Vicente Grau

Development of an anatomically detailed MRI-derived rabbit ventricular model and assessment of its impact on simulations of electrophysiological function

Recent advances in magnetic resonance (MR) imaging technology have unveiled a wealth of information regarding cardiac histoanatomical complexity. However, methods to faithfully translate this level of fine-scale structural detail into computational whole ventricular models are still in their infancy, and, thus, the relevance of this additional complexity for simulations of cardiac function has yet to be elucidated. Here, we describe the development of a highly detailed finite-element computational model (resolution: ∼125 μm) of rabbit ventricles constructed from high-resolution MR data (raw data resolution: 43 × 43 × 36 μm), including the processes of segmentation (using a combination of level-set approaches), identification of relevant anatomical features, mesh generation, and myocyte orientation representation (using a rule-based approach). Full access is provided to the completed model and MR data. Simulation results were compared with those from a simplified model built from the same images but excluding finer anatomical features (vessels/endocardial structures). Initial simulations showed that the presence of trabeculations can provide shortcut paths for excitation, causing regional differences in activation after pacing between models. Endocardial structures gave rise to small-scale virtual electrodes upon the application of external field stimulation, which appeared to protect parts of the endocardium in the complex model from strong polarizations, whereas intramural virtual electrodes caused by blood vessels and extracellular cleft spaces appeared to reduce polarization of the epicardium. Postshock, these differences resulted in the genesis of new excitation wavefronts that were not observed in more simplified models. Furthermore, global differences in the stimulus recovery rates of apex/base regions were observed, causing differences in the ensuing arrhythmogenic episodes. In conclusion, structurally simplified models are well suited for a large range of cardiac modeling applications. However, important differences are seen when behavior at microscales is relevant, particularly when examining the effects of external electrical stimulation on tissue electrophysiology and arrhythmia induction. This highlights the utility of histoanatomically detailed models for investigations of cardiac function, in particular for future patient-specific modeling.

Remodeling of the Connective Tissue Microarchitecture of the Lamina Cribrosa in Early Experimental Glaucoma

PURPOSE To characterize the trabeculated connective tissue microarchitecture of the lamina cribrosa (LC) in terms of total connective tissue volume (CTV), connective tissue volume fraction (CTVF), predominant beam orientation, and material anisotropy in monkeys with early experimental glaucoma (EG). METHODS The optic nerve heads from three monkeys with unilateral EG and four bilaterally normal monkeys were three dimensionally reconstructed from tissues perfusion fixed at an intraocular pressure of 10 mm Hg. A three-dimensional segmentation algorithm was used to extract a binary, voxel-based representation of the porous LC connective tissue microstructure that was regionalized into 45 subvolumes, and the following quantities were calculated: total CTV within the LC, mean and regional CTVF, regional predominant beam orientation, and mean and regional material anisotropy. RESULTS Regional variation within the laminar microstructure was considerable within the normal eyes of all monkeys. The laminar connective tissue was generally most dense in the central and superior regions for the paired normal eyes, and laminar beams were radially oriented at the periphery for all eyes considered. CTV increased substantially in EG eyes compared with contralateral normal eyes (82%, 44%, 45% increases; P<0.05), but average CTVF changed little (-7%, 1%, and -2% in the EG eyes). There were more laminar beams through the thickness of the LC in the EG eyes than in the normal controls (46%, 18%, 17% increases). CONCLUSIONS The substantial increase in laminar CTV with little change in CTVF suggests that significant alterations in connective and nonconnective tissue components in the laminar region occur in the early stages of glaucomatous damage.

Registration of Multiview Real-Time 3-D Echocardiographic Sequences

Real-time 3-D echocardiography opens up the possibility of interactive, fast 3-D analysis of cardiac anatomy and function. However, at the present time its quantitative power cannot be fully exploited due to the limited quality of the images. In this paper, we present an algorithm to register apical and parasternal echocardiographic datasets that uses a new similarity measure, based on local orientation and phase differences. By using phase and orientation to guide registration, the effect of artifacts intrinsic to ultrasound images is minimized. The presented method is fully automatic except for initialization. The accuracy of the method was validated qualitatively, resulting in 85% of the cardiac segments estimated having a registration error smaller than 2 mm, and no segments with an error larger than 5 mm. Robustness with respect to landmark initialization was validated quantitatively, with average errors smaller than 0.2 mm and 0.5o for initialization landmarks rotations of up to 15o and translations of up to 10 mm.

Three-Dimensional Models of Individual Cardiac Histoanatomy: Tools and Challenges

Abstract:  There is a need for, and utility in, the acquisition of data sets of cardiac histoanatomy, with the vision of reconstructing individual hearts on the basis of noninvasive imaging, such as MRI, enriched by reference to detailed atlases of serial histology obtained from representative samples. These data sets would be useful not only as a repository of knowledge regarding the specifics of cardiac histoanatomy, but could form the basis for generation of individualized high‐resolution cardiac structure–function models. The current article presents a step in this general direction: it illustrates how whole‐heart noninvasive imaging can be combined with whole‐heart histology in an approach to achieve automated construction of histoanatomically detailed models of cardiac 3D structure and function at hitherto unprecedented resolution and accuracy (based on 26.4 × 26.4 × 24.4 μm MRI voxel size, and enriched by histological detail). It provides an overview of the tools used in this quest and outlines challenges posed by the approach in the light of applications that may benefit from the availability of such data and tools.

Fractional diffusion models of cardiac electrical propagation: role of structural heterogeneity in dispersion of repolarization

Impulse propagation in biological tissues is known to be modulated by structural heterogeneity. In cardiac muscle, improved understanding on how this heterogeneity influences electrical spread is key to advancing our interpretation of dispersion of repolarization. We propose fractional diffusion models as a novel mathematical description of structurally heterogeneous excitable media, as a means of representing the modulation of the total electric field by the secondary electrical sources associated with tissue inhomogeneities. Our results, analysed against in vivo human recordings and experimental data of different animal species, indicate that structural heterogeneity underlies relevant characteristics of cardiac electrical propagation at tissue level. These include conduction effects on action potential (AP) morphology, the shortening of AP duration along the activation pathway and the progressive modulation by premature beats of spatial patterns of dispersion of repolarization. The proposed approach may also have important implications in other research fields involving excitable complex media.

The Systems Biology Approach to Drug Development: Application to Toxicity Assessment of Cardiac Drugs

Side effects account for most of the instances of failure of candidate drugs at late stages of development. These development failures contribute to the exorbitant cost of bringing new compounds to market: a single withdrawal can represent a loss of more than

The evaluation of single-view and multi-view fusion 3D echocardiography using image-driven segmentation and tracking

1 billion. Many unwanted actions of drugs affect the heart, resulting in potentially proarrhythmic alteration of ion channel function. Because these can be fatal, potential electrophysiological cardiotoxicity is among the most stringent exclusion criteria in the licensing process.

Adaptive multiscale ultrasound compounding using phase information

Real-time 3D echocardiography (RT3DE) promises a more objective and complete cardiac functional analysis by dynamic 3D image acquisition. Despite several efforts towards automation of left ventricle (LV) segmentation and tracking, these remain challenging research problems due to the poor-quality nature of acquired images usually containing missing anatomical information, speckle noise, and limited field-of-view (FOV). Recently, multi-view fusion 3D echocardiography has been introduced as acquiring multiple conventional single-view RT3DE images with small probe movements and fusing them together after alignment. This concept of multi-view fusion helps to improve image quality and anatomical information and extends the FOV. We now take this work further by comparing single-view and multi-view fused images in a systematic study. In order to better illustrate the differences, this work evaluates image quality and information content of single-view and multi-view fused images using image-driven LV endocardial segmentation and tracking. The image-driven methods were utilized to fully exploit image quality and anatomical information present in the image, thus purposely not including any high-level constraints like prior shape or motion knowledge in the analysis approaches. Experiments show that multi-view fused images are better suited for LV segmentation and tracking, while relatively more failures and errors were observed on single-view images.

Multiview RT3D Echocardiography Image Fusion

The recent availability of real-time three-dimensional echocardiography offers a convenient, low-cost alternative for detection and diagnosis of heart pathologies. However, a complete description of the heart can be obtained only by combining the information provided by different acoustic windows. We present a new method for compounding 3D ultrasound scans acquired from different views. The method uses multiscale information about ocal structure definition and orientation to weight the contributions of the images. We propose to use image phase to obtain these image characteristics while keeping invariance to image contrast. The monogenic signal provides a convenient, integrated approach for this purpose. We have evaluated our algorithm on synthetic images and heart scans from volunteers, showing it provides a significant improvement in image quality when compared to traditional compounding methods.

Multiview Fusion 3-d Echocardiography: Improving the Information and Quality of Real-Time 3-D Echocardiography

Real-time three-dimensional echocardiography (RT3DE) permits the acquisition and visualization of the beating heart in 3D. However, its actual utility is limited due to missing anatomical structures and limited field-of-view (FOV). We present an automatic two-stage registration and fusion method to integrate multiple single-view RT3DE images. The registration scheme finds a rigid transformation by using a multiresolution algorithm. The fusion is based on the 3D wavelet transform, utilizing the separation of the image into low- and high-frequency wavelet subbands. The qualitative and quantitative results, from 12 subjects, demonstrate that the proposed fusion framework helps in: (i) filling-in missing anatomical information, (ii) extending the FOV, and (iii) increasing the structural information and image contrast.