title: Atrial-selective targeting of arrhythmogenic phase-3 early afterdepolarizations in human myocytes.
abstract: We have previously shown that non-equilibrium Na(+) current (INa) reactivation drives isoproterenol-induced phase-3 early afterdepolarizations (EADs) in mouse ventricular myocytes. In these cells, EAD initiation occurs secondary to potentiated sarcoplasmic reticulum Ca(2+) release and enhanced Na(+)/Ca(2+) exchange (NCX). This can be abolished by tetrodotoxin-blockade of INa, but not ranolazine, which selectively inhibits ventricular late INa.
  
  
  
  Since repolarization of human atrial myocytes is similar to mouse ventricular myocytes in that it is relatively rapid and potently modulated by Ca(2+), we investigated whether similar mechanisms can evoke EADs in human atrium. Indeed, phase-3 EADs have been shown to re-initiate atrial fibrillation (AF) during autonomic stimulation, which is a well-recognized initiator of AF.
  
  
  
  We integrated a Markov model of INa gating in our human atrial myocyte model. To simulate experimental results, we rapidly paced this cell model at 10Hz in the presence of 0.1μM acetylcholine and 1μM isoproterenol, and assessed EAD occurrence upon return to sinus rhythm (1Hz).
  
  
  
  Cellular Ca(2+) loading during fast pacing results in a transient period of hypercontractility after return to sinus rhythm. Here, fast repolarization and enhanced NCX facilitate INa reactivation via the canonical gating mode (i.e., not late INa burst mode), which drives EAD initiation. Simulating ranolazine administration reduces atrial peak INa and leads to faster repolarization, during which INa fails to reactivate and EADs are prevented.
  
  
  
  Non-equilibrium INa reactivation can critically contribute to arrhythmias, specifically in human atrial myocytes. Ranolazine might be beneficial in this context by blocking peak (not late) atrial INa.
authors.affiliation: Department of Pharmacology, University of California Davis, Davis, CA, USA.
authors.forename: Stefano
authors.initials: S
authors.lastname: Morotti
authors.affiliation: Department of Bioengineering, University of California San Diego, La Jolla, CA, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: McCulloch
authors.affiliation: Department of Pharmacology, University of California Davis, Davis, CA, USA.
authors.forename: Donald M
authors.initials: DM
authors.lastname: Bers
authors.affiliation: Institute for Experimental Medicine, Oslo University Hospital Ullevål, Oslo, Norway; Simula Research Laboratory, Lysaker, Norway.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Edwards
authors.affiliation: Department of Pharmacology, University of California Davis, Davis, CA, USA. Electronic address: ele.grandi@gmail.com.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Grandi
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D016275:Atrial Function / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D015640:Ion Channel Gating; D008390:Markov Chains; D051379:Mice; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000494:pharmacology; D019831:Sodium-Calcium Exchanger
chemical_list: D000318:Adrenergic beta-Agonists; D026941:Sodium Channel Blockers; D019831:Sodium-Calcium Exchanger; D012964:Sodium; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium
keywords: Atrial fibrillation; Computer model; Na(+) current; Phase-3 EAD; Ranolazine