Antiarrhythmic properties of ranolazine: A review of the current evidence

doi:10.1016/j.ijcard.2015.03.324

International Journal of Cardiology

Volume 187, 6 May 2015, Pages 66-74

https://doi.org/10.1016/j.ijcard.2015.03.324 Get rights and content

Highlights

•
Ranolazine was developed as an antianginal agent and has been approved by the FDA for use in chronic stable angina pectoris.
•
Multiple experimental and clinical studies have shown that it also has antiarrhythmic properties.
•
Recent clinical studies have also shown its efficacy in both atrial and ventricular arrhythmias.
•
This review discusses the available preclinical and clinical data on the antiarrhythmic effects of this novel antianginal agent.

Abstract

Ranolazine was developed as an antianginal agent and was approved by the Food and Drug Administration in 2006 for use in chronic stable angina pectoris. Experimental and clinical studies have shown that it also has antiarrhythmic properties based on the frequency-dependent blockade of peak sodium channel current (peak I_Na) and rapidly activating delayed rectifier potassium current (I_Kr) in the atria and blockade of late phase of the inward sodium current (late I_Na) in the ventricles. Recent clinical studies have revealed the efficacy of ranolazine in prevention of atrial fibrillation in patients with acute coronary syndromes, prevention as well as conversion of postoperative atrial fibrillation after cardiac surgery, conversion of recent-onset atrial fibrillation and maintenance of sinus rhythm in recurrent atrial fibrillation. Ranolazine has also been shown to reduce ventricular tachycardia and drug-refractory implantable cardioverter defibrillator shocks. The antiarrhythmic effect of ranolazine is preserved in the setting of chronic heart failure and clinical studies have demonstrated its safety in patients with heart failure. This review discusses the available preclinical and clinical data on the antiarrhythmic effects of this novel antianginal agent.

Introduction

Ranolazine {Ranexa, Gilead Sciences, Foster City, Calif., USA; N-(2,6 dimethylphenyl)-4(2-hydroxy-3-{2-methoxyphenoxy}-propyl)-1-piperazine acetamide dihydrochloride}, a sustained-release, hemodynamically inert anti-anginal drug was approved by the Food and Drug Administration in 2006 for use in patients with chronic stable angina pectoris [1], [2], [3], [4], [5], [6], [7], [8]. Although initially developed as an antianginal agent, it was found to additionally exert antiarrhythmic actions [9], [10], [11], [12], [13]. Ranolazine has been shown to inhibit a number of ion currents that play a role in the genesis of the transmembrane cardiac action potential [14], [15], [16], [17], [18], [19]. Table 1 reviews the IC₅₀ (concentration that causes 50% inhibition) values of ranolazine for the various ion currents. In the ventricles, ranolazine exercises its antiarrhythmic effects mainly through inhibition of the late phase of the inward sodium current (late I_Na) and the rapidly activating delayed rectifier potassium current (I_Kr). In atria, in addition to the blockade of late I_Na and I_Kr, inhibition of the early or peak sodium channel current (peak I_Na) by ranolazine plays an important role [14]. This review discusses the electrophysiological basis of the antiarrhythmic actions of ranolazine and summarizes the relevant preclinical and clinical data on its use as an antiarrhythmic agent.

Section snippets

Study selection

Relevant peer-reviewed literature was selected in Pubmed, Google Scholar and Cochrane Library using terms ‘ranolazine’, ‘arrhythmia’, and ‘late sodium channel inhibitors’. The search was limited to English language publications, without date limitation.

Effect of ranolazine on peak and late I_Na, other ion channel currents and cardiac action potential

The late I_Na was first described by Coraboeuf et al. in 1979, when they found that tetrodotoxin reduces action potential (APD) in dog Purkinje fibers at concentrations lower than those at which the maximum rate of rise of action potential upstroke (V_max) decreases. They concluded that “this current, which is more sensitive to tetrodotoxin than the normal rapid (or peak) sodium current, flows through a background sodium conductance and/or a small proportion of sodium channels with no activation

Ranolazine in atrial arrhythmias

Rhythm control still remains an important strategy in the treatment of symptomatic atrial fibrillation (AF). However, the currently available antiarrhythmic drugs are associated with potentially severe cardiac and extra-cardiac side effects such as ventricular proarrhythmia, hypotension, and lung toxicity [48]. Also, in the setting of heart failure with reduced ejection fraction, antiarrhythmic therapy is more or less limited to amiodarone, as other class III agents as well as class I agents

Ranolazine in ventricular arrhythmias

Ventricular arrhythmias associated with reduced repolarization reserve due to an increased late I_Na, reduced I_Kr or a combination of both, are effectively suppressed by ranolazine. An increase in late I_Na is associated with prolongation of APD and destabilization of repolarization. Also, enhanced late I_Na increases sodium influx, and therefore, increased intracellular calcium via the I_NCX. Intracellular calcium overload leads to spontaneous release of calcium from sarcoplasmic reticulum,

Conclusion

In recent years, there has been an increased interest in the electrophysiological effects of ranolazine. This article summarizes the current evidence for the therapeutic role of ranolazine in treatment of atrial and ventricular arrhythmias in addition to its current antianginal role. The drug has been studied in several small clinical studies. The only multicenter randomized-control data supporting its use as an antiarrhythmic agent comes from the MERLIN-TIMI 36 trial. However, this study was

Conflicts of interest

None.

Source of funding

None.

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The results revealed that hypothyroid animals presented ECG alterations (e.g. increased QTc) with the presence of spontaneous sustained ventricular tachycardia. These changes were associated with depolarized resting membrane potential in isolated cardiomyocytes and increased AP duration and dispersion at 90 % of the repolarization. Aberrant AP waveforms were related to increased Ca²⁺ sparks and out-of-pace Ca²⁺ waves. These changes were observed in a scenario of enhanced I_Na,late. Interestingly, ranolazine, a clinically used blocker of I_Na,late, restored the ECG alterations, reduced Ca²⁺ sparks and aberrant waves, decreased the in vitro events and the severity of arrhythmias observed in isolated cardiomyocytes from hypothyroid animals. Using the in vivo dobutamine + caffeine protocol, animals with hypothyroidism developed catecholaminergic bidirectional ventricular tachycardia, but pre-treatment with ranolazine prevented this.
We concluded that animals with hypothyroidism have increased susceptibility to developing arrhythmias and ranolazine, a clinically used blocker of I_Na,late, is able to correct the arrhythmic phenotype.
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In our kindred family, members with AF carrying the SCN5A mutation did not respond to non-mechanism-based antiarrhythmic therapy. However, based on our findings using patient-specific iPSC-aCMs, it is plausible that a mechanism-based therapy such as the FDA-approved drug ranolazine may be more efficacious as it specifically blocks the INa,L (Gupta et al., 2015; Polytarchou and Manolis, 2015). Furthermore, some antiarrhythmic drugs are associated with serious toxicities, including drug-induced long QT syndrome, highlighting the importance of screening platforms for precision medicine.
Mutations in SCN5A, encoding the cardiac sodium channel, are linked with familial atrial fibrillation (AF) but the underlying pathophysiologic mechanisms and implications for therapy remain unclear. To characterize the pathogenesis of AF-linked SCN5A mutations, we generated patient-specific induced pluripotent stem cell-derived atrial cardiomyocytes (iPSC-aCMs) from two kindreds carrying SCN5A mutations (E428K and N470K) and isogenic controls using CRISPR-Cas9 gene editing. We showed that mutant AF iPSC-aCMs exhibited spontaneous arrhythmogenic activity with beat-to-beat irregularity, prolonged action potential duration, and triggered-like beats. Single-cell recording revealed enhanced late sodium currents (I_Na,L) in AF iPSC-aCMs that were absent in a heterologous expression model. Gene expression profiling of AF iPSC-aCMs showed differential expression of the nitric oxide (NO)-mediated signaling pathway underlying enhanced I_Na,L. We showed that patient-specific AF iPSC-aCMs exhibited striking in vitro electrophysiological phenotype of AF-linked SCN5A mutations, and transcriptomic analyses supported that the NO signaling pathway modulated the I_Na,L and triggered AF.
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ReviewAntiarrhythmic properties of ranolazine: A review of the current evidence

Highlights

Abstract

Introduction

Section snippets

Study selection

Effect of ranolazine on peak and late INa, other ion channel currents and cardiac action potential

Ranolazine in atrial arrhythmias

Ranolazine in ventricular arrhythmias

Conclusion

Conflicts of interest

Source of funding

Lancet

Int. J. Cardiol.

Int. J. Cardiol.

Int. J. Cardiol.

Int. J. Cardiol.

Int. J. Cardiol.

Int. J. Cardiol.

Int. J. Cardiol.

J. Am. Coll. Cardiol.

Heart Rhythm.

J. Mol. Cell. Cardiol.

Pharmacol. Ther.

J. Am. Coll. Cardiol.

J. Am. Coll. Cardiol.

J. Am. Coll. Cardiol.

J. Am. Coll. Cardiol.

J. Am. Coll. Cardiol.

Heart Rhythm.

J. Electrocardiol.

Int. J. Cardiol.

J. Am. Coll. Cardiol.

Am. J. Cardiol.

Heart Rhythm.

J. Am. Coll. Cardiol.

Heart Rhythm.

J. Am. Coll. Cardiol.

J. Card. Fail.

Heart Rhythm.

Heart Rhythm.

Heart Rhythm.

Use of ranolazine in patients with stable angina pectoris

Cardiology

Ranolazine for the treatment of chronic angina and potential use in other cardiovascular conditions

Circulation

Ranolazine: drug overview and possible role in primary microvascular angina management

Int. J. Cardiol.

A focus on antiarrhythmic properties of ranolazine

J. Cardiovasc. Pharmacol. Ther.

Late sodium current inhibition: the most promising antiarrhythmic principle in the near future?

Curr. Med. Chem.

Electrophysiological effects of ranolazine, a novel antianginal agent with antiarrhythmic properties

Circulation

Antagonism by ranolazine of the pro-arrhythmic effects of increasing late INa in guinea pig ventricular myocytes

J. Cardiovasc. Pharmacol.

Ranolazine improves abnormal repolarization and contraction in left ventricular myocytes of dogs with heart failure by inhibiting late sodium current

J. Cardiovasc. Electrophysiol.

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

Circulation

Effect of tetrodotoxin on action potentials of the conducting system in the dog heart

Am. J. Physiol.

Role of late sodium channel current block in the management of atrial fibrillation

Cardiovasc. Drugs Ther.

Late sodium current is a new therapeutic target to improve contractility and rhythm in failing heart

Cardiovasc. Hematol. Agents Med. Chem.

Larger late sodium conductance in M cells contributes to electrical heterogeneity in canine ventricle

Am. J. Physiol. Heart Circ. Physiol.

Review
Antiarrhythmic properties of ranolazine: A review of the current evidence

Effect of ranolazine on peak and late I_Na, other ion channel currents and cardiac action potential