In Silico Screening of the Key Cellular Remodeling Targets in Chronic Atrial Fibrillation

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. To approach this problem, we performed in silico experiments in a computational model of the human atrial myocyte. The remodeled function of cellular components was based on a broad literature review 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 intracellular calcium handling also has a substantial impact on the chronic AF phenotype. We additionally found that the reduction in amplitude of the calcium transient in chronic AF as compared to normal sinus rhythm is primarily due to the 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 decreased cellular excitability and the subsequent inducibility of repolarization abnormalities in the human atrial myocyte in chronic AF. We conclude that the presented results highlight the complexity of both intrinsic cellular interactions and emergent properties of human atrial myocytes in chronic AF. Therefore, reversing remodeling for a single remodeled component does little to restore the normal sinus rhythm phenotype. These findings may have important implications for developing novel therapeutic approaches for chronic AF.Author Summary: Atrial fibrillation is a complex disease which, at the level of individual atrial muscle cells, is a result of changes in a number of ion channels and transporters, as well as in cellular structure. How these alterations, together and separately, affect electrical and contractile function of the atrial cells is not well understood. In this study, we evaluated the effect of these changes using a computational approach. Our results show that abnormal function of both calcium and potassium ion channels at the sarcolemma has the largest impact on the electrical properties of the human atrial myocyte. Changes in intracellular calcium handling and cellular geometry are also significant for cellular function. Finally, our results highlight the interactions and additive effect of these abnormalities, in that a hypothetical restoration of any single modification does not result in recovery of function to a healthy phenotype. These findings have potentially important implications for developing novel treatment options for atrial fibrillation.