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

Authors


  • This study was funded by CV Therapeutics, Inc., of Palo Alto, CA.

  • Dr. Belardinelli is an employee of CV Therapeutics, Inc.

  • Dr. Verrier holds research grants on atrial and ventricular properties of ranolazine.

  • Manuscript received 8 February 2008; Revised manuscript received 11 March 2008; Accepted for publication 12 March 2008.

Address for correspondence: Richard L. Verrier, Ph.D., F.A.C.C., Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center, Harvard-Thorndike Electrophysiology Institute, Harvard Institutes of Medicine, 77 Avenue Louis Pasteur, Room 223, Boston, MA 02115, USA. Fax: 617-975-5270; E-mail: rverrier@bidmc.harvard.edu

Abstract

Introduction: 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.

Methods and Results: Effects of ranolazine (9.2 ± 2.1 μM, 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. DFT50 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 Tpeak-Tend 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). DFT50 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.

Conclusions: 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.

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