Modeling Spatial Organization of Cardiac Cell Function: Application to Calcium Waves and Arrhythmia

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0929633RudyThe long-term goal of this application is to introduce the spatial dimension into models of the cardiac action potential and calcium cycling and to develop new modeling tools that will be used to address unanswered questions regarding the cellular origins of cardiac arrhythmias. Specifically, the mechanisms that underlie the local (subcellular) effects of the calcium-dependent signaling pathways on the temporal and spatial dynamic properties of calcium cycling and the cardiac action potential will be studied. The model will account for calcium diffusion, thus allowing for simulation of calcium waves and their arrhythmogenic effects on the cell electrophysiology. This model will provide, for the first time, a theoretical tool for simulating experimental calcium fluorescence images and for reconstructing from these images the actual calcium transients. Using this model, the mechanism of calcium - wave initiation and propagation, their modulation by signaling pathways activity, and their role in abnormal action potential repolarization and arrhythmogenic afterdepolarizations will be investigated.The proposed project encompasses several strata of intellectual merit. From a scientific perspective, it is aimed at bringing mathematical models of cardiac cells to the next level of physiological detail by incorporating important elements of cell architecture. The proposed model takes the important next steps of incorporating the spatial dimension and calcium-dependent signaling pathways in the cell models. From the healthcare perspective, there is increasing evidence that calcium wave dynamics underlie life threatening arrhythmias and sudden cardiac death in heart failure patients and in individuals who carry mutations in proteins that participate in calcium cycling. Mathematical modeling will provide mechanistic insights into these processes that are essential for developing novel effective approaches to diagnosis, prevention and treatment. Finally, from the educational perspective, their cell models have been used extensively in many institutions as teaching and developing tools in engineering, physiology, biophysics and pharmacology, and for training physicians and scientists at various levels (medical students, residents, and fellows specializing in cardiac electrophysiology and arrhythmia). Adding the sub-cellular spatial organization and its major role in cell function will enhance significantly these learning experiences. While this proposal focuses on cardiac cells, spatial organization of the calcium subsystem, calcium signaling and calcium waves are essential components of cell excitation and contraction in other muscle systems, including skeletal and smooth muscle cells. Formulation of a cardiac cell model that incorporates these properties could serve as a paradigm for these other muscle systems. For the cardiac research community, the new class of cell models will provide cellular building blocks for integrating into higher levels of organization (multicellular tissue, whole heart) in a multi-scale approach for studying cardiac electrophysiology and arrhythmia. The students and fellows will be trained in cardiac cell modeling. To this end, and to facilitate use of the models by other laboratories and academic institutions, the models developed under this proposal in the Matlab platform with Interactive Graphical User Interface will be fully available on the website and assistance for their implementation will be provided.