Author + information
- Received October 9, 2012
- Revision received November 29, 2012
- Accepted December 5, 2012
- Published online April 1, 2013.
- Lars S. Maier, MD∗∗ (, )
- Beth Layug, MD†,
- Ewa Karwatowska-Prokopczuk, MD, PhD†,
- Luiz Belardinelli, MD†,
- Stella Lee, MS†,
- Julia Sander, MS∗,
- Christian Lang, MS∗,
- Rolf Wachter, MD∗,
- Frank Edelmann, MD∗,
- Gerd Hasenfuss, MD∗ and
- Claudius Jacobshagen, MD∗
- ↵∗Reprint requests and correspondence:
Dr. Lars S. Maier, Department of Cardiology and Pneumology, Heart Center/Georg-August-University Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany.
Objectives This study investigated whether inhibiting late Na+ current by using ranolazine improved diastolic function in patients with heart failure with preserved ejection fraction (HFpEF).
Background HFpEF accounts for >50% of all HF patients, but no specific treatment exists.
Methods The RALI-DHF (RAnoLazIne for the Treatment of Diastolic Heart Failure) study was a prospective, randomized, double-blind, placebo-controlled small proof-of-concept study. Inclusion criteria were EF ≥45%, a mitral E-wave velocity/mitral annular velocity ratio (E/E′) >15 or N-terminal pro–B-type natriuretic peptide (NT-proBNP) concentration >220 pg/ml, a left ventricular end-diastolic pressure (LVEDP) ≥18 mm Hg, and time-constant of relaxation (tau) ≥50 ms. Patients were randomized to ranolazine (n = 12) or placebo (n = 8). Treatment consisted of intravenous infusion for 24 h, followed by oral treatment for 13 days.
Results After 30 min of infusion, LVEDP (p = 0.04) and pulmonary capillary wedge pressure (p = 0.04) decreased in the ranolazine group but not in the placebo group. Mean pulmonary artery pressure showed a trend toward a decrease in the ranolazine group that was significant under pacing conditions at 120 beats/min (p = 0.02), but not for the placebo group. These changes occurred without changes in left ventricular end-systolic pressure or systemic or pulmonary resistance but in the presence of a small but significant decrease in cardiac output (p = 0.04). Relaxation parameters (e.g., tau, rate of decline of left ventricular pressure per minute [dP/dtmin]) were unaltered. Echocardiographically, the E/E′ ratio did not significantly change after 22 h. After 14 days of treatment, no significant changes were observed in echocardiographic or cardiopulmonary exercise test parameters. There were no significant effects on NT-pro-BNP levels.
Conclusions Results of this proof-of-concept study revealed that ranolazine improved measures of hemodynamics but that there was no improvement in relaxation parameters. (Ranolazine in Diastolic Heart Failure [RALI-DHF]; NCT01163734)
This study was funded by Gilead Sciences, Inc. Dr. Maier was funded by Deutsche Forschungsgemeinschaft (DFG) (MA1982/4-2, TPA03 SFB 1002) and Fondation Leducq as well as by the DZHK (Deutsches Zentrum für Herz-Kreislauf-Forschung). Dr. Maier received research grants from Gilead, Inc.; and serves as consultant with Berlin-Chemie. Drs. Jacobshagen, Wachter, and Edelmann have received honoraria from Berlin-Chemie. Drs. Layug, Karwatowska-Prokopczuk, Belardinelli, and Lee are employees of Gilead, Inc.
- Received October 9, 2012.
- Revision received November 29, 2012.
- Accepted December 5, 2012.
- American College of Cardiology Foundation