Ranolazine for atrial fibrillation: buy one get three beneficial mechanisms!

Heart failure is a major problem in our societies, with high morbidity and mortality. Arrhythmias are known to contribute to the progression of and even can induce heart failure. The most common arrhythmia is atrial fibrillation, but antiarrhythmic drugs in patients with heart failure are sparse, have major side effects (e.g. amiodarone), or are even contraindicated like flecainide. Since the first report by Burashnikov et al. in 2007 in isolated canine atria, several experimental studies in cultured cells, and in isolated animal and human tissue have investigated the mechanisms of the antiarrhythmic properties of ranolazine (for a review, see Sossalla and Maier). These studies showed that ranolazine not only inhibits late Na current but it may also act as an atrial selective peak Na current blocker. The reasons for this include the fact that the half-inactivation voltage is more negative in atrial as compared with ventricular myocytes with a more depolarized resting membrane potential in atrial cells. The consequence is an increased fraction of inactivated Na channels at a given membrane potential. Accordingly, ranolazine produced a use-dependent depression of several Na channel parameters which can be also found in human atrial myocytes even at higher stimulation rates. Aidonidis et al. recently investigated right atrial monophasic action potentials in a rabbit model of inducible atrial tachyarrhythmias in vivo using intracardial catheters. The authors showed that ranolazine has antiarrhythmic effects due to an increase in atrial post-repolarization refractoriness resulting in depressed electrical excitability and impediment of arrhythmia initiation even at higher heart rates. Post-repolarization refractoriness was calculated when subtracting 75% of total monophasic action potential duration from the effective refractory period, and was suggested to be due to Na currents. Ranolazine also increased the action potential duration at any given pacing cycle length, which the authors mainly attributed to its additional effects on the main repolarizing K current IKr. The study by Frommeyer et al. in this issue of the European Journal of Heart Failure adds to the existing body of evidence and expands previous work by that group by using a rabbit heart failure model investigating action potentials mapped from the epicardium of isolated Langendorff-perfused rabbit hearts ex vivo. Perhaps surprisingly to some clinicians, the authors found an increased action potential duration in the atria of this heart failure model, although increased ventricular action potential duration in failing hearts is a well accepted hallmark. In atrial fibrillation, however, major known determinants of electrical remodelling include (i) reduced action potential duration; (ii) decreased L-type Ca current amplitude; and (iii) altered K currents, thereby favouring a re-entry mechanism, which are underlined by reduced effective refractory periods. In addition, Nattel and Dobrev in a recent review stressed the importance of early and delayed afterdepolarizations and triggered activity associated with altered Ca handling, including spontaneous Ca release from the sarcoplasmic reticulum and diastolic overload. These proarrhythmogenic triggers have now been shown by several authors. Intracellular Ca and Na handling are closely coupled and therefore it is possible that both mechanisms exist in parallel. Alternatively, altered Na handling due to increased late Na current can contribute to cytosolic Ca overload through the Na/Ca exchanger and/or thus may lead to a transient inward current with delayed afterdepolarizations. In addition, original data from a recently published LQT3 mouse model presenting with atrial fibrillation and increased late Na current showed early afterdepolarizations in the presence of long atrial action potentials. Finally, late phase 3 delayed and