Hartmann, Nico and Mason, Fleur E. and Braun, Inga and Pabel, Steffen and Voigt, Niels and Schotola, Hanna and Fischer, Thomas H. and Dobrev, Dobromir and Danner, Bernhard C. and Renner, Andre and Gummert, Jan and Belardinelli, Luiz and Frey, Norbert and Maier, Lars S. and Hasenfuss, Gerd and Sossalla, Samuel (2016) The combined effects of ranolazine and dronedarone on human atrial and ventricular electrophysiology. JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 94. pp. 95-106. ISSN 0022-2828, 1095-8584
Full text not available from this repository. (Request a copy)Abstract
Introduction: Pharmacological rhythm control of atrial fibrillation (AF) in patients with structural heart disease is limited. Ranolazine in combination with low dose dronedarone remarkably reduced AF-burden in the phase II HARMONY trial. We thus aimed to investigate the possible mechanisms underlying these results. Methods and results: Patch clamp experiments revealed that ranolazine (5 mu M), low-dose dronedarone (0.3 mu M), and the combination significantly prolonged action potential duration (APD(90)) in atrial myocytes from patients in sinus rhythm (prolongation by 23.5 +/- 0.1%, 31.7 +/- 0.1% and 25.6 +/- 0.1% respectively). Most importantly, in atrial myocytes from patients with AF ranolazine alone, but more the combination with dronedarone, also prolonged the typically abbreviated APD(90) (prolongation by 21.6 +/- 0.1% and 31.9 +/- 0.1% respectively). It was clearly observed that neither ranolazine, dronedarone nor the combination significantly changed the APD or contractility and twitch force in ventricular myocytes or trabeculae from patients with heart failure (HF). Interestingly ranolazine, and more so the combination, but not dronedarone alone, caused hyperpolarization of the resting membrane potential in cardiomyocytes from AF. As measured by confocal microscopy (Fluo-3), ranolazine, dronedarone and the combination significantly suppressed diastolic sarcoplasmic reticulum (SR) Ca2+ leak in myocytes from sinus rhythm (reduction by ranolazine: 89.0 +/- 30.7%, dronedarone: 75.6 +/- 27.4% and combination: 78.0 +/- 272%), in myocytes from AF (reduction by ranolazine: 67.6 +/- 33.7%, dronedarone: 86.5 +/- 31.7% and combination: 81.0 +/- 33.3%), as well as in myocytes from HF (reduction by ranolazine: 64.8 +/- 26.5% and dronedarone: 65.9 +/- 29.3%). Conclusions: Electrophysiological measurements during exposure to ranolazine alone or in combination with low-dose dronedarone showed APD prolongation, cellular hyperpolarization and reduced SR Ca2+ leak in human atrial myocytes. The combined inhibitory effects on various currents, in particular Na+ and K+ currents, may explain the anti-AF effects observed in the HARMONY trial. Therefore, the combination of ranolazine and dronedarone, but also ranolazine alone, may be promising new treatment options for AF, especially in patients with HF, and merit further clinical investigation. (C) 2016 Elsevier Ltd. All rights reserved.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ACUTE-CORONARY-SYNDROME; RETICULUM CA2+ LEAK; LATE SODIUM CURRENT; PROTEIN-KINASE-II; RANDOMIZED CONTROLLED-TRIAL; SUDDEN CARDIAC DEATH; RYANODINE RECEPTOR; ANTIANGINAL AGENT; HEART-FAILURE; NA+ CURRENTS; Atrial fibrillation; Heart failure; Anti-arrhythmic therapy; Ranolazine; Dronedarone; Electrophysiology |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin II |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 25 Mar 2019 10:26 |
| Last Modified: | 25 Mar 2019 10:26 |
| URI: | https://pred.uni-regensburg.de/id/eprint/2974 |
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