CCBM: Anatomical and Electrical Remodeling in Heart

Both ventricular geometry and fiber orientation play a critical role in shaping electrical propagation and force production in the cadiac ventricles. A detailed knowledge of these factors, how they may be remodeled in cardiac pathology, and the effects of this remodeling on ventricular conduction is therefore of fundamental importance to the understanding of cardiac ventricular electro-mechanics in health and disease. We propose to investigate how remodeling of ventricular geometry and fiber organization influences ventricular conduction. There are four major tasks that must be accomplished if we are to understand this structure-function relationship. First, we must identify an appropriate experimental model in which to study effects of remodeling. Second, we must develop methods for rapid measurement of the geometry and fiber organization of the cardiac ventricles in order to characterize the nature of remodeling. Third, we must develop and apply mathematical methods for identifying statistically significant changes in ventricular geometry and fiber organization that occur during remodeling. Fourth, we must relate these anatomic changes to changes in properties of electrical conduction, both through experimentation and computer modeling. We will pursue these goals using the canine tachycardia pacing-induced model of heart failure as a model system. Specific aims of this four year proposal are:

Aim 1: Continue development of diffusion tensor magnetic resonance imaging (DTMRI) techniques for three-dimensional reconstruction of cardiac fiber orientation by: a) improving imaging methods to optimize spatial resolution, signal-to-noise-ratio and data acquisition time; b) testing the hypothesis that measures based on anisotropy of diffusion can be used to detect regions of myofiber disarray

Aim 2: Develop a transformation-based probabilistic atlas describing variation of ventricular geometry and fiber organization in normal human and canine ventricles by: a) using DTRMI to reconstruct ventricular geometry and fiber orientation/anisotropy in a population of human and canine hearts; b) using the theory of large deformation mapping to transform the geometry of a template heart into the geometries of target hearts, computing the metric distances of the transformations required to register these geometries as a measure of the geometric differences between template and target, and building probability distributions describing variability of geometry of target hearts in terms of the variability of these transformations; c) extending the procedures of Aim 2b to describe variability of fiber structure

Aim 3 : Develop a transformation-based probabilistic atlas of the failing human and canine ventricles, and test the hypothesis that ventricular fiber orientation and anisotropy in failing hearts differs from that of normal hearts by: a) using DTMRI to reconstruct ventricular geometry and fiber orientation/anisotropy in a population of failing human and canine hearts; b) using the mathematical approaches of Aim 2 to determine if statistically significant differences of fiber orientation/anisotropy are present in failing versus normal hearts

Aim 4 : Test the hypothesis that structural remodeling of ventricular geometry and fiber organization contributes to changes in electrical conduction properties in end-stage heart failure by: a) measuring epicardial patterns of electrical conduction prior to DTMRI using electrode arrays for each of the canine hearts studied in Aims 2-3, and correlating measured changes in conduction properties with measured changes in ventricular geometry and fiber structure ; b) undertaking computer modeling studies in which electrical conduction is measured experimentally in normal and failing canine hearts and then compared with predictions made using computational models of these same hearts; c) using the DTMRI data of Aims 2-3 to develop computational models of electrical conduction in normal and failing human heart, and relating changes in anatomic structure to changes in conduction properties simulated using the models.

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