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

The effects of leaflet material properties on the simulated function of regurgitant mitral valves

Advances in three-dimensional imaging provide the ability to construct and analyze finite element (FE) models to evaluate the biomechanical behavior and function of atrioventricular valves. However, while obtaining patient-specific valve geometry is now possible, non-invasive measurement of patient-specific leaflet material properties remains nearly impossible. Both valve geometry and tissue properties play a significant role in governing valve dynamics, leading to the central question of whether clinically relevant insights can be attained from FE analysis of atrioventricular valves without precise knowledge of tissue properties. As such we investigated 1) the influence of tissue extensibility and 2) the effects of constitutive model parameters and leaflet thickness on simulated valve function and mechanics. We compared metrics of valve function (e.g., leaflet coaptation and regurgitant orifice area) and mechanics (e.g., stress and strain) across one normal and three regurgitant mitral valve (MV) models with common mechanisms of regurgitation (annular dilation, leaflet prolapse, leaflet tethering) of both moderate and severe degree. We developed a novel fully-automated approach to accurately quantify regurgitant orifice areas of complex valve geometries. We found that the relative ordering of the mechanical and functional metrics was maintained across a group of valves using material properties up to 15% softer than the representative adult mitral constitutive model. Our findings suggest that FE simulations can be used to qualitatively compare how differences and alterations in valve structure affect relative atrioventricular valve function even in populations where material properties are not precisely known

Moving Domain Computational Fluid Dynamics to Interface with an Embryonic Model of Cardiac Morphogenesis

Peristaltic contraction of the embryonic heart tube produces time- and spatial-varying wall shear stress (WSS) and pressure gradients (∇P) across the atrioventricular (AV) canal. Zebrafish (Danio rerio) are a genetically tractable system to investigate cardiac morphogenesis. The use of Tg(fli1a:EGFP)y1 transgenic embryos allowed for delineation and two-dimensional reconstruction of the endocardium. This time-varying wall motion was then prescribed in a two-dimensional moving domain computational fluid dynamics (CFD) model, providing new insights into spatial and temporal variations in WSS and ∇P during cardiac development. The CFD simulations were validated with particle image velocimetry (PIV) across the atrioventricular (AV) canal, revealing an increase in both velocities and heart rates, but a decrease in the duration of atrial systole from early to later stages. At 20-30 hours post fertilization (hpf), simulation results revealed bidirectional WSS across the AV canal in the heart tube in response to peristaltic motion of the wall. At 40-50 hpf, the tube structure undergoes cardiac looping, accompanied by a nearly 3-fold increase in WSS magnitude. At 110-120 hpf, distinct AV valve, atrium, ventricle, and bulbus arteriosus form, accompanied by incremental increases in both WSS magnitude and ∇P, but a decrease in bi-directional flow. Laminar flow develops across the AV canal at 20-30 hpf, and persists at 110-120 hpf. Reynolds numbers at the AV canal increase from 0.07±0.03 at 20-30 hpf to 0.23±0.07 at 110-120 hpf (p< 0.05, n=6), whereas Womersley numbers remain relatively unchanged from 0.11 to 0.13. Our moving domain simulations highlights hemodynamic changes in relation to cardiac morphogenesis; thereby, providing a 2-D quantitative approach to complement imaging analysis. © 2013 Lee et al

A patient-specific adaptation of the Living Human Heart Model in application to pulmonary hypertension

The Living Heart Project aims to offer medical practitioners and researchers a full-heart electromechanical computational platform to explore and assess clinical cases pertaining to the left ventricle (LV), and the less addressed right ventricle (RV). It does not, however, provide an easy solution to applying this platform to patient-specific cases that account for a large variability among cases. We, therefore, present a solution to modify the Living Human Heart Model (LHHM) to obtain a patient-specific geometry using the thermal expansion method, with iteratively adjusted parameters that accurately simulate the case of a 72-year-old female patient suffering from secondary pulmonary hypertension caused by mitral valve regurgitation (MR). The patient underwent MV replacement and we simulate the heart from magnetic resonance imaging (MRI) images prior to surgery and 3 days following surgery. A mean pulmonary arterial pressure (mPAP) of approximately 64 mmHg was demonstrated before surgery, along with a severe lack of coaptation of the mitral valve. Reduced function of the cardiac chambers is exhibited in the reduced ejection fraction (EF). We also demonstrate left-side failure, an increase in Global Longitudinal Strain (GLS) and the location of maximum cardiac wall stress located at the mid anterolateral wall of the RV where dilation traditionally manifests. Comparison of patient geometry pre-operation and post-surgery showed a change in shape of the Tricuspid Annulus (TA) in systole. A rigid constraint across the TA was used to simulate an annuloplasty ring, and an increase in ring-widening forces was observed post-operation, with a significant reduction in forces being present in contractile forces on the ring. This model led us to conclude that the patient will likely develop TV annular dilatation and subsequent regurgitation in the absence of intervention. We verify the use of the LHHM for assessing potential remodeling and subclinical RV dysfunction, and subsequent intervention and attenuation of pulmonary hypertension by a mitral valve replacement. The lack of personalization and wide variability have remained a significant reason for the slow adoption rate of computational tools among medical practitioners, but we see this work as a substantial addition to computational cardiology, and foresee a closer integration of such technology to mainstream application among members of the medical community

DEVELOPMENT AND IMPLEMENTATION OF NOVEL STRATEGIES TO EXPLOIT 3D ULTRASOUND IMAGING IN CARDIOVASCULAR COMPUTATIONAL BIOMECHANICS

Introduction In the past two decades, major advances have been made in cardiovascular diseases assessment and treatment owing to the advent of sophisticated and more accurate imaging techniques, allowing for better understanding the complexity of 3D anatomical cardiovascular structures1. Volumetric acquisition enables the visualization of cardiac districts from virtually any perspective, better appreciating patient-specific anatomical complexity, as well as an accurate quantitative functional evaluation of chamber volumes and mass avoiding geometric assumptions2. Additionally, this scenario also allowed the evolution from generic to patient-specific 3D cardiac models that, based on in vivo imaging, faithfully represent the anatomy and different cardiac features of a given alive subject, being pivotal either in diagnosis and in planning guidance3. Precise morphological and functional knowledge about either the heart valves\u2019 apparatus and the surrounding structures is crucial when dealing with diagnosis as well as preprocedural planning4. To date, computed tomography (CT) and real-time 3D echocardiography (rt3DE) are typically exploited in this scenario since they allow for encoding comprehensive structural and dynamic information even in the fourth dimension (i.e., time)5,6. However, owing to its cost-effectiveness and very low invasiveness, 3D echocardiography has become the method of choice in most situations for performing the evaluation of cardiac function, developing geometrical models which can provide quantitative anatomical assessment7. Complementing this scenario, computational models have been introduced as numerical engineering tools aiming at adding qualitative and quantitative information on the biomechanical behavior in terms of stress-strain response and other multifactorial parameters8. In particular, over the two last decades, their applications have been ranging from elucidating the heart biomechanics underlying different patho-physiological conditions9 to predicting the effects of either surgical or percutaneous procedures, even comparing several implantation techniques and devices10. At the early stage, most of the studies focused on FE modeling in cardiac environment were based on paradigmatic models11\u201315, being mainly exploited to explore and investigate biomechanical alterations following a specific pathological scenario or again to better understand whether a surgical treatment is better or worse than another one. Differently, nowadays the current generation of computational models heavily exploits the detailed anatomical information yielded by medical imaging to provide patient-specific analyses, paving the way toward the development of virtual surgical-planning tools16\u201319. In this direction, cardiac magnetic resonance (CMR) and CT/micro-CT are the mostly accomplished imaging modality, since they can provide well-defined images thanks to their spatial and temporal resolutions20\u201325. Nonetheless, they cannot be applied routinely in clinical practice, as it can be differently done with rt3DE, progressively became the modality of choice26 since it has no harmful effects on the patient and no radiopaque contrast agent is needed. Despite these advantages, 3D volumetric ultrasound imaging shows intrinsic limitations beyond its limited resolution: i) the deficiency of morphological detail owing to either not so easy achievable detection (e.g., tricuspid valve) or not proper acoustic window, ii) the challenge of tailoring computational models to the patient-specific scenario mimicking the morphology as well as the functionality of the investigated cardiac district (e.g., tethering effect exerted by chordal apparatus in mitral valve insufficiency associated to left ventricular dilation), and iii) the needing to systematically analyse devices performances when dealing with real-life cases where ultrasound imaging is the only performable technique but lacking of standardized acquisition protocol. Main findings In the just described scenario, the main aim of this work was focused on the implementation, development and testing of numerical strategies in order to overcome issues when dealing with 3D ultrasound imaging exploitation towards predictive patient-specific modelling approaches focused on both morphological and biomechanical analyses. Specifically, the first specific objective was the development of a novel approach integrating in vitro imaging and finite element (FE) modeling to evaluate tricuspid valve (TV) biomechanics, facing with the lack of information on anatomical features owing to the clinically evident demanding detection of this anatomical district through in vivo imaging. \u2022 An innovative and semi-automated framework was implemented to generate 3D model of TV, to quantitively describe its 3D morphology and to assess its biomechanical behaviour. At this aim, an image-based in vitro experimental approach was integrated with numerical models based on FE strategy. Experimental measurements directly performed on the benchmark (mock circulation loop) were compared with geometrical features computed on the 3D reconstructed model, pinpointing a global good consistency. Furthermore, obtained realistic reconstructions were used as the input of the FE models, even accounting for proper description of TV leaflets\u2019 anisotropic mechanical response. As done experimentally, simulations reproduced both \u201cincompetent\u201d (FTR) and \u201ccompetent-induced\u201d (PMA), proving the efficiency of such a treatment and suggesting translational potential to the clinic. The second specific aim was the implementation of a computational framework able to reproduce a functionally equivalent model of the mitral valve (MV) sub-valvular apparatus through chordae tendineae topology optimization, aiming at chordae rest length arrangement to be able to include their pre-stress state associated to specific ventricular conformation. \u2022 We sought to establish a framework to build geometrically tractable, functionally equivalent models of the MV chordae tendineae, addressing one of the main topics of the computational scientific literature towards the development of faithful patient-specific models from in vivo imaging. Exploiting the mass spring model (MSM) approach, an iterative tool was proposed aiming to the topology optimization of a paradigmatic chordal apparatus of MVs affected by functional regurgitation, in order to be able to equivalently account for tethering effect exerted by the chordae themselves. The results have shown that the algorithm actually lowered the error between the simulated valve and ground truth data, although the intensity of this improvement is strongly valve-dependent.Finally, the last specific aim was the creation of a numerical strategy able to allow for patient-specific geometrical reconstruction both pre- and post- LVAD implantation, in a specific high-risk clinical scenario being rt3DE the only available imaging technique to be used but without any acquisition protocol. \u2022 We proposed a numerical approach which allowed for a systematic and selective analysis of the mechanism associated to intraventricular thrombus formation and thrombogenic complications in a LVAD-treated dilated left ventricle (LV). Ad-hoc geometry reconstruction workflow was implemented to overcome limitations associated to imaging acquisition in this specific scenario, thus being able to generate computational model of the LV assisted with LVAD. In details, results suggested that blood stasis is influenced either by LVAD flow rate and, to a greater extent, by LV residual contractility, being the positioning of the inflow cannula insertion mandatory to be considered when dealing with LVAD thrombogenic potential assessment

Functional and Biomechanical Effects of the Edge-to-Edge Repair in the Setting of Mitral Regurgitation: Consolidated Knowledge and Novel Tools to Gain Insight into Its Percutaneous Implementation

Mitral regurgitation is the most prevalent heart valve disease in the western population. When severe, it requires surgical treatment, repair being the preferred option. The edge-to-edge repair technique treats mitral regurgitation by suturing the leaflets together and creating a double-orifice valve. Due to its relative simplicity and versatility, it has become progressively more widespread. Recently, its percutaneous version has become feasible, and has raised interest thanks to the positive results of the Mitraclip(\uae) device. Edge-to-edge features and evolution have stimulated debate and multidisciplinary research by both clinicians and engineers. After providing an overview of representative studies in the field, here we propose a novel computational approach to the most recent percutaneous evolution of the edge-to-edge technique. Image-based structural finite element models of three mitral valves affected by posterior prolapse were derived from cine-cardiac magnetic resonance imaging. The models accounted for the patient-specific 3D geometry of the valve, including leaflet compound curvature pattern, patient-specific motion of annulus and papillary muscles, and hyperelastic and anisotropic mechanical properties of tissues. The biomechanics of the three valves throughout the entire cardiac cycle was simulated before and after Mitraclip(\uae) implantation, assessing the biomechanical impact of the procedure. For all three simulated MVs, Mitraclip(\uae) implantation significantly improved systolic leaflets coaptation, without inducing major alterations in systolic peak stresses. Diastolic orifice area was decreased, by up to 58.9%, and leaflets diastolic stresses became comparable, although lower, to systolic ones. Despite established knowledge on the edge-to-edge surgical repair, latest technological advances make its percutanoues implementation a challenging field of research. The modeling approach herein proposed may be expanded to analyze clinical scenarios that are currently critical for Mitraclip(\uae) implantation, helping the search for possible solutions

Investigations of the Tricuspid Heart Valve Function: An Integrated Computational-Experimental Approach

The objective of this research is to employ both in silico modeling and in vitro experimental characterization methods to enhance the understanding of the biomechanical function of the tricuspid heart valve. A finite element (FE)-based computational model of the tricuspid valve (TV) is first developed. Specifically, the geometry used in this computational model is based on parametric representations of the TV leaflets from porcine and ovine hearts and a parametric representation of the chordae tendineae. A nonlinear, isotropic constitutive model is used to describe of the mechanical behaviors of the TV leaflets, while the TV chordae tendineae are modeled as a nonlinear, elastic solid. The developed FE model of the TV apparatus is then used to simulate various pathological states including: (i) pulmonary hypertension, (ii) TV annulus dilation, (iii) papillary muscle displacement associated with right ventricular enlargement, (iv) flattening of the TV annulus, and (v) the rupture of the TV chordae tendineae. Numerical results from this study, as compared to available clinical observations, suggest that the TV annulus dilation and papillary muscle displacement resulting from right ventricular enlargement are key contributors to TV regurgitation. On the other hand, pulmonary hypertension resulted in the largest increase in TV leaflet stress (+65%) indicating pulmonary hypertension may be a key contributor to the adverse remodeling of the leaflet and myocardium tissues. In addition, the simulations of the chordae rupture scenarios reveal that those chordae tendineae attached to the TV anterior and septal leaflets may be more important to preventing TV leaflet prolapse. Extensive biaxial mechanical testing of the TV leaflets is conducted to expand on the limited number of mechanical characterizations of the TV leaflets. These experimental efforts include: (i) a quantification of the TV leaflets’ biaxial mechanical responses, (ii) an investigation of the loading-rate and temperature effects on the TV leaflet tissue mechanics, (iii) an examination of the influence of species and aging on the TV leaflet’s mechanical properties, (iv) an evaluation of the spatial variations of the TV leaflet’s tissue mechanics, and (v) a determination of the contribution of the glycosaminoglycans (GAGs) to the TV leaflet’s mechanical responses. These in vitro experimental results suggest that (i) the TV leaflets are more extensible than the mitral valve leaflets, (ii) the TV leaflets’ responses depend slightly on the loading rate and temperature, (iii) the mechanical responses of the TV leaflets become stiffer with aging (+3.5%-6.1%), (iv) the TV leaflets exhibit spatial variance in the mechanical properties, and (v) the removal of the GAGs leads to an increased extensibility of the TV leaflets (+4.7%-7.6%). Finally, a constitutive modeling framework, based on the hyperelasticity theory, is formulated to describe the mechanical behaviors of the heart valve leaflets from the acquired biaxial mechanical data. Through the differential evolution optimization, model parameters of two strain energy density functions commonly adopted in the soft tissue biomechanics society are estimated by fitting to the representative biaxial mechanical testing data. Results from this numerical study suggest that a refined strain energy density function may be warranted, as part of the future extensions, to fully capture the complex mechanical responses of the heart valve leaflet, especially under combined tensile and compressive loading

Nonresectional-Graded Neo Chordal Dynamic Repair of Mitral Valve: Stress Analysis Induced Surgical Innovation

Drawbacks persist relating to irreversibility of leaflet resection, time-consuming leaflet reconstruction with sliding annuloplasty, monoleaflet function, and systolic anterior motion (SAM) risk. Graded neochordal reconstruction mitigates many of these but has the challenge of precise sizing and possibility of leaving excessive tissue, risking SAM. When this reconstruction is based on stress analysis and shear analysis methods the outcome gives the best results. Short term evaluation has been done with good outcomes

Simulating Cardiac Fluid Dynamics in the Human Heart

Cardiac fluid dynamics fundamentally involves interactions between complex blood flows and the structural deformations of the muscular heart walls and the thin, flexible valve leaflets. There has been longstanding scientific, engineering, and medical interest in creating mathematical models of the heart that capture, explain, and predict these fluid-structure interactions. However, existing computational models that account for interactions among the blood, the actively contracting myocardium, and the cardiac valves are limited in their abilities to predict valve performance, resolve fine-scale flow features, or use realistic descriptions of tissue biomechanics. Here we introduce and benchmark a comprehensive mathematical model of cardiac fluid dynamics in the human heart. A unique feature of our model is that it incorporates biomechanically detailed descriptions of all major cardiac structures that are calibrated using tensile tests of human tissue specimens to reflect the heart's microstructure. Further, it is the first fluid-structure interaction model of the heart that provides anatomically and physiologically detailed representations of all four cardiac valves. We demonstrate that this integrative model generates physiologic dynamics, including realistic pressure-volume loops that automatically capture isovolumetric contraction and relaxation, and predicts fine-scale flow features. None of these outputs are prescribed; instead, they emerge from interactions within our comprehensive description of cardiac physiology. Such models can serve as tools for predicting the impacts of medical devices or clinical interventions. They also can serve as platforms for mechanistic studies of cardiac pathophysiology and dysfunction, including congenital defects, cardiomyopathies, and heart failure, that are difficult or impossible to perform in patients

The Cellular and Molecular Mechanisms of Myxomatous Mitral Valve Disease and Associated Mitral Valve Prolapse: The Role of Dchs1 and Filamin-A

Mitral valve prolapse (MVP) affects 1 in 40 people worldwide and is the leading cause of mitral valve surgery. MVP is defined as the displacement of one or both leaflets during ventricular systole and commonly leads to mitral regurgitation as well as other secondary cardiac defects including arrhythmias, congestive heart failure, and sudden cardiac death. Structural changes observed in MVP patients include myxomatous degeneration of the mitral leaflets, which is characterized by collagen fragmentation and accumulation of proteoglycans. Additionally, hyperproliferation and activation of interstitial cells (to myofibroblasts) also contribute to valve enlargement and degeneration, respectively. The molecular and genetic etiology of nonsyndromic MVP is unknown. This is likely due to the lack of knowledge regarding specific genes that cause nonsyndromic MVP in the human population. Work presented here identifies the first genetic mutations in patients with nonsyndromic MVP. Using linkage analysis and deep sequencing, mutations in the cell‐polarity gene, DCHS1 were identified. These mutations were shown to be loss of function by in vitro assays and zebrafish knockdown. Consistent with this finding, we observe Dchs1 heterozygote mice (Dchs1+/‐) exhibit structural (myxomatous degeneration), functional (MVP), and molecular (altered Erk1/2 signaling) defects that phenocopy MVP patients. x We traced the etiology of the disease in the Dchs1+/- mice to defects during valve development where valve morphogenetic defects in tissue shape coincident with aberrant myofibroblast differentiation and elevated pErk1/2 activation. We additionally confirm a developmental origin for the disease in another mouse model that conditionally deletes filamin-A from valve tissue resulting in myxomatous valvular dystrophy, which leads to MVP. The filamin‐A mice exhibit developmental defects in valvular cytoskeletal organization and matrix remodeling, which lead to myxomatous mitral leaflets with elevated pErk1/2 activities and increased hematopoietic cell infiltration in the adult. Importantly, defects in both models of disease are observed prior to myxomatous degeneration suggesting processes that control valve shape and maturation are critical for maintaining the valve in a non-­‐degenerative state. Thus, we hypothesize that the cell polarity gene Dchs1 regulates adhesion, migration, and alignment of pre‐valvular fibroblasts, and filamin‐A regulates matrix remodeling during normal valve morphogenisis. All of which work together to build and shape mitral leaflets during the post‐EndoMT stage of valve development. As a corollary hypothesis, we propose that infiltration of circulating progenitor cells contribute to disease through the Erk1/2 signaling pathway. The goal of this work is to define molecular and cellular mechanisms by which Dchs1 and filamin‐A regulate valve morphogenesis and to identify common pathogenic mechanisms of myxomatous degeneration, with the potential benefit of targeting the MEK/Erk pathway and/or immune cell infiltration to abrogate MVP disease pathogenesis