Biventricular finite element modeling of the fetal heart in health and during critical aortic stenosis.

Finite Element simulations are a robust way of investigating cardiac biomechanics. To date, it has only been performed with the left ventricle (LV) alone for fetal hearts, even though results are likely different with biventricular (BiV) simulations. In this research, we conduct BiV simulations of the fetal heart based on 4D echocardiography images to show that it can capture the biomechanics of the normal healthy fetal heart, as well as those of fetal aortic stenosis better than the LV alone simulations. We found that performing LV alone simulations resulted in overestimation of LV stresses and pressures, compared to BiV simulations. Interestingly, inserting a compliance between the LV and right ventricle (RV) in the lumped parameter model of the LV only simulation effectively resolved these overestimations, demonstrating that the septum could be considered to play a LV-RV pressure communication role. However, stresses and strains spatial patterns remained altered from BiV simulations after the addition of the compliance. The BiV simulations corroborated previous studies in showing disease effects on the LV, where fetal aortic stenosis (AS) drastically elevated LV pressures and reduced strains and stroke volumes, which were moderated down with the addition of mitral regurgitation (MR). However, BiV simulations enabled an evaluation of the RV as well, where we observed that effects of the AS and MR on pressures and stroke volumes were generally much smaller and less consistent. The BiV simulations also enabled investigations of septal dynamics, which showed a rightward shift with AS, and partial restoration with MR. Interestingly, AS tended to enhance RV stroke volume, but MR moderated that down.

US2Mask: Image-to-mask generation learning via a conditional GAN for cardiac ultrasound image segmentation.

Cardiac ultrasound (US) image segmentation is vital for evaluating clinical indices, but it often demands a large dataset and expert annotations, resulting in high costs for deep learning algorithms. To address this, our study presents a framework utilizing artificial intelligence generation technology to produce multi-class RGB masks for cardiac US image segmentation. The proposed approach directly performs semantic segmentation of the heart's main structures in US images from various scanning modes. Additionally, we introduce a novel learning approach based on conditional generative adversarial networks (CGAN) for cardiac US image segmentation, incorporating a conditional input and paired RGB masks. Experimental results from three cardiac US image datasets with diverse scan modes demonstrate that our approach outperforms several state-of-the-art models, showcasing improvements in five commonly used segmentation metrics, with lower noise sensitivity. Source code is available at https://github.com/energy588/US2mask.

Pre-intervention myocardial stress is a good predictor of aortic valvoluplasty outcome for fetal critical aortic stenosis and evolving HLHS.

Fetal critical aortic stenosis with evolving hypoplastic left heart syndrome (CAS-eHLHS) causes biomechanical and functional aberrations, leading to a high risk of progression to hypoplastic left heart syndrome (HLHS) at birth. Fetal aortic valvuloplasty (FAV) can resolve outflow obstruction and may reduce progression risk. However, it is currently difficult to accurately predict which patients will respond to the intervention and become functionally biventricular (BV) at birth, as opposed to becoming functionally univentricular (UV). This prediction is important for patient selection, parental counselling, and surgical planning. Therefore, we investigated whether biomechanics parameters from pre-FAV image-based computations could robustly distinguish between CAS-eHLHS cases with BV or UV outcomes in a retrospective cohort. To do so we performed image-based finite element biomechanics modelling of nine CAS-eHLHS cases undergoing intervention and six healthy fetal control hearts, and found that a biomechanical parameter, peak systolic myofibre stress, showed a uniquely large difference between BV and UV cases, which had a larger magnitude effect than echocardiography parameters. A simplified equation was derived for quick and easy estimation of myofibre stress from echo measurements via principal component analysis. When tested on a retrospective cohort of 37 CAS-eHLHS cases, the parameter outperformed other parameters in predicting UV versus BV outcomes, and thus has a high potential of improving outcome predictions, if incorporated into patient selection procedures. Physiologically, high myocardial stresses likely indicate a healthier myocardium that can withstand high stresses and resist pathological remodelling, which can explain why it is a good predictor of BV outcomes. KEY POINTS: Predicting the morphological birth outcomes (univentricular versus biventricular) of fetal aortic valvuloplasty for fetal aortic stenosis with evolving HLHS is important for accurate patient selection, parental counselling and management decisions. Computational simulations show that a biomechanics parameter, pre-intervention peak systolic myofibre stress, is uniquely robust in distinguishing between such outcomes, outperforming all echo parameters. An empirical equation was developed to quickly compute peak systolic myofibre stress from routine echo measurements and was the best predictor of outcomes among a wide range of parameters tested.

Role of tissue biomechanics in the formation and function of myocardial trabeculae in zebrafish embryos.

Cardiac trabeculae are uneven ventricular muscular structures that develop during early embryonic heart development at the outer curvature of the ventricle. Their biomechanical function is not completely understood, and while their formation is known to be mechanosensitive, it is unclear whether ventricular tissue internal stresses play an important role in their formation. Here, we performed imaging and image-based cardiac biomechanics simulations on zebrafish embryonic ventricles to investigate these issues. Microscopy-based ventricular strain measurements show that the appearance of trabeculae coincided with enhanced deformability of the ventricular wall. Image-based biomechanical simulations reveal that the presence of trabeculae reduces ventricular tissue internal stresses, likely acting as structural support in response to the geometry of the ventricle. Passive ventricular pressure-loading experiments further reveal that the formation of trabeculae is associated with a spatial homogenization of ventricular tissue stiffnesses in healthy hearts, but gata1 morphants with a disrupted trabeculation process retain a spatial stiffness heterogeneity. Our findings thus suggest that modulating ventricular wall deformability, stresses, and stiffness are among the biomechanical functions of trabeculae. Further, experiments with gata1 morphants reveal that a reduction in fluid pressures and consequently ventricular tissue internal stresses can disrupt trabeculation, but a subsequent restoration of ventricular tissue internal stresses via vasopressin rescues trabeculation, demonstrating that tissue stresses are important to trabeculae formation. Overall, we find that tissue biomechanics is important to the formation and function of embryonic heart trabeculation. KEY POINTS: Trabeculations are fascinating and important cardiac structures and their abnormalities are linked to embryonic demise. However, their function in the heart and their mechanobiological formation processes are not completely understood. Our imaging and modelling show that tissue biomechanics is the key here. We find that trabeculations enhance cardiac wall deformability, reduce fluid pressure stresses, homogenize wall stiffness, and have alignments that are optimal for providing load-bearing structural support for the heart. We further discover that high ventricular tissue internal stresses consequent to high fluid pressures are needed for trabeculation formation through a rescue experiment, demonstrating that myocardial tissue stresses are as important as fluid flow wall shear stresses for trabeculation formation.

Safe and Efficacious Near Superhydrophobic Hemostat for Reduced Blood Loss and Easy Detachment in Traumatic Wounds.

Hemorrhage is the leading cause of trauma death, and innovation in hemostatic technology is important. The strongly hydrophobic carbon nanofiber (CNF) coating has previously been shown to have excellent hemostatic properties. However, the understanding of how CNF coating guides the coagulation cascade and the biosafety of CNF as hemostatic agents has yet to be explored. Here, our thrombin generation assay investigation showed that CNF induced fast blood coagulation via factor (F) XII activation of the intrinsic pathway. We further performed studies of a rat vein injury and demonstrated that the CNF gauze enabled a substantial reduction of blood loss compared to both the plain gauze and kaolin-imbued gauze (QuikClot). Analysis of blood samples from the model revealed no acute toxicity from the CNF gauze, with no detectable CNF deposition in any organ, suggesting that the immobilization of CNF on our gauze prevented the infiltration of CNF into the bloodstream. Direct injection of CNF into the rat vein was also investigated and found not to elicit overt acute toxicity or affect animal survival or behavior. Finally, toxicity assays with primary keratinocytes revealed minimal toxicity responses to CNF. Our studies thus supported the safety and efficacy of the CNF hemostatic gauze, highlighting its potential as a promising approach in the field of hemostatic control.

A numerical study of a left ventricular expander for heart failure with preserved ejection fraction.

Increased cardiac stiffness hinders proper left ventricular (LV) expansion, resulting in decreased volume and diastolic dysfunction. LV expanders are spring-like devices designed to improve diastolic function by facilitating mechanical outward expansion. Implantations in animals and humans have shown promising results, yet further evaluation is needed to assess a range of functions and the risk of use. In this computational study, the effectiveness and potential use of a generic LV expander were assessed by using previously generated finite-element models of induced heart failure with preserved ejection fraction (HFpEF). Following implantation, the treated models were compared to the corresponding untreated and healthy pre-induction models. The influence of device orientation and its material properties was also examined. Our results demonstrated a reduction in LV pressure and a volumetric improvement. Computed LV stresses have shown no gross irregularities. The device contributed to stress elevation during diastole while having a minor effect during systole, supporting a basic safety profile. This is the first study to use numerical analysis to assess LV expanders' performance on different HFpEF phenotypes. Improvement in heart function was demonstrated in both subjects, suggesting its potential use in various HFpEF manifestations, yet customization and optimal deployment are essential to improve heart performance.

Effects of myocardial sheetlet sliding on left ventricular function.

Left ventricle myocardium has a complex micro-architecture, which was revealed to consist of myocyte bundles arranged in a series of laminar sheetlets. Recent imaging studies demonstrated that these sheetlets re-orientated and likely slided over each other during the deformations between systole and diastole, and that sheetlet dynamics were altered during cardiomyopathy. However, the biomechanical effect of sheetlet sliding is not well-understood, which is the focus here. We conducted finite element simulations of the left ventricle (LV) coupled with a windkessel lumped parameter model to study sheetlet sliding, based on cardiac MRI of a healthy human subject, and modifications to account for hypertrophic and dilated geometric changes during cardiomyopathy remodeling. We modeled sheetlet sliding as a reduced shear stiffness in the sheet-normal direction and observed that (1) the diastolic sheetlet orientations must depart from alignment with the LV wall plane in order for sheetlet sliding to have an effect on cardiac function, that (2) sheetlet sliding modestly aided cardiac function of the healthy and dilated hearts, in terms of ejection fraction, stroke volume, and systolic pressure generation, but its effects were amplified during hypertrophic cardiomyopathy and diminished during dilated cardiomyopathy due to both sheetlet angle configuration and geometry, and that (3) where sheetlet sliding aided cardiac function, it increased tissue stresses, particularly in the myofibre direction. We speculate that sheetlet sliding is a tissue architectural adaptation to allow easier deformations of the LV walls so that LV wall stiffness will not hinder function, and to provide a balance between function and tissue stresses. A limitation here is that sheetlet sliding is modeled as a simple reduction in shear stiffness, without consideration of micro-scale sheetlet mechanics and dynamics.

Myocardial Biomechanics and the Consequent Differentially Expressed Genes of the Left Atrial Ligation Chick Embryonic Model of Hypoplastic Left Heart Syndrome.

Left atrial ligation (LAL) of the chick embryonic heart is a model of the hypoplastic left heart syndrome (HLHS) where a purely mechanical intervention without genetic or pharmacological manipulation is employed to initiate cardiac malformation. It is thus a key model for understanding the biomechanical origins of HLHS. However, its myocardial mechanics and subsequent gene expressions are not well-understood. We performed finite element (FE) modeling and single-cell RNA sequencing to address this. 4D high-frequency ultrasound imaging of chick embryonic hearts at HH25 (ED 4.5) were obtained for both LAL and control. Motion tracking was performed to quantify strains. Image-based FE modeling was conducted, using the direction of the smallest strain eigenvector as the orientations of contractions, the Guccione active tension model and a Fung-type transversely isotropic passive stiffness model that was determined via micro-pipette aspiration. Single-cell RNA sequencing of left ventricle (LV) heart tissues was performed for normal and LAL embryos at HH30 (ED 6.5) and differentially expressed genes (DEG) were identified.After LAL, LV thickness increased by 33%, strains in the myofiber direction increased by 42%, while stresses in the myofiber direction decreased by 50%. These were likely related to the reduction in ventricular preload and underloading of the LV due to LAL. RNA-seq data revealed potentially related DEG in myocytes, including mechano-sensing genes (Cadherins, NOTCH1, etc.), myosin contractility genes (MLCK, MLCP, etc.), calcium signaling genes (PI3K, PMCA, etc.), and genes related to fibrosis and fibroelastosis (TGF-ß, BMP, etc.). We elucidated the changes to the myocardial biomechanics brought by LAL and the corresponding changes to myocyte gene expressions. These data may be useful in identifying the mechanobiological pathways of HLHS.

A survey, review, and future trends of skin lesion segmentation and classification.

The Computer-aided Diagnosis or Detection (CAD) approach for skin lesion analysis is an emerging field of research that has the potential to alleviate the burden and cost of skin cancer screening. Researchers have recently indicated increasing interest in developing such CAD systems, with the intention of providing a user-friendly tool to dermatologists to reduce the challenges encountered or associated with manual inspection. This article aims to provide a comprehensive literature survey and review of a total of 594 publications (356 for skin lesion segmentation and 238 for skin lesion classification) published between 2011 and 2022. These articles are analyzed and summarized in a number of different ways to contribute vital information regarding the methods for the development of CAD systems. These ways include: relevant and essential definitions and theories, input data (dataset utilization, preprocessing, augmentations, and fixing imbalance problems), method configuration (techniques, architectures, module frameworks, and losses), training tactics (hyperparameter settings), and evaluation criteria. We intend to investigate a variety of performance-enhancing approaches, including ensemble and post-processing. We also discuss these dimensions to reveal their current trends based on utilization frequencies. In addition, we highlight the primary difficulties associated with evaluating skin lesion segmentation and classification systems using minimal datasets, as well as the potential solutions to these difficulties. Findings, recommendations, and trends are disclosed to inform future research on developing an automated and robust CAD system for skin lesion analysis.

Fluid Mechanical Effects of Fetal Aortic Valvuloplasty for Cases of Critical Aortic Stenosis with Evolving Hypoplastic Left Heart Syndrome.

Fetuses with critical aortic stenosis (FAS) are at high risk of progression to HLHS by the time of birth (and are thus termed "evolving HLHS"). An in-utero catheter-based intervention, fetal aortic valvuloplasty (FAV), has shown promise as an intervention strategy to circumvent the progression, but its impact on the heart's biomechanics is not well understood. We performed patient-specific computational fluid dynamic (CFD) simulations based on 4D fetal echocardiography to assess the changes in the fluid mechanical environment in the FAS left ventricle (LV) directly before and 2 days after FAV. Echocardiograms of five FAS cases with technically successful FAV were retrospectively analysed. FAS compromised LV stroke volume and ejection fraction, but FAV rescued it significantly. Calculations to match simulations to clinical measurements showed that FAV approximately doubled aortic valve orifice area, but it remained much smaller than in healthy hearts. Diseased LVs had mildly stenotic mitral valves, which generated fast and narrow diastolic mitral inflow jet and vortex rings that remained unresolved directly after FAV. FAV further caused aortic valve damage and high-velocity regurgitation. The high-velocity aortic regurgitation jet and vortex ring caused a chaotic flow field upon impinging the apex, which drastically exacerbated the already high energy losses and poor flow energy efficiency of FAS LVs. Two days after the procedure, FAV did not alter wall shear stress (WSS) spatial patterns of diseased LV but elevated WSS magnitudes, and the poor blood turnover in pre-FAV LVs did not significantly improve directly after FAV. FAV improved FAS LV's flow function, but it also led to highly chaotic flow patterns and excessively high energy losses due to the introduction of aortic regurgitation directly after the intervention. Further studies analysing the effects several weeks after FAV are needed to understand the effects of such biomechanics on morphological development.

Contribution of Ventricular Motion and Sampling Location to Discrepancies in Two-Dimensional Versus Three-Dimensional Fetal Ventricular Strain Measures.

BACKGROUND: Echocardiographic quantification of fetal cardiac strain is important to evaluate function and the need for intervention, with both two-dimensional (2D) and three-dimensional (3D) strain measurements currently feasible. However, discrepancies between 2D and 3D measurements have been reported, the etiologies of which are unclear. This study sought to determine the etiologies of the differences between 2D and 3D strain measurements. METHODS: A validated cardiac motion-tracking algorithm was used on 3D cine ultrasound images acquired in 26 healthy fetuses. Both 2D and 3D myocardial strain quantifications were performed on each image set for controlled comparisons. Finite element modeling of 2 left ventricle (LV) models with minor geometrical differences were performed with various helix angle configurations for validating image processing results. RESULTS: Three-dimensional longitudinal strain (LS) was significantly lower than 2D LS for the LV free wall and septum but not for the right ventricular (RV) free wall, while 3D circumferential strain (CS) was significantly higher than 2D CS for the LV, RV, and septum. The LS discrepancy was due to 2D long-axis imaging not capturing the out-of-plane motions associated with LV twist, while the CS discrepancy was due to the systolic motion of the heart toward the apex that caused out-of-plane motions in 2D short-axis imaging. A timing mismatch between the occurrences of peak longitudinal and circumferential dimensions caused a deviation in zero-strain referencing between 2D and 3D strain measurements, contributing to further discrepancies between the 2. CONCLUSIONS: Mechanisms for discrepancies between 2D and 3D strain measurements in fetal echocardiography were identified, and inaccuracies associated with 2D strains were highlighted. Understanding of this mechanism is useful and important for future standardization of fetal cardiac strain measurements, which we propose to be important in view of large discrepancies in measured values in the literature.

The dependency of fetal left ventricular biomechanics function on myocardium helix angle configuration.

The helix angle configuration of the myocardium is understood to contribute to the heart function, as finite element (FE) modeling of postnatal hearts showed that altered configurations affected cardiac function and biomechanics. However, similar investigations have not been done on the fetal heart. To address this, we performed image-based FE simulations of fetal left ventricles (LV) over a range of helix angle configurations, assuming a linear variation of helix angles from epicardium to endocardium. Results showed that helix angles have substantial influence on peak myofiber stress, cardiac stroke work, myocardial deformational burden, and spatial variability of myocardial strain. A good match between LV myocardial strains from FE simulations to those measured from 4D fetal echo images could only be obtained if the transmural variation of helix angle was generally between 110 and 130°, suggesting that this was the physiological range. Experimentally discovered helix angle configurations from the literature were found to produce high peak myofiber stress, high cardiac stroke work, and a low myocardial deformational burden, but did not coincide with configurations that would optimize these characteristics. This may suggest that the fetal development of myocyte orientations depends concurrently on several factors rather than a single factor. We further found that the shape, rather than the size of the LV, determined the manner at which helix angles influenced these characteristics, as this influence changed significantly when the LV shape was varied, but not when a heart was scaled from fetal to adult size while retaining the same shape. This may suggest that biomechanical optimality would be affected during diseases that altered the geometric shape of the LV.

Morphological, functional, and biomechanical progression of LV remodelling in a porcine model of HFpEF.

Heart failure (HF) with preserved ejection fraction (HFpEF) accounts for about half of heart failure cases, but the progression of cardiac biomechanics during pathogenesis is not completely understood. We investigated a published porcine model of HFpEF, generated by progressive constriction of an aortic cuff causing progressive left ventricle (LV) pressure overload, and characterized by hypertrophy, diastolic dysfunction and overt HF with elevated plasma beta natriuretic peptide (BNP). We characterized morphological and functional features and performed image-based finite element modelling over multiple time points, so as to understand how biomechanics evolved with morphological and functional changes during pathogenesis, and to provide data for future growth and remodeling investigations. Results showed that the hypertrophic responses quickly manifested and were effective at preventing an elevation of systolic myocardial stresses, suggesting active compensated remodeling. Consequent to the hypertrophy, diastolic myocardial stresses decreased despite the elevations in diastolic pressures. The left ventricle hypertrophy (LVH) myocardium also exhibited a quick elevation of active tension at the onset of the disease. There was a progressive and significant decrease in myocardial strain, which was more significant in the longitudinal direction. Further, elevated myocardial stiffness and diastolic pressures, which reflected diastolic dysfunction, also manifested, but this was delayed from the onset of the disease. Correlation analysis showed that hypertrophy was closely correlated to systolic pressure, active tension and systolic myocardial stress, suggesting that these factors may play a role in initiating hypertrophy. Myocardial stiffness was weakly correlated to LV pressures and myocardial stresses.

Material property alterations for phenotypes of heart failure with preserved ejection fraction: A numerical study of subject-specific porcine models.

A substantial proportion of heart failure patients have a preserved left ventricular (LV) ejection fraction (HFpEF). This condition carries a high burden of morbidity and mortality and has limited therapeutic options. left ventricular pressure overload leads to an increase in myocardial collagen content, causing left ventricular stiffening that contributes to the development of heart failure patients have a preserved left ventricular ejection fraction. Although several heart failure patients have a preserved left ventricular ejection fraction models have been developed in recent years to aid the investigation of mechanical alterations, none has investigated different phenotypes of the disease and evaluated the alterations in material properties. In this study, two similar healthy swine were subjected to progressive and prolonged pressure overload to induce diastolic heart failure characteristics, providing a preclinical model of heart failure patients have a preserved left ventricular ejection fraction. Cardiac magnetic resonance imaging (cMRI) scans and intracardiac pressures were recorded before and after induction. In both healthy and disease states, a corresponding finite element (FE) cardiac model was developed via mesh morphing of the Living Heart Porcine model. The material properties were derived by calibrating to its passive and active behavior. The change in the passive behavior was predominantly isotropic when comparing the geometries before and after induction. Myocardial thickening allowed for a steady transition in the passive properties while maintaining tissue incompressibility. This study highlights the importance of hypertrophy as an initial compensatory response and might also pave the way for assessing disease severity.

Biventricular biaxial mechanical testing and constitutive modelling of fetal porcine myocardium passive stiffness.

The evaluation of fetal heart mechanical function is becoming increasingly important for determining the prognosis and making subsequent decisions on the treatment and management of congenital heart diseases. Finite Element (FE) modelling can potentially provide detailed information on fetal hearts, and help perform virtual interventions to assist in predicting outcomes and supporting clinical decisions. Previous FE studies have enabled an improved understanding of healthy and diseased fetal heart biomechanics. However, to date, the mechanical properties of the fetal myocardium have not been well characterized which limits the reliability of such modelling. Here, we characterize the passive mechanical properties of late fetal and neonatal porcine hearts via biaxial mechanical testing as a surrogate for human fetal heart mechanical properties. We used samples from both the right and left ventricles over the late gestational period from 85 days of gestation to birth. Constitutive modelling was subsequently performed with a transversely isotropic Fung-type model and a Humphrey-type model, using fiber orientations identified with histology. We found no significant difference in mechanical stiffness across all age groups and between the right and left ventricular samples. This was likely due to the similarity in LV and RV pressures in the fetal heart, and similar gestational maturity across these late gestational ages. We thus recommend using the constitutive model for the average stress-stress behaviour of the tissues in future modelling work. Furthermore, we characterized the variability of the stiffness to inform such work.

Fluid mechanics of the zebrafish embryonic heart trabeculation.

Embryonic heart development is a mechanosensitive process, where specific fluid forces are needed for the correct development, and abnormal mechanical stimuli can lead to malformations. It is thus important to understand the nature of embryonic heart fluid forces. However, the fluid dynamical behaviour close to the embryonic endocardial surface is very sensitive to the geometry and motion dynamics of fine-scale cardiac trabecular surface structures. Here, we conducted image-based computational fluid dynamics (CFD) simulations to quantify the fluid mechanics associated with the zebrafish embryonic heart trabeculae. To capture trabecular geometric and motion details, we used a fish line that expresses fluorescence at the endocardial cell membrane, and high resolution 3D confocal microscopy. Our endocardial wall shear stress (WSS) results were found to exceed those reported in existing literature, which were estimated using myocardial rather than endocardial boundaries. By conducting simulations of single intra-trabecular spaces under varied scenarios, where the translational or deformational motions (caused by contraction) were removed, we found that a squeeze flow effect was responsible for most of the WSS magnitude in the intra-trabecular spaces, rather than the shear interaction with the flow in the main ventricular chamber. We found that trabecular structures were responsible for the high spatial variability of the magnitude and oscillatory nature of WSS, and for reducing the endocardial deformational burden. We further found cells attached to the endocardium within the intra-trabecular spaces, which were likely embryonic hemogenic cells, whose presence increased endocardial WSS. Overall, our results suggested that a complex multi-component consideration of both anatomic features and motion dynamics were needed to quantify the trabeculated embryonic heart fluid mechanics.

Fluid Mechanics of Fetal Left Ventricle During Aortic Stenosis with Evolving Hypoplastic Left Heart Syndrome.

In cases of fetal aortic stenosis and evolving Hypoplastic Left Heart Syndrome (feHLHS), aortic stenosis is associated with specific abnormalities such as retrograde or bidirectional systolic transverse arch flow. Many cases progressed to hypoplastic left heart syndrome (HLHS) malformation at birth, but fetal aortic valvuloplasty can prevent the progression in many cases. Since both disease and intervention involve drastic changes to the biomechanical environment, in-vivo biomechanics likely play a role in inducing and preventing disease progression. However, the fluid mechanics of feHLHS is not well-characterized. Here, we conduct patient-specific echocardiography-based flow simulations of normal and feHLHS left ventricles (LV), to understand the essential fluid dynamics distinction between the two cohorts. We found high variability across feHLHS cases, but also the following unifying features. Firstly, feHLHS diastole mitral inflow was in the form of a narrowed and fast jet that impinged onto the apical region, rather than a wide and gentle inflow in normal LVs. This was likely due to a malformed mitral valve with impaired opening dynamics. This altered inflow caused elevated vorticity dynamics and wall shear stresses (WSS) and reduced oscillatory shear index at the apical zone rather than mid-ventricle. Secondly, feHLHS LV also featured elevated systolic and diastolic energy losses, intraventricular pressure gradients, and vortex formation numbers, suggesting energy inefficiency of flow and additional burden on the LV. Thirdly, feHLHS LV had poor blood turnover, suggesting a hypoxic environment, which could be associated with endocardial fibroelastosis that is often observed in these patients.

Effects of Hypertrophic and Dilated Cardiac Geometric Remodeling on Ejection Fraction.

Background: Both heart failure (HF) with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF) can present a wide variety of cardiac morphologies consequent to cardiac remodeling. We sought to study if geometric changes to the heart during such remodeling will adversely affect the ejection fraction (EF) parameter's ability to serve as an indicator of heart function, and to identify the mechanism for it. Methods and Results: A numerical model that simulated the conversion of myocardial strain to stroke volume was developed from two porcine animal models of heart failure. Hypertrophic wall thickening was found to elevate EF, while left ventricle (LV) dilation was found to depress EF when myocardial strain was kept constant, causing EF to inaccurately represent the overall strain function. This was caused by EF being calculated using the endocardial boundary rather than the mid-wall layer. Radial displacement of the endocardial boundary resulted in endocardial strain deviating from the overall LV strain, and this deviation varied with LV geometric changes. This suggested that using the epi- or endo-boundaries to calculate functional parameters was not effective, and explained why EF could be adversely affected by geometric changes. Further, when EF was modified by calculating it at the mid-wall layer instead of at the endocardium, this shortcoming was resolved, and the mid-wall EF could differentiate between healthy and HFpEF subjects in our animal models, while the traditional EF could not. Conclusion: We presented the mechanism to explain why EF can no longer effectively indicate cardiac function during cardiac geometric changes relevant to HF remodeling, losing the ability to distinguish between hypertrophic diseased hearts from healthy hearts. Measuring EF at the mid-wall location rather than endocardium can avoid the shortcoming and better represent the cardiac strain function.

Cardiac mesh morphing method for finite element modeling of heart failure with preserved ejection fraction.

Numerical modeling of heart biomechanics can realistically capture morphological variations in diseases and has been helpful in advancing our understanding of the physiology. Subject-specific models require anatomic representation of medical images, and it is desirable to have a consistently repeatable models for any given morphology. In this study, we propose a novel and easily adaptable cardiac reconstruction algorithm by morphing an existing discretized mesh of an advanced finite element (FE) model, to match anatomies acquired from porcine cardiac magnetic resonance imaging (cMRI) scans. The morphing algorithm involves iterative FE simulations with visco-hyperelastic material properties. The living heart porcine model (LHPM) was chosen as the input baseline FE mesh, in order to preserve detailed anatomical features that cannot be captured in routine scans such as myofiber orientations and conduction pathways. The algorithm was demonstrated for the recreation of porcine hearts of a healthy subject and of a subject induced with heart failure with preserved ejection fraction (HFpEF) conditions, where there were substantial hypertrophy and anatomical alterations. We further used the morphed meshes for FE modeling of cardiac contraction and relaxation, thus demonstrating the applicability of the proposed algorithm in producing viable meshes. The results show that our algorithm can recreate the characteristic anatomical changes of cardiac remodeling, including heart muscle thickening, as well as replicate the reduction in ventricular volume. This algorithm allows for the creation of subject-specific models with the same mesh connectivity, thus enabling spatial comparison and analysis of pathologic progress.

Bioelectric signaling and the control of cardiac cell identity in response to mechanical forces.

Developing cardiovascular systems use mechanical forces to take shape, but how ubiquitous blood flow forces instruct local cardiac cell identity is still unclear. By manipulating mechanical forces in vivo, we show here that shear stress is necessary and sufficient to promote valvulogenesis. We found that valve formation is associated with the activation of an extracellular adenosine triphosphate (ATP)­dependent purinergic receptor pathway, specifically triggering calcium ion (Ca2+) pulses and nuclear factor of activated T cells 1 (Nfatc1) activation. Thus, mechanical forces are converted into discrete bioelectric signals by an ATP-Ca2+-Nfatc1­mechanosensitive pathway to generate positional information and control valve formation.