Synergistic effect of the combination of ranolazine and dronedarone to suppress atrial fibrillation.

OBJECTIVES The aim of this study was to evaluate the effectiveness of a combination of dronedarone and ranolazine in suppression of atrial fibrillation (AF). BACKGROUND Safe and effective pharmacological management of AF remains one of the greatest unmet medical needs. METHODS The electrophysiological effects of dronedarone (10 μmol/l) and a relatively low concentration of ranolazine (5 μmol/l) separately and in combination were evaluated in canine isolated coronary-perfused right and left atrial and left ventricular preparations as well as in pulmonary vein preparations. RESULTS Ranolazine caused moderate atrial-selective prolongation of action potential duration and atrial-selective depression of sodium channel-mediated parameters, including maximal rate of rise of the action potential upstroke, leading to the development of atrial-specific post-repolarization refractoriness. Dronedarone caused little or no change in electrophysiological parameters in both atrial and ventricular preparations. The combination of dronedarone and ranolazine caused little change in action potential duration in either chamber but induced potent use-dependent atrial-selective depression of the sodium channel-mediated parameters (maximal rate of rise of the action potential upstroke, diastolic threshold of excitation, and the shortest cycle length permitting a 1:1 response) and considerable post-repolarization refractoriness. Separately, dronedarone or a low concentration of ranolazine prevented the induction of AF in 17% and 29% of preparations, respectively. In combination, the 2 drugs suppressed AF and triggered activity and prevented the induction of AF in 9 of 10 preparations (90%). CONCLUSIONS Low concentrations of ranolazine and dronedarone produce relatively weak electrophysiological effects and weak suppression of AF when used separately but when combined exert potent synergistic effects, resulting in atrial-selective depression of sodium channel-dependent parameters and effective suppression of AF.

[1]  C. Antzelevitch,et al.  Potent Antiarrhythmic Effects of Chronic Amiodarone in Canine Pulmonary Vein Sleeve Preparations , 2009, Journal of cardiovascular electrophysiology.

[2]  D. Murdock,et al.  The Use Of Oral Ranolazine To Convert New Or Paroxysmal Atrial Fibrillation: A Review Of Experience With Implications For Possible "Pill In The Pocket" Approach To Atrial Fibrillation , 2009, Indian pacing and electrophysiology journal.

[3]  P. Chatelain,et al.  SR 33589, a New Amiodarone‐like Antiarrhythmic Agent: Electrophysiological Effects in Anesthetized Dogs , 1995, Journal of cardiovascular pharmacology.

[4]  A. Capucci,et al.  Dronedarone for prevention of atrial fibrillation: a dose-ranging study. , 2003, European heart journal.

[5]  Patrick Gautier,et al.  Electrophysiologic Characterization of Dronedarone in Guinea Pig Ventricular Cells , 2003, Journal of cardiovascular pharmacology.

[6]  Bramahn . Singh,et al.  Electrophysiological effects of dronedarone (SR33589), a noniodinated benzofuran derivative, in the rabbit heart : comparison with amiodarone. , 1999, Circulation.

[7]  Andrew C. Zygmunt,et al.  Electrophysiological Effects of Ranolazine, a Novel Antianginal Agent With Antiarrhythmic Properties , 2004, Circulation.

[8]  C. Antzelevitch,et al.  Late‐Phase 3 EAD. A Unique Mechanism Contributing to Initiation of Atrial Fibrillation , 2006, Pacing and clinical electrophysiology : PACE.

[9]  S. Connolly,et al.  Effect of dronedarone on cardiovascular events in atrial fibrillation. , 2009, The New England journal of medicine.

[10]  Kapil Kumar,et al.  Ranolazine Exerts Potent Effects on Atrial Electrical Properties and Abbreviates Atrial Fibrillation Duration in the Intact Porcine Heart , 2009, Journal of cardiovascular electrophysiology.

[11]  C. Antzelevitch,et al.  New developments in atrial antiarrhythmic drug therapy , 2010, Nature Reviews Cardiology.

[12]  J Clémenty,et al.  Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. , 1998, The New England journal of medicine.

[13]  Andrew C. Zygmunt,et al.  Atrium-Selective Sodium Channel Block as a Strategy for Suppression of Atrial Fibrillation: Differences in Sodium Channel Inactivation Between Atria and Ventricles and the Role of Ranolazine , 2007, Circulation.

[14]  R. Vest.  Comparative Efficacy of Dronedarone and Amiodarone for the Maintenance of Sinus Rhythm in Patients With Atrial Fibrillation , 2010 .

[15]  E. Aliot,et al.  Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. , 2007, The New England journal of medicine.

[16]  Charles Antzelevitch,et al.  Synergistic Electrophysiologic and Antiarrhythmic Effects of the Combination of Ranolazine and Chronic Amiodarone in Canine Atria , 2010, Circulation. Arrhythmia and electrophysiology.

[17]  J. McMurray,et al.  Increased mortality after dronedarone therapy for severe heart failure. , 2008, The New England journal of medicine.

[18]  C. Antzelevitch,et al.  Atrial-selective sodium channel block for the treatment of atrial fibrillation , 2009, Expert opinion on emerging drugs.

[19]  J. Papp,et al.  Electrophysiological effects of dronedarone (SR 33589), a noniodinated amiodarone derivative in the canine heart: comparison with amiodarone , 2001, British journal of pharmacology.

[20]  D. Murdock,et al.  The effect of ranolazine on maintaining sinus rhythm in patients with resistant atrial fibrillation , 2008, Indian pacing and electrophysiology journal.

[21]  S. Sicouri,et al.  In Vitro Effects of Acute Amiodarone and Dronedarone on Epicardial, Endocardial, and M Cells of the Canine Ventricle , 2007, Journal of Cardiovascular Pharmacology and Therapeutics.

[22]  C. Antzelevitch,et al.  Antiarrhythmic effects of ranolazine in canine pulmonary vein sleeve preparations. , 2008, Heart rhythm.

[23]  M. Koren,et al.  Long-term safety of a novel antianginal agent in patients with severe chronic stable angina: the Ranolazine Open Label Experience (ROLE). , 2007, Journal of the American College of Cardiology.

[24]  R. Lazzara,et al.  Triggered firing in pulmonary veins initiated by in vitro autonomic nerve stimulation. , 2005, Heart rhythm.

[25]  J. M. Di Diego,et al.  Atrial-selective effects of chronic amiodarone in the management of atrial fibrillation. , 2008, Heart rhythm.

[26]  Bramahn . Singh,et al.  Chronic and Acute Effects of Dronedarone on the Action Potential of Rabbit Atrial Muscle Preparations: Comparison With Amiodarone , 2002, Journal of cardiovascular pharmacology.