title: In silico optimization of atrial fibrillation-selective sodium channel blocker pharmacodynamics.
abstract: Atrial fibrillation (AF) is the most common type of clinical arrhythmia. Currently available anti-AF drugs are limited by only moderate efficacy and an unfavorable safety profile. Thus, there is a recognized need for improved antiarrhythmic agents with actions that are selective for the fibrillating atrium. State-dependent Na(+)-channel blockade potentially allows for the development of drugs with maximal actions on fibrillating atrial tissue and minimal actions on ventricular tissue at resting heart rates. In this study, we applied a mathematical model of state-dependent Na(+)-channel blocking (class I antiarrhythmic drug) action, along with mathematical models of canine atrial and ventricular cardiomyocyte action potentials, AF, and ventricular proarrhythmia, to determine the relationship between their pharmacodynamic properties and atrial-selectivity, AF-selectivity (atrial Na(+)-channel block at AF rates versus ventricular block at resting rates), AF-termination effectiveness, and ventricular proarrhythmic properties. We found that drugs that target inactivated channels are AF-selective, whereas drugs that target activated channels are not. The most AF-selective drugs were associated with minimal ventricular proarrhythmic potential and terminated AF in 33% of simulations; slightly fewer AF-selective agents achieved termination rates of 100% with low ventricular proarrhythmic potential. Our results define properties associated with AF-selective actions of class-I antiarrhythmic drugs and support the idea that it may be possible to develop class I antiarrhythmic agents with optimized pharmacodynamic properties for AF treatment.
authors.affiliation: Department of Medicine, University of Montreal, Montreal, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Aguilar-Shardonofsky
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Vigmond
authors.forename: Stanley
authors.initials: S
authors.lastname: Nattel
authors.forename: Philippe
authors.initials: P
authors.lastname: Comtois
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D019295:Computational Biology; D004285:Dogs; D006325:Heart Atria / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D007700:Kinetics; D008954:Models, Biological; D026941:Sodium Channel Blockers / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D015222:Sodium Channels / Q000378:metabolism*
chemical_list: D000889:Anti-Arrhythmia Agents; D026941:Sodium Channel Blockers; D015222:Sodium Channels