BACKGROUND: Ranolazine inhibits late Na(+) and K(+) currents. Earlier studies have reported an antiarrhythmic effect. The aim of the present study was to understand whether ranolazine could still preserve its antiarrhythmic properties in the settings of chronic heart failure (CHF). METHODS AND RESULTS: In 12 female rabbits, CHF was induced by 4 weeks of rapid ventricular pacing leading to a decrease in ejection fraction. Twelve rabbits underwent sham operation. Isolated hearts were Langendorff perfused and demonstrated a significant QT prolongation after induction of heart failure. Ranolazine caused a concentration-dependent (10 and 30 μmol/L) increase of action potential duration (APD(90)) in sham-operated and failing hearts. Eight endo- and epicardial monophasic action potentials revealed a nonsignificant increase in spatial and temporal dispersion of repolarization. The increase in APD(90) was accompanied by a greater increase in refractory period, resulting in a significant increase in postrepolarization refractoriness in sham-operated (+29 ms and +55 ms; P < .01) and failing (+22 ms and +30 ms; P < .05) hearts. In control conditions, programmed ventricular stimulation and a burst pacing protocol led to ventricular fibrillation (VF) in 5 of the 12 sham-operated (6 episodes) and in 7 of the 12 failing (18 episodes) hearts. In the presence of ranolazine, VF was inducible in only 2 of 12 failing hearts (5 episodes). In the presence of low [K(+)], only 1 ranolazine-treated sham-operated heart developed early afterdepolarizations and ventricular tachyarrhythmias despite significant QT prolongation. CONCLUSIONS: Ranolazine decreases inducibility of VF in the presence of a significant increase in postrepolarization refractoriness. This antiarrhythmic effect in the intact heart is preserved in CHF and is not associated with drug-induced proarrhythmia.
BACKGROUND:Ranolazine inhibits late Na(+) and K(+) currents. Earlier studies have reported an antiarrhythmic effect. The aim of the present study was to understand whether ranolazine could still preserve its antiarrhythmic properties in the settings of chronic heart failure (CHF). METHODS AND RESULTS: In 12 female rabbits, CHF was induced by 4 weeks of rapid ventricular pacing leading to a decrease in ejection fraction. Twelve rabbits underwent sham operation. Isolated hearts were Langendorff perfused and demonstrated a significant QT prolongation after induction of heart failure. Ranolazine caused a concentration-dependent (10 and 30 μmol/L) increase of action potential duration (APD(90)) in sham-operated and failing hearts. Eight endo- and epicardial monophasic action potentials revealed a nonsignificant increase in spatial and temporal dispersion of repolarization. The increase in APD(90) was accompanied by a greater increase in refractory period, resulting in a significant increase in postrepolarization refractoriness in sham-operated (+29 ms and +55 ms; P < .01) and failing (+22 ms and +30 ms; P < .05) hearts. In control conditions, programmed ventricular stimulation and a burst pacing protocol led to ventricular fibrillation (VF) in 5 of the 12 sham-operated (6 episodes) and in 7 of the 12 failing (18 episodes) hearts. In the presence of ranolazine, VF was inducible in only 2 of 12 failing hearts (5 episodes). In the presence of low [K(+)], only 1 ranolazine-treated sham-operated heart developed early afterdepolarizations and ventricular tachyarrhythmias despite significant QT prolongation. CONCLUSIONS:Ranolazine decreases inducibility of VF in the presence of a significant increase in postrepolarization refractoriness. This antiarrhythmic effect in the intact heart is preserved in CHF and is not associated with drug-induced proarrhythmia.
Authors: Gerrit Frommeyer; Henning von der Ahe; Benedict Brücher; Dirk G Dechering; Philipp S Lange; Florian Reinke; Kristina Wasmer; Julia Köbe; Christian Pott; Gerold Mönnig; Lars Eckardt Journal: Naunyn Schmiedebergs Arch Pharmacol Date: 2016-07-12 Impact factor: 3.000
Authors: K F Weipert; H Bogossian; P Conzen; G Frommeyer; C Gemein; I Helmig; R Chasan; L Eckardt; M Seyfarth; B Lemke; M Zarse; C W Hamm; J Schmitt; D Erkapic Journal: Clin Res Cardiol Date: 2018-05-11 Impact factor: 5.460
Authors: Gerrit Frommeyer; André Mittelstedt; Julian Wolfes; Christian Ellermann; Simon Kochhäuser; Patrick Leitz; Dirk G Dechering; Lars Eckardt Journal: Naunyn Schmiedebergs Arch Pharmacol Date: 2017-08-06 Impact factor: 3.000
Authors: Johanna K Freundt; Gerrit Frommeyer; Tilmann Spieker; Fabian Wötzel; Jochen Schulze Grotthoff; Jörg Stypmann; Georg Hempel; Michael Schäfers; Andreas H Jacobs; Lars Eckardt; Philipp S Lange Journal: BMC Pharmacol Toxicol Date: 2019-03-06 Impact factor: 2.483