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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. This study was funded by the Qatar National Research Fund (QNRF), National Priority Research Program (NPRP 10-0123-170222). Open access funding was provided by the Qatar National Library.

The hemodynamic forces and wall shear stresses (WSS) play an important role during the fetal heart development. Abnormal levels of flow-driven shear stress can deteriorate the proper functioning of the cells responsible for the growth and remodeling of the heart and lead to congenital heart defects (CHDs). Hypoplastic left heart syndrome (HLHS) is a critical CHD with severely underdeveloped left ventricle and responsible for 25-40% of all neonatal cardiac deaths. To characterize the main differences between the healthy and HLHS fetal hearts in terms of morphology, flow behavior, and WSS levels, will help to understand the mechanobiological development of the human fetal hearts. The comparison of healthy and HLHS fetal hearts is important to understand the embryonic development of HLHS. Computational fluid dynamics (CFD) modeling is performed to elucidate the flow behavior and WSS levels in the heart chambers. First, the model geometries are generated using the medical images. Then, the flow domain is discretized in spatial and time domains for solving the governing fluid flow equations. Inlet flow conditions are determined using the Doppler ultrasound velocity measurements. The analyses cover the range of gestational week 16 and week 34. HLHS hearts have higher peak flow rates at the valves compared to the control hearts. The turbulent activity in the left side of the heart is higher than the right side. For the control hearts, there is a balance between the left and right sides of the heart, which is preserved during the development. The ratio of the cross-sectional area between the left and right sides of the heart is about 57.5% to 42.5% for the control hearts. HLHS significantly reduces the cross-sectional area of the left side of the heart. For HLHS hearts, the ratio between the left and right sides becomes about 30% to 70%. The average WSS levels significantly increase at the left side of the HLHS hearts. This study indicates the critical importance of the altered inflow hemodynamics during the human fetal heart development. CFD analysis can be used to predict the initiation and growth of CHDs. The presence of CHDs significantly changes the biomechanical environment in the fetal hearts.

Calcification and bicuspid valve formation are important aortic valve disorders that disturb the hemodynamics and the valve function. The detailed analysis of aortic valve hemodynamics would lead to a better understanding of the disease’s etiology. We computationally modeled the aortic valve using simplified three-dimensional geometry and inlet velocity conditions obtained via echocardiography. We examined various calcification severities and bicuspid valve formation. Fluid-structure interaction (FSI) analyses were adapted using ANSYS Workbench to incorporate both flow dynamics and leaflet deformation accurately. Simulation results were validated by comparing leaflet movements in B-mode echo recordings. Results indicate that the biomechanical environment is significantly changed for calcified and bicuspid valves. High flow jet velocities are observed in the calcified valves which results in high transvalvular pressure difference (TPG). Wall shear stresses (WSS) increased with the calcification on both fibrosa (aorta side) and ventricularis (left ventricle side) surfaces of the leaflet. The WSS distribution is regular on the ventricularis, as the WSS values proportionally increase from the base to the tip of the leaflet. However, WSS patterns are spatially complex on the fibrosa side. Low WSS levels and spatially complex WSS patterns on the fibrosa side are considered as promoting factors for further calcification and valvular diseases Qatar National Research Fund

Aortic valve calcification is an important cardiovascular disorder that deteriorates the accurate functioning of the valve leaflets. The increasing stiffness due to the calcification prevents the complete closure of the valve and therefore leads to significant hemodynamic alterations. Computational fluid dynamics (CFD) modeling enables the investigation of the entire flow domain by processing medical images from aortic valve patients. In this study, we computationally modeled and simulated a 3D aortic valve using patient-specific dimensions of the aortic root and aortic sinus. Leaflet stiffness is deteriorated in aortic valve disease due to calcification. In order to investigate the influence of leaflet calcification on flow dynamics, three different leaflet-stiffness values were considered for healthy, mildly calcified, and severely calcified leaflets. Time-dependent CFD results were used for applying the Lagrangian coherent structures (LCS) technique by performing finite-time Lyapunov exponent (FTLE) computations along with Lagrangian particle residence time (PRT) analysis to identify unique vortex structures at the front and backside of the leaflets. Obtained results indicated that the peak flow velocity at the valve orifice increased with the calcification rate. For the healthy aortic valve, a low-pressure field was observed at the leaflet tips. This low-pressure field gradually expanded through the entire aortic sinus as the calcification level increased. FTLE field plots of the healthy and calcified valves showed a variety of differences in terms of flow structures. When the number of fluid particles in the healthy valve model was taken as reference, 1.59 and 1.74 times more particles accumulated in the mildly and severely calcified valves, respectively, indicating that the calcified valves were not sufficiently opened to allow normal mass flow rates.

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. This work is internally supported by Middle East Technical University (METU) Scientific Research Project (BAP) under grant number BAP-03-02-2015-006. The authors would like to thank BTech Innovation (Ankara, Turkey) for providing technical support for the reconstruction of the three-dimensional models. The authors would also like to acknowledge the financial support from the Turkish Scientific and Technical Research Council (TUBITAK) under the 2211/C program.

Background: Motile cilia are hair-like microscopic structures, which move the fluids along the epithelial surfaces. Cilia cover a wide range of regions in the nervous system, such as the nasal cavity, spinal cord central canal, and brain ventricles. Motile cilia-driven cerebrospinal fluid (CSF) flow in the brain ventricles has an important role in the brain development. Embryos lacking motile cilia develop neurological defects due to altered CSF flow. Aim: To investigate the effect of motile-cilia motion on the altered CSF flow, and to understand the role of CSF flow in the brain development and physiology. Methods: The dynamics of motile-cilia driven flow is analyzed employing computational fluid dynamics (CFD) modeling. A 2D model is generated using the time-lapse microscopic movies showing movements of a fluorescently labeled motile-cilia in a zebrafish embryo (48-hour post-fertilization). The effects on the generated flow are elucidated by investigating the cilia beating angle, multiple cilia formations, and the phase difference between different ciliary beats. Results: Ciliary beating generated a directional flow in the form of a circulating vortex. The angle of ciliary beating significantly affected the flow velocity. As the angle between the wall and cilia decreases, the flow becomes more efficient by achieving higher velocities. Multiple cilia formations increased the flow velocity but the significance of multiple cilia is not as critical as the beating angle. Interestingly, phase difference between the multiple cilia beats increased the directional flow velocity. Conclusion: Motile-cilia generated flow dynamics are investigated, and it is concluded that out-of-phase multiple ciliary beating is the optimum form of beating in order to generate a directional flow.

Background: Aortic valve diseases affect about 25% of the population over 65 years of age. Aortic valve separates the left ventricle from the aorta, and consists of three half-moon shaped leaflets. The leaflets are highly dynamic structures which open during the ventricle contraction and close during the ventricle relaxation. Calcification on leaflet surfaces results in poor valve functioning which deteriorates the valve hemodynamics. Wall shear stresses (WSS) on the leaflet surfaces are considered to be strongly related with the initiation and progression of calcification. Aim: To investigate the effect of altered hemodynamics on the valve leaflet calcification, and to understand the role of WSS patterns in the progression of the aortic valve diseases. Methods: We investigate the hemodynamics of aortic valves using computational modeling. Fluid-structure interaction approach is employed to accurately determine the complex dynamic motion of valve leaflets. A 3D patient-specific aortic valve model is generated. Using finite element modeling, blood flow velocities, pressures, and WSS values are determined within the entire model, employing numerical techniques to obtain the characteristics of altered hemodynamics and spatial WSS patterns. Results: In case of calcification, WSS values are increased at both surfaces of the leaflets. On the ventricularis surface, there is a spatially-regular WSS distribution, which gradually increase from the leaflet attachment region to the leaflet tip. However, a spatially-complex WSS distribution is observed on the aortic leaflet surface. Conclusion: Relatively low WSS levels and spatiallycomplex WSS patterns on the aortic leaflet surface are observed as potential risk factors for the initiation and progression of aortic valve calcification.

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.

Background: Hemodynamics, forces from the flowing blood in the heart, is a major epigenetic factor for heart development. Disturbed hemodynamics were shown to induce cardiac malformations in the embryonic heart. Clinically relevant congenital heart defects (CHDs) can be introduced surgically in the lab by disturbing the hemodynamics, like Hypoplastic left heart syndrome (HLHS), characterized by underdeveloped left ventricle is underdeveloped. Left atrial ligation (LAL) on chick embryo is an experimental technique to produce a HLHS-like phenotype. Aims: To reveal mechanobiological mechanisms associated with disturbed hemodynamics that influence the progression of left ventricular hypoplasia using chick embryo model. We also introduce a new technique which we called right atrial ligation (RAL), to examine effect of flow disturbance in right heart. Methods: We combined multiple novel techniques in this research: Heart function was assessed via Echocardiography. Computational fluid dynamics (CFD) analysis was adapted for detailed hemodynamics assessment, such as wall shear stress and blood flow patterns. Heart morphology was assessed by histology, and micro-CT. Results: Echocardiography and CFD analysis showed flow and WSS levels decreased for the flow constricted side resulting in the flow diversion to the opposite side: LAL diverted flow to right side and RAL to left side. This disturbance resulted in underdevelopment of left heart (valve and ventricle) in LAL and underdevelopment of right heart in RAL, revealed with histology and micro-CT. Left side was affected more compared to right side, demonstrating higher plasticity in left heart. Conclusion: This study indicates the critical importance of altered inflow hemodynamics in cardiac development specifically valve and ventricle development. Our comprehensive approach can be used to predict the initiation and growth of congenital heart defects.

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.

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 .

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 600Hz. 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. (C) 2017 Acoustical Society of America.

Constricted flow in a thin cylindrical shell with an idealized blunt constriction is modeled using ADINA. Highly disturbed recirculation region is observed at the constriction exit where pressure fluctuations and consequential vessel wall vibrations display broadband spectral content over a range of several hundred Hz. Maximum dynamic pressure and vibration amplitudes are observed around the reattachment point and they gradually decrease along downstream of flow. Results obtained by numerical simulations are compared with relevant studies in the literature and are in good agreement in terms of general spectral behavior. However, the amplitudes were significantly lower as compared to experimental results.

Arterial stenosis is a form of cardiovascular disease which leads to highest rate of fatalities worldwide. When stenosis is present in arteries feeding the heart, it leads to heart attack and often sudden death. If occlusion is present in arteries feeding brain, it causes stroke and rapid loss of brain functions. Arterial disease is usually not confined to critical organs such as the heart and the brain but observed throughout the peripheral cardiovascular system. Acoustic radiation due to stenosis propagates through soft tissues and reaches to skin surface. Therefore, these signals detected on skin surface may provide valuable information for diagnostic purposes. In this study, effects of acoustic radiation on skin surface due to a stenosis are investigated. Human upper arm is modeled using commercial finite element software ADINA. Realistic geometries and soft tissue mechanical properties are employed. Acoustic pressure distribution due to constriction is modeled using related studies in literature and applied on inner surface of blood vessel. Harmonic analysis is performed for upper arm and pressure distribution on skin surface is obtained. It is observed that increasing level of stenosis leads to an increase in pressure amplitudes on skin surface where the region which is closest to the constricted artery has the highest pressure amplitudes.