Cardiac electrophysiological homeostasis

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The membrane potential, cell volume, and intracellular ion concentrations are fundamental cellular parameters that exert profound influences upon cellular, tissue and organ physiology. Electrophysiological homeostasis is the process of controlling these parameters, despite significant changes in the demands that are placed on the heart during normal activity. Much previous experimental and theoretical work has focused on the control of each parameter individually, yet their values are strongly interdependent. These complex interdependencies must be fully characterized in order to understand the relationship between cardiac electrical activity and the underlying properties of ion channels and pumps. The aim of this proposal is to create a model that will permit a thorough investigation of cardiac electrophysiological homeostasis. Predictions of the model will be tested in focused experiments in normal mice and mice with strategic mutations of ion channel functions. I have introduced and tested a novel modelling technique based on strict physical conservation principles, termed charge-difference modelling. I have shown in a recent review article that this method of modelling has significant advantages over existing cardiac models in that it accurately predicts the determinants of intracellular ion concentrations, cell volume and the membrane potential, whereas existing models do not (Fraser & Huang, 2007; Prog. Biophys. Mol. Biol. 94, 336-372). In addition, it allows the simulation of volume changes, electroneutral fluxes, multiple interacting electrically-charged compartments and non-isoelectric compartments, allowing accurate organelle as well as cytosolic simulation. My previous work has involved modelling skeletal muscle using this method. This lead to the development and successful experimental testing of a unifying theory for determination, regulation and maintenance of the membrane potential, cell volume and intracellular ion concentrations in skeletal muscle. I will now: (1) extend these novel modelling techniques to investigate ionic homeostasis in cardiac muscle cells and thereby provide the first formulation amongst available cardiac myocyte models that attains true steady states that are independent of initial intracellular ion concentrations. In turn, this will permit: (2) Use of the model to generate experimentally-testable hypotheses regarding the determinants of electrophysiological homeostasis in cardiac myocytes; and (3) Use of the model to investigate the influence of variations in electrophysiological homeostatic steady-state upon the cell-to-cell spread of electrical activity that is required for the normal pattern of cardiac excitation