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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Surgery and Bioengineering Study Section (SB)
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Lathrop, David A
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Johns Hopkins University
Biomedical Engineering
Schools of Medicine
United States
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Molitoris, Jared M; Paliwal, Saurabh; Sekar, Rajesh B et al. (2016) Precisely parameterized experimental and computational models of tissue organization. Integr Biol (Camb) 8:230-242
Thompson, Susan A; Blazeski, Adriana; Copeland, Craig R et al. (2014) Acute slowing of cardiac conduction in response to myofibroblast coupling to cardiomyocytes through N-cadherin. J Mol Cell Cardiol 68:29-37
Chang, Marvin G; Chang, Connie Y; de Lange, Enno et al. (2012) Dynamics of early afterdepolarization-mediated triggered activity in cardiac monolayers. Biophys J 102:2706-14
Weinberg, Seth H; Tung, Leslie (2012) Oscillation in cycle length induces transient discordant and steady-state concordant alternans in the heart. PLoS One 7:e40477
Thompson, Susan A; Burridge, Paul W; Lipke, Elizabeth A et al. (2012) Engraftment of human embryonic stem cell derived cardiomyocytes improves conduction in an arrhythmogenic in vitro model. J Mol Cell Cardiol 53:15-23
Thompson, Susan A; Copeland, Craig R; Reich, Daniel H et al. (2011) Mechanical coupling between myofibroblasts and cardiomyocytes slows electric conduction in fibrotic cell monolayers. Circulation 123:2083-93
Kim, Deok-Ho; Lipke, Elizabeth A; Kim, Pilnam et al. (2010) Nanoscale cues regulate the structure and function of macroscopic cardiac tissue constructs. Proc Natl Acad Sci U S A 107:565-70
Weinberg, Seth; Lipke, Elizabeth A; Tung, Leslie (2010) In vitro electrophysiological mapping of stem cells. Methods Mol Biol 660:215-37
Limpitikul, Worawan; Christoforou, Nicolas; Thompson, Susan A et al. (2010) Influence of Electromechanical Activity on Cardiac Differentiation of Mouse Embryonic Stem Cells. Cardiovasc Eng Technol 1:179-193
Weinberg, Seth; Malhotra, Neha; Tung, Leslie (2010) Vulnerable windows define susceptibility to alternans and spatial discordance. Am J Physiol Heart Circ Physiol 298:H1727-37

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