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). Methods and Results This study investigates the electrophysiological, anti- and pro-arrhythmic effects of a clinically-relevant concentration of ranolazine (5 μM) 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/min; n=17). Transmembrane action potentials were recorded using standard microelectrode techniques. In atria, ranolazine slightly prolonged action potential duration but very significantly depressed sodium channel current (INa)-dependent parameters causing a reduction of maximum rate of rise of the action potential upstroke, a prolongation of the effective refractory period secondary to development of post-repolarization refractoriness, 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 INa in atrial cells isolated from HF vs. normal dogs. A single premature beat reproducibly induced self-terminating AF in 10/17 atria. Ranolazine (5 μM) suppressed induction of AF in 7/10 (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 non-failing 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.

The HARMONY Trial

“…However, preclinical studies 26,[36][37][38][39][40][41][42] indicate that it can suppress atrial arrhythmia triggers and AF even in the settings of HF and atrial stretch 39,40 Moreover, multiple reports (none large multicenter) indicate ranolazine (500-1000 mg BID) can terminate recent onset AF, reduce PAF recurrence, and possibly reduce late AF recurrences after cardioversion. 25,27,43 As no trial has directly compared ranolazine against an active control, the relative potency of ranolazine for such effects versus other AADs is unknown.…”

Antiarrhythmic Mechanisms of SK Channel Inhibition in the Rat Atrium

“…Work done by Antzelevitch et al previously reported intracellular recorded episodes of AF in canine isolated right atrial preparations. 27 However, these arrhythmias were reported to be more atrial flutter-like, which might be a consequence of the longer ERP in the canine atrium, compared with the rat, not generating substrate for fibrillating rotors to perpetuate AF.…”

Regional variation of the inwardly rectifying potassium current in the canine heart and the contributions to differences in action potential repolarization

“…Since the canine heart is used as both a model for safety pharmacology and to stimulate cardiac electrophysiological diseases, such as atrial fibrillation 30 , Long QT 31, 32 and Brugada Syndromes 33 , the present study compares the electrophysiological and molecular constituents of I K1 in single myocytes isolated from the canine heart. Here we show that the maximal rate of repolarization of the AP strongly depends on external K + ([K + ] o ) in ventricle, but not in Purkinje.…”