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Aims: Antiarrhythmic medications for the treatment of atrial fibrillation (AF) have limited efficacy and rare but potentially life-threatening side effects. Ranolazine is an antianginal agent that may have antiarrhythmic activity in AF., Methods and Results: Using the Duke Enterprise Data Unified Content Explorer database, we analysed a cohort of AF patients on ranolazine. Patients served as their own historic control. Electrocardiograms (ECGs) were analysed before and after ranolazine initiation to determine the effect of ranolazine on dominant frequency (DF), f-wave amplitude, and organizational index (OI). We identified 15 patients with ECGs in AF before and after ranolazine. Ranolazine was associated with lower DF by an average of 10% (5.10 ± 0.74 vs. 5.79 ± 0.96 Hz, P = 0.04) but not with changes in OI (0.47 ± 0.11 vs. 0.50 ± 0.12, P = 0.71) or amplitude (0.47 ± 0.43 vs. 0.41 ± 0.40 mV, P = 0.82). Ranolazine was also associated with lower DF in patients (n = 10) not on concomitant antiarrhythmic therapy (5.25 ± 0.78 vs. 6.03 ± 0.79 Hz, P = 0.04)., Conclusion: Ranolazine is associated with lower AF DF but no change in OI or fibrillatory wave amplitude. Prospective trials are needed to evaluate ranolazine's potential as a novel antiarrhythmic drug for AF., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Objective: The fate of an impulse arising from stimulation is determined by the ability of the wave front to recruit sufficient Na channels from adjacent cells. Previous numerical studies of mutant Na channels revealed both the velocity of a conditioning wave and the recruiting capacity of the front as determinants of the vulnerable period (VP), an interval within which excitation results in unidirectional conduction. Drugs that block excitatory Na channels in a voltage dependent manner, such as antiarrhythmics, abused substances and antidepressants, slow the restoration of Na conductance trailing an action potential and are associated with proarrhythmia and sudden cardiac death. We hypothesized that drug-induced slowing of Na conductance recovery would flatten the Na conductance restoration gradient thereby reducing the recruiting capacity of a front, extending the VP and increasing the probability of unidirectional propagation., Methods: In a cable of ventricular cells, we explored the sensitivity of the VP to voltage-dependent blockade. While varying the unbinding time constant from 100 ms to 5 s, we measured the Na conductance restoration gradient, the liminal length, the refractory period (RP) and the VP., Results: Reducing the rate of drug unbinding flattened the restoration gradient, diminished the recruiting capacity of a premature impulse and extended the liminal length, RP and the VP. The VP was linearly dependent on the drug unbinding time constant. Rapidly unbinding drugs (time constant <1 s) reduced the liminal length below that of a quiescent cable., Conclusions: Slowing the unbinding rate of voltage-dependent drug block of Na channels extended the RP and the VP. Drugs with unbinding time constants greater than 1 s dramatically increased the probability of unidirectional propagation, reflecting increases in both the RP and the VP. This study provides a new mechanism linking Na channel function, compromised by voltage-dependent Na channel drug block, with proarrhythmic conditions that can lead to sudden cardiac death following premature stimulation.

The role of inactivation as a central mechanism in blockade of the cardiac Na(+) channel by antiarrhythmic drugs remains uncertain. We have used whole-cell and single channel recordings to examine the block of wild-type and inactivation-deficient mutant cardiac Na(+) channels, IFM/QQQ, stably expressed in HEK-293 cells. We studied the open-channel blockers disopyramide and flecainide, and the lidocaine derivative RAD-243. All three drugs blocked the wild-type Na(+) channel in a use-dependent manner. There was no use-dependent block of IFM/QQQ mutant channels with trains of 20 40-ms pulses at 150-ms interpulse intervals during disopyramide exposure. Flecainide and RAD-243 retained their use-dependent blocking action and accelerated macroscopic current relaxation. All three drugs reduced the mean open time of single channels and increased the probability of their failure to open. From the abbreviation of the mean open times, we estimated association rates of approximately 10(6)/M/s for the three drugs. Reducing the burst duration contributed to the acceleration of macroscopic current relaxation during exposure to flecainide and RAD-243. The qualitative differences in use-dependent block appear to be the result of differences in drug dissociation rate. The inactivation gate may play a trapping role during exposure to some sodium channel blocking drugs.

Drugs remain the mainstay of treatment of patients with atrial fibrillation (AF). An understanding of the mechanisms of AF and of atrioventricular (AV) conduction provides a basis for the understanding of the mechanisms of antiarrhythmic drug action. Although ectopic activity from a focus may initiate AF, re-entry is the usual mechanism of maintenance. In its classical form, reentry takes the form of circus movements around fixed anatomic structures. However, leading circle and anisotropic variants of reentry may arise as a result of functional variations of refractoriness or anistropic conduction. Electrical remodeling during AF favors its persistence. Reentry may be prevented by prolongation of the refractory period. Class III antiarrhythmic drugs prolong refractoriness by blockade of outward potassium currents. Class I drugs prolong refractoriness by delaying the recovery of of the sodium current. Many class I drugs also have potassium channel-blocking action. In AF the rate of conduction of rapid impulses to the ventricle is controlled by conduction over the AV node. Blockade of the L-type calcium channels, activation of the muscarinic and adenosine A1 receptors, or beta-adrenergic blockade will slow conduction over the AV node. The adverse cardiovascular effects of drugs used to treat AF can be predicted on the basis of their mechanisms of action. The current focus of drug development is on specific potassium channel blockers.

The goal of developing an antiarrhythmic agent effective against malignant ventricular arrhythmias while maintaining a low side-effect profile remains elusive. The class III drugs amiodarone and sotalol are the best available agents. However, both drugs possess properties outside the realm of a pure class III effect, and their use is limited by a variety of dose-related side effects. There are several drugs with more selective class III properties currently in development. This review provides an overview of the optimal characteristics of an effective theoretical class III drug and a summary of the properties of a number of class III drugs under active investigation. An ideal class III antiarrhythmic agent for a reentrant arrhythmia should provide use-dependent prolongation of the action potential duration with slow onset and rapid offset kinetics. This drug would prolong the effective refractory period of cardiac tissue selectively at the rapid heart rates achieved during ventricular tachycardia or fibrillation with a delayed onset of action, and a rapid resolution of its effects on resumption of physiologic heart rates. With little effect on the refractory period at normal or slow heart rates, the ability to induce torsade de pointes would be lessened. In contrast to these ideal properties, most currently available and investigational agents have a reverse use-dependent effect on the action potential duration, producing more effects on the refractory period at slower heart rates. This property results in part from preferential block of the rapidly activating component of the delayed rectifier potassium channel (IKr), with little or no effect on the slowly activating component (IKs). The development of a drug with favorable blocking kinetics that selectively blocks IKs may results in lower proarrhythmic events while still maintaining effective antiarrhythmic properties.

Over the past decade, the strategies for arrhythmia management have been in transition. Physical methods to treat arrhythmias, such as ICDs and RF ablation, have undergone considerable refinement and wider application. Ischemic heart disease and congestive heart failure have been identified as clinical situations in which antiarrhythmic drugs have a significant proarrhythmic potential. However, drugs retain an important role in arrhythmia management. Strategies to mitigate the structural and functional changes that occur in hypertrophy, ischemia, and infarction have not been thoroughly explored. Membrane ion channels and receptors are the targets for the action of currently available drugs. The cloning and sequencing of these ion channels and receptors should improve the efficacy and specificity of drug design. Cardiac Na+, Ca2+, K+, and nonspecific cation channels have a clearly defined role in the generation of the normal action potential. Their specific roles in the various clinical arrhythmias is less certain. There are sufficient data to associate specific ionic channels with normal and abnormal automaticity and with reentry occurring in specific regions of the heart. A rational choice of antiarrthymic drugs can be made when an arrhythmogenic mechanism and the putative underlying membrane currents can be identified based on the clinical characteristics of the arrhythmia. For a majority of clinical arrhythmias, this ideal has not been achieved. When a particular drug is used to treat an arrhythmia, the full complement of its actions will depend on which multiple ion channels or receptors are blocked and the kinetics of drug interaction with these sites.

Propafenone is a sodium channel blocking antiarrhythmic drug. It also has beta-adrenergic, potassium channel, and weak calcium channel blocking activity. The drug is metabolized in the liver with rates dependent on the debrisoquin phenotype. The saturable metabolism results in nonlinear pharmacokinetics. The metabolites retain sodium channel blocking activity but little beta-adrenergic blocking activity. Both controlled and noncontrolled studies have documented its efficacy in a variety of supraventricular arrhythmias. Intravenous propafenone is effective in converting atrial fibrillation to normal sinus rhythm. Chronic oral administration decreases the frequency of recurrence of atrial fibrillation and paroxysmal supraventricular tachycardia. The drug is particularly effective in the Wolff-Parkinson-White syndrome. The drug may produce SA block in patients with underlying sinus node dysfunction. Propafenone has comparatively few noncardiac side effects. It is a useful primary drug or an alternative to more commonly used drugs used for the treatment of supraventricular arrhythmias.

Antiarrhythmic drugs have relative specificity for blocking each of the major classes of ion channels that control the action potential. The kinetics of block is determined by the state of the channel. Those channel states occupied at depolarized potentials generally have greater affinity for the blocking drugs. The kinetics of the drug-channel interaction is important in determining the blocking profile observed clinically. The increased mortality resulting from drug treatment in CAST and several atrial fibrillation trials has resulted in a shift in antiarrhythmic drug development from the Na+ channel blocking (Class I) drugs to the K+ channel blocking (Class III) drugs. While both Classes of drugs have a proarrhythmic potential, this may be less for the Class III agents. Their lack of negative inotropy also make them more attractive. It is important that the potential advantages of these agents be evaluated in controlled clinical trials. In several laboratories, the techniques of molecular biology and biophysics are being combined to determine the block site of available drugs. This information will aid in the future development of agents with greater specificity, and hopefully greater efficacy and safety than those currently in clinical use.

The Na+ channel is an important target for the action of antiarrhythmic drugs. Application of contemporary biophysical, biochemical and molecular biological techniques have added considerably to our knowledge of its structure, function, modulation and block by antiarrhythmic drugs. The increased mortality from the use of these drugs for prophylaxis of cardiac arrhythmias has forced a re-evaluation of their use and of the entire pharmacological strategy of arrhythmia management. Gus Grant and David Wendt review recent studies on the block and modulation of cardiac Na+ channels and the place of Na+ channel blockers in future antiarrhythmic drug development.

Cardiac arrhythmias arise from disturbances in the functioning of the specific ion channels that normally control excitation or from the functional expression of previously latent channels. Antiarrhythmic agents act by blocking the membrane sodium, potassium, and calcium channels, but no agent has exclusive action on a given type of channel. Arrhythmias resulting from reentry form the largest group of clinically significant arrhythmias. Most arrhythmias result from depressed sodium channel function. The local anesthetic class of sodium channel blockers (class I agents) acts by slowing conduction and converting regions of unidirectional block to bidirectional block. Class III agents act by prolonging the action potential duration. Because potassium currents are normally responsible for repolarization of the cardiac action potentials, these agents are generally assumed to be potassium channel blockers. Class IV antiarrhythmics--calcium channel blockers--are used when a group of reentrant arrhythmias arises in regions in which conduction is primarily sustained by increases in permeability to calcium ions. The mechanisms of action of antiarrhythmic agents are discussed with respect to the basic cellular mechanisms of cardiac arrhythmias.

The local anesthetic-class of anti-arrhythmic drugs block the inward sodium current in nerve and cardiac muscle. A number of models for the interaction of these drugs with the neuronal sodium channel have been extended to cardiac muscle. The models assume a single binding site for the entire class of agents. The kinetics of drug interaction with this site depend on the Na channel conformation, open and inactivated channels having greater affinity than resting channels. An alternative formulation considers drug-receptor affinity as fixed, but access to the binding site is controlled by channel gating. Several clinically relevant predictions, such as competitive displacement of multiple agents, can be made from these models.

Background: The use of flecainide and encainide was terminated in the Cardiac Arrhythmia Suppression Trial because of an excess of sudden cardiac deaths in the active treatment group. Such events might arise from reentrant rhythms initiated by premature stimulation in the presence of anisotropic sodium channel availability. Drugs that bind to sodium channels increase the functional dispersion of refractoriness by slowing (a result of the drug-unbinding process) the transition from an inexcitable state to an excitable state. It is interesting that encainide and flecainide unbind slowly (15-20 seconds), whereas lidocaine and moricizine unbind rapidly (0.2-1.3 seconds)., Methods and Results: With a computer representation of a cable with Beeler-Reuter membrane properties, we found a small (6 msec) vulnerable window that occurred 338 msec after the last drive stimulus. Premature stimuli falling within the vulnerable window resulted in unidirectional block and reentrant activation. In the presence of a slowly unbinding drug, the window was delayed an additional 341 msec, and its duration was extended to 38 msec. The delay (antiarrhythmic effect) before the onset of the vulnerable window and its duration (proarrhythmic effect) were both dependent on the sodium channel availability and the recovery process. Both effects were also prolonged when sodium channel availability was reduced by membrane depolarization. Defining the proarrhythmic potential as the duration of the vulnerable window, we found that hypothetical use-dependent class I drugs have a greater proarrhythmic potential than non-use-dependent drugs., Conclusions: The antiarrhythmic and proarrhythmic properties of pure sodium channel antagonists are both dependent on sodium channel availability. Consequently, the price for increased antiarrhythmic efficacy (suppressed premature ventricular contractions) is an increased proarrhythmic vulnerability to unsuppressed premature ventricular contractions.