title: In-silico assessment of the dynamic effects of amiodarone and dronedarone on human atrial patho-electrophysiology.
abstract: OBJECTIVE
  The clinical efficacy in preventing the recurrence of atrial fibrillation (AF) is higher for amiodarone than for dronedarone. Moreover, pharmacotherapy with these drugs is less successful in patients with remodelled substrate induced by chronic AF (cAF) and patients suffering from familial AF. To date, the reasons for these phenomena are only incompletely understood. We analyse the effects of the drugs in a computational model of atrial electrophysiology.
  
  
  RESULTS
  The Courtemanche-Ramirez-Nattel model was adapted to represent cAF remodelled tissue and hERG mutations N588K and L532P. The pharmacodynamics of amiodarone and dronedarone were investigated with respect to their dose and heart rate dependence by evaluating 10 descriptors of action potential morphology and conduction properties. An arrhythmia score was computed based on a subset of these biomarkers and analysed regarding circadian variation of drug concentration and heart rate. Action potential alternans at high frequencies was observed over the whole dronedarone concentration range at high frequencies, while amiodarone caused alternans only in a narrow range. The total score of dronedarone reached critical values in most of the investigated dynamic scenarios, while amiodarone caused only minor score oscillations. Compared with the other substrates, cAF showed significantly different characteristics resulting in a lower amiodarone but higher dronedarone concentration yielding the lowest score.
  
  
  CONCLUSIONS
  Significant differences exist in the frequency and concentration-dependent effects between amiodarone and dronedarone and between different atrial substrates. Our results provide possible explanations for the superior efficacy of amiodarone and may aid in the design of substrate-specific pharmacotherapy for AF.
authors.affiliation: Institute of Biomedical Engineering, Karlsruhe Institute of Technology (KIT), Kaiserstr. 12, 76128 Karlsruhe, Germany publications@ibt.kit.edu.
authors.forename: Axel
authors.initials: A
authors.lastname: Loewe
authors.affiliation: Institute of Biomedical Engineering, Karlsruhe Institute of Technology (KIT), Kaiserstr. 12, 76128 Karlsruhe, Germany.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Lutz
authors.affiliation: Institute of Biomedical Engineering, Karlsruhe Institute of Technology (KIT), Kaiserstr. 12, 76128 Karlsruhe, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Wilhelms
authors.affiliation: Department of Internal Medicine I-Klinikum rechts der Isar, Technische Universität München, 80636 München, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Sinnecker
authors.affiliation: Department of Internal Medicine I-Klinikum rechts der Isar, Technische Universität München, 80636 München, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Barthel
authors.affiliation: Department of Internal Medicine III, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Eberhard P
authors.initials: EP
authors.lastname: Scholz
authors.affiliation: Institute of Biomedical Engineering, Karlsruhe Institute of Technology (KIT), Kaiserstr. 12, 76128 Karlsruhe, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Dössel
authors.affiliation: Department of Internal Medicine I-Klinikum rechts der Isar, Technische Universität München, 80636 München, Germany DZHK (German Center for Cardiovascular Research) partner site Munich Heart Alliance, Munich, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Schmidt
authors.affiliation: Institute of Biomedical Engineering, Karlsruhe Institute of Technology (KIT), Kaiserstr. 12, 76128 Karlsruhe, Germany.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Seemann
mesh_terms: D000200:Action Potentials; D000638:Amiodarone / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000889:Anti-Arrhythmia Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001281:Atrial Fibrillation / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D000077764:Dronedarone; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics / Q000378:metabolism; D006325:Heart Atria / Q000187:drug effects* / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008955:Models, Cardiovascular; D009154:Mutation; D009716:Numerical Analysis, Computer-Assisted; D012008:Recurrence; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000889:Anti-Arrhythmia Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D000077764:Dronedarone; D000638:Amiodarone
keywords: Amiodarone; Atrial fibrillation; Dronedarone; Drug safety; Mathematical model