|Authors||J. Koivumäki, G. Seemann, M. Maleckar and P. Tavi|
|Title||In Silico Screening of the Key Cellular Remodeling Targets in Chronic Atrial Fibrillation|
|Afilliation||Scientific Computing, , Scientific Computing|
|Project(s)||Center for Biomedical Computing (SFF)|
|Publication Type||Journal Article|
|Year of Publication||2014|
|Journal||PLoS Computational Biology|
Background - Chronic atrial fibrillation (AF) is a complex disease, with underlying changes in electrophysiology, calcium signaling and the structure of atrial myocytes. How these individual remodeling targets and their emergent interactions contribute to cell physiology in chronic AF is not well understood. Methodology/Principal Findings - In silico experiments were performed in a computational model of the human atrial myocyte. Remodeled function of cellular components was based on a broad review of the literature of in vitro findings in chronic AF, and these were integrated into the model to define a cohort of virtual cells. Simulation results indicate that while the altered function of calcium and potassium ion channels alone causes a pronounced decrease in action potential duration, remodeling of calcium handling has a substantial impact on the chronic AF phenotype as well. We also found that the reduction of intracellular calcium transient amplitude in chronic AF in comparison to normal sinus rhythm is mostly due to remodeling of calcium channel function, calcium handling and cellular geometry. Finally, we found that decreased electrical resistance of the membrane together with remodeled calcium handling synergistically decrease cellular excitability and inducibility of repolarization abnormalities in the human atrial myocyte in chronic AF. Conclusions/Significance - The results highlight the complexity of both intrinsic cellular interactions and emergent properties of human atrial myocytes in chronic AF. Therefore, reversing the remodeling for a single remodeled component does very little to restore the normal sinus rhythm phenotype. These findings may have important implications for developing novel therapeutic approaches for chronic AF.