Reentrant mechanisms play a primary role in many types of arrhythmias, including tachycardia and flutter in the atria, ventricles, and atrioventricular node. Reentry may involve anatomical pathways, or it may be functional, with leading circle, figure-eight, anisotropic, and spiral wave variants. The primary goal of this research is to establish a simple and reproducible cultured cell model for the study of anatomical and functional cardiac reentry under well-controlled experimental conditions. We propose to use voltage-sensitive dyes and high- resolution optical mapping to monitor reentrant activity in monolayers of neonatal rat heart cells. A detailed computational model will be verified against experimental data drawn from action potential and intracellular calcium measurements, and their restitution and rate-dependent behavior in this experimental model. The computational model will be used to identify the ionic currents and biophysical mechanisms responsible for reentry behavior. New microfabrication and surface chemical approaches will also be used to develop patterned substrates that direct the growth of cells in the monolayers. The combined experimental and computational approach that is proposed in this study will permit a detailed quantitative analysis and dissection of tissue behavior down to the cellular level. We will, 1) formulate an experimentally-based, biophysical model of the neonatal rat cardiac cell monolayer 2) characterize reentry in confluent monolayers of cultured neonatal rat heart cells, and 3) determine the electrophysiological properties and role of the core of the reentrant circuits. Issues of critical mass, excitable gap, and leading circle vs. spiral wave reentry will be addressed.
These aims will establish the cultured cell monolayer as a well-controlled, versatile and quantitative experimental model for basic studies of reentry- based arrhythmias. The simplicity and flexibility of this model system provides numerous advantages over existing tissue models of reentrant arrhythmia. Moreover, the cell culture is well suited for studies involving pharmacological, genetic and molecular manipulation.
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