Bayesian Optimization-Based Inverse Finite Element Analysis for Atrioventricular Heart Valves.

Inverse finite element analysis (iFEA) of the atrioventricular heart valves (AHVs) can provide insights into the in-vivo valvular function, such as in-vivo tissue strains; however, there are several limitations in the current state-of-the-art that iFEA has not been widely employed to predict the in-vivo, patient-specific AHV leaflet mechanical responses. In this exploratory study, we propose the use of Bayesian optimization (BO) to study the AHV functional behaviors in-vivo. We analyzed the efficacy of Bayesian optimization to estimate the isotropic Lee-Sacks material coefficients in three benchmark problems: (i) an inflation test, (ii) a simplified leaflet contact model, and (iii) an idealized AHV model. Then, we applied the developed BO-iFEA framework to predict the leaflet properties for a patient-specific tricuspid valve under a congenital heart defect condition. We found that the BO could accurately construct the objective function surface compared to the one from a [Formula: see text] grid search analysis. Additionally, in all cases the proposed BO-iFEA framework yielded material parameter predictions with average element errors less than 0.02 mm/mm (normalized by the simulation-specific characteristic length). Nonetheless, the solutions were not unique due to the presence of a long-valley minima region in the objective function surfaces. Parameter sets along this valley can yield functionally equivalent outcomes (i.e., closing behavior) and are typically observed in the inverse analysis or parameter estimation for the nonlinear mechanical responses of the AHV. In this study, our key contributions include: (i) a first-of-its-kind demonstration of the BO method used for the AHV iFEA; and (ii) the evaluation of a candidate AHV in-silico modeling approach wherein the chordae could be substituted with equivalent displacement boundary conditions, rendering the better iFEA convergence and a smoother objective surface.

Tricuspid Valve Regurgitation in Hypoplastic Left Heart Syndrome: Current Insights and Future Perspectives.

Hypoplastic Left Heart Syndrome (HLHS) is a congenital heart defect that requires a three-stage surgical palliation to create a single ventricle system in the right side of the heart. Of patients undergoing this cardiac palliation series, 25% will develop tricuspid regurgitation (TR), which is associated with an increased mortality risk. Valvular regurgitation in this population has been extensively studied to understand indicators and mechanisms of comorbidity. In this article, we review the current state of research on TR in HLHS, including identified valvular anomalies and geometric properties as the main reasons for the poor prognosis. After this review, we present some suggestions for future TR-related studies to answer the central question: What are the predictors of TR onset during the three palliation stages? These studies involve (i) the use of engineering-based metrics to evaluate valve leaflet strains and predict tissue material properties, (ii) perform multivariate analyses to identify TR predictors, and (iii) develop predictive models, particularly using longitudinally tracked patient cohorts to foretell patient-specific trajectories. Regarded together, these ongoing and future efforts will result in the development of innovative tools that can aid in surgical timing decisions, in prophylactic surgical valve repair, and in the refinement of current intervention techniques.

The Lasso Suture: Ex Vivo Testing of an Alternative to the High-Tension Deep Dermal Stitch.

SUMMARY: Wound dehiscence, with an estimated occurrence rate greater than 4% in plastic surgery, is generally underreported, and can be an indicator of increased mortality and remission rates. The authors developed the lasso suture as a stronger alternative to the current standard patterns. The lasso suture takes less time to perform than the standard high-tension wound repair method. The authors dissected caprine skin specimens to create full-thickness wounds for suture repair using simple interrupted, vertical mattress, horizontal mattress, and deep dermal with running intradermal (DDR) sutures ( n = 10) and lasso sutures ( n = 9). They then conducted uniaxial failure testing to quantify the suture rupture stresses and strains. They also measured the suture operating time with medical students and residents (PGY or MS programs) performing wound repair (10-cm wide, 2-cm deep, 2-0 polydioxanone sutures) on soft-fixed human cadaver skin. The lasso stitch had a greater first-suture rupture stress compared with all other patterns ( P < 0.001): 2.46 ± 0.27 MPa for lasso versus 0.69 ± 0.14 MPa for simple interrupted, 0.68 ± 0.13 MPa for vertical mattress, 0.50 ± 0.10 MPa for horizontal mattress, and 1.17 ± 0.28 MPa for DDR sutures. Performing the lasso suture was 28% faster than performing standard DDR (264 ± 21 versus 349 ± 25 seconds; P = 0.027). In summary, the authors showed that the lasso has superior mechanical properties compared with the studied traditional sutures, and that the new technique can be performed more quickly than the current standard (DDR stitch) for high-tension wounds. Future animal and in-clinic studies will be helpful to confirm the authors' findings in this proof-of-concept study. CLINICAL RELEVANCE STATEMENT: The authors propose the lasso suture, a new suturing method with improved tensile performance compared with traditional techniques and a faster operative time than the deep dermal stitch typically used for high-tension wounds in reconstructive surgery to prevent wound dehiscence.

A Physics-Guided Neural Operator Learning Approach to Model Biological Tissues From Digital Image Correlation Measurements.

We present a data-driven workflow to biological tissue modeling, which aims to predict the displacement field based on digital image correlation (DIC) measurements under unseen loading scenarios, without postulating a specific constitutive model form nor possessing knowledge of the material microstructure. To this end, a material database is constructed from the DIC displacement tracking measurements of multiple biaxial stretching protocols on a porcine tricuspid valve anterior leaflet, with which we build a neural operator learning model. The material response is modeled as a solution operator from the loading to the resultant displacement field, with the material microstructure properties learned implicitly from the data and naturally embedded in the network parameters. Using various combinations of loading protocols, we compare the predictivity of this framework with finite element analysis based on three conventional constitutive models. From in-distribution tests, the predictivity of our approach presents good generalizability to different loading conditions and outperforms the conventional constitutive modeling at approximately one order of magnitude. When tested on out-of-distribution loading ratios, the neural operator learning approach becomes less effective. To improve the generalizability of our framework, we propose a physics-guided neural operator learning model via imposing partial physics knowledge. This method is shown to improve the model's extrapolative performance in the small-deformation regime. Our results demonstrate that with sufficient data coverage and/or guidance from partial physics constraints, the data-driven approach can be a more effective method for modeling biological materials than the traditional constitutive modeling.

A pilot investigation of the tricuspid valve annulus in newborns with hypoplastic left heart syndrome.

Objective: Hypoplastic left heart syndrome (HLHS) is a congenital disease characterized by an underdevelopment of the anatomical components inside the left heart. Approximately 30% of HLHS newborns will develop tricuspid regurgitation (TR), and it is currently unknown how the valve annulus mechanics and geometry are associated with regurgitation. Thus, we present an engineering mechanics-based analysis approach to quantify the mechanics and geometry of the HLHS-afflicted tricuspid valve (TV), using 4-dimensional echocardiograms. Methods: Infants born with hypoplastic left heart syndrome (n=8) and healthy newborns (n=4) had their tricuspid valves imaged, and the data was imported to the 3D Slicer. The annular curves were defined at five points in the cardiac cycle. The geometry and deformation (strain) of the TV annulus were calculated to elucidate the mechanics of this critical structure, and compare them between HLHS and normal neonates. Results: For the annular geometry, HLHS-afflicted newborns had significantly larger annular circumferences (20-30%) and anterior-posterior diameters (35-45%) than the healthy patients. From a biomechanics perspective, the HLHS patients had significantly smaller strains in the anterior segments (-0.1±2.6%) during end diastolic and end isovolumetric relaxation (1.7±3.0%) compared to the healthy counterparts (-13.3±2.9% and 6.8±0.9%, respectively). Conclusions: The image-based analysis in this study may provide novel insights into the geometric and mechanistic differences in the TV annulus between healthy and HLHS newborns. Future longitudinal studies of the biomechanics of TV annulus and other subvalvular structures may inform our understanding of the initiation and development of TR and the design of optimal repairs in this challenging population.

Benchtop characterization of the tricuspid valve leaflet pre-strains.

The pre-strains of biological soft tissues are important when relating their in vitro and in vivo mechanical behaviors. In this study, we present the first-of-its-kind experimental characterization of the tricuspid valve leaflet pre-strains. We use 3D photogrammetry and the reproducing kernel method to calculate the pre-strains within the central 10×10 mm region of the tricuspid valve leaflets from n=8 porcine hearts. In agreement with previous pre-strain studies for heart valve leaflets, our results show that all the three tricuspid valve leaflets shrink after being explanted from the ex vivo heart. These calculated strains are leaflet-specific and the septal leaflet experiences the most compressive changes. Furthermore, the strains observed after dissection of the central 10×10 mm region of the leaflet are smaller than when the valve is explanted, suggesting that our computed pre-strains are mainly due to the release of in situ annulus and chordae connections. The leaflets are then mounted on a biaxial testing device and preconditioned using force-controlled equibiaxial loading. We show that the employed preconditioning protocol does not 100% restore the leaflet pre-strains as removed during tissue dissection, and future studies are warranted to explore alternative preconditioning methods. Finally, we compare the calculated biomechanically oriented metrics considering five stress-free reference configurations. Interestingly, the radial tissue stretches and material anisotropies are significantly smaller compared to the post-preconditioning configuration. Extensions of this work can further explore the role of this unique leaflet-specific leaflet pre-strains on in vivo valve behavior via high-fidelity in-silico models. STATEMENT OF SIGNIFICANCE: This study provides a first of its kind benchtop characterization of tricuspid valve leaflet pre-strains. We used 3D photogrammetry to reconstruct the central region of the tricuspid valve leaflets in three configurations. The associated configurational changes revealed compressive, leaflet-specific strains after dissection of the valve from its in situ environment. Interestingly, we found that biaxial preconditioning did not restore the measured pre-strains of the leaflets. Depending on the selection of the stress-free reference configuration, this led to substantial differences in the leaflet mechanics. Our findings and methodology are crucial when it comes to relating in vitro mechanical behaviors to valve function in vivo. Future studies can integrate our quantified pre-strains into in-silico simulations to get more realistic predictions about the valve function.

Ex vivo experimental characterizations for understanding the interrelationship between tissue mechanics and collagen microstructure of porcine mitral valve leaflets.

Unidirectional blood flow in the left side of the heart is regulated by the mitral valve. To better understand the mitral valve function, researchers have examined the structural and mechanical properties of the mitral valve leaflets; however, limitations of the previous studies include the use of mechanics- and structure-altering tissue modifications (e.g., optical clearing) that limit the ability to quantify the unique load-dependent reorientation and realignment of the collagen fibers as well as their interrelation with the valve tissue mechanics. Herein, we aimed to circumvent these limitations by utilizing an integrated polarized-light imaging and biaxial testing system for understanding the mechanics-microstructure interrelationship for porcine mitral valve leaflets. We further performed constitutive modeling and evaluated the accuracy of the affine fiber kinematics theory. From the tissue mechanics perspective, the posterior leaflet was more extensible in the radial direction than the anterior leaflet (14.2% difference in radial tissue stretch), while exhibiting smaller collagen and elastin moduli based on the determined constitutive model parameters. From the collagen microstructure's standpoint, the posterior leaflet had smaller increases in optical anisotropy (closely related to the degree of fiber alignment) than the anterior leaflet (32.8±7.7% vs. 50.0±19.7%). Further, the leaflets were found to possess two distinct fiber families - one family oriented along the circumferential tissue direction, and another more disperse family with a 30°-40° offset from the first fiber family. Finally, affine fiber kinematics consistently underpredicted the collagen fiber reorientations Overall, this study improved our understanding of the mitral valve leaflets that is essential for facilitating tissue-emulated valve replacement and cardiac valve modeling frameworks.

Effects of enzyme-based removal of collagen and elastin constituents on the biaxial mechanical responses of porcine atrioventricular heart valve anterior leaflets.

The leaflets of the atrioventricular heart valves (AHVs) regulate the one-directional flow of blood through a coordination of the extracellular matrix components, including the collagen fibers, elastin, and glycosaminoglycans. Dysfunction of the AHVs, such as those caused by unfavorable microstructural remodeling, lead to valvular heart diseases and improper blood flow, which can ultimately cause heart failure. In order to better understand the mechanics and remodeling of the AHV leaflets and how therapeutics can inadvertently cause adverse microstructural changes, a systematic characterization of the role of each constituent in the biomechanical properties is appropriate. Previous studies have quantified the contributions of the individual microstructural components to tissue-level behavior for the semilunar valve cusps, but not for the AHV leaflets. In this study, for the first time, we quantify the relationships between microstructure and mechanics of the AHV leaflet using a three-step experimental procedure: (i) biaxial tension and stress relaxation testing of control (untreated) porcine AHV anterior leaflet specimens; (ii) enzyme treatment to remove a portion of either the collagen or elastin constituent; and (iii) biaxial tensile and stress relaxation testing of the constituent-removed (treated) specimens. We have observed that the removal of ∼100% elastin resulted in a ∼10% decrease in the tissue extensibility with biaxial tension and a ∼10% increase in the overall stress reduction with stress relaxation. In contrast, removal of 46% of the collagen content insignificantly affected tissue extensibility with biaxial tension and significantly increased stress decay (10%) with stress relaxation. These findings provide an insight into the microstructure-mechanics relationship of the AHVs and will be beneficial for future developments and refinements of microstructurally informed constitutive models for the simulation of diseased and surgically intervened AHV function. STATEMENT OF SIGNIFICANCE: This study presents, for the first time, a thorough mechanical characterization of the atrioventricular heart valve leaflets before and after enzymatic removal of elastin and collagen. We found that the biaxial tensile properties of elastin-deficient tissues and collagen-deficient are stiffer. The fact of elastin supporting low-stress valve function and collagen as the main load-bearing component was evident in a decrease in the low-tension modulus for elastin-deficient tissues and in the high-tension modulus for collagen-deficient tissues. Our quantification and experimental technique could be useful in predicting the disease-related changes in heart valve mechanics. The information obtained from this work is valuable for refining the constitutive models that describe the essential microstructure-mechanics relationship.

Evaluation of affine fiber kinematics in porcine tricuspid valve leaflets using polarized spatial frequency domain imaging and planar biaxial testing.

Collagen fibers are the primary load-bearing microstructural constituent of bodily soft tissues, and, when subjected to external loading, the collagen fibers reorient, uncrimp, and elongate. Specific to the atrioventricular heart valve leaflets, the collagen fiber kinematics form the basis of many constitutive models; however, some researchers claim that modeling the affine fiber kinematics (AFK) are sufficient for accurately predicting the macroscopic tissue deformations, while others state that modeling the non-affine kinematics (i.e., fiber uncrimping together with elastic elongation) is required. Experimental verification of the AFK theory has been previously performed for the mitral valve leaflets in the left-side heart; however, this same evaluation has yet to be performed for the morphologically distinct tricuspid valve (TV) leaflets in the right-side heart. In this work, we, for the first time, evaluated the AFK theory for the TV leaflets using an integrated biaxial testing-polarized spatial frequency domain imaging device to experimentally quantify the load-dependent collagen fiber reorientations for comparison to the AFK theory predictions. We found that the AFK theory generally underpredicted the fiber reorientations by 3.1°, on average, under the applied equibiaxial loading with greater disparity when the tissue was subjected to the applied non-equibiaxial loading. Furthermore, increased AFK errors were observed with increasing collagen fiber reorientations (Pearson coefficient r = -0.36, equibiaxial loading), suggesting the AFK theory is better suited for relatively smaller reorientations. Our findings suggest the AFK theory may require modification for more accurate predictions of the collagen fiber kinematics in the TV leaflets, which will be useful in refining modeling efforts for more accurate TV simulations.

Quantification of load-dependent changes in the collagen fiber architecture for the strut chordae tendineae-leaflet insertion of porcine atrioventricular heart valves.

Atrioventricular heart valves (AHVs) regulate the unidirectional flow of blood through the heart by opening and closing of the leaflets, which are supported in their functions by the chordae tendineae (CT). The leaflets and CT are primarily composed of collagen fibers that act as the load-bearing component of the tissue microstructures. At the CT-leaflet insertion, the collagen fiber architecture is complex, and has been of increasing focus in the previous literature. However, these previous studies have not been able to quantify the load-dependent changes in the tissue's collagen fiber orientations and alignments. In the present study, we address this gap in knowledge by quantifying the changes in the collagen fiber architecture of the mitral and tricuspid valve's strut CT-leaflet insertions in response to the applied loads by using a unique approach, which combines polarized spatial frequency domain imaging with uniaxial mechanical testing. Additionally, we characterized these microstructural changes across the same specimen without the need for tissue fixatives. We observed increases in the collagen fiber alignments in the CT-leaflet insertion with increased loading, as described through the degree of optical anisotropy. Furthermore, we used a leaflet-CT-papillary muscle entity method during uniaxial testing to quantify the chordae tendineae mechanics, including the derivation of the Ogden-type constitutive modeling parameters. The results from this study provide a valuable insight into the load-dependent behaviors of the strut CT-leaflet insertion, offering a research avenue to better understand the relationship between tissue mechanics and the microstructure, which will contribute to a deeper understanding of AHV biomechanics.

A Pilot Study on Linking Tissue Mechanics with Load-Dependent Collagen Microstructures in Porcine Tricuspid Valve Leaflets.

The tricuspid valve (TV) is composed of three leaflets that coapt during systole to prevent deoxygenated blood from re-entering the right atrium. The connection between the TV leaflets' microstructure and the tissue-level mechanical responses has yet to be fully understood in the TV biomechanics society. This pilot study sought to examine the load-dependent collagen fiber architecture of the three TV leaflets, by employing a multiscale, combined experimental approach that utilizes tissue-level biaxial mechanical characterizations, micro-level collagen fiber quantification, and histological analysis. Our results showed that the three TV leaflets displayed greater extensibility in the tissues' radial direction than in the circumferential direction, consistently under different applied biaxial tensions. Additionally, collagen fibers reoriented towards the direction of the larger applied load, with the largest changes in the alignment of the collagen fibers under radially-dominant loading. Moreover, collagen fibers in the belly region of the TV leaflets were found to experience greater reorientations compared to the tissue region closer to the TV annulus. Furthermore, histological examinations of the TV leaflets displayed significant regional variation in constituent mass fraction, highlighting the heterogeneous collagen microstructure. The combined experimental approach presented in this work enables the connection of tissue mechanics, collagen fiber microstructure, and morphology for the TV leaflets. This experimental methodology also provides a new research platform for future developments, such as multiscale models for the TVs, and the design of bioprosthetic heart valves that could better mimic the mechanical, microstructural, and morphological characteristics of the native tricuspid valve leaflets.

Mechanics and Microstructure of the Atrioventricular Heart Valve Chordae Tendineae: A Review.

The atrioventricular heart valves (AHVs) are responsible for directing unidirectional blood flow through the heart by properly opening and closing the valve leaflets, which are supported in their function by the chordae tendineae and the papillary muscles. Specifically, the chordae tendineae are critical to distributing forces during systolic closure from the leaflets to the papillary muscles, preventing leaflet prolapse and consequent regurgitation. Current therapies for chordae failure have issues of disease recurrence or suboptimal treatment outcomes. To improve those therapies, researchers have sought to better understand the mechanics and microstructure of the chordae tendineae of the AHVs. The intricate structures of the chordae tendineae have become of increasing interest in recent literature, and there are several key findings that have not been comprehensively summarized in one review. Therefore, in this review paper, we will provide a summary of the current state of biomechanical and microstructural characterizations of the chordae tendineae, and also discuss perspectives for future studies that will aid in a better understanding of the tissue mechanics-microstructure linking of the AHVs' chordae tendineae, and thereby improve the therapeutics for heart valve diseases caused by chordae failures.

Mechanics of Porcine Heart Valves' Strut Chordae Tendineae Investigated as a Leaflet-Chordae-Papillary Muscle Entity.

Proper blood flow through the atrioventricular heart valves (AHVs) relies on the holistic function of the valve and subvalvular structures, and a failure of any component can lead to life-threatening heart disease. A comprehension of the mechanical characteristics of healthy valvular components is necessary for the refinement of heart valve computational models. In previous studies, the chordae tendineae have been mechanically characterized as individual structures, usually in a clamping-based approach, which may not accurately reflect the in vivo chordal interactions with the leaflet insertion and papillary muscles. In this study, we performed uniaxial mechanical testing of strut chordae tendineae of the AHVs under a unique tine-based leaflet-chordae-papillary muscle testing to observe the chordae mechanics while preserving the subvalvular component interactions. Results of this study provided insight to the disparity of chordae tissue stress-stretch responses between the mitral valve (MV) and the tricuspid valve (TV) under their respective emulated physiological loading. Specifically, strut chordae tendineae of the MV anterior leaflet had peak stretches of 1.09-1.16, while peak stretches of 1.08-1.11 were found for the TV anterior leaflet strut chordae. Constitutive parameters were also derived for the chordae tissue specimens using an Ogden model, which is useful for AHV computational model refinement. Results of this study are beneficial to the eventual improvement of treatment methods for valvular disease.

An investigation of the effect of freezing storage on the biaxial mechanical properties of excised porcine tricuspid valve anterior leaflets.

The atrioventricular heart valve (AHV) leaflets are critical to the facilitation of proper unidirectional blood flow through the heart. Previously, studies have been conducted to understand the tissue mechanics of healthy AHV leaflets to inform the development of valve-specific computational models and replacement materials for use in diagnosing and treating valvular heart disease. Generally, these studies involved biaxial mechanical testing of the AHV leaflet tissue specimens to extract relevant mechanical properties. Most of those studies considered freezing-based storage systems based on previous findings for other connective tissues such as aortic tissue or skin. However, there remains no study that specifically examines the effects of freezing storage on the characterized mechanical properties of the AHV leaflets. In this study, we aimed to address this gap in knowledge by performing biaxial mechanical characterizations of the tricuspid valve anterior leaflet (TVAL) tissue both before and after a 48-h freezing period. Primary findings of this study include: (i) a statistically insignificant change in the tissue extensibilities, with the frozen tissues being slightly stiffer and more anisotropic than the fresh tissues; and (ii) minimal variations in the stress relaxation behaviors between the fresh and frozen tissues, with the frozen tissues demonstrating slightly lessened relaxation. The findings from this study suggested that freezing-based storage does not significantly impact the observed mechanical properties of one of the five AHV leaflets-the TVAL. The results from this study are useful for reaffirming the experimental methodologies in the previous studies, as well as informing the tissue preservation methods of future investigations of AHV leaflet mechanics.

An investigation of the glycosaminoglycan contribution to biaxial mechanical behaviours of porcine atrioventricular heart valve leaflets.

The atrioventricular heart valve (AHV) leaflets have a complex microstructure composed of four distinct layers: atrialis, ventricularis, fibrosa and spongiosa. Specifically, the spongiosa layer is primarily proteoglycans and glycosaminoglycans (GAGs). Quantification of the GAGs' mechanical contribution to the overall leaflet function has been of recent focus for aortic valve leaflets, but this characterization has not been reported for the AHV leaflets. This study seeks to expand current GAG literature through novel mechanical characterizations of GAGs in AHV leaflets. For this characterization, mitral and tricuspid valve anterior leaflets (MVAL and TVAL, respectively) were: (i) tested by biaxial mechanical loading at varying loading ratios and by stress-relaxation procedures, (ii) enzymatically treated for removal of the GAGs and (iii) biaxially mechanically tested again under the same protocols as in step (i). Removal of the GAG contents from the leaflet was conducted using a 100 min enzyme treatment to achieve approximate 74.87% and 61.24% reductions of all GAGs from the MVAL and TVAL, respectively. Our main findings demonstrated that biaxial mechanical testing yielded a statistically significant difference in tissue extensibility after GAG removal and that stress-relaxation testing revealed a statistically significant smaller stress decay of the enzyme-treated tissue than untreated tissues. These novel findings illustrate the importance of GAGs in AHV leaflet behaviour, which can be employed to better inform heart valve therapeutics and computational models.

An investigation of layer-specific tissue biomechanics of porcine atrioventricular valve anterior leaflets.

Atrioventricular heart valves (AHVs) are composed of structurally complex and morphologically heterogeneous leaflets. The coaptation of these leaflets during the cardiac cycle facilitates unidirectional blood flow. Valve regurgitation is treated preferably by surgical repair if possible or replacement based on the disease state of the valve tissue. A comprehensive understanding of valvular morphology and mechanical properties is crucial to refining computational models, serving as a patient-specific diagnostic and surgical tool for preoperative planning. Previous studies have modeled the stress distribution throughout the leaflet's thickness, but validations with layer-specific biaxial mechanical experiments are missing. In this study, we sought to fill this gap in literature by investigating the impact of microstructure constituents on mechanical behavior throughout the thickness of the AHVs' anterior leaflets. Porcine mitral valve anterior leaflets (MVAL) and tricuspid valve anterior leaflets (TVAL) were micro-dissected into three layers (atrialis/spongiosa, fibrosa, and ventricular) and two layers (atrialis/spongiosa and fibrosa/ventricularis), respectively, based on their relative distributions of extracellular matrix components as quantified by histological analyses: collagen, elastin, and glycosaminoglycans. Our results suggest that (i) for both valves, the atrialis/spongiosa layer is the most extensible and anisotropic layer, possibly due to its relatively low collagen content as compared to other layers, (ii) the intact TVAL response is stiffer than the atrialis/spongiosa layer but more compliant than the fibrosa/ventricularis layer, and (iii) the MVAL fibrosa and ventricularis layers behave nearly isotropic. These novel findings emphasize the biomechanical variances throughout the AHV leaflets, and our results could better inform future AHV computational model developments. STATEMENT OF SIGNIFICANCE: This study, which is the first of its kind for atrioventricular heart valve (AHV) leaflet tissue layers, rendered a mechanical characterization of the biaxial mechanical properties and distributions of extracellular matrix components (collagen, elastin, and glycosaminoglycans) of the mitral and tricuspid valve anterior leaflet layers. The novel findings from the present study emphasize the biomechanical variances throughout the thickness of AHV leaflets, and our results indicate that the previously-adopted homogenous leaflet in the AHV biomechanical modeling may be an oversimplification of the complex leaflet anatomy. Such improvement in the understanding of valvular morphology and tissue mechanics is crucial to future refinement of AHV computational models, serving as a patient-specific diagnostic and surgical tool, at the preoperative stage, for treating valvular heart diseases.

Mechanics of the Tricuspid Valve-From Clinical Diagnosis/Treatment, In-Vivo and In-Vitro Investigations, to Patient-Specific Biomechanical Modeling.

Proper tricuspid valve (TV) function is essential to unidirectional blood flow through the right side of the heart. Alterations to the tricuspid valvular components, such as the TV annulus, may lead to functional tricuspid regurgitation (FTR), where the valve is unable to prevent undesired backflow of blood from the right ventricle into the right atrium during systole. Various treatment options are currently available for FTR; however, research for the tricuspid heart valve, functional tricuspid regurgitation, and the relevant treatment methodologies are limited due to the pervasive expectation among cardiac surgeons and cardiologists that FTR will naturally regress after repair of left-sided heart valve lesions. Recent studies have focused on (i) understanding the function of the TV and the initiation or progression of FTR using both in-vivo and in-vitro methods, (ii) quantifying the biomechanical properties of the tricuspid valve apparatus as well as its surrounding heart tissue, and (iii) performing computational modeling of the TV to provide new insight into its biomechanical and physiological function. This review paper focuses on these advances and summarizes recent research relevant to the TV within the scope of FTR. Moreover, this review also provides future perspectives and extensions critical to enhancing the current understanding of the functioning and remodeling tricuspid valve in both the healthy and pathophysiological states.