Synergistic effect of the combination of ranolazine and dronedarone to suppress atrial fibrillation

Abstract

Objectives: The aim of this study was to evaluate the effectiveness of a combination of dronedarone and ranolazine in suppression of atrial fibrillation (AF).

Background: Safe and effective pharmacological management of AF remains one of the greatest unmet medical needs.

Methods: The electrophysiological effects of dronedarone (10 μmol/l) and a relatively low concentration of ranolazine (5 μmol/l) separately and in combination were evaluated in canine isolated coronary-perfused right and left atrial and left ventricular preparations as well as in pulmonary vein preparations.

Results: Ranolazine caused moderate atrial-selective prolongation of action potential duration and atrial-selective depression of sodium channel-mediated parameters, including maximal rate of rise of the action potential upstroke, leading to the development of atrial-specific post-repolarization refractoriness. Dronedarone caused little or no change in electrophysiological parameters in both atrial and ventricular preparations. The combination of dronedarone and ranolazine caused little change in action potential duration in either chamber but induced potent use-dependent atrial-selective depression of the sodium channel-mediated parameters (maximal rate of rise of the action potential upstroke, diastolic threshold of excitation, and the shortest cycle length permitting a 1:1 response) and considerable post-repolarization refractoriness. Separately, dronedarone or a low concentration of ranolazine prevented the induction of AF in 17% and 29% of preparations, respectively. In combination, the 2 drugs suppressed AF and triggered activity and prevented the induction of AF in 9 of 10 preparations (90%).

Conclusions: Low concentrations of ranolazine and dronedarone produce relatively weak electrophysiological effects and weak suppression of AF when used separately but when combined exert potent synergistic effects, resulting in atrial-selective depression of sodium channel-dependent parameters and effective suppression of AF.

Figure 1. Synergistic Effect of Ranolazine and Dronedarone to Atrial-Selectively Induce PRR

Atrial-selective induction of post-repolarization refractoriness (PRR) by ranolazine (Ran) and dronedarone (Dron) alone and in combination (PRR was approximated by the difference between the effective refractory period [ERP] and the action potential duration measured at 70% repolarization [APD₇₀] in the atria and between the ERP and the action potential duration measured at 90% repolarization [APD₉₀] in the ventricles; ERP corresponds to APD_70–75 in the atria and to APD₉₀ in the ventricles). (A) 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 (n = 7 to 8). *p < 0.05 versus respective control (C). †p < 0.05 versus washout. ‡p < 0.05 versus Dron 10 μmol/l. #p<0.05 versus respective ERP. **p < 0.05, change in ERP induced by combination of Ran and Dron (from washout) versus the sum of changes caused by Ran and Dron independently (both from washout). Cycle length = 500 ms.

Figure 2. Synergistic Effect of Ranolazine and Dronedarone to Atrial-Selectively Depress V_max

Atrial-selective synergetic depression of the maximal rate of rise of the action potential (AP) upstroke (V_max) by the combination of dronedarone (Dron) and ranolazine (Ran) at rapid activation rates. Shown are AP tracings and corresponding V_max values recorded during acceleration of pacing rate from a cycle length (CL) of 500 to 300 ms in atrial (A) and ventricular (B) perfused preparations. Composite data of V_max of atrial and ventricular preparations paced at a CL of 500 ms (C, left) expressed as percentage of control (C). Composite data of V_max of atrial and ventricular APs after acceleration from a CL of 500 to 300 ms expressed as percentage of V_max value recorded at a CL of 500 ms in controls (C, right). “Atria” represent combined pectinate muscle and crista terminalis data. “Ventricles” represent combined epicardial and M-cell data from ventricular wedge preparations (n = 7 to 8). *p < 0.05 versus respective control. †p < 0.05 versus washout. ‡p < 0.05 versus Dron 10 μmol/l. #p < 0.05 versus respective atrial values. **p < 0.01, change in V_max induced by the combination of Ran and Dron (from washout) versus the sum of changes caused by Ran and Dron independently (both from washout).

Figure 3. Synergistic Effect of Ranolazine and Dronedarone to Depress V_max in PV

Synergistic effect of the combination of ranolazine and dronedarone on maximal rate of rise of the action potential upstroke (V_max) after an abrupt change in rate in pulmonary vein (PV) sleeve preparations. (A) V_max traces recorded after a change in cycle length (CL) from 5,000 to 300 ms. (B) Graph displaying composite data of V_max changes after acceleration of pacing rate from a CL of 5,000 to 300 ms (n = 4 to 8). *p < 0.05 versus control. †p < 0.05 versus ranolazine or dronedarone alone. **p < 0.05, change in V_max induced by combination ranolazine plus dronedarone (from washout) versus the sum of changes caused by ranolazine and dronedarone independently (both from washout).

Figure 4. Synergistic Effect of Ranolazine and Dronedarone to Atrial-Selectively Depress Excitability

Effect of ranolazine (Ran) (5 μmol/l), dronedarone (Dron) (10 μmol/l), and their combination to prolong the shortest cycle length (CL) permitting 1:1 activation and to increase the diastolic threshold of excitation (DTE). The combination of Dron and Ran caused greater changes in these parameters in atrial than in ventricular preparations (n = 4to8). *p < 0.05 versus respective control (C). †p < 0.05 versus washout and Dron. ‡p < 0.05 versus Ran. #p < 0.001 versus respective atrial values. **p < 0.05, change in V_max caused by combination of ranolazine and dronedarone (relative to washout) versus the sum of changes induced by ranolazine and dronedarone independently.

Figure 5. Effect of Dronedarone and Ranolazine to Suppress AF

The combination of dronedarone (10 μmol/l) and ranolazine (5 μmol/l) is effective in terminating persistent atrial fibrillation (AF) and/or preventing its induction in coronary-perfused right atria. (A) Persistent acetylcholine (ACh) (0.5 μmol/l)–mediated AF is terminated by the drug combination. AF is initially converted to flutter and then to sinus rhythm. (B) The combination of dronedarone and ranolazine prevents rapid-pacing induction of AF after pretreatment with ACh (1 μmol/l), likely because of depression of the sodium channel (see reduction of maximal rate of rise of the action potential [AP] upstroke). Acceleration of pacing rate from a cycle length (CL) of 500 to 130 ms leads to failure of a 1:1 response. ECG = electrocardiogram.

Figure 6. Synergistic Effect of Ranolazine and Dronedarone to Suppress DAD

The combination of ranolazine (5 μmol/l) and dronedarone (10 μmol/l) abolishes delayed afterdepolarization (DAD)–induced triggered activity in pulmonary vein sleeve preparations. (A) Isoproterenol (1 μmol/l) and high calcium (5.4 mmol/l) induce DAD and triggered response. Ranolazine (5 μmol/l) eliminates the triggered response but not the DAD. Washout of ranolazine restores the triggered response, followed by a DAD. Dronedarone (10 μmol/l) abolishes 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 umol/l) 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).