A Focus on Antiarrhythmic Properties of Ranolazine

Abstract

Ranolazine is an antianginal drug that inhibits a number of ion currents that are important for the genesis of transmembrane cardiac action potential. It was initially developed as an antianginal agent but was found to additionally exert antiarrhythmic actions, due to its multichannel-blocking properties. In recent years, several studies about the antiarrhythmic properties of ranolazine were conducted, demonstrating the beneficial effects of this drug in both atrial and ventricular arrhythmias, such as atrial fibrillation, ventricular premature beats, ventricular tachycardia, torsades de pointes, and ventricular fibrillation. Our aim is to briefly review the main points of these studies, most more experimental than clinical.

Introduction

Ranolazine is an antianginal drug that inhibits a number of ion currents that are important for the genesis of transmembrane cardiac action potential. It was initially developed as an antianginal agent but was found to additionally exert antiarrhythmic actions. In the ventricles, ranolazine inhibits the late phase of inward sodium current (late I_Na), an effect expected to shorten action potential duration, and reduces the rapidly activating delayed rectifier potassium current (I_Kr), an effect expected to lengthen the action potential duration. In atria, in addition to blocking late I_Na and I_Kr, ranolazine inhibits the early or peak sodium channel current (peak I_Na). ¹ It also has some effects on others currents, such as I_CaL, I_Na-Ca, and I_Ks (Figure 1 and Table 1). Based on its effects on these channels, some authors have proposed ranolazine as an antiarrhythmic agent.

Figure 1.

Myocardial action potential. I_K1 indicates inward rectifier K⁺ current; I_Na, rapid Na⁺ channels; I_to, transient outward K⁺ and Cl⁻ currents; I_Ca-L, L-type calcium channels; I_Ks, slow delayed rectifier K⁺ channels; I_Kr, rapid delayed rectifier K⁺ channels.

Table 1.

Ranolazine Inhibition of Atrial and Ventricular Ion Channel Currents

Atria		Ventricles
Ion Currents	Inhibition by Ranolazine	Ion Currents	Inhibition by Ranolazine
Inward		Inward
Peak INa	++	Peak INa	+
Late INa	+++	Late INa	+++
ICa-L	+	ICa-L	+
Outward		Outward
IKr	++	IKr	++
IKs	+	IKs	+
IK1	=	IK1	=
Ito	=	Ito	=

Abbreviations: I_K1, inward rectifier K⁺ current; I_Na, rapid Na⁺ channels; I_to, transient outward K⁺ and Cl⁻ currents; I_Ca-L, L-type calcium channels; I_Ks, slow delayed rectifier K⁺ channels; I_Kr, rapid delayed rectifier K⁺ channels.

Atrial Fibrillation

In atria, ranolazine seems to suppress atrial tachyarrhythmias and atrial fibrillation (AF); this is probably due to its multichannel-blocking properties. Some authors suggest that blocking a single atrial-specific target may be insufficient for AF termination and prevention, and multichannel-blocking properties may be a useful alternative approach. ² Ranolazine causes an atrial-selective rate-dependent reduction in parameters depending on Na⁺-channel function, such as action potential upstroke velocity, diastolic threshold of excitation, and post-repolarization refractoriness. In atrial myocytes of patients with persistent AF, Sossalla et al observed that the inhibitory effects of ranolazine on late I_Na was stronger in patients with AF compared with patients with sinus rhythm; ranolazine also suppressed the premature atrial contractions in right atrial trabeculae and reduced diastolic tension in these preparations. ³ In the Holter monitor data from the MERLIN-TIMI 36 trial, ranolazine was associated with a reduction in a number of several arrhythmias, including new episodes of AF: in comparison with placebo, treatment with ranolazine resulted in fewer episodes of ventricular tachycardia ([VT] 5.3% vs 8.3%; P < .001) and in fewer episodes of supraventricular tachycardia (44.7% vs 55%; P < .001) and new-onset AF (1.7% vs 2.4%, P = .08). ^4,5 In dogs, ranolazine suppressed the triggers of AF that originated from the sleeves of pulmonary veins. ⁶ Burashnikov et al observed that the combination of ranolazine (5 μmol/L) and dronedarone (10 μmol/L) in canine isolated coronary-perfused atrial and pulmonary vein preparations suppressed AF and triggered activity preventing the induction of AF in 9 of 10 preparations (90%), ⁷ demonstrating a greater effect in combination than alone. It was also observed by the same authors that ranolazine terminates AF in an acetylcholine-mediated in vitro model: in this study, ranolazine was more effective than lidocaine in terminating persistent AF and in preventing the induction of AF. ⁸ In a small study of 7 patients, ranolazine was initiated soon after AF (500-1000 mg/twice per day) after stopping all other antiarrhythmic therapy and was found to be useful in maintaining sinus rhythm: most of these patients had structural heart diseases where more established antiarrhythmic drugs had failed. ⁹ The same authors suggested the use of ranolazine to convert AF even with a “pill in the pocket” approach. Two thousand milligrams of ranolazine was administered to 18 patients with new or paroxysmal AF of at least 3 but not greater than 48 hours of duration: 13 of 18 patients converted to sinus rhythm within 6 hours of dose administration; the 72% conversion rate was comparable to other reported “pill in the pocket” protocols. ¹⁰ These results are incredibly promising, despite the relatively small size of these studies. Recently, Miles et al have compared ranolazine and amiodarone in the prevention of AF after coronary artery bypass graft (CABG): a total of 393 consecutive patients undergoing CABG (mean age 65 ± 10 years, 72% men) received either amiodarone (400 mg preoperatively followed by 200 mg twice daily for 10-14 days) or ranolazine (1500 mg preoperatively followed by 1000 mg twice daily for 10-14 days). Atrial fibrillation occurred in 26.5% of the amiodarone-treated patients compared to 17.5% of the ranolazine-treated patients (P = .035). They observed that ranolazine was independently associated with a significant reduction of AF compared to amiodarone after CABG, with no difference in the incidence of adverse events. ¹¹ Despite these results, according to Schotten et al, it remains to be investigated whether the decreased incidence of supraventricular tachycardias and new-onset AF during ranolazine treatment result from direct effects on atrial electrophysiology, from improvement of atrial metabolism, or from improvement of ventricular function, thereby indirectly reducing atrial arrhythmogenesis. ¹² In the study performed by Wang et al, ¹³ for example, ranolazine was shown to be protective against myocardial ischemic injury, improving cardiac function in response to various stressors, in comparison to a new inhibitor of fatty acid oxidation: this metabolic role of ranolazine is probably due to ischemic protection rather than inhibition of fatty acid oxidation and could have a role in protection from arrhythmias. These remaining doubts about ranolazine's direct electrophysiologic effects were dispelled by the study of Lemoine et al ¹⁴ that clearly showed the electrophysiological effects of ranolazine in preventing and suppressing atrial arrhythmias in a murine genetic QT syndrome model. According to the authors, their data add support to the notion that ranolazine may suppress arrhythmias in patients with AF directly by acting on I_NaL. It is reasonable to think that ranolazine has a direct electrophysiological effect, in addition to metabolic effects, which is useful in suppressing arrhythmias.

Ventricular Arrhythmias

In the ventricles, ranolazine effectively suppresses arrhythmogenesis associated with reduced repolarization reserve caused by an increased late I_Na, reduced I_Kr, or a combination of both. ¹ The group of Antzelevitch et al first pointed out the effect of ranolazine to suppress early afterdepolarizations (EADs) and delayed afterdepolarizations. ^{6,15 –17} These observations first suggested an alleged role of ranolazine in preventing arrhythmias. In the isolated perfused hearts of guinea pig and rabbit, ranolazine has been shown to suppress EADs and VT induced by drugs that block I_Kr. ^18,19 In 6560 patients surviving an acute coronary syndrome, the MERLIN investigators noted that ranolazine was associated with a significant reduction in a variety of atrial and ventricular arrhythmias as recorded on prolonged Holter monitoring, including VT. ^4,5 Dhalla et al observed that ranolazine reduces ventricular arrhythmias (such as ventricular premature beats, VT, and ventricular fibrillation) induced by ischemia and ischemia/reperfusion in an anesthetized rat model of transient (5 minutes) ligation of the left coronary artery, followed by reperfusion: in particular, ranolazine significantly reduced the incidence of ventricular fibrillation (67% in controls vs 42%, P = .414; 30%, P = .198; and 8%, P = .0094 in ranolazine at 2, 4, and 8 μmol/L, respectively). ²⁰ Similar results were obtained recently by Kloner et al who for the first time compared ranolazine with other antiarrhythmic agents, like sotalol and lidocaine, as therapeutic doses, in an ischemia/reperfusion model. They observed that ranolazine was as effective as either sotalol or lidocaine in reducing reperfusion-induced ventricular arrhythmias: in fact, the incidence of ventricular arrhythmias in the sotalol (S), lidocaine (L), ranolazine (R), and control (C) groups was 7 of 20, 10 of 20, 9 of 20, and 16 of 20, respectively (P = .01 S vs C, P = .1 L vs C, and P = .048 R vs C). ²¹

Long QT Syndromes

Due to its multichannel-blocking activity, ranolazine causes a modest increase in the mean QT interval over the therapeutic range. Ranolazine inhibits I_Kr which is expected to prolong the QT interval; but at the same time it inhibits the late I_Na, which is expected to shorten the QT interval; the net effect is that ranolazine only causes a modest prolongation of the QT interval, on the order of less than 10 milliseconds, at therapeutic plasma levels. Therefore, for current clinical use, ranolazine should be avoided in patients with preexisting QT prolongation and in combination with other QT-prolonging drugs. It is also noteworthy that ranolazine reduces torsades de pointes (TdP) induced by other means in LQT1, LQT2, and LQT3 experimental models. ^13,22 In fact, none of the 4 major clinical trials—the MARISA, the CARISA, the ERICA, and the MERLIN-TIMI 36 trial—produced evidence of that phenomenon. The principal protective mechanism of ranolazine against TdP is its potent inhibition of late I_Na. ¹ Moreover, it was observed that ranolazine manages to suppress the arrhythmogenic effects induced by a variety of other QT-prolonging drugs. In an anesthetized dog model with acute complete AV block, at doses that prolonged the QT interval by approximately 5% to 11% above control, ranolazine did not cause spontaneous TdP or TdP facilitated by an intravenous bolus of phenylephrine (which increases the susceptibility to TdP) in 5 dogs, whereas sotalol induced TdP in all 5 dogs. ²³ Finally, in accordance with its action of blocking late I_Na in the ventricle, ranolazine has been shown to cause a dose-dependent abbreviation of the QT interval in patients with the LQT3 type of LQTS, a monogenic disorder in which the electrophysiologic phenotype is due to an increase in late I_Na. ¹⁹ Moss et al hypothesized that ranolazine could reverse 2 abnormalities observed in this syndrome: the impaired diastolic relaxation and the prolonged QT interval. Five adults with LQT3 syndrome and overt QT prolongation received intravenous ranolazine in increasing concentration. As expected, echocardiography showed improvement in diastolic dysfunction, and mean QT, QTc, and QT peak shortened during the infusion: ranolazine, at a plasma concentration of 2074 ng/mL (≈4 μmol/L), caused a mean abbreviation of QTc ranging from 22 to 40 ms from time-matched baseline QTc values. ²⁴

Conclusions

These results show that in recent years there has been an increased interest in the electrophysiological effects of ranolazine. A large number of experimental studies conducted to date has opened important scenarios from the therapeutic point of view. On the other hand, a greater number of clinical trials should be conducted. The few existing clinical trials have some limitations. First, most of these studies are based on a relatively small patient sample size. Second, in only a few of these studies were electrocardiographic effects or arrhythmia monitoring documented. Finally, despite growing experimental and clinical evidence that ranolazine possesses antiarrhythmic activity, no randomized placebo-controlled clinical trial has specifically tested this hypothesis. ¹ Actually, the only multicenter randomized placebo-controlled trial that had shown a beneficial effect of ranolazine on arrhythmias is the MERLIN-TIMI 36; nevertheless, in this study only patients with CAD were analyzed, and it would be interesting to observe the behavior of ranolazine as an antiarrhythmic agent also in nonischemic patients. Furthermore, there are only small clinical studies on the role of ranolazine in preventing or treating AF. Finally, except for the MERLIN study, clinical trials that have tested this drug in ventricular arrhythmias (such as frequent premature ventricular complexes, couplet or triplet) do not exist. This drug may be beneficial in reducing the frequency of arrhythmias in patients with left ventricular systolic dysfunction (from ischemic and nonischemic etiology), in which the most widely used drugs (eg, amiodarone) are not free from significant systemic side effects. These first promising results need further investigation in order to avoid them becoming a missed opportunity.