title: The combined effects of ranolazine and dronedarone on human atrial and ventricular electrophysiology.
abstract: Pharmacological rhythm control of atrial fibrillation (AF) in patients with structural heart disease is limited. Ranolazine in combination with low dose dronedarone remarkably reduced AF-burden in the phase II HARMONY trial. We thus aimed to investigate the possible mechanisms underlying these results.
  
  
  
  Patch clamp experiments revealed that ranolazine (5μM), low-dose dronedarone (0.3μM), and the combination significantly prolonged action potential duration (APD90) in atrial myocytes from patients in sinus rhythm (prolongation by 23.5±0.1%, 31.7±0.1% and 25.6±0.1% respectively). Most importantly, in atrial myocytes from patients with AF ranolazine alone, but more the combination with dronedarone, also prolonged the typically abbreviated APD90 (prolongation by 21.6±0.1% and 31.9±0.1% respectively). It was clearly observed that neither ranolazine, dronedarone nor the combination significantly changed the APD or contractility and twitch force in ventricular myocytes or trabeculae from patients with heart failure (HF). Interestingly ranolazine, and more so the combination, but not dronedarone alone, caused hyperpolarization of the resting membrane potential in cardiomyocytes from AF. As measured by confocal microscopy (Fluo-3), ranolazine, dronedarone and the combination significantly suppressed diastolic sarcoplasmic reticulum (SR) Ca(2+) leak in myocytes from sinus rhythm (reduction by ranolazine: 89.0±30.7%, dronedarone: 75.6±27.4% and combination: 78.0±27.2%), in myocytes from AF (reduction by ranolazine: 67.6±33.7%, dronedarone: 86.5±31.7% and combination: 81.0±33.3%), as well as in myocytes from HF (reduction by ranolazine: 64.8±26.5% and dronedarone: 65.9±29.3%).
  
  
  
  Electrophysiological measurements during exposure to ranolazine alone or in combination with low-dose dronedarone showed APD prolongation, cellular hyperpolarization and reduced SR Ca(2+) leak in human atrial myocytes. The combined inhibitory effects on various currents, in particular Na(+) and K(+) currents, may explain the anti-AF effects observed in the HARMONY trial. Therefore, the combination of ranolazine and dronedarone, but also ranolazine alone, may be promising new treatment options for AF, especially in patients with HF, and merit further clinical investigation.
authors.affiliation: Department of Cardiology and Pneumology, Georg August University Göttingen, Göttingen, Germany.
authors.forename: Nico
authors.initials: N
authors.lastname: Hartmann
authors.affiliation: Department of Cardiology and Pneumology, Georg August University Göttingen, Göttingen, Germany.
authors.forename: Fleur E
authors.initials: FE
authors.lastname: Mason
authors.affiliation: Department of Cardiology and Pneumology, Georg August University Göttingen, Göttingen, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Braun
authors.affiliation: Department of Cardiology and Pneumology, Georg August University Göttingen, Göttingen, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Pabel
authors.affiliation: Institute of Pharmacology, West German Heart and Vascular Center, Faculty of Medicine, University Duisburg-Essen, Essen, Germany.
authors.forename: Niels
authors.initials: N
authors.lastname: Voigt
authors.affiliation: Department of Anesthesiology, Emergency and Intensive Care Medicine, Georg August University Göttingen, Göttingen, Germany.
authors.forename: Hanna
authors.initials: H
authors.lastname: Schotola
authors.affiliation: Department of Cardiology and Pneumology, Georg August University Göttingen, Göttingen, Germany.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Fischer
authors.affiliation: Institute of Pharmacology, West German Heart and Vascular Center, Faculty of Medicine, University Duisburg-Essen, Essen, Germany.
authors.forename: Dobromir
authors.initials: D
authors.lastname: Dobrev
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Georg August University Göttingen, Göttingen, Germany.
authors.forename: Bernhard C
authors.initials: BC
authors.lastname: Danner
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Heart and Diabetes Center NRW, Ruhr University Bochum, Bad Oeynhausen, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Renner
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Heart and Diabetes Center NRW, Ruhr University Bochum, Bad Oeynhausen, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Gummert
authors.affiliation: Department of Biology, Cardiovascular, Therapeutic Area, Gilead Sciences, Foster, City, CA, USA.
authors.forename: Luiz
authors.initials: L
authors.lastname: Belardinelli
authors.affiliation: Department of Internal Medicine III: Cardiology and Angiology, University of Kiel, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Frey
authors.affiliation: Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany.
authors.forename: Lars S
authors.initials: LS
authors.lastname: Maier
authors.affiliation: Department of Cardiology and Pneumology, Georg August University Göttingen, Göttingen, Germany; DZHK (German Centre for Cardiovascular Research), partner site Göttingen, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Hasenfuss
authors.affiliation: Department of Cardiology and Pneumology, Georg August University Göttingen, Göttingen, Germany; Department of Internal Medicine III: Cardiology and Angiology, University of Kiel, Germany; DZHK (German Centre for Cardiovascular Research), partner site Göttingen, Germany. Electronic address: ssossalla@med.uni-goettingen.de.
authors.forename: Samuel
authors.initials: S
authors.lastname: Sossalla
mesh_terms: D000368:Aged; D000638:Amiodarone / Q000031:analogs & derivatives* / Q000494:pharmacology; D016275:Atrial Function / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002317:Cardiovascular Agents / Q000494:pharmacology; D000077764:Dronedarone; D004359:Drug Therapy, Combination; D005260:Female; D006325:Heart Atria / Q000187:drug effects*; D006352:Heart Ventricles / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D000069458:Ranolazine / Q000494:pharmacology*; D012518:Sarcomeres / Q000187:drug effects / Q000378:metabolism; D016276:Ventricular Function / Q000187:drug effects*
chemical_list: D002317:Cardiovascular Agents; D000069458:Ranolazine; D000077764:Dronedarone; D000638:Amiodarone; D002118:Calcium
keywords: Anti-arrhythmic therapy; Atrial fibrillation; Dronedarone; Electrophysiology; Heart failure; Ranolazine