Chronic Nicotine Exposure Induces Murine Aortic Remodeling and Stiffness Segmentation—Implications for Abdominal Aortic Aneurysm Susceptibility

Aim: Arterial stiffness is a significant risk factor for many cardiovascular diseases, including abdominal aortic aneurysms (AAA). Nicotine, the major active ingredient of e-cigarettes and tobacco smoke, induces acute vasomotor effects that may temporarily increase arterial stiffness. Here, we investigated the effects of long-term nicotine exposure on structural aortic stiffness.Methods: Mice (C57BL/6) were infused with nicotine for 40 days (20 mg/kg/day). Arterial stiffness of the thoracic (TS) and abdominal (AS) aortic segments was analyzed using ultrasound (PWV, pulse wave velocity) and ex vivo pressure myograph measurements. For mechanistic studies, aortic matrix-metalloproteinase (MMP) expression and activity as well as medial elastin architecture were analyzed.Results: Global aortic stiffness increased with nicotine. In particular, local stiffening of the abdominal segment occurred after 10 days, while thoracic aortic stiffness was only increased after 40 days, resulting in aortic stiffness segmentation. Mechanistically, nicotine exposure enhanced expression of MMP-2/-9 and elastolytic activity in both aortic segments. Elastin degradation occurred in both segments; however, basal elastin levels were higher in the thoracic aorta. Finally, MMP-inhibition significantly reduced nicotine-induced MMP activity, elastin destruction, and aortic stiffening.Conclusion: Chronic nicotine exposure induces aortic MMP expression and structural aortic damage (elastin fragmentation), irreversibly increasing aortic stiffness. This process predominantly affects the abdominal aortic segment, presumably due in part to a lower basal elastin content. This novel phenomenon may help to explain the role of nicotine as a major risk factor for AAA formation and has health implications for ECIGs and other modes of nicotine delivery

Chronic Nicotine Exposure Induces Murine Aortic Remodeling and Stiffness Segmentation - Implications for Abdominal Aortic Aneurysm Susceptibility

Aim: Arterial stiffness is a significant risk factor for many cardiovascular diseases, including abdominal aortic aneurysms (AAA). Nicotine, the major active ingredient of e-cigarettes and tobacco smoke, induces acute vasomotor effects that may temporarily increase arterial stiffness. Here, we investigated the effects of long-term nicotine exposure on structural aortic stiffness. Methods: Mice (C57BL/6) were infused with nicotine for 40 days (20 mg/kg/day). Arterial stiffness of the thoracic (TS) and abdominal (AS) aortic segments was analyzed using ultrasound (PVVV, pulse wave velocity) and ex vivo pressure myograph measurements. For mechanistic studies, aortic matrix-metalloproteinase (MMP) expression and activity as well as medial elastin architecture were analyzed. Results: Global aortic stiffness increased with nicotine. In particular, local stiffening of the abdominal segment occurred after 10 days, while thoracic aortic stiffness was only increased after 40 days, resulting in aortic stiffness segmentation. Mechanistically, nicotine exposure enhanced expression of MMP-2/-9 and elastolytic activity in both aortic segments. Elastin degradation occurred in both segments;however, basal elastin levels were higher in the thoracic aorta. Finally, MMP-inhibition significantly reduced nicotine-induced MMP activity, elastin destruction, and aortic stiffening. Conclusion: Chronic nicotine exposure induces aortic MMP expression and structural aortic damage (elastin fragmentation), irreversibly increasing aortic stiffness. This process predominantly affects the abdominal aortic segment, presumably due in part to a lower basal elastin content. This novel phenomenon may help to explain the role of nicotine as a major risk factor for AM formation and has health implications for ECIGs and other modes of nicotine delivery

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 Chill 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 Chill as a key mediator in this context. Our data raise concerns regarding the potentially harmful long-term effects of e-cig nicotine vaping. [GRAPHICS]

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 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

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

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

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

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 &gt;80% in vitro cell viability and &gt;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