Instrumentation and computational modeling tools for cardiac electrophysiology

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Mice and rats are commonly used as models of cardiovascular disease. In particular, the rat heart has long been a very frequently used experimental model in the context of development and testing of new pharmaceutical agents. This has created a need for instrumentation and methods for assessing cardiovascular function in mice and rats, and for a better understanding of the murine (mouse and rat) heart. This proposal aims to develop a combination of experimental and computer modeling techniques applicable specifically to the electrophysiology of the murine heart. By closely coordinating experimental research and computer modeling, we hope to obtain more information than could be obtained if the two were carried out separately. Computer modeling results can, e.g., help highlight areas where theoretical predictions differ from experimental observations. Experimental observations can help refine computational descriptions by providing additional data. The focus of this proposal is on methods used to measure electrical coupling among neighbouring cells in the heart, a property which is frequently affected by heart disease. Optical mapping, the primary experimental method proposed, uses voltage-sensitive dyes that insert into the cell membrane. These dyes emit a fluorescent signal that is proportional to the voltage across the cell membrane. By recording this signal with a video camera, one can obtain non-contact recordings of electrical activation of the heart. This allows the researcher to quantify the pattern (order) of activation of different parts of the heart as well as the speed of conduction of electrical activation across the heart. The results obtained with this technique will be compared to electrical measurements of the impedance of heart tissue, as well as to results obtained with corresponding computer models. Overall, the objective is to establish 1) knowledge about how electrical coupling affects the behaviour of the heart and 2) tools for measuring electrical coupling. These outcomes will be of use in basic medical research as well as for development of pharmaceutical therapies for heart disease.