Simulation of Mitral Valve Plasticity in Response to Myocardial Infarction.

Left ventricular myocardial infarction (MI) has broad and debilitating effects on cardiac function. In many cases, MI leads to ischemic mitral regurgitation (IMR), a condition characterized by incompetency of the mitral valve (MV). IMR has many deleterious effects as well as a high mortality rate. While various clinical treatments for IMR exist, success of these procedures remains limited, in large part because IMR dramatically alters the geometry and function of the MV in ways that are currently not well understood. Previous investigations of post-MI MV remodeling have elucidated that MV tissues have a significant ability to undergo a form of permanent inelastic deformations in the first phase of the post-MI period. These changes appear to be attributable to the altered loading and boundary conditions on the MV itself, as opposed to an independent pathophysiological process. Mechanistically, these results suggest that the MV mostly responds passively to MI during the first 8 weeks post-MI by undergoing a permanent deformation. In the present study, we developed the first computational model of this post-MI MV remodeling process, which we term "mitral valve plasticity." Integrating methodologies and insights from previous studies of in vivo ovine MV function, image-based patient-specific model development, and post-MI MV adaptation, we constructed a representative geometric model of a pre-MI MV. We then performed finite element simulations of the entire MV apparatus under time-dependent boundary conditions and accounting for changes to material properties equivalent to those observed 0-8 weeks post-MI. Our results suggest that during this initial period of adaptation, the MV response to MI can be accurately modeled using a soft tissue plasticity approach, similar to permanent set frameworks that have been applied previously in the context of exogenously crosslinked tissues.

In vivo assessment of mitral valve leaflet remodelling following myocardial infarction.

Each year, more than 40,000 people undergo mitral valve (MV) repair surgery domestically to treat regurgitation caused by myocardial infarction (MI). Although continual MV tissue remodelling following repair is believed to be a major contributor to regurgitation recurrence, the effects of the post-MI state on MV remodelling remain poorly understood. This lack of understanding limits our ability to predict the remodelling of the MV both post-MI and post-surgery to facilitate surgical planning. As a necessary first step, the present study was undertaken to noninvasively quantify the effects of MI on MV remodelling in terms of leaflet geometry and deformation. MI was induced in eight adult Dorset sheep, and real-time three-dimensional echocardiographic (rt-3DE) scans were collected pre-MI as well as at 0, 4, and 8 weeks post-MI. A previously validated image-based morphing pipeline was used to register corresponding open- and closed-state scans and extract local in-plane strains throughout the leaflet surface at systole. We determined that MI induced permanent changes in leaflet dimensions in the diastolic configuration, which increased with time to 4 weeks, then stabilised. MI substantially affected the systolic shape of the MV, and the range of stretch experienced by the MV leaflet at peak systole was substantially reduced when referred to the current time-point. Interestingly, when we referred the leaflet strains to the pre-MI configuration, the systolic strains remained very similar throughout the post-MI period. Overall, we observed that post-MI ventricular remodeling induced permanent changes in the MV leaflet shape. This predominantly affected the MV's diastolic configuration, leading in turn to a significant decrease in the range of stretch experienced by the leaflet when referenced to the current diastolic configuration. These findings are consistent with our previous work that demonstrated increased plastic (i.e. non-recoverable) leaflet deformations post-MI, that was completely accounted for by the associated changes in collagen fiber structure. Moreover, we demonstrated through noninvasive methods that the state of the MV leaflet can elucidate the progression and extent of MV adaptation following MI and is thus highly relevant to the design of current and novel patient specific minimally invasive surgical repair strategies.

Pre-surgical Prediction of Ischemic Mitral Regurgitation Recurrence Using In Vivo Mitral Valve Leaflet Strains.

Ischemic mitral regurgitation (IMR) is a prevalent cardiac disease associated with substantial morbidity and mortality. Contemporary surgical treatments continue to have limited long-term success, in part due to the complex and multi-factorial nature of IMR. There is thus a need to better understand IMR etiology to guide optimal patient specific treatments. Herein, we applied our finite element-based shape-matching technique to non-invasively estimate peak systolic leaflet strains in human mitral valves (MVs) from in-vivo 3D echocardiographic images taken immediately prior to and post-annuloplasty repair. From a total of 21 MVs, we found statistically significant differences in pre-surgical MV size, shape, and deformation patterns between the with and without IMR recurrence patient groups at 6 months post-surgery. Recurrent MVs had significantly less compressive circumferential strains in the anterior commissure region compared to the recurrent MVs (p = 0.0223) and were significantly larger. A logistic regression analysis revealed that average pre-surgical circumferential leaflet strain in the Carpentier A1 region independently predicted 6-month recurrence of IMR (optimal cutoff value - 18%, p = 0.0362). Collectively, these results suggest greater disease progression in the recurrent group and underscore the highly patient-specific nature of IMR. Importantly, the ability to identify such factors pre-surgically could be used to guide optimal treatment methods to reduce post-surgical IMR recurrence.

Mitral valve leaflet response to ischaemic mitral regurgitation: from gene expression to tissue remodelling.

Ischaemic mitral regurgitation (IMR), a frequent complication following myocardial infarction (MI), leads to higher mortality and poor clinical prognosis if untreated. Accumulating evidence suggests that mitral valve (MV) leaflets actively remodel post MI, and this remodelling increases both the severity of IMR and the occurrence of MV repair failures. However, the mechanisms of extracellular matrix maintenance and modulation by MV interstitial cells (MVICs) and their impact on MV leaflet tissue integrity and repair failure remain largely unknown. Herein, we sought to elucidate the multiscale behaviour of IMR-induced MV remodelling using an established ovine model. Leaflet tissue at eight weeks post MI exhibited significant permanent plastic radial deformation, eliminating mechanical anisotropy, accompanied by altered leaflet composition. Interestingly, no changes in effective collagen fibre modulus were observed, with MVICs slightly rounder, at eight weeks post MI. RNA sequencing indicated that YAP-induced genes were elevated at four weeks post MI, indicating elevated mechanotransduction. Genes related to extracellular matrix organization were downregulated at four weeks post MI when IMR occurred. Transcriptomic changes returned to baseline by eight weeks post MI. This multiscale study suggests that IMR induces plastic deformation of the MV with no functional damage to the collagen fibres, providing crucial information for computational simulations of the MV in IMR.

Development of a Functionally Equivalent Model of the Mitral Valve Chordae Tendineae Through Topology Optimization.

Ischemic mitral regurgitation (IMR) is a currently prevalent disease in the US that is projected to become increasingly common as the aging population grows. In recent years, image-based simulations of mitral valve (MV) function have improved significantly, providing new tools to refine IMR treatment. However, clinical implementation of MV simulations has long been hindered as the in vivo MV chordae tendineae (MVCT) geometry cannot be captured with sufficient fidelity for computational modeling. In the current study, we addressed this challenge by developing a method to produce functionally equivalent MVCT models that can be built from the image-based MV leaflet geometry alone. We began our analysis using extant micron-resolution 3D imaging datasets to first build anatomically accurate MV models. We then systematically simplified the native MVCT structure to generate a series of synthetic models by consecutively removing key anatomic features, such as the thickness variations, branching patterns, and chordal origin distributions. In addition, through topology optimization, we identified the minimal structural complexity required to capture the native MVCT behavior. To assess the performance and predictive power of each synthetic model, we analyzed their performance by comparing the mismatch in simulated MV closed shape, as well as the strain and stress tensors, to ground-truth MV models. Interestingly, our results revealed a substantial redundancy in the anatomic structure of native chordal anatomy. We showed that the closing behavior of complete MV apparatus under normal, diseased, and surgically repaired scenarios can be faithfully replicated by a functionally equivalent MVCT model comprised of two representative papillary muscle heads, single strand chords, and a uniform insertion distribution with a density of 15 insertions/cm2. Hence, even though the complete sub-valvular structure is mostly missing in in vivo MV images, we believe our approach will allow for the development of patient-specific complete MV models for surgical repair planning.

A noninvasive method for the determination of in vivo mitral valve leaflet strains.

Assessment of mitral valve (MV) function is important in many diagnostic, prognostic, and surgical planning applications for treatment of MV disease. Yet, to date, there are no accepted noninvasive methods for determination of MV leaflet deformation, which is a critical metric of MV function. In this study, we present a novel, completely noninvasive computational method to estimate MV leaflet in-plane strains from clinical-quality real-time three-dimensional echocardiography (rt-3DE) images. The images were first segmented to produce meshed medial-surface leaflet geometries of the open and closed states. To establish material point correspondence between the two states, an image-based morphing pipeline was implemented within a finite element (FE) modeling framework in which MV closure was simulated by pressurizing the open-state geometry, and local corrective loads were applied to enforce the actual MV closed shape. This resulted in a complete map of local systolic leaflet membrane strains, obtained from the final FE mesh configuration. To validate the method, we utilized an extant in vitro database of fiducially labeled MVs, imaged in conditions mimicking both the healthy and diseased states. Our method estimated local anisotropic in vivo strains with less than 10% error and proved to be robust to changes in boundary conditions similar to those observed in ischemic MV disease. Next, we applied our methodology to ovine MVs imaged in vivo with rt-3DE and compared our results to previously published findings of in vivo MV strains in the same type of animal as measured using surgically sutured fiducial marker arrays. In regions encompassed by fiducial markers, we found no significant differences in circumferential(P = 0.240) or radial (P = 0.808) strain estimates between the marker-based measurements and our novel noninvasive method. This method can thus be used for model validation as well as for studies of MV disease and repair.

A comprehensive pipeline for multi-resolution modeling of the mitral valve: Validation, computational efficiency, and predictive capability.

Multiple studies have demonstrated that the pathological geometries unique to each patient can affect the durability of mitral valve (MV) repairs. While computational modeling of the MV is a promising approach to improve the surgical outcomes, the complex MV geometry precludes use of simplified models. Moreover, the lack of complete in vivo geometric information presents significant challenges in the development of patient-specific computational models. There is thus a need to determine the level of detail necessary for predictive MV models. To address this issue, we have developed a novel pipeline for building attribute-rich computational models of MV with varying fidelity directly from the in vitro imaging data. The approach combines high-resolution geometric information from loaded and unloaded states to achieve a high level of anatomic detail, followed by mapping and parametric embedding of tissue attributes to build a high-resolution, attribute-rich computational models. Subsequent lower resolution models were then developed and evaluated by comparing the displacements and surface strains to those extracted from the imaging data. We then identified the critical levels of fidelity for building predictive MV models in the dilated and repaired states. We demonstrated that a model with a feature size of about 5 mm and mesh size of about 1 mm was sufficient to predict the overall MV shape, stress, and strain distributions with high accuracy. However, we also noted that more detailed models were found to be needed to simulate microstructural events. We conclude that the developed pipeline enables sufficiently complex models for biomechanical simulations of MV in normal, dilated, repaired states.

The Three-Dimensional Microenvironment of the Mitral Valve: Insights into the Effects of Physiological Loads.

INTRODUCTION: In the mitral valve (MV), numerous pathological factors, especially those resulting from changes in external loading, have been shown to affect MV structure and composition. Such changes are driven by the MV interstitial cell (MVIC) population via protein synthesis and enzymatic degradation of extracellular matrix (ECM) components. METHODS: While cell phenotype, ECM composition and regulation, and tissue level changes in MVIC shape under stress have been studied, a detailed understanding of the three-dimensional (3D) microstructural mechanisms are lacking. As a first step in addressing this challenge, we applied focused ion beam scanning electron microscopy (FIB-SEM) to reveal novel details of the MV microenvironment in 3D. RESULTS: We demonstrated that collagen is organized into large fibers consisting of an average of 605 ± 113 fibrils, with a mean diameter of 61.2 ± 9.8 nm. In contrast, elastin was organized into two distinct structural subtypes: (1) sheet-like lamellar elastin, and (2) circumferentially oriented elastin struts, based on both the aspect ratio and transmural tilt. MVICs were observed to have a large cytoplasmic volume, as evidenced by the large mean surface area to volume ratio 3.68 ± 0.35, which increased under physiological loading conditions to 4.98 ± 1.17. CONCLUSIONS: Our findings suggest that each MVIC mechanically interacted only with the nearest 3-4 collagen fibers. This key observation suggests that in developing multiscale MV models, each MVIC can be considered a mechanically integral part of the local fiber ensemble and is unlikely to be influenced by more distant structures.

Multi-resolution geometric modeling of the mitral heart valve leaflets.

An essential element of cardiac function, the mitral valve (MV) ensures proper directional blood flow between the left heart chambers. Over the past two decades, computational simulations have made marked advancements toward providing powerful predictive tools to better understand valvular function and improve treatments for MV disease. However, challenges remain in the development of robust means for the quantification and representation of MV leaflet geometry. In this study, we present a novel modeling pipeline to quantitatively characterize and represent MV leaflet surface geometry. Our methodology utilized a two-part additive decomposition of the MV geometric features to decouple the macro-level general leaflet shape descriptors from the leaflet fine-scale features. First, the general shapes of five ovine MV leaflets were modeled using superquadric surfaces. Second, the finer-scale geometric details were captured, quantified, and reconstructed via a 2D Fourier analysis with an additional sparsity constraint. This spectral approach allowed us to easily control the level of geometric details in the reconstructed geometry. The results revealed that our methodology provided a robust and accurate approach to develop MV-specific models with an adjustable level of spatial resolution and geometric detail. Such fully customizable models provide the necessary means to perform computational simulations of the MV at a range of geometric accuracies in order to identify the level of complexity required to achieve predictive MV simulations.

Mitral Valve Chordae Tendineae: Topological and Geometrical Characterization.

Mitral valve (MV) closure depends upon the proper function of each component of the valve apparatus, which includes the annulus, leaflets, and chordae tendineae (CT). Geometry plays a major role in MV mechanics and thus highly impacts the accuracy of computational models simulating MV function and repair. While the physiological geometry of the leaflets and annulus have been previously investigated, little effort has been made to quantitatively and objectively describe CT geometry. The CT constitute a fibrous tendon-like structure projecting from the papillary muscles (PMs) to the leaflets, thereby evenly distributing the loads placed on the MV during closure. Because CT play a major role in determining the shape and stress state of the MV as a whole, their geometry must be well characterized. In the present work, a novel and comprehensive investigation of MV CT geometry was performed to more fully quantify CT anatomy. In vitro micro-tomography 3D images of ovine MVs were acquired, segmented, then analyzed using a curve-skeleton transform. The resulting data was used to construct B-spline geometric representations of the CT structures, enriched with a continuous field of cross-sectional area (CSA) data. Next, Reeb graph models were developed to analyze overall topological patterns, along with dimensional attributes such as segment lengths, 3D orientations, and CSA. Reeb graph results revealed that the topology of ovine MV CT followed a full binary tree structure. Moreover, individual chords are mostly planar geometries that together form a 3D load-bearing support for the MV leaflets. We further demonstrated that, unlike flow-based branching patterns, while individual CT branches became thinner as they propagated further away from the PM heads towards the leaflets, the total CSA almost doubled. Overall, our findings indicate a certain level of regularity in structure, and suggest that population-based MV CT geometric models can be generated to improve current MV repair procedures.

Ex Vivo Methods for Informing Computational Models of the Mitral Valve.

Computational modeling of the mitral valve (MV) has potential applications for determining optimal MV repair techniques and risk of recurrent mitral regurgitation. Two key concerns for informing these models are (1) sensitivity of model performance to the accuracy of the input geometry, and, (2) acquisition of comprehensive data sets against which the simulation can be validated across clinically relevant geometries. Addressing the first concern, ex vivo micro-computed tomography (microCT) was used to image MVs at high resolution (~40 micron voxel size). Because MVs distorted substantially during static imaging, glutaraldehyde fixation was used prior to microCT. After fixation, MV leaflet distortions were significantly smaller (p < 0.005), and detail of the chordal tree was appreciably greater. Addressing the second concern, a left heart simulator was designed to reproduce MV geometric perturbations seen in vivo in functional mitral regurgitation and after subsequent repair, and maintain compatibility with microCT. By permuting individual excised ovine MVs (n = 5) through each state (healthy, diseased and repaired), and imaging with microCT in each state, a comprehensive data set was produced. Using this data set, work is ongoing to construct and validate high-fidelity MV biomechanical models. These models will seek to link MV function across clinically relevant states.