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This study was an unplanned exploratory analysis of a subset of participants from the Telmisartan in the Management of Abdominal Aortic Aneurysm (TEDY) trial. It aimed to assess the efficacy of the angiotensin 1 receptor blocker telmisartan in reducing abdominal aortic aneurysm (AAA) peak wall stress (PWS) and peak wall rupture index (PWRI) among individuals with small AAAs.Participants with AAAs measuring 35 - 49 mm in maximum diameter were randomised to receive telmisartan 40 mg or identical placebo in the TEDY trial. Participants who had computed tomography angiography performed at entry and at least one other time point during the trial (12 or 24 months) were included in the current study. Orthogonal AAA diameter, PWS, and PWRI were measured using previously validated methods. The annual change in PWS and PWRI from baseline was compared between participants allocated telmisartan or placebo using linear mixed effects models. These models were either unadjusted or adjusted for risk factors that were different in the groups at entry (p.100) or systolic blood pressure (SBP) at one year.Of the 207 participants recruited to TEDY, 124 were eligible for inclusion in this study. This study included 65 and 59 participants from the telmisartan and placebo groups, respectively. The PWS and PWRI were not significantly different in the two groups at baseline. Participants allocated telmisartan had a slower annual increase in PWS (-4.19; 95% CI -8.24, -0.14 kPa/year; p = .043) and PWRI (-0.014; 95% CI -0.026, -0.001; p = .032) compared with those allocated placebo after adjusting for risk factors. After adjustment for SBP at one year, telmisartan did not significantly reduce annual increases in PWS or PWRI.The findings of this study suggest that telmisartan limits the rate of increase in PWS and PWRI of small AAAs by reducing blood pressure.

Objective The aim of this study was to assess whether aortic peak wall stress (PWS) and peak wall rupture index (PWRI) were associated with the risk of abdominal aortic aneurysm (AAA) rupture or repair (defined as AAA events) among participants with small AAAs. Methods PWS and PWRI were estimated from computed tomography angiography (CTA) scans of 210 participants with small AAAs (≥ 30 and ≤ 50 mm) prospectively recruited between 2002 and 2016 from two existing databases. Participants were followed for a median of 2.0 (inter-quartile range 1.9, 2.8) years to record the incidence of AAA events. The associations between PWS and PWRI with AAA events were assessed using Cox proportional hazard analyses. The ability of PWS and PWRI to reclassify the risk of AAA events compared to the initial AAA diameter was examined using net reclassification index (NRI) and classification and regression tree (CART) analysis. Results After adjusting for other risk factors, one standard deviation increase in PWS (hazard ratio, HR, 1.56, 95% confidence intervals, CI 1.19, 2.06; p = 0.001) and PWRI (HR 1.74, 95% CI 1.29, 2.34; p 0.562. PWRI, but not PWS, significantly improved the classification of risk of AAA events compared to the initial AAA diameter alone. Conclusion PWS and PWRI predicted the risk of AAA events but only PWRI significantly improved the risk stratification compared to aortic diameter alone. Key Points • Aortic diameter is an imperfect measure of abdominal aortic aneurysm (AAA) rupture risk. • This observational study of 210 participants found that peak wall stress (PWS) and peak wall rupture index (PWRI) predicted the risk of aortic rupture or AAA repair. • PWRI, but not PWS, significantly improved the risk stratification for AAA events compared to aortic diameter alone.

Intimal calcification and vascular stiffening are predominant features of end-stage atherosclerosis. However, their role in atherosclerotic plaque instability and how the extent and spatial distribution of calcification influence plaque biology remain unclear. We recently showed that extensive macro calcification can be a stabilizing feature of late-stage human lesions, associated with a reacquisition of more differentiated properties of plaque smooth muscle cells (SMCs) and extracellular matrix (ECM) remodeling. Here, we hypothesized that biomechanical forces related to macro-calcification within plaques influence SMC phenotype and contribute to plaque stabilization. We generated a finite element modeling (FEM) pipeline to assess plaque tissue stretch based on image analysis of preoperative computed tomography angiography (CTA) of carotid atherosclerotic plaques to visualize calcification and soft tissues (lipids and extracellular matrix) within the lesions. Biomechanical stretch was significantly reduced in tissues in close proximity to macro calcification, while increased levels were observed within distant soft tissues. Applying this data to an in vitro stretch model on primary vascular SMCs revealed upregulation of typical markers for differentiated SMCs and contractility under low stretch conditions but also impeded SMC alignment. In contrast, high stretch conditions in combination with calcifying conditions induced SMC apoptosis. Our findings suggest that the load bearing capacities of macro calcifications influence SMC differentiation and survival and contribute to atherosclerotic plaque stabilization.

Intimal calcification and vascular stiffening are predominant features of end-stage atherosclerosis. However, their role in atherosclerotic plaque instability and how the extent and spatial distribution of calcification influence plaque biology remain unclear. We recently showed that extensive macro calcification can be a stabilizing feature of late-stage human lesions, associated with a reacquisition of more differentiated properties of plaque smooth muscle cells (SMCs) and extracellular matrix (ECM) remodeling. Here, we hypothesized that biomechanical forces related to macro-calcification within plaques influence SMC phenotype and contribute to plaque stabilization. We generated a finite element modeling (FEM) pipeline to assess plaque tissue stretch based on image analysis of preoperative computed tomography angiography (CTA) of carotid atherosclerotic plaques to visualize calcification and soft tissues (lipids and extracellular matrix) within the lesions. Biomechanical stretch was significantly reduced in tissues in close proximity to macro calcification, while increased levels were observed within distant soft tissues. Applying this data to an in vitro stretch model on primary vascular SMCs revealed upregulation of typical markers for differentiated SMCs and contractility under low stretch conditions but also impeded SMC alignment. In contrast, high stretch conditions in combination with calcifying conditions induced SMC apoptosis. Our findings suggest that the load bearing capacities of macro calcifications influence SMC differentiation and survival and contribute to atherosclerotic plaque stabilization.

The computational analysis of fiber network fracture is an emerging field with application to paper, rubber-like materials, hydrogels, soft biological tissue, and composites. Fiber networks are often described as probabilistic structures of interacting one-dimensional elements, such as truss-bars and beams. Failure may then be modeled as strong discontinuities in the displacement field that are directly embedded within the structural finite elements. As for other strain-softening materials, the tangent stiffness matrix can be non-positive definite, which diminishes the robustness of the solution of the coupled (monolithic) two-field problem. Its uncoupling, and thus the use of a staggered solution method where the field variables are solved alternatingly, avoids such difficulties and results in a stable, but sub-optimally converging solution method. In the present work, we evaluate the staggered against the monolithic solution approach and assess their computational performance in the analysis of fiber network failure. We then propose a hybrid solution technique that optimizes the performance and robustness of the computational analysis. It represents a matrix regularization technique that retains a positive definite element stiffness matrix while approaching the tangent stiffness matrix of the monolithic problem. The approach is general and may also accelerate the computational analysis of other failure problems., Comment: Numerical Analysis (math.NA)

A versatile constitutive model for load-carrying soft biological tissue should incorporate salient microstructural deformation mechanisms and be able to reliably predict complex non-linear viscoelastic behavior. The advancement of treatment and rehabilitation strategies for soft tissue injuries is inextricably linked to our understanding of the underlying tissue microstructure and how this defines its macroscopic material properties. Towards this long-term objective, we present a generalized multiscale constitutive framework based on a novel description of collagen, the most mechanically significant extracellular matrix protein. The description accounts for the gradual recruitment of undulated collagen fibrils and introduces proteoglycan mediated time-dependent fibrillar sliding. Crucially, the proteoglycan deformation allows for the reduction of overstressed fibrils towards a preferential homeostatic stress. An implicit Finite Element implementation of the model uses an interpolation strategy towards collagen fiber stress determination and results in a memory-efficient representation of the model. A number of test cases, including patient-specific geometries, establish the efficiency of the description and demonstrate its ability to explain qualitative properties reported from macroscopic experimental studies of tendon and vascular tissue.

It remains difficult to predict when which patients with abdominal aortic aneurysm (AAA) will require surgery. The aim was to study the accuracy of geometric and biomechanical analysis of small AAAs to predict reaching the threshold for surgery, diameter growth rate and rupture or symptomatic aneurysm. 189 patients with AAAs of diameters 40–50 mm were included, 161 had undergone two CTAs. Geometric and biomechanical variables were used in prediction modelling. Classifications were evaluated with area under receiver operating characteristic curve (AUC) and regressions with correlation between observed and predicted growth rates. Compared with the baseline clinical diameter, geometric-biomechanical analysis improved prediction of reaching surgical threshold within four years (AUC 0.80 vs 0.85, p = 0.031) and prediction of diameter growth rate (r = 0.17 vs r = 0.38, p = 0.0031), mainly due to the addition of semiautomatic diameter measurements. There was a trend towards increased precision of volume growth rate prediction (r = 0.37 vs r = 0.45, p = 0.081). Lumen diameter and biomechanical indices were the only variables that could predict future rupture or symptomatic AAA (AUCs 0.65–0.67). Enhanced precision of diameter measurements improves the prediction of reaching the surgical threshold and diameter growth rate, while lumen diameter and biomechanical analysis predicts rupture or symptomatic AAA.

Rupture of unstable atherosclerotic plaques with a large lipid-rich necrotic core and a thin fibrous cap cause myocardial infarction and stroke. Yet it has not been possible to assess this for individual patients. Clinical guidelines still rely on use of luminal narrowing, a poor indicator but one that persists for lack of effective means to do better. We present a case study demonstrating the assessment of biomechanical indices pertaining to plaque rupture risk non-invasively for individual patients enabled by histologically validated tissue characterization.Routinely acquired clinical images of plaques were analyzed to characterize vascular wall tissues using software validated by histology (ElucidVivo, Elucid Bioimaging Inc.). Based on the tissue distribution, wall stress and strain were then calculated at spatial locations with varied fibrous cap thicknesses at diastolic, mean and systolic blood pressures.The von Mises stress of 152 [131, 172] kPa and the equivalent strain of 0.10 [0.08, 0.12] were calculated where the fibrous cap thickness was smallest (560 μm) (95% CI in brackets). The stress at this location was at a level predictive of plaque failure. Stress and strain at locations with larger cap thicknesses were calculated to be lower, demonstrating a clinically relevant range of risk levels.Patient specific tissue characterization can identify distributions of stress and strain in a clinically relevant range. This capability may be used to identify high-risk lesions and personalize treatment decisions for individual patients with cardiovascular disease and improve prevention of myocardial infarction and stroke.

Background Prior studies have suggested aortic peak wall stress (PWS) and peak wall rupture index (PWRI) can estimate the rupture risk of an abdominal aortic aneurysm (AAA), but whether these measurements have independent predictive ability over assessing AAA diameter alone is unclear. The aim of this systematic review was to compare PWS and PWRI in participants with ruptured and asymptomatic intact AAAs of similar diameter. Methods and Results Web of Science, Scopus, Medline, and The Cochrane Library were systematically searched to identify studies assessing PWS and PWRI in ruptured and asymptomatic intact AAAs of similar diameter. Random‐effects meta‐analyses were performed using inverse variance‐weighted methods. Leave‐one‐out sensitivity analyses were conducted to assess the robustness of findings. Risk of bias was assessed using a modification of the Newcastle‐Ottawa scale and standard quality assessment criteria for evaluating primary research papers. Seven case‐control studies involving 309 participants were included. Meta‐analyses suggested that PWRI (standardized mean difference, 0.42; 95% CI, 0.14–0.70; P =0.004) but not PWS (standardized mean difference, 0.13; 95% CI, −0.18 to 0.44; P =0.418) was greater in ruptured than intact AAAs. Sensitivity analyses suggested that the findings were not dependent on the inclusion of any single study. The included studies were assessed to have a medium to high risk of bias. Conclusions Based on limited evidence, this study suggested that PWRI, but not PWS, is greater in ruptured than asymptomatic intact AAAs of similar maximum aortic diameter.

Coronary heart disease is a major and global health care challenge, and its biomechanical analysis has been shown to be a useful complement in answering related clinical questions. Compelling evidence has been accumulated showing that two primary biomechanical factors predispose to the disease: low or oscillating wall shear stress and high wall mechanical stress (or strain) of plaque tissue components. While the level of sophistication with which vascular biomechanical analysis can be made has increased dramatically, the utility of biomechanical models in clinical practice remains very limited and their capability is by far not fully exploited. This chapter aims at reviewing the principles of the biomechanical analysis of coronary arteries in relation to the interplay of biomechanical, biochemical, and clinical factors. Techniques, methods, and modeling assumptions are discussed in relation to their clinical relevance, and thus toward the feasibility of translating research results and developing new treatment techniques and diagnostic tools.

To model fiber failures in random fiber networks, we have developed an elastoplastic Timoshenko beam finite element with embedded discontinuities. The method is based on the theory of strong discontinuities where the generalized displacement field is enhanced by a jump. The continuum mechanics formulation accounts for a fracture process zone and a bulk material while retaining traction continuity across the discontinuity. The additional degrees of freedom that are associated with the discontinuity are represented by a midpoint node, which is statically condensed to enable the implementation in commercial software through the user element interface . We propose a quasi-brittle fracture model, where the failure-related deformation is uncoupled from the plastic deformation in the bulk material. To retain the positive definite finite element stiffness matrix of the bulk material, we neglect the fracture-related softening of the discontinuity and employ a modified Newton iteration in the strain softening domain. Our implementation facilitates the integration into commercial finite element software and examples illustrate the robustness of the method. The FORTRAN source code is freely available to benchmark our model. We show that fiber failures contribute to the nonlinear stress–strain response of paper. Together with fiber–fiber bond failures, they can potentially explain the nonlinear stress–strain response of paper and nanopaper.

Hip fractures are a major health problem with high socio-economic costs. Subject-specific finite element (FE) models have been suggested to improve the fracture risk assessment, as compared to clinical tools based on areal bone mineral density, by adding an estimate of bone strength. Typically, such FE models are limited to estimate bone strength and possibly the fracture onset, but do not model the fracture process itself. The aim of this study was to use a discrete damage approach to simulate the full fracture process in subject-specific femur models under stance loading conditions. A framework based on the partition of unity finite element method (PUFEM), also known as XFEM, was used. An existing PUFEM framework previously used on a homogeneous generic femur model was extended to include a heterogeneous material description together with a strain-based criterion for crack initiation. The model was tested on two femurs, previously mechanically tested in vitro. Our results illustrate the importance of implementing a subject-specific material distribution to capture the experimental fracture pattern under stance loading. Our models accurately predicted the fracture pattern and bone strength (1% and 5% error) in both investigated femurs. This is the first study to simulate complete fracture paths in subject-specific FE femur models and it demonstrated how discrete damage models can provide a more complete picture of fracture risk by considering both bone strength and fracture toughness in a subject-specific fashion.

The aim of this work is to propose a recruitment and damage constitutive model for collagen fibres in soft biological tissues. Similarly to other published models, our model employs probability distribution functions in order to capture the progressive recruitment and damage of fibrils in a collagen fibre. We rigorously investigate the continuum mechanical treatment of recruitment and damage using a multiplicative decomposition of the deformation gradient. Our proposed model stems from the correction, generalisation and extension to damage of the recruitment model proposed by Martufi and Gasser (2011, J. Biomech. , 44, 2544–2550). We demonstrate that the generalised model is equivalent to the recruitment and damage model proposed by Hurschler et al. (1997, J. Biomech. Eng. , 119, 392–399). Finally, we explore the sensitivity of the proposed model to the parameters describing recruitment and damage, implement the model into Finite Elements and show an example of application, which gives good agreement with published experimental data.

Background The intraluminal thrombi (ILT) of abdominal aortic aneurysms (AAA) contain neutrophils, which can secrete elastase. We evaluated whether plasma neutrophil elastase-derived cross-linked fibrin degradation products (E-XDP) could reveal the presence, size and mechanical stress of AAAs and its ILTs. Methods E-XDP and D-dimer were measured in plasma from 37 male patients with AAA and 42 male controls. The ILT volumes of the AAAs and any coexisting aneurysms could be measured in 29 patients and finite element analysis was performed to estimate mechanical stress of the ILT. E-XDP, neutrophil elastase and neutrophil marker CD66acd were evaluated in aortic tissue with immunohistochemistry (IHC). The association between ILT volume and E-XDP was validated in a separate cohort (n = 51). Results E-XDP levels were elevated in patients with AAA compared with controls (p = 5.8e-13), indicated AAA with 98% sensitivity, 86% specificity and increased with presence of coexisting aneurysms. The association between AAA and increased E-XDP was independent of smoking, comorbidities and medication. E-XDP correlated with volume of all ILTs (r = 0.76, p = 4.5e-06), mean ILT stress (r = 0.46, p = 0.013) and the volume of the AAA-associated ILT (r = 0.64, p = 0.00017). E-XDP correlated stronger with ILT volume compared with D-dimer (r = 0.76 vs. r = 0.64, p = 0.018). The correlation between E-XDP and ILT volume was validated in the separate cohort (r = 0.53, p = 7.6e-05). IHC revealed E-XDP expression in the ILT, spatially related to neutrophil elastase and neutrophils. Conclusion E-XDP is a marker of the presence of AAA and coexisting aneurysms as well as the volume and mechanical stress of the ILT.

External (mechanical) stimuli influence cell function at the level of gene expression and thereby contribute to the overall control of Soft Biological Tissues' (SBT) structure and function. SBT seem to adapt towards stable homeostatic mechanical conditions, and failure of reaching homeostasis may result in pathologies. SBT adaptation has to obey basic physical principles, and even within these constraints, a large number of SBT adaptation models have been proposed. Recent SBT models integrated the tissue's microstructure and directly addressed length scales of individual tissue constituents, which in turn allowed linking biomechanical and biochemical adaptation aspects. Despite adaptation models being based on very different hypotheses, many of them lead to physically reasonable results. Most interestingly, the recently developed homogenized Constrained Mixture Model reported very similar predictions than the original Constrained Mixture Model. This key observation indicates that the simpler kinematics-based approach is indeed able to capture the overall consequences of the continuous production and degradation of SBT constituents. However, mainly due to the scarcity of relevant experiment data, not a single model has been thoroughly validated against clearly specified modeling objectives. Consequently, much more interdisciplinary experimental work is required to guide SBT modeling activities. Nevertheless, predictive biomechanical SBT adaption models would not only be of considerable scientific interest, but would also have a large number of practical applications.

Objective: Several studies of biomechanical rupture risk assessment (BRRA) showed its advantage over the diameter criterion in rupture risk assessment of abdominal aortic aneurysm (AAA). However, BRRA studies have not investigated the predictability of biomechanical risk indices at different time points ahead of rupture, nor have they been performed blinded for biomechanical analysts. The objective of this study was to test the predictability of the BRRA method against diameter-based risk indices in a quasi-prospective patient cohort study. Methods: In total, 12 women and 31 men with intact AAAs at baseline have been selected retrospectively at two medical centers. Within 56 months, 19 cases ruptured, whereas 24 cases remained intact within 2 to 56 months. This outcome was kept confidential until all biomechanical activities in this study were finished. The biomechanical AAA rupture risk was calculated at baseline using high-fidelity and low-fidelity finite element method models. The capability of biomechanics-based and diameter-based risk indices to predict the known outcomes at 1 month, 3 months, 6 months, 9 months, and 12 months after baseline was validated. Besides common cohort statistics, the area under the curve (AUC) of receiver operating characteristic curves has been used to grade the different rupture risk indices. Results: Up to 9 months ahead of rupture, the receiver operating characteristic analysis of biomechanics-based risk indices showed a higher AUC than diameter-based indices. Six months ahead of rupture, the largest difference was observed with an AUC of 0.878 for the high-fidelity biomechanical risk index, 0.859 for the low-fidelity biomechanical risk index, 0.789 for the diameter, and 0.821 for the sex-adjusted diameter. In predictions beyond 9 months, none of the risk indices proved to be superior. Conclusions: High-fidelity biomechanical modeling improves the predictability of AAA rupture. Asymptomatic AAA patients with high biomechanical AAA rupture risk indices have an increased risk of rupture. Integrating biomechanics-based diagnostic indices may significantly decrease the false-positive rate in AAA treatment. Clinical Relevance: Rupture of abdominal aortic aneurysm (AAA) is the tenth leading cause of death in men older than 60 years; however, the currently used maximal diameter criterion has a high false-positive rate. In this study, we have compared this criterion with biomechanical rupture risk assessment on the unique data set of 43 asymptomatic AAAs, of which 19 ruptured later. Moreover, the AAA outcome was blinded to the operator for the first time. Our data demonstrated that the biomechanical rupture risk assessment is superior to maximal diameter in predicting AAA rupture up to 9 months ahead and significantly decreases the false-positive rate.

Biologically compatible membranes are of high interest for several biological and medical applications. Tissue engineering, for example, would greatly benefit from ultrathin, yet easy‐to‐handle, biodegradable membranes that are permeable to proteins and support cell growth. In this work, nanomembranes are formed by self‐assembly of a recombinant spider silk protein into a nanofibrillar network at the interface of a standing aqueous solution. The membranes are cm‐sized, free‐standing, bioactive and as thin as 250 nm. Despite their nanoscale thickness, the membranes feature an ultimate engineering strain of over 220% and a toughness of 5.2 MPa. Moreover, they are permeable to human blood plasma proteins and promote cell adherence and proliferation. Human keratinocytes seeded on either side of the membrane form a confluent monolayer within three days. The significance of these results lays in the unique combination of nanoscale thickness, elasticity, toughness, biodegradability, protein permeability and support for cell growth, as this may enable new applications in tissue engineering including bi‐layered in vitro tissue models and support for clinical transplantation of coherent cell layers. QC 20200819

The structural properties of the Extracellular Matrix change in response to many factors, such as mechanical stress, age, disease and lifestyle. The ECM ensures not only the vessel wall’s structural integrity, but it also defines the micro-mechanical environment within which vascular cells are embedded and to which they respond. Its mechanical properties are governed by the delicate interaction of elastin, collagen, ProteoGlycans, fibronectin, fibrilin and other, constituents which are synthesized by vascular cells and degraded, mainly by Matrix MetalloProteinases. The present chapter discusses the structural organization of the vessel wall towards the multi-scale mechanical characterization of the aneurysmatic aorta. It is assumed that aneurysmatic vessel wall properties are mainly governed by collagen fibrils, with their undulation and orientation being the most influential micro-histological parameters. Purely passive constitutive descriptions are further complemented by collagen turnover kinetics, and all models are set-up such that they may be used for organ-level vascular biomechanics simulations.

Abdominal aortic aneurysm (AAA) rupture is a local event in the aneurysm wall that naturally demands tools to assess the risk for local wall rupture. Consequently, global parameters like the maximum diameter and its expansion over time can only give very rough risk indications; therefore, they frequently fail to predict individual risk for AAA rupture. In contrast, the Biomechanical Rupture Risk Assessment (BRRA) method investigates the wall’s risk for local rupture by quantitatively integrating many known AAA rupture risk factors like female sex, large relative expansion, intraluminal thrombus-related wall weakening, and high blood pressure. The BRRA method is almost 20 years old and has progressed considerably in recent years, it can now potentially enrich the diameter indication for AAA repair. The present paper reviews the current state of the BRRA method by summarizing its key underlying concepts (i.e., geometry modeling, biomechanical simulation, and result interpretation). Specifically, the validity of the underlying model assumptions is critically disused in relation to the intended simulation objective (i.e., a clinical AAA rupture risk assessment). Next, reported clinical BRRA validation studies are summarized, and their clinical relevance is reviewed. The BRRA method is a generic, biomechanics-based approach that provides several interfaces to incorporate information from different research disciplines. As an example, the final section of this review suggests integrating growth aspects to (potentially) further improve BRRA sensitivity and specificity. Despite the fact that no prospective validation studies are reported, a significant and still growing body of validation evidence suggests integrating the BRRA method into the clinical decision-making process (i.e., enriching diameter-based decision-making in AAA patient treatment).

Objective In a population-based cohort of ruptured abdominal aortic aneurysms (rAAAs), our aim was to investigate clinical, morphological and biomechanical features in patients with small rAAAs. Methods All patients admitted to an emergency department in Stockholm and Gotland, a region with a population of 2.1 million, between 2009-2013 with a CT-verified rupture (n = 192) were included, and morphological measurements were performed. Patients with small rAAAs, maximal diameter (Dmax) ≤ 60 mm were selected (n = 27), and matched 2:1 by Dmax, sex and age to intact AAA (iAAAs). For these patients, morphology including volume and finite element analysis-derived biomechanics were assessed. Results The mean Dmax for all rAAAs was 80.8 mm (SD = 18.9 mm), women had smaller Dmax at rupture (73.4 ± 18.4 mm vs 83.1 ± 18.5 mm, p = 0.003), and smaller neck and iliac diameters compared to men. Aortic size index (ASI) was similar between men and women (4.1 ± 3.1 cm/m2 vs 3.8 ± 1.0 cm/m2). Fourteen percent of all patients ruptured at Dmax ≤ 60 mm, and a higher proportion of women compared to men ruptured at Dmax ≤ 60 mm: 27% (12/45) vs. 10% (15/147), p = 0.005. Also, a higher proportion of patients with a chronic obstructive pulmonary disease ruptured at Dmax ≤ 60 mm (34.6% vs 14.6%, p = 0.026). Supra-renal aortic size index (14.0, IQR 13.3-15.3 vs 12.8, IQR = 11.4-14.0) and peak wall rupture index (PWRI, 0.35 ± 0.08 vs 0.43 ± 0.11, p = 0.016) were higher for small rAAAs compared to matched iAAAs. Aortic size index, peak wall stress and aneurysm volume did not differ. Conclusion More than one tenth of ruptures occur at smaller diameters, women continuously suffer an even higher risk of presenting with smaller diameters, and this must be considered in surveillance programs. The increased supra-renal aortic size index and PWRI are potential markers for rupture risk, and patients under surveillance with these markers may benefit from increased attention, and potentially from timely repair.

The artery is a dynamic organ that is able to maintain conditions for optimal mechanical operation. Arterial properties are critical to the entire cardiovascular system, and the study of their biomechanics may, among others, help understand the role of tissue stress and strain in cardiovascular diseases. The present article reviews artery wall histology and morphology in relation to its key mechanical properties. Specifically, the role of cellular and extracellular components in artery biomechanics is discussed. Then, this information is related to reported constitutive descriptions with the focus on histomechanical and passive artery wall models. Concluding remarks relate to open problems in artery biomechanics like uncertainty and variability of input information.

Intraluminal thrombus (ILT) is present in most abdominal aortic aneurysms (AAAs), although its role in AAA progression is controversial.A literature search was performed to identify studies that investigated the association between ILT volume and AAA rupture. A study assessment tool was developed to assess the methodologic quality of included studies. A meta-analysis was conducted using an inverse variance-weighted random-effects model to compare the ILT volume in ruptured and asymptomatic intact AAAs. Leave-one-out sensitivity analyses were conducted to assess the robustness of the findings. A subanalysis was performed including studies in which patients with asymptomatic intact and ruptured AAAs were matched for aortic diameter. Interstudy heterogeneity was assessed using the IEight studies involving 672 patients were included in this systematic review. Meta-analysis of all studies found a greater ILT volume in patients with ruptured AAAs than in patients with asymptomatic intact AAAs (standardized mean difference, 0.56; 95% confidence interval, 0.17-0.96; P = .005; IThis meta-analysis suggests that ILT volume is greater in patients with ruptured AAAs than in patients with asymptomatic intact AAAs, although this is most likely due to the larger diameter of ruptured AAAs.

Purpose: To investigate how 2-dimensional geometric parameters differ between ruptured and asymptomatic abdominal aortic aneurysms (AAAs) and provide a biomechanical explanation for the findings. Methods: The computed tomography angiography (CTA) scans of 30 patients (mean age 77±10 years; 23 men) with ruptured AAAs and 60 patients (mean age 76±8 years; 46 men) with asymptomatic AAAs were used to measure maximum sac diameter along the center lumen line, the cross-sectional lumen area, the total vessel area, the intraluminal thrombus (ILT) area, and corresponding volumes. The CTA data were segmented to create 3-dimensional patient-specific models for finite element analysis to compute peak wall stress (PWS) and the peak wall rupture index (PWRI). To reduce confounding from the maximum diameter, 2 diameter-matched groups were selected from the initial patient cohorts: 28 ruptured AAAs and another with 15 intact AAAs (diameters 74±12 vs 73±11, p=0.67). A multivariate model including the maximum diameter, the lumen area, and the ILT area of the 60 intact aneurysms was employed to predict biomechanical rupture risk parameters. Results: In the diameter-matched subgroup comparison, ruptured AAAs had a significantly larger cross-sectional lumen area (1954±1254 vs 1120±623 mm2, p=0.023) and lower ILT area ratio (55±24 vs 68±24, p=0.037). The ILT area (2836±1462 vs 2385±1364 mm2, p=0.282) and the total vessel area (3956±1170 vs 4338±1388 mm2, p=0.384) did not differ statistically between ruptured and intact aneurysms. The PWRI was increased in ruptured AAAs (0.80 vs 0.48, p

Intraluminal thrombus (ILT) is a pseudo-tissue that develops from coagulated blood, and is found in most abdominal aortic aneurysms (AAAs) of clinically relevant size. A number of studies have suggested that ILT mechanical characteristics may be related to AAA risk of rupture, even though there is still great controversy in this regard. ILT is isotropic and inhomogeneous and may appear as a soft (single-layered) or stiff (multilayered fibrotic) tissue. This paper aims to investigate how ILT constitution and topology influence the magnitude and location of peak wall stress (PWS). In total 21 patient-specific AAAs (diameter 4.2–5.4 cm) were reconstructed from computer tomography images and biomechanically analyzed using state-of-the-art modeling assumptions. Results indicated that PWS correlated stronger with ILT volume (ρ = 0.44, p = 0.05) and minimum thickness of ILT layer (ρ = 0.73, p = 0.001) than with maximum AAA diameter (ρ = 0.05, p = 0.82). On average PWS was 20% (SD 12%) higher for FE models that used soft instead of stiff ILT models (p

Background An abdominal aortic aneurysm (AAA) is a focal dilation of the abdominal aorta and is associated with a risk of fatal rupture. Experimental studies suggest that myo-inositol may exert beneficial effects on AAAs through favourable changes to biological pathways implicated in AAA pathology. The aim of the Inositol in the MAnaGemENt of abdominal aortic aneurysm (IMAGEN) trial is to assess if myo-inositol will reduce AAA growth. Methods/design IMAGEN is a multi-centre, prospective, parallel-group, randomised, double-blind, placebo-controlled trial. A total of 164 participants with an AAA measuring ≥ 30 mm will be randomised to either 2 g of myo-inositol or identical placebo twice daily for 12 months. The primary outcome measure will be AAA growth estimated by increase in total infrarenal aortic volume measured on computed tomographic scans. Secondary outcome measures will include AAA diameter assessed by computed tomography and ultrasound, AAA peak wall stress and peak wall rupture index, serum lipids, circulating AAA biomarkers, circulating RNAs and health-related quality of life. All analysis will be based on the intention-to-treat principle at the time of randomisation. All patients who meet the eligibility criteria, provide written informed consent and are enrolled in the study will be included in the primary analysis, regardless of adherence to dietary allocation. Discussion Currently, there is no known medical therapy to limit AAA progression. The IMAGEN trial will be the first randomised trial, to our knowledge, to assess the value of myo-inositol in limiting AAA growth. Trial registration Australian New Zealand Clinical Trials Registry, ACTRN12615001209583. Registered on 6 November 2015. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2304-x) contains supplementary material, which is available to authorized users.

An Abdominal Aortic Aneurysm (AAA) is an enlargement of the infrarenal aorta, a serious condition whose clinical treatment requires assessing its risk of rupture. This chapter reviews the current state of the Biomechanical Rupture Risk Assessment (BRRA), a non-invasive diagnostic method to calculate such AAA rupture risk, and emphasizes on constitutive modeling of AAA tissues. Histology and mechanical properties of the normal and aneurysmatic walls are summarized and related to proposed constitutive descriptions. Models for the passive vessel wall as well as their adaptation in time are discussed. Reported clinical BRRA validation studies are summarized and their clinical relevance is discussed. Despite open problems in AAA biomechanics, like robust modeling vascular tissue adaptation to mechanical and biochemical environments, a significant body of current validation evidence suggests integrating the BRRA method into the clinical decision-making process.

Objective: An abdominal aortic aneurysm (AAA) ruptures if the vessel wall stress exceeds its strength, with high mortality as a result. The effect of biomechanical load on AAA gene expression is currently not well understood. Methods: Aortic tissue samples from 64 patients with an AAA that had been imaged with computed tomography angiography (CTA) before surgery were collected from the Stockholm AAA Biobank (STAAAB), separated into intima/media and adventitia wall layers and analyzed with Affymetrix HTA 2.0 microarrays. The aortas were segmented from the CTAs into three-dimensional digital models, which were then subjected to finite element analysis (FEA) without informing the software (VASCOPS A4clinics Research Edition) about age, gender, family history or blood pressure. Peak wall rupture index (PWRI), derived from the FEA, was used as a marker of biomechanical rupture risk. Differential gene expression, adjusted for age and gender, was studied with R. Enriched gene ontology processes were examined for annotated transcripts with GOrilla and REVIGO online tools. Results: No transcript was significantly associated with PWRI after 5% false discovery rate correction was performed, in either media nor adventitia. However, there were 1203 and 872 transcripts associated with PWRI at a nominal p-value of < 0.05 in media and adventitia, respectively. Analysis of enriched biological processes using the entire annotated transcript list ranked by fold-change revealed that extracellular matrix and structure organization in the media and nucleic acid metabolism and RNA metabolism in the adventitia, were the most enriched biological processes in aneurysms with high PWRI. Conclusion: These results suggest that biomechanical rupture risk associates with expression of extracellular matrix genes as well as the level of bulk gene activity.

Evolution has developed a complex cardiovascular system, the analysis of which involves many physical disciplines. Specifically, cardiovascular function critically depends on the proper interaction between blood and the vessel wall, such that haemodynamics-based biomechanical factors are a common denominator of cardiovascular pathologies. This chapter reviews biomechanics-related physical processes in the vessel. Specifically, mechanical load transition mechanisms in blood and the vessel wall, blood-wall interaction phenomena, as well as simple analytical solutions to Newton’s second law of mechanics are discussed. Albeit that such simple analytical relations are very useful when exploring physical processes in the vasculature, their application is limited and cardiovascular analysis often requires more advanced computational methods so as to draw conclusions from Newton’s law. Most important, the proper application of either simple or more advanced physical models requires close interaction between engineering and medical disciplines.

Background The prevalence for thoracic aortic aneurysms (TAAs) is significantly increased in patients with a bicuspid aortic valve (BAV) compared with patients who have a normal tricuspid aortic valve (TAV). TAA rupture is a life-threatening event, and biomechanics-based simulations of the aorta may help to disentangle the molecular mechanism behind its development and progression. The present study used polarized microscopy and macroscopic in vitro tensile testing to explore collagen organization and mechanical properties of TAA wall specimens from BAV and TAV patients. Methods Circumferential sections of aneurysmal aortic tissue from BAV and TAV patients were obtained during elective operations. The distribution of collagen orientation was captured by a Bingham distribution, and finite element models were used to estimate constitutive model parameters from experimental load-displacement curves. Results Collagen orientation was almost identical in BAV and TAV patients, with a highest probability of alignment along the circumferential direction. The strength was almost two times higher in BAV samples (0.834 MPa) than in TAV samples (0.443 MPa; p C f ) was significantly increased in BAV compared with TAV patients ( C f = 7.45 MPa vs 3.40 MPa; p = 0.003), whereas the elastin-related stiffness was similar in both groups. A trend toward a decreased wall thickness was seen in BAV patients ( p = 0.058). Conclusions The aneurysmal aortas of BAV patients show a higher macroscopic strength, mainly due to an increased collagen-related stiffness, compared with TAV patients. The increased wall stiffness in BAV patients may contribute to the higher prevalence for TAAs in this group.

Applying Findings of Computational Studies in Vascular Clinical Practice : Fact, Fiction, or Misunderstanding?

Background— The relationship between biomechanical properties and biological activities in aortic aneurysms was investigated with finite element simulations and 18 F-fluoro-deoxy-glucose ( 18 F-FDG) positron emission tomography. Methods and Results— The study included 53 patients (45 men) with aortic aneurysms, 47 infrarenal (abdominal aortic) and 6 thoracic (thoracic aortic), who had ≥1 18 F-FDG positron emission tomography/computed tomography. During a 30-month period, more clinical events occurred in patients with increased 18 F-FDG uptake on their last examination than in those without (5 of 18 [28%] versus 2 of 35 [6%]; P =0.03). Wall stress and stress/strength index computed by finite element simulations and 18 F-FDG uptake were evaluated in a total of 68 examinations. Twenty-five (38%) examinations demonstrated ≥1 aneurysm wall area of increased 18 F-FDG uptake. The mean number of these areas per examination was 1.6 (18 of 11) in thoracic aortic aneurysms versus 0.25 (14 of 57) in abdominal aortic aneurysms, whereas the mean number of increased uptake areas colocalizing with highest wall stress and stress/strength index areas was 0.55 (6 of 11) and 0.02 (1 of 57), respectively. Quantitatively, 18 F-FDG positron emission tomographic uptake correlated positively with both wall stress and stress/strength index ( P 18 F-FDG uptake was particularly high in subjects with personal history of angina pectoris and familial aneurysm. Conclusions— Increased 18 F-FDG positron emission tomographic uptake in aortic aneurysms is strongly related to aneurysm location, wall stress as derived by finite element simulations, and patient risk factors such as acquired and inherited susceptibilities.

A biomechanical stress analysis could help to identify carotid plaques that are vulnerable to rupture, and hence reduce the risk of thrombotic strokes. Mechanical stress predictions critically depend on the plaque's constitutive properties, and the present study introduces a concept to derive viscoelastic parameters through an experimental-numerical approach. Carotid plaques were harvested from two patients during carotid endarterectomy (CEA), and, in total, nine test specimens were investigated. A novel in-vitro mechanical testing protocol, which allows for dynamic testing, keeping the carotid plaque components together, was introduced. Macroscopic pictures overlaid by histological stains allowed for the segmentation of plaque tissues, in order to develop high-fidelity and low-fidelity Finite Element Method (FEM) models of the test specimens. The FEM models together with load-displacement data from the mechanical testing were used to extract constitutive parameters through inverse parameter estimation. The applied inverse parameter estimation runs in stages, first addressing the hyperelastic parameters then the viscoelastic ones. Load-displacement curves from the mechanical testing showed strain stiffening and viscoelasticity, as is expected for both normal and diseased carotid tissue. The estimated constitutive properties of plaque tissue were comparable to previously reported studies. Due to the highly non-linear elasticity of vascular tissue, the applied parameter estimation approach is, as with many similar approaches, sensitive to the initial guess of the parameters.