title: Ranolazine effectively suppresses atrial fibrillation in the setting of heart failure.
abstract: BACKGROUND
  There is a critical need for safer and more effective pharmacological management of atrial fibrillation (AF) in the setting of heart failure (HF).
  
  
  RESULTS
  This study investigates the electrophysiological, antiarrhythmic, and proarrhythmic effects of a clinically relevant concentration of ranolazine (5 μmol/L) in coronary-perfused right atrial and left ventricular preparations isolated from the hearts of HF dogs. HF was induced by ventricular tachypacing (2-6 weeks at 200-240 beats per minute; n=17). Transmembrane action potentials were recorded using standard microelectrode techniques. In atria, ranolazine slightly prolonged action potential duration but significantly depressed sodium channel current-dependent parameters causing a reduction of maximum rate of rise of the action potential upstroke, a prolongation of the effective refractory period secondary to the development of postrepolarization refractoriness, and an increase in diastolic threshold of excitation and atrial conduction time. Ranolazine did not significantly alter these parameters or promote arrhythmias in the ventricles. Ranolazine produced greater inhibition of peak sodium channel current in atrial cells isolated from HF versus normal dogs. A single premature beat reproducibly induced self-terminating AF in 10 of 17 atria. Ranolazine (5 μmol/L) suppressed induction of AF in 7 of 10 (70%) atria. In the remaining 3 atria, ranolazine reduced frequency and duration of AF.
  
  
  CONCLUSIONS
  Our results demonstrate more potent suppression of AF by ranolazine in the setting of HF than previously demonstrated in nonfailing hearts and absence of ventricular proarrhythmia. The data suggest that ranolazine may be of benefit as an alternative to amiodarone and dofetilide in the management of AF in patients with HF.
authors.affiliation: From the Masonic Medical Research Laboratory, Utica, NY (A.B., J.M.D.D., H.B.-M., D.H., A.C.Z., J.M.C., C.A.); Department of Clinical and Biological Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY (N.S.M., B.G.K.); and Gilead Sciences, Foster City, CA (L.B.). ca@mmrl.edu sasha@mmrl.edu.
authors.forename: Alexander
authors.initials: A
authors.lastname: Burashnikov
authors.affiliation: From the Masonic Medical Research Laboratory, Utica, NY (A.B., J.M.D.D., H.B.-M., D.H., A.C.Z., J.M.C., C.A.); Department of Clinical and Biological Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY (N.S.M., B.G.K.); and Gilead Sciences, Foster City, CA (L.B.).
authors.forename: José M
authors.initials: JM
authors.lastname: Di Diego
authors.affiliation: From the Masonic Medical Research Laboratory, Utica, NY (A.B., J.M.D.D., H.B.-M., D.H., A.C.Z., J.M.C., C.A.); Department of Clinical and Biological Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY (N.S.M., B.G.K.); and Gilead Sciences, Foster City, CA (L.B.).
authors.forename: Hector
authors.initials: H
authors.lastname: Barajas-Martínez
authors.affiliation: From the Masonic Medical Research Laboratory, Utica, NY (A.B., J.M.D.D., H.B.-M., D.H., A.C.Z., J.M.C., C.A.); Department of Clinical and Biological Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY (N.S.M., B.G.K.); and Gilead Sciences, Foster City, CA (L.B.).
authors.forename: Dan
authors.initials: D
authors.lastname: Hu
authors.affiliation: From the Masonic Medical Research Laboratory, Utica, NY (A.B., J.M.D.D., H.B.-M., D.H., A.C.Z., J.M.C., C.A.); Department of Clinical and Biological Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY (N.S.M., B.G.K.); and Gilead Sciences, Foster City, CA (L.B.).
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Zygmunt
authors.affiliation: From the Masonic Medical Research Laboratory, Utica, NY (A.B., J.M.D.D., H.B.-M., D.H., A.C.Z., J.M.C., C.A.); Department of Clinical and Biological Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY (N.S.M., B.G.K.); and Gilead Sciences, Foster City, CA (L.B.).
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Cordeiro
authors.affiliation: From the Masonic Medical Research Laboratory, Utica, NY (A.B., J.M.D.D., H.B.-M., D.H., A.C.Z., J.M.C., C.A.); Department of Clinical and Biological Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY (N.S.M., B.G.K.); and Gilead Sciences, Foster City, CA (L.B.).
authors.forename: N Sydney
authors.initials: NS
authors.lastname: Moise
authors.affiliation: From the Masonic Medical Research Laboratory, Utica, NY (A.B., J.M.D.D., H.B.-M., D.H., A.C.Z., J.M.C., C.A.); Department of Clinical and Biological Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY (N.S.M., B.G.K.); and Gilead Sciences, Foster City, CA (L.B.).
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Kornreich
authors.affiliation: From the Masonic Medical Research Laboratory, Utica, NY (A.B., J.M.D.D., H.B.-M., D.H., A.C.Z., J.M.C., C.A.); Department of Clinical and Biological Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY (N.S.M., B.G.K.); and Gilead Sciences, Foster City, CA (L.B.).
authors.forename: Luiz
authors.initials: L
authors.lastname: Belardinelli
authors.affiliation: From the Masonic Medical Research Laboratory, Utica, NY (A.B., J.M.D.D., H.B.-M., D.H., A.C.Z., J.M.C., C.A.); Department of Clinical and Biological Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY (N.S.M., B.G.K.); and Gilead Sciences, Foster City, CA (L.B.). ca@mmrl.edu sasha@mmrl.edu.
authors.forename: Charles
authors.initials: C
authors.lastname: Antzelevitch
mesh_terms: D000083:Acetanilides / Q000008:administration & dosage*; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001281:Atrial Fibrillation / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005500:Follow-Up Studies; D006325:Heart Atria / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006329:Heart Conduction System / Q000187:drug effects* / Q000503:physiopathology; D006333:Heart Failure / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018408:Patch-Clamp Techniques; D010879:Piperazines / Q000008:administration & dosage*; D000069458:Ranolazine; D026941:Sodium Channel Blockers
chemical_list: D000083:Acetanilides; D004791:Enzyme Inhibitors; D010879:Piperazines; D026941:Sodium Channel Blockers; D000069458:Ranolazine
keywords: anti-arrhythmia agents; arrhythmias, cardiac; electrophysiology; pharmacology; sodium channel blockers