3D Echocardiogram Visualization: A New Method Based on "Focus + Context".

3D echocardiography (3DE) is the standard modality for visualizing heart valves and their surrounding anatomical structures. Commercial cardiovascular ultrasound systems commonly offer a set of parameters that allow clinical users to modify, in real time, visual aspects of the information contained in the echocardiogram. To our knowledge, there is currently no work that demonstrates if the methods currently used by commercial platforms are optimal. In addition, current platforms have limitations in adjusting the visibility of anatomical structures, such as reducing information that obstructs anatomical structures without removing essential clinical information. To overcome this, the present work proposes a new method for 3DE visualization based on "focus + context" (F+C), a concept which aims to present a detailed region of interest while preserving a less detailed overview of the surrounding context. The new method is intended to allow clinical users to modify parameter values differently within a certain region of interest, independently from the adjustment of contextual information. To validate this new method, a user study was conducted amongst clinical experts. As part of the user study, clinical experts adjusted parameters for five echocardiograms of patients with complete atrioventricular canal defect (CAVC) using both the method conventionally used by commercial platforms and the proposed method based on F+C. The results showed relevance for the F+C-based method to visualize 3DE of CAVC patients, where users chose significantly different parameter values with the F+C-based method.

Euclidean and Shape-Based Analysis of the Dynamic Mitral Annulus in Children using a Novel Open-Source Framework.

BACKGROUND: The dynamic shape of the normal adult mitral annulus has been shown to be important to mitral valve function. However, annular dynamics of the healthy mitral valve in children have yet to be explored. The aim of this study was to model and quantify the shape and major modes of variation of pediatric mitral valve annuli in four phases of the cardiac cycle using transthoracic echocardiography. METHODS: The mitral valve annuli of 100 children and young adults with normal findings on three-dimensional echocardiography were modeled in four different cardiac phases using the SlicerHeart extension for 3D Slicer. Annular metrics were quantified using SlicerHeart, and optimal normalization to body surface area was explored. Mean annular shapes and the principal components of variation were computed using custom code implemented in a new SlicerHeart module (Annulus Shape Analyzer). Shape was regressed over metrics of age and body surface area, and mean shapes for five age-stratified groups were generated. RESULTS: The ratio of annular height to commissural width of the mitral valve ("saddle shape") changed significantly throughout age for systolic phases (P < .001) but within a narrow range (median range, 0.20-0.25). Annular metrics changed statistically significantly between the diastolic and systolic phases of the cardiac cycle. Visually, the annular shape was maintained with respect to age and body surface area. Principal-component analysis revealed that the pediatric mitral annulus varies primarily in size (mode 1), ratio of annular height to commissural width (mode 2), and sphericity (mode 3). CONCLUSIONS: The saddle-shaped mitral annulus is maintained throughout childhood but varies significantly throughout the cardiac cycle. The major modes of variation in the pediatric mitral annulus are due to size, ratio of annular height to commissural width, and sphericity. The generation of age- and size-specific mitral annular shapes may inform the development of appropriately scaled absorbable or expandable mitral annuloplasty rings for children.

Introduction of transcatheter edge-to-edge repair in patients with congenital heart disease at a children's hospital.

BACKGROUND: Atrioventricular valve regurgitation (AVVR) is a devastating complication in children and young adults with congenital heart disease (CHD), particularly in patients with single ventricle physiology. Transcatheter edge-to-edge repair (TEER) is a rapidly expanding, minimally invasive option for the treatment of AVVR in adults that avoids the morbidity and mortality associated with open heart surgery. However, application of TEER in in CHD and in children is quite novel. We describe the development of a peri-procedural protocol including image-derived pre-intervention simulation, with successful application to four patients. AIMS: To describe the initial experience using the MitraClip system for TEER of dysfunctional systemic atrioventricular valves in patients with congential heart disease within a pediatric hospital. METHODS: A standardized screening and planning process was developed using cardiac magnetic resonance imaging, three dimensional echocardiography and both virtual and physical simulation. Procedures were performed using the MitraClip G4 system and patients were clinically followed post-intervention. RESULTS: A series of four CHD patients with at least severe AVVR were screened for suitability for TEER with the MitraClip system: three patients had single ventricle physiology and Fontan palliation, and one had repair of a common atrioventricular canal defect. Each patient had at least severe systemic AVVR and was considered at prohibitively high risk for surgical repair. Each patient underwent a standardized preprocedural screening protocol and image-derived modeling followed by the TEER procedure with successful clip placement at the intended location in all cases. CONCLUSIONS: The early results of our protocolized efforts to introduce TEER repair of severe AV valve regurgitation with MitraClip into the CHD population within our institution are encouraging. Further investigations of the use of TEER in this challenging population are warranted.

Modeling of the Tricuspid Valve and Right Ventricle in Hypoplastic Left Heart Syndrome With a Fontan Circulation.

BACKGROUND: In hypoplastic left heart syndrome, tricuspid regurgitation (TR) is associated with circulatory failure and death. We hypothesized that the tricuspid valve (TV) structure of patients with hypoplastic left heart syndrome with a Fontan circulation and moderate or greater TR differs from those with mild or less TR, and that right ventricle volume is associated with TV structure and dysfunction. METHODS: TV of 100 patients with hypoplastic left heart syndrome and a Fontan circulation were modeled using transthoracic 3-dimensional echocardiograms and custom software in SlicerHeart. Associations of TV structure to TR grade and right ventricle function and volume were investigated. Shape parameterization and analysis was used to calculate the mean shape of the TV leaflets, their principal modes of variation, and to characterize associations of TV leaflet shape to TR. RESULTS: In univariate modeling, patients with moderate or greater TR had larger TV annular diameters and area, greater annular distance between the anteroseptal commissure and anteroposterior commissure, greater leaflet billow volume, and more laterally directed anterior papillary muscle angles compared to valves with mild or less TR (all P<0.001). In multivariate modeling greater total billow volume, lower anterior papillary muscle angle, and greater distance between the anteroposterior commissure and anteroseptal commissure were associated with moderate or greater TR (P<0.001, C statistic=0.85). Larger right ventricle volumes were associated with moderate or greater TR (P<0.001). TV shape analysis revealed structural features associated with TR, but also highly heterogeneous TV leaflet structure. CONCLUSIONS: Moderate or greater TR in patients with hypoplastic left heart syndrome with a Fontan circulation is associated with greater leaflet billow volume, a more laterally directed anterior papillary muscle angle, and greater annular distance between the anteroseptal commissure and anteroposterior commissure. However, there is significant heterogeneity of structure in the TV leaflets in regurgitant valves. Given this variability, an image-informed patient-specific approach to surgical planning may be needed to achieve optimal outcomes in this vulnerable and challenging population.

Physical Simulation of Transcatheter Edge-to-Edge Repair using Image-Derived 3D Printed Heart Models.

Background: Transcatheter edge-to-edge valve repair (TEER) is a complex procedure requiring delivery and alignment of the device to the target valve, which can be challenging in atypical or surgically palliated anatomy. We demonstrate application of virtual and physical simulation to plan optimal TEER access and catheter path in normal and congenitally abnormal cardiac anatomy. Methods: Three heart models were created from three-dimensional (3D) images and 3D printed, including two with congenital heart disease. TEER catheter course was simulated both virtually and physically using a commercial TEER system. Results: We demonstrate application of modeling in three patients, including two with congenital heart disease and a Fontan circulation. Access site and pathway to device delivery was simulated by members of a multidisciplinary valve team. Virtual and physical simulation were compared. Conclusions: Virtual and physical simulation of TEER using 3D printed heart models is feasible and may be beneficial for planning and simulation, particularly in patients with complex anatomy. Future work is required to demonstrate application in the clinical setting.

SlicerHeart: An open-source computing platform for cardiac image analysis and modeling.

Cardiovascular disease is a significant cause of morbidity and mortality in the developed world. 3D imaging of the heart's structure is critical to the understanding and treatment of cardiovascular disease. However, open-source tools for image analysis of cardiac images, particularly 3D echocardiographic (3DE) data, are limited. We describe the rationale, development, implementation, and application of SlicerHeart, a cardiac-focused toolkit for image analysis built upon 3D Slicer, an open-source image computing platform. We designed and implemented multiple Python scripted modules within 3D Slicer to import, register, and view 3DE data, including new code to volume render and crop 3DE. In addition, we developed dedicated workflows for the modeling and quantitative analysis of multi-modality image-derived heart models, including heart valves. Finally, we created and integrated new functionality to facilitate the planning of cardiac interventions and surgery. We demonstrate application of SlicerHeart to a diverse range of cardiovascular modeling and simulation including volume rendering of 3DE images, mitral valve modeling, transcatheter device modeling, and planning of complex surgical intervention such as cardiac baffle creation. SlicerHeart is an evolving open-source image processing platform based on 3D Slicer initiated to support the investigation and treatment of congenital heart disease. The technology in SlicerHeart provides a robust foundation for 3D image-based investigation in cardiovascular medicine.

Visualization and Quantification of the Unrepaired Complete Atrioventricular Canal Valve Using Open-Source Software.

BACKGROUND: Repair of complete atrioventricular canal (CAVC) is often complicated by residual left atrioventricular valve regurgitation. The structure of the mitral and tricuspid valves in biventricular hearts has previously been shown to be associated with valve dysfunction. However, the three-dimensional (3D) structure of the entire unrepaired CAVC valve has not been quantified. Understanding the 3D structure of the CAVC may inform optimized repair. METHODS: Novel open-source work flows were created in SlicerHeart for the modeling and quantification of CAVC valves on the basis of 3D echocardiographic images. These methods were applied to model the annulus, leaflets, and papillary muscle (PM) structure of 35 patients (29 with trisomy 21) with CAVC using transthoracic 3D echocardiography. The mean leaflet and annular shapes were calculated and visualized using shape analysis. Metrics of the complete native CAVC valve structure were compared with those of normal mitral valves using the Mann-Whitney U test. Associations between CAVC structure and atrioventricular valve regurgitation were analyzed. RESULTS: CAVC leaflet metrics varied throughout systole. Compared with normal mitral valves, the left CAVC PMs were more acutely angled in relation to the annular plane (P < .001). In addition, the anterolateral PM was laterally and inferiorly rotated in CAVC, while the posteromedial PM was more superiorly and laterally rotated, relative to normal mitral valves (P < .001). Lower native CAVC atrioventricular valve annular height and annular height-to-valve width ratio before repair were both associated with moderate or greater left atrioventricular valve regurgitation after repair (P < .01). CONCLUSIONS: It is feasible to model and quantify 3D CAVC structure using 3D echocardiographic images. The results demonstrate significant variation in CAVC structure across the cohort and differences in annular, leaflet, and PM structure compared with the mitral valve. These tools may be used in future studies to catalyze future research intended to identify structural associations of valve dysfunction and to optimize repair in this vulnerable and complex population.

Statistical shape analysis of the tricuspid valve in hypoplastic left heart sydrome.

Hypoplastic left heart syndrome (HLHS) is a congenital heart disease characterized by incomplete development of the left heart. Children with HLHS undergo a series of operations which result in the tricuspid valve (TV) becoming the only functional atrioventricular valve. Some of those patients develop tricuspid regurgitation which is associated with heart failure and death and necessitates further surgical intervention. Repair of the regurgitant TV, and understanding the connections between structure and function of this valve remains extremely challenging. Adult cardiac populations have used 3D echocardiography (3DE) combined with computational modeling to better understand cardiac conditions affecting the TV. However, these structure-function analyses rely on simplistic point-based techniques that do not capture the leaflet surface in detail, nor do they allow robust comparison of shapes across groups. We propose using statistical shape modeling and analysis of the TV using Spherical Harmonic Representation Point Distribution Models (SPHARM-PDM) in order to generate a reproducible representation, which in turn enables high dimensional low sample size statistical analysis techniques such as principal component analysis and distance weighted discrimination. Our initial results suggest that visualization of the differences in regurgitant vs. non-regurgitant valves can precisely locate populational structural differences as well as how an individual regurgitant valve differs from the mean shape of functional valves. We believe that these results will support the creation of modern image-based modeling tools, and ultimately increase the understanding of the relationship between valve structure and function needed to inform and improve surgical planning in HLHS.

Skeletal model-based analysis of the tricuspid valve in hypoplastic left heart syndrome.

Hypoplastic left heart syndrome (HLHS) is a congenital heart disease characterized by incomplete development of the left heart. Children with HLHS undergo a series of operations which result in the tricuspid valve (TV) becoming the only functional atrioventricular valve. Many HLHS patients develop tricuspid regurgitation and right ventricle enlargement which is associated with heart failure and death without surgical intervention on the valve. Understanding the connections between the geometry of the TV and its function remains extremely challenging and hinders TV repair planning. Traditional analysis methods rely on simple anatomical measures which do not capture information about valve geometry in detail. Recently, surface-based shape representations such as SPHARM-PDM have been shown to be useful for tasks such as discriminating between valves with normal or poor function. In this work we propose to use skeletal representations (s-reps), a more feature-rich geometric representation, for modeling the leaflets of the tricuspid valve. We propose an extension to previous s-rep fitting approaches to incorporate application-specific anatomical landmarks and population information to improve correspondence. We use several traditional statistical shape analysis techniques to evaluate the efficiency of this representation: using principal component analysis (PCA) we observe that it takes fewer modes of variation compared to boundary-based approaches to represent 90% of the population variation, while distance-weighted discrimination (DWD) shows that s-reps provide for more significant classification between valves with less regurgitation and those with more. These results show the power of using s-reps for modeling the relationship between structure and function of the tricuspid valve.

Segmentation of Tricuspid Valve Leaflets From Transthoracic 3D Echocardiograms of Children With Hypoplastic Left Heart Syndrome Using Deep Learning.

Hypoplastic left heart syndrome (HLHS) is a severe congenital heart defect in which the right ventricle and associated tricuspid valve (TV) alone support the circulation. TV failure is thus associated with heart failure, and the outcome of TV valve repair are currently poor. 3D echocardiography (3DE) can generate high-quality images of the valve, but segmentation is necessary for precise modeling and quantification. There is currently no robust methodology for rapid TV segmentation, limiting the clinical application of these technologies to this challenging population. We utilized a Fully Convolutional Network (FCN) to segment tricuspid valves from transthoracic 3DE. We trained on 133 3DE image-segmentation pairs and validated on 28 images. We then assessed the effect of varying inputs to the FCN using Mean Boundary Distance (MBD) and Dice Similarity Coefficient (DSC). The FCN with the input of an annular curve achieved a median DSC of 0.86 [IQR: 0.81-0.88] and MBD of 0.35 [0.23-0.4] mm for the merged segmentation and an average DSC of 0.77 [0.73-0.81] and MBD of 0.6 [0.44-0.74] mm for individual TV leaflet segmentation. The addition of commissural landmarks improved individual leaflet segmentation accuracy to an MBD of 0.38 [0.3-0.46] mm. FCN-based segmentation of the tricuspid valve from transthoracic 3DE is feasible and accurate. The addition of an annular curve and commissural landmarks improved the quality of the segmentations with MBD and DSC within the range of human inter-user variability. Fast and accurate FCN-based segmentation of the tricuspid valve in HLHS may enable rapid modeling and quantification, which in the future may inform surgical planning. We are now working to deploy this network for public use.

Modeling Tool for Rapid Virtual Planning of the Intracardiac Baffle in Double-Outlet Right Ventricle.

PURPOSE: Biventricular repair of double-outlet right ventricle (DORV) necessitates the creation of a complex intracardiac baffle. Creation of the optimal baffle design and placement thereof can be challenging to conceptualize, even with 2-dimensional and 3-dimensional images. This report describes a recently developed methodology for creating virtual baffles to inform intraoperative repair. DESCRIPTION: A total of 3 heart models of DORV were created from cardiac magnetic resonance images. Baffles were created and visualized using custom software. EVALUATION: This report demonstrates application of the tool to virtual planning of the baffle for repair of DORV in 3 cases. Models were examined by a multidisciplinary team, on screen and in virtual reality. Baffles could be rapidly created and revised to facilitate planning of the surgical procedure. CONCLUSIONS: Virtual modeling of the baffle pathway by using cardiac magnetic resonance, creation of physical templates for the baffle, and visualization in virtual reality are feasible and may be beneficial for preoperative planning of complex biventricular repairs in DORV. Further work is needed to demonstrate clinical benefit or improvement in outcomes.

Successful integration of a three-dimensional transthoracic echocardiography-derived model with an electroanatomic mapping system to guide catheter ablation of WPW.

Three-dimensional transthoracic echocardiography (3DE)-derived heart models have not previously been utilized to guide catheter ablation. In this case report, we describe the creation of a 3DE model from transthoracic echocardiography, import of the model into CARTO3, and successful use of the model as a guide during mapping and ablation of a right lateral accessory pathway. We believe this technique represents a valuable alternative to the integration of computed tomography or magnetic resonance imaging-derived anatomic data, and that it has the potential to improve the definition of the atrioventricular valve annuli during catheter ablation of accessory pathways.

Interneurons Regulate Locomotion Quiescence via Cyclic Adenosine Monophosphate Signaling During Stress-Induced Sleep in Caenorhabditis elegans.

Sleep is evolutionarily conserved, thus studying simple invertebrates such as Caenorhabditis elegans can provide mechanistic insight into sleep with single cell resolution. A conserved pathway regulating sleep across phylogeny involves cyclic adenosine monophosphate (cAMP), a ubiquitous second messenger that functions in neurons by activating protein kinase A. C. elegans sleep in response to cellular stress caused by environmental insults [stress-induced sleep (SIS)], a model for studying sleep during sickness. SIS is controlled by simple neural circuitry, thus allowing for cellular dissection of cAMP signaling during sleep. We employed a red-light activated adenylyl cyclase, IlaC22, to identify cells involved in SIS regulation. We found that pan-neuronal activation of IlaC22 disrupts SIS through mechanisms independent of the cAMP response element binding protein. Activating IlaC22 in the single DVA interneuron, the paired RIF interneurons, and in the CEPsh glia identified these cells as wake-promoting. Using a cAMP biosensor, epac1-camps, we found that cAMP is decreased in the RIF and DVA interneurons by neuropeptidergic signaling from the ALA neuron. Ectopic overexpression of sleep-promoting neuropeptides coded by flp-13 and flp-24, released from the ALA, reduced cAMP in the DVA and RIFs, respectively. Overexpression of the wake-promoting neuropeptides coded by pdf-1 increased cAMP levels in the RIFs. Using a combination of optogenetic manipulation and in vivo imaging of cAMP we have identified wake-promoting neurons downstream of the neuropeptidergic output of the ALA. Our data suggest that sleep- and wake-promoting neuropeptides signal to reduce and heighten cAMP levels during sleep, respectively.