In silico screening of the key cellular remodeling targets in chronic atrial fibrillation

PLoS Comput Biol. 2014 May 22;10(5):e1003620. doi: 10.1371/journal.pcbi.1003620. eCollection 2014 May.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / physiology*
  • Atrial Fibrillation / physiopathology*
  • Atrial Remodeling
  • Calcium / metabolism
  • Calcium Channels / physiology
  • Calcium Signaling / physiology*
  • Cells, Cultured
  • Computer Simulation
  • Heart Atria / pathology
  • Heart Atria / physiopathology*
  • Heart Conduction System / pathology
  • Heart Conduction System / physiopathology*
  • Humans
  • Ion Channel Gating / physiology
  • Models, Cardiovascular*
  • Myocytes, Cardiac / physiology*

Substances

  • Calcium Channels
  • Calcium

Grants and funding

This work was supported by the Finnish Foundation for Cardiovascular Research (http://www.sydantutkimussaatio.fi/), Sigrid Juselius Foundation (www.sigridjuselius.fi), Academy of Finland (#125739, #217677, http://www.aka.fi/fi/A/), Paavo Nurmi Foundation (http://www.paavonurmensaatio.fi). JTK and MMM also gratefully acknowledge support via partnership in the Center for Cardiological Innovation at Oslo University Hospital and by a Center of Excellence grant from the Research Council of Norway to the Center for Biomedical Computing at Simula Research Laboratory. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.