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

Mechanics of the mitral valve after surgical repair-an in vitro study

Mitral valve disease is widely prevalent among pediatric and adult population across the world, and it encompasses a spectrum of lesions which include congenital valve defects, degenerative valve lesions, and valve dysfunction due to secondary pathologies. Though replacement of the diseased mitral valves with artificial heart valves has been the standard of care until early 1990's, current trends have veered towards complete surgical repair. These trends are encouraging, but current repair techniques are plagued with lack of durability and high rates of failure within 10 years after repair. With increasing number of patients receiving mitral valve repair, there is now an immediate need to understand the mechanisms of repair failure, and assess the role of several clinical risk factors on valve repair. In this thesis, an in vitro pulsatile left heart simulator was developed to mimic the congenital and adult mitral valve pathological morphologies in normal porcine valves, and simulate the pathological valve hemodynamics and mechanics. Different surgical repair techniques were used to correct the valve lesions, and the post repair valve hemodynamics, mechanics and geometry were assessed using quantitative measurement techniques. The extent to which each repair restores physiological valve function and mechanics was assessed, and the impact of different pathological risk factors on repair failure mechanisms was investigated. It is expected that the knowledge from this thesis would play an important role in the evolution of mitral valve surgical repair, and guide the development of more effective and long-lasting heart valve repair technologies.Ph.D.Committee Chair: Yoganathan, Ajit; Committee Member: Adams, David; Committee Member: Del Nido, Pedro; Committee Member: Gleason, Rudolph; Committee Member: Oshinski, John; Committee Member: Thourani, Vino

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

Deep learning tools for outcome prediction in a trial fibrilation from cardiac MRI

Tese de mestrado integrado em Engenharia Biomédica e Biofísica (Engenharia Clínica e Instrumentação Médica), Universidade de Lisboa, Faculdade de Ciências, 2021Atrial fibrillation (AF), is the most frequent sustained cardiac arrhythmia, described by an irregular and rapid contraction of the two upper chambers of the heart (the atria). AF development is promoted and predisposed by atrial dilation, which is a consequence of atria adaptation to AF. However, it is not clear whether atrial dilation appears similarly over the cardiac cycle and how it affects ventricular volumes. Catheter ablation is arguably the AF gold standard treatment. In their current form, ablations are capable of directly terminating AF in selected patients but are only first-time effective in approximately 50% of the cases. In the first part of this work, volumetric functional markers of the left atrium (LA) and left ventricle (LV) of AF patients were studied. More precisely, a customised convolutional neural network (CNN) was proposed to segment, across the cardiac cycle, the LA from short axis CINE MRI images acquired with full cardiac coverage in AF patients. Using the proposed automatic LA segmentation, volumetric time curves were plotted and ejection fractions (EF) were automatically calculated for both chambers. The second part of the project was dedicated to developing classification models based on cardiac MR images. The EMIDEC STACOM 2020 challenge was used as an initial project and basis to create binary classifiers based on fully automatic classification neural networks (NNs), since it presented a relatively simple binary classification task (presence/absence of disease) and a large dataset. For the challenge, a deep learning NN was proposed to automatically classify myocardial disease from delayed enhancement cardiac MR (DE-CMR) and patient clinical information. The highest classification accuracy (100%) was achieved with Clinic-NET+, a NN that used information from images, segmentations and clinical annotations. For the final goal of this project, the previously referred NNs were re-trained to predict AF recurrence after catheter ablation (CA) in AF patients using pre-ablation LA short axis in CINE MRI images. In this task, the best overall performance was achieved by Clinic-NET+ with a test accuracy of 88%. This work shown the potential of NNs to interpret and extract clinical information from cardiac MRI. If more data is available, in the future, these methods can potentially be used to help and guide clinical AF prognosis and diagnosis

Combined numerical and morphological study of the heart: development of a scalable mitral valve morphometric model and assessment of modelling criteria for the right atrium

Frameworks for the computational modelling of heart components are continuously evolving, either to create models in a faster manner, or to represent its components more accurately. The mitral valve on the left side of the heart, for example, has a very complex geometry, and shape alterations induced by surgical procedures affect the long-term restoration of function. While several frameworks that recreate mitral valve shape from patient-specific images have been developed, allowing for the development of computational simulations of pre- and post-repaired cases, they are not flexible enough to yield a variety of models. On the other hand, accurate computational models of the right side of the heart are lacking, and since the right heart is used as a platform for clinical treatments such as haemodialysis, the development and validation of a computational model representing its function is necessary. The overall aim of this thesis was to develop computational modelling frameworks for two components of the heart: the mitral valve on the left side, and the right atrium on the right side. A mathematical evaluation of mitral valve morphometry through correlation analysis and evaluation of prediction equations for its shape was performed by using imaging datasets obtained in collaboration with clinicians and from the literature. This information led to the development of a computational toolbox enabling the quick generation of anatomically accurate and clinically useful parametric models of the mitral valve. This toolbox, implemented in MATLAB, generates the mitral valve geometry and respective mesh, and assigns boundary conditions and material properties, necessary for finite element analysis. A sensitivity analysis of boundary conditions was performed to determine their influence on mitral valve biomechanics, with the chosen conditions being incorporated in the tool. A healthy valve geometry was generated and analysed, and the respective computational predictions for valve physiology were validated against data in the literature. Moreover, two patient-specific mitral valve models including geometric alterations associated with disease were generated and analysed. Mitral valve function was compromised in both models, as given by the presence of regurgitating areas, elevated stress on the leaflets and unbalanced subvalvular apparatus forces. These results showcase the importance of a healthy mitral valve shape for adequate function; further, they demonstrate the potential of the computational toolbox, which allows for the automatic finite element analysis of the mitral valve in a variety of clinical cases, useful to study the biomechanics of patient-specific shapes. In addition, a physiological blood flow model of the right atrium was developed and validated against data in the literature. This model was used as a simulation platform to evaluate the performance of four catheter designs for haemodialysis: while the symmetric tip had the best haemodynamic results, associated with low recirculation of flow and shear stress values, the step tip designs yielded the worst haemodynamic outcomes. The presence of side holes at the tip led to a decrease in recirculating flow, associated with improved catheter performance. The present simulation platform therefore enables the assessment of the performance of several catheter designs before their release on the market. The work presented in this thesis bridges engineering and medicine through the development of two computational frameworks with primary clinical objectives: a computational tool for the evaluation of mitral valve biomechanics for a variety of geometries and assessment of current and novel mitral interventions; and a right atrium simulation platform which potentially highlights haemodialysis catheter design features requiring optimisation for optimal performance

Image based computational modeling of intracardiac flows

With continuous advancements in four-dimensional medical imaging technologies, increasing computational speeds, and widespread availability of high performance computing facilities, computational modeling of intracardiac flows is becoming increasingly viable and has the potential to become a powerful non-invasive diagnostic tool for the diagnosis and treatment of cardiovascular disease. The motive of the current study is to develop a modeling framework that facilitates image-based analysis of intracardiac flows in health as well as disease and to use this framework to gain fundamental insights into intracardiac hemodynamics. A procedure is developed for constructing computational fluid dynamics (CFD) – ready models from in vivo imaging data. The key components of this procedure are the registration and segmentation of the 4D data for several (~20) key frames, template based mapping to ensure surface grid conformality and high-fidelity simulations using a sharp-interface immersed boundary solver. A physiologically representative, kinematic model of the mitral valve is also developed for use in these simulations. As a precursor, a comprehensive quantitative validation of the flow solver is performed using experimental data in a simple model of the left ventricle. A quantitative comparison of the phase-averaged velocity and vorticity fields between the simulation and the experiment shows a reasonable agreement. The detailed assessment of this comparison is used to identify and discuss the key challenges and uncertainties associated in conducting such a validation study. The vast majority of computational investigations of intracardiac flows have focused either on the left or the right ventricles while the corresponding atria were modeled in highly simplistic ways. However, the impact of this simplification on the hemodynamics of the ventricular filling has not been clearly understood. Additionally, the surface of the ventricle has been assumed to be smooth although it is well known that the left ventricle is highly corrugated with surface protrusions or trabeculae and papillary muscles extending deep into the ventricular cavity. Hence, separate studies were conducted to understand the effect of complex atrial flows on the intraventricular flow development and also to understand and quantify the impact of the trabeculae and papillary muscles on ventricular hemodynamics Results indicate that the trabeculae and papillary muscles significantly impact ventricular flow resulting in a deeper penetration of the mitral jet into the ventricle during filling. These anatomical features are also found to produce a “squeezing” effect that enhances apical washout. It is also demonstrated that the complex flow dynamics developed inside the left atrium have minimal influence on the flow inside the left ventricle, which is primarily governed by the mitral valve leaflets configuration. The complex vortical structures inside the left atrium are rapidly dissipated due to the complex interaction of multiple vortex rings leading to breakup, annihilation and enhanced viscous dissipation so that the flow is smoothly streamlined as it enters the mitral orifice and produces a near-uniform velocity profile at the level of the mitral annulus. The implications of these findings on the modeling of the intra-ventricular flows are also discussed

Mathematical modelling of myocardial perfusion: coronary flow and myocardial mechanics

Coronary artery disease (CAD) is a condition characterised by the narrowing or blockage of the major blood vessels that supply blood to the heart muscle. This can cause insufficient myocardial perfusion to the heart and deficient cardiac outputs, leading to the possibility of heart failure. CAD is one of the leading causes of morbidity and mortality worldwide. Early and accurate diagnosis and treatment of CAD are essential to minimise the risk of complications, including heart attack or heart failure. In cardiovascular research, computational modelling of coronary circulation is proving to be a valuable tool for gaining insights and information. It enables researchers to isolate the effects of various physiological and pathological conditions on the coronary circulation. Thus, this thesis aimed to develop computational models of one dimensional (1D) coronary flow and three-dimensional (3D) heart. Both models included detailed geometric information tosimulate and predict physiologically realistic results. A one- way coupling of the coronary flow model and the heart model was achieved and produced physiologically accurate myocardial perfusion. Specifically, we first investigated the effect of intramyocardial pressure (IMP) on coronary flow and developed a 1D finite difference coronary flow model. A coronary network based on experimental data was constructed to simulate coronary flow along the complete path of the coronary vasculature. Utilising an assumed aortic pressure, right atrial pressure, and IMP, our simulated coronary pressure and flow rates were in good agreement with published experimental data. It was observed that the majority of the coronary arterial flow on the left side occurs during diastole, while the flow slows down or even reverses during systole. Secondly, we developed a 3D finite element model of the left ventricle (LV) to obtain a more realistic IMP. The LV model was constructed from a patient-specific geometry. The simulated pressure and volume of the LV cavity in repeated cardiac cycles, as well as the ejection fraction, were all within published physiological ranges. We further analysed the stress distributions within the LV wall. Thirdly, a brief review of experimental IMP, as well as calculations of IMP from lumped parameter models and 3D heart models, were presented. Through analysis, we determined a formula for calculating IMP from our 3D LV model. Additionally, we proposed an assignment scheme of the epicardial coronary arteries to the 17 segments of the LV wall recommended by the American Heart Association. Based on the assignment, we devised the one-way coupling framework between the coronary flow model and the LV model to investigate myocardial perfusion. We further developed a bi-ventricular model to investigate the effect of pulmonary regurgitation (PR) on cardiac function. The model provided a computational approach for exploring the influence of PR on right ventricle (RV) dilation and the interaction between LV and RV. Our simulated RV end-diastolic volumes under varying degrees ofPR were comparable with published magnetic resonance imaging data. Moreover, from the long-axis and short-axis views of the bi-ventricular geometry, we observed clearly the motion of the interventricular septum from the baseline case to the severe PR case. This bi-ventricular model was intended to further couple with the coronary flow model to investigate the interaction of right coronary arterial flow and left coronary arterial flow. However, due to time constraints, this has not yet been undertaken. The computational models of the coronary flow and heart developed in this thesis exhibit promising capabilities for providing physiologically accurate predictions of coronary flow and myocardial mechanics. Further application of these models has the potential to deepen our understanding of the underlying mechanisms in physiological coronary flow and various CAD

Doppler vortography : detection and quantification of the vortices in the left ventricle

Nous proposons une nouvelle méthode pour quantifier la vorticité intracardiaque (vortographie Doppler), basée sur l’imagerie Doppler conventionnelle. Afin de caractériser les vortex, nous utilisons un indice dénommé « Blood Vortex Signature (BVS) » (Signature Tourbillonnaire Sanguine) obtenu par l’application d’un filtre par noyau basé sur la covariance. La validation de l’indice BVS mesuré par vortographie Doppler a été réalisée à partir de champs Doppler issus de simulations et d’expériences in vitro. Des résultats préliminaires obtenus chez des sujets sains et des patients atteints de complications cardiaques sont également présentés dans ce mémoire. Des corrélations significatives ont été observées entre la vorticité estimée par vortographie Doppler et la méthode de référence (in silico: r2 = 0.98, in vitro: r2 = 0.86). Nos résultats suggèrent que la vortographie Doppler est une technique d’échographie cardiaque prometteuse pour quantifier les vortex intracardiaques. Cet outil d’évaluation pourrait être aisément appliqué en routine clinique pour détecter la présence d’une insuffisance ventriculaire et évaluer la fonction diastolique par échocardiographie Doppler.We propose a new method for quantification of intra-cardiac vorticity (Doppler vortography) based on conventional Doppler images. To characterize the vortices, an index called “blood vortex signature” (BVS) was obtained using a specific covariance-based kernel filter. The reliability of BVS measured by Doppler vortography was assessed in mock Doppler fields issued from simulations and in vitro experimentations. Some preliminary results issued from healthy subjects and patients with heart disease were also presented in this research project. Strong correlations were obtained between the Doppler vortography-derived and ground-truth vorticities (in silico: r2 = 0.98, in vitro: r2 = 0.86, in vivo: p = 0.004). Our results demonstrated that Doppler vortography is a potentially promising echocardiographic tool for quantification of intra-ventricular vortex flow. This technique can be easily implemented for routine checks to recognize ventricular insufficiency and abnormal blood patterns at early stages of heart failure to decrease the morbidity of cardiac disease