Effect of Intraluminal Thrombus Burden on the Risk of Abdominal Aortic Aneurysm Rupture.

Abdominal aortic aneurysm (AAA) is a critical health disorder, where the abdominal aorta dilates more than 50% of its normal diameter. Enlargement in abdominal aorta alters the hemodynamics and flow-induced forces on the AAA wall. Depending on the flow conditions, the hemodynamic forces on the wall may result in excessive mechanical stresses that lead to AAA rupture. The risk of rupture can be predicted using advanced computational techniques such as computational fluid dynamics (CFD) and fluid-structure interaction (FSI). For a reliable rupture risk assessment, formation of intraluminal thrombus (ILT) and uncertainty in arterial material properties should be taken into account, mainly due to the patient-specific differences and unknowns in AAAs. In this study, AAA models are computationally investigated by performing CFD simulations combined with FSI analysis. Various levels of ILT burdens are artificially generated in a realistic AAA geometry, and the peak effective stresses are evaluated to elucidate the effect of material models and ILT formation. The results indicate that increasing the ILT burden leads to lowered effective stresses on the AAA wall. The material properties of the artery and ILT are also effective on the stresses; however, these effects are limited compared to the effect of ILT volume in the AAA sac.

How does hemodynamics affect rupture tissue mechanics in abdominal aortic aneurysm: Focus on wall shear stress derived parameters, time-averaged wall shear stress, oscillatory shear index, endothelial cell activation potential, and relative residence time.

An abdominal aortic aneurysm (AAA) is a critical health condition with a risk of rupture, where the diameter of the aorta enlarges more than 50% of its normal diameter. The incidence rate of AAA has increased worldwide. Currently, about three out of every 100,000 people have aortic diseases. The diameter and geometry of AAAs influence the hemodynamic forces exerted on the arterial wall. Therefore, a reliable assessment of hemodynamics is crucial for predicting the rupture risk. Wall shear stress (WSS) is an important metric to define the level of the frictional force on the AAA wall. Excessive levels of WSS deteriorate the remodeling mechanism of the arteries and lead to abnormal conditions. At this point, WSS-related hemodynamic parameters, such as time-averaged WSS (TAWSS), oscillatory shear index (OSI), endothelial cell activation potential (ECAP), and relative residence time (RRT) provide important information to evaluate the shear environment on the AAA wall in detail. Calculation of these parameters is not straightforward and requires a physical understanding of what they represent. In addition, computational fluid dynamics (CFD) solvers do not readily calculate these parameters when hemodynamics is simulated. This review aims to explain the WSS-derived parameters focusing on how these represent different characteristics of disturbed hemodynamics. A representative case is presented for spatial and temporal formulation that would be useful for interested researchers for practical calculations. Finally, recent hemodynamics investigations relating WSS-related parameters with AAA rupture risk assessment are presented. This review will be useful to understand the physical representation of WSS-related parameters in cardiovascular flows and how they can be calculated practically for AAA investigations.

Computational Modeling of Motile Cilia-Driven Cerebrospinal Flow in the Brain Ventricles of Zebrafish Embryo.

Motile cilia are hair-like microscopic structures which generate directional flow to provide fluid transport in various biological processes. Ciliary beating is one of the sources of cerebrospinal flow (CSF) in brain ventricles. In this study, we investigated how the tilt angle, quantity, and phase relationship of cilia affect CSF flow patterns in the brain ventricles of zebrafish embryos. For this purpose, two-dimensional computational fluid dynamics (CFD) simulations are performed to determine the flow fields generated by the motile cilia. The cilia are modeled as thin membranes with prescribed motions. The cilia motions were obtained from a two-day post-fertilization zebrafish embryo previously imaged via light sheet fluorescence microscopy. We observed that the cilium angle significantly alters the generated flow velocity and mass flow rates. As the cilium angle gets closer to the wall, higher flow velocities are observed. Phase difference between two adjacent beating cilia also affects the flow field as the cilia with no phase difference produce significantly lower mass flow rates. In conclusion, our simulations revealed that the most efficient method for cilia-driven fluid transport relies on the alignment of multiple cilia beating with a phase difference, which is also observed in vivo in the developing zebrafish brain.

Blood Flow Disturbance and Morphological Alterations Following the Right Atrial Ligation in the Chick Embryo.

Collectively known as congenital heart defects (CHDs), cardiac abnormalities at birth are the most common forms of neonatal defects. Being principally responsible for the heart's pumping power, ventricles are particularly affected by developmental abnormalities, such as flow disturbances or genomic defects. Hypoplastic Right Heart Syndrome (HRHS) is a rare disease where the right ventricle is underdeveloped. In this study, we introduce a surgical procedure performed on chick embryo, termed right atrial ligation (RAL) for disturbing hemodynamics within the right heart aiming in order to generate an animal model of HRHS. RAL is a new surgical manipulation, similar to the well-studied left atrial ligation (LAL) surgery but it induces the hemodynamic change into the right side of the heart. After inducing RAL, We utilized techniques such as Doppler ultrasound, x-ray micro-CT, histology, and computational fluid dynamics (CFD) analysis, for a comprehensive functional and structural analysis of a developing heart. Our results displayed that RAL does not induce severe flow disturbance and ventricular abnormalities consistent with clinical findings. This study allows us to better understand the hemodynamics-driven CHD development and sensitivities of ventricles under disturbed flows.

Hemodynamic and Structural Comparison of Human Fetal Heart Development Between Normally Growing and Hypoplastic Left Heart Syndrome-Diagnosed Hearts.

Congenital heart defects (CHDs) affect a wide range of societies with an incidence rate of 1.0-1.2%. These defects initiate at the early developmental stage and result in critical health disorders. Although genetic factors play a role in the formation of CHDs, the occurrence of cases in families with no history of CHDs suggests that mechanobiological forces may also play a role in the initiation and progression of CHDs. Hypoplastic left heart syndrome (HLHS) is a critical CHD, which is responsible for 25-40% of all prenatal cardiac deaths. The comparison of healthy and HLHS hearts helps in understanding the main hemodynamic differences related to HLHS. Echocardiography is the most common imaging modality utilized for fetal cardiac assessment. In this study, we utilized echocardiographic images to compare healthy and HLHS human fetal hearts for determining the differences in terms of heart chamber dimensions, valvular flow rates, and hemodynamics. The cross-sectional areas of chamber dimensions are determined from 2D b-mode ultrasound images. Valvular flow rates are measured via Doppler echocardiography, and hemodynamic quantifications are performed with the use of computational fluid dynamics (CFD) simulations. The obtained results indicate that cross-sectional areas of the left and right sides of the heart are similar for healthy fetuses during gestational development. The left side of HLHS heart is underdeveloped, and as a result, the hemodynamic parameters such as flow velocity, pressure, and wall shear stress (WSS) are significantly altered compared to those of healthy hearts.

Numerical Investigation of the Fetal Left Heart Hemodynamics During Gestational Stages.

Flow-driven hemodynamic forces on the cardiac tissues have critical importance, and have a significant role in the proper development of the heart. These mechanobiological mechanisms govern the cellular responses for the growth and remodeling of the heart, where the altered hemodynamic environment is believed to be a major factor that is leading to congenital heart defects (CHDs). In order to investigate the mechanobiological development of the normal and diseased hearts, identification of the blood flow patterns and wall shear stresses (WSS) on these tissues are required for an accurate hemodynamic assessment. In this study, we focus on the left heart hemodynamics of the human fetuses throughout the gestational stages. Computational fetal left heart models are created for the healthy fetuses using the ultrasound images at various gestational weeks. Realistic inflow boundary conditions are implemented in the models using the Doppler ultrasound measurements for resolving the specific blood flow waveforms in the mitral valve. Obtained results indicate that WSS and vorticity levels in the fetal left heart decrease with the development of the fetus. The maximum WSS around the mitral valve is determined around 36 Pa at the gestational week of 16. This maximum WSS decreases to 11 Pa at the gestational week of 27, indicating nearly three-times reduction in the peak shear stress. These findings reveal the highly dynamic nature of the left heart hemodynamics throughout the development of the human fetus and shed light into the relevance of hemodynamic environment and development of CHDs.

Computational Modeling of Blood Flow Hemodynamics for Biomechanical Investigation of Cardiac Development and Disease.

The heart is the first functional organ in a developing embryo. Cardiac development continues throughout developmental stages while the heart goes through a serious of drastic morphological changes. Previous animal experiments as well as clinical observations showed that disturbed hemodynamics interfere with the development of the heart and leads to the formation of a variety of defects in heart valves, heart chambers, and blood vessels, suggesting that hemodynamics is a governing factor for cardiogenesis, and disturbed hemodynamics is an important source of congenital heart defects. Therefore, there is an interest to image and quantify the flowing blood through a developing heart. Flow measurement in embryonic fetal heart can be performed using advanced techniques such as magnetic resonance imaging (MRI) or echocardiography. Computational fluid dynamics (CFD) modeling is another approach especially useful when the other imaging modalities are not available and in-depth flow assessment is needed. The approach is based on numerically solving relevant physical equations to approximate the flow hemodynamics and tissue behavior. This approach is becoming widely adapted to simulate cardiac flows during the embryonic development. While there are few studies for human fetal cardiac flows, many groups used zebrafish and chicken embryos as useful models for elucidating normal and diseased cardiogenesis. In this paper, we explain the major steps to generate CFD models for simulating cardiac hemodynamics in vivo and summarize the latest findings on chicken and zebrafish embryos as well as human fetal hearts.

Effect of left atrial ligation-driven altered inflow hemodynamics on embryonic heart development: clues for prenatal progression of hypoplastic left heart syndrome.

Congenital heart defects (CHDs) are abnormalities in the heart structure present at birth. One important condition is hypoplastic left heart syndrome (HLHS) where severely underdeveloped left ventricle (LV) cannot support systemic circulation. HLHS usually initiates as localized tissue malformations with no underlying genetic cause, suggesting that disturbed hemodynamics contribute to the embryonic development of these defects. Left atrial ligation (LAL) is a surgical procedure on embryonic chick resulting in a phenotype resembling clinical HLHS. In this study, we investigated disturbed hemodynamics and deteriorated cardiac growth following LAL to investigate possible mechanobiological mechanisms for the embryonic development of HLHS. We integrated techniques such as echocardiography, micro-CT and computational fluid dynamics (CFD) for these analyses. Specifically, LAL procedure causes an immediate flow disturbance over atrioventricular (AV) cushions. At later stages after the heart septation, it causes hemodynamic disturbances in LV. As a consequence of the LAL procedure, the left-AV canal and LV volume decrease in size, and in the opposite way, the right-AV canal and right ventricle volume increase. According to our CFD analysis, LAL results in an immediate decrease in the left AV canal WSS levels for 3.5-day (HH21) pre-septated hearts. For 7-day post-septated hearts (HH30), LAL leads to further reduction in WSS levels in the left AV canal, and relatively increased WSS levels in the right AV canal. This study demonstrates the critical importance of the disturbed hemodynamics during the heart valve and ventricle development.

Advanced blood flow assessment in Zebrafish via experimental digital particle image velocimetry and computational fluid dynamics modeling.

Over the past few decades, Zebrafish has become a widely used vertebrate model for cardiovascular research. Easy genetic manipulation, low cost, high fecundity, embryonic transparency, and ability to survive in the early stages of development without active circulation are among the advantages of Zebrafish. Cardiac malformations can be induced through genetic manipulations for elucidating the influence of mechanobiological stimuli on the development and progress of the cardiovascular diseases. For this purpose, a reliable in vivo assessment of cardiac function and disturbed hemodynamics is required. Therefore, it is necessary to accurately determine the complex blood flow patterns and associated hemodynamic shear stresses within the developing heart and cardiovascular system. In the traditional approach, brightfield microscopy is used to track the motion of cells in two-dimensions (2D). However, with the development of advanced modalities such as light-sheet fluorescent microscopy, it is now possible to perform 4D (three-dimensional space + time) imaging of Zebrafish embryo and larvae. The integration of digital particle image velocimetry (DPIV) and computational fluid dynamics (CFD) provide an opportunity for detailed investigations using in vivo images. In this review, DPIV and CFD methods are explained for blood flow assessment, and recent relevant research findings from Zebrafish studies are summarized.

Biomechanical Investigation of Disturbed Hemodynamics-Induced Tissue Degeneration in Abdominal Aortic Aneurysms Using Computational and Experimental Techniques.

Abdominal aortic aneurysm (AAA) is the dilatation of the aorta beyond 50% of the normal vessel diameter. It is reported that 4-8% of men and 0.5-1% of women above 50 years of age bear an AAA and it accounts for ~15,000 deaths per year in the United States alone. If left untreated, AAA might gradually expand until rupture; the most catastrophic complication of the aneurysmal disease that is accompanied by a striking overall mortality of 80%. The precise mechanisms leading to AAA rupture remains unclear. Therefore, characterization of disturbed hemodynamics within AAAs will help to understand the mechanobiological development of the condition which will contribute to novel therapies for the condition. Due to geometrical complexities, it is challenging to directly quantify disturbed flows for AAAs clinically. Two other approaches for this investigation are computational modeling and experimental flow measurement. In computational modeling, the problem is first defined mathematically, and the solution is approximated with numerical techniques to get characteristics of flow. In experimental flow measurement, once the setup providing physiological flow pattern in a phantom geometry is constructed, velocity measurement system such as particle image velocimetry (PIV) enables characterization of the flow. We witness increasing number of applications of these complimentary approaches for AAA investigations in recent years. In this paper, we outline the details of computational modeling procedures and experimental settings and summarize important findings from recent studies, which will help researchers for AAA investigations and rupture mechanics.

Computational analysis for non-invasive detection of stenosis in peripheral arteries.

Atherosclerosis usually affects the entire cardiovascular system, including peripheral blood vessels. Peripheral arterial stenosis may indicate possible serious vascular disorders related to more vital organs. If peripheral arterial stenosis can be discerned at an early stage, it can serve as a warning sign to take precautions, such as using more invasive diagnostic techniques or adopting a healthier life style. In this study, peripheral regions, such as the thigh, upper arm, and neck are modelled considering stenosis of their major arteries. Stenosis generates a fluctuating pressure field on the arterial wall, which leads to vibration on the skin's surface. This stenosis-induced pressure field is modelled as a harmonic load and applied to the inner surface of the arterial structure. The vibration response on bare skin is computationally determined using the superposition of modal responses. Realistic geometries and hyperelastic material properties are used in modelling the layers of skin, fat, muscle, and bones. The results indicate that stenosis severities higher than 70% lead to a considerable increase in vibration-response amplitudes, especially at frequencies greater than 250 Hz. The detailed analysis of skin responses provides useful information to detect the stenosis location, where the sum of the vibration amplitudes attains its maximum value around the stenosis.

Experimental and numerical investigation on soft tissue dynamic response due to turbulence-induced arterial vibration.

Peripheral arterial occlusive disease is a serious cardiovascular disorder. The arterial occlusion leads to turbulent flow and arterial sound generation on the inner vessel wall. Stenosis-induced vibro-acoustic waves propagate through the surrounding soft tissues and reach the skin surface. In this study, the feasibility of noninvasive acoustic detection of the peripheral arterial stenosis is investigated using the vibration responses by means of experimental and computational models. Latex rubber tube is used to model the artery, and it is surrounded by a tissue mimicking phantom made of bovine gelatin. Vibration responses on phantom surface are measured using laser Doppler vibrometer, and computational results are obtained performing modal analysis. Experimental findings and computational results showed well agreement in terms of spectral content and vibration amplitudes. The effects of various stenosis severities, flow rates, and phantom thicknesses on the vibration responses are investigated from diagnostic perspective. Stenosis severities greater than 70% resulted in a considerable increase in vibration amplitudes. The structural mode shapes of the tissue phantom are dominant between 0 and 100 Hz, suppressing the signals generated by the stenosis. The optimum range of frequency for acoustic stenosis detection is concluded to be between 200 and 500 Hz, particularly around 300 Hz. Graphical abstract .

Flow-induced vibration analysis of constricted artery models with surrounding soft tissue.

Arterial stenosis is a vascular pathology which leads to serious cardiovascular diseases. Blood flow through a constriction generates sound and vibration due to fluctuating turbulent pressures. Generated vibro-acoustic waves propagate through surrounding soft tissues and reach the skin surface and may provide valuable insight for noninvasive diagnostic purposes. Motivated by the aforementioned phenomena, vibration of constricted arteries is investigated employing computational models. The flow-induced pressure field in an artery is modeled as broadband harmonic pressure loading based on previous studies in the literature and applied on the inner artery wall. Harmonic analysis is performed for determining radial velocity responses on the outer surface of the models. Results indicate that stenosis severities higher than 70% lead to significant increase in response amplitudes, especially at high frequencies between 250 and 600 Hz. The findings agree well with experimental and theoretical results in the literature considering bending mode frequencies, amplitude scales, and mainly excited frequency ranges. It is seen that artery vibration is sensitive to the phase behavior of pressure loading but its effect becomes less significant with the presence of surrounding tissue. As the surrounding tissue thickness increases, radial velocity response amplitudes decrease but the effect of changes in tissue elastic modulus is more pronounced.