This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. (A) OBJECTIVES Cardiac fibrillation is disorganized electrical behavior of the heart, and its consequence is the loss of coordinated muscle contraction. Electrical defibrillation by timely application of a strong electric shock to the heart has long been used as an effective therapy for this otherwise lethal disturbance of cardiac rhythm. In recent years defibrillation therapy has dramatically expanded due to its improved accessibility and functionality. Despite the critical role that the technique plays in saving human life, the fundamental mechanisms by which electrical shocks halt life-threatening disturbances in cardiac rhythm are not completely understood. Mechanical contraction follows the electrical activation of the heart. However, it has long been known that there is a cross-talk between the electrical and mechanical processes which could play a role in anti-arrhythmia therapy. Owing to the complexities in cardiac structure and behavior, mechanical contributions have never before been considered in the investigation of cardiac defibrillation mechanisms. The objective of this research is to determine the contribution of mechanoelectrical feedback in the process of cardiac defibrillation, and thus, to increase our knowledge of the mechanisms by which the exposure of the heart to strong electric shocks terminates fibrillation. This application seeks to continue the collaboration between the Computational Cardiac Electrophysiology Group at Johns Hopkins University and the National Biomedical Computation Resource. As a collaborative project of the NBCR this research will promote extensions to the development of Continuity and its anatomic, electrical and mechanical models and algorithms that will permit greater integration with bidomain models of the heart and torso, opening it up to the large array of applications in cardiac pacing, shock and electrocardiography. The following specific aims are proposed: + Specific Aim 1: To develop an anatomically-accurate three-dimensional electromechanical model of defibrillation in dog and mouse hearts building on the existing anatomic models developed at UCSD. + Specific Aim 2: Using the dog and mouse defibrillation models to analyze the mechanisms responsible for the increase in defibrillation threshold in volume overloaded hearts.
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