Effect of Ranolazine on Ventricular Vulnerability and Defibrillation Threshold in the Intact Porcine Heart

Abstract

Extensive in vitro studies and clinical evidence (MERLIN trial) indicate an antiarrhythmic potential of ranolazine, a novel antianginal agent. Programmed electrophysiologic testing was performed to quantify ranolazine's effects on ventricular vulnerability and defibrillation thresholds and to gain insights into mechanisms. Effects of ranolazine (9.2 +/- 2.1 microM, plasma level) on surface ECG, right ventricular effective refractory period (ERP), and repetitive extrasystole (RE), ventricular fibrillation (VF), and defibrillation (DFT) thresholds were determined in 29 normal closed-chest anesthetized pigs. The single extrastimulus method was employed for ERP and for RE and VF thresholds. DFT(50) was determined using an up-down testing protocol with an implantable cardioverter-defibrillator. Ranolazine increased rate-corrected QT interval from 490 +/- 30 to 527 +/- 24 ms (P < 0.05) but did not alter T(peak)-T(end) interval (59 +/- 8 to 62 +/- 11, P = 0.65). ERP increased by 40 +/- 6 ms (P < 0.001). Compared with baseline, ranolazine raised RE threshold from 20 +/- 6 to 34 +/- 9 mA (P < 0.001) and VF threshold from 38 +/- 4 to 48 +/- 10 mA (P < 0.05). DFT(50) was unchanged (baseline: 14 +/- 2 J; ranolazine: 14 +/- 2 J; P = 0.6), whereas diastolic pacing threshold increased from baseline pulse width of 0.07 +/- 0.03 to 0.17 +/- 0.07 ms (P < 0.01) with 1V pulse amplitude. Ranolazine, at therapeutic concentrations, produces a mild increase in QT interval and a marked increase in both RE and VF thresholds. Thus, ranolazine does not augment and may improve dispersion of ventricular repolarization, suggesting a potential antiarrhythmic action. Ranolazine is unlikely to affect the margin of safety of defibrillation, given no significant effect on DFT, but could result in a mild increase in pacing threshold.