Ascending Thoracic Aortic Aneurysm Research Articles

Comparative analysis of Zero Pressure Geometry and prestress methods in cardiovascular Fluid-Structure Interaction

Background and Objective:Modelling patient-specific aortic biomechanics with advanced computational techniques, such as Fluid–Structure Interaction (FSI), can be crucial to provide effective decision-making indices to enhance current clinical practices. To effectively simulate Ascending Thoracic Aortic Aneurysms (ATAA), the stress-free configuration must be defined. The Zero Pressure Geometry (ZPG) and the Prestress Tensor (PT) are two of the main approaches to tackle this issue. However, their impact on the numerical results is yet to be analysed. Computed Tomography Angiography (CTA) and Magnetic Resonance Imaging (MRI) data were used to develop patient-specific 2-way FSI frameworks. Methods:Three models were developed considering different tissue prestressing approaches to account for the reference configuration and their numerical results were compared. The selected approaches were: (i) ZPG, (ii) PT and (iii) a combination of the PT approach with a regional mapping of material properties (PTCAL). Results:The pressure fields estimated by all models were equivalent. The estimation of Wall Shear Stress (WSS) based metrics revealed good correspondence between all models except the Relative Residence Time (RRT). Regarding ATAA wall mechanics, the proposed extension to the PT approach presented a closer agreement with the ZPG model than its counterpart. Additionally, the PT and PTCAL approaches required around 60% fewer iterations to achieve cycle-to-cycle convergence than the ZPG algorithm. Conclusion:Using a regional mapping of material properties in combination with the PT method presented a better correspondence with the ZPG approach. The outcomes of this study can pave the way for advancing the accuracy and convergence of ATAA numerical models using the PT methodology.

The Influence of Material Properties and Wall Thickness on Predicted Wall Stress in Ascending Aortic Aneurysms: A Finite Element Study.

Finite element analysis (FEA) has been used to predict wall stress in ascending thoracic aortic aneurysm (ATAA) in order to evaluate risk of dissection or rupture. Patient-specific FEA requires detailed information on ATAA geometry, loading conditions, material properties, and wall thickness. Unfortunately, measuring aortic wall thickness and mechanical properties non-invasively poses a significant challenge, necessitating the use of non-patient-specific data in most FE simulations. This study aimed to assess the impact of employing non-patient-specific material properties and wall thickness on ATAA wall stress predictions. FE simulations were performed on 13 ATAA geometries reconstructed from computed tomography angiography (CTA) images. Patient-specific material properties and wall thicknesses were made available from a previous study where uniaxial tensile testing was performed on tissue samples obtained from the same patients. The ATAA wall models were discretised with hexahedral elements and prestressed. For each ATAA model, FE simulations were conducted using patient-specific material properties and wall thicknesses, and group-mean values derived from all tissue samples included in the same experimental study. Literature-based material property and wall thickness were also obtained from the literature and applied to 4 representative cases. Additional FE simulations were performed on these 4 cases by employing group-mean and literature-based wall thicknesses. FE simulations using the group-mean material property produced peak wall stresses comparable to those obtained using patient-specific material properties, with a mean deviation of 7.8%. Peak wall stresses differed by 20.8% and 18.7% in patients with exceptionally stiff or compliant walls, respectively. Comparison to results using literature-based material properties revealed larger discrepancies, ranging from 5.4% to 28.0% (mean 20.1%). Bland-Altman analysis showed significant discrepancies in areas of high wall stress, where wall stress obtained using patient-specific and literature-based properties differed by up to 674kPa, compared to 227kPa between patient-specific and group-mean properties. Regarding wall thickness, using the literature-based value resulted in even larger discrepancies in predicted peak stress, ranging from 24.2% to 30.0% (mean 27.3%). Again, using the group-mean wall thickness offered better predictions with a difference less than 5% in three out of four cases. While peak wall stresses were most affected by the choice of mechanical properties or wall thickness, the overall distribution of wall stress hardly changed. Our study demonstrated the importance of incorporating patient-specific material properties and wall thickness in FEA for risk prediction of aortic dissection or rupture. Our future efforts will focus on developing inverse methods for non-invasive determination of patient-specific wall material parameters and wall thickness.

In Vivo Quantification of Ascending Thoracic Aortic Aneurysm Wall Stretch Using MRI: Relationship to Repair Threshold Diameter and Ex Vivo Wall Failure Behavior.

Ascending thoracic aortic aneurysms (aTAAs) can lead to life-threatening dissection and rupture. Recent studies have highlighted aTAA mechanical properties as relevant factors associated with progression. The aim of this study was to quantify in vivo aortic wall stretch in healthy participants and aTAA patients using displacement encoding with stimulated echoes (DENSE) magnetic resonance imaging. Moreover, aTAA wall stretch between surgical and nonsurgical patients was investigated. Finally, DENSE measurements were compared to reference-standard mechanical testing on aTAA specimens from surgical repairs. In total, 18 subjects were recruited, six healthy participants and 12 aTAA patients, for this prospective study. Electrocardiogram-gated DENSE imaging was performed to measure systole-diastole wall stretch, as well as the ratio of aTAA stretch to unaffected descending thoracic aorta stretch. Free-breathing and breath-hold DENSE protocols were used. Uniaxial tensile testing-measured indices were correlated to DENSE measurements in five harvested specimens. in vivo aortic wall stretch was significantly lower in aTAA compared to healthy subjects (1.75±1.44% versus 5.28±1.92%, respectively, P = 0.0004). There was no correlation between stretch and maximum aTAA diameter (P = 0.56). The ratio of aTAA to unaffected thoracic aorta wall stretch was significantly lower in surgical candidates compared to nonsurgical candidates (0.993±0.011 versus 1.017±0.016, respectively, P = 0.0442). Finally, in vivo aTAA wall stretch correlated to wall failure stress and peak modulus of the intima (P = 0.017 and P = 0.034, respectively), while the stretch ratio correlated to whole-wall thickness failure stretch and stress (P = 0.013 and P = 0.040, respectively). Aortic DENSE has the potential to assess differences in aTAA mechanical properties and progressions.

From Biomechanical Properties to Morphological Variations: Exploring the Interplay between Aortic Valve Cuspidity and Ascending Aortic Aneurysm.

Background: This research explores the biomechanical and structural characteristics of ascending thoracic aortic aneurysms (ATAAs), focusing on the differences between bicuspid aortic valve aneurysms (BAV-As) and tricuspid aortic valve aneurysms (TAV-As) with non-dilated aortas to identify specific traits of ATAAs. Methods: Clinical characteristics, laboratory indices, and imaging data from 26 adult patients operated on for aneurysms (BAV-A: n = 12; TAV-A: n = 14) and 13 controls were analyzed. Biomechanical parameters (maximal aortic diameter, strain, and stress) and structural analyses (collagen fiber organization, density, fragmentation, adipocyte deposits, and immune cell infiltration) were assessed. Results: Significant differences in biomechanical parameters were observed. Median maximal strain was 40.0% (control), 63.4% (BAV-A), and 45.3% (TAV-A); median maximal stress was 0.59 MPa (control), 0.78 MPa (BAV-A), and 0.48 MPa (TAV-A). BAV-A showed higher tangential modulus and smaller diameter, with substantial collagen fragmentation (p < 0.001 vs. TAV and controls). TAV-A exhibited increased collagen density (p = 0.025), thickening between media and adventitia layers, and disorganized fibers (p = 0.036). BAV-A patients had elevated adipocyte deposits and immune cell infiltration. Conclusions: This study highlights distinct pathological profiles associated with different valve anatomies. BAV-A is characterized by smaller diameters, higher biomechanical stress, and significant collagen deterioration, underscoring the necessity for tailored clinical strategies for effective management of thoracic aortic aneurysm.

Region-specific delamination strength of ascending thoracic aortic aneurysm of elderly hypertensive patients with bicuspid and tricuspid aortic valves

Both ageing and hypertension are clinical factors that may lead to a higher propensity for dissection or rupture of ascending thoracic aortic aneurysms (ATAAs). This study sought to investigate effect of valve morphology on regional delamination strength of ATAAs in the elderly hypertensive patients. Whole fresh ATAA samples were harvested from 23 hypertensive patients (age, 71 ± 8 years) who underwent elective aortic surgery. Peeling tests were performed to measure region-specific delamination strengths of the ATAAs, which were compared between patients with bicuspid aortic valve (BAV) and tricuspid aortic valve (TAV). The regional delamination strengths of the ATAAs were further correlated with patient ages and aortic diameters for BAV and TAV groups. In the anterior and right lateral regions, the longitudinal delamination strengths of the ATAAs were statistically significantly higher for BAV patients than TAV patients (33 ± 7 vs. 23 ± 8 mN/mm, p = 0.01; 30 ± 7 vs. 19 ± 9 mN/mm, p = 0.02). For both BAV and TAV patients, the left lateral region exhibited significantly higher delamination strengths in both directions than the right lateral region. Histology revealed that disruption of elastic fibers in the right lateral region of the ATAAs was more severe for the TAV patients than the BAV patients. A strong inverse correlation between longitudinal delamination strength and age was identified in the right lateral region of the ATAAs of the TAV patients. Results suggest that TAV-ATAAs are more vulnerable to aortic dissection than BAV-ATAAs for the elderly hypertensive patients. Regardless of valve morphotypes, the right lateral region may be a special quadrant which is more likely to initiate dissection when compared with other regions.

The Fbn1 gene variant governs passive ascending aortic mechanics in the mgΔlpn mouse model of Marfan syndrome when superimposed to perlecan haploinsufficiency.

Ascending thoracic aortic aneurysms arise from pathological tissue remodeling that leads to abnormal wall dilation and increases the risk of fatal dissection/rupture. Large variability in disease manifestations across family members who carry a causative genetic variant for thoracic aortic aneurysms suggests that genetic modifiers may exacerbate clinical outcomes. Decreased perlecan expression in the aorta of mgΔlpn mice with severe Marfan syndrome phenotype advocates for exploring perlecan-encoding Hspg2 as a candidate modifier gene. To determine the effect of concurrent Hspg2 and Fbn1 mutations on the progression of thoracic aortopathy, we characterized the microstructure and passive mechanical response of the ascending thoracic aorta in female mice of four genetic backgrounds: wild-type, heterozygous with a mutation in the Fbn1 gene (mgΔlpn), heterozygous with a mutation in the Hspg2 gene (Hspg2+/-), and double mutants carrying both the Fbn1 and Hspg2 variants (dMut). Elastic fiber fragmentation and medial disarray progress from the internal elastic lamina outward as the ascending thoracic aorta dilates in mgΔlpn and dMut mice. Concurrent increase in total collagen content relative to elastin reduces energy storage capacity and cyclic distensibility of aortic tissues from mice that carry the Fbn1 variant. Inherent circumferential tissue stiffening strongly correlates with the severity of aortic dilatation in mgΔlpn and dMut mice. Perlecan haploinsufficiency superimposed to the mgΔlpn mutation curbs the viability of dMut mice, increases the occurrence of aortic enlargement, and reduces the axial stretch in aortic tissues. Overall, our findings show that dMut mice are more vulnerable than mgΔlpn mice without an Hspg2 mutation, yet later endpoints and additional structural and functional readouts are needed to identify causative mechanisms.

Male-female differences in the natural history of ascending thoracic aortic aneurysms: insights from the dissexion study

Abstract Background The natural history of ascending thoracic aortic aneurysms (ATAAs) remains poorly understood, including potential male-female differences. Purpose Therefore, this study sought to evaluate the natural history and outcomes of patients with ATAAs, with an emphasis on aortic growth and male-female differences. Methods Adult patients who received diagnostic and/or follow-up imaging of an ATAA (≥40mm) in two academic centers between 2007-2021 were included. Aortic growth was modeled non-linearly through mixed-effects models using repeated measurements, including age and sex through interaction terms. Joint models were constructed to adjust for the effect of nonrandom dropout due to surgical intervention. Secondary outcomes were male-female differences in presentation, aneurysm characteristics, time to intervention, acute aortic syndromes and survival relative to the age- and sex-matched general Dutch population. Cox models were employed to evaluate predictors of intervention and survival. Results In total, 1,858 patients were included (31.6% female). Median clinical follow-up was 5.9 [IQR: 3.0-10.0] years. Median age was 65.4 years [53.4-71.7y] for females and 59.0 years [IQR: 49.3-68.0y] for males (p&amp;lt;0.001). Males had more bicuspid aortic valve (BAV) disease (male: 27.5%, female: 18.2%; p&amp;lt;0.001) and were more likely to have had a previous dissection or aneurysm in a major artery other than the thoracic aorta (male: 8.9%, female: 4.9%; p=0.004) before diagnosis. Maximum absolute aortic diameter at diagnosis did not differ between males (46.5mm) and females (45.0mm; p=0.388). Unadjusted 10-year survival was 76% (68%-78%) for females (relative survival: 68.8%) and 78% (75%-81%) for males (relative survival: 78.7%). For females, tubular ascending aortic growth was faster compared to males (p=0.005), particularly in the first 6 years after diagnosis. Contrarily, SoV growth was faster in males compared to females (p=0.002). Surgical intervention occurred more quickly after diagnosis in females (HR: 2.5 (1.2-5.2), corrected for BAV, diameter and age. Twenty-three type A dissections (TAD) occurred with an incidence rate ratio between females and males of 3.4 (95%CI:1.5-8.0, p=0.004). The last known aortic diameter before TAD was comparable between males (47.5mm [47.0-50.8]) and females (47.0mm [43.0-51.0]; p=0.416). Conclusions Ascending aortic aneurysms show a strikingly different growth pattern between males and females at the level of the SoV and tubular ascending aorta, suggesting that although females present at an older age, their aortic disease progresses faster and with more TAD compared to males, and warranting an even more careful follow-up. Absolute known aortic diameter before TAD was comparable between males and females. These insights can be used to fuel discussion about male-female specific follow-up and treatment recommendations in future clinical guidelines development.Ascending aortic growth (A) &amp; sinus (B)Freedom from intervention from diagnosis

Abstract 18901: Critical Role of Endothelial Injury in the Initiation of Aortic Dissection

Introduction: Endothelium forms a protective barrier and maintains vascular hemostasis. However, the role of endothelial injury in aortic aneurysms and dissections (AAD) remains poorly understood. Receptor-interacting protein kinase 3 (RIP3)-mediated necroptosis and gasdermin D (GSDMD)-mediated pyroptosis trigger necrotic cell death. We hypothesize endothelial cell (EC) death induced by necroptosis and pyroptosis contributes to AAD formation. Methods: Endothelial integrity and gene expression were examined in ascending aortic tissues from ascending thoracic aortic aneurysm (ATAA) patients (n=9) and organ donor controls (n=8) by single-cell transcriptome analysis. Effects of EC death on AAD formation were determined in EC-specific Rip3 knockout (EC-Rip3 -/- , n=26), EC-specific Gsdmd knockout (EC-Gsdmd -/- , n=21), and necroptosis/pyroptosis inhibitor necrosulfonamide (NSA) treated mice (n=15) in sporadic AAD models induced by angiotensin II (Ang II) infusion. Evans blue staining and nanoparticle-mediated contrast-enhanced CT (n-CECT) detected endothelial hyperpermeability Results: Single-cell transcriptome and immunostaining analyses revealed significant upregulation of pro-death genes (e.g., RIP3 and GSDMD), but downregulation of cell junction genes (e.g., TJP1 and GJA1) in ECs of ATAA patients compared with controls. In the mouse AAD model, endothelial injury and hyperpermeability were detected 2-5 days after Ang II infusion and were associated with intramural nanoparticle accumulation, elastic fiber fragmentation, and macrophage infiltration. Importantly, EC-Rip3 -/- mice and EC-Gsdmd -/- mice showed preserved EC barrier function, reduced nanoparticle accumulation and elastic fiber fragmentation, and reduced AAD incidence (including aneurysm, dissection, and rupture) compared to their littermate controls (EC-Rip3 -/- mice: 52% vs 23.1%, P=0.033; EC-Gsdmd -/- mice: 52.6% vs 14.3%, P=0.01). Blocking necroptosis/pyroptosis by NSA treatment reduced the incidence (65% vs 27%; P=0.04) and severity of AAD. Conclusions: Endothelial injury and subsequent barrier dysfunction and infiltration are key features of AAD formation. Prevention of EC necrotic cell death can be a potential AAD therapeutic target.

Evidence Accumulates: Patients with Ascending Aneurysms Are Strongly Protected from Atherosclerotic Disease.

Ascending thoracic aortic aneurysms may be fatal upon rupture or dissection and remain a leading cause of death in the developed world. Understanding the pathophysiology of the development of ascending thoracic aortic aneurysms may help reduce the morbidity and mortality of this disease. In this review, we will discuss our current understanding of the protective relationship between ascending thoracic aortic aneurysms and the development of atherosclerosis, including decreased carotid intima-media thickness, low-density lipoprotein levels, coronary and aortic calcification, and incidence of myocardial infarction. We also propose several possible mechanisms driving this relationship, including matrix metalloproteinase proteins and transforming growth factor-β.

Regional biomechanical characterization of human ascending aortic aneurysms: Microstructure and biaxial mechanical response.

The ascending thoracic aortic aneurysm (ATAA) is a permanent dilatation of the vessel with a high risk of adverse events, and shows heterogeneous properties. To investigate regional differences in the biomechanical properties of ATAAs, tissue samples were collected from 10 patients with tricuspid aortic valve phenotype and specimens from minor, anterior, major, and posterior regions were subjected to multi-ratio planar biaxial extension tests and second-harmonic generation (SHG) imaging. Using the data, parameters of a microstructure-motivated constitutive model were obtained considering fiber dispersion. SHG imaging showed disruptions in the organization of the layers. Structural and material parameters did not differ significantly between regions. The non-symmetric fiber dispersion model proposed by Holzapfel etal. [25] was used to fit the data. The mean angle of collagen fibers was negatively correlated between minor and anterior regions, and the parameter associated with collagen fiber stiffness was positively correlated between minor and major regions. Furthermore, correlations were found between the stiffness of the ground matrix and the mean fiber angle, and between the parameter associated with the collagen fiber stiffness and the out-of-plane dispersion parameter in the posterior and minor regions, respectively. The experimental data collected in this study contribute to the biomechanical data available in the literature on human ATAAs. Region-specific parameters for the constitutive models are fundamental to improve the current risk stratification strategies, which are mainly based on aortic size. Such investigations can facilitate the development of more advanced finite element models capable of capturing the regional heterogeneity of pathological tissues. STATEMENT OF SIGNIFICANCE: Tissue samples of human ascending thoracic aortic aneurysms (ATAA) were collected. Samples from four regions underwent multi-ratio planar biaxial extension tests and second-harmonic generation imaging. Region-specific parameters of a microstructure-motivated model considering fiber dispersion were obtained. Structural and material parameters did not differ significantly between regions, however, the mean fiber angle was negatively correlated between minor and anterior regions, and the parameter associated with collagen fiber stiffness was positively correlated between minor and major regions. Furthermore, correlations were found between the stiffness of the ground matrix and the mean fiber angle, and between the parameter associated with the collagen fiber stiffness and the out-of-plane dispersion parameter in the posterior and minor regions, respectively. This study provides a unique set of mechanical and structural data, supporting the microstructural influence on the tissue response. It may facilitate the development of better finite element models capable of capturing the regional tissue heterogeneity.

Identification of co-diagnostic effect genes for aortic dissection and metabolic syndrome by multiple machine learning algorithms

Aortic dissection (AD) is a life-threatening condition in which the inner layer of the aorta tears. It has been reported that metabolic syndrome (MS) has a close linkage with aortic dissection. However, the inter-relational mechanisms between them were still unclear. This article explored the hub gene signatures and potential molecular mechanisms in AD and MS. We obtained five bulk RNA-seq datasets of AD, one single cell RNA-seq (scRNA-seq) dataset of ascending thoracic aortic aneurysm (ATAA), and one bulk RNA-seq dataset of MS from the gene expression omnibus (GEO) database. Identification of differentially expressed genes (DEGs) and key modules via weighted gene co-expression network analysis (WGCNA), functional enrichment analysis, and machine learning algorithms (Random Forest and LASSO regression) were used to identify hub genes for diagnosing AD with MS. XGBoost further improved the diagnostic performance of the model. The receiver operating characteristic (ROC) and precision-recall (PR) curves were developed to assess the diagnostic value. Then, immune cell infiltration and metabolism-associated pathways analyses were created to investigate immune cell and metabolism-associated pathway dysregulation in AD and MS. Finally, the scRNA-seq dataset was performed to confirm the expression levels of identified hub genes. 406 common DEGs were identified between the merged AD and MS datasets. Functional enrichment analysis revealed these DEGs were enriched for applicable terms of metabolism, cellular processes, organismal systems, and human diseases. Besides, the positively related key modules of AD and MS were mainly enriched in transcription factor binding and inflammatory response. In contrast, the negatively related modules were significantly associated with adaptive immune response and regulation of nuclease activity. Through machine learning, nine genes with common diagnostic effects were found in AD and MS, including MAD2L2, IMP4, PRPF4, CHSY1, SLC20A1, SLC9A1, TIPRL, DPYD, and MAPKAPK2. In the training set, the AUC of the hub gene on RP and RR curves was 1. In the AD verification set, the AUC of the Hub gene on RP and RR curves were 0.946 and 0.955, respectively. In the MS set, the AUC of the Hub gene on RP and RR curves were 0.978 and 0.98, respectively. scRNA-seq analysis revealed that the SLC20A1 was found to be relevant in fatty acid metabolic pathways and expressed in endothelial cells. Our study revealed the common pathogenesis of AD and MS. These common pathways and hub genes might provide new ideas for further mechanism research.

Evidence in Clinical Studies for the Role of Wall Thickness in Ascending Thoracic Aortic Aneurysms: A Scoping Review.

Ascending thoracic aortic aneurysm is a chronic degenerative pathology characterized by dilatation of this segment of the aorta. Clinical guidelines use aortic diameter and growth rate as predictors of rupture and dissection. However, these guidelines neglect the effects of tissue remodeling, which may affect wall thickness. The present study aims to systematically review observational studies to examine to what extent wall thickness is considered and measured in clinical practice. Using PubMed and Web of Science, studies were identified with data on ascending aortic wall thickness, morphology, aortic diameter, and measurement techniques. 15 included studies report several methods by which wall thickness is measured. No association was observed between wall thickness and aortic diameter across included studies. Wall thickness values appear not materially different between aneurysmatic aortas and non-aneurysmal aortas. The effects on and consequences of wall thickness changes during ATAA formation are ill-defined. Wall thickness values for aneurysmatic aortas can be similar to aortas with normal diameters. Given the existing notion that wall thickness is a determinant of mechanical stress homeostasis, our review exposes a clear need for consistent as well as clinically applicable methods and studies to quantify wall thickness in ascending aortic aneurysm research.

Ascending aortic volume: A feasible indicator for ascending aortic aneurysm elective surgery?

Diameter-based criterion have been widely adopted for preventive surgery of ascending thoracic aortic aneurysm (ATAA). However, recent and growing evidence has shown that diameter-based methods may not be sufficient for identifying patients who are at risk of an ATAA. In this study, fluid-structure interaction (FSI) analysis was performed on one-hundred ATAA geometries reconstructed from clinical data to examine the relationship between hemodynamic conditions, ascending aortic volume (AAV), ascending aortic curvature, and aortic ratios measured from the reconstructed 3D models. The simulated hemodynamic and biomechanical parameters were compared among different groups of ATAA geometries classified based on AAV. The ATAAs with enlarged AAV showed significantly compromised hemodynamic conditions and higher mechanical wall stress. The maximum oscillatory shear index (OSI), particle residence time (PRT) and wall stress (WS) were significantly higher in enlarged ATAAs compared with controls (0.498 [0.497, 0.499] vs 0.499 [0.498, 0.499], p = 0.002, 312.847 [207.445, 519.391] vs 996.047 [640.644, 1573.140], p < 0.001, 769.680 [668.745, 879.795] vs 1072.000 [873.060, 1280.000] kPa, p < 0.001, respectively). Values were reported as median with interquartile range (IQR). AAV was also found to be more strongly correlated with these parameters compared to maximum diameter. The correlation coefficient between AAV and average WS was as high as 0.92 (p < 0.004), suggesting that AAV might be a feasible risk identifier for ATAAs. Statement of SignificanceAscending thoracic aortic aneurysm is associated with the risk of dissection or rupture, creating life-threatening conditions. Current surgical intervention guidelines are mostly diameter based. Recently, many studies proposed to incorporate other morphological parameters into the current clinical guidelines to better prevent severe adverse aortic events like rupture or dissection. The purpose of this study is to gain a better understanding of the relationship between morphological parameters and hemodynamic parameters in ascending aortic aneurysms using fluid-solid-interaction analysis on patient-specific geometries. Our results suggest that ascending aortic volume may be a better indicator for surgical intervention as it shows a stronger association with pathogenic hemodynamic conditions.

Comparison of Genes Associated with Thoracic and Abdominal Aortic Aneurysms.

Aneurysms impacting the ascending thoracic aorta and the abdominal aorta affect patient populations with distinct clinical characteristics. Through a literature review, this paper compares the genetic associations of ascending thoracic aortic aneurysm (ATAA) with abdominal aortic aneurysms (AAA). Genes related to atherosclerosis, lipid metabolism, and tumor development are associated specifically with sporadic AAA, while genes controlling extracellular matrix (ECM) structure, ECM remodeling, and tumor growth factor β function are associated with both AAA and ATAA. Contractile element genes uniquely predispose to ATAA. Aside from known syndromic connective tissue disease and poly-aneurysmal syndromes (Marfan disease, Loeys-Dietz syndrome, and Ehlers-Danlos syndrome), there is only limited genetic overlap between AAA and ATAA. The rapid advances in genotyping and bioinformatics will elucidate further the various pathways associated with the development of aneurysms affecting various parts of the aorta.

Effect of hypertension on the delamination and tensile strength of ascending thoracic aortic aneurysm with a focus on right lateral region

Hypertension is a major predisposing factor to initiate thoracic aortopathy. The objective of this study is to investigate effect of hypertension on delamination and tensile strength of ascending thoracic aortic aneurysms (ATAAs). A total of 35 fresh ATAA samples were harvested from 19 hypertensive and 16 non-hypertensive patients during elective aortic surgery. Peeling tests with two extension rates were performed to determine delamination strength, while uniaxial tensile (UT) tests were employed to measure failure stresses. The delamination strength and failure stresses of the ATAAs were further correlated with patient ages for hypertensive and non-hypertensive groups. The delamination strength to peel apart the ATAA tissue along the longitudinal direction was statistically significantly lower for the hypertensive patients than that of the non-hypertensive patients (35 ± 11 vs. 49 ± 9 mN/mm, p = 0.02). A higher delamination strength was measured if peeling was performed with a higher extension rate. The circumferential failure stresses were significantly lower for the hypertensive ATAAs than those of the non-hypertensive ATAAs (1.03 ± 0.27 vs. 1.43 ± 0.38 MPa, p = 0.02). Histology showed that laminar structures of elastic fibers were mainly disrupted in the hypertensive ATAAs. The longitudinal delamination strength of the ATAAs was significantly decreased and strongly correlated with ages for the hypertensive patients. Strong inverse correlations were also identified between the circumferential and longitudinal failure stresses of the ATAAs and ages for the hypertensive patients. Results suggest that the ATAAs of the elderly hypertensive patients may have a higher propensity for dissection or rupture. The dissection properties of the ATAA tissue are rate dependent.

Analysis of immunogenic cell death in ascending thoracic aortic aneurysms based on single-cell sequencing data.

At present, research on immunogenic cell death (ICD) is mainly associated with cancer therapy. Little is known about the role of ICD in cardiovascular disease, especially in ascending thoracic aortic aneurysms (ATAA). ATAA single-cell RNA (scRNA) sequencing data were analyzed to identify the involved cell types and determine their transcriptomic characteristics. The chi-square test, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, Gene Set Enrichment Analysis (GSEA), and CellChat for cell-to-cell communication analysis from the Gene Expression Omnibus (GEO) database were used. A total of 10 cell types were identified, namely, monocytes, macrophages, CD4 T/NK (CD4+ T cells and natural killer T cells), mast cells, B/Plasma B cells, fibroblasts, endothelial cells, cytotoxic T cells (CD8+ T cells, CTLs), vascular smooth muscle cells (vSMCs), and mature dendritic cells (mDCs). A large number of inflammation-related pathways were present in the GSEA results. A large number of ICD-related pathways were found in the KEGG enrichment analysis of differentially expressed genes in endothelial cells. The number of mDCs and CTLs in the ATAA group was significantly different from that in the control group. A total of 44 pathway networks were obtained, of which 9 were associated with ICD in endothelial cells (CCL, CXCL, ANNEXIN, CD40, IL1, IL6, TNF, IFN-II, GALECTIN). The most important ligand-receptor pair by which endothelial cells act on CD4 T/NK cells, CTLs and mDCs is CXCL12-CXCR4. The most important ligand-receptor pair by which endothelial cells act on monocytes and macrophages is ANXA1-FPR1. The most important ligand-receptor pair by which CD4 T/NK cells and CTLs act on endothelial cells is CCL5-ACKR1. The most important ligand-receptor pair that myeloid cells (macrophages, monocytes and mDCs) act on endothelial cells is CXCL8-ACKR1. Moreover, vSMCs and fibroblasts mainly promote inflammatory responses through the MIF signaling pathway. ICD is present in ATAA and plays an important role in the development of ATAA. The target cells of ICD may be mainly endothelial cells, in which the aortic endothelial cell ACKR1 receptor can not only promote T-cell infiltration through the CCL5 ligand but also promote myeloid cell infiltration through the CXCL8 ligand. ACKR1 and CXCL12 may become target genes for ATAA drug therapy in the future.

Lengthwise regional mechanics of the human aneurysmal ascending thoracic aorta.

The prognosis of patients undergoing emergency endovascular repair of ascending thoracic aortic aneurysm (ATAA) depends on defect location, with root disease bearing worse outcomes than proximal or distal aortopathy. We speculate that a spatial gradient in aneurysmal tissue mechanics through the length of the ascending thoracic aorta may fuel noted survival discrepancies. To this end, we performed planar biaxial testing on 153 root, proximal, and distal segments of ATAA samples collected from 80 patients receiving elective open surgical repair. Following data averaging via surface fitting-based interpolation of strain-controlled protocols, we combined in-vitro and in-vivo measurements of loads and geometry to resolve inflation-extension kinematics and evaluate mechanical metrics of stress, stiffness, and energy at consistent deformation levels. Representative (averaged) experimental data and simulated in-vivo conditions revealed significantly larger biaxial stiffness at the root compared to either proximal or distal tissues, which persisted as the entire aorta stiffened during aging. Advancing age further reduced biaxial stretch and energy storage, a measure of aortic function, across all ATAA segments. Importantly, age emerged as a stronger predictor of tissue mechanics in ATAA disease than either bicuspid aortic valve or connective tissue disorders. Besides strengthening the general understanding of aneurysmal disease, our findings provide specifications to customize the design of stent-grafts for the treatment of ATAA disease. Optimization of deployment and interaction of novel endovascular devices with the local native environment is expected to carry significant potential for improving clinical outcomes. STATEMENT OF SIGNIFICANCE: Elucidating the lengthwise regional mechanics of ascending thoracic aortic aneurysms (ATAAs) is critical for the design of endovascular devices tailored to the ascending aorta. Stent-grafts provide a less invasive alternative to support the long-term survival of ATAA patients ineligible for open surgical repair. In this study, we developed a numerical framework that combines semi-inverse constitutive and forward modeling with in-vitro and in-vivo data to extract mechanical descriptors of ATAA tissue behavior at physiologically meaningful deformation. Moving distally from the aortic root to the first ascending aortic branch, we observed a progressive decline in biaxial stiffness. Furthermore, we showed that aging leads to reduced aortic function and is a stronger predictor of mechanics than either valve morphology or underlying syndromic disorder.

Avant-Garde Endovascular Stent Graft Insertion in Dissected Ascending Thoracic Aortic Aneurysm.

Current guidelines and regulatory parameters for cardiothoracic surgery in the United States establish that open surgery is the first front line for treating ascending thoracic aortic aneurysms (ATAA). Despite advances in performing endovascular procedures in thoracic aortic aneurysms, there are no approved state-of-the-art techniques that allow endovascular procedures to be performed in ATAA. Thus, thoracic endovascular aortic repair (TEVAR) of the ascending aorta, as we will demonstrate, is a useful and effective technical opportunity for treating high-risk patients with type A dissections, intramural hematomas, and pseudoaneurysms. In this case, an 88-year-old female patient was consulted due to a preliminary diagnosed descending thoracic aortic aneurysm. As a result of uncertainty regarding the initial diagnosis, abdominal-pelvic and chest computed tomography scan tests contradicted the original conclusion and surprisingly yielded a different scenario; in fact, the patient had a dissected ATAA. Using the TEVAR procedure, the patient's ATAA was treated with a thoracic GORE TAG endograft stent (W. L. Gore & Associates, Inc., Newark, DE, USA). Four weeks later, the aneurysm was completely thrombosed, and the stent-graft was properly in place.

Bicuspid aortopathy does not require earlier surgical intervention

ObjectivesGuidelines for surgical correction of patients with ascending thoracic aortic aneurysm (ATAA) with a bicuspid aortic valve (BAV) have oscillated over the years. In this study, we outline the natural history of the ascending aorta in patients with BAV and trileaflet aortic valve (TAV) ATAA followed over time, to ascertain if their behavior differs and to determine if a different threshold for intervention is required. MethodsAortic diameters and long-term complications (ie, adverse aortic events) of 2428 patients (554 BAV and 1874 TAV) with ATAA before operative repair were reviewed. Growth rates, yearly complication rates, event-free survival, and risk of complications as a function of aortic size were calculated. Long-term follow-up and precise cause of death granularity was achieved via a comprehensive 6-pronged approach. ResultsAortic growth rate in patients with BAV vs TAV ATAA was 0.20 and 0.17 cm/year, respectively (P = .009), with the rate increasing with increasing aortic size. Yearly adverse aortic events rates increased with ATAA size and were lower for patients with BAV. The relative risk of adverse aortic events exhibited an exponential increase with aortic diameter. Patients with BAV had a lower all-cause and ascending aorta-specific adverse aortic events hazard. Age-adjusted 10-year event-free survival was significantly better for patients with BAV, and BAV emerged as a protective factor against type A dissection, rupture, and ascending aortic death. ConclusionsThe threshold for surgical repair of ascending aneurysm with BAV should not differ from that of TAV. Prophylactic surgery should be considered at 5.0 cm for patients with TAV (and BAV) at expert centers.

Fate of the unoperated ascending thoracic aortic aneurysm: three-decade experience from the Aortic Institute at Yale University.

This study aims to outline the 'true' natural history of ascending thoracic aortic aneurysm (ATAA) based on a cohort of patients not undergoing surgical intervention. The outcomes, risk factors, and growth rates of 964 unoperated ATAA patients were investigated, over a median follow-up of 7.9 (maximum of 34) years. The primary endpoint was adverse aortic events (AAE), including dissection, rupture, and aortic death. At aortic sizes of 3.5-3.9, 4.0-4.4, 4.5-4.9, 5.0-5.4, 5.5-5.9, and ≥6.0 cm, the average yearly risk of AAE was 0.2%, 0.2%, 0.3%, 1.4%, 2.0%, and 3.5%, respectively (P < 0.001), and the 10-year survival free from AAE was 97.8%, 98.2%, 97.3%, 84.6%, 80.4%, and 70.9%, respectively (P < 0.001). The risk of AAE was relatively flat until 5 cm of aortic size, at which it began to increase rapidly (P for non-linearity <0.001). The mean annual growth rate was estimated to be 0.10 ± 0.01 cm/year. Ascending thoracic aortic aneurysms grew in a very slow manner, and aortic growth over 0.2 cm/year was rarely seen. Multivariable Cox regression identified aortic size [hazard ratio (HR): 1.78, 95% confidence interval (CI): 1.50-2.11, P < 0.001] and age (HR: 1.02, 95% CI: 1.00-1.05, P = 0.015) as significant independent risk factors for AAE. Interestingly, hyperlipidemia (HR: 0.46, 95% CI: 0.23-0.91, P = 0.025) was found to be a significant protective factor for AAE in univariable Cox regression. An aortic size of 5 cm, rather than 5.5 cm, may be a more appropriate intervention criterion for prophylactic ATAA repair. Aortic growth may not be an applicable indicator for intervention.