Electrophysiologic basis for the antiarrhythmic actions of ranolazine

Abstract

Ranolazine is a Food and Drug Administration-approved antianginal agent. Experimental and clinical studies have shown that ranolazine has antiarrhythmic effects in both ventricles and atria. In the ventricles, ranolazine can suppress arrhythmias associated with acute coronary syndrome, long QT syndrome, heart failure, ischemia, and reperfusion. In atria, ranolazine effectively suppresses atrial tachyarrhythmias and atrial fibrillation (AF). Recent studies have shown that the drug may be effective and safe in suppressing AF when used as a pill-in-the pocket approach, even in patients with structurally compromised hearts, warranting further study. The principal mechanism underlying ranolazine's antiarrhythmic actions is thought to be primarily via inhibition of late I(Na) in the ventricles and via use-dependent inhibition of peak I(Na) and I(Kr) in the atria. Short- and long-term safety of ranolazine has been demonstrated in the clinic, even in patients with structural heart disease. This review summarizes the available data regarding the electrophysiologic actions and antiarrhythmic properties of ranolazine in preclinical and clinical studies.

Figure 1

Ranolazine produces a much greater rate-dependent inhibition of the maximal action potential upstroke velocity (V_max) in atria than in ventricles. Shown are V_max and action potential (AP) recordings obtained from coronary-perfused canine right atrium and left ventricle before (C) and after ranolazine (10 μM). Ranolazine prolongs late repolarization in atria, but not ventricles (due to I_Kr inhibition ) and acceleration of rate leads to elimination of the diastolic interval in the atrium. Reprinted from J Electrocardiol, Vol 42, Antzelevitch C, Burashnikov A, Atrial-selective sodium channel block as a novel strategy for the management of atrial fibrillation, 543–548, 2009, with permission from Elsevier.

Figure 2

Ranolazine (200 μg/kg/min) abbreviates ventricular repolarization and suppresses Torsade de Pointes (TdP) arrhythmias in anesthetized rabbit. Shown are representative ECG and left ventricular endocardial monophonic action potential (MAP) tracings. Repolarization was prolonged and TdP was induced by the combination of methoxamine (15 μg/kg/min) and clofilium (100 ng/kg/min). Modified with permission from Wang WQ, Robertson C, Dhalla AK, Belardinelli L. Antitorsadogenic effects of ({+/−})-N-(2,6-dimethyl-phenyl)-(4[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-piperazine (ranolazine) in anesthetized rabbits. J Pharmacol Exp Ther, 325(3):875–881.

Figure 3

Ranolazine suppresses AF and/or prevents its induction in two experimental models involving isolated canine arterially-perfused right atria. A: Persistent ACh (0.5 μM)-mediated AF is suppressed by ranolazine (10 μM). AF initially converts to flutter and then to sinus rhythm. B: ERP measured at a CL of 500 ms is 140 ms. Attempts to re-induce AF fail because ranolazine-induced depression of excitability leads to 1:1 activation failure soon after CL is reduced from 500 to 200 ms (right panel). C: Rapid-pacing induces non-sustained AF (48 sec duration) following ischemia/reperfusion plus isoproterenol (Iso, 0.2 μmol/L) (left panel). Ranolazine (5 μM) prevents pacing-induced AF due to 1:1 activation failure (right panel). In both models, ranolazine causes prominent use-dependent induction of PRR. Reproduced with permission from Burashnikov A, Di Diego JM, Zygmunt AC, Belardinelli L, Antzelevitch C. 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,116(13):1449–1457.

Figure 4

Combination of ranolazine (5 μM) and dronedarone (10 μM) eliminates delayed afterdepolarization (DAD)-induced triggered activity in canine PV sleeve preparations. A: Isoproterenol (1 μM) and high calcium (5.4 mM) induce DAD and DAD-induced triggered activity. Ranolazine (5 μM) eliminates the triggered activity, but not the DAD. Washout of ranolazine restores the triggered response followed by a DAD. Dronedarone (10 μM) eliminates the triggered response, but the DAD persists. The combination of ranolazine and dronedarone eliminates all DAD activity and induces 2:1 activation failure; an increase of stimulus intensity restores 1:1 activation, but not the DAD. B: In another preparation, the same protocol yielded multiple triggered beats. Ranolazine is seen to abolish all of ectopic activity, but not the DAD, whereas dronedarone (5 uM) reduces the number of triggered responses. A single triggered beat followed by a DAD persists. The combination of ranolazine and dronedarone eliminates all DAD activity and induces 2:1 activation failure; an increase of stimulus intensity restores 1:1 activation, but not the DAD. Basic cycle length (BCL) = 120 ms (A) and 150 ms (B). Modified from J Am Coll Cardiol, Vol 56, Burashnikov A, Sicouri S, Di Diego JM, Belardinelli L, Antzelevitch C, Synergistic effect of the combination of dronedarone and ranolazine to suppress atrial fibrillation, 1216–1224, 2010 with permission from Elsevier.

Figure 5

Atrial-selective induction of post-repolarization refractoriness (PRR) by ranolazine (Ran), dronedarone (Dron) alone and in combination (PRR was approximated by the difference between effective refractory period (ERP) and action potential duration measured at 70% repolarization (APD₇₀) in atria and between ERP and APD measured at 90% repolarization (APD₉₀) in ventricles; ERP corresponds to APD_70–75 in atria and to APD₉₀ in ventricles. A: Shown are superimposed action potentials demonstrating relatively small changes with dronedarone and ranolazine and their combination. B: Summary data of atrial-selective induction of PRR. Ventricular data were obtained from epicardium and atrial data from endocardial pectinate muscle (PM). n=7–8. * p<0.05 vs. respective control (C). † p<0.05 vs. washout. ‡ p<0.05 vs. Dron 10. # p<0.05 vs. respective ERP. ** - p<0.05 - change in ERP induced by combination of Ran and Dron (from washout) vs. the sum of changes caused by Ran and Dron independently (both from washout). CL = 500 ms. Reprinted from J Am Coll Cardiol, Vol 56, Burashnikov A, Sicouri S, Di Diego JM, Belardinelli L, Antzelevitch C, Synergistic effect of the combination of dronedarone and ranolazine to suppress atrial fibrillation, 1216–1224, 2010 with permission from Elsevier.