Challenges of applying circulating biomarkers for abdominal aortic aneurysm progression

As a prevalent potentially life-threatening condition, abdominal aortic aneurysm (AAA) presents increasing risk of rupture as its diameter grows. However, rapid progression and rupture may occasionally occur in smaller AAAs. Earlier surgery for patients with high risk of disease progression may improve the outcome. Therefore, more precise indicators for invasive treatment in addition to diameter and abdominal symptoms are demanded. This systematic review aimed to identify potential circulating biomarkers that may predict growth rate of AAA. Cochrane and PubMed library were searched (until August 2020) for researches which reported circulating biomarkers associated with AAA expansion, and 25 papers were included. Twenty-eight identified biomarkers were further classified into five categories (inflammation and oxidative stress, matrix degradation, hematology and lipid metabolism, thrombosis and fibrinolysis, and others), and discussed further with their correlation and regression analysis results. Larger prospective trials are required to establish and evaluate prognostic models with highest values with these markers.     

Regional distribution of wall thickness and failure properties of human abdominal aortic aneurysm

The regional distribution of wall thickness and failure properties in human abdominal aortic aneurysm (AAA) was explored. Three unruptured and one ruptured AAA were harvested as a whole during necropsy. Thickness was measured at about every 1.5 cm² wall surface area for an average of 100 measurement sites per AAA. Multiple longitudinally oriented rectangular specimen strips were cut at various locations from each AAA for a total of 48 strips. The strips were subjected to uniaxial extension until failure. Wall thickness varied regionally and between AAA from as low as 0.23 mm at a rupture site to 4.26 mm at a calcified site (median=1.48 mm). Wall thickness was slightly lower in the posterior and right regions. The failure tension (ultimate) of specimen strips varied regionally and between AAA from 5.5 N/cm close to a blister site in the ruptured AAA to 42.3 N/cm at the undilated neck of a 4 cm diameter unruptured AAA (median=14.8 N/cm). Failure stress (ultimate) varied from 33.6 to 235.1 N/cm² (median=126.6 N/cm²). There was no perceptible pattern in failure properties along the circumference. Failure tension of specimen strips at or close to blisters was mostly low. The rupture site in the ruptured aneurysm had the lowest recorded wall thickness of 0.23 mm with only slightly higher readings within a 1 cm radius. The failure tension of the specimen strip close to the rupture site was low (11.1 N/cm) compared to its neighborhood in the ruptured aneurysm.     

Joint models for multivariate longitudinal and multivariate survival data

Joint modeling of longitudinal and survival data is becoming increasingly essential in most cancer and AIDS clinical trials. We propose a likelihood approach to extend both longitudinal and survival components to be multidimensional. A multivariate mixed effects model is presented to explicitly capture two different sources of dependence among longitudinal measures over time as well as dependence between different variables. For the survival component of the joint model, we introduce a shared frailty, which is assumed to have a positive stable distribution, to induce correlation between failure times. The proposed marginal univariate survival model, which accommodates both zero and nonzero cure fractions for the time to event, is then applied to each marginal survival function. The proposed multivariate survival model has a proportional hazards structure for the population hazard, conditionally as well as marginally, when the baseline covariates are specified through a specific mechanism. In addition, the model is capable of dealing with survival functions with different cure rate structures. The methodology is specifically applied to the International Breast Cancer Study Group (IBCSG) trial to investigate the relationship between quality of life, disease-free survival, and overall survival.     

Finite element and photoelastic modelling of an abdominal aortic aneurysm: a comparative study

Rupture prediction of abdominal aortic aneurysms (AAAs) remains a clinical challenge. Finite element analysis (FEA) may allow for improved identification for intervention timing, but the method needs further substantiation. In this study, experimental photoelastic method and finite element techniques were compared using an idealised AAA geometry. There was good agreement between the numerical and experimental results. At the proximal and distal end of the AAA model, the maximum differences in principle strain for an internal pressure of 120 mmHg had differences ranging from 0.03 to 10.01%. The maximum difference in principle strain for the photoelastic and the finite element model at a pressure of 120 mmHg was 0.167 and 0.158, respectively. The current research strengthens the case for using FEA as an adjunct to the current clinical practice of utilising diameter measurement for intervention timing.     

Joint analysis of longitudinal data and recurrent episodes data with application to medical cost analysis

This paper discusses regression analysis of longitudinal data in which the observation process may be related to the longitudinal process of interest. Such data have recently attracted a great deal of attention and some methods have been developed. However, most of those methods treat the observation process as a recurrent event process, which assumes that one observation can immediately follow another. Sometimes, this is not the case, as there may be some delay or observation duration. Such a process is often referred to as a recurrent episode process. One example is the medical cost related to hospitalization, where each hospitalization serves as a single observation. For the problem, we present a joint analysis approach for regression analysis of both longitudinal and observation processes and a simulation study is conducted that assesses the finite sample performance of the approach. The asymptotic properties of the proposed estimates are also given and the method is applied to the medical cost data that motivated this study.     

Hemodynamic investigation of a patient-specific abdominal aortic aneurysm with iliac artery tortuosity

Abstract

This paper describes a systematic investigation on the hemodynamic environment in a patient-specific AAA with tortuous common iliac artery(CIA) and external iliac artery (EIA). 3D reconstructions from CT scans and subsequent computational simulation are carried out. It is found out that the Newtonian and non-Newtonian models have very similar flow field and WSS distribution. More importantly, it is revealed that the torturous CIA maintained its helical flow. It is concluded that the assumption of Newtonian blood is adequate in capturing the intra-aneurysmal hemodynamics. Moreover, it is speculated that the physiological spiral flow protects the twisted CIA from the thrombosis formation.     

Mixed effects logistic regression models for longitudinal ordinal functional response data with multiple-cause drop-out from the longitudinal study of aging

In the context of analyzing ordinal functional limitation responses from the Longitudinal Study of Aging, we investigate the association between current functional limitation and previous year's limitation and its modification by physical activity and multiple causes of drop-out. We accommodate the longitudinal nature of the multiple causes of informative drop-out (death and unknown loss-to-follow-up) with a mixed effects logistic model. Under the proposed model with a random intercept and slope, the ordinal functional outcome and multiple discrete time survival profiles share a common random effect structure. This shared parameter selection model assumes that the multiple causes of drop-out are conditionally independent of the functional limitation outcome given the underlying random effect representing an individual's trajectory of general health status across time. Although it is not possible to fully assess the adequacy of this assumption, we assess the robustness of the approach by varying the assumptions underlying the proposed model, such as the random effects distribution and the drop-out component. It appears that between-subject differences in initial functional limitation are strongly associated with future functional limitation and that this association is stronger for those who do not have physical activity regardless of the random effects and informative drop-out specifications. In contrast, the association between current functional limitation and previous trajectory of functional status within an individual is weaker and more sensitive to changes in the random effects and drop-out assumptions.     

Stochastic modelling of wall stresses in abdominal aortic aneurysms treated by a gene therapy

A stochastic mechanical model using the membrane theory was used to simulate the in vivo mechanical behaviour of abdominal aortic aneurysms (AAAs) in order to compute the wall stresses after stabilisation by gene therapy. For that, both length and diameter of AAAs rats were measured during their expansion. Four groups of animals, control and treated by an endovascular gene therapy during 3 or 28 days were included. The mechanical problem was solved analytically using the geometric parameters and assuming the shape of aneurysms by a ‘parabolic–exponential curve’. When compared to controls, stress variations in the wall of AAAs for treated arteries during 28 days decreased, while they were nearly constant at day 3. The measured geometric parameters of AAAs were then investigated using probability density functions (pdf) attributed to every random variable. Different trials were useful to define a reliable confidence region in which the probability to have a realisation is equal to 99%. The results demonstrated that the error in the estimation of the stresses can be greater than 28% when parameters uncertainties are not considered in the modelling. The relevance of the proposed approach for the study of AAA growth may be studied further and extended to other treatments aimed at stabilisation AAAs, using biotherapies and pharmacological approaches.     

Model studies of the flow in abdominal aortic aneurysms during resting and exercise conditions

Pulsatile flow in abdominal aortic aneurysm (AAA) models has been examined in order to understand the hemodynamics that may contribute to growth of an AAA. The model studies were conducted by experiments (flow visualization and laser Doppler velocimetry) and by numerical simulation using physiologically realistic resting and exercise flow conditions. We characterize the flow for two AAA model shapes and sizes emulating early AAA development through moderate AAA growth (mean and peak Reynolds numbers of 362<Re_mean<1053 and 3308<Re_peak<5696 with Womersley parameter 16.4<<21.2). The results of our investigation indicate that AAA flow can be divided into three flow regimes: (i) Attached flow over the entire cycle in small AAAs at resting conditions, (ii) vortex formation and translation in moderate size AAAs at resting conditions, and (iii) vortex formation, translation and turbulence in moderate size AAAs under exercise conditions. The second two regimes are classified in the medical literature as disturbed flow conditions that have been correlated with atherogenesis as well as thrombogenesis. Thus, AAA disturbed hemodynamics may be a contributing factor to AAA growth by accelerating the degeneration of the arterial wall. Our investigation also concluded that vortex development is considerably weaker in an asymmetric AAA. Furthermore, turbulence was not observed in the asymmetric model. Finally, our investigation suggests a new mode of transition to turbulence: vortex ring instability and bursting to turbulence. The transition process depends on a combination of the pulsatile flow conditions and the tube cross-sectional area change.     

A two-part joint model for the analysis of survival and longitudinal binary data with excess zeros

Summary .   Many longitudinal studies generate both the time to some event of interest and repeated measures data. This article is motivated by a study on patients with a renal allograft, in which interest lies in the association between longitudinal proteinuria (a dichotomous variable) measurements and the time to renal graft failure. An interesting feature of the sample at hand is that nearly half of the patients were never tested positive for proteinuria (≥1g/day) during follow-up, which introduces a degenerate part in the random-effects density for the longitudinal process. In this article we propose a two-part shared parameter model framework that effectively takes this feature into account, and we investigate sensitivity to the various dependence structures used to describe the association between the longitudinal measurements of proteinuria and the time to renal graft failure.     

Flow of a blood analogue fluid in a compliant abdominal aortic aneurysm model: Experimental modelling

The aim of this work is to develop a unique in vitro set-up in order to analyse the influence of the shear thinning fluid-properties on the flow dynamics within the bulge of an abdominal aortic aneurysm (AAA). From an experimental point of view, the goals are to elaborate an analogue shear thinning fluid mimicking the macroscopic blood behaviour, to characterise its rheology at low shear rates and to propose an experimental device able to manage such an analogue fluid without altering its feature while reproducing physiological flow rate and pressure, through compliant AAA. Once these experimental prerequisites achieved, the results obtained in the present work show that the flow dynamics is highly dependent on the fluid rheology. The main results point out that the propagation of the vortex ring, generated in the AAA bulge, is slower for shear thinning fluids inducing a smaller travelled distance by the vortex ring so that it never impacts the anterior wall in the distal region, in opposition to Newtonian fluids. Moreover, scalar shear rate values are globally lower for shear thinning fluids inducing higher maximum stress values than those for the Newtonian fluids. Consequently, this work highlights that a Newtonian fluid model is finally inadequate to obtain a reliable prediction of the flow dynamics within AAA.     

MicroRNA-29a-3p regulates abdominal aortic aneurysm development and progression via direct interaction with PTEN

Various research studies have been conducted in deducing the role of microRNAs (miRNAs) in the pathogenesis and physiological processes of various systematic diseases. This study aims at demonstration of the important role played by miR-29a-3p, through association with phosphatase and tensin homolog (PTEN), in the regulation of abdominal aortic aneurysm development and progression. Quantitative real-time polymerase chain reaction (RT-qPCR) examined miRNA-19a-3p and PMEPA1 expression in multiplied vascular smooth muscle cells (VSMCs). Cell transfection upregulated or downregulated the genes and cell counting kit-8 assay determined cellular viability. RT-qPCR detected cellular proliferation and cell death using the cell proliferation and apoptosis biomarkers Ki87 and proliferating cell nuclear antigen, caspase-8 and caspase-3, respectively. Furthermore, luciferase assay analyzed the luciferase activity and western blot analysis determined miRNA-19a-3p and PMEPA1 protein expression in proliferation and apoptosis biomarkers. TargetScan 4.2 online software ( www.targetscan.org ) was used to perform the bioinformatics analysis so as to forecast the putative targets of miR-29a-3p and PTEN. The results inferred that there was an increased expression of miRNA-29a-3p found in AAA-mimic cells with increased cellular viability and significant pathological apoptosis. Further, when the expression of miRNA-29a-3p was downregulated, it reduced the cell viability of AAA cells. On the basis of the gene interplays, it can be understood that the PTEN was directly targeted by miRNA-29a-3p so as to regulate the AAA progression. Thus, PTEN was found to strengthen the proliferation effect of miRNA-29a-3p in AAA cells. The current study thus shed more insights about the molecular mechanistic roles of miRNA-29a-3p and PTEN, opening doors for novel therapeutic approach to AAA.     

CCL7 contributes to angiotensin II-induced abdominal aortic aneurysm by promoting macrophage infiltration and pro-inflammatory phenotype

Chemokine C-C motif ligand 7 (CCL7), a member of CC chemokine subfamily, plays pivotal roles in numerous inflammatory diseases. Hyper-activation of inflammation is an important characteristic of abdominal aortic aneurysm (AAA). Therefore, in the present study, we aimed to determine the effect of CCL7 on AAA formation. CCL7 abundance in aortic tissue and macrophage infiltration were both increased in angiotensin II (Ang II)-induced AAA mice. Ex vivo, CCL7 promoted macrophage polarization towards M1 phenotype. This effect was reversed by the blockage of CCR1, a receptor of CCL7. CCL7 up-regulated JAK2/STAT1 protein level in macrophage, and CCL7-induced M1 activation was suppressed by JAK2/STAT1 pathway inhibition. To verify the effect of CCL7 on AAA in vivo, either CCL7-neutralizing antibody (CCL7-nAb) or vehicles were intraperitoneally injected 24 hours prior to Ang II infusion and subsequently every three days for 4 weeks. CCL7-nAb administration significantly attenuated Ang II-induced luminal and external dilation as well as pathological remodelling. Immunostaining showed that CCL7-nAb administration significantly decreased aneurysmal macrophage infiltration. In conclusion, CCL7 contributed to Ang II-induced AAA by promoting M1 phenotype of macrophage through CCR1/JAK2/STAT1 signalling pathway.     

Serpina3n attenuates granzyme B-mediated decorin cleavage and rupture in a murine model of aortic aneurysm

Granzyme B (GZMB) is a proapoptotic serine protease that is released by cytotoxic lymphocytes. However, GZMB can also be produced by other cell types and is capable of cleaving extracellular matrix (ECM) proteins. GZMB contributes to abdominal aortic aneurysm (AAA) through an extracellular, perforin-independent mechanism involving ECM cleavage. The murine serine protease inhibitor, Serpina3n (SA3N), is an extracellular inhibitor of GZMB. In the present study, administration of SA3N was assessed using a mouse Angiotensin II-induced AAA model. Mice were injected with SA3N (0–120 μg/kg) before pump implantation. A significant dose-dependent reduction in the frequency of aortic rupture and death was observed in mice that received SA3N treatment compared with controls. Reduced degradation of the proteoglycan decorin was observed while collagen density was increased in the aortas of mice receiving SA3N treatment compared with controls. In vitro studies confirmed that decorin, which regulates collagen spacing and fibrillogenesis, is cleaved by GZMB and that its cleavage can be prevented by SA3N. In conclusion, SA3N inhibits GZMB-mediated decorin degradation leading to enhanced collagen remodelling and reinforcement of the adventitia, thereby reducing the overall rate of rupture and death in a mouse model of AAA.     

Silencing of NONO inhibits abdominal aortic aneurysm in apolipoprotein E‐knockout mice via collagen deposition and inflammatory inhibition

The role of Non‐POU‐domain‐containing octamer‐binding protein (NONO) in the formation and development of angiotensin II (Ang II)‐induced abdominal aortic aneurysm (AAA) in apolipoprotein E‐knockout (ApoE^?/?) mice is still unknown. In Part I, the protein level of NONO was suggestively greater in the AAA tissues compare to that in the normal abdominal aortas. In Part II, 20 ApoE^?/? male mice were used to examine the transfection efficiency of lentivirus by detecting GFP fluorescence. In Part III, mice were arbitrarily separated into two groups: one was the control group without Ang II infusion, and another was the Ang II group. Mice treated with Ang II were further randomly divided into three groups to receive the same volume of physiological saline (NT group), sh‐negative control lentivirus (sh‐NC group) and si‐NONO lentivirus (sh‐NONO group). NONO silencing suggestively reduced the occurrence of AAA and abdominal aortic diameter. Compare to the NT group, NONO silencing markedly augmented the content of collagen and vascular smooth muscle cells but reduced macrophage infiltration in AAA. In addition, knockdown of NONO also increased the expression of prolyl‐4‐hydroxylase α1, whereas also decreased the levels of collagen degradation and pro‐inflammatory cytokines in AAA. We detected the interface of NONO and NF‐κB p65, and found that NONO silencing inhibited both the nuclear translocation and the phosphorylation levels of NF‐κB p65. Silencing of NONO prevented Ang II‐influenced AAA in ApoE^?/? mice through increasing collagen deposition and inhibiting inflammation. The mechanism may be that silencing of NONO decreases the nuclear translocation and phosphorylation of NF‐κB.     

The biaxial mechanical behaviour of abdominal aortic aneurysm intraluminal thrombus: Classification of morphology and the determination of layer and region specific properties

Intraluminal thrombus (ILT) is present in 75% of clinically-relevant abdominal aortic aneurysms (AAAs) yet, despite much research effort, its role in AAA biomechanics remains unclear. The aim of this work is to further evaluate the biomechanics of ILT and determine if different ILT morphologies have varying mechanical properties.     

Joint modeling and analysis of longitudinal data with informative observation times

Summary .  In analysis of longitudinal data, it is often assumed that observation times are predetermined and are the same across study subjects. Such an assumption, however, is often violated in practice. As a result, the observation times may be highly irregular. It is well known that if the sampling scheme is correlated with the outcome values, the usual statistical analysis may yield bias. In this article, we propose joint modeling and analysis of longitudinal data with possibly informative observation times via latent variables. A two-step estimation procedure is developed for parameter estimation. We show that the resulting estimators are consistent and asymptotically normal, and that the asymptotic variance can be consistently estimated using the bootstrap method. Simulation studies and a real data analysis demonstrate that our method performs well with realistic sample sizes and is appropriate for practical use.