Nicotine Affects Murine Aortic Stiffness and Fatigue Response During Supraphysiological Cycling.

Nicotine exposure is a major risk factor for several cardiovascular diseases. Although the deleterious effects of nicotine on aortic remodeling processes have been studied to some extent, the biophysical consequences are not fully elucidated. In this investigation, we applied quasi-static and dynamic loading to quantify ways in which exposure to nicotine affects the mechanical behavior of murine arterial tissue. Segments of thoracic aortas from C57BL/6 mice exposed to 25 mg/kg/day of subcutaneous nicotine for 28 days were subjected to uniaxial tensile loading in an open-circumferential configuration. Comparing aorta segments from nicotine-treated mice relative to an equal number of control counterparts, stiffness in the circumferential direction was nearly twofold higher (377 kPa ± 165 kPa versus 191 kPa ± 65 kPa, n = 5, p = 0.03) at 50% strain. Using a degradative power-law fit to fatigue data at supraphysiological loading, we observed that nicotine-treated aortas exhibited significantly higher peak stress, greater loss of tension, and wider oscillation band than control aortas (p ≤ 0.01 for all three variables). Compared to simple stress relaxation tests, fatigue cycling is shown to be more sensitive and versatile in discerning nicotine-induced changes in mechanical behavior over many cycles. Supraphysiological fatigue cycling thus may have broader potential to reveal subtle changes in vascular mechanics caused by other exogenous toxins or pathological conditions.

Gimme' the Loop: Modifications to the Squid-Capture Technique for Laser-Fenestrated Thoracic Endografting.

PURPOSE: Laser-fenestrated thoracic endovascular aortic repair (LfTEVAR) in the aortic arch with covering of the left subclavian artery (LSA) orifice is challenging. To optimize fenestration, the so-called squid-capture technique has been introduced. We present here a modification to the technique that may help improve time-efficiency and safety. TECHNIQUE:: During the originally proposed squid-capture maneuver, the stent-graft is deployed in a preset snare wire loop, which is used to pull the stent graft toward the penetration device during in-situ fenestration. In preparation, the guidewire needs to be passed through the loop inside the aortic arch, which can be difficult and may predispose for embolic events. We propose here the creation of a "guidewire-through-snare-loop" configuration outside the body, which can then be reliably transferred into the aortic arch. The modified technique was successfully applied in a patient undergoing LfTEVAR for penetrating aortic ulcers. CONCLUSION: The proposed modification may help facilitate the squid-capture technique for LfTEVAR while saving time and resources. Given that LfTEVAR is becoming more frequently used, it is important to ensure technical success and safety of the procedure.

MicroRNA-Mediated Therapy Modulating Blood-Brain Barrier Disruption Improves Vascular Cognitive Impairment.

OBJECTIVE: There are currently no effective treatments for the prevention of dementia associated with vascular cognitive impairment. MicroRNAs regulate gene expression at the post-transcriptional level and play key roles in vascular disorders. TNFα (tumor necrosis factor-α) regulates blood-brain barrier breakdown through modification of cerebral tight junctions. Here, we sought key TNFα-responsive microRNAs that might influence blood-brain barrier breakdown via cerebral tight junction disruption in vascular cognitive impairment. APPROACH AND RESULTS: Using a mouse model of vascular cognitive impairment, chronic cerebral hypoperfusion within the white matter was induced with bilateral common carotid artery stenosis (BCAS) surgery. TNFα gene expression was increased in white matter post-BCAS surgery, and TNFα stimulation decreased claudin-5, ZO-1 (tight-junction protein 1), and occludin gene expression in murine brain endothelial cells. In silico analysis predicted 8 candidate microRNAs as regulators of claudin-5, ZO-1, and occludin gene expression. Of these, only miR-501-3p was upregulated by TNFα in vitro and was upregulated in the white matter after BCAS surgery. Further, miR-501-3p directly bound to the 3'-untranslated region of human ZO-1 and downregulated transendothelial electric resistance. In vivo administration of a locked nucleic acid -modified antisense oligonucleotide versus miR-501-3p suppressed BCAS-induced reduction of ZO-1 gene expression and blood-brain barrier disruption within the white matter and significantly ameliorated working memory deficits after BCAS surgery. CONCLUSIONS: We here provide the first evidence that the TNFα-miR-501-3p-ZO-1 axis plays an important role in the pathogenesis of cerebral hypoperfusion-induced working memory deficits and white matter lesions, as a result of blood-brain barrier breakdown via tight junction disruption. Therapeutic manipulation of miR-501-3p holds promise for limiting vascular cognitive impairment progression.

Controlled isoflurane anesthesia exposure is required for reliable behavioral testing in murine surgical models.

We investigated the effects of variations in anesthesia exposure time prior to conducting anxiety response behavioral testing in sham controls from an experimental murine model. The staying time in the center area of the Open Field test in the "long exposure" group was significantly decreased compared to that of the "short exposure" group. Significant correlation was found between anesthesia time and the duration of staying time in the center area. We conclude that anesthesia time may have a significant impact on behavioral anxiety testing in this context, and advise careful control of this parameter in protocol optimization in related surgical animal models.

Retrograde Aortomesenteric Bypass with Left Retrorenal Route-"French Bypass" in 16 Cases of Chronic Mesenteric Ischemia.

BACKGROUND: There are several options for treating patients suffering from chronic mesenteric ischemia (CMI). One possibility contains bypass grafting following a left renal route to avoid inter alia kinking of the bypass. This study reviews the results of 16 patients suffering from CMI treated with this bypass technique, called "French Bypass" (FB). METHODS: A retrospective study conducted between June 1, 2002, and December 31, 2015. Sixteen patients were included with an average age of 54.6 years (10 women) who were treated with FB. Risk factors, surgical course, and follow-up were evaluated. RESULTS: Average stay in hospital took 28.4 days, with mostly minor complications occurring. Overall, 4 cases of FB occlusion were diagnosed in between 30 days after surgery, of which 3 made interventions necessary. Primary patency rates were 75%/56%/56% after 12/24/60 months. Overall survival rate after 60 month was 78%. CONCLUSIONS: The FB is a sufficient option for treatment of CMI combining advantages of anterograde and retrograde bypass grafting, with comparable outcome to established techniques in visceral vessel reconstruction.

Relative Thrombus Burden Ratio Reveals Overproportioned Intraluminal Thrombus Growth-Potential Implications for Abdominal Aortic Aneurysm.

Background: An intraluminal, non-occlusive thrombus (ILT) is a common feature in an abdominal aortic aneurysm (AAA). This study investigated the relative progression of ILT vs. AAA volume using a novel parameter, the so-called thrombus burden ratio (TBR), in non-treated AAAs. Parameters potentially associated with TBR progression were analyzed and TBR progression in large vs. small and fast- vs. slow-growing AAAs was assessed. Methods: This retrospective, single-center study analyzed sequential contrast-enhanced computed tomography angiography (CTA) scans between 2009 and 2018 from patients with an AAA before surgical treatment. Patients' medical data and CTA scans were analyzed at two given time points. The TBR was calculated as a ratio of ILT and AAA volume, and relative TBR progression was calculated by normalization for time between sequential CTA scans. Spearman's correlation was applied to identify morphologic parameters correlating with TBR progression, and multivariate linear regression analysis was used to evaluate the association of clinical and morphological parameters with TBR progression. Results: A total of 35 patients were included. The mean time between CT scans was 16 ± 15.9 months. AAA volume progression was 12 ± 3% and ILT volume progression was 36 ± 13%, resulting in a TBR progression of 11 ± 4%, suggesting overproportioned ILT growth. TBR progression was 0.8 ± 0.8% per month. Spearman's correlation verified ILT growth as the most relevant parameter contributing to TBR progression (R = 0.51). Relative TBR progression did not differ significantly in large vs. small and fast- vs. slow-growing AAAs. In the multivariate regression analysis, none of the studied factors were associated with TBR progression. Conclusion: TBR increases during AAA development, indicating an overproportioned ILT vs. AAA volume growth. The TBR may serve as a useful parameter, as it incorporates the ILT volume growth relative to the AAA volume, therefore combining two important parameters that are usually reported separately. Yet, the clinical relevance in helping to identify potential corresponding risk factors and the evaluation of patients at risk needs to be further validated in a larger study cohort.

Radiation Exposure and Contrast Agent Use during Endovascular Aortic Repair Using Mobile Versus Fixed Angiography Systems.

BACKGROUND: For (thoracic) endovascular aortic repair ((T)EVAR) procedures, both mobile (standard operating room (SOR)) and fixed C-arm (hybrid operating room (HOR)) systems are available. This study evaluated differences in key procedural parameters, and procedural success for (T)EVAR in the SOR versus the HOR. METHODS: All patients who underwent standard elective (T)EVAR at the Clinic for Vascular and Endovascular Surgery at the University Hospital Duesseldorf, Germany, between 1 January 2012 and 1 January 2019 were included. Data were retrieved from archived medical records. Endpoints were analyzed for SOR versus HOR during (T)EVAR. RESULTS: A total of 93 patients, including 50 EVAR (SOR (n = 20); HOR (n = 30)) and 43 TEVAR (SOR (n = 22); HOR (n= 21)) were included. The dose area product (DAP) for EVAR and TEVAR was lower in the SOR than in the HOR (EVAR, SOR: 1635 ± 1088 cGy·cm2; EVAR, HOR: 7819 ± 8928 cGy·cm2; TEVAR, SOR: 8963 ± 34,458 cGy·cm2; TEVAR, HOR: 14,591 ± 11,584 cGy·cm2 (p < 0.05)). Procedural fluoroscopy time was shorter in the SOR than in the HOR for EVAR and TEVAR (EVAR, SOR: 7 ± 4 min; EVAR, HOR: 18.8 ± 11.3 min; TEVAR, SOR: 6.6 ± 9.6 min; TEVAR, HOR: 13.9 ± 11.8 min (p < 0.05)). Higher volumes of contrast agent were applied during EVAR and TEVAR in the SOR than in the HOR (EVAR, SOR: 57.5 ± 20 mL; EVAR: HOR: 33.3 ± 5 mL (p < 0.05); TEVAR; SOR: 71.5 ± 53.4 mL, TEVAR, HOR: 48.2 ± 27.5 mL (p ≥ 0.05). CONCLUSION: The use of a fixed C-arm angiography system in the HOR results in higher radiation exposure and longer fluoroscopy times but lower contrast agent volumes when compared with mobile C-arm systems in the SOR. Because stochastic radiation sequelae are more likely to be tolerated in an older patient population and, in addition, there is a higher incidence of CKD in this patient population, allocation of patients to the HOR for standard (T)EVAR seems particularly advisable based on our results.

[Challenges and options for advanced training in surgery : An interdisciplinary position paper against the background of the hospital structural reform in Germany]. / Herausforderungen und Chancen für die chirurgische Weiterbildung : Ein fachgesellschaftsübergreifendes Positionspapier vor dem Hintergrund der Krankenhausstrukturreform.

BACKGROUND: Even now the further training in surgery faces considerable challenges. The planned hospital structural reform will result in new bureaucratic and organizational hurdles, which could lead to a considerable loss of quality in advanced surgical training across all disciplines. OBJECTIVE: The aim of this position paper is to describe the current and future challenges for advanced surgical training and to identify possible approaches and opportunities for the further development against the background of the planned hospital structural reform. MATERIAL AND METHODS: For the development of this position paper a committee of representatives of the Young Forums of the German surgical societies identified and critically discussed current problems and challenges of the present residency training system and formulated a list of demands for a sustainable residency training concept. RESULTS: The planned shift to outpatient treatment and centralization were identified as central challenges for surgical residency training. Surgical training must be considered consistently and from the outset in all political reform efforts. In addition to a transparent and cost-appropriate financing of residency training, we call for the involvement of all German surgical societies in the reform process. Furthermore, the social framework conditions for junior surgeons should be considered. CONCLUSION: The structural change in the hospital landscape in Germany, which is being forced by politicians, harbors the risk of a further loss of quality and experience in surgical treatment and training. At the same time, the planned hospital reform offers a unique opportunity to address existing problems and challenges in surgical training and to consider them as a starting point for structural changes which are fit for the future.

Crosstalk of platelets with macrophages and fibroblasts aggravates inflammation, aortic wall stiffening, and osteopontin release in abdominal aortic aneurysm.

AIMS: Abdominal aortic aneurysm (AAA) is a highly lethal disease with progressive dilatation of the abdominal aorta accompanied by degradation and remodelling of the vessel wall due to chronic inflammation. Platelets play an important role in cardiovascular diseases, but their role in AAA is poorly understood. METHODS AND RESULTS: The present study revealed that platelets play a crucial role in promoting AAA through modulation of inflammation and degradation of the extracellular matrix (ECM). They are responsible for the up-regulation of SPP1 (osteopontin, OPN) gene expression in macrophages and aortic tissue, which triggers inflammation and remodelling and also platelet adhesion and migration into the abdominal aortic wall and the intraluminal thrombus (ILT). Further, enhanced platelet activation and pro-coagulant activity result in elevated gene expression of various cytokines, Mmp9 and Col1a1 in macrophages and Il-6 and Mmp9 in fibroblasts. Enhanced platelet activation and pro-coagulant activity were also detected in AAA patients. Further, we detected platelets and OPN in the vessel wall and in the ILT of patients who underwent open repair of AAA. Platelet depletion in experimental murine AAA reduced inflammation and ECM remodelling, with reduced elastin fragmentation and aortic diameter expansion. Of note, OPN co-localized with platelets, suggesting a potential role of OPN for the recruitment of platelets into the ILT and the aortic wall. CONCLUSION: In conclusion, our data strongly support the potential relevance of anti-platelet therapy to reduce AAA progression and rupture in AAA patients.

The Comparison of Endovascular and Open Surgical Treatment for Ruptured Abdominal Aortic Aneurysm in Terms of Safety and Efficacy on the Basis of a Single-Center 30-Year Experience.

OBJECTIVE: Ruptured abdominal aortic aneurysm (rAAA) is a critical condition with a high mortality rate. Over the years, endovascular aortic repair (EVAR) has evolved as a viable treatment option in addition to open repair (OR). The primary objective of this study was to compare the safety and efficacy of EVAR and OR for the treatment of rAAA based on a comprehensive analysis of our single-centre 30-year experience. METHODS: Patients treated for rAAA at the Department of Vascular and Endovascular Surgery, University Hospital Düsseldorf, Germany from 1 January 1993 to 31 December 2022 were included. Relevant information was retrieved from archived medical records. Patient survival and surgery-related complications were analysed. RESULTS: None of the patient-specific markers, emergency department-associated parameters, and co-morbidities were associated with patient survival. The 30-day and in-hospital mortality was higher in the OR group vs. in the EVAR group (50% vs. 8.7% and 57.1% vs. 13%, respectively). OR was associated with more frequent occurrence of more severe complications when compared to EVAR. Overall patient survival was 56 ± 5% at 12 months post-surgery (52 ± 6% for OR vs. 73 ± 11% for EVAR, respectively) (p < 0.05). Patients ≥70 years of age showed poorer survival in the OR group, with a 12-month survival of 42 ± 7% vs. 70 ± 10% for patients <70 years of age (p < 0.05). In the EVAR group, this age-related survival advantage was not found (12-month survival: ≥70 years: 67 ± 14%, <70 years: 86 ± 13%). Gender-specific survival was similar regardless of the applied method of care. CONCLUSION: OR was associated with more severe complications in our study. EVAR initially outperformed OR for rAAA regarding patient survival while re-interventions following EVAR negatively affect survival in the long-term. Elderly patients should be treated with EVAR. Gender does not seem to have a significant impact on survival.

Ethanol Enhances Endothelial Rigidity by Targeting VE-Cadherin-Implications for Acute Aortic Dissection.

(1) Background: Acute aortic dissection (AAD) is caused by an endothelial entry tear followed by intimomedial delamination of the outer layers of the vessel wall. The established risk factors include hypertension and smoking. Another rising candidate risk factor is excessive alcohol consumption. This experimental study explores the effects of nicotine (Nic), angiotensin II (Ang II), and ethanol (EtOH) on human aortic endothelial cells (hAoEC). (2) Methods: HAoECs were exposed to Nic, Ang II, and EtOH at different dose levels. Cell migration was studied using the scratch assay and live-cell imaging. The metabolic viability and permeability capacity was investigated using the water-soluble tetrazolium (WST)-1 assay and an in vitro vascular permeability assay. Cell adherence was studied by utilizing the hanging drop assay. The transcriptional and protein level changes were analyzed by RT-qPCR, Western blotting and immunohistochemistry for major junctional complexing proteins. (3) Results: We observed reduced metabolic viability following Ang II and EtOH exposure vs. control. Further, cell adherence was enhanced by EtOH exposure prior to trituration and by all risk factors after trituration, which correlated with the increased gene and protein expression of VE-cadherin upon EtOH exposure. The cell migration capacity was reduced upon EtOH exposure vs. controls. (4) Conclusion: Marked functional changes were observed upon exposure to established and potential risk factors for AAD development in hAoECs. Our findings advocate for an enhanced mechanical rigidity in hAoECs in response to the three substances studied, which in turn might increase endothelial rigidity, suggesting a novel mechanism for developing an endothelial entry tear due to reduced deformability in response to increased shear and pulsatile stress.

E-cigarette exposure augments murine abdominal aortic aneurysm development: role of Chil1.

AIMS: Abdominal aortic aneurysm (AAA) is a common cardiovascular disease with a strong correlation to smoking, although underlying mechanisms have been minimally explored. Electronic cigarettes (e-cigs) have gained recent broad popularity and can deliver nicotine at comparable levels to tobacco cigarettes, but effects on AAA development are unknown. METHODS AND RESULTS: We evaluated the impact of daily e-cig vaping with nicotine on AAA using two complementary murine models and found that exposure enhanced aneurysm development in both models and genders. E-cigs induced changes in key mediators of AAA development including cytokine chitinase-3-like protein 1 (CHI3L1/Chil1) and its targeting microRNA-24 (miR-24). We show that nicotine triggers inflammatory signalling and reactive oxygen species while modulating miR-24 and CHI3L1/Chil1 in vitro and that Chil1 is crucial to e-cig-augmented aneurysm formation using a knockout model. CONCLUSIONS: In conclusion our work shows increased aneurysm formation along with augmented vascular inflammation in response to e-cig exposure with nicotine. Further, we identify Chil1 as a key mediator in this context. Our data raise concerns regarding the potentially harmful long-term effects of e-cig nicotine vaping.

Platelet pannexin-1 channels modulate neutrophil activation and migration but not the progression of abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) is a common disease and highly lethal if untreated. The progressive dilatation of the abdominal aorta is accompanied by degradation and remodeling of the vessel wall due to chronic inflammation. Pannexins represent anion-selective channels and play a crucial role in non-vesicular ATP release to amplify paracrine signaling in cells. Thus, pannexins are involved in many (patho-) physiological processes. Recently, Panx1 channels were identified to be significantly involved in abdominal aortic aneurysm formation through endothelial derived Panx1 regulated inflammation and aortic remodeling. In platelets, Panx1 becomes activated following activation of glycoprotein (GP) VI. Since platelets play a role in cardiovascular diseases including abdominal aortic aneurysm, we analyzed the contribution of platelet Panx1 in the progression of abdominal aortic aneurysm. We detected enhanced Panx1 plasma levels in abdominal aortic aneurysm patients. In experimental abdominal aortic aneurysm using the pancreatic porcine elastase (PPE) mouse model, a major contribution of platelet Panx1 channels in platelet activation, pro-coagulant activity of platelets and platelet-mediated inflammation has been detected. In detail, platelets are important for the migration of neutrophils into the aortic wall induced by direct cell interaction and by activation of endothelial cells. Decreased platelet activation and inflammation did not affect ECM remodeling or wall thickness in platelet-specific Panx1 knock-out mice following PPE surgery. Thus, aortic diameter expansion at different time points after elastase infusion of the aortic wall was unaltered in platelet-specific Panx1 deficient mice suggesting that the modulation of inflammation alone does not affect abdominal aortic aneurysm formation and progression. In conclusion, our data strongly supports the role of platelets in inflammatory responses in abdominal aortic aneurysm via Panx1 channels and adds important knowledge about the significance of platelets in abdominal aortic aneurysm pathology important for the establishment of an anti-platelet therapy for abdominal aortic aneurysm patients.

The Role of Spatial Aortic Arch Architecture in Type B Aortic Dissection.

OBJECTIVE: The incidence of type B aortic dissection (TBAD) is increasing worldwide; however, the underlying pathomechanisms are not conclusively understood. This study explores the geometric architecture of the aortic arch and supra-aortic branches in TBAD patients as opposed to non-TBAD patients. METHODS: Patient characteristics were retrieved from archived medical records. Computer-assisted tomography (CAT) scans of patients with TBAD and carotid stenosis (CS) from two high-volume centers were analyzed. Various aortic arch parameters and take-off angles of the supra-aortic branches of TBAD patients were measured following centerline normalization in comparison CS patients. A compression index (C-index) was calculated from the para-sagittal, and a torsion index (T-index) was calculated from the para-coronal take-off angles of the supra-aortic branches to analyze aortic arch tortuosity. RESULTS: A total of 199 CAT scans were analyzed, namely, 85 in the TBAD group and 114 in the CS group. The average age was 61.5 ± 13.1 years among the TBAD patients and 71 ± 9.3 years among the CS patients. We found a significantly higher proportion of type III aortic arch configurations in TBAD patients compared with CS patients. Further, the aortic arch angle was steeper in the TBAD group. In the para-sagittal plane, the left subclavian artery (LSA) take-off angle was less steep in TBAD patients. In the para-coronal plane, the left carotid artery (LCA) had a less steep take-off angle, while the LSA had a more obtuse take-off angle in the TBAD group when compared with the CS group. In addition, the inter-vessel distance was increased in TBAD patients. Finally, the T-index was increased, suggesting a significant torsion resulting from the deviating take-off angles of the supra-aortic branches supplying the left half of the body as opposed to the innominate artery (IA) in TBAD patients. CONCLUSIONS: Our results suggest several aortic arch-specific geometric configurations in patients suffering from TBAD that significantly differ from those in CS patients. Further functional studies are needed to verify the pathogenetic relevance of our results and their disease-specific causality. Although our data are not mechanistically explorative, they may serve as a basis for identifying future patients with aortic arch morphology at higher risk for TBAD development and who may benefit from more stringent adjustment of risk factors as a primary prevention concept.

Time-dependent effects of cellulose and gelatin-based hemostats on cellular processes of wound healing.

Introduction: Oxidized regenerated cellulose-based (ORC - TABOTAMP), oxidized non-regenerated cellulose-based (ONRC - RESORBA CELL), and gelatin-based (GELA - GELITA TUFT-IT) hemostats are commonly used in surgery. However, their impact on the wound healing process remains largely unexplored. We here assess time-dependent effects of exposure to these hemostats on fibroblast-related wound healing processes. Material and methods: Hemostats were applied to fibroblast cell cultures for 5-10 (short-), 30 and 60 min (intermediate-) and 24 h (long-term). Representative images of the hemostat degradation process were obtained, and the pH value was measured. Cell viability, apoptosis and migration were analyzed after the above exposure times at 3, 6 and 24 h follow-up. Protein levels for tumor necrosis factor α (TNF-α) and transforming-growth factor ß (TGF-ß) were assessed. Results: ORC and ONRC reduced pH values during degradation, while GELA proved to be pH-neutral. Hemostat structural integrity was prolonged for GELA (vs. ORC and ONRC). TGF-ß and TNF-α levels were reduced for ORC and ONRC (vs. GELA and control) (p < 0.05). Further, exposure of ORC and ONRC for longer than 5-10 min reduced cell viability vs. GELA and control at 3 h post-exposure (p < 0.05). Similarly, cell migration was impaired with ORC and ONRC exposure longer than 60 min at 24 h follow-up (p < 0.05). Conclusions: Short-term exposure to ORC and ONRC impairs relevant wound healing-related processes in fibroblasts, and alters protein levels of key mediating cytokines. GELA does not show similar effects. We conclude that GELA may be preferred over ORC and ONRC over short-, intermediate- and long-term exposures. Future validation of the clinical relevance is warranted.

Nicotine Potentially Alters Endothelial Inflammation and Cell Adhesion via LGALS9.

BACKGROUND: The endothelial cell layer is essential for the maintenance of various blood vessel functions. Major risk factors for endothelial dysfunction that contribute to aortic pathologies such as abdominal aortic aneurysm (AAA) and aortic dissection (AD) include smoking tobacco cigarettes and hypertension. This study explores the effects of nicotine (Nic) and angiotensin II (Ang II) on human aortic endothelial cells (HAoECs) at a transcriptional level. METHODS: HAoECs were exposed to 100 nM Nic and/or 100 nM Ang II. RNA sequencing (RNA-Seq) was performed to identify regulated genes following exposure. Results were validated applying RT-qPCR. GeneMANIA was used to perform in silico analysis aiming to identify potential downstream interacting genes in inflammatory, cell-adhesion, endothelial cell proliferation, and coagulation pathways. RESULTS: RNA-Seq identified LGALS9 (Galectin-9) as being potentially regulated following Nic exposure, while subsequent RT-qPCR experiments confirmed the transcriptional regulation (p < 0.05). Subsequent in silico analysis identified potential candidate genes for interacting with LGALS9 in different gene sets. Of the top 100 genes potentially interacting with LGALS9, 18 were inflammatory response genes, 28 were involved in cell adhesion, 2 in cell proliferation, and 6 in coagulation. CONCLUSION: Nic exposure of HAoECs causes a significant increase in LGALS9 at a transcriptional level. LGALS9 itself may serve as key regulator for essential endothelial cell processes via interfering with various signaling pathways and may thus represent a potentially novel target in the pathogenesis of aortic pathologies.

Outflow Through Aortic Side Branches Drives False Lumen Patency in Type B Aortic Dissection.

Objective: Thoracic endovascular aortic repair (TEVAR) for type B aortic dissection (TBAD) aims to induce false lumen (FL) thrombosis by sealing intimal tears between the true (TL) and the FL, and blocking the inflow into the FL. Incomplete thrombosis of the FL is correlated with poor clinical outcome. We hypothesize that the number of major and minor branches arising from the FL affects FL patency and may negatively influence TEVAR induced FL thrombosis. Methods: Computed tomography (CT)-scans from 89 patients diagnosed with TBAD [best medical treatment (BMT) n = 52, TEVAR n = 37] from two high-volume vascular surgery centers were analyzed retrospectively. Analysis included evaluation of the FL patency status, the number, location and size of intimal tears, and the presence of minor and major side branches originating from the FL. Multiple regression analysis was conducted to evaluate obtained parameters as predictors for FL thrombosis status. Results: In univariate analysis, the strongest correlation for FL patency was found for the number of major (R = 0.79) and minor (R = 0.86) side branches originating from the FL. When applying a multiple linear regression model, the number of major (normalized beta 0.37; P < 0.001) and minor (normalized beta 0.41; P < 0.01) side branches arising from the FL were valid predictors for the axial length of the patent and non-patent FL, and additionally determined the length of the patent FL at 12-month follow-up in patients that underwent TEVAR. Conclusions: Our data suggest that the number of minor side branches that originate from the FL in TBAD is an important determinant of FL patency, to a greater degree than previously assumed.

peri-Adventitial delivery of smooth muscle cells in porous collagen scaffolds for treatment of experimental abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) is associated with the loss of vascular smooth muscle cells (SMCs) within the vessel wall. Direct delivery of therapeutic cells is challenging due to impaired mechanical integrity of the vessel wall. We hypothesized that porous collagen scaffolds can be an effective vehicle for the delivery of human-derived SMCs to the site of AAA. The purpose was to evaluate if the delivery of cell-seeded scaffolds can abrogate progressive expansion in a mouse model of AAA. Collagen scaffolds seeded with either primary human aortic SMCs or induced pluripotent stem cell derived-smooth muscle progenitor cells (iPSC-SMPs) had >80% in vitro cell viability and >75% cell penetrance through the scaffold's depth, while preserving smooth muscle phenotype. The cell-seeded scaffolds were successfully transplanted onto the murine aneurysm peri-adventitia on day 7 following AAA induction using pancreatic porcine elastase infusion. Ultrasound imaging revealed that SMC-seeded scaffolds significantly reduced the aortic diameter by 28 days, compared to scaffolds seeded with iPSC-SMPs or without cells (acellular scaffold), respectively. Bioluminescence imaging demonstrated that both cell-seeded scaffold groups had cellular localization to the aneurysm but a decline in survival with time. Histological analysis revealed that both cell-seeded scaffold groups had more SMC retention and less macrophage invasion into the medial layer of AAA lesions, when compared to the acellular scaffold treatment group. Our data suggest that scaffold-based SMC delivery is feasible and may constitute a platform for cell-based AAA therapy.

Hyperlipidemia does not affect development of elastase-induced abdominal aortic aneurysm in mice.

BACKGROUND AND AIMS: Hyperlipidemia is a suggested risk factor for abdominal aortic aneurysm (AAA). However, whether hyperlipidemia is causally involved in AAA progression remains elusive. Here, we tested the hypothesis that hyperlipidemia aggravates AAA formation in the widely used porcine pancreatic elastase (PPE) model of AAA in mice with varying levels of plasma lipids. METHODS: Prior to PPE-surgery, 8-week-old male C57BL/6J mice (n = 32) received 1·1011 viral genomes of rAAV8-D377Y-mPcsk9 or control rAAV8 via the tail vein. Mice were fed either western type diet or regular chow. At baseline and during the 28 days following PPE-surgery, mice underwent weekly ultrasonic assessment of AAA progression. Experiments were repeated using Apolipoprotein E knockout (ApoE-/-) mice (n = 7) and wildtype C57BL/6J mice (n = 5). RESULTS: At sacrifice, maximal intergroup plasma cholesterol and non-HDL/HDL ratio differences were >5-fold and >20-fold, respectively. AAA diameters expanded to 150% of baseline, but no intergroup differences were detected. This was verified in an independent experiment comparing 8-week-old male ApoE-/- mice with wildtype mice. Histological evaluation of experimental AAA lesions revealed accumulated lipid in neointimal and medial layers, and analysis of human AAA lesions (n = 5) obtained from open repair showed medial lipid deposition. CONCLUSIONS: In summary, we find that lipid deposition in the aortic wall is a feature of PPE-induced AAA in mice as well as human AAA lesions. Despite, our data do not support the hypothesis that hyperlipidemia contributes to AAA progression.

Endovascular Occlusion of a Renal Arteriovenous Fistula with Renal Vein Aneurysm Formation for Rupture Prevention.

PURPOSE: To report the effectiveness of left renal artery (LRA) occlusion using Amplatzer Vascular Plug (AVP) II as treatment for a high-flow renal arteriovenous fistula (RAVF) with multiple renal vein aneurysms (RVA) to prevent aneurysm rupture and cardiac decompensation. CASE REPORT: A 59-year-old female suffering from a post-traumatic RAVF presented with tachycardia and increased cardiac output (CO). Doppler ultrasonography and computed tomography (CT) scan revealed a high-flow RAVF with multiple RVAs and unilateral critically reduced kidney function. Appreciating recent interventional therapeutic advances, the patient was treated with endovascular placement of AVP II into the left renal artery (LRA) resulting in complete occlusion of the RAVF to effectively reduce the risk of RVA rupture and cardiac decompensation. No anti-platelet medication was administrated after the occlusion of the LRA. The patient's physical capacity improved since right heart volume strain was normalized, and CO was reduced. CONCLUSION: Transbrachial AVP II occlusion of the LRA is effective to occlude high-flow RAVFs to prevent risk of life-threatening RVA rupture. Additional follow-up is warranted to verify long-term effectiveness of this approach.