A multi-method approach towards understanding the pathophysiology of aortic dissections – the complementary role of in-silico, in-vitro and in-vivo information

Management and follow-up of chronic aortic dissections continues to be a clinical challenge due to progressive aortic dilatation. To predict dilatation, guidelines suggest follow-up of the aortic diameter. However, dilatation is triggered by haemodynamic parameters (pressure and wall shear stresses (WSS)), and geometry of false (FL) and true lumen (TL). We aimed at a better understanding of TL and FL haemodynamics by performing in-silico (CFD) and in-vitro studies on an idealized dissected aorta and compared this to a typical patient. We observed an increase in diastolic pressure and wall stress in the FL and the presence of diastolic retrograde flow. The inflow jet increased WSS at the proximal FL while a large variability in WSS was induced distally, all being risk factors for wall weakening. In-silico, in-vitro and in-vivo findings were very similar and complementary, showing that their combination can help in a more integrated and extensive assessment of aortic dissections, improving understanding of the haemodynamic conditions and related clinical evolution

Validation of numerical flow simulations against in vitro phantom measurements in different type B aortic dissection scenarios

An aortic dissection (AD) is a serious condition defined by the splitting of the arterial wall, thus generating a secondary lumen [the false lumen (FL)]. Its management, treatment and follow-up are clinical challenges due to the progressive aortic dilatation and potentially severe complications during follow-up. It is well known that the direction and rate of dilatation of the artery wall depend on haemodynamic parameters such as the local velocity profiles, intra-luminal pressures and resultant wall stresses. These factors act on the FL and true lumen, triggering remodelling and clinical worsening. In this study, we aimed to validate a computational fluid dynamic (CFD) tool for the haemodynamic characterisation of chronic (type B) ADs. We validated the numerical results, for several dissection geometries, with experimental data obtained from a previous in vitro study performed on idealised dissected physical models. We found a good correlation between CFD simulations and experimental measurements as long as the tear size was large enough so that the effect of the wall compliance was negligible.Postprint (published version

Study of a medical device to treat aortic dissection with Finite Element Analysis

Treballs Finals de Grau d'Enginyeria Biomèdica. Facultat de Medicina i Ciències de la Salut. Universitat de Barcelona. Curs: 2022-2023. Tutor/Director: Carmona Flores, Manuel, Soudah Prieto, EduardoThe aortic dissection is a cardiovascular disease that results from the rupture of the inner layer of the aorta. Type B aortic dissections commonly become a chronic disease with a high long-term morbidity and mortality rates. Current treatments include open surgery repair and thoracic endovascular aortic repair (TEVAR). However, new non-invasive treatments are being developed that favour the own regeneration of the tissue, avoiding the permanent presence of a foreign device in the body. This project focuses on the understanding of a new treatment with a medical device, an aortic patch, by in silico testing. The goal is to determine the performance of the patch in a simulated aortic dissection and then compare it with the current treatment with the stent graft (TEVAR), to determine if it would avoid the hypertension that can be caused by the stent. To do the first part, it was created a model of the aortic dissection, but due to complications with the simulation, this part of the project couldn’t be finished, and the performance of the patch in the aortic dissection couldn’t be determined. To do the second part three models were created: healthy aorta, aortic dissection with stent graft and aortic dissection with patch. A transient simulation was run for the three models and the pressure waveform was analyzed. The results show that the pressure in the stent graft model is higher, and the patch has a similar response to the healthy aorta. However, all the models presented hypertension (including the healthy aorta) and the differences between the models are too small to be concluding, so it cannot be assured that the patch is a better option than the stent graft to avoid causing hypertension in the aortic dissection treatment

A Perspective Review on Numerical Simulations of Hemodynamics in Aortic Dissection

Aortic dissection, characterized by separation of the layers of the aortic wall, poses a significant challenge for clinicians. While type A aortic dissection patients are normally managed using surgical treatment, optimal treatment strategy for type B aortic dissection remains controversial and requires further evaluation. Although aortic diameter measured by CT angiography has been clinically used as a guideline to predict dilation in aortic dissection, hemodynamic parameters (e.g., pressure and wall shear stress), geometrical factors, and composition of the aorta wall are known to substantially affect disease progression. Due to the limitations of cardiac imaging modalities, numerical simulations have been widely used for the prediction of disease progression and therapeutic outcomes, by providing detailed insights into the hemodynamics. This paper presents a comprehensive review of the existing numerical models developed to investigate reasons behind tear initiation and progression, as well as the effectiveness of various treatment strategies, particularly the stent graft treatment

The impact of the number of tears in patient-specific Stanford type B aortic dissecting aneurysm: CFD simulation

It is believed that the progression of Stanford type B aortic dissection is closely associated with vascular geometry and hemodynamic parameters. The hemodynamic differences owing to the presence of greater than two tears have not been explored. The focus of the present study is to investigate the impact of an additional re-entry tear on the flow, pressure and wall shear stress distribution in the dissected aorta. A 3D aorta model with one entry and one re-entry tear was generated from computed tomography (CT) angiographic images of a patient with Stanford Type B aortic dissection. To investigate the hemodynamic effect of more than two tear locations, an additional circular re-entry tear was added 24mm above the original re-entry tear. Our simulation results showed that the presence of an additional re-entry tear provided an extra return path for blood back to the true lumen during systole, and an extra outflow path into the false lumen during diastole. The presence of this additional path led to a decrease in the false lumen pressure, particularly at the distal region. Meanwhile, the presence of this additional tear causes no significant difference on the time average wall shear stress (TAWSS) distribution except at regions adjacent to re-entry tear 2. Moderate and concentrated TAWSS was observed at the bottom region of this additional tear which may lead to further extension of the tear distally

Genetics and genomics of aortic form and function

The thoracic aorta is a dynamic organ which adapts and remodels throughout life. Thoracic aortic size, shape and function are important contributors to both cardiovascular health and disease and risk of aortic disease. A complex interaction of environmental, genetic and haemodynamic factors is mediated by cells of the aortic wall. This thesis presents aortic phenotyping, genotyping and genome-wide associations of aortic traits in a large healthy cohort of 1218 volunteers. This is the largest study to report normal parameters for healthy thoracic aortic size, shape and function derived from cardiovascular magnetic resonance imaging. Anthropometric and cardiovascular risk factors such as age, gender, body fat mass and lipid profile are identified as significant determinants of aortic phenotype. The work suggests that cardiovascular risk factors could impair normal adaptive aortic remodelling with age. Genome-wide association studies of aortic dimensions and function identify new common variants, genes and pathways which could be important in aortic biology and cardiovascular risk. These include genes involved in cardiovascular development (eg PCDH7 and SON associated with aortic root diameter), autonomic cardiovascular responses (eg GABA receptor genes associated with aortic root diameter), fibrosis (eg ACTC1, AGTR1 associated with ascending aortic distensibility, BAMBI and MYOD associated with descending aortic distensibility) and obesity (eg ARID5B and IRX3 associated with aortic pulse wave velocity and ascending aortic area respectively). Multiple regulatory pathways including TGF-ß and IGF signalling (IGF1R, IGF2R), are identified which are associated with aortic dimensions and function. Joint trait analysis of aortic root dimensions identifies a new genome-wide significant association with TENM4, a key driver of early mesodermal development, and suggestive association with PTN, which is functionally related and plays a key role in angiogenesis. The primary analyses are complemented by exploratory assessment of rare genetic variation in bicuspid aortic valve (BAV) using panel sequencing in 177 patients. Rare variants might cause, or modify phenotype in BAV, but the clinical utility of panel sequencing remains poor. A further complementary study investigates the interaction of haemodynamics with aortic cellular phenotype, using microarray assessment of aortic endothelial cell transcriptomic response to shear stress pattern. Several genes of interest in atherosclerosis and aortic disease are differentially expressed with shear stress pattern, such as FABP4, ANGPT2, FILIP1, KIT, DCHS1, TGFBR3 and LOX. This work yields new insights into aortic phenotype, identifies key loci which might determine aortic traits and explores the complex interdependence of genetics, haemodynamics and environmental variables in aortic biology.Open Acces

Computational analysis of the hemodynamic performance of novel endovascular and surgical procedures for complex aortic diseases

Novel branched stent-grafts (BSG) have been developed for endovascular repair of complex thoracic aortic aneurysms (TAA) involving the aortic arch or thoracoabdominal aorta, but their haemodynamic performance has not been adequately studied. In addition, surgical replacement of the ascending aorta with a Dacron graft remains the gold standard for type A aortic dissection (TAAD), although 12% of patients are at risk of aortic rupture due to further dilatation of the residual dissected aorta. The underlying mechanisms for progressive aortic dilatation following TAAD repair are poorly understood, but haemodynamic and biomechanical factors are believed to play an important role. Therefore, the present study aims to provide more insights into the haemodynamics in novel BSGs developed for treating complex aortic diseases, and a comprehensive evaluation of flow and biomechanical conditions in post-surgery TAADs by means of state-of-the-art computational methods. The first part of this thesis focuses on evaluating the haemodynamic performance of novel BSG designs, including thoracoabdominal branch endoprosthesis (TAMBE) and dual-branched thoracic endograft. Haemodynamics in idealised and patient-specific BSG models has been analysed by examining side branch outflow waveforms, wall shear stress related indices, and displacement forces, in order to assess their long-term durability. The numerical results show that all the stent-graft models examined in this study are capable of providing normal blood perfusion to side vessels, and are at low risk of in-stent thrombosis and device migration. Furthermore, it has been shown that geometric variations in TAMBE do not affect the key haemodynamic results, indicating its potential suitability for a variety of visceral artery anatomies. Comparisons of dual-branched thoracic endograft models with different inner tunnel diameters suggest that BSGs with larger inner tunnel diameters than the respective vessels would be preferred. Comparisons between the pre- and post-intervention models show that insertion of a dual-branched stent-graft significantly alters the flow pattern in the aortic arch, some of which may have a detrimental effect in the long term, thus requiring follow-up studies. The second part of the thesis provides a comprehensive analysis of the haemodynamic and biomechanical conditions in surgically repaired TAAD. Geometric and haemodynamic parameters have been analyzed and compared between the group of patients with stable aortic diameter and another group with progressive aortic dilatation. The number of re-entry tears (6±5 vs 2±1;P= 0.02) and luminal pressure difference (1.3 ±1 vs 11.7 ±14.6 mmHg;P= 0.001) have been identified as potential predictors of progressive aortic dilatation in TAAD patients following surgical repair. This is an important finding and can potentially assist clinicians to make the most appropriate choice or surgical plan for individual patients. Based on the finite element analysis of four patient-specific cases, there are no clear differences in biomechanical parameters between the stable and unstable groups. Furthermore, a preliminary fluid-solid interaction (FSI) simulation performed on a single TAAD model has demonstrated the important influence of wall compliance on pressures in the true and false lumen. Compared to a rigid wall model, the FSI simulation results show a reduction in systolic pressure by up to 10 mmHg and a slight increase in diastolic pressure. However, pressures in the true and false lumen are affected in the same way, so that the luminal pressure difference remains the same between the rigid and FSI models.Open Acces

Thoracic aortic aneurysms and dissections: genetic analysis of Mendelian and complex cases

The present doctoral thesis deals with the still partially unraveled genetic component of thoracic aortic aneurysms and dissections, a frequently asymptomatic but potentially lethal condition and major cause of sudden death. Our main objective was to contribute to further elucidate the genetics behind it, from both Mendelian and complex perspectives. We analyzed single and familial, forensic and clinical mendelian cases applying either a candidate-gene or whole exome massive parallel sequencing approach, respectively. We were able to solve approximately 23% of the forensic single cases and identified two strong candidate mutations in TGFB2 and PRKG1 genes in the two non-syndromic familial cases analyzed. For the analysis of complex cases we chose a population-based approach. We selected bicuspid aortic valve patients with and without concomitant thoracic aortic dilation and faced them against general population controls. We were not able to identify any consistently significant association, though a promising one arose involving HMCN2 and calcium metabolism that should be considered in future studies. The direct clinical consequences some of these results had supported molecular diagnosis, reliable genotype-phenotype correlations, and risk stratification as important tools for clinical management of these patients and family members at risk, as well as the need of research to continue