Characterization of disturbed hemodynamics due to stenosed aortic jets with a Lagrangian Coherent structures technique

Isfahan University of Technology. The aortic valve is located at left ventricular outlet and is exposed to the highest pressure in the cardiovascular system. Problems associated with the valve leaflet movement can cause complications for the heart. Specifically, aortic stenosis (AS) arises when aortic leaflets do not efficiently open. In the present study, Lagrangian Coherent Structures (LCSs) were utilized by processing a variety of Computational Fluid Dynamics (CFD) models velocity vector data further to identify the characteristics of AS jets. Particularly, effective orifice areas (EOA) for different cases were accurately identified from unstable manifolds of finite time Lyapunov exponent (FTLE) fields. Calcified leaflets were modeled by setting the leaflet's Young modulus to 10 MPa and 20 MPa for moderately and severely calcified leaflets respectively while a healthy leaflet's Young modulus was assigned to be 2 MPa. Increase in calcification degree of the leaflet caused destruction of the vortex structures near the fibrosa layer of the leaflet indicating a malfunctioning for the movement mechanism of the leaflet. Furthermore, when we analyzed stable manifolds, we identified a blockage region at the flow upstream due to the stagnant blood here. Compared to a healthy case, for the calcified valve, this blockage region was enlarged, implying an increase in AS jet velocity and wall shear stress on leaflets. As a conclusion, results from the present study indicate that aortic leaflet malfunctioning could be accurately evaluated when LCS technique was employed by post processing velocity vector data from CFD. Such precise analysis is not possible using the Eulerian CFD approach or a Doppler echocardiography since these methods are based on only analyzing instantaneous flow quantities and they overlook fluid flow characteristics of highly unsteady flows

The Oscillatory Shear Index: Quantifications for Valve Tissue Engineering and a Novel Interpretation for Calcification

Heart valve tissue engineering (HVTE) stands as a potential intervention that could reduce the prevalence of congenital heart valve disease in juvenile patients. Prior studies in our laboratory have utilized mechanobiological testing to quantify the forces involved in the development of heart valve tissue, utilizing a Flow-Stretch-Flexure (FSF) bioreactor to condition bone marrow stem cells (BMSCs)-derived valve tissue. Simulations have demonstrated that certain sets of flow conditions can introduce specific levels of oscillatory shear stress (OSS)-induced stimuli, augmenting the growth of engineered valves as well as influencing collagen formation, extracellular matrix (ECM) composition and gene expression. The computational findings discussed in this thesis outline the methods in which flow conditions, when physiologically relevant, induce specific oscillatory shear stresses which could not only lead to an optimized valve tissue phenotype (at 0.18≤ OSI≤ 0.23), but could identify native valve tissue remodeling indicative of aortic valve disease

Mechanical Regulation of Apoptosis and Calcification within Valvular Interstitial Cells

Calcific aortic valvular disease (CAVD) is the most common valvular pathology in the developed world. CAVD results in calcifications forming on the aortic valve leaflets, inhibiting proper closure and causing complications of stenosis and regurgitation. Although, the mechanisms behind the disease initiation are unknown, it is believed to be a cell-mediated phenomenon, and not the result of passive degradation of the valve as once believed due to the increased prevalence with age. Currently, there are no pharmaceutical options for the prevention or reversal of calcifications, the only treatment option is complete valve replacement, an imperfect solution. Hindering the development of potential therapeutics is that currently there are no adequate animal models which replicate the calcification and cell death seen in disease explanted valves. An in vitro model has been develop where valvular interstitial cells (VICs), the main cell type of the valve, are seeded at high density into tissue culture polystyrene dishes and cultured with TGF-β1. This results in VICs activating to the myofibroblast phenotype and forming cell aggregates. Due to currently unknown mechanisms, apoptosis occurs within the center of the aggregates and calcification ensues. Although simplistic, this model has been used to show that rate and frequency of aggregation is affected by cellular tension; conditions of high tension increase aggregation response, while conditions of low tension prevent aggregation and calcification from occurring. It is important to note; however, that despite its wide usage, the current model is limited as the aggregation and subsequent calcification are random occurrences and are not consistent across literature where same conditions for control samples are used. The motivation of the presented work is two-fold. First, high intracellular tension has been suggested as one of the mechanisms leading to disease in the valve. Despite the clear and important role of cell tension, VIC tension has never before been measured in a dynamic environment. The ways in which dynamic stimulation affects individual VIC tension is not known. In aim one, a method is developed to allow for long-term cyclic stretch of VICs with measurement of cell traction force. It was found that cyclic stretch decreased cell tension in cells with high prestress and increased cell tension for conditions of low prestress. Combined, these findings indicate a homeostatic cellular tension which is dependent upon the mechanical environment. In the second aim, a novel method for creating VIC aggregates is validated. Micro-contact printing, essentially “stampingâ€� of a protein in a defined pattern, is used to create circular aggregates on polyacrylamide gels. This method allows for the separation of the aggregation from the subsequent calcification, an improvement over the current in vitro model. The method is then used to explore the role of the distribution of tension in the initiation of diseas

Population-specific material properties of the implantation site for transcatheter aortic valve replacement finite element simulations

Patient-specific computational models are an established tool to support device development and test under clinically relevant boundary conditions. Potentially, such models could be used to aid the clinical decision-making process for percutaneous valve selection; however, their adoption in clinical practice is still limited to individual cases. To be fully informative, they should include patient-specific data on both anatomy and mechanics of the implantation site. In this work, fourteen patient-specific computational models for transcatheter aortic valve replacement (TAVR) with balloon-expandable Sapien XT devices were retrospectively developed to tune the material parameters of the implantation site mechanical model for the average TAVR population. Pre-procedural computed tomography (CT) images were post-processed to create the 3D patient-specific anatomy of the implantation site. Balloon valvuloplasty and device deployment were simulated with finite element (FE) analysis. Valve leaflets and aortic root were modelled as linear elastic materials, while calcification as elastoplastic. Material properties were initially selected from literature; then, a statistical analysis was designed to investigate the effect of each implantation site material parameter on the implanted stent diameter and thus identify the combination of material parameters for TAVR patients. These numerical models were validated against clinical data. The comparison between stent diameters measured from post-procedural fluoroscopy images and final computational results showed a mean difference of 2.5 ± 3.9%. Moreover, the numerical model detected the presence of paravalvular leakage (PVL) in 79% of cases, as assessed by post-TAVR echocardiographic examination. The final aim was to increase accuracy and reliability of such computational tools for prospective clinical applications

Hemodynamics of aortic valve stenoses

The aortic valve of a human heart is located between the left ventricle and the aorta. Its function is to open during the systole, allowing the blood to flow to the aorta in order to feed the organs and close during the diastole, preventing blood flow back into the left ventricle. Disease can lead to dysfunctionalities of the aortic valve and affect its performance. Calcific aortic valve disease (CAVD) is one of the most common valvular heart diseases which causes malfunctioning of the aortic valve leading to stroke, aortic aneurysm, heart attack and failure over time. Over the past few decades, researchers have investigated the effects of stenosis of the aortic valve on its hemodynamics and performance using in-vitro and in-vivo experiments, as well as numerical models. In-vitro experimentation and in-vivo measurements are broadly used for the investigation of the effect of aortic valve stenosis on the hemodynamics in the aortic root and the performance of the aortic valve. Numerical methods also play an important role in the modelling of the stenosis of the aortic valve and have obtained considerable attention in biomechanics application due to their very cost effective nature. Significant developments have been made in modelling the stenosis of the aortic valve and the effects on its hemodynamics and malfunctioning, however, the influence of vortex structures in the sinus on the aortic root and the coronary artery hemodynamics, as well as the performance of the valve and its correlation with the development of CAVD, are still unknown. The aim of this thesis is to develop an understanding of the flow behaviour inside the sinus cavity of the aortic valve in order to predict the shear stress distribution on the aortic valve leaflets and its correlation with CAVD. This aim has been achieved by answering the following research questions: (i) how stenosis of the aortic valve affects the aortic root and coronary artery hemodynamics; (ii) how the geometrical parameters of the aortic valve, such as the locations of the coronary artery ostia and the shape of the sinuses, influences the sinus hemodynamics, especially vortex structures within the sinuses; (iii) what are the effects of coronary artery stenosis on the shear stress distribution on the aortic valve leaflets; (iv) how vortex structures in the sinuses can change the wall shear stress distribution on the leaflets and its correlation with CAVD. In order to answer all of the above-mentioned questions and achieve the main objective of the project, the following tasks have been defined: • A brief overview of cardiovascular heart diseases with a focus on valvular heart diseases, and various techniques frequently used for diagnostics and treatment of stenosis of the aortic valve has been provided. • A comprehensive review of different techniques used for modelling aortic valve stenosis has been provided with a focus on the numerical Fluid-Structure Interaction (FSI) method and its advantages in modelling. • Two dimensional models of a healthy and a stenosed aortic valve have been extracted from the 2D echocardiography images available in the literature and developed in ANSYS- Fluent software. • Dynamic motion simulation of the aortic valve leaflets have been used to investigate the effects of stenosis of the aortic valve on the sinus vortex structures, coronary artery hemodynamics, wall shear stress on the leaflets and its correlation with CAVD. • A unique test rig has been designed, fabricated, and used for validation of the transvalvular pressure gradient and flow rate profile of the aortic valve. The test rig experimentally replicates the left ventricle of the heart and is capable of producing the heart beat flow conditions of different patients. The flow rate profile of the aortic valve and the pressure difference through the aortic valve are measured and compared with the simulated results. The developed model is capable of mimicking the dynamic motion of the aortic valve leaflets and predicting the wall shear stress distribution on the leaflets, which is associated with CAVD. The most important findings of the project showed that the wall shear stress distribution on the leaflets is highly dependent on the geometrical parameters of the aortic valve, such as the locations of the coronary artery ostia, as well as the shape of the sinuses. For example, an aortic valve with proximal coronary artery ostia experiences lower ranges of wall shear stress distribution on the leaflets. This means that a healthy valve with proximal coronary artery ostia are more prone to calcification over time in comparison with a healthy valve with distal and middle coronary artery ostia. Furthermore, the results demonstrated that a severely calcified aortic valve exhibits a lower range of wall shear stress distribution on the leaflets with higher probability of having smaller wall shear stress on the leaflets compared to a healthy valveThesis (Ph.D.) -- University of Adelaide, School of Mechanical Engineering, 202

Mechanical Activation Of Valvular Interstitial Cell Phenotype

During heart valve remodeling, and in many disease states, valvular interstitial cells (VICs) shift to an activated myofibroblast phenotype which is characterized by enhanced synthetic and contractile activity. Pronounced alpha smooth muscle actin (alpha-SMA)-containing stress fibers, the hallmark of activated myofibroblasts, are also observed when VICs are placed under tension due to altered mechanical loading in vivo or during in vitro culture on stiff substrates or under high mechanical loads and in the presence of transforming growth factor-beta 1 (TGF-beta 1). The work presented herein describes three distinct model systems for application of controlled mechanical environment to VICs cultured in vitro. The first system uses polyacrylamide (PA) gels of defined stiffness to evaluate the response of VICs over a large range of stiffness levels and TGF-beta 1 concentration. The second system controls the boundary stiffness of cell-populated gels using springs of defined stiffness. The third system cyclically stretches soft or stiff two-dimensional (2D) gels while cells are cultured on the gel surface as it is deformed. Through the use of these model systems, we have found that the level of 2D stiffness required to maintain the quiescent VIC phenotype is potentially too low for a material to both act as matrix to support cell growth in the non-activated state and also to withstand the mechanical loading that occurs during the cardiac cycle. Further, we found that increasing the boundary stiffness on a three-dimensional (3D) cell populated collagen gel resulted in increased cellular contractile forces, alpha-SMA expression, and collagen gel (material)stiffness. Finally, VIC morphology is significantly altered in response to stiffness and stretch. On soft 2D substrates, VICs cultured statically exhibit a small rounded morphology, significantly smaller than on stiff substrates. Following equibiaxial cyclic stretch, VICs spread to the extent of cells cultured on stiff substrates, but did not reorient in response to uniaxial stretch to the extent of cells stretched on stiff substrates. These studies provide critical information for characterizing how VICs respond to mechanical stimuli. Characterization of these responses is important for the development of tissue engineered heart valves and contributes to the understanding of the role of mechanical cues on valve pathology and disease onset and progression. While this work is focused on valvular interstitial cells, the culture conditions and methods for applying mechanical stimulation could be applied to numerous other adherent cell types providing information on the response to mechanical stimuli relevant for optimizing cell culture, engineered tissues or fundamental research of disease states

Mechanical Activation of Valvular Interstitial Cell Phenotype: A Dissertation

During heart valve remodeling, and in many disease states, valvular interstitial cells (VICs) shift to an activated myofibroblast phenotype which is characterized by enhanced synthetic and contractile activity. Pronounced alpha smooth muscle actin (αSMA)-containing stress fibers, the hallmark of activated myofibroblasts, are also observed when VICs are placed under tension due to altered mechanical loading in vivo or during in vitro culture on stiff substrates or under high mechanical loads and in the presence of transforming growth factor-beta1 (TGF-β1). The work presented herein describes three distinct model systems for application of controlled mechanical environment to VICs cultured in vitro. The first system uses polyacrylamide (PA) gels of defined stiffness to evaluate the response of VICs over a large range of stiffness levels and TGF-β1 concentration. The second system controls the boundary stiffness of cell-populated gels using springs of defined stiffness. The third system cyclically stretches soft or stiff two-dimensional (2D) gels while cells are cultured on the gel surface as it is deformed. Through the use of these model systems, we have found that the level of 2D stiffness required to maintain the quiescent VIC phenotype is potentially too low for a material to both act as matrix to support cell growth in the non-activated state and also to withstand the mechanical loading that occurs during the cardiac cycle. Further, we found that increasing the boundary stiffness on a three-dimensional (3D) cell populated collagen gel resulted in increased cellular contractile forces, αSMA expression, and collagen gel (material) stiffness. Finally, VIC morphology is significantly altered in response to stiffness and stretch. On soft 2D substrates, VICs cultured statically exhibit a small rounded morphology, significantly smaller than on stiff substrates. Following equibiaxial cyclic stretch, VICs spread to the extent of cells cultured on stiff substrates, but did not reorient in response to uniaxial stretch to the extent of cells stretched on stiff substrates. These studies provide critical information for characterizing how VICs respond to mechanical stimuli. Characterization of these responses is important for the development of tissue engineered heart valves and contributes to the understanding of the role of mechanical cues on valve pathology and disease onset and progression. While this work is focused on valvular interstitial cells, the culture conditions and methods for applying mechanical stimulation could be applied to numerous other adherent cell types providing information on the response to mechanical stimuli relevant for optimizing cell culture, engineered tissues or fundamental research of disease states