Effects of Ranolazine on Paroxysmal and Persistent Atrial Fibrillation in Isolated Sheep Hearts

Abstract

Background Ranolazine inhibits the peak Na+ current in the atria and has been shown to suppress paroxysmal atrial fibrillation (PxAF). However, the underlying mechanisms are not clear, and its antiarrhythmic efficacy in persistent AF (PsAF) is unknown. Methods We investigated the effects of ranolazine in Langendorff-perfused sheep hearts. PxAF was induced by burst pacing during acute stretch (12 mm H2O; N = 5). PsAF was induced in chronically implanted animals (single-chamber pacemaker, right atrial lead) by intermittent pacing (20 Hz) maintained for 6 months (N = 3). Epicardial and endocardial optical mapping of the left atrial appendage (LAA) and the posterior left atrium (PLA), respectively, was performed simultaneously. Following a control period of 50 minutes of AF, 10 μM ranolazine was perfused for 20 minutes. If sinus rhythm (SR) was not restored, the concentration of ranolazine was increased to 20 μM. LAA samples were taken for Western blot (WB) analysis to determine the expression of Na+ channel protein (NaV1.5) in PxAF vs PsAF. Results In PxAF, the baseline dominant frequency (DF) in the PLA was 10.1 ± 1.6 Hz. Ranolazine at 10 μM decreased DF to 7.2 ± 0.9 Hz (P = .008, N = 5) and terminated AF in all hearts after 15 ± 4 minutes. Ranolazine also significantly decreased the number of singularity points (SP) in PxAF (51.9 ± 11.9/cm2 to 29.5 ± 4.6/cm2, per 5 seconds, P = .005). AF could be reinduced in 4 5 hearts, but was nonsustained (median duration = 28 seconds). In PsAF, baseline DF in the PLA was 10.9 ± 2.9 Hz. Ranolazine 10 μM decreased DF to 7.2 ± 1.1 Hz (P = .05, N = 3) but did not terminate AF. Increasing concentration to 20 μM decreased DF to 5.8 ± 1.1 Hz (P = .019) but without reversal to SR. Ranolazine did not decrease the SP in PsAF, even at 20 μM (17.3 ± 3.6/cm2 to 10.7 ± 3.6/cm2, per 5 seconds, P = NS). WB analysis of LAA showed a 59.4% decrease in NaV1.5 in PsAF (N = 3) compared with PxAF (N = 3, P Conclusions Ranolazine exerts an antiarrhythmic effect in PxAF by reducing both DF and SP. In contrast, ranolazine did not terminate PsAF despite reducing DF. This is partly due to the lack of effect of ranolazine in altering the number of SP (representing wavebreaks), thus allowing AF to sustain, and may be related to electrical and/or structural remodeling of the atria occurring in PsAF.