Advanced echocardiography and clinical surrogates to risk stratify and manage patients with structural heart disease

Part I focuses on the potential role of 3-dimensional echocardiography. At first a clinical risk score model for prediction of outcome in patients undergoing TAVI is presented (Chapter 2). Second the role of 3D-echocardiography is explored in depth in patients with mitral valve disease. Different non-invasive cardiac imaging modalities to evaluate mitral valve function and anatomy are described and the use of 3D-echocardiography is put into perspective (Chapter 3). We then evaluate the role of the latter to gain insights in patients with functional mitral regurgitation (Chapter 4), to select patients and guide procedures regarding percutaneous mitral valve repair using Mitra-Clip (Chapter 5) and to assess the effect of Mitra-Clip on the mitral valve (Chapter 6). In Part II we further elaborate the potential role of risk stratification by ECG and myocardial deformation imaging (strain), as surrogate markers of fibrosis. Surface ECG fragmentation in primary HCM is first evaluated (Chapter 7). The important future role of fibrosis imaging in valvular heart disease patients is then reviewed (Chapter 8). Finally the role of left atrial structure and function is evaluated in patients with mitral regurgitation (Chapter 9) and primary HCM (Chapter 10, 11).UBL - phd migration 201

Multiscale Multimodal Characterization and Simulation of Structural Alterations in Failed Bioprosthetic Heart Valves.

Calcific degeneration is the most frequent type of heart valve failure, with rising incidence due to the ageing population. The gold standard treatment to date is valve replacement. Unfortunately, calcification oftentimes re-occurs in bioprosthetic substitutes, with the governing processes remaining poorly understood. Here, we present a multiscale, multimodal analysis of disturbances and extensive mineralisation of the collagen network in failed bioprosthetic bovine pericardium valve explants with full histoanatomical context. In addition to highly abundant mineralized collagen fibres and fibrils, calcified micron-sized particles previously discovered in native valves were also prevalent on the aortic as well as the ventricular surface of bioprosthetic valves. The two mineral types (fibres and particles) were detectable even in early-stage mineralisation, prior to any macroscopic calcification. Based on multiscale multimodal characterisation and high-fidelity simulations, we demonstrate that mineral occurrence coincides with regions exposed to high haemodynamic and biomechanical indicators. These insights obtained by multiscale analysis of failed bioprosthetic valves may serve as groundwork for the evidence-based development of more durable alternatives. STATEMENT OF SIGNIFICANCE: Bioprosthetic valve calcification is a well-known clinically significant phenomenon, leading to valve failure. The nanoanalytical characterisation of bioprosthetic valves gives insights into the highly abundant, extensive calcification and disorganization of the collagen network and the presence of calcium phosphate particles previously reported in native cardiovascular tissues. While the collagen matrix mineralisation can be primarily attributed to a combination of chemical and mechanical alterations, the calcified particles are likely of host cellular origin. This work presents a straightforward route to mineral identification and characterization at high resolution and sensitivity, and with full histoanatomical context, hence providing design cues for improved bioprosthetic valve alternatives

Fast Image-Based Mitral Valve Simulation from Individualized Geometry

International audienceBackground: Common surgical procedures on the mitral valve of the heart include modifications to the chordae tendineae. Such interventions are used when there is extensive leaflet prolapse caused by chordae rupture or elongation. Understanding the role of individual chordae tendineae before operating could be helpful to predict if the mitral valve will be competent at peak systole. Biomechanical modeling and simulation can achieve this goal.Methods: We present a method to semi-automatically build a mitral valve computational model from micro CT (computed tomography) scans: after manually picking chordae fiducial points, the leaflets are segmented and the boundary conditions as well as the loading conditions are automatically defined. Fast Finite Element Method (FEM) simulation is carried out using Simulation Open Framework Architecture (SOFA) to reproduce leaflet closure at peak systole. We develop three metrics to evaluate simulation results: i) point-to-surface error with the ground truth reference extracted from the CT image, ii) coaptation surface area of the leaflets and iii) an indication if the simulated closed leaflets leak.Results: We validate our method on three explanted porcine hearts and show that our model predicts the closed valve surface with point-to-surface error of appoximately 1mm, a reasonable coaptation surface area, and absence of leak at peak systole (maximum closed pressure). We also evaluate the sensitivity of our model to changes in various parameters (tissue elasticity, mesh accuracy, and the transformation matrix used for CT scan registration). We also measure the influence of the chordae tendineae positions on simulation results and show that marginal chordae have a greater influence on the final shape than intermediate chordae.Conclusions: The mitral valve simulation can help the surgeon understand valve behaviour and anticipate the outcome of a procedure

The Role of Fiber Bundle and Membrane Subunits in Aortic Valve Function

Heart valves are complex arrangements of collagen fibers and membranes that oppose retrograde blood flow during contraction of the cardiac chambers. Through its amazing lifetime, the normal healthy valve cycles over 3 billion times. However, disease (such as stenosis/calcification or mechanical wear) can cause the valve to malfunction, permitting backflow or failing to properly open. When a valve cannot be salvaged, treatment can require replacement of the valve to improve hydrodynamic behavior. Replacements are either a mechanical valve or, more commonly, a bioprosthetic valve made of either porcine valves or bovine pericardium. Although bioprosthetic implants are highly successful short-term, their long term durability is still limited. Alternatively, the patient can use a synthetic mechanical valve which will likely necessitate blood thinners for the remainder of his/her life. Thus, there is need for replacement valves that possess both superior durability and hemodynamic function. Current bioprosthetic and mechanical designs do not fully consider the underlying native fiber structure of the aortic valve, nor their fiber-scale biomechanical properties. In the past, the challenge of testing at the fiber bundle length scale precluded experimentation. Thus, there was little previously known regarding how the fiber bundles and membrane structures are arranged as well as their exact role in aortic valve function. The overall objective of this work was to perform experimental and analytical analyses of the individual collagen fiber and membrane "mesostructures" of the aortic valve. We developed a novel experimental/analytical system to investigate these structures in detail. Using this system, we were able to perform a detailed characterization of the substructures’ morphology and the first quantification of their biomechanical properties. This work offers new insights in structure-function adaptations of the native aortic valve at the tissue level. In addition to the application of a more effective replacement valve design, the results of this thesis can be used in the generation of more precise mathematical models of aortic valve loading behavior.Ph.D., Biomedical Engineering -- Drexel University, 201

Multiscale multimodal characterization and simulation of structural alterations in failed bioprosthetic heart valves

Calcific degeneration is the most frequent type of heart valve failure, with rising incidence due to the ageing population. The gold standard treatment to date is valve replacement. Unfortunately, calcification oftentimes re-occurs in bioprosthetic substitutes, with the governing processes remaining poorly understood. Here, we present a multiscale, multimodal analysis of disturbances and extensive mineralisation of the collagen network in failed bioprosthetic bovine pericardium valve explants with full histoanatomical context. In addition to highly abundant mineralized collagen fibres and fibrils, calcified micron-sized particles previously discovered in native valves were also prevalent on the aortic as well as the ventricular surface of bioprosthetic valves. The two mineral types (fibres and particles) were detectable even in early-stage mineralisation, prior to any macroscopic calcification. Based on multiscale multimodal characterisation and high-fidelity simulations, we demonstrate that mineral occurrence coincides with regions exposed to high haemodynamic and biomechanical indicators. These insights obtained by multiscale analysis of failed bioprosthetic valves may serve as groundwork for the evidence-based development of more durable alternatives. STATEMENT OF SIGNIFICANCE: Bioprosthetic valve calcification is a well-known clinically significant phenomenon, leading to valve failure. The nanoanalytical characterisation of bioprosthetic valves gives insights into the highly abundant, extensive calcification and disorganization of the collagen network and the presence of calcium phosphate particles previously reported in native cardiovascular tissues. While the collagen matrix mineralisation can be primarily attributed to a combination of chemical and mechanical alterations, the calcified particles are likely of host cellular origin. This work presents a straightforward route to mineral identification and characterization at high resolution and sensitivity, and with full histoanatomical context, hence providing design cues for improved bioprosthetic valve alternatives

Three-dimensional transoesophageal echocardiography: how to use and when to use-a clinical consensus statement from the European Association of Cardiovascular Imaging of the European Society of Cardiology.

peer reviewedThree-dimensional transoesophageal echocardiography (3D TOE) has been rapidly developed in the last 15 years. Currently, 3D TOE is particularly useful as an additional imaging modality for the cardiac echocardiographers in the echo-lab, for cardiac interventionalists as a tool to guide complex catheter-based procedures cardiac, for surgeons to plan surgical strategies, and for cardiac anaesthesiologists and/or cardiologists, to assess intra-operative results. The authors of this document believe that acquiring 3D data set should become a 'standard part' of the TOE examination. This document provides (i) a basic understanding of the physic of 3D TOE technology which enables the echocardiographer to obtain new skills necessary to acquire, manipulate, and interpret 3D data sets, (ii) a description of valvular pathologies, and (iii) a description of non-valvular pathologies in which 3D TOE has shown to be a diagnostic tool particularly valuable. This document has a new format: instead of figures randomly positioned through the text, it has been organized in tables which include figures. We believe that this arrangement makes easier the lecture by clinical cardiologists and practising echocardiographers

Development of a Tissue Engineered Mitral Valve

Heart valve diseases affect nearly 8 million people every year in the United States. Of these patients, 72% are affected by mitral valve diseases. Stenosis, regurgitation, and prolapse of the mitral valve are the primary pathologies affecting valve function resulting in atrial fibrillation, arterial thromboembolism, pulmonary edema, pulmonary hypertension, cardiac hypertrophy and heart failure. Surgical options to repair or replace the mitral valve are only palliative, especially for children with congenital defects, and do not exclude the need for reoperation. A tissue-engineered option is feasible and holds great potential through the combination of decellularized scaffolds, patient stem cells, and heart valve bioreactors. Development of living tissue engineered mitral valves have not been reported in the recent literature. The primary focus of my research was threefold: 1) develop an acellular ECM scaffold which is mechanically robust, and allows for sufficient bioactivity for cellular seeding and signaling by use of a non-toxic matrix-binding polyphenolic antioxidant, pentagalloyl glucose (PGG); 2) confirm this scaffold to be biologically compatible with future hosts and limiting inflammatory responses in vivo by virtue of PGG\u27s antioxidant properties; 3) achieve recellularization of the mitral valve scaffold and direct differentiation and maturation through bioreactor preconditioning. First, a complete decellularization of porcine mitral valves was established and optimized to remove all cellular and nuclear material from the scaffolds while still preserving ECM components and basal lamina proteins. Treatment with PGG recovered lost mechanical integrity due to the decellularization process. Seeded cells were able to grow and proliferate on and in the acellular scaffold confirming cytocompatibility. An in vivo rat study was conducted to evaluate the scaffolds\u27 biocompatibility. In comparing non-treated and PGG-treated groups, PGG –treatment regularly and significantly showed increased resistance to degradation, polarization of macrophages to the pro-healing M2 phenotype, discouragement of inflammatory markers, and no limitations towards cell infiltration. Lastly, PGG-treated acellular scaffolds were recellularized with pre-differentiated fibroblasts and endothelial cells and placed in a newly developed mitral valve bioreactor. Design of the bioreactor required a full understanding and appreciation for the four tissue types present in the mitral apparatus. Preconditioning of the seeded constructs yielded a mitral construct similar to a native valve. The overarching goal of this research was to develop a stable mitral valve construct. It is expected that the progress made by this project will have a positive impact on those that suffer from mitral valve pathologies. Our translatable approach towards this tissue engineered mitral valve should allow clinicians to readily adopt this regenerative replacement and contribute as a whole to the field of cardiovascular tissue engineering

Multi- Modal Characterization Of Left Ventricular Diastolic Filling Physiology

Multiple modalities are clinically used to quantify cardiovascular function. Most clinical indexes derived from these modalities are empirically derived or correlation- based rather than causality based. Hence these indexes don\u27t provide insight into cardiac physiology and the mechanism of dysfunction. Our group has previously developed and validated a mathematical model using a kinematic paradigm of suction- initiated ventricular filling to understand the mechanics of early transmitral flow and the associated physiology/ pathophysiology. The model characterizes the kinematics of early transmitral flow analogous to a damped simple harmonic oscillator with lumped parameters- ventricular stiffness, ventricular viscoelasticity/ relaxation and ventricular load. The current research develops the theme of causal mechanism based quantification of physiology and uses the kinematic model to study intraventricular fluid mechanics in diastole. In the first project, the role of vortex rings in efficient diastolic filling was investigated. Vortex rings had been previously characterized by a dimensionless index called vortex formation time (VFT). We re- expressed VFT in terms of ventricular kinematic properties- stiffness, viscoelasticity and volumetric preload, using the kinematic model. This VFTkinematic could be calculated using data from a clinical echocardiographic study. The VFTkinematic was a sensitive to physiologic changes as verified by its correlation with a clinically used echo- based index of filling pressure. Additionally, we demonstrated that VFTkinematic, by factoring the ventricular expansion rate, could differentiate between normal filling pattern and pseudonormal filling pattern which is characteristic of moderate DD. Continuing on our study of intraventricular fluid mechanics, we next studied the development of vortex ring in the ventricle. We discovered that as the vortex ring develops, the leading edge of the circulating flow passes through the main inflow tract. This causes an extra flow wave recorded in transmitral Doppler echocardiography (in addition to early and late filling waves) that had been observed previously. By using cardiac magnetic resonance (CMR) and echocardiography to independently measure intraventricular vortexes we were able to provide a causal explanation for the extra flow wave and its clinical consequences. We developed another approach to quantify the effect of chamber kinematics on filling via directional flow impedances. In the ventricle, both pressure and flow rate are oscillatory and pressure oscillations cause flow rate changes. Hence a frequency based approach via impedance, to quantify the relationship between pressure and flow rate is intuitive. We developed expressions for longitudinal and transverse flow impedances which could be computed from cardiac catheterization and echocardiographic data. Longitudinal and transverse flow impedances allowed us to quantify the previously observed directionality of filling as a function of harmonics and use it as an index to measure pathophysiologic changes. While fluid mechanics based indexes provide a method to evaluate LV chamber kinematics in diastole, an alternate approach for DF quantification is LV hemodynamic assessment. Since, LV filling is influenced by pressure changes before and during filling, we investigated the spatial pressure gradient in the LV. We measured the pressure difference between the LV apex and mid-LV using catheterization and we found a larger gradient exists during isovolumic relaxation (2- 3 times) as compared to filling. Additionally, the rate of pressure decay as quantified by different models of relaxation was also significantly different at the two locations. Additionally, we developed a new method for load independent hemodynamic analysis of the cardiac cycle. Load represents the pressure against which the ventricle has to fill and eject and most LV function indexes are load dependent, which can confound the diagnosis of dysfunction. We computed load independent cardiac cycle hemodynamics by normalizing LV pressure and the rate of change of pressure (dP/dt). Normalization revealed the presence of conserved kinematics during isovolumic relaxation particularly the normalized pressure at peak negative dP/dt while a similar feature was not observed during the contraction. These studies demonstrate the advantage of mechanism based approaches to quantify diastolic physiology

Toward Growth-Accommodating Polymeric Heart Valves with Graphene-Network Reinforcement

Graphene is a 2D material well known for its high intrinsic strength of 100 GPa and Young’s modulus of 1 TPa. Because of its 2D nature, the most promising avenues to utilize graphene as a mechanical material include incorporating it as reinforcement in a nanocomposite and creating free-standing foams and aerogels. However, the current techniques are not well-controlled – the reinforcing graphene particles are often discontinuous and randomly dispersed – making it difficult to accurately model and predict the resulting material properties. Here we aim to develop a framework for a new class of nanocomposites reinforced not by discrete nanoparticles, but by a continuous 3D graphene network. These 3D graphene networks were formed by chemical vapor deposition of graphene on periodic metallic microlattices, thereby providing mechanical reinforcement for the lattices. To assist in the lattice design, analytical models were derived for the mechanical properties of core/shell composite lattices and experimentally validated through compression testing of polymer lattices coated with electroless Ni-P. The models and experiments showed good agreement at lower shell thicknesses, while there was divergence at higher thicknesses, likely due to fabrication imperfections. The analytical models were also applied to hollow metallic lattices coated with graphene and compared to experimental data. The results showed that the models are plausible and suggest that graphene has a significant strengthening effect on the microlattices. These studies represent a paradigm shift in the design and fabrication of nanocomposites as one may now precisely prescribe the placement of the reinforcing nanomaterials. On a broader scale, this work also lays the framework for using a 2D material to span 3D space, enabling further exploration of 2D material properties and applications. One potential application area for a graphene-reinforced polymer composite is in prosthetic heart valves. The tissue of a human heart valve leaflet is heavily reinforced with networks of collagen and elastin fibers. One could similarly incorporate a graphene network as reinforcement within the polymeric leaflets of a prosthetic valve. One promising application of polymeric valves is in growth-accommodating implants for pediatric patients. Here we aim to develop a polymeric valved conduit that can be expanded by transcatheter balloon dilation to match a child’s growth. We designed the valve, characterized and selected materials, fabricated the devices and performed benchtop in vitro testing. The first generation of an expandable biostable valved conduit displayed excellent hydrodynamic performance before and after permanent balloon dilation from 22 to 25 mm. The second generation has shown the potential for a greater dilation from 12 to 24 mm. These results demonstrate concept feasibility and motivate further development of a polymeric balloon-expandable device to replace valves in children and avoid reoperations

The Triplex BioValsalva Prostheses To Reconstruct the Aortic Valve and the Aortic Root

The Bentall procedure introduced in 1968 represents an undisputed cure to treat multiple pathologies involving the aortic valve and the ascending thoracic aorta. Over the years, multiple modifications have been introduced as well as a standardized approach to the operation with the goal to prevent long-term adverse events. The BioValsalva prosthesis provides a novel manner to more efficiently reconstruct the aortic valve together with the anatomy of the aortic root with the implantation of a valved conduit. This prosthesis comprises three sections: the collar supporting the valve; the skirt mimicking the Valsalva, which is suitable for the anastomoses with the coronary arteries; and the main body of the graft, which is designed to replace the ascending aorta. The BioValsalva prosthesis allows the Bentall operation to be used in patients whose aortic valve cannot be spared