title: Refractoriness in human atria: Time and voltage dependence of sodium channel availability.
abstract: BACKGROUND
  Refractoriness of cardiac cells limits maximum frequency of electrical activity and protects the heart from tonic contractions. Short refractory periods support major arrhythmogenic substrates and augmentation of refractoriness is therefore seen as a main mechanism of antiarrhythmic drugs. Cardiomyocyte excitability depends on availability of sodium channels, which involves both time- and voltage-dependent recovery from inactivation. This study therefore aims to characterise how sodium channel inactivation affects refractoriness in human atria.
  
  
  RESULTS
  Steady-state activation and inactivation parameters of sodium channels measured in vitro in isolated human atrial cardiomyocytes were used to parameterise a mathematical human atrial cell model. Action potential data were acquired from human atrial trabeculae of patients in either sinus rhythm or chronic atrial fibrillation. The ex vivo measurements of action potential duration, effective refractory period and resting membrane potential were well-replicated in simulations using this new in silico model. Notably, the voltage threshold potential at which refractoriness was observed was not different between sinus rhythm and chronic atrial fibrillation tissues and was neither affected by changes in frequency (1 vs. 3Hz).
  
  
  CONCLUSIONS
  Our results suggest a preferentially voltage-dependent, rather than time-dependent, effect with respect to refractoriness at physiologically relevant rates in human atria. However, as the resting membrane potential is hyperpolarized in chronic atrial fibrillation, the voltage-dependence of excitability dominates, profoundly increasing the risk for arrhythmia re-initiation and maintenance in fibrillating atria. Our results thereby highlight resting membrane potential as a potential target in pharmacological management of chronic atrial fibrillation.
authors: Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: Lasse
authors: L
authors: Skibsbye
authors: Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: Thomas
authors: T
authors: Jespersen
authors: Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Germany; DZ HK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck,Germany.
authors: Torsten
authors: T
authors: Christ
authors: Center for Cardiological Innovation and Center for Biomedical Computing, Simula Research Laboratory, Oslo, Norway.
authors: Mary M
authors: MM
authors: Maleckar
authors: Center for Cardiological Innovation and Center for Biomedical Computing, Simula Research Laboratory, Oslo, Norway.
authors: Jonas
authors: J
authors: van den Brink
authors: Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
authors: Pasi
authors: P
authors: Tavi
authors: Center for Cardiological Innovation and Center for Biomedical Computing, Simula Research Laboratory, Oslo, Norway; Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland. Electronic address: jussi.koivumaki@iki.fi.
authors: Jussi T
authors: JT
authors: Koivumäki
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D016275:Atrial Function; D003198:Computer Simulation; D006325:Heart Atria / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000378:metabolism; D015222:Sodium Channels / Q000378:metabolism*; D013997:Time Factors
chemical_list: D015222:Sodium Channels
keywords: Atrial fibrillation; Electrophysiology; Ion channels; Mathematical modeling; Refractory period