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.
Simula Research Laboratory, Center for Cardiological Innovation and Center for Biomedical Computing, Oslo, Norway; Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
Jussi T
JT
Koivumäki
Institute of Biomedical Engineering, Karlsruhe Institute of Technology, Karlsruhe, Germany.
Gunnar
G
Seemann
Simula Research Laboratory, Center for Cardiological Innovation and Center for Biomedical Computing, Oslo, Norway.
Mary M
MM
Maleckar
Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
Pasi
P
Tavi
D000200:Action Potentials / Q000502:physiology*; D001281:Atrial Fibrillation / Q000503:physiopathology*; D064752:Atrial Remodeling; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000502:physiology; D020013:Calcium Signaling / Q000502:physiology*; D002478:Cells, Cultured; D003198:Computer Simulation; D006325:Heart Atria / Q000473:pathology / Q000503:physiopathology*; D006329:Heart Conduction System / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000502:physiology*
D015220:Calcium Channels; D002118:Calcium