Monolayer Cell Cultures as Model Systems for Studying Paroxysmal Atrial Fibrillation Gil Bub, PhD, and Nabil El-Sherif, MD Atrial fibrillation is often paroxysmal in nature, characterized by periods of rapid irregular activity inter-dispersed with periods of normal sinus rhythm. Paroxysmal atrial fibrillation (PAF) is often associated with serious symptoms, such as dizzi- ness, increased chance of thrombosis, and may also lead to sustained atrial fibrillation via remodeling of the tissue over time(1). The mechanisms that lead to PAF are thought to be similar to sustained AF, in that they include reentrant mechanisms, rapid pul- monary vein ectopy, or a combination of the two (2,3). Mechanisms that lead to the initiation and termination of AF are difficult to elucidate due to the complex geometry of the atria, which displays significant intra and inter species differences. Per- haps the greatest difficulty in understanding PAF is due to the heterogeneous nature of the substrate, which consists of pacemaker cells embedded in excitable and fibrotic tissue. A first step to under- standing PAF is to develop an experimental and theoretical framework for studying the dynamics such heterogeneous substrates. This paper outlines tissue culture models that are potential systems for studying fundamental processes related to the sud- den onset and offset of complex rhythms. Mapping Conduction in Cardiac Cell Culture Heart cell monolayers are thin layers of tissue grown in culture dishes from embryonic or neona- tal cardiac cells. Cardiac cells from very young animals have the capacity to easily form gap junc- tional connections with neighboring cells in cul- ture. After a few days in culture, embryonic cardiac cells are capable of supporting propagating waves of excitation over long distances. Cardiac monolayers were popular 30 years ago as model systems of two-dimensional conduction (4). More recently, the availability of potential mapping techniques have renewed interest in cultured monolayers, as they allow controlled environments for studying conduction on microscopic and macroscopic scales. Optical mapping experiments on cultured cardiac monolayers have several advantages when com- pared to mapping conduction in intact tissue. Sig- nals from individual cells can be identified and mapped with subcellular resolution in cell culture while optical signals from intact tissue are com- pound signals from cells at the surface and deeper intramural layers. The geometry of cell cultures can be precisely controlled, allowing conduction pat- terns to be observed independent of the influence of micro and macro anatomy. In addition, cardiac monolayers can be grown in conditions that cause cells to have similar anisotropy, connectivity and longitudinal to transverse cell diameter ratios to cells in intact tissue. As a result of these advantages, several fundamental experiments have been per- formed on cell culture systems that could not easily be addressed in whole tissue studies. Measuring Microscopic Conduction Patterns: Factors that Effect Conduction Propagation in cardiac muscle depends on both excitable and passive electrical properties of the From the VA Medical Center, Brooklyn NY. Reprint requests: Gil Bub, PhD, SUNY Downstate Medical Center, VA Medical Center, 800 Poly Place, room 7-100, Brook- lyn, NY 11203; e-mail: gil@cnd.mcgill.ca © 2004 Elsevier Inc. All rights reserved. 0022-0736/04/370S-0013$30.00/0 doi:10.1016/j.jelectrocard.2004.08.014 Journal of Electrocardiology Vol. 37 Supplement 2004 44