title: Balance between sodium and calcium currents underlying chronic atrial fibrillation termination: An in silico intersubject variability study.
abstract: Atrial remodeling as a result of long-standing persistent atrial fibrillation (AF) induces substrate modifications that lead to different perpetuation mechanisms than in paroxysmal AF and a reduction in the efficacy of antiarrhythmic treatments.
  
  
  
  The purpose of this study was to identify the ionic current modifications that could destabilize reentries during chronic AF and serve to personalize antiarrhythmic strategies.
  
  
  
  A population of 173 mathematical models of remodeled human atrial tissue with realistic intersubject variability was developed based on action potential recordings of 149 patients diagnosed with AF. The relationship of each ionic current with AF maintenance and the dynamics of functional reentries (rotor meandering, dominant frequency) were evaluated by means of 3-dimensional simulations.
  
  
  
  Self-sustained reentries were maintained in 126 (73%) of the simulations. AF perpetuation was associated with higher expressions of INaand ICaL(P <.01), with no significant differences in the remaining currents. ICaLblockade promoted AF extinction in 30% of these 126 models. The mechanism of AF termination was related with collisions between rotors because of an increase in rotor meandering (1.71 ± 2.01cm2) and presented an increased efficacy in models with a depressed INa(P <.01).
  
  
  
  Mathematical simulations based on a population of models representing intersubject variability allow the identification of ionic mechanisms underlying rotor dynamics and the definition of new personalized pharmacologic strategies. Our results suggest that the underlying mechanism of the diverging success of ICaLblock as an antiarrhythmic strategy is dependent on the basal availability of sodium and calcium ion channel conductivities.
authors: ITACA, Universitat Politècnica de València, València, Spain; Cardiology Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain. Electronic address: alejandroliberos@gmail.com.
authors: Alejandro
authors: A
authors: Liberos
authors: Department of Computer Science, University of Oxford, Oxford, United Kingdom.
authors: Alfonso
authors: A
authors: Bueno-Orovio
authors: ITACA, Universitat Politècnica de València, València, Spain.
authors: Miguel
authors: M
authors: Rodrigo
authors: Department of Pharmacology and Toxicology, Technical University Dresden, Dresden, Germany.
authors: Ursula
authors: U
authors: Ravens
authors: Cardiology Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain; Department of Signal Theory and Communications, Rey Juan Carlos University, Fuenlabrada, Madrid, Spain.
authors: Ismael
authors: I
authors: Hernandez-Romero
authors: Cardiology Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain.
authors: Francisco
authors: F
authors: Fernandez-Aviles
authors: ITACA, Universitat Politècnica de València, València, Spain.
authors: Maria S
authors: MS
authors: Guillem
authors: Department of Computer Science, University of Oxford, Oxford, United Kingdom.
authors: Blanca
authors: B
authors: Rodriguez
authors: Cardiology Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain.
authors: Andreu M
authors: AM
authors: Climent
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001281:Atrial Fibrillation / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D064752:Atrial Remodeling; D015220:Calcium Channels / Q000378:metabolism*; D003198:Computer Simulation; D006801:Humans; D008955:Models, Cardiovascular; D015222:Sodium Channels / Q000378:metabolism*
chemical_list: D000889:Anti-Arrhythmia Agents; D015220:Calcium Channels; D015222:Sodium Channels
keywords: Atrial fibrillation; Calcium current; Ionic currents; Mathematical modeling; Rotor dynamics