Showing papers in "Cardiovascular Engineering and Technology in 2021"

The Glycocalyx and Its Role in Vascular Physiology and Vascular Related Diseases

Abstract: In 2007 the two senior authors wrote a review on the structure and function of the endothelial glycocalyx layer (Weinbaum in Annu Rev Biomed Eng 9:121–167, 2007). Since then there has been an explosion of interest in this hydrated gel-like structure that coats the luminal surface of endothelial cells that line our vasculature due to its important functions in (A) basic vascular physiology and (B) vascular related diseases. This review will highlight the major advances that have occurred since our 2007 paper. A literature search mainly focusing on the role of the glycocalyx in the two major areas described above was performed using electronic databases. In part (A) of this review, the new formulation of the century old Starling principle, now referred to as the Michel–Weinbaum glycoclayx model or revised Starling hypothesis, is described including new subtleties and physiological ramifications. New insights into mechanotransduction and release of nitric oxide due to fluid shear stress sensed by the glycocalyx are elaborated. Major advances in understanding the organization and function of glycocalyx components, and new techniques for measuring both its thickness and spatio-chemical organization based on super resolution, stochastic optical reconstruction microscopy (STORM) are presented. As discussed in part (B) of this review, it is now recognized that artery wall stiffness associated with hypertension and aging induces glycocalyx degradation, endothelial dysfunction and vascular disease. In addition to atherosclerosis and cardiovascular diseases, the glycocalyx plays an important role in lifestyle related diseases (e.g., diabetes) and cancer. Infectious diseases including sepsis, Dengue, Zika and Corona viruses, and malaria also involve the glycocalyx. Because of increasing recognition of the role of the glycocalyx in a wide range of diseases, there has been a vigorous search for methods to protect the glycocalyx from degradation or to enhance its synthesis in disease environments. As we have seen in this review, many important developments in our basic understanding of GCX structure, function and role in diseases have been described since the 2007 paper. The future is wide open for continued GCX research.

Analysis of Turbulence Effects in a Patient-Specific Aorta with Aortic Valve Stenosis

Abstract: Blood flow in the aorta is often assumed laminar, however aortic valve pathologies may induce transition to turbulence and our understanding of turbulence effects is incomplete. The aim of the study was to provide a detailed analysis of turbulence effects in aortic valve stenosis (AVS). Large-eddy simulation (LES) of flow through a patient-specific aorta with AVS was conducted. Magnetic resonance imaging (MRI) was performed and used for geometric reconstruction and patient-specific boundary conditions. Computed velocity field was compared with 4D flow MRI to check qualitative and quantitative consistency. The effect of turbulence was evaluated in terms of fluctuating kinetic energy, turbulence-related wall shear stress (WSS) and energy loss. Our analysis suggested that turbulence was induced by a combination of a high velocity jet impinging on the arterial wall and a dilated ascending aorta which provided sufficient space for turbulence to develop. Turbulent WSS contributed to 40% of the total WSS in the ascending aorta and 38% in the entire aorta. Viscous and turbulent irreversible energy losses accounted for 3.9 and 2.7% of the total stroke work, respectively. This study demonstrates the importance of turbulence in assessing aortic haemodynamics in a patient with AVS. Neglecting the turbulent contribution to WSS could potentially result in a significant underestimation of the total WSS. Further work is warranted to extend the analysis to more AVS cases and patients with other aortic valve diseases.

Left Atrial Remodeling Mechanisms Associated with Atrial Fibrillation.

Abstract: Heart disease has always been one of the important diseases that endanger health and cause death. Therefore, it is particularly important to understand left atrium reconstruction and atrial fibrillation before heart image processing. The purpose of this paper is to provide an important review of the mechanisms of left atrial remodeling (LAR) associated with atrial fibrillation (AF). LAR refers to the spectrum of pathophysiological changes in (i) atrial structure and physiological function, and (ii) electric, ionic, and molecular milieu of the LA, in response to stresses imposed by conditions such as hypertension, myocardial ischemia, autonomic denervation and congestive heart failure. The main mechanisms of LAR include electrical remodeling, structural remodeling, metabolic remodeling, autonomic remodeling, neurohormones and inflammation, and other influencing factors. LAR is not only the basic mechanism of AF and heart failure, but also the pathophysiological basis of its progression. In clinical practice, AF is the most common persistent arrhythmia, and is believed to be the result of a combination of mechanisms that have triggers and maintenance mechanisms, including spontaneous ectopic pacing and multiple wavelet reentry. While LA electrophysiological, structural, and ultra-structural changes trigger AF, in turn, AF alters the LA electrical and structural properties that promote its maintenance and recurrence. Chronic AF leads to extensive changes in atrial cellular substructures, including loss of myofibrils, accumulation of glycogen, changes in mitochondrial shape and size, fragmentation of sarcoplasmic reticulum, and dispersion of nuclear chromatin. Electrical remodeling and structural remodeling of the atria during AF, involving structural changes and functional impairment of the left atrium, can lead to serious decline in left ventricular function and severe heart failure. Therefore, LAR and AF are inter-activating phenomena, and the resulting complications can cause serious disabling and fatal events. In this paper, we present (i) the mechanisms of LAR, in the form of structural, electrical, metabolic, and neurohormonal changes, and (ii) their interactive roles in initiating and maintaining AF. These in-depth understanding of the atrial remodeling mechanisms can in turn provide useful insights into the treatment of AF and heart failure.

Delivery of siRNA to Endothelial Cells In Vivo Using Lysine/Histidine Oligopeptide-Modified Poly(β-amino ester) Nanoparticles.

Abstract: Endothelial cell (EC) dysfunction underlies the pathology of multiple disease conditions including cardiovascular and pulmonary diseases. Dysfunctional ECs have a distinctive gene expression profile compared to healthy ECs. RNAi therapy is a powerful therapeutic approach that can be used to silence multiple genes of interests simultaneously. However, the delivery of RNAi to ECs in vivo continues to be a major challenge. Here, we optimized a polymer formulation based on poly(β-amino ester)s (pBAEs) to deliver siRNA to vascular ECs. We developed a library of bioinspired oligopeptide-modified pBAE nanoparticles (NPs) with different physicochemical proprieties and screened them for cellular uptake and efficacy of RNAi delivery in vitro using ECs, vascular smooth muscle cells, and THP-1 monocytes. From the screening, the lysine-/histidine-oligopeptide modified pBAE (C6-KH) NP was selected and further tested ex vivo using mouse aorta and in mice to determine efficiency of siRNA delivery in vivo. The in vitro screening study showed that C6-KH was most efficient in delivering siRNA to ECs. Ex vivo study showed that C6-KH nanoparticles containing siRNAs accumulated in the endothelial layer of mouse aortas. In vivo study showed that C6-KH nanoparticles carrying siICAM2 injected via tail-vein in mice significantly reduced ICAM2 level in the artery endothelium (55%), lung (52%), and kidney (31%), but not in the liver, heart, and thymus, indicating a tissue-specific delivery pattern. We demonstrate that C6-KH pBAE can used for delivery of siRNAs to the artery endothelium and lung, while minimizing potential side or toxic effects in the liver and heart.

In Vitro Assessment of Right Ventricular Outflow Tract Anatomy and Valve Orientation Effects on Bioprosthetic Pulmonary Valve Hemodynamics

Abstract: The congenital heart defect Tetralogy of Fallot (ToF) affects 1 in 2500 newborns annually in the US and typically requires surgical repair of the right ventricular outflow tract (RVOT) early in life, with variations in surgical technique leading to large disparities in RVOT anatomy among patients. Subsequently, often in adolescence or early adulthood, patients usually require surgical placement of a xenograft or allograft pulmonary valve prosthesis. Valve longevity is highly variable for reasons that remain poorly understood. This work aims to assess the performance of bioprosthetic pulmonary valves in vitro using two 3D printed geometries: an idealized case based on healthy subjects aged 11 to 13 years and a diseased case with a 150% dilation in vessel diameter downstream of the valve. Each geometry was studied with two valve orientations: one with a valve leaflet opening posterior, which is the native pulmonary valve position, and one with a valve leaflet opening anterior. Full three-dimensional, three-component, phase-averaged velocity fields were obtained in the physiological models using 4D flow MRI. Flow features, particularly vortex formation and reversed flow regions, differed significantly between the RVOT geometries and valve orientations. Pronounced asymmetry in streamwise velocity was present in all cases, while the diseased geometry produced additional asymmetry in radial flows. Quantitative integral metrics demonstrated increased secondary flow strength and recirculation in the rotated orientation for the diseased geometry. The compound effects of geometry and orientation on bioprosthetic valve hemodynamics illustrated in this study could have a crucial impact on long-term valve performance.

Similar but Distinct Roles of Membrane and Interior Fluid Viscosities in Capsule Dynamics in Shear Flows.

Abstract: The dynamics of biological capsules and red blood cells in shear flows has been studied extensively with experimental, analytical, and numerical methods. In particular, the effects of various parameters, including the shear rate or shear stress, membrane elasticity, capsule shape, and interior fluid viscosity, have been investigated carefully. The role of the membrane viscosity for capsule deformation dynamics has not been examined adequately. In previous studies, the so-called energy dissipation ratio has been used to account for the membrane viscosity effect by increasing the interior viscosity; however, the applicability and accuracy of this treatment have not been evaluated carefully. In this study, using the recently developed finite-difference scheme for immersed boundary simulations of viscoelastic membranes, we conduct comprehensive numerical simulations of the deformation processes of an originally spherical capsule in shear flows with various combinations of membrane and interior fluid viscosities. Our results show that the membrane and interior fluid viscosity have similar however different effects on the capsule deformation dynamics. While the capsule deformation decreases with both membrane and interior fluid viscosities, a typical decrease-then-increase variation is observed for the inclination angle as the membrane viscosity increases, instead of the monotonic decrease in the inclination angle with the interior fluid viscosity increase. Also, although both large membrane and interior fluid viscosity values can introduce oscillations in the capsule deformation and inclination, larger aptitudes and slow decay processes are noticed at larger membrane viscosities. The variations of other dynamic parameters of the capsule, including the circumference, average membrane velocity, and rotation frequency, are also analyzed, and an intuitive mechanism is proposed to relate the membrane velocity and rotation frequency to the capsule deformation and inclination angle. The simple mechanism is then applied to explain the spoon-like variation patterns for membrane velocity and rotation frequency observed in our results. Furthermore, we examine the validity of the energy dissipation ratio approach based on the mathematical functional dependence. Our results and analysis show that the dissipation ratio is a system and process dependent variable and it cannot be treated as a constant even for the same capsule. This research is valuable for a better understanding of the complex capsule dynamics in flows and also suggests that the membrane viscosity needs to be considered explicitly for accurate and reliable results in future studies.

A Brush-Spin-Coating Method for Fabricating In Vitro Patient-Specific Vascular Models by Coupling 3D-Printing.

Abstract: In vitro patient-specific flexible vascular models are helpful for understanding the haemodynamic changes before and after endovascular treatment and for effective training of neuroendovascular interventionalists. However, it is difficult to fabricate models of overall unified or controllable thickness using existing manufacturing methods. In this study, we developed an improved and easily implemented method by combining 3D printing and brush-spin–coating processes to produce a transparent silicone model of uniform or varied thickness. First, a water-soluble inner-skeleton model, based on clinical data, was printed on a 3D printer. The skeleton model was subsequently fixed in a single-axis-rotation machine to enable continuous coating of silicone, the thickness of which was manually controlled by adsorption and removal of excess silicone in a brush-spinning operation. After the silicone layer was solidified, the inner skeleton was further dissolved in a hot water bath, affording a transparent vascular model with real geometry. To verify the controllability of the coating thickness by using this method, a straight tube, an idealised aneurysm model, a patient-specific aortic arch model, and an abdominal aortic aneurysm model were manufactured. The different thicknesses of the manufactured tubes could be well controlled, with the relative standard deviations being 5.6 and 8.1% for the straight and aneurysm tubes, respectively. Despite of the diameter changing from 33 to 20 mm in the patient-specific aorta, the thickness of the fabricated aortic model remains almost the same along the longitudinal direction with a lower standard deviation of 3.1%. In the more complex patient-specific abdominal aneurysm model, varied thicknesses were realized to mimic the measured data from the CT images, where the middle of the aneurysm was with 2 mm and abdominal aorta as well as the iliac arteries had the normal thickness of 2.3 mm. Through the brush–spin–coating method, models of different sizes and complexity with prescribed thickness can be manufactured, which will be helpful for developing surgical treatment strategies or training neuroendovascular interventionalists.

Anisodamine Hydrobromide Protects Glycocalyx and Against the Lipopolysaccharide-Induced Increases in Microvascular Endothelial Layer Permeability and Nitric Oxide Production.

Abstract: Anisodamine hydrobromide (Ani HBr) has been used to improve the microcirculation during cardiovascular disorders and sepsis. Glycocalyx plays an important role in preserving the endothelial cell (EC) barrier permeability and nitric oxide (NO) production. We aimed to test the hypothesis that Ani HBr could protect the EC against permeability and NO production via preventing glycocalyx shedding. A human cerebral microvascular EC hCMEC/D3 injury model induced by lipopolysaccharide (LPS) was established. Ani HBr was administrated to ECs with the LPS challenge. Cell viability was performed by Cell Counting Kit-8 assay. Cell proliferation and apoptosis were detected by EdU and Hoechst 33342 staining. Apoptosis and cell cycle were also assessed by flow cytometry with annexin V staining and propidium iodide staining, respectively. Then, adherens junction integrity was evaluated basing on the immunofluorescence staining of vascular endothelial cadherin (VE-cadherin). The glycocalyx component heparan sulfate (HS) was stained in ECs. The cell permeability was evaluated by leakage of fluorescein isothiocyanate (FITC)-dextran. Cellular NO production was measured by the method of nitric acid reductase. Ani HBr at 20 μg/mL significantly increased the viability of ECs with LPS challenge, but significantly inhibited the cell viability at 80 μg/mL, showing a bidirectional regulation of cell viability by Ani HBr. Ani HBr had not significantly change the LPS-induced EC proliferation. Ani HBr significantly reversed the induction of LPS on EC apoptosis. Ani HBr reinstated the LPS-induced glycocalyx and VE-cadherin shedding and adherens junction disruption. Ani HBr significantly alleviated LPS-induced EC layer permeability and NO production. Ani HBr protects ECs against LPS-induced increase in cell barrier permeability and nitric oxide production via preserving the integrity of glycocalyx. Ani HBr is a promising drug to rescue or protect the glycocalyx.

Predictive Model for Thrombus Formation After Transcatheter Valve Replacement.

Abstract: 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.

Endothelial Glycocalyx-Mediated Intercellular Interactions: Mechanisms and Implications for Atherosclerosis and Cancer Metastasis.

Abstract: The endothelial glycocalyx (GCX) plays a critical role in the health of the vascular system. Degradation of the GCX has been implicated in the onset of diseases like atherosclerosis and cancer because it disrupts endothelial cell (EC) function that is meant to protect from atherosclerosis and cancer. Examples of such EC function include interendothelial cell communication via gap junctions and receptor-mediated interactions between endothelial and tumor cells. This review focuses on GCX-dependent regulation of these intercellular interactions in healthy and diseased states. The ultimate goal is to build new knowledge that can be applied to developing GCX regeneration strategies that can control intercellular interaction in order to combat the progression of diseases such as atherosclerosis and cancer. In vitro and in vivo studies were conducted to determine the baseline expression of GCX in physiologically relevant conditions. Chemical and mechanical GCX degradation approaches were employed to degrade the GCX. The impact of intact versus degraded GCX on intercellular interactions was assessed using cytochemistry, histochemistry, a Lucifer yellow dye transfer assay, and confocal, intravital, and scanning electron microscopy techniques. Relevant to atherosclerosis, we found that GCX stability determines the expression and functionality of Cx43 in gap junction-mediated EC-to-EC communication. Relevant to cancer metastasis, we found that destabilizing the GCX through either disturbed flow-induced or enzyme induced GCX degradation results in increased E-selectin receptor-mediated EC-tumor cell interactions. Our findings lay a foundation for future endothelial GCX-targeted therapy, to control intercellular interactions and limit the progression of atherosclerosis and cancer.

Cell-Laden Bioactive Poly(ethylene glycol) Hydrogels for Studying Mesenchymal Stem Cell Behavior in Myocardial Infarct-Stiffness Microenvironments

Abstract: Cellular therapy with mesenchymal stem cells (MSCs) shows promise for restoring function after myocardial infarction (MI). However, cellular therapy has yet to be clinically translated, in part because of difficulty in studying how MSCs interact with the post-MI scar microenvironment. This study aimed to design an in vitro model to study MSC behavior in the post-MI scar stiffness microenvironment. Using poly(ethylene glycol)-acrylate (PEG) conjugated to bioactive peptides, rat MSCs were encapsulated in hydrogels of varying stiffnesses and crosslinking densities. Cell viability was assessed through 14 days using calcein and ethidium homodimer staining. To simulate post-MI pro-fibrotic signaling, transforming growth factor-beta (TGFβ) was added to selected cultures. Immunofluorescence and qRT-PCR were used to assess changes in cardiac transdifferentiation or paracrine secretion, two proposed methods of MSCs in cellular therapy. Bioactivated PEG hydrogels with stiffnesses between 1.6 and 151.0 kPa were prepared. Rat MSCs demonstrated up to 71.6% viability after 3 days of encapsulated culture, and survived within the hydrogels up to 14 days. Encapsulation decreased MSC expression of cardiac troponin T and most growth factors, except interleukin-6. Meanwhile, TGFβ caused increased cardiac troponin T expression but decreased secreted factor expression. Varying hydrogel stiffness did not have an effect on cardiac troponin T or secreted factor expression. These findings suggest that a 3D microenvironment hinders two key mechanisms by which MSCs could improve cardiac function after post-MI scar formation, namely cardiac transdifferentiation and secreted factor production. Future studies incorporating MSCs other cell types should broaden understanding of the post-MI scar microenvironment.

The Role of Tricellular Junctions in the Transport of Macromolecules Across Endothelium.

Abstract: Transport of water and solutes across vascular endothelium is important in normal physiology and critical in the development of various diseases, including atherosclerosis. However, there is debate about the routes for such transport. We recently showed that an albumin-sized tracer crossed endothelium at bicellular and tricellular junctions, a tracer having the size of high density lipoprotein crossed only through tricellular junctions, and a tracer with the size of low density lipoprotein was unable to cross by either route and instead traversed the cells themselves. Here we review previous work on the structure and function of tricellular junctions. We then describe a study in which we assessed the role of such junctions in the transport of an albumin-sized tracer. We examined normal endothelial monolayers, the effect of agonists that modify their permeability, and the influence of different patterns of shear stress. Under normal conditions, approximately 85% of transendothelial transport occurred through tricellular junctions. This fraction was unchanged when permeability was reduced by sphingosine-1-phosphate or increased by thrombin, and also did not differ between endothelium exposed to multidirectional as opposed to uniaxial shear stress despite a > 50% difference in permeability. These data show that tricellular junctions dominate normal transport of this tracer and largely determine influences of agonists and shear. The effects were attributable to changes in both the number and conductivity of the junctions. Further investigation of these structures will lead to increased understanding of endothelial barrier function and may suggest new therapeutic strategies in disease.

Computational Assessment of Valvular Dysfunction in Discrete Subaortic Stenosis: A Parametric Study

Abstract: Discrete subaortic stenosis (DSS) is a left-ventricular outflow tract (LVOT) obstruction caused by a membranous lesion. DSS is associated with steep aortoseptal angles (AoSAs) and is a risk factor for aortic regurgitation (AR). However, the etiology of AR secondary to DSS remains unknown. This study aimed at quantifying computationally the impact of AoSA steepening and DSS on aortic valve (AV) hemodynamics and AR. An LV geometry reconstructed from cine-MRI data was connected to an AV geometry to generate a unified 2D LV-AV model. Six geometrical variants were considered: unobstructed (CTRL) and DSS-obstructed LVOT (DSS), each reflecting three AoSA variations (110°, 120°, 130°). Fluid-structure interaction simulations were run to compute LVOT flow, AV leaflet dynamics, and regurgitant fraction (RF). AoSA steepening and DSS generated vortex dynamics alterations and stenotic flow conditions. While the CTRL-110° model generated the highest degree of leaflet opening asymmetry, DSS preferentially altered superior leaflet kinematics, and caused leaflet-dependent alterations in systolic fluttering. LVOT steepening and DSS subjected the leaflets to increasing WSS overloads (up to 94% increase in temporal shear magnitude), while DSS also increased WSS bidirectionality on the inferior leaflet belly (+ 0.30-point in oscillatory shear index). Although AoSA steepening and DSS increased diastolic transvalvular backflow, regurgitant fractions (RF < 7%) remained below the threshold defining clinical mild AR. The mechanical interactions between AV leaflets and LVOT steepening/DSS hemodynamic derangements do not cause AR. However, the leaflet WSS abnormalities predicted in those anatomies provide new support to a mechanobiological etiology of AR secondary to DSS.

Proper Orthogonal Decomposition Analysis of the Flow Downstream of a Dysfunctional Bileaflet Mechanical Aortic Valve

Abstract: Aortic valve replacement remains the only viable solution for symptomatic patients with severe aortic valve stenosis. Despite their improved design and long history of successful operation, bileaflet mechanical heart valves are still associated with post-operative complications leading to valve dysfunction. Thus, the flow dynamics can be highly disturbed downstream of the dysfunctional valve. In this in vitro study, the flow dynamics downstream of healthy and dysfunctional bileaflet mechanical heart valves have been investigated using particle image velocimetry measurements. Proper orthogonal decomposition of the velocity field has been performed in order to explore the coherent flow features in the ascending aorta in the presence of a dysfunctional bileaflet mechanical heart valve. The ability of proper orthogonal decomposition derived metrics to differentiate between heathy and dysfunctional cases is reported. Moreover, reduced-order modeling using proper orthogonal decomposition is thoroughly investigated not only for the velocity field but also for higher order flow characteristics such as time average wall shear stress, oscillatory shear index and viscous energy dissipation. Considering these results, proper orthogonal decomposition can provide a rapid binary classifier to evaluate if the bileaflet mechanical valve deviates from its normal operating conditions. Moreover, the study shows that the size of the reduced-order model depends on which flow parameter is required to be reconstructed.

Influence of Distal Re-entry Tears on False Lumen Thrombosis After Thoracic Endovascular Aortic Repair in Type B Aortic Dissection Patients: A Computational Fluid Dynamics Simulation

Abstract: Distal re-entry tears play a significant role in false lumen (FL) thrombosis, which will strongly affect the postoperative long-term survival of patients with type B aortic dissection (TBAD) after thoracic endovascular aortic repair (TEVAR). This study aimed to investigate the influence of a peculiar morphological parameter of the residual re-entry tears in TBAD patients after TEVAR on long-term FL thrombosis using the computational fluid dynamics. Ideal population-based three-dimensional models of post-operative TBAD were established. Numerical simulation was performed to investigate the hemodynamic differences caused by different tear features, including the tear count, the maximum distance between tears, and the tear area. Although the low relative residence time (RRT) area did not change significantly when the tear distance was fixed, the area of oscillatory shear index (OSI) > 0.45 and endothelial cell activation potential (ECAP) > 1.5 decreased significantly with the tear count and area increased and a dramatic increase in blood flow into the FL was also observed. When tear count and total area were fixed, for each 10-mm increase in the maximum distance between tears, the area of low RRT in the FL increased significantly, while the average pressure difference increased by 10.85%. The different morphology of the re-entry tears had different effects on the thrombosis-related hemodynamic parameters in FL following TEVAR. and the number of re-entry tears was most crucial to the potential thrombosis in the post-TEVAR FL of TBAD patients.

On Valve Interstitial Cell Signaling: The Link Between Multiscale Mechanics and Mechanobiology.

Abstract: Heart valves function in one of the most mechanically demanding environments in the body to ensure unidirectional blood flow The resident valve interstitial cells respond to this mechanical environment and maintain the structure and integrity of the heart valve tissues to preserve homeostasis While the mechanics of organ-tissue-cell heart valve function has progressed, the intracellular signaling network downstream of mechanical stimuli has not been fully elucidated This has hindered efforts to both understand heart valve mechanobiology and rationally identify drug targets for treating valve disease In the present work, we review the current literature on VIC mechanobiology and then propose mechanistic mathematical modeling of the mechanically-stimulated VIC signaling response to comprehend the coupling between VIC mechanobiology and valve mechanics

Influence of Tissue Technology on Pannus Formation on Bioprosthetic Heart Valves.

Abstract: Bioprosthetic heart valves have several modes of failure. Tissue degeneration and calcification are the major modes of failure with the highest focus of attention, however pannus formation can also be problematic. We studied the effect of a new tissue technology with the absence of any glutaraldehyde-based storage solution and a stable aldehyde capping process on pannus formation. Using a juvenile sheep model of mitral valve replacement, valves with the new tissue technology were compared to control valves with contemporary bovine pericardial tissue, regarding pannus formation. Valves were implanted for either a 5- or 8-month period. Explanted valves were examined macroscopically and histologically. Histological observations were made by an independent pathologist, blinded to group identity. Pannus area measured macroscopically on the test valves was significantly lower than the pannus on the control tissue. This was confirmed on the histological samples, where the total pannus overgrowth was significantly lower in the test group compared to the control. The new tissue technology leads to less pannus formation. This may beneficially influence both short- and long-term valve behavior of bioprosthetic valves

In Vitro Clot Trapping Efficiency of the FDA Generic Inferior Vena Cava Filter in an Anatomical Model: An Experimental Fluid-Structure Interaction Benchmark.

Abstract: Robust experimental data for performing validation of fluid–structure interaction (FSI) simulations of the transport of deformable solid bodies in internal flow are currently lacking. This in vitro experimental study characterizes the clot trapping efficiency of a new generic conical-type inferior vena cava (IVC) filter in a rigid anatomical model of the IVC with carefully characterized test conditions, fluid rheological properties, and clot mechanical properties. Various sizes of spherical and cylindrical clots made of synthetic materials (nylon and polyacrylamide gel) and bovine blood are serially injected into the anatomical IVC model under worst-case exercise flow conditions. Clot trapping efficiencies and their uncertainties are then quantified for each combination of clot shape, size, and material. Experiments reveal the clot trapping efficiency increases with increasing clot diameter and length, with trapping efficiencies ranging from as low as approximately 42% for small 3.2 mm diameter spherical clots up to 100% for larger clot sizes. Because of the asymmetry of the anatomical IVC model, the data also reveal the iliac vein of clot origin influences the clot trapping efficiency, with the trapping efficiency for clots injected into the left iliac vein up to a factor of 7.5 times greater than that for clots injected into the right iliac (trapping efficiencies of approximately 10% versus 75%, respectively). Overall, this data set provides a benchmark for validating simulations predicting IVC filter clot trapping efficiency and, more generally, low-Reynolds number FSI modeling.

Equivalent Scalar Stress Formulation Taking into Account Non-Resolved Turbulent Scales.

Abstract: Cardiovascular engineering includes flows with fluid-dynamical stresses as a parameter of interest. Mechanical stresses are high-risk factors for blood damage and can be assessed by computational fluid dynamics. By now, it is not described how to calculate an adequate scalar stress out of turbulent flow regimes when the whole share of turbulence is not resolved by the simulation method and how this impacts the stress calculation. We conducted direct numerical simulations (DNS) of test cases (a turbulent channel flow and the FDA nozzle) in order to access all scales of flow movement. After validation of both DNS with literature und experimental data using magnetic resonance imaging, the mechanical stress is calculated as a baseline. Afterwards, same flows are calculated using state-of-the-art turbulence models. The stresses are computed for every result using our definition of an equivalent scalar stress, which includes the influence from respective turbulence model, by using the parameter dissipation. Afterwards, the results are compared with the baseline data. The results show a good agreement regarding the computed stress. Even when no turbulence is resolved by the simulation method, the results agree well with DNS data. When the influence of non-resolved motion is neglected in the stress calculation, it is underpredicted in all cases. With the used scalar stress formulation, it is possible to include information about the turbulence of the flow into the mechanical stress calculation even when the used simulation method does not resolve any turbulence.

Validated Guidelines for Simulating Centrifugal Blood Pumps

Abstract: Rotary blood pumps (RBPs) employed as ventricular assist devices are developed to support the ventricles of patients suffering from heart failure. Computational Fluid Dynamics (CFD) is frequently used to predict the performance and haemocompatibility of these pumps during development, however different simulation techniques employed by various research groups result in inconsistent predictions. This inconsistency is further compounded by the lack of standardised model validation, thus it is difficult to determine which simulation techniques are accurate. To address these problems, the US Food and Drug Administration (FDA) proposed a simplified centrifugal RBP benchmark model. The aim of this paper was to determine simulation settings capable of producing accurate predictions using the published FDA results for validation. This paper considers several studies to investigate the impact of simulation options on the prediction of pressure and flow velocities. These included evaluation of the mesh density and interface position through steady simulations as well as time step size and turbulence models (k-e realizable, k-ω SST, k-ω SST Intermittency, RSM ω-based, SAS and SBES) using a sliding mesh approach. The most accurate steady simulation using the k-ω turbulence model predicted the pressure to within 5% of experimental results, however experienced issues with unphysical velocity fields. A more computationally expensive transient simulation that used the Stress-Blended Eddy Simulation (SBES) turbulence model provided a more accurate prediction of the velocity field and pressure rise to within experimental variation. The findings of the study strongly suggest that SBES can be used to better predict RBP performance in the early development phase.

3D-Encoded DENSE MRI with Zonal Excitation for Quantifying Biventricular Myocardial Strain During a Breath-Hold

Abstract: Right ventricular (RV) function is increasingly recognized for its prognostic value in many disease states. As with the left ventricle (LV), strain-based measurements may have better prognostic value than typical chamber volumes or ejection fraction. Complete functional characterization of the RV requires high-resolution, 3D displacement tracking methods, which have been prohibitively challenging to implement. Zonal excitation during Displacement ENcoding with Stimulated Echoes (DENSE) magnetic resonance imaging (MRI) has helped reduce scan time for 2D LV strain quantification. We hypothesized that zonal excitation could alternatively be used to reproducibly acquire higher resolution, 3D-encoded DENSE images for quantification of bi-ventricular strain within a single breath-hold. We modified sequence parameters for a 3D zonal excitation DENSE sequence to achieve in-plane resolution < 2 mm and acquired two sets of images in eight healthy adult male volunteers with median (IQR) age 32.5 (32.0–33.8) years. We assessed the inter-test reproducibility of this technique, and compared computed strains and torsion with previously published data. Data for one subject was excluded based on image artifacts. Reproducibility for LV (CoV: 6.1–9.0%) and RV normal strains (CoV: 6.3–8.2%) and LV torsion (CoV = 7.1%) were all very good. Reproducibility of RV torsion was lower (CoV = 16.7%), but still within acceptable limits. Computed global strains and torsion were within reasonable agreement with published data, but further studies in larger cohorts are needed to confirm. Reproducible acquisition of 3D-encoded biventricular myocardial strain data in a breath-hold is feasible using DENSE with zonal excitation.

Relationship of Catheter Contact Angle and Contact Force with Contact Area on the Surface of Heart Muscle Tissue in Cardiac Catheter Ablation

Abstract: The aims of this study were to develop an experimental procedure for setting the catheter angle with respect to the surface of the heart muscle and the catheter contact force and to investigate the catheter contact area on the heart muscle as a function of catheter contact angle and force. Visualization tests were performed for 5 contact angles (0°, 30°, 45°, 60°, and 90°) and 8 contact forces (2, 4, 6, 10, 15, 20, 30, and 40 gf). Each experiment was repeated 6 times with 2 different commercially available catheter tips. The morphology of the contact area was classified into rectangular, circular, ellipsoidal, and semi-ellipsoidal. The correlation between contact force and contact area was a logarithmic function; increasing contact force was associated with increased contact area. At the same contact force, the correlation between contact angle and contact area was inverse; decreasing contact angle was associated with a corresponding increase in contact area. Both the catheter contact angle and contact force substantially impact the contact area and morphology in catheter ablation procedures.

Testing a Patient-Specific In-Silico Model to Noninvasively Estimate Central Blood Pressure

Abstract: To show some preliminary results about the possibility to exploit a cardiovascular mathematical model—made patient-specific by noninvasive data routinely measured during ordinary clinical examinations—in order to obtain sufficiently accurate central blood pressure (BP) estimates. A closed-loop multiscale (0D and 1D) model of the cardiovascular system is made patient-specific by using as model inputs the individual mean heart rate and left-ventricular contraction time, weight, height, age, sex and mean/pulse brachial BPs. The resulting framework is used to determine central systolic, diastolic, mean and pulse pressures, which are compared with the beat-averaged invasive pressures of 12 patients aged 72 ± 6.61 years. Errors in central systolic, diastolic, mean and pulse pressures by the model are 4.26 ± 2.81, 5.86 ± 4.38, 4.98 ± 3.95 and 3.51±2.38 mmHg, respectively. The proposed modeling approach shows a good patient-specific response and appears to be potentially useful in clinical practice. However, this approach needs to be evaluated in a larger cohort of patients and could possibly be improved through more accurate oscillometric BP measurement methods.

Establishment of a Modular Hemodynamic Simulator for Accurate In Vitro Simulation of Physiological and Pathological Pressure Waveforms in Native and Bioartificial Blood Vessels

Abstract: In vitro stimulation of native and bioartificial vessels in perfusable systems simulating natural mechanical environments of the human vasculature represents an emerging approach in cardiovascular research. Promising results have been achieved for applications in both regenerative medicine and etiopathogenetic investigations. However, accurate and reliable simulation of the wide variety of physiological and pathological pressure environments observed in different vessels still remains an unmet challenge. We established a modular hemodynamic simulator (MHS) with interchangeable and modifiable components suitable for the perfusion of native porcine—(i.e. the aorta, brachial and radial arteries and the inferior vena cava) and bioartificial fibrin-based vessels with anatomical site specific pressure curves. Additionally, different pathological pressure waveforms associated with cardiovascular diseases including hyper- and hypotension, tachy- and bradycardia, aortic valve stenosis and insufficiency, heart failure, obstructive cardiomyopathy and arterial stiffening were simulated. Pressure curves, cyclic distension and shear stress were measured for each vessel and compared to ideal clinical pressure waveforms. The pressure waveforms obtained in the MHS showed high similarity to the ideal anatomical site specific pressure curves of different vessel types. Moreover, the system facilitated accurate emulation of physiological and different pathological pressure conditions in small diameter fibrin-based vessels. The MHS serves as a variable in vitro platform for accurate emulation of physiological and pathological pressure environments in biological probes. Potential applications of the system include bioartificial vessel maturation in cardiovascular tissue engineering approaches as well as etiopathogenetic investigations of various cardiovascular pathologies.

Chondroitin Sulfate Promotes Interstitial Cell Activation and Calcification in an In Vitro Model of the Aortic Valve.

Abstract: Purpose Calcific aortic valve disease (CAVD), has been characterized as a cascade of cellular changes leading to leaflet thickening and valvular calcification. In diseased aortic valves, glycosaminoglycans (GAGs) normally found in the valve spongiosa migrate to the collagen I-rich fibrosa layer near calcified nodules. Current treatments for CAVD are limited to valve replacement or drugs tailored to other cardiovascular diseases. Methods Porcine aortic valve interstitial cells and porcine aortic valve endothelial cells were seeded into collagen I hydrogels of varying initial stiffness or initial stiffness-matched collagen I hydrogels containing the glycosaminoglycans chondroitin sulfate (CS), hyaluronic acid (HA), or dermatan sulfate (DS). Assays were performed after 2 weeks in culture to determine cell gene expression, protein expression, protein secretion, and calcification. Multiple regression analyses were performed to determine the importance of initial hydrogel stiffness, GAGs, and the presence of endothelial cells on calcification, both with and without osteogenic medium. Results High initial stiffness hydrogels and osteogenic medium promoted calcification, while for DS or HA the presence of endothelial cells prevented calcification. CS was found to increase the expression of pro-calcific genes, increase activated myofibroblast protein expression, induce the secretion of collagen I by activated interstitial cells, and increase calcified nodule formation. Conclusion This study demonstrates a more complete model of aortic valve disease, including endothelial cells, interstitial cells, and a stiff and disease-like ECM. In vitro models of both healthy and diseased valves can be useful for understanding the mechanisms of CAVD pathogenesis and provide a model for testing novel therapeutics.

Coupled Hemodynamics and Oxygen Diffusion in Abdominal Aortic Aneurysm: A Computational Sensitivity Study

Abstract: Abdominal Aortic Aneurysms (AAA) have extreme medical prevalence as an asymptomatic cause of death in developed countries. The probability of AAA rupture is promoted by the localized oxygen loss in the AAA wall which occurs in part because many AAAs contain a layer called intraluminal thrombus (ILT). Considering this strong clinical association, the purpose of this study is to investigate the key features that constitute to the oxygen diffusion, and therefore hypoxia in AAA. A three-dimensional model of AAA containing ILT is created and numerical simulations are performed to simulate blood flow and oxygen distribution within the AAA. The model accounts for blood flow in the lumen and oxygen transport in the lumen, ILT, and arterial wall. The sub-model of the ILT is fully coupled with the wall sub-model as well as with the subdomain of the blood flow. The sensitivity of the oxygen flow with respect to the parameters of the problem is also analyzed. Model simulations are used to investigate the relation between AAA physical properties, hemodynamics, and oxygen concentration in different geometries of AAA. The results demonstrate that the diameter of the AAA bulge has little effect on the oxygen flow, but that the thickness of the ILT layer has a profound effect. Moreover, a significant sensitivity to the oxygen supply from vasa vasorum and its notable impact on oxygen transport within AAA are observed. The variability of the arterial wall oxygen concentration to the oxygen reaction rate remains however very low. The presence of an ILT significantly impairs oxygen transport from the lumen to the wall. This study confirms that consideration of ILT size and anatomy may be important in considering the severity of a AAA, however, other parameters can also affect thrombus-mediated oxygen delivery within the aneurysmal wall.

A 1D-3D Hybrid Model of Patient-Specific Coronary Hemodynamics.

Abstract: 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.

A Model for Studying the Biomechanical Effects of Varying Ratios of Collagen Types I and III on Cardiomyocytes

Abstract: To develop a novel model composed solely of Col I and Col III with the lower and upper limits set to include the ratios of Col I and Col III at 3:1 and 9:1 in which the structural and mechanical behavior of the resident CM can be studied. Further, the progression of fibrosis due to change in ratios of Col I:Col III was tested. Collagen gels with varying Col I:Col III ratios to represent a healthy (3:1) and diseased myocardial tissue were prepared by manually casting them in wells. Absorbance assay was performed to confirm the gelation of the gels. Rheometric analysis was performed on each of the collagen gels prepared to determine the varying stiffnesses and rheological parameters of the gels made with varying ratios of Col I:Col III. Second Harmonic Generation (SHG) was performed to observe the 3D characterization of the collagen samples. Scanning Electron microscopy was used for acquiring cross sectional images of the lyophilized collagen gels. AC16 CM (human) cell lines were cultured in the prepared gels to study cell morphology and behavior as a result of the varying collagen ratios. Cellular proliferation was studied by performing a Cell Trace Violet Assay and the applied force on each cell was measured by means of Finite Element Analysis (FEA) on CM from each sample. Second harmonic generation microscopy used to image Col I, displayed a decrease in acquired image intensity with an increase in the non-second harmonic Col III in 3:1 gels. SEM showed a fiber-rich structure in the 3:1 gels with well-distributed pores unlike the 9:1 gels or the 1:0 controls. Rheological analysis showed a decrease in substrate stiffness with an increase of Col III, in comparison with other cases. CM cultured within 3:1 gels exhibited an elongated rod-like morphology with an average end-to-end length of 86 ± 28.8 µm characteristic of healthy CM, accompanied by higher cell growth in comparison with other cases. Finite element analysis used to estimate the forces exerted on CM cultured in the 3:1 gels, showed that the forces were well dispersed, and not concentrated within the center of cells, in comparison with other cases. This study model can be adopted to simulate various biomechanical environments in which cells crosstalk with the Collagen-matrix in diseased pathologies to generate insights on strategies for prevention of fibrosis.

Transcatheter Aortic Valve Thrombogenesis: A Foreign Materials Perspective.

Abstract: The initiation of thrombus formation in transcatheter aortic valves (TAVs) is not well understood. The foreign material components of a TAV may play a key role in TAV thrombogenesis. The goal of this study was to evaluate the thrombogenic potential of a TAV (entire valve) and its stent (with skirt). Blood was collected from eight human donors with citrate anticoagulation and later reconstituted with calcium chloride. A low-volume steady flow loop (flow rate = 0.8 L/min) was designed to facilitate three separate conditions (experimental duration = 1 h) per donor blood: (1) control (n = 8), (2) stent-with-skirt (leaflets removed from a 23 mm SAPIEN XT valve; n = 8) and (3) entire valve (an intact 23 mm SAPIEN XT valve; n = 8). Samples were collected at the start and end of each experiment. Serum D-Dimer and thrombin–antithrombin (TAT) concentrations were measured as markers of thrombogenicity. There was no significant change in serum D-Dimer and TAT concentration with time for the control group. An increasing trend in D-Dimer and TAT concentration was observed with time for the stent-with-skirt group. Interestingly, there was a decreasing trend in serum D-Dimer and TAT concentration with time for the entire valve (leaflet dominating) group. Moreover, changes in D-Dimer and TAT concentration were significantly different between the stent-with-skirt and entire valve (leaflet dominating) groups. Stent-with-skirt was found to impart the most prominent thrombogenic effect, indicating the significance of blood-stent and blood-skirt interactions in TAV thrombosis.

Alterations in Intracardiac Flow Patterns Affect Mitral Leaflets Dynamics in a Model of Ischemic Mitral Regurgitation

Abstract: This study was to evaluate the effects of ischemic mitral regurgitation (IMR) on vortex formation and leaflet dynamics using an established porcine infarct model of IMR. Using direct coronary ligation, five animals were subjected to a posterolateral myocardial infarction (MI) followed by an MRI at 12-weeks post MI. MR imaging consisted of 4D time-resolved left ventricular (LV) flow, full coverage 2D LV cine, and high resolution 2D cine of mitral valve dynamics. Five additional naive animals underwent identical imaging protocols to serve as controls. Image analysis was performed to obtain mitral transvalvular flows as well as LV volumes throughout the cardiac cycle. In addition, anterior to posterior mid-leaflet tip distances were measured throughout the cardiac cycle for determination of temporal leaflet dynamics. It was found IMR caused asymmetric vortex ring formation with the anterior vortex having a lower vorticity relative to its posterior counterpart. In contrast, normal ventricles create symmetric and tightly curled vortices in the basal chamber just underneath the mitral leaflets which conserve kinetic energy and aid in effective ejection. IMR animals were also evaluated for leaflet separation and were found to have a greater leaflet opening and achieved peak vorticity and peak leaflet opening later than control animals. In conclusion, this study shows the effects that altered vortex formation, due to IMR, can have on ventricular filling and leaflet dynamics. These findings have important implications for understanding blood flow through the dilated heart and how ring annuloplasty and volume reduction interventions may influence mitral valve dynamics.