methods Over a 24-month recruitment period, a total of 100 patients undergoing EVAR in four vascular centres (i.e. Klinikum rechts der Isar of the Technical University of Munich, University Hospital Augsburg, University Hospital Dresden, St. Joseph’s Hospital Wiesbaden) are to be included in the present study. Patients at high risk for T2EL (i.e. ≥ 5 efferent vessels covered by endograft or aneurysmal thrombus volume <40%) are randomized to one group receiving standard EVAR and another group receiving EVAR with SE. Follow-up assessments postoperatively, after 30 days, and 6 months involve contrast-enhanced ultrasound scans (CEUS) and after 12 months an additional computed tomography angiography (CTA) scan. The presence of T2EL detected by CEUS or CTA after 12 months is the primary endpoint. Secondary endpoints comprise quality of life (quantified by the SF-36 questionnaire), reintervention rate, occurrence of type I/III endoleak, aortic rupture, death, alteration of aneurysm volume, or diameter. Standardized evaluation of CTA scans happens through a core lab. The study will be terminated after the final follow-up visit of the ultimate patient. Discussion Although preexisting studies repeatedly indicated a beneficial effect of SE on T2EL rates after EVAR, patient relevant outcomes have not been assessed until now. The present study is the first randomized controlled multicentre study to assess the impact of SE on quality of life. Further unique features include employment of easily assessable high-risk criteria, a contemporary follow-up protocol, and approval to use any commercially available coil material. Overcoming limitations of previous studies might help SE to be implemented in daily practice and to enhance patient safety. Trial registration ClinicalTrials.gov NCT05665101. Registered on 23 December 2022

Changes in monocyte subsets are associated with an increased risk of AAA and are surrogate markers for AAA morphology in patients with late-stage disease

IntroductionMonocytes play a role in the pathology of abdominal aortic aneurysm (AAA) and can display immunophenotypic heterogeneity. Alterations in monocyte subsets are associated with cardiovascular risk, but their profile in AAA is poorly understood.AimWe aimed to comprehensively define associations of monocyte phenotypes with AAA risk and AAA morphology.MethodsMonocyte subsets (CD14++CD16−, CD14++/CD16+, and CD14+/CD16++) were analyzed in an observational study in patients with AAA (n = 33) and varicose veins (n = 33) using flow cytometry.ResultsClassical monocytes were 3% lower (p = 0.001) in AAA, while intermediate and non-classical monocytes were 1.8-fold (p = 0.019) and 1.9-fold (p = 0.025) higher in AAA, respectively. The differences remained significant after adjusting for age, sex, and peripheral artery disease. A decrease in classical monocytes [odds ratio (OR): 0.73, p = 0.002] and increases in intermediate (OR: 1.41, p = 0.006) and non-classical monocytes (OR: 1.54, p = 0.030) were associated with a higher risk of AAA. Non-classical monocytes showed an inverse correlation with AAA diameter (rP = −0.64, p = 0.001) and AAA volume (rP = −0.50, p = 0.003).ConclusionThe present study revealed age- and sex-independent shifts in monocytes, all of which were associated with the risk of AAA disease. Non-classical monocytes were inversely correlated with AAA diameter and volume and thus may be surrogate markers for AAA morphology

Pharmacotherapies and Aortic Heme Oxygenase-1 Expression in Patients with Abdominal Aortic Aneurysm

Background: Treatment of cardiovascular risk factors slows the progression of small abdominal aortic aneurysms (AAA). Heme oxygenase-1 (HO-1) is a stress- and hemin-induced enzyme providing cytoprotection against oxidative stress when overexpressed. However, nothing is known about the effects of cardiometabolic standard therapies on HO-1 expression in aortic walls in patients with end-stage AAA. Methods: The effects of statins, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), calcium channel blockers (CCBs), betablockers, diuretics, acetylsalicylic acid (ASA), and therapeutic anticoagulation on HO-1 mRNA and protein expressions were analyzed in AAA patients using multivariate logistic regression analysis and comparison of monotherapy. Results: Analysis of monotherapy revealed that HO-1 mRNA and protein expressions were higher in patients on diuretics and lower in patients on statin therapy. Tests on combinations of antihypertensive medications demonstrated that ACE inhibitors and diuretics, ARBs and diuretics, and beta-blockers and diuretics were associated with increase in HO-1 mRNA expression. ASA and therapeutic anticoagulation were not linked to HO-1 expression. Conclusion: Diuretics showed the strongest association with HO-1 expression, persisting even in combination with other antihypertensive medications. Hence, changes in aortic HO-1 expression in response to different medical therapies and their effects on vessel wall degeneration should be analyzed in future studies

NOX4 mRNA correlates with plaque stability in patients with carotid artery stenosis

Carotid artery stenosis (CAS) develops from atherosclerotic lesions and plaques. Plaque rupture or stenosis may result in occlusion of the carotid artery. Accordingly, the asymptomatic disease becomes symptomatic, characterized by ischemic stroke or transient ischemic attacks, indicating an urgent need for better understanding of the underlying molecular mechanisms and eventually prevent symptomatic CAS. NOX4, a member of the NADPH oxidase family, has anti-atherosclerotic and anti-inflammatory properties in animal models of early atherosclerosis. We hypothesized that NOX4 mRNA expression is linked to protective mechanisms in CAS patients with advanced atherosclerotic lesions as well. Indeed, NOX4 mRNA expression is lower in patients with symptomatic CAS. A low NOX4 mRNA expression is associated with an increased risk of the development of clinical symptoms. In fact, NOX4 appears to be linked to plaque stability, apoptosis and plaque hemorrhage. This is supported by cleaved caspase-3 and glycophorin C and correlates inversely with plaque NOX4 mRNA expression. Even healing of a ruptured plaque appears to be connected to NOX4, as NOX4 mRNA expression correlates to fibrous cap collagen and is reciprocally related to MMP9 activity. In conclusion, low intra-plaque NOX4 mRNA expression is associated with an increased risk for symptomatic outcome and with reduced plaque stabilizing mechanisms suggesting protective effects of NOX4 in human advanced atherosclerosis

Completing the view – histologic insights from circular AAA specimen including 3D imaging

Abdominal aortic aneurysm (AAA) is a pathologic enlargement of the infrarenal aorta with an associated risk of rupture. However, the responsible mechanisms are only partially understood. Based on murine and human samples, a heterogeneous distribution of characteristic pathologic features across the aneurysm circumference is expected. Yet, complete histologic workup of the aneurysm sac is scarcely reported. Here, samples from five AAAs covering the complete circumference partially as aortic rings are investigated by histologic means (HE, EvG, immunohistochemistry) and a new method embedding the complete ring. Additionally, two different methods of serial histologic section alignment are applied to create a 3D view. The typical histopathologic features of AAA, elastic fiber degradation, matrix remodeling with collagen deposition, calcification, inflammatory cell infiltration and thrombus coverage were distributed without recognizable pattern across the aneurysm sac in all five patients. Analysis of digitally scanned entire aortic rings facilitates the visualization of these observations. Immunohistochemistry is feasible in such specimen, however, tricky due to tissue disintegration. 3D image stacks were created using open-source and non-generic software correcting for non-rigid warping between consecutive sections. Secondly, 3D image viewers allowed visualization of in-depth changes of the investigated pathologic hallmarks. In conclusion, this exploratory descriptive study demonstrates a heterogeneous histomorphology around the AAA circumference. Warranting an increased sample size, these results might need to be considered in future mechanistic research, especially in reference to intraluminal thrombus coverage. 3D histology of such circular specimen could be a valuable visualization tool for further analysis

Nicht-invasive Evaluation des Aortenaneurysmas

Bei einer Rupturletalität von > 90% ist eine rechtzeitige Sanierung des abdominallen Aortenaneurysmas (AAA) entscheidend. Anhand klinischer Praediktoren ist jedoch bislang keine individuelle Rupturrisikoeinschätzung möglich. Mittels moderner Bildgebung und biomechanische Computersimulation können jedoch prinzipiell Erkenntnisse über ultrastrukturelle Veränderungen in der Aortenwand und die dort auftretenden Kräfte gewonnen werden. In der durchgeführten Habilitationsarbeit wurde hierbei gezeigt, dass mittels FDG-PET/CT der individuelle Glukosemetabolismus in der Aneurysmawand abgebildet und quantifiziert werden kann und dabei hochgradig mit destruktiven inflammatorisch-proteolytischen Prozessen korreliert und insbesondere bei rupturgefährdeten AAA erhöht ist. Parallel wurde die Rolle biomechanischer Computer-Simulationen bei der Risikostratifizierung des AAA analysiert. Hierbei wurden neue teils essentielle numerische Verfahren entwickelt. Hierbei konnte gezeigt werden, dass nur mittels solcher fortschrittlichen FE-Simulationen realistische Deformationen und Belastungen innerhalb physiologischer Grenzen generiert werden und eine bessere Unterscheidung rupturgefährdeter AA von stabilen AAA möglich ist. Zudem konnte erstmalig durch die Koanalyse des individuellen FDGStoffwechsels und Spannungssimulationen eine auch quantitative Korrelation von biomechanischer Belastung mit inflammatorisch-proteolytischen Prozessen in der AAA-Wand belegt werden

Biomechanics and gene expression in abdominal aortic aneurysm.

The aim of the study was to detect inter-relations between the mechanical conditions and material properties of abdominal aortic aneurysm (AAA) wall and the underlying local gene expression of destabilizing inflammatory, proteolytic, and structural factors.During open surgery, 51 tissue samples from 31 AAA patients were harvested. Gene expression of collagen types I and III, inflammatory factors CD45 and MSR1, proteolytic enzymes matrix metalloproteinases 2 and 9, and tissue inhibitor of matrix metalloproteinase 1 was analyzed by reverse transcription-polymerase chain reaction. Material properties of corresponding AAA tissue samples were assessed by cyclic sinusoidal and destructive testing. Local mechanical conditions of stress and strain were determined by advanced nonlinear finite element analysis based on patient-specific three-dimensional AAA models derived from preoperative computed tomography data.In the AAA wall, all parameters analyzed were significantly expressed at the messenger RNA level. With respect to mechanical properties of the aneurysmatic wall, expression of collagen III correlated with the stiffness parameter ? (r = -0.348; P = .017), and matrix metalloprotease 2 correlated with the stiffness parameter ? and wall strength (r = -0.438 and -0.593; P = .005 and P < .001). Furthermore, significant relationships were observed between local AAA diameter and the expression of CD45, MSR1, and tissue inhibitor of matrix metalloproteinase 1 (r = 0.285, 0.551, 0.328; P < .05). However, we found no inter-relation of local calculated wall stresses and strains with gene expression.Our results show for the first time that gene expressions of destabilizing factors within AAA tissue might be correlated to geometric and mechanical properties of the AAA wall. However, we found no influence of local mechanical conditions on gene expression of these factors. Therefore, these preliminary results are still ambiguous