A Modular Framework for Implicit 3D-0D Coupling in Cardiac Mechanics.

In numerical simulations of cardiac mechanics, coupling the heart to a model of the circulatory system is essential for capturing physiological cardiac behavior. A popular and efficient technique is to use an electrical circuit analogy, known as a lumped parameter network or zero-dimensional (0D) fluid model, to represent blood flow throughout the cardiovascular system. Due to the strong physical interaction between the heart and the blood circulation, developing accurate and efficient numerical coupling methods remains an active area of research. In this work, we present a modular framework for implicitly coupling three-dimensional (3D) finite element simulations of cardiac mechanics to 0D models of blood circulation. The framework is modular in that the circulation model can be modified independently of the 3D finite element solver, and vice versa. The numerical scheme builds upon a previous work that combines 3D blood flow models with 0D circulation models (3D fluid - 0D fluid). Here, we extend it to couple 3D cardiac tissue mechanics models with 0D circulation models (3D structure - 0D fluid), showing that both mathematical problems can be solved within a unified coupling scheme. The effectiveness, temporal convergence, and computational cost of the algorithm are assessed through multiple examples relevant to the cardiovascular modeling community. Importantly, in an idealized left ventricle example, we show that the coupled model yields physiological pressure-volume loops and naturally recapitulates the isovolumic contraction and relaxation phases of the cardiac cycle without any additional numerical techniques. Furthermore, we provide a new derivation of the scheme inspired by the Approximate Newton Method of Chan (1985), explaining how the proposed numerical scheme combines the stability of monolithic approaches with the modularity and flexibility of partitioned approaches.

Design optimization of a cardiovascular stent with application to a balloon expandable prosthetic heart valve.

A cardiovascular stent design optimization method is proposed with application to a pediatric balloon-expandable prosthetic heart valve. The prosthetic valved conduit may be expanded to a larger permanent diameter in vivo via subsequent transcatheter balloon dilation procedures. While multiple expandable prosthetic heart valves are currently at different stages of development, this work is focused on one particular design in which a stent is situated inside of an expandable polymeric valved conduit. Since the valve and conduit must be joined with a robust manufacturing technique, a polymeric glue layer is inserted between the two, which results in radial retraction of the valved region after expansion. Design of an appropriate stent is proposed to counteract this phenomenon and maintain the desired permanent diameter throughout the device after a single non-compliant balloon dilation procedure. The finite element method is used to compute performance metrics related to the permanent expansion diameter and required radial force. Additionally, failure due not only to high cycle fatigue but also due to ductile fracture is incorporated into the design study through the use of an existing ductile fracture criterion for metals. Surrogate models are constructed with the results of the high fidelity simulations and are subsequently used to numerically obtain a set of Pareto-optimal stent designs. Finally, a single design is identified by optimizing a normalized aggregate objective function with equal weighting of all design objectives.

Correction: A method to quantify mechanobiologic forces during zebrafish cardiac development using 4-D light sheet imaging and computational modeling.

[This corrects the article DOI: 10.1371/journal.pcbi.1005828.].

A method to quantify mechanobiologic forces during zebrafish cardiac development using 4-D light sheet imaging and computational modeling.

Blood flow and mechanical forces in the ventricle are implicated in cardiac development and trabeculation. However, the mechanisms of mechanotransduction remain elusive. This is due in part to the challenges associated with accurately quantifying mechanical forces in the developing heart. We present a novel computational framework to simulate cardiac hemodynamics in developing zebrafish embryos by coupling 4-D light sheet imaging with a stabilized finite element flow solver, and extract time-dependent mechanical stimuli data. We employ deformable image registration methods to segment the motion of the ventricle from high resolution 4-D light sheet image data. This results in a robust and efficient workflow, as segmentation need only be performed at one cardiac phase, while wall position in the other cardiac phases is found by image registration. Ventricular hemodynamics are then quantified by numerically solving the Navier-Stokes equations in the moving wall domain with our validated flow solver. We demonstrate the applicability of the workflow in wild type zebrafish and three treated fish types that disrupt trabeculation: (a) chemical treatment using AG1478, an ErbB2 signaling inhibitor that inhibits proliferation and differentiation of cardiac trabeculation; (b) injection of gata1a morpholino oligomer (gata1aMO) suppressing hematopoiesis and resulting in attenuated trabeculation; (c) weak-atriumm58 mutant (wea) with inhibited atrial contraction leading to a highly undeveloped ventricle and poor cardiac function. Our simulations reveal elevated wall shear stress (WSS) in wild type and AG1478 compared to gata1aMO and wea. High oscillatory shear index (OSI) in the grooves between trabeculae, compared to lower values on the ridges, in the wild type suggest oscillatory forces as a possible regulatory mechanism of cardiac trabeculation development. The framework has broad applicability for future cardiac developmental studies focused on quantitatively investigating the role of hemodynamic forces and mechanotransduction during morphogenesis.

Hemodynamics in the Left Atrium and Its Effect on Ventricular Flow Patterns.

In the present study, we investigate the hemodynamics inside left atrium (LA) and understand its impact on the development of ventricular flow patterns. We construct the heart model using dynamic-computed tomographic images and perform simulations using an immersed boundary method based flow solver. We show that the atrial hemodynamics is characterized by a circulatory flow generated by the left pulmonary veins (LPVs) and a direct stream from the right pulmonary veins (RPVs). The complex interaction of the vortex rings formed from each of the PVs leads to vortex breakup and annihilation, thereby producing a regularized flow at the mitral annulus. A comparison of the ventricular flow velocities between the physiological and a simplified pipe-based atrium model shows that the overall differences are limited to about 10% of the peak mitral flow velocity. The implications of this finding on the functional morphology of the left heart as well the computational and experimental modeling of ventricular hemodynamics are discussed.

Venous Thromboembolism: Review of Clinical Challenges, Biology, Assessment, Treatment, and Modeling.

Venous thromboembolism (VTE) is a massive clinical challenge, annually affecting millions of patients globally. VTE is a particularly consequential pathology, as incidence is correlated with extremely common risk factors, and a large cohort of patients experience recurrent VTE after initial intervention. Altered hemodynamics, hypercoagulability, and damaged vascular tissue cause deep-vein thrombosis and pulmonary embolism, the two permutations of VTE. Venous valves have been identified as likely locations for initial blood clot formation, but the exact pathway by which thrombosis occurs in this environment is not entirely clear. Several risk factors are known to increase the likelihood of VTE, particularly those that increase inflammation and coagulability, increase venous resistance, and damage the endothelial lining. While these risk factors are useful as predictive tools, VTE diagnosis prior to presentation of outward symptoms is difficult, chiefly due to challenges in successfully imaging deep-vein thrombi. Clinically, VTE can be managed by anticoagulants or mechanical intervention. Recently, direct oral anticoagulants and catheter-directed thrombolysis have emerged as leading tools in resolution of venous thrombosis. While a satisfactory VTE model has yet to be developed, recent strides have been made in advancing in silico models of venous hemodynamics, hemorheology, fluid-structure interaction, and clot growth. These models are often guided by imaging-informed boundary conditions or inspired by benchtop animal models. These gaps in knowledge are critical targets to address necessary improvements in prediction and diagnosis, clinical management, and VTE experimental and computational models.

Blood flow assessment technology in aortic surgery: a narrative review.

Background and Objective: Blood flow assessment is an emerging technique that allows for assessment of hemodynamics in the heart and blood vessels. Recent advances in cardiovascular imaging technologies have made it possible for this technique to be more accessible to clinicians and researchers. Blood flow assessment typically refers to two techniques: measurement-based flow visualization using echocardiography or four-dimensional flow magnetic resonance imaging (4D flow MRI), and computer-based flow simulation based on computational fluid dynamics modeling. Using these methods, blood flow patterns can be visualized and quantitative measurements of mechanical stress on the walls of the ventricles and blood vessels, most notably the aorta, can be made. Thus, blood flow assessment has been enhancing the understanding of cardiac and aortic diseases; however, its introduction to clinical practice has been negligible yet. In this article, we aim to discuss the clinical applications and future directions of blood flow assessment in aortic surgery. We then provide our unique perspective on the technique's translational impact on the surgical management of aortic disease. Methods: Articles from the PubMed database and Google Scholar regarding blood flow assessment in aortic surgery were reviewed. For the initial search, articles published between 2013 and 2023 were prioritized, including original articles, clinical trials, case reports, and reviews. Following the initial search, additional articles were considered based on manual searches of the references from the retrieved literature. Key Content and Findings: In aortic root pathology and ascending aortic aneurysms, blood flow assessment can elucidate postoperative hemodynamic changes after surgical reconfiguration of the aortic valve complex or ascending aorta. In cases of aortic dissection, analysis of blood flow can predict future aortic dilatation. For complicated congenital aortic anomalies, surgeons may use preoperative imaging to perform "virtual surgery", in which blood flow assessment can predict postoperative hemodynamics for different surgical reconstructions and assist in procedural planning even before entering the operating room. Conclusions: Blood flow assessment and computational modeling can evaluate hemodynamics and flow patterns by visualizing blood flow and calculating biomechanical forces in patients with aortic disease. We anticipate that blood flow assessment will become an essential tool in the treatment planning and understanding of the progression of aortic disease.

Mitral regurgitation mechanisms related to systolic anterior motion in hypertrophic cardiomyopathy.

Background: Systolic anterior motion (SAM) of the mitral valve can result in mitral regurgitation (MR) and adverse outcomes in patients with obstructive hypertrophic cardiomyopathy (HCM). However, the mechanism and characteristics of MR severity mediated by SAM are unresolved. This study aimed to elucidate the anatomic and hemodynamic associations of MR and the impact of septal myectomy on changes in MR severity in patients with HCM. Methods: We retrospectively reviewed patients who underwent septal myectomy with SAM and interpretable imaging between 2017-2022. Significant MR was defined as moderate or more MR. The mitral valve, papillary muscle, and left ventricular geometry were quantitatively evaluated via echocardiography and cardiac computed tomography. Results: Out of 34 patients, two groups were identified: those with preoperative significant MR (n=16) and those without significant MR (n=18). Patients with significant preoperative MR exhibited worse heart failure symptoms at baseline than those without. Following myectomy, these patients showed higher residual left ventricular outflow tract (LVOT) gradients at rest and with provocative measures than those without preoperative MR. Multivariate regression analysis revealed a significant association between the tenting area and MR severity. Additionally, the chordal cutting procedure alleviated the tenting area [2.1 (1.8-2.6) vs. 1.4 (1.2-1.6) cm2] compared to those without it. Conclusions: Our preliminary data suggested that chordal cutting with septal myectomy was associated with an improvement in the tenting area, contributing to MR severity. This procedure may serve as an effective therapy for patients with SAM and significant MR.

In Vitro Proof of Concept of a First-Generation Growth-Accommodating Heart Valved Conduit for Pediatric Use.

Currently available heart valve prostheses have no growth potential, requiring children with heart valve diseases to endure multiple valve replacement surgeries with compounding risks. This study demonstrates the in vitro proof of concept of a biostable polymeric trileaflet valved conduit designed for surgical implantation and subsequent expansion via transcatheter balloon dilation to accommodate the growth of pediatric patients and delay or avoid repeated open-heart surgeries. The valved conduit is formed via dip molding using a polydimethylsiloxane-based polyurethane, a biocompatible material shown here to be capable of permanent stretching under mechanical loading. The valve leaflets are designed with an increased coaptation area to preserve valve competence at expanded diameters. Four 22 mm diameter valved conduits are tested in vitro for hydrodynamics, balloon dilated to new permanent diameters of 23.26 ± 0.38 mm, and then tested again. Upon further dilation, two valved conduits sustain leaflet tears, while the two surviving devices reach final diameters of 24.38 ± 0.19 mm. After each successful dilation, the valved conduits show increased effective orifice areas and decreased transvalvular pressure differentials while maintaining low regurgitation. These results demonstrate concept feasibility and motivate further development of a polymeric balloon-expandable device to replace valves in children and avoid reoperations.

Fluid-structure interaction simulation of tissue degradation and its effects on intra-aneurysm hemodynamics.

Tissue degradation plays a crucial role in vascular diseases such as atherosclerosis and aneurysms. Computational modeling of vascular hemodynamics incorporating both arterial wall mechanics and tissue degradation has been a challenging task. In this study, we propose a novel finite element method-based approach to model the microscopic degradation of arterial walls and its interaction with blood flow. The model is applied to study the combined effects of pulsatile flow and tissue degradation on the deformation and intra-aneurysm hemodynamics. Our computational analysis reveals that tissue degradation leads to a weakening of the aneurysmal wall, which manifests itself in a larger deformation and a smaller von Mises stress. Moreover, simulation results for different heart rates, blood pressures and aneurysm geometries indicate consistently that, upon tissue degradation, wall shear stress increases near the flow-impingement region and decreases away from it. These findings are discussed in the context of recent reports regarding the role of both high and low wall shear stress for the progression and rupture of aneurysms.

Experimental and Mouse-Specific Computational Models of the Fbln4SMKO Mouse to Identify Potential Biomarkers for Ascending Thoracic Aortic Aneurysm.

PURPOSE: To use computational methods to explore geometric, mechanical, and fluidic biomarkers that could correlate with mouse lifespan in the Fbln4SMKO mouse. Mouse lifespan was used as a surrogate for risk of a severe cardiovascular event in cases of ascending thoracic aortic aneurysm. METHODS: Image-based, mouse-specific fluid-structure-interaction models were developed for Fbln4SMKO mice (n = 10) at ages two and six months. The results of the simulations were used to quantify potential biofluidic biomarkers, complementing the geometrical biomarkers obtained directly from the images. RESULTS: Comparing the different geometrical and biofluidic biomarkers to the mouse lifespan, it was found that mean oscillatory shear index (OSImin) and minimum time-averaged wall shear stress (TAWSSmin) at six months showed the largest correlation with lifespan (r2 = 0.70, 0.56), with both correlations being positive (i.e., mice with high OSImean and high TAWSSmin tended to live longer). When change between two and six months was considered, the change in TAWSSmin showed a much stronger correlation than OSImean (r2 = 0.75 vs. 0.24), and the correlation was negative (i.e., mice with increasing TAWSSmin over this period tended to live less long). CONCLUSION: The results highlight potential biomarkers of ATAA outcomes that can be obtained through noninvasive imaging and computational simulations, and they illustrate the potential synergy between small-animal and computational models.

Left ventricular remodeling following septal myectomy in hypertrophic obstructive cardiomyopathy.

Objectives: The purpose of this study is to determine whether or not left ventricular remodeling can be induced after septal myectomy in patients with obstructive hypertrophic cardiomyopathy, and if so, how it occurs, using gated cardiac computed tomography. Methods: Fifty patients with hypertrophic obstructive cardiomyopathy who underwent septal myectomy along the septal band between March 2016 and July 2020 were retrospectively reviewed. Recent consecutive 19 patients underwent postoperative cardiac computed tomography. In these patients, volumes of the septal band and thickness of 17 left ventricular myocardial segments were measured to determine the changes after surgery. Results: The resection volume predicted by preoperative computed tomography and the actual resection volume were 6.7 ± 3.3 mL and 6.4 ± 2.7 mL. In-hospital mortality was 0%. Moderate or greater mitral valve regurgitation and systolic anterior motion decreased from 56% to 6% and 86% to 6%, respectively. Median preoperative ventricular septal thickness and left ventricular outflow tract pressure gradient at rest decreased from 20.0 mm (interquartile range, 17.0-24.0 mm) and 74.0 mm Hg (interquartile range, 42.5-92.5 mm Hg) to 14.0 mm (interquartile range, 11.5-16.0 mm) and 15.5 mm Hg (interquartile range, 12.1-21.5 mm Hg), respectively. Postoperative computed tomography confirmed a reduction in septal band volume of 5.7 ± 2.8 mL. Total left ventricular myocardial volume was reduced by 12.9 ± 8.8 mL, which exceeded the volume reduction of the resected septal band. All segments except the basal inferior and basal inferolateral regions showed a significant decrease in wall thickness by a median of 6.4%. Conclusions: Properly performed septal myectomy may induce remodeling of the entire left ventricle, not just the resected area.

Computational simulations of the 4D micro-circulatory network in zebrafish tail amputation and regeneration.

Wall shear stress (WSS) contributes to the mechanotransduction underlying microvascular development and regeneration. Using computational fluid dynamics, we elucidated the interplay between WSS and vascular remodelling in a zebrafish model of tail amputation and regeneration. The transgenic Tg (fli1:eGFP; Gata1:ds-red) zebrafish line was used to track the three-dimensional fluorescently labelled vascular endothelium for post-image segmentation and reconstruction of the fluid domain. Particle image velocimetry was used to validate the blood flow. Following amputation to the dorsal aorta and posterior cardinal vein (PCV), vasoconstriction developed in the dorsal longitudinal anastomotic vessel (DLAV) along with increased WSS in the proximal segmental vessels (SVs) from amputation. Angiogenesis ensued at the tips of the amputated DLAV and PCV where WSS was minimal. At 2 days post amputation (dpa), vasodilation occurred in a pair of SVs proximal to amputation, followed by increased blood flow and WSS; however, in the SVs distal to amputation, WSS normalized to the baseline. At 3 dpa, the blood flow increased in the arterial SV proximal to amputation and through anastomosis with DLAV formed a loop with PCV. Thus, our in silico modelling revealed the interplay between WSS and microvascular adaptation to changes in WSS and blood flow to restore microcirculation following tail amputation.

On the Potential Self-Amplification of Aneurysms Due to Tissue Degradation and Blood Flow Revealed From FSI Simulations.

Tissue degradation plays a crucial role in the formation and rupture of aneurysms. Using numerical computer simulations, we study the combined effects of blood flow and tissue degradation on intra-aneurysm hemodynamics. Our computational analysis reveals that the degradation-induced changes of the time-averaged wall shear stress (TAWSS) and oscillatory shear index (OSI) within the aneurysm dome are inversely correlated. Importantly, their correlation is enhanced in the process of tissue degradation. Regions with a low TAWSS and a high OSI experience still lower TAWSS and higher OSI during degradation. Furthermore, we observed that degradation leads to an increase of the endothelial cell activation potential index, in particular, at places experiencing low wall shear stress. These findings are robust and occur for different geometries, degradation intensities, heart rates and pressures. We interpret these findings in the context of recent literature and argue that the degradation-induced hemodynamic changes may lead to a self-amplification of the flow-induced progressive damage of the aneurysmal wall.

Preoperative Computed Tomography Angiography Reveals Leaflet-Specific Calcification and Excursion Patterns in Aortic Stenosis.

BACKGROUND: Computed tomography-based evaluation of aortic stenosis (AS) by calcium scoring does not consider interleaflet differences in leaflet characteristics. Here, we sought to examine the functional implications of these differences. METHODS: We retrospectively reviewed the computed tomography angiograms of 200 male patients with degenerative calcific AS undergoing transcatheter aortic valve replacement and 20 male patients with normal aortic valves. We compared the computed tomography angiography (CTA)-derived aortic valve leaflet calcification load (AVLCCTA), appearance, and systolic leaflet excursion (LEsys) of individual leaflets. We performed computer simulations of normal valves to investigate how interleaflet differences in LEsys affect aortic valve area. We used linear regression to identify predictors of leaflet-specific calcification in patients with AS. RESULTS: In patients with AS, the noncoronary cusp (NCC) carried the greatest AVLCCTA (365.9 [237.3-595.4] Agatston unit), compared to the left coronary cusp (LCC, 278.5 [169.2-478.8] Agatston unit) and the right coronary cusp (RCC, 240.6 [137.3-439.0] Agatston unit; both P<0.001). However, LCC conferred the least LEsys (42.8° [38.8°-49.0°]) compared to NCC (44.8° [41.1°-49.78°], P=0.001) and RCC (47.7° [42.0°-52.3°], P<0.001) and was more often characterized as predominantly thickened (23.5%) compared to NCC (12.5%) and RCC (16.5%). Computer simulations of normal valves revealed greater reductions in aortic valve area following closures of NCC (-32.2 [-38.4 to -25.8]%) and RCC (-35.7 [-40.2 to -32.9]%) than LCC (-24.5 [-28.5 to -18.3]%; both P<0.001). By linear regression, the AVLCCTA of NCC and RCC, but not LCC, predicted LEsys (both P<0.001) in patients with AS. Both ostial occlusion and ostial height of the right coronary artery predicted AVLCCTA, RCC (P=0.005 and P=0.001). CONCLUSIONS: In male patients, the AVLCCTA of NCC and RCC contribute more to AS than that of LCC. LCC's propensity for noncalcific leaflet thickening and worse LEsys, however, should not be underestimated when using calcium scores to assess AS severity.

Fluid-structure interaction simulations of patient-specific aortic dissection.

Credible computational fluid dynamic (CFD) simulations of aortic dissection are challenging, because the defining parallel flow channels-the true and the false lumen-are separated from each other by a more or less mobile dissection membrane, which is made up of a delaminated portion of the elastic aortic wall. We present a comprehensive numerical framework for CFD simulations of aortic dissection, which captures the complex interplay between physiologic deformation, flow, pressures, and time-averaged wall shear stress (TAWSS) in a patient-specific model. Our numerical model includes (1) two-way fluid-structure interaction (FSI) to describe the dynamic deformation of the vessel wall and dissection flap; (2) prestress and (3) external tissue support of the structural domain to avoid unphysiologic dilation of the aortic wall and stretching of the dissection flap; (4) tethering of the aorta by intercostal and lumbar arteries to restrict translatory motion of the aorta; and a (5) independently defined elastic modulus for the dissection flap and the outer vessel wall to account for their different material properties. The patient-specific aortic geometry is derived from computed tomography angiography (CTA). Three-dimensional phase contrast magnetic resonance imaging (4D flow MRI) and the patient's blood pressure are used to inform physiologically realistic, patient-specific boundary conditions. Our simulations closely capture the cyclical deformation of the dissection membrane, with flow simulations in good agreement with 4D flow MRI. We demonstrate that decreasing flap stiffness from [Formula: see text] to [Formula: see text] kPa (a) increases the displacement of the dissection flap from 1.4 to 13.4 mm, (b) decreases the surface area of TAWSS by a factor of 2.3, (c) decreases the mean pressure difference between true lumen and false lumen by a factor of 0.63, and (d) decreases the true lumen flow rate by up to 20% in the abdominal aorta. We conclude that the mobility of the dissection flap substantially influences local hemodynamics and therefore needs to be accounted for in patient-specific simulations of aortic dissection. Further research to accurately measure flap stiffness and its local variations could help advance future CFD applications.

Contractile and hemodynamic forces coordinate Notch1b-mediated outflow tract valve formation.

Biomechanical forces and endothelial-to-mesenchymal transition (EndoMT) are known to mediate valvulogenesis. However, the relative contributions of myocardial contractile and hemodynamic shear forces remain poorly understood. We integrated 4-D light-sheet imaging of transgenic zebrafish models with moving-domain computational fluid dynamics to determine effects of changes in contractile forces and fluid wall shear stress (WSS) on ventriculobulbar (VB) valve development. Augmentation of myocardial contractility with isoproterenol increased both WSS and Notch1b activity in the developing outflow tract (OFT) and resulted in VB valve hyperplasia. Increasing WSS in the OFT, achieved by increasing blood viscosity through EPO mRNA injection, also resulted in VB valve hyperplasia. Conversely, decreasing myocardial contractility by Tnnt2a morpholino oligonucleotide (MO) administration, 2,3-butanedione monoxime treatment, or Plcγ1 inhibition completely blocked VB valve formation, which could not be rescued by increasing WSS or activating Notch. Decreasing WSS in the OFT, achieved by slowing heart rate with metoprolol or reducing viscosity with Gata1a MO, did not affect VB valve formation. Immunofluorescent staining with the mesenchymal marker, DM-GRASP, revealed that biomechanical force-mediated Notch1b activity is implicated in EndoMT to modulate valve morphology. Altogether, increases in WSS result in Notch1b- EndoMT-mediated VB valve hyperplasia, whereas decreases in contractility result in reduced Notch1b activity, absence of EndoMT, and VB valve underdevelopment. Thus, we provide developmental mechanotransduction mechanisms underlying Notch1b-mediated EndoMT in the OFT.

Simulating Developmental Cardiac Morphology in Virtual Reality Using a Deformable Image Registration Approach.

While virtual reality (VR) has potential in enhancing cardiovascular diagnosis and treatment, prerequisite labor-intensive image segmentation remains an obstacle for seamlessly simulating 4-dimensional (4-D, 3-D + time) imaging data in an immersive, physiological VR environment. We applied deformable image registration (DIR) in conjunction with 3-D reconstruction and VR implementation to recapitulate developmental cardiac contractile function from light-sheet fluorescence microscopy (LSFM). This method addressed inconsistencies that would arise from independent segmentations of time-dependent data, thereby enabling the creation of a VR environment that fluently simulates cardiac morphological changes. By analyzing myocardial deformation at high spatiotemporal resolution, we interfaced quantitative computations with 4-D VR. We demonstrated that our LSFM-captured images, followed by DIR, yielded average dice similarity coefficients of 0.92 ± 0.05 (n = 510) and 0.93 ± 0.06 (n = 240) when compared to ground truth images obtained from Otsu thresholding and manual segmentation, respectively. The resulting VR environment simulates a wide-angle zoomed-in view of motion in live embryonic zebrafish hearts, in which the cardiac chambers are undergoing structural deformation throughout the cardiac cycle. Thus, this technique allows for an interactive micro-scale VR visualization of developmental cardiac morphology to enable high resolution simulation for both basic and clinical science.

Spatial and temporal variations in hemodynamic forces initiate cardiac trabeculation.

Hemodynamic shear force has been implicated as modulating Notch signaling-mediated cardiac trabeculation. Whether the spatiotemporal variations in wall shear stress (WSS) coordinate the initiation of trabeculation to influence ventricular contractile function remains unknown. Using light-sheet fluorescent microscopy, we reconstructed the 4D moving domain and applied computational fluid dynamics to quantify 4D WSS along the trabecular ridges and in the groves. In WT zebrafish, pulsatile shear stress developed along the trabecular ridges, with prominent endocardial Notch activity at 3 days after fertilization (dpf), and oscillatory shear stress developed in the trabecular grooves, with epicardial Notch activity at 4 dpf. Genetic manipulations were performed to reduce hematopoiesis and inhibit atrial contraction to lower WSS in synchrony with attenuation of oscillatory shear index (OSI) during ventricular development. γ-Secretase inhibitor of Notch intracellular domain (NICD) abrogated endocardial and epicardial Notch activity. Rescue with NICD mRNA restored Notch activity sequentially from the endocardium to trabecular grooves, which was corroborated by observed Notch-mediated cardiomyocyte proliferations on WT zebrafish trabeculae. We also demonstrated in vitro that a high OSI value correlated with upregulated endothelial Notch-related mRNA expression. In silico computation of energy dissipation further supports the role of trabeculation to preserve ventricular structure and contractile function. Thus, spatiotemporal variations in WSS coordinate trabecular organization for ventricular contractile function.