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Ex Vivo Mechanical Tests and Multiscale Computational Modeling Highlight the Importance of Intramural Shear Stress in Ascending Thoracic Aortic Aneurysms.

ABSTRACT: Ascending thoracic aortic aneurysms (ATAAs) are anatomically complex in terms of architecture and geometry, and both complexities contribute to unpredictability of ATAA dissection and rupture in vivo. The goal of this work was to examine the mechanism of ATAA failure using a combination of detailed mechanical tests on human tissue and a multiscale computational model. We used (1) multiple, geometrically diverse, mechanical tests to characterize tissue properties, (2) a multiscale computational model to translate those results into a broadly usable form, and (3) a model-based computer simulation of the response of an ATAA to the stresses generated by the blood pressure. Mechanical tests were performed in uniaxial extension, biaxial extension, shear lap, and peel geometries. ATAA tissue was strongest in circumferential extension and weakest in shear, presumably because of the collagen and elastin in the arterial lamellae. A multiscale, fiber-based model using different fiber properties for collagen, elastin, and interlamellar connections was specified to match all of the experimental data with one parameter set. Finally, this model was used to simulate ATAA inflation using a realistic geometry. The predicted tissue failure occurred in regions of high stress, as expected; initial failure events involved almost entirely interlamellar connections, consistent with arterial dissection - the elastic lamellae remain intact, but the connections between them fail. The failure of the interlamellar connections, paired with the weakness of the tissue under shear loading, is suggestive that shear stress within the tissue may contribute to ATAA dissection.

SUBMITTER: Korenczuk CE

PROVIDER: S-EPMC7104749 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Ex Vivo Mechanical Tests and Multiscale Computational Modeling Highlight the Importance of Intramural Shear Stress in Ascending Thoracic Aortic Aneurysms.

Korenczuk Christopher E CE Dhume Rohit Y RY Liao Kenneth K KK Barocas Victor H VH

Journal of biomechanical engineering 20191201 12

Ascending thoracic aortic aneurysms (ATAAs) are anatomically complex in terms of architecture and geometry, and both complexities contribute to unpredictability of ATAA dissection and rupture in vivo. The goal of this work was to examine the mechanism of ATAA failure using a combination of detailed mechanical tests on human tissue and a multiscale computational model. We used (1) multiple, geometrically diverse, mechanical tests to characterize tissue properties; (2) a multiscale computational m ...[more]

PMID: 31633165

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Project description:ObjectivesThis study aims to characterize the material properties of ascending thoracic aortic aneurysmal tissue, using regional biomechanical assessment of both tensile and dissection propagation peel strength.MethodsThirty-four aneurysm specimens (proximal thoracic aorta) were harvested en-bloc from patients undergoing surgery for aneurysm replacement. Specimens were processed into regional samples of similar shapes covering the whole aneurysm isosurface, according to a structured protocol, in both orientations (longitudinal and circumferential). Thickness mapping, uniaxial tensile and peel tests were conducted, enabling calculation of the following parameters: true stress/strain, tangential modulus, tensile strength, peeling force and dissection energy. Two constitutive material models were used (hyperelastic models of Delfino and Ogden) to fit the data. A circumferential strip of tissue was also obtained for computational histology [regional quantification of (i) elastin, (ii) collagen and (iii) smooth muscle cells].ResultsThe aortic wall was thinner on the outer curve (2.21, standard deviation (SD) 0.4 mm vs inner curve 2.50, SD 0.12 mm). Advanced patient age and higher pulse wave velocity (externally measured) were predictors of increased aortic wall thickness. Tensile strength was higher in the circumferential versus longitudinal direction when analysed according to anatomical regions. Both peel force (35.5, 22 N/m) and dissection energy (88.5, 69 J/m2) were on average lowest at the outer curve of the aneurysm in the longitudinal orientation. Delfino and Ogden model constants varied throughout anatomical regions, with the outer curve being associated a higher ɑ constant (Delfino) and lower µ1 constant (Ogden) (P < 0.05) indicating increased stiffness. Histologically, collagen abundance was significantly related to circumferential and longitudinal strength (P= 0.010), whilst smooth muscle cell count had no relation with any mechanical property (P > 0.05).ConclusionsOur results suggest that the outer aortic curve is more prone to dissection propagation and perhaps less prone to rupture than the inner aortic curve. This strengthens the notion of disease heterogeneity in ascending thoracic aortic aneurysms and has implications for the pathogenesis of aortic dissection.

Project description:ObjectiveGuidelines for repair of bicuspid aortic valve-associated ascending thoracic aortic aneurysms have been changing, most recently to the same criteria as tricuspid aortic valve-ascending thoracic aortic aneurysms. Rupture/dissection occurs when wall stress exceeds wall strength. Recent studies suggest similar strength of bicuspid aortic valve versus tricuspid aortic valve-ascending thoracic aortic aneurysms; thus, comparative wall stress may better predict dissection in bicuspid aortic valve versus tricuspid aortic valve-ascending thoracic aortic aneurysms. Our aim was to determine whether bicuspid aortic valve-ascending thoracic aortic aneurysms had higher wall stresses than their tricuspid aortic valve counterparts.MethodsPatients with bicuspid aortic valve- and tricuspid aortic valve-ascending thoracic aortic aneurysms (bicuspid aortic valve = 17, tricuspid aortic valve = 19) greater than 4.5 cm underwent electrocardiogram-gated computed tomography angiography. Patient-specific 3-dimensional geometry was reconstructed and loaded to systemic pressure after accounting for prestress geometry. Finite element analyses were performed using the LS-DYNA solver (LSTC Inc, Livermore, Calif) with user-defined fiber-embedded material model to determine ascending thoracic aortic aneurysm wall stress.ResultsBicuspid aortic valve-ascending thoracic aortic aneurysms 99th-percentile longitudinal stresses were 280 kPa versus 242 kPa (P = .028) for tricuspid aortic valve-ascending thoracic aortic aneurysms in systole. These stresses did not correlate to diameter for bicuspid aortic valve-ascending thoracic aortic aneurysms (r = -0.004) but had better correlation to tricuspid aortic valve-ascending thoracic aortic aneurysms diameter (r = 0.677). Longitudinal stresses on sinotubular junction were significantly higher in bicuspid aortic valve-ascending thoracic aortic aneurysms than in tricuspid aortic valve-ascending thoracic aortic aneurysms (405 vs 329 kPa, P = .023). Bicuspid aortic valve-ascending thoracic aortic aneurysm 99th-percentile circumferential stresses were 548 kPa versus 462 kPa (P = .033) for tricuspid aortic valve-ascending thoracic aortic aneurysms, which also did not correlate to bicuspid aortic valve-ascending thoracic aortic aneurysm diameter (r = 0.007).ConclusionsCircumferential and longitudinal stresses were greater in bicuspid aortic valve- than tricuspid aortic valve-ascending thoracic aortic aneurysms and were more pronounced in the sinotubular junction. Peak wall stress did not correlate with bicuspid aortic valve-ascending thoracic aortic aneurysm diameter, suggesting diameter alone in this population may be a poor predictor of dissection risk. Our results highlight the need for patient-specific aneurysm wall stress analysis for accurate dissection risk prediction.

Project description:BackgroundThoracic Aortic Aneurysms (TAAs) develop asymptomatically and are characterized by dilatation of the aorta. This is considered a life-threatening vascular disorder due to the risk of aortic dissection and rupture. There is an urgent need to identify blood-borne biomarkers for the early detection of TAA. The goal of the present study was to identify potential protein biomarkers associated with TAAs, using proteomic analysis of aortic tissue and plasma samples.MethodsExtracted proteins from 14 aneurysmal and 12 non-aneurysmal thoracic aortic tissue specimens as well as plasma samples from six TAA patients collected pre-and postoperatively and six healthy controls (HC), were analyzed by liquid chromatography-tandem mass spectrometry. Proteomic data were further processed and following filtering criteria, one protein was selected for verification and validation in a larger cohort of patients and controls using a targeted quantitative proteomic approach and enzyme-linked immunosorbent assay, respectively.ResultsA total of 1593 and 363 differentially expressed proteins were identified in tissue and plasma samples, respectively. Pathway enrichment analysis on the differentially expressed proteins revealed a number of dysregulated molecular pathways that might be implicated in aneurysm pathology including complement and coagulation cascades, focal adhesion, and extracellular matrix receptor interaction pathways. Alpha-2-HS glycoprotein (AHSG) was selected for further verification in 36 TAA and 21 HC plasma samples using targeted quantitative proteomic approach. The results showed a significantly decreased concentration of AHSG (p = 0.0002) in the preoperative plasma samples compared with HC samples. Further analyses using a larger validation dataset revealed that AHSG protein levels were significantly lower (p = 0.03) compared with HC. Logistic regression analysis on the validation dataset revealed males, advanced age, hypertension and hyperlipidaemia as significant risk factors for TAA.ConclusionAHSG concentrations distinguish plasma samples derived from TAA patients and controls. The findings of this study suggest that AHSG may be a potential biomarker for TAA that could lead to better diagnostic capabilities.

Project description:BackgroundAt 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).MethodATAA 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.ResultA 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.ConclusionICD 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.

Dataset Information

Ex Vivo Mechanical Tests and Multiscale Computational Modeling Highlight the Importance of Intramural Shear Stress in Ascending Thoracic Aortic Aneurysms.

Publications

Ex Vivo Mechanical Tests and Multiscale Computational Modeling Highlight the Importance of Intramural Shear Stress in Ascending Thoracic Aortic Aneurysms.

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