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Abstract Atherosclerosis causes blockages to the main arteries such as the aorta preventing blood flow from delivering oxygen to the organs. Non-invasive diagnosis of these blockages is difficult, particularly in primary healthcare. In this paper, the effect of arterial blockage development and growth is investigated at the descending aorta on some possible non-invasive assessment parameters including the blood pressure waveform, wall shear stress (WSS), time-average WSS (TAWSS) and the oscillation shear index (OSI). Blockage severity growth is introduced in a simulation model as 25%, 35%, 50% and 65% stenosis at the descending aorta based on specific healthy control aorta data clinically obtained. A 3D aorta model with invasive pulsatile waveforms (blood flow and pressure) is used in the CFD simulation. Blockage severity is assessed by using blood pressure measurements at the left subclavian artery. An arterial blockage growth more than 35% of the lumen diameter significantly affects the pressure. A strong correlation is also observed between the ascending aorta pressure values, pressure at the left subclavian artery and the relative residence time (RRT). An increase of RRT downstream from the stenosis indicates a 35% stenosis at the descending aorta which results in high systolic and diastolic pressure readings. The findings of this study could be further extended by transferring the waveform reading from the left subclavian artery to the brachial artery. Graphical abstract

In this study, the biomechanical role of intraluminal thrombus (ILT) in an abdominal aortic aneurysm (AAA) is investigated. The implications of ILT in AAA are controversial in literature. Previous studies have demonstrated that ILT provides a biomechanical advantage by decreasing wall stress, whereas other studies have associated ILT with inhibiting oxygen transport and inducing aortic wall weakening. Therefore, we sought to explore the connection between ILT, mechanical stresses, and oxygen flow in different geometries of patient-specific aneurysms with varying ILT morphologies. The objective is to investigate the extent to which ILT influences the prediction of aneurysmal wall stresses that are associated with rupture, as well as oxygen concentrations to measure tissue oxygen deprivation. Three patient-specific AAA geometries are considered, and two models, one with ILT and one without ILT, are created for each patient to assess the effect of ILT presence. A fluid-structure interaction approach is used to couple the blood flow, wall deformation, and oxygen mass transport. Results are presented for hemodynamics patterns, wall stress measures, and oxygen metrics within the arterial wall. While ILT is found to reduce wall stress, simulations confirm that ILT decreases oxygen transport within the tissue significantly, leading to wall hypoxia.

A comprehensive computational study is performed to investigate the effectiveness of vortex generators (VGs) applied to mechanical bi-leaflet heart valves. Co-rotating and counter-rotating VG configurations are compared to a control valve without VGs. Detailed flow fields are obtained and used to elucidate the underlying flow physics. It was found that VGs reduce flow separation over the leaflets and hence reduce the Reynolds shear stress (RSS) in the vicinity regions of heart valve. The co-rotating VG configuration demonstrates a better performance compared with the counter-rotating configuration in terms of the RSS, turbulent kinetic energy production and velocity distributions, especially in the peripheral jet flows. The fraction of blood damage in the co-rotating configuration shows a 4.7% reduction in comparison to the control case, while a 3.7% increase is observed in the counter-rotating configuration. The passive flow control technique of applying co-rotating VG illustrates a great potential to help mitigate the hemodynamic factors leading to potential blood damage risk.

INTRODUCTION: A comparative analysis between intravascular guidewire-obtained and computational fluid dynamic (CFD) flow velocity and pressure data using simplified carotid stenosis models was performed. This information was used to evaluate the viability of using guidewire pressure data to provide inlet conditions for CFD flow, and to study the relationship between stenotic length and hemodynamic behavior. METHODS: Carotid stenosis models differing in diameter and length were prepared and connected to a vascular pulsatile flow simulator. Time-dependent flow velocity and pressure measurements were taken by microcatheter guidewires and compared with CFD data. RESULTS: Guidewire and CFD-generated pressure profiles matched closely in all measurement locations. The guidewire was unable to reliably measure flow velocity at areas associated with higher CFD flow velocities (r = 0.92). CFD results showed that an increased length of stenosis generated expansive regions of elevated wall shear stress (WSS) within and distal to the stenosis. Low WSS was found immediately outside the stenosis outlet. An increase in stenotic length produced higher flow velocities with minimal lengthening of the distal high velocity flow jet due to faster dissipation of translational kinetic energy through turbulence. CONCLUSION: We found the accuracy of guidewire-obtained velocity measurements is limited to regions unaffected by disturbed flow. WSS and turbulence behavior distal to the stenosis may be important markers to evaluate the severity of atherosclerotic progression as a function of stenotic length.

Computer modelling of blood vessels based on biomedical imaging provides important hemodynamic and biomechanical information for vascular disease studies and diagnosis. However due to lacking well-defined physiological blood flow profiles, the accuracy of the simulation results is often not guaranteed. Flow velocity profiles of a specific cross section of a blood vessel were obtained by in vivo Doppler intravascular optical coherence tomography (IVOCT) lately. However due to the influence of the catheter, the velocity profile imaged by IVOCT can't be applied to simulation directly.A simulation-experiment combined method to determine the inlet flow boundary based on in vivo porcine carotid Doppler IVOCT imaging is proposed. A single conduit carotid model was created from the 3D IVOCT structural images using an image processing-computer aided design combined method.With both high- resolution arterial model and near physiological blood flow profile, stress analysis by fluid-structure interaction and computational fluid dynamics were performed. The influence of the catheter to the wall shear stress, the hemodynamics and the stresses of the carotid wall under the measured inlet flow and various outlet pressure boundary conditions, are analyzed.This study provides a solution to the difficulty of getting inlet flow boundary for numerical simulation of arteries. It paves the way for developing IVOCT based vascular stress analysis and imaging methods for the studies and diagnosis of vascular diseases.

Aortic stenosis is a common cardiac condition that impacts the aorta’s hemodynamics downstream of the affected valve. We sought to better understand how non-uniform stiffening of a stenotic aortic valve would affect the wall shear stress (WSS) experienced by the walls of the aorta and the residence time near the valve. Several experimental configurations were created by individually stiffening leaflets of a polymer aortic valve. These configurations were mounted inside an in vitro experimental setup. Digital particle image velocimetry (DPIV) was used to measure velocity profiles inside a model aorta. The DPIV results were used to estimate the WSS and residence time. Our analysis suggests that leaflet asymmetry greatly affects the amount of WSS by vectoring the systolic jet and stiffened leaflets have an increased residence time. This study indicates that valve leaflets with different stiffness conditions can have a more significant impact on wall shear stress than stenosis caused by the uniform increase in all three leaflets (and the subsequent increased systolic velocity) alone. This finding is promising for creating customizable (patient-specific) prosthetic heart valves tailored to individual patients.

The blood-brain barrier (BBB) greatly restricts the entry of biological and engineered therapeutic molecules into the brain. Due to challenges in translating results from animal models to the clinic, relevant in vitro human BBB models are needed to assess pathophysiological molecular transport mechanisms and enable the design of targeted therapies for neurological disorders. This protocol describes an in vitro model of the human BBB self-assembled within microfluidic devices from stem-cell-derived or primary brain endothelial cells, and primary brain pericytes and astrocytes. This protocol requires 1.5 d for device fabrication, 7 d for device culture and up to 5 d for downstream imaging, protein and gene expression analyses. Methodologies to measure the permeability of any molecule in the BBB model, which take 30 min per device, are also included. Compared with standard 2D assays, the BBB model features relevant cellular organization and morphological characteristics, as well as values of molecular permeability within the range expected in vivo. These properties, coupled with a functional brain endothelial expression profile and the capability to easily test several repeats with low reagent consumption, make this BBB model highly suitable for widespread use in academic and industrial laboratories.

PURPOSE Leaflet thrombosis is a significant adverse event after transcatheter aortic valve (TAV) replacement (TAVR). The purpose of our study was to present a semi-empirical, mathematical model that links patient-specific anatomic, valve, and flow parameters to predict likelihood of leaflet thrombosis. METHODS The two main energy sources of neo-sinus (NS) washout after TAVR include the jet flow downstream of the TAV and NS geometric change in volume due to the leaflets opening and closing. Both are highly dependent on patient anatomic and hemodynamic factors. As rotation of blood flow is prevalent in both the sinus of Valsalva and then the NS, we adopted the vorticity flux or circulation (Г) as a metric quantifying overall washout. Leaflet thrombus volumes were segmented based on hypo-attenuating leaflet thickening (HALT) in post-TAVR patient's gated computed tomography. Г was assessed using dimensional scaling as well as computational fluid dynamics (CFD) respectively and correlated to the thrombosis volumes using sensitivity and specificity analysis. RESULTS Г in the NS, that accounted for patient flow and anatomic conditions derived from scaling arguments significantly better predicted the occurrence of leaflet thrombus than CFD derived measures such as stasis volumes or wall shear stress. Given results from the six patient datasets considered herein, a threshold Г value of 28.0 yielded a sensitivity and specificity of 100% where patients with Gamma < 28 developed valve thrombosis. A 10% error in measurements of all variables can bring the sensitivity specificity down to 87%. CONCLUSION A predictive model relating likelihood of valve thrombosis using Г in the NS was developed with promising sensitivity and specificity. With further studies and improvements, this predictive technology may lead to alerting physicians on the risk for thrombus formation following TAVR.

The human aorta is a high-risk area for vascular diseases, which are commonly restored by thoracic endovascular aortic repair. In this paper, we report a promising shear-activated targeted nanoparticle drug delivery strategy to assist in the treatment of coarctation of the aorta and aortic aneurysm. Idealized three-dimensional geometric models of coarctation of the aorta and aortic aneurysm are designed, respectively. The unique hemodynamic environment of the diseased aorta is used to improve nanoparticle drug delivery. Micro-carriers with nanoparticle drugs would be targeting activated to release nanoparticle drugs by local abnormal shear stress rate (SSR). Coarctation of the aorta provides a high SSR hemodynamic environment, while the aortic aneurysm is exposed to low SSR. We propose a method to calculate the SSR thresholds for the diseased aorta. Results show that the upstream near-wall area of the diseased location is an ideal injection location for the micro-carriers, which could be activated by the abnormal SSR. Released nanoparticle drugs would be successfully targeted delivered to the aortic diseased wall. Besides, the high diffusivity of the micro-carriers and nanoparticle drugs has a significant impact on the surface drug concentrations of the diseased aortic walls, especially for aortic aneurysms. This study preliminary demonstrates the feasibility of shear-activated targeted nanoparticle drug delivery in the treatment of aortic diseases and provides a theoretical basis for developing the drug delivery system and novel therapy., 22 pages, 7 figures

Bicuspid aortic valve (BAV) is the most common congenital heart disease. Calcific aortic valve disease (CAVD) accounts for the majority of aortic stenosis (AS) cases. Half of the patients diagnosed with AS have a BAV, which has an accelerated progression rate. This study aims to develop a computational modeling approach of both the calcification progression in BAV, and its biomechanical response incorporating fluid-structure interaction (FSI) simulations during the disease progression. The calcification is patient-specifically reconstructed from Micro-CT images of excised calcified BAV leaflets, and processed with a novel reverse calcification technique that predicts prior states of CAVD using a density-based criterion, resulting in a multilayered calcified structure. Four progressive multilayered calcified BAV models were generated: healthy, mild, moderate, and severe, and were modeled by FSI simulations during the full cardiac cycle. A valve apparatus model, composed of the excised calcified BAV leaflets, was tested in an in-vitro pulse duplicator, to validate the severe model. The healthy model was validated against echocardiography scans. Progressive AS was characterized by higher systolic jet flow velocities (2.08, 2.3, 3.37, and 3.85 m s(−1)), which induced intense vortices surrounding the jet, coupled with irregular recirculation backflow patterns that elevated viscous shear stresses on the leaflets. This study shed light on the fluid-structure mechanism that drives CAVD progression in BAV patients.

The objective is to know the stress distributions in the arterial walls under residual stresses based on two-layer model. Human common carotid arteries were analysed to show stress distributions at physiological and supraphysiological intraluminal pressures. The analyses for the loaded states were performed with stretch ratios with reference to a Riemannian stress-free configuration which is a 3D non-Euclidean manifold due to the nonzero Riemann curvature tensor. The experimental data obtained by other literature were used for the common carotid arteries to analyse the stretch and stress distributions in the arterial wall although kinematics is different from the literature. The stretches and stresses were calculated for the unloaded state, i.e. the residual stretches and stresses. And those at the axial stretch ratio 1.1 with reference to the unloaded state were calculated at the intraluminal pressures 16, 50, and 100 kPa. The stresses increased from the inner surface to the outer surface at all pressures analysed. These results suggest that in the human arteries the mechanical loads are mainly supported with the adventitia even though the media and intima play an important role to control of physiological functions.

Coronary flow is affected by evolving events such as atherosclerotic plaque formation, rupture, and thrombosis, resulting in myocardial ischemia and infarction. Highly resolved 3D hemodynamic data at the stenosis is essential to model shear-sensitive thrombotic events in coronary artery disease. We developed a hybrid 1D–3D simulation framework to compute patient-specific coronary hemodynamics efficiently. A 1D model of the coronary flow is coupled to an image-based 3D model of the region of interest. This framework affords the advantages of reduced-order modeling, decreasing the global computational cost, without sacrificing the accuracy of the quantities of interest. We validated our 1D–3D model against full 3D coronary simulations in healthy and diseased conditions. Our results showed good agreement between the 3D and the 1D–3D models while reducing the computational cost by 40-fold compared to the 3D simulation. The 1D–3D model predicted left/right coronary flow distribution within 3% and provided an accurate estimation of fractional flow reserve and wall shear stress distribution at the stenosis comparable to the 3D simulation. Savings in computational cost may be significant in situations with changing geometry, such as growing thrombosis. Also, this approach would allow quantifying the time-dependent effect of thrombotic growth and occlusion on the global coronary circulation.

The effect of repair techniques on the biomechanics of the aorta is poorly understood, resulting in significant levels of postoperative complications for patients worldwide. This study presents a computational analysis of the influence of Nitinol-based devices on the biomechanical performance of a healthy patient-specific human aorta. Simulations reveal that Nitinol stent-grafts stretch the artery wall so that collagen is stretched to a straightened high-stiffness configuration. The high-compliance regime (HCR) associated with low diastolic lumen pressure is eliminated, and the artery operates in a low-compliance regime (LCR) throughout the entire cardiac cycle. The slope of the lumen pressure–area curve for the LCR post-implantation is almost identical to that of the native vessel during systole. This negligible change from the native LCR slope occurs because the stent-graft increases its diameter from the crimped configuration during deployment so that it reaches a low-stiffness unloading plateau. The effective radial stiffness of the implant along this unloading plateau is negligible compared to the stiffness of the artery wall. Provided the Nitinol device unloads sufficiently during deployment to the unloading plateau, the degree of oversizing has a negligible effect on the pressure–area response of the vessel, as each device exerts approximately the same radial force, the slope of which is negligible compared to the LCR slope of the native artery. We show that 10% oversizing based on the observed diastolic diameter in the mid descending thoracic aorta results in a complete loss of contact between the device and the wall during systole, which could lead to an endoleak and stent migration. 20% oversizing reaches the Dacron enforced area limit (DEAL) during the pulse pressure and results in an effective zero-compliance in the later portion of systole.

Recent computational fluid dynamics (CFD) studies have demonstrated the concurrence of atherosclerotic changes in regions exposed to prolonged blood residence. In this proof-of-concept study, we investigated a small but homogeneous cohort of large, cavernous carotid aneurysms (CCAs) to establish the clinical feasibility of CFD analysis in treatment planning, based on the association between pathophysiology and hemodynamics. This study included 15 patients with individual large CCAs. We identified calcifications, which indicated atherosclerotic changes, using the masking data of digital subtraction angiography. We conducted a CFD simulation under patient-specific inlet flow rates measured using magnetic resonance (MR) velocimetry. In the post-CFD analysis, we calculated the blood residence time ( $$\xi$$ ) and segmented the surface exposed to blood residence time over 1 s ( $${S}_{\xi >1}$$ ). We measured the decrease in volume after flow diversion using the original time-of-flight MR angiography data. Calcifications were observed in the region with $${S}_{\xi >1}$$ . In addition, the ratio of $${S}_{\xi >1}$$ to the surface of the aneurysmal domain exhibited a negative relationship with the rate of volume reduction at the 6- and 12-month follow-ups. Post-CFD visualization demonstrated that intra-aneurysmal swirling flow prolonged blood residence time under the condition of a small inlet flow rate, when compared to the aneurysmal volume. The results of this study suggest the usefulness of CFD analysis for the diagnosis of atherosclerotic changes in large CCAs that may affect the therapeutic response after flow diversion.

PURPOSE: Mock circulatory loops (MCLs) can reproducibly generate physiologically relevant pressures and flows for cardiovascular device testing. These systems have been extensively used to characterize the performance of therapeutic cardiac devices, but historically MCLs have had limited use for assessing patient monitoring systems. Here, we adapted an MCL to include peripheral components and evaluated its utility for qualitative and quantitative benchtop testing of hemodynamic monitoring devices. METHODS: An MCL was designed to simulate three physiological hemodynamic states: normovolemia, cardiogenic shock, and hyperdynamic circulation. The system was assessed for stability in pressure and flow values over time, repeatability, waveform morphology, and systemic-peripheral pressure relationships. RESULTS: For each condition, cardiac output was controlled to the nearest 0.2 L/min, and flow rate and mean arterial pressure remained stable and repeatable over a 60-second period (n=5, standard deviation of ± 0.1 L/min and ± 0.84 mmHg, respectively). Transfer function analyses showed that the system-peripheral relationships could be adequately manipulated. The results from this MCL were comparable to those from other published MCLs and computational simulations. However, resolving current limitations of the system would further improve its utility. Three pulse contour analysis algorithms were applied to the pressure and flow data from the MCL to demonstrate the potential role of MCLs in characterizing hemodynamic monitoring systems. CONCLUSION: Overall, the development of robust analysis methods in conjunction with modified MCLs can expand device testing applications to hemodynamic monitoring systems. Properly validated MCLs can create a stable and reproducible environment for testing patient monitoring systems over their entire operating ranges prior to clinical use.

The formation and progress of cerebral aneurysm is highly associated with hemodynamic factors and blood flow feature. In this study, comprehensive efforts are done to investigate the blood hemodynamic effects on the creation and growth of the Internal Carotid Artery. The computational fluid dynamic method is used for the visualization of the bloodstream inside the aneurysm. Transitional, non-Newtonian and incompressible conditions are considered for solving the Navier–Stokes equation to achieve the high-risk region on the aneurysm wall. OSI and WSS of the aneurysm wall are compared within different blood flow stages. The effects of blood viscosity and coiling treatment on these factors are presented in this work. Our study shows that in male patients (HCT = 0.45), changing the porosity of coiling from 0.89 with 0.79 would decreases maximum OSI up to 75% (in maximum acceleration). However, this effect is limited to about 45% for female patients (HCT = 0.35).

Personalized models of cardiac electrophysiology (EP) that match clinical observation with high fidelity, referred to as cardiac digital twins (CDTs), show promise as a tool for tailoring cardiac precision therapies. Building CDTs of cardiac EP relies on the ability of models to replicate the ventricular activation sequence under a broad range of conditions. Of pivotal importance is the His–Purkinje system (HPS) within the ventricles. Workflows for the generation and incorporation of HPS models are needed for use in cardiac digital twinning pipelines that aim to minimize the misfit between model predictions and clinical data such as the 12 lead electrocardiogram (ECG). We thus develop an automated two stage approach for HPS personalization. A fascicular-based model is first introduced that modulates the endocardial Purkinje network. Only emergent features of sites of earliest activation within the ventricular myocardium and a fast-conducting sub-endocardial layer are accounted for. It is then replaced by a topologically realistic Purkinje-based representation of the HPS. Feasibility of the approach is demonstrated. Equivalence between both HPS model representations is investigated by comparing activation patterns and 12 lead ECGs under both sinus rhythm and right-ventricular apical pacing. Predominant ECG morphology is preserved by both HPS models under sinus conditions, but elucidates differences during pacing. Supplementary Information The online version contains supplementary material available at 10.1007/s10439-021-02825-9.

Thoracic endovascular aortic repair (TEVAR) has been accepted as the mainstream treatment for type B aortic dissection, but post-TEVAR biomechanical-related complications are still a major drawback. Unfortunately, the stent-graft (SG) configuration after implantation and biomechanical interactions between the SG and local aorta are usually unknown prior to a TEVAR procedure. The ability to obtain such information via personalised computational simulation would greatly assist clinicians in pre-surgical planning. In this study, a virtual SG deployment simulation framework was developed for the treatment for a complicated aortic dissection case. It incorporates patient-specific anatomical information based on pre-TEVAR CT angiographic images, details of the SG design and the mechanical properties of the stent wire, graft and dissected aorta. Hyperelastic material parameters for the aortic wall were determined based on uniaxial tensile testing performed on aortic tissue samples taken from type B aortic dissection patients. Pre-stress conditions of the aortic wall and the action of blood pressure were also accounted for. The simulated post-TEVAR configuration was compared with follow-up CT scans, demonstrating good agreement with mean deviations of 5.8% in local open area and 4.6 mm in stent strut position. Deployment of the SG increased the maximum principal stress by 24.30 kPa in the narrowed true lumen but reduced the stress by 31.38 kPa in the entry tear region where there was an aneurysmal expansion. Comparisons of simulation results with different levels of model complexity suggested that pre-stress of the aortic wall and blood pressure inside the SG should be included in order to accurately predict the deformation of the deployed SG.

Intra-saccular devices (ID), developed for the treatment of bifurcation aneurysms, offer new alternatives for treating complex terminal and bifurcation aneurysms. In this work, a complete workflow going from medical images to post-treatment CFD analysis is described and used in the assessment of a concrete clinical problem. Two different intra-saccular device sizes were virtually implanted in 3D models of the patient vasculature using the ID-Fit method. After deployment, the local porosity at the closed end of the device in contact with the blood flow was computed. This porosity was then used to produce a CFD porous medium model of the device. Velocities and wall shear stress were assessed for each model. Six patients treated with intra-saccular devices were included in this work. For each case, 2 different device sizes were virtually implanted and 3 CFD simulations were performed: after deployment simulation with each size and before deployment simulation (untreated). A visible reduction in velocities was observed after device implantation. Velocity and WSS reduction was statistically significant (K–S statistics, $$p

We address a mathematical model for oxygen transfer in the microcirculation. The model includes blood flow and hematocrit transport coupled with the interstitial flow, oxygen transport in the blood and the tissue, including capillary-tissue exchange effects. Moreover, the model is suited to handle arbitrarily complex vascular geometries. The purpose of this study is the validation of the model with respect to classical solutions and the further demonstration of its adequacy to describe the heterogeneity of oxygenation in the tissue microenvironment. Finally, we discuss the importance of these effects in the treatment of cancer using radiotherapy.

Flow-sensitive four-dimensional Cardiovascular Magnetic Resonance Imaging (4D Flow CMR) has increasingly been utilised to characterise patients' blood flow, in association with patiens' state of health and disease, even though spatial and temporal resolutions still constitute a limit. Computational fluid dynamics (CFD) is a powerful tool that could expand these information and, if integrated with experimentally-obtained velocity fields, would enable to derive a large variety of the flow descriptors of interest. However, the accuracy of the flow parameters is highly influenced by the quality of the input data such as the anatomical model and boundary conditions typically derived from medical images including 4D Flow CMR. We previously proposed a novel approach in which 4D Flow CMR and CFD velocity fields are integrated to obtain an Enhanced 4D Flow CMR (EMRI), allowing to overcome the spatial-resolution limitation of 4D Flow CMR, and enable an accurate quantification of flow. In this paper, the proposed approach is validated in a U bend channel, an idealised model of the human aortic arch. The flow patterns were studied with 4D Flow CMR, CFD and EMRI, and compared with high resolution 2D PIV experiments obtained in pulsatile conditions. The main strengths and limitations of 4D Flow CMR and CFD were illustrated by exploiting the accuracy of PIV by comparing against PIV velocity fields. EMRI flow patterns showed a better qualitative and quantitative agreement with PIV results than the other techniques. EMRI enables to overcome the experimental limitations of MRI-based velocity measurements and the modelling simplifications of CFD, allowing an accurate prediction of complex flow patterns observed experimentally, while satisfying mass and momentum balance equations.

Patients receiving transcatheter aortic valve replacement (TAVR) can benefit from continuous, longitudinal monitoring of valve prosthesis to prevent leaflet thrombosis-related complications. We present a computational proof-of-concept study of a novel, non-invasive and non-toxic valve monitoring technique for TAVs which uses pressure measurements from microsensors embedded on the valve stent. We perform a data-driven analysis to determine the signal processing and machine learning required to detect reduced mobility in individual leaflets. We use direct numerical simulations to describe hemodynamic differences in transvalvular flow in ascending aorta models with healthy and stenotic valves. A Cartesian-grid flow solver and a reduced-order valve model simulate the complex dynamics of blood flow and leaflet motion, respectively. The two-way fluid-structure interaction coupling is achieved using a sharp interface immersed boundary method. From a dataset of 21 simulations, we show leaflets with reduced mobility result in large, asymmetric pressure fluctuations in their vicinity, particularly in the region extending from the aortic sinus to the sino-tubular junction (STJ). We train a linear classifier algorithm by correlating sinus and STJ pressure measurements on the stent surface to individual leaflet status. The algorithm was shown to have >90% accuracy for prospective detection of individual leaflet dysfunction. We demonstrate that using only two discrete pressure measurements, per leaflet, on the TAV stent, individual leaflet status can be accurately predicted. Such a sensorized TAV system could enable safe and inexpensive detection of prosthetic valve dysfunction.

This paper aims to investigate detailed mechanical interactions between the pulmonary haemodynamics and left heart function in pathophysiological situations (e.g. atrial fibrillation and acute mitral regurgitation). This is achieved by developing a complex computational framework for a coupled pulmonary circulation, left atrium and mitral valve model. The left atrium and mitral valve are modelled with physiologically realistic three-dimensional geometries, fibre-reinforced hyperelastic materials and fluid–structure interaction, and the pulmonary vessels are modelled as one-dimensional network ended with structured trees, with specified vessel geometries and wall material properties. This new coupled model reveals some interesting results which could be of diagnostic values. For example, the wave propagation through the pulmonary vasculature can lead to different arrival times for the second systolic flow wave (S2 wave) among the pulmonary veins, forming vortex rings inside the left atrium. In the case of acute mitral regurgitation, the left atrium experiences an increased energy dissipation and pressure elevation. The pulmonary veins can experience increased wave intensities, reversal flow during systole and increased early-diastolic flow wave (D wave), which in turn causes an additional flow wave across the mitral valve (L wave), as well as a reversal flow at the left atrial appendage orifice. In the case of atrial fibrillation, we show that the loss of active contraction is associated with a slower flow inside the left atrial appendage and disappearances of the late-diastole atrial reversal wave (AR wave) and the first systolic wave (S1 wave) in pulmonary veins. The haemodynamic changes along the pulmonary vessel trees on different scales from microscopic vessels to the main pulmonary artery can all be captured in this model. The work promises a potential in quantifying disease progression and medical treatments of various pulmonary diseases such as the pulmonary hypertension due to a left heart dysfunction.

Cardiovascular diseases have consistently been one of the leading causes of mortality, despite investigations by many scientists and clinicians. Animal models are versatile platforms to illustrate various mechanisms of different diseases, but are lacking in accurately portraying cardiovascular disease phenotypes. The advent of human pluripotent stem cells (PSCs) has led to much development in the construction of cardiovascular disease models. In this review, we provide a brief overview of the history and utilization of PSCs for cardiovascular precision medicine, including disease modeling, drug screening, and gene editing, and elaborate on the current updated research status of patient-specific induced pluripotent stem cell (iPSC)-based disease models for cardiac channelopathies, cardiomyopathies, and other cardiovascular diseases. Furthermore, we highlight the development of novel human iPSC-derived engineered heart tissues for cardiovascular disease modeling. Finally, we put forward our own views on the existing advantages and difficulties for moving forward in this field.

Despite numerous experimental observations regarding heart failure with preserved ejection fraction (HFpEF), which is characterized mainly by left ventricular hypertrophy and a left ventricular ejection fraction over 50%, myocardial dynamics under HFpEF have not yet been fully clarified, particularly regarding the relationship between myocardial strain distribution and myocardial work. To address this issue, we numerically investigated radial distribution of myocardial strain during a cardiac cycle with fixed internal volume at the end of the systolic and diastolic phases under different mechanical conditions, such as those involving myocardial thickness and elasticity of myocardial fibers. The myocardium was a modeled as a visco-hyperelastic continuous material. This model was taken into account that active contractile stress along the myocardial fiber direction depends on membrane potential change. Our numerical results showed that both radial and circumferential strains decreased as wall thickness increased, which reflected cardiac hypertrophy, but that myocardial work became larger than that observed with thin ventricular walls. Further, the change in left ventricular diastolic internal pressure caused circumferential strain, while fiber stiffness contributed to radial strain. Since peak circumferential strain was well estimated by the maximum difference between total internal and myocardial volumes, measuring the epicardial contraction rate should be helpful in understanding patients with HFpEF.

The vascular network is established and maintained through the processes of vasculogenesis and angiogenesis, which are tightly regulated during embryonic and postnatal life. The formation of a functional vasculature requires critical cellular mechanisms, such as cell migration, proliferation and adhesion, which are dependent on the activity of small Rho GTPases, controlled in part by the dedicator of cytokinesis (DOCK) protein family. Whilst the majority of DOCK proteins are associated with neuronal development, a growing body of evidence has indicated that members of the DOCK family may have key functions in the control of vasculogenic and angiogenic processes. This is supported by the involvement of several angiogenic signalling pathways, including chemokine receptor type 4 (CXCR4), vascular endothelial growth factor (VEGF) and phosphatidylinositol 3-kinase (PI3K), in the regulation of specific DOCK proteins. This review summarises recent progress in understanding the respective roles of DOCK family proteins during vascular development. We focus on existing in vivo and in vitro models and known human disease phenotypes and highlight potential mechanisms of DOCK protein dysfunction in the pathogenesis of vascular disease.

In the last decade, many computational models have been developed to describe the transport of drug eluted from stents and the subsequent uptake into arterial tissue. Each of these models has its own set of limitations: for example, models typically employ simplified stent and arterial geometries, some models assume a homogeneous arterial wall, and others neglect the influence of blood flow and plasma filtration on the drug transport process. In this study, we focus on two common limitations. Specifically, we provide a comprehensive investigation of the influence of arterial curvature and plaque composition on drug transport in the arterial wall following drug-eluting stent implantation. The arterial wall is considered as a three-layered structure including the subendothelial space, the media and the adventitia, with porous membranes separating them (endothelium, internal and external elastic lamina). Blood flow is modelled by the Navier–Stokes equations, while Darcy’s law is used to calculate plasma filtration through the porous layers. Our findings demonstrate that arterial curvature and plaque composition have important influences on the spatiotemporal distribution of drug, with potential implications in terms of effectiveness of the treatment. Since the majority of computational models tend to neglect these features, these models are likely to be under- or over-estimating drug uptake and redistribution in arterial tissue.

A pathologically formed blood clot or thrombus is central to major cardiovascular diseases like heart attack and stroke. Detailed quantitative evaluation of flow and flow-mediated transport processes in the thrombus neighborhood within large artery hemodynamics is crucial for understanding disease progression and assessing treatment efficacy. This, however, remains a challenging task owing to the complexity of pulsatile viscous flow interactions with arbitrary shape and heterogeneous microstructure of realistic thrombi. Here, we address this challenge by conducting a systematic parametric simulation based study on characterizing unsteady hemodynamics and flow-mediated transport in the neighborhood of an arterial thrombus. We use a hybrid particle-continuum based finite element approach to handle arbitrary thrombus shape and microstructural variations. Results from a cohort of 50 different unsteady flow scenarios are presented, including unsteady vortical structures, pressure-gradient across the thrombus boundary, finite time Lyapunov exponents, and dynamic coherent structures that organize advective transport. We clearly illustrate the combined influence of three key parameters - thrombus shape, microstructure, and extent of wall disease - in terms of: (a) determining hemodynamic features in the thrombus neighborhood; and (b) governing the balance between advection, permeation, and diffusion to regulate transport processes in the thrombus neighborhood.

[EN] Tissue-level biomechanical properties and function derive from underlying cell signaling, which regulates mass deposition, organization, and removal. Here, we couple two existing modeling frameworks to capture associated multiscale interactions¿one for vessel-level growth and remodeling and one for cell-level signaling¿and illustrate utility by simulating aortic remodeling. At the vessel level, we employ a constrained mixture model describing turnover of individual wall constituents (elastin, intramural cells, and collagen), which has proven useful in predicting diverse adaptations as well as disease progression using phenomenological constitutive relations. Nevertheless, we now seek an improved mechanistic understanding of these processes; we replace phenomenological relations in the mixture model with a logic-based signaling model, which yields a system of ordinary differential equations predicting changes in collagen synthesis, matrix metalloproteinases, and cell proliferation in response to altered intramural stress, wall shear stress, and exogenous angiotensin II. This coupled approach promises improved understanding of the role of cell signaling in achieving tissue homeostasis and allows us to model feedback between vessel mechanics and cell signaling. We verify our model predictions against data from the hypertensive murine infrarenal abdominal aorta as well as results from validated phenomenological models, and consider effects of noisy signaling and heterogeneous cell populations., This work was supported by Grants from the US NIH (R01 HL105297, P01 HL134605, R01 HL139796, U01 HL142518, R01 HL146723)

The most common type of cardiac arrhythmia is atrial fibrillation (AF), which is characterised by irregular and ineffective atrial contraction. This behaviour results into the formation of thrombi, mainly in the left atrial appendage (LAA), responsible for thromboembolic events. Very different approaches are considered as therapy for AF patients. Therefore, it is necessary to yield insight into the flow physics of thrombi formation to determine which is the most appropriate strategy in each case. Computational Fluid Dynamics (CFD) has proven successful in getting a better understanding of the thrombosis phenomenon, but it still requires validation by means of accurate flow field in vivo atrial measurements. As an alternative, in this paper it is proposed an in vitro flow validation, consisting in an idealised model that captures the main flow features observed in the human LA which, once combined with Particle Image Velocimetry (PIV) measurements, provides readily accessible, easy to emulate, detailed velocity fields. These results have been used to validate our laminar and Large Eddy Simulation (LES) simulations. Besides, we have run a parametric study of different boundary conditions sets previously employed in the literature. These data can be used as a benchmark for further development of LA CFD models.

Critical aortic stenosis (AS) of the fetal heart causes a drastic change in the cardiac biomechanical environment. Consequently, a substantial proportion of such cases will lead to a single-ventricular birth outcome. However, the biomechanics of the disease is not well understood. To address this, we performed Finite Element (FE) modelling of the healthy fetal left ventricle (LV) based on patient-specific 4D ultrasound imaging, and simulated various disease features observed in clinical fetal AS to understand their biomechanical impact. These features included aortic stenosis, mitral regurgitation (MR) and LV hypertrophy, reduced contractility, and increased myocardial stiffness. AS was found to elevate LV pressures and myocardial stresses, and depending on severity, can drastically decrease stroke volume and myocardial strains. These effects are moderated by MR. AS alone did not lead to MR velocities above 3 m/s unless LV hypertrophy was included, suggesting that hypertrophy may be involved in clinical cases with high MR velocities. LV hypertrophy substantially elevated LV pressure, valve flow velocities and stroke volume, while reducing LV contractility resulted in diminished LV pressure, stroke volume and wall strains. Typical extent of hypertrophy during fetal AS in the clinic, however, led to excessive LV pressure and valve velocity in the FE model, suggesting that reduced contractility is typically associated with hypertrophy. Increased LV passive stiffness, which might represent fibroelastosis, was found to have minimal impact on LV pressures, stroke volume, and wall strain. This suggested that fibroelastosis could be a by-product of the disease progression and does not significantly impede cardiac function. Our study demonstrates that FE modelling is a valuable tool for elucidating the biomechanics of congenital heart disease and can calculate parameters which are difficult to measure, such as intraventricular pressure and myocardial stresses. Electronic supplementary material The online version of this article (10.1007/s10439-020-02683-x) contains supplementary material, which is available to authorized users.

Existing hemodynamic studies on aortic dissection after thoracic endovascular aortic repair (TEVAR) apply geometric simplifications. This study aims to evaluate the necessity of more accurate geometries at the proximal landing zone in computational fluid dynamic (CFD) studies. Three patient-specific 3D aortic dissection models with different geometric accuracies at the proximal landing zone were manually fabricated for CFD simulations: (i) model 1 without the stent graft (SG), (ii) model 2 with the metal stent, and (iii) model 3 with the SG. The flow distribution, flow pattern, and wall shear stress (WSS)-related indicators in these three models were compared. The flow distributions were quite similar for the three models, with a maximum absolute difference of 0.27% at the left suclavian artery (LSA) between models 1 and 3 because of partial coverage. A more chaotic flow pattern was observed at the proximal landing zone in model 3, with significant regional differences in the WSS-related indicator distributions. The upstream and downstream WSS-related indicator distributions were quite similar for the three models. The flow pattern and hemodynamic parameter distributions were affected by the geometric accuracy only in a small region near the proximal landing zone. The flow split was hardly affected by the LSA partial coverage, indicating that the coverage may have slight effects on short-term blood perfusion. However, this conclusion needs to be verified in future studies with larger sample sizes.

Coronary flow induces hemodynamic alterations in the aortic sinus region. The objectives of this study are to: (1) investigate the differences among sinus hemodynamics and leaflet wall shear stresses engendered by the left versus right versus non-coronary flow and (2) correlate respective wall shear stresses with leaflet calcification in patients. A left heart simulator flow loop with a tunable coronary circuit provided physiological coronary flow waveforms corresponding to the left coronary cusp case (LCC), right coronary cusp case (RCC), and non-coronary cusp case (NCC). High spatio-temporal resolution particle image velocimetry was conducted to quantify leaflet wall shear stress and sinus vorticity fields and to measure aortic leaflet tip kinematics. Thirty-one patients with severe calcific aortic valve disease were segmented from CT data for the calcific volumes in their respective left, right, and non-coronary cusps. Leaflet tip position during systole shows the RCC has a wider leaflet opening compared to LCC and NCC. Velocity and vorticity fields combined with leaflet position data show that sinus vorticity is diminished (peak ~ 43 s−1) in the LCC while RCC and NCC maintain high vorticity (~ 1200 and ~ 950 s−1 respectively). WSS magnitudes greater than 0.3 Pa show 20 and 81% greater occurrences in the LCC and RCC respectively compared to NCC. Significant differences [X2 (2, n = 31) = 7.31, p = 0.0258] between the calcification levels in each cusp of the patient population. Coronary flow differences between LCC, RCC, and NCC show significant impact on leaflet kinematics and sinus flow hemodynamics. Clinical data correlations of the coronary flow cases indicate the left coronary cusp has a higher likelihood of calcification compared to the right.

Transcatheter aortic valve (TAV) leaflet thrombosis is a clinical risk with potentially fatal consequences. Studies have identified neo-sinus flow stasis as a cause of leaflet thrombosis. Flow stasis is influenced by the TAV leaflets, which affect the local fluid dynamics in the aortic sinus and neo-sinus. This study evaluated the effects of TAV leaflet features on the neo-sinus flow as a measure of leaflet thrombosis risk. Five TAVs of varied leaflet length and insertion height were tested in a simulator. Hydrodynamics and leaflet kinematics through en-phase imaging were quantified. Velocity fields were assessed using high-speed particle image velocimetry. Regions of flow stasis and particle residence times (PRTs) were quantified. TAVs with shorter leaflet length exhibited larger orifice areas and lower transvalvular pressure gradients. Shorter leaflet length and increased leaflet insertion TAVs additionally exhibited lower neo-sinus PRTs (0.44 ± 0.21 vs 2.83 ± 0.48 cycles, p

An exponential rise in patient data provides an excellent opportunity to improve the existing health care infrastructure. In the present work, a method to enable cardiovascular digital twin is proposed using inverse analysis. Conventionally, accurate analytical solutions for inverse analysis in linear problems have been proposed and used. However, these methods fail or are not efficient for nonlinear systems, such as blood flow in the cardiovascular system (systemic circulation) that involves high degree of nonlinearity. To address this, a methodology for inverse analysis using recurrent neural network for the cardiovascular system is proposed in this work, using a virtual patient database. Blood pressure waveforms in various vessels of the body are inversely calculated with the help of long short-term memory (LSTM) cells by inputting pressure waveforms from three non-invasively accessible blood vessels (carotid, femoral and brachial arteries). The inverse analysis system built this way is applied to the detection of abdominal aortic aneurysm (AAA) and its severity using neural networks.

Purpose: this study aims to quantify the patient-specific hemodynamics of complex conduit routing configurations of coronary artery bypass grafting (CABG) operation which are specifically suitable for off-pump surgeries. Coronary perfusion efficacy and local hemodynamics of multiple left internal mammary artery (LIMA) with sequential and end-to-side anastomosis are investigated. Using a full anatomical model comprised of aortic arch and coronary artery branches the optimum perfusion configuration in multi-vessel coronary artery stenosis is desired. Methodology: two clinically relevant CABG configurations are created using a virtual surgical planning tool where for each configuration set, the stenosis level, anastomosis distance and angle were varied. A non-Newtonian computational fluid dynamics solver in OpenFOAM incorporated with resistance boundary conditions representing the coronary perfusion physiology was developed. The numerical accuracy is verified and results agreed well with a validated commercial cardiovascular flow solver and experiments. For segmental performance analysis, new coronary perfusion indices to quantify deviation from the healthy scenario were introduced. Results: the first simulation configuration set;-a CABG targeting two stenos sites on the left anterior descending artery (LAD), the LIMA graft was capable of 31 mL/min blood supply for all the parametric cases and uphold the healthy LAD perfusion in agreement with the clinical experience. In the second end-to-side anastomosed graft configuration set;-the radial artery graft anastomosed to LIMA, a maximum of 64 mL/min flow rate in LIMA was observed. However, except LAD, the obtuse marginal (OM) and second marginal artery (m2) suffered poor perfusion. In the first set, average wall shear stress (WSS) were in the range of 4 to 35 dyns/cm(2)for in LAD. Nevertheless, for second configuration sets the WSS values were higher as the LIMA could not supply enough blood to OM and m2. Conclusion: the virtual surgical configurations have the potential to improve the quality of operation by providing quantitative surgical insight. The degree of stenosis is a critical factor in terms of coronary perfusion and WSS. The sequential anastomosis can be done safely if the anastomosis angle is less than 90 degrees regardless of degree of stenosis. The smaller proposed perfusion index value,O(0.04 - 0) x 10(2), enable us to quantify the post-op hemodynamic performance by comparing with the ideal healthy physiological flow., Scientific and Technological Research Council of Turkey (TÜBİTAK); 1003 Priority-Research Program Grant; European Union (EU); Horizon 2020; European Research Council (ERC) Proof of Concept Grant; KidsSurgicalPlan

Interventional cardiology devices and especially stents are constantly evolving. A good radiopacity is essential to properly position the stent and to reduce the risk of complications during percutaneous coronary intervention (PCI). We wanted to assess the radiopacity of coronary stents. 9 stents were evaluated. Stents were deployed in a silicon bifurcation model and several pulsed fluoroscopy acquisitions (7.5 and 15 pulses/s) of each device were performed in a catheterization laboratory. Quantitative radiopacity assessment was performed using a radiopacity visual scale and qualitative radiopacity assessment was performed by showing the images to three experienced operators, single-blind. Our study showed statistically significant differences between stents regarding radiopacity assessed in a quantitative analysis (p < 0.000001) or a qualitative analysis (p < 0.000001), whether the acquisitions were made in 7.5 or 15 pulses/s. Resolute Onyx and Synergy were the most radio-opaque in both qualitative and qualitative analysis. Moreover, there was a statistically significant correlation between the radiopacity of stents, their strut thickness (p < 0.0001) and the presence of platinum in their metallic alloy (p < 0.0001). This study highlighted significant differences in the radiopacity of coronary stents deployed in a bench test model. The strut thickness and the presence of platinum increased the radiopacity.

Cardiac electrophysiological simulation is a very complex computational process, which can be run on graphics processing unit (GPU) to save computational cost greatly. The use of adaptive time-step can further effectively speed up the simulation of heart cells. However, if the adaptive time-step method applies to GPU, it suffers synchronization problem on GPU, weakening the acceleration of adaptive time-step method. The previous work ran on a single GPU with the adaptive time-step to get only 1.5 times (× 1.5) faster than the fixed time-step. This study proposes a memory allocation method, which can effectively implement the adaptive time-step method on GPU. The proposed method mainly focuses on the stimulus point and potential memory arrangement in order to achieve optimal memory storage efficiency. All calculation is implemented on GPU. Large matrices such as potential are arranged in column order, and the cells on the left are stimulated. The Luo-Rudy passive (LR1) and dynamic (LRd) ventricular action potential models are used with adaptive time-step methods, such as the traditional hybrid method (THM) and Chen-Chen-Luo's (CCL) "quadratic adaptive algorithm" method. As LR1 is solved by the THM or CCL on a single GPU, the acceleration is × 34 and × 75 respectively compared with the fixed time-step. With 2 or 4 GPUs, the acceleration of the THM and CCL is × 34 or × 35 and × 73 or × 75, but it would decrease to × 5 or × 3 and × 20 or × 15 without optimization. In an LRd model, the acceleration reaches × 27 or × 85 as solved by the THM or CCL compared with the fixed time-step on multi-GPU with linear speed up increase versus the number of GPU. However, with the increase of GPUs number, the acceleration of the THM and CCL is continuously weakened before optimization. The mixed root mean square error (MRMSE) lower than 5% is applied to ensure the accuracy of simulation. The result shows that the proposed memory arrangement method can save computational cost a lot to speed up the heart simulation greatly. Graphical abstract Acceleration ratio compared with CPU with fixed time-step (dt = 0.001 ms).

Mechanical heart valves (MHVs) are widely used to replace diseased heart valves, but it may suffer from cavitation due to the rapid closing velocity of the leaflets, resulting in the damage of red blood cells and platelets. The aim of this study is to apply computational fluid dynamics (CFD) method to investigate the cavitation in bileaflets mechanical heart valves (BMHVs) and discuss the effects of the conduit and leaflet geometries on cavitation intensity. Firstly, CFD method together with moving-grid technology were applied and validated by comparing with experimental results obtained from other literature. Then the leaflets movement and the flow rate of BMHVs with different conduit geometries and leaflet geometries are compared. At last, the duration time of the saturated vapor pressure and the closing velocity of leaflets at the instant of valve closure were used to represent the cavitation intensity. Larger closing velocity of leaflets at the instant of valve closure means higher cavitation intensity. For BMHVs with different conduit geometries, the conduit with Valsalva sinuses has the maximum cavitation intensity and the straight conduit has the minimum cavitation intensity, but the leaflets cannot reach the fully opened state in a straight conduit. For BMHVs with different leaflet geometries, in order to minimize the cavitation intensity, the leaflets are better to have a large thickness and a small rotational radius. CFD method is a promising method to deal with cavitation in BMHVs, and the closing velocity of leaflets has the same trend with the cavitation intensity. By using CFD method, the effects of the conduit geometry and the leaflet geometry on cavitaion in BMHVs are found out.

Computational models of cardiovascular structures rely on their accurate mechanical characterization. A validated method able to infer the material properties of patient-specific large vessels is currently lacking. The aim of the present study is to present a technique starting from the flow-area (QA) method to retrieve basic material properties from magnetic resonance (MR) imaging. The proposed method was developed and tested, first, in silico and then in vitro. In silico, fluid-structure interaction (FSI) simulations of flow within a deformable pipe were run with varying elastic modules (E) between 0.5 and 32 MPa. The proposed QA-based formulation was assessed and modified based on the FSI results to retrieve E values. In vitro, a compliant phantom connected to a mock circulatory system was tested within MR scanning. Images of the phantom were acquired and post-processed according to the modified formulation to infer E of the phantom. Results of in vitro imaging assessment were verified against standard tensile test. In silico results from FSI simulations were used to derive the correction factor to the original formulation based on the geometrical and material characteristics. In vitro, the modified QA-based equation estimated an average E = 0.51 MPa, 2% different from the E derived from tensile tests (i.e. E = 0.50 MPa). This study presented promising results of an indirect and non-invasive method to establish elastic properties from solely MR images data, suggesting a potential image-based mechanical characterization of large blood vessels.

The fast hybrid operator splitting (HOS) and stable uniformization (UNI) methods have been proposed to save computation cost and enhance stability for Markov chain model in cardiac cell simulations. Moreover, Chen-Chen-Luo's quadratic adaptive algorithm (CCL) combined with HOS or UNI was used to improve the tradeoff between speedup and stability, but without considering accuracy. To compromise among stability, acceleration, and accuracy, we propose a generalized Trotter operator splitting (GTOS) method combined with CCL independent of the asymptotic property of a particular ion-channel model. Due to the accuracy underestimation of the mixed root mean square error (MRMSE) method, threshold root mean square error (TRMSE) is proposed to evaluate computation accuracy. With the fixed time-step RK4 as a reference, the second-order GTOS combined with CCL (30.8-fold speedup) for the wild-type Markov chain model with nine states (WT-9 model) or (7.4-fold) for the wild-type Markov chain model with eight states (WT-8 model) is faster than UNI combined with CCL (15.6-fold) for WT-9 model or (1.2-fold) for WT-8 model, separately. Besides, the second-order GTOS combined with CCL has 3.81% TRMSE for WT-9 model or 4.32% TRMSE for WT-8 model more accurate than 72.43% TRMSE for WT-9 model or 136.17% TRMSE for WT-8 model of HOS combined with CCL. To compromise speedup and accuracy, low-order GTOS combined with CCL is suggested to have the advantages of high precision and low computation cost. For high-accuracy requirements, high-order GTOS combined with CCL is recommended. Graphical abstract.

Atherosclerosis preferentially occurs near the junction of branching vessels, where blood recirculation tends to occur (Malek et al. in J Am Med Assoc 282(21):2035-2042, 1999, https://doi.org/10.1001/jama.282.21.2035 ). For decades, CFD has been used to predict flow patterns such as separation and recirculation zones in hemodynamic models, but those predictions have rarely been validated with experimental data. In the context of verification and validation (VV), we first conduct a CFD benchmark calculation that reproduces the vortex detection experiments of Karino and Goldsmith (1980) with idealised branching blood vessels (Karino and Goldsmith in Trans. Am. Soc. Artif. Internal Organs 26:500-506, 1980). The critical conditions for the formation of recirculation vortices, the so-called critical Reynolds numbers, are the main parameters for comparison with the experimental data to demonstrate the credibility of the CFD workflow. We then characterise the wall shear stresses and develop a surrogate model for the size of formed vortices.An automated parametric study generating more than 12,000 CFD simulations was performed, sweeping the geometries and flow conditions found in the experiments by Karino and Goldsmith. The flow conditions were restricted to steady-state laminar flow, with a range of inflow Reynolds numbers up to 350, with various flow ratios between the main branch outlet and side branch outlet. The side branch diameter was scaled relative to the main branch diameter, ranging from 1.05/3 to 3/3; and the branching angles ranged in size from [Formula: see text] to [Formula: see text]. Recirculation vortices were detected by the inversion of the velocity vector at certain locations, as well as by the inversion of the wall shear stress (WSS) vector.The CFD simulations demonstrated good agreement with the experimental data on the critical Reynolds numbers. The spatial distributions of WSS on each branch were analysed to identify potential regions of disease. Once a vortex is formed, the size of the vortex increases by the square root of the Reynolds number. The CFD data was fitted to a surrogate model that accurately predicts the vortex size without the need to run computationally more expensive CFD simulations.This benchmark study validates the CFD simulation of vortex detection in idealised branching vessels under comprehensive flow conditions. This work also proposes a surrogate model for the size of the vortex, which could reduce the computational requirements in the studies related to branching vessels and complex vascular systems.

We purpose a novel method that combines modified frequency slice wavelet transform (MFSWT) and convolutional neural network (CNN) for classifying normal and abnormal heart sounds. A hidden Markov model is used to find the position of each cardiac cycle in the heart sound signal and determine the exact position of the four periods of S1, S2, systole, and diastole. Then the one-dimensional cardiac cycle signal was converted into a two-dimensional time-frequency picture using the MFSWT. Finally, two CNN models are trained using the aforementioned pictures. We combine two CNN models using sample entropy (SampEn) to determine which model is used to classify the heart sound signal. We evaluated our model on the heart sound public dataset provided by the PhysioNet Computing in Cardiology Challenge 2016. Experimental classification performance from a 10-fold cross-validation indicated that sensitivity (Se), specificity (Sp) and mean accuracy (MAcc) were 0.95, 0.93, and 0.94, respectively. The results showed the proposed method can classify normal and abnormal heart sounds with efficiency and high accuracy. Graphical abstract Block diagram of heart sound classification.

Aortic dissection (AD) is one of the most catastrophic cardiovascular diseases. AD occurs when a layer inside the aorta is disrupted and gives rise to the formation of a true lumen and a false lumen. These lumens can be connected through tears in the intimal flap which are known as entries. Despite being known for about two centuries, the effects of many factors on the morbidity and mortality of this disease are still unknown. As the blood interaction with the aorta is crucial in the severity and the progression of the aortic dissection, a biomechanical approach is chosen to investigate the influence of different morphologies on the severity of this disease. Using the finite element method (FEM) and the fluid-structure interaction (FSI) approach, we have evaluated the blood flow characteristics along the diseased aorta, in conjunction with the deformation of the aortic wall. In this study, an idealized geometry of a dissected descending aorta (type B) with two entries has been studied. The values for the diameter of the entry tear were chosen to be 5 mm and 10 mm. Therefore, a total of four conditions were investigated. According to our results, the retrograde flow through the proximal tear is dependent on the size of the distal re-entry and vice versa. Our results revealed that when both entry and re-entry tears are 10 mm in diameter, the flow passes through the true and false lumens with smaller resistance, resulting in a smaller flutter of the intimal flap, and therefore more stable intimal flap. Major oscillation frequencies of 2.5 Hz and 7.4 Hz were observed for the oscillation of the intimal flap, and amplitudes of the waves with higher frequencies were negligible.

Aneurysm rupture has been suggested to be related to aneurysm geometry, morphology, and complex flow activity; therefore, understanding aneurysm-specific hemodynamics is crucial. 4D Flow MRI has been shown to be a feasible tool for assessing hemodynamics in intracranial aneurysms with high spatial resolution. However, it requires averaging over multiple heartbeats and cannot account for cycle-to-cycle hemodynamics variations. This study aimed to assess cycle-to-cycle flow dynamics variations in a patient-specific intracranial aneurysm model using tomographic particle image velocimetry (tomo-PIV) at a high image rate under pulsatile flow conditions. Time-resolved and time-averaged velocity flow fields within the aneurysm sac and estimations of wall shear stress (WSS) were compared with those from 4D Flow MRI. A one-way ANOVA showed a significant difference between cardiac cycles (p value

Bicuspid aortic valve (BAV) is a congenital heart malformation with phenotypic heterogeneity. There is no prior computational study that assesses the haemodynamic and valve mechanics associated with BAV type 2 against a healthy tricuspid aortic valve (TAV) and other BAV categories. A proof-of-concept study incorporating three-dimensional fluid-structure interaction (FSI) models with idealised geometries (one TAV and six BAVs, namely type 0 with lateral and anterior-posterior orientations, type 1 with R–L, N–R and N–L leaflet fusion and type 2) has been developed. Transient physiological boundary conditions have been applied and simulations were run using an Arbitrary Lagrangian–Eulerian formulation. Our results showed the presence of abnormal haemodynamics in the aorta and abnormal valve mechanics: type 0 BAVs yielded the best haemodynamical and mechanical outcomes, but cusp stress distribution varied with valve orifice orientation, which can be linked to different cusp calcification location onset; type 1 BAVs gave rise to similar haemodynamics and valve mechanics, regardless of raphe position, but this position altered the location of abnormal haemodynamic features; finally, type 2 BAV constricted the majority of blood flow, exhibiting the most damaging haemodynamic and mechanical repercussions when compared to other BAV phenotypes. The findings of this proof-of-concept work suggest that there are specific differences across haemodynamics and valve mechanics associated with BAV phenotypes, which may be critical to subsequent processes associated with their pathophysiology processes.

Coronary arteries have high curvatures, and hence, flow through them causes disturbed flow patterns, resulting in stenosis and atherosclerosis. This in turn decreases the myocardial flow perfusion, causing myocardial ischemia and infarction. Therefore, in order to understand the mechanisms of these phenomena caused by high curvatures and branching of coronary arteries, we have conducted elaborate hemodynamic analysis for both (i) idealized coronary arteries with geometrical parameters representing realistic curvatures and stenosis and (ii) patient-specific coronary arteries with stenoses. Firstly, in idealized coronary arteries with approximated realistic arterial geometry representative of their curvedness and stenosis, we have computed the hemodynamic parameters of pressure drop, wall shear stress (WSS) and wall pressure gradient (WPG), and their association with the geometrical parameters of curvedness and stenosis. Secondly, we have similarly determined the wall shear stress and wall pressure gradient distributions in four patient-specific curved stenotic right coronary arteries (RCAs), which were reconstructed from medical images of patients diagnosed with atherosclerosis and stenosis; our results show high WSS and WPG regions at the stenoses and inner wall of the arterial curves. This paper provides useful insights into the causative mechanisms of the high incidence of atherosclerosis in coronary arteries. It also provides guidelines for how simulation of blood flow in patient's coronary arteries and determination of the hemodynamic parameters of WSS and WPG can provide a medical assessment of the risk of development of atherosclerosis and plaque formation, leading to myocardial ischemia and infarction. The novelty of our paper is in our showing how in actual coronary arteries (based on their CT imaging) curvilinearity and narrowing complications affect the computed WSS and WPG, associated with risk of atherosclerosis. This is very important for cardiologists to be able to properly take care of their patients and provide remedial measures before coronary complications lead to myocardial infarctions and necessitate stenting or coronary bypass surgery. We want to go one step further and provide clinical application of our research work. For that, we are offering to cardiologists worldwide to carry out hemodynamic analysis of the medically imaged coronary arteries of their patients and compute the values of the hemodynamic parameters of WSS and WPG, so as to provide them an assessment of the risk of atherosclerosis for their patients. Graphical abstract Theme and aims: Coronary arteries have high curvatures, and hence flow through them causes disturbed flow patterns, resulting in stenosis and atherosclerosis. This in turn decreases the myocardial flow perfusion, causing myocardial ischemia and infarction. Therefore, in order to understand the mechanisms of these phenomena caused by high curvatures and branching of coronary arteries, we have conducted elaborate hemodynamic analysis for both (i) idealized coronary arteries with geometrical parameters representing curvatures and stenosis, and (ii) patient-specific coronary arteries with stenoses. Methods and results: Firstly, in idealized coronary arteries with approximated realistic arterial geometry representative of their curvedness and stenosis, we have computed the hemodynamic parameters of pressure drop, wall shear stress (WSS) and wall pressure gradient (WPG), and their association with the geometrical parameters of curvedness and stenosis. Then, we have determined the wall shear stress and wall pressure gradient distributions in four patient-specific curved stenotic right coronary arteries (RCAs), that were reconstructed from medical images of patients diagnosed with atherosclerosis and stenosis, as illustrated in Figure 1, in which the locations of the stenoses are highlighted by arrows. Figure 1: Three-dimensional CT visualization of arteries in patients with suspected coronary disease. The arteries can be seen as a combination of various curved segments with stenoses at unspecific locations highlighted by arrows. Our results show high WSS and WPG regions at the stenoses and inner wall of the arterial curves, as depicted in Figure 2. Therein, the encapsulations show (i) high WSS, and (ii) high WPG regions at the stenosis and inner wall of the arterial curves. Figure 2: WSS and WPG surface plot of realistic arteries (a), (b), (c) and (d), wherein the small squared parts are enlarged to show the detailed localized contour plots at the stenotic regions. Therein, the circular encapsulations show (i) high WSS and (ii) high WPG regions at the stenosis and inner wall of the arterial curves. Conclusion and novelty: This paper provides useful insights into the causative mechanisms of the high incidence of atherosclerosis in coronary arteries. It also provides guidelines for how simulation of blood flow in patient coronary arteries and determination of the hemodynamic parameters of WSS and WPG can provide a medical assessment of the risk of development of atherosclerosis and plaque formation, leading to myocardial ischemia and infarction. The novelty of our paper is our showing how in actual coronary arteries (based on their CT imaging), curvilinearity and narrowing complications affect the computed WSS and WPG associated with risk of atherosclerosis. This is very important for cardiologists to be able to properly take care of their patients and provide remedial measures before coronary complications lead to myocardial infarctions and necessitate stenting or coronary bypass surgery.

Thrombosis within an occluded coronary arterial fistula (CAF) may cause angina and myocardial infarction. This study aims to estimate how the occlusion position of CAFs with terminal aneurysm affects the risk stratification of thrombosis in the fistula in terms of hemodynamics. Twelve CAF models were reconstructed based on patient-specific computed tomography angiogram (CTA) images. They were classified into three groups: preserved group (untreated fistula), aneurysm-reserved group (occluded at the fistula terminal: distal occlusion) and aneurysm-removed group (occluded before the aneurysm: proximal occlusion). Hemodynamics results were analyzed and compared with the clinical follow-up results. The results showed that: (1) Hemodynamic patterns within the fistula before and after treatment were significantly different among patients. (2) Aneurysm-removed occlusions showed better improvements with respect to the CAF blood-stealing phenomena. (3) Irrespective of whether aneurysms were removed or not, a disturbed flow pattern was observed. Areas having high OSI and low TAWSS were present in the post-occluded CAFs. The removal of the aneurysm, however, would alleviate the flow disturbance, and decrease the proportion of the area of OSI > 0.3. (4) The thrombosis region spotted in the follow-up patient CTAs was consistent with the computed high OSI area. A proximal occlusion, namely, removing the aneurysm of the CAF, may help in reducing the risk of thrombosis after surgery. However, follow-up studies with a larger cohort should be carried out to test and verify this speculation in the future.

Mathematical action potential (AP) modeling is a well-established but still-developing area of research to better understand physiological and pathological processes. In particular, changes in AP mechanisms in the isoproterenol (ISO) -induced hypertrophic heart model are incompletely understood. Here we present a mathematical model of the rat AP based on recordings from rat ventricular myocytes. In our model, for the first time, all channel kinetics are defined with a single type of function that is simple and easy to apply. The model AP and channels dynamics are consistent with the APs recorded from rats for both Control (absence of ISO) and ISO-treated cases. Our mathematical model helps us to understand the reason for the prolongation in AP duration after ISO application while ISO treatment helps us to validate our mathematical model. We reveal that the smaller density and the slower gating kinetics of the transient K+ current help explain the prolonged AP duration after ISO treatment and the increasing amplitude of the rapid and the slow inward rectifier currents also contribute to this prolongation alongside the flux in Ca2+ currents. ISO induced an increase in the density of the Na+ current that can explain the faster upstroke. We believe that AP dynamics from rat ventricular myocytes can be reproduced very well with this mathematical model and that it provides a powerful tool for improved insights into the underlying dynamics of clinically important AP properties such as ISO application. This study was supported by The Scientific and Technological Research Council of Turkey (TUBITAK, Project No: 117F020). These funding sources had no involvement in study design, writing of the report, decision to publish, or the collection, analysis, and interpretation of data.

Finite element (FE) modeling is becoming increasingly prevalent in the world of cardiac mechanics; however, many existing FE models are phenomenological and thus do not capture cellular-level mechanics. This work implements a cellular-level contraction scheme into an existing nonlinear FE code to model ventricular contraction. Specifically, this contraction model incorporates three myosin states: OFF-, ON-, and an attached force-generating state. It has been speculated that force-dependent transitions from the OFF- to ON-state may contribute to length-dependent activation at the cellular level. The current work investigates the contribution of force-dependent recruitment out of the OFF-state to ventricular-level function, specifically the Frank-Starling relationship, as seen through the end-systolic pressure-volume relationship (ESPVR). Five FE models were constructed using geometries of rat left ventricles obtained via cardiac magnetic resonance imaging. FE simulations were conducted to optimize parameters for the cellular contraction model such that the differences between FE predicted ventricular pressures for the models and experimentally measured pressures were minimized. The models were further validated by comparing FE predicted end-systolic strain to experimentally measured strain. Simulations mimicking vena cava occlusion generated descending pressure volume loops from which ESPVRs were calculated. In simulations with the inclusion of the OFF-state, using a force-dependent transition to the ON-state, the ESPVR calculated was steeper than in simulations excluding the OFF-state. Furthermore, the ESPVR was also steeper when compared to models that included the OFF-state without a force-dependent transition. This suggests that the force-dependent recruitment of thick filament heads from the OFF-state at the cellular level contributes to the Frank-Starling relationship observed at the organ level.