Effects of Ranolazine and its Combination with Amiodarone on Rapid Pacing-induced Reentrant Atrial Tachycardia in Rabbits

Abstract

Ranolazine (RAN) has previously been shown to lower the onset of cholinergic atrial fibrillation in intact animals; however, its efficacy in the setting of atrial tachycardia (AT) is unknown. The purpose of this study was to investigate the effects of RAN alone or in combination with amiodarone (AMIO) on rapid pacing-evoked right AT in rabbit hearts. Right atrial monophasic action potentials (MAPs) were recorded in 11 anesthetized rabbits, using combination MAP pacing catheters. Vulnerability to AT was tested by employing consecutive trains of rapid burst pacing prior to and after 2.4 mg/kg of RAN alone delivered intravenously and then in combination with 3 mg/kg of AMIO as a 15-minute infusion. Primary endpoints were postdrug AT reproducibility as well as cycle length (CL) and tachycardia duration. MAP duration at 75% repolarization and the effective refractory period (ERP) were assessed during programmed pacing to calculate the atrial postrepolarization refractoriness (aPRR = ERP - MAPD_75%). AT was elicited in eight out of 11 rabbits; only these animals were included for further investigation. RAN did not abolish the inducibility of AT in any experiment; however, it prolonged its CL (baseline vs. RAN: 120 ± 16 ms vs. 138 ± 18 ms; p = 0.053). Supplemental AMIO further increased the AT CL (baseline vs. RAN + AMIO: 120 ± 16 ms vs. 152 ± 23 ms; p = 0.006), without affecting arrhythmia reinducibility. Slowing of the tachycardia after RAN or RAN + AMIO was associated with spontaneous termination of the arrhythmia. RAN prolonged the aPRR significantly, while AMIO in addition to RAN potentiated this effect. Neither RAN alone nor its combination with AMIO abolished the elicitation of AT in this model. However, both agents synergistically prolonged the aPRR, resulting in the slowing of AT and promoting spontaneous termination of the arrhythmia.

Keywords: Amiodarone; atrial pacing; atrial tachycardia; rabbit heart; ranolazine.

Figure 1:

RAN significantly prolonged aPRR; the addition of AMIO tended to strengthen the RAN’s effect on refractoriness. CON: control; AMIO: amiodarone; aPRR: atrial post-repolarization refractoriness; RAN: ranolazine.

Figure 2:

Mechanism possibly involved in the spontaneous termination of AT induced after RAN. MAPs recorded simultaneously from the right atrial endocardium during the course of tachycardia (left side of the figure) and after its termination (right side of the figure) show a 2:1 atrial block (vertical arrows) in the proximal atrial region, whilst the distal MAP electrode reveals a regular activation pattern. Elimination of block in the proximal area (horizontal arrow) was associated with conversion of the tachycardia into sinus rhythm. In the proximal area, phase 0 of MAP started earlier than in the distal phase in correspondence with the beginning of P-wave on the surface ECG. Note that only half of the atrial depolarizations during tachycardia reached the ventricles (AV block). AT: atrial tachycardia; AV; atrioventricular: ECG: electrocardiogram; MAP: monophasic action potentials; RAN: ranolazine.

Figure 3:

RAN alone yielded a better course of AT; the combination of RAN and AMIO significantly improved its efficacy by further increasing the AT CL. AT: atrial tachycardia; RAN: ranolazine; AMIO: amiodarone; AT CL: cycle length of the atrial tachycardia.

Figure 4:

Effects of RAN or its combination with AMIO on pacing-induced sAT during control pacing conditions (baseline). Although the inducibility of the tachycardia was not abolished by RAN or RAN + AMIO, both treatment regimens effectively increased the AT CL. ps: paper speed. RAN: ranolazine; AMIO: amiodarone; AT CL: cycle length of atrial tachycardia; sAT: sustained atrial tachycardia.