Digitalis Promotes Ventricular Arrhythmias in Flecainide- and Ranolazine-Pretreated Hearts. 2019

Christian Ellermann, and Julian Wolfes, and Dirk Puckhaber, and Nils Bögeholz, and Patrick Leitz, and Philipp S Lange, and Lars Eckardt, and Gerrit Frommeyer
Department of Cardiology II - Electrophysiology, University Hospital Münster, Münster, Germany. christian.ellermann@ukmuenster.de.

A post hoc analysis of the PALLAS trial suggested life-threatening interactions of digitalis and dronedarone. Thus, there is concern about an interplay between digitalis and other drugs that influence cardiac electrophysiology. We therefore investigated the interaction between digitalis and flecainide or ranolazine. Twenty-five rabbit hearts were Langendorff-perfused and treated with flecainide (2 µM, 12 hearts) or ranolazine (10 µM, 13 hearts). Infusion of flecainide prolonged mean action potential duration [APD90, from 153 ms (interquartile range (IQR): 29.7 ms) to 159 ms (IQR: 24.9 ms, p = 0.04)] and effective refractory period [ERP, 170 ms (IQR: 40 ms) vs. 200 ms (IQR: 32.5 ms, p < 0.01)]. Administration of ranolazine prolonged APD90 [144 ms (IQR: 34.3 ms)) vs. 157 ms (IQR: 31.2 ms, p < 0.01)] and ERP [180 ms (IQR: 40 ms) vs. 200 ms (IQR: 30 ms, p < 0.01)]. Additional infusion of the digitalis glycoside ouabain (0.2 µM) abbreviated APD90 and ERP in both groups (flecainide: APD90: to 128 ms (IQR: 19 ms), ERP: to 170 ms (IQR: 20 ms), p < 0.01 each; ranolazine: APD90: to 141 ms (IQR: 40 ms), ERP: to 160 ms (IQR: 30 ms), p < 0.01 each). Ventricular vulnerability was assessed by a pacing protocol employing premature extra stimuli and burst stimulation. No proarrhythmic effect was observed with flecainide (1 vs. 3 episodes at baseline) or ranolazine (3 vs. 11 episodes at baseline). However, further infusion of ouabain had a proarrhythmic effect for both drugs (flecainide: 15 episodes, p = 0.04; ranolazine: 21 episodes, p = 0.09). Concomitant treatment of the sodium channel blockers flecainide or ranolazine with digitalis seems to be proarrhythmic. Abbreviation of repolarization and refractoriness that can facilitate re-entry was found as underlying mechanism.

UI MeSH Term Description Entries
D010042 Ouabain A cardioactive glycoside consisting of rhamnose and ouabagenin, obtained from the seeds of Strophanthus gratus and other plants of the Apocynaceae; used like DIGITALIS. It is commonly used in cell biological studies as an inhibitor of the NA(+)-K(+)-EXCHANGING ATPASE. Acocantherin,G-Strophanthin,Acolongifloroside K,G Strophanthin
D011817 Rabbits A burrowing plant-eating mammal with hind limbs that are longer than its fore limbs. It belongs to the family Leporidae of the order Lagomorpha, and in contrast to hares, possesses 22 instead of 24 pairs of chromosomes. Belgian Hare,New Zealand Rabbit,New Zealand Rabbits,New Zealand White Rabbit,Rabbit,Rabbit, Domestic,Chinchilla Rabbits,NZW Rabbits,New Zealand White Rabbits,Oryctolagus cuniculus,Chinchilla Rabbit,Domestic Rabbit,Domestic Rabbits,Hare, Belgian,NZW Rabbit,Rabbit, Chinchilla,Rabbit, NZW,Rabbit, New Zealand,Rabbits, Chinchilla,Rabbits, Domestic,Rabbits, NZW,Rabbits, New Zealand,Zealand Rabbit, New,Zealand Rabbits, New,cuniculus, Oryctolagus
D012032 Refractory Period, Electrophysiological The period of time following the triggering of an ACTION POTENTIAL when the CELL MEMBRANE has changed to an unexcitable state and is gradually restored to the resting (excitable) state. During the absolute refractory period no other stimulus can trigger a response. This is followed by the relative refractory period during which the cell gradually becomes more excitable and the stronger impulse that is required to illicit a response gradually lessens to that required during the resting state. Period, Neurologic Refractory,Periods, Neurologic Refractory,Refractory Period, Neurologic,Tetanic Fade,Vvedenskii Inhibition,Wedensky Inhibition,Inhibition, Vvedenskii,Inhibition, Wedensky,Neurologic Refractory Period,Neurologic Refractory Periods,Neuromuscular Fade,Neuromuscular Transmission Fade,Refractory Period, Neurological,Refractory Periods, Neurologic,Electrophysiological Refractory Period,Electrophysiological Refractory Periods,Fade, Neuromuscular,Fade, Neuromuscular Transmission,Fade, Tetanic,Neurological Refractory Period,Neurological Refractory Periods,Refractory Periods, Electrophysiological,Refractory Periods, Neurological,Transmission Fade, Neuromuscular
D004071 Digitalis Glycosides Glycosides from plants of the genus DIGITALIS. Some of these are useful as cardiotonic and anti-arrhythmia agents. Included also are semi-synthetic derivatives of the naturally occurring glycosides. The term has sometimes been used more broadly to include all CARDIAC GLYCOSIDES, but here is restricted to those related to Digitalis. Glycosides, Digitalis
D004347 Drug Interactions The action of a drug that may affect the activity, metabolism, or toxicity of another drug. Drug Interaction,Interaction, Drug,Interactions, Drug
D005424 Flecainide A potent anti-arrhythmia agent, effective in a wide range of ventricular and atrial ARRHYTHMIAS and TACHYCARDIAS. Flecainide Acetate,Apocard,Flecadura,Flecainid-Isis,Flecainide Monoacetate,Flecainide Monoacetate, (+-)-Isomer,Flecainide Monoacetate, (R)-Isomer,Flecainide Monoacetate, (S)-Isomer,Flecainide, (R)-Isomer,Flecainide, (S)-Isomer,Flecainide, 5-HO-N-(6-oxo)-Derivative,Flecainide, 5-HO-N-(6-oxo)-Derivative, (+-)-Isomer,Flecatab,Flécaïne,R818,Tambocor,Flecainid Isis
D006339 Heart Rate The number of times the HEART VENTRICLES contract per unit of time, usually per minute. Cardiac Rate,Chronotropism, Cardiac,Heart Rate Control,Heartbeat,Pulse Rate,Cardiac Chronotropy,Cardiac Chronotropism,Cardiac Rates,Chronotropy, Cardiac,Control, Heart Rate,Heart Rates,Heartbeats,Pulse Rates,Rate Control, Heart,Rate, Cardiac,Rate, Heart,Rate, Pulse
D000067268 Isolated Heart Preparation Method of isolation and maintenance of a working heart for various cardiac measurements. The model allows for the separation of cardiac and systemic variables in the denervated heart. Isolated Heart Preparation Technique,Isolated Perfused Heart Model,Langendorff Perfused Heart,Langendorff Perfused Isolated Heart Preparation,Working Heart Preparation,Working Heart Preparation Technique,Working Heart Technique,Heart, Langendorff Perfused,Isolated Heart Preparations,Perfused Heart, Langendorff,Preparation, Isolated Heart,Preparation, Working Heart,Preparations, Isolated Heart,Preparations, Working Heart,Technique, Working Heart,Techniques, Working Heart,Working Heart Preparations,Working Heart Techniques
D000069458 Ranolazine An acetanilide and piperazine derivative that functions as a SODIUM CHANNEL BLOCKER and prevents the release of enzymes during MYOCARDIAL ISCHEMIA. It is used in the treatment of ANGINA PECTORIS. N-(2,6-dimethylphenyl)-4-(2-hydroxy-3-(2-methoxyphenoxy)propyl)-1-piperazineacetamide,RS 43285,RS 43285-193,RS-43285,Ranexa,Ranolazine Dihydrochloride,Ranolazine HCl,Ranolazine Hydrochloride,Renolazine,43285, RS,Dihydrochloride, Ranolazine,HCl, Ranolazine,Hydrochloride, Ranolazine,RS 43285 193,RS 43285193,RS43285
D000200 Action Potentials Abrupt changes in the membrane potential that sweep along the CELL MEMBRANE of excitable cells in response to excitation stimuli. Spike Potentials,Nerve Impulses,Action Potential,Impulse, Nerve,Impulses, Nerve,Nerve Impulse,Potential, Action,Potential, Spike,Potentials, Action,Potentials, Spike,Spike Potential

Related Publications

Christian Ellermann, and Julian Wolfes, and Dirk Puckhaber, and Nils Bögeholz, and Patrick Leitz, and Philipp S Lange, and Lars Eckardt, and Gerrit Frommeyer
July 2017, Journal of cardiovascular medicine (Hagerstown, Md.),
Christian Ellermann, and Julian Wolfes, and Dirk Puckhaber, and Nils Bögeholz, and Patrick Leitz, and Philipp S Lange, and Lars Eckardt, and Gerrit Frommeyer
October 2016, Journal of cardiovascular pharmacology,
Christian Ellermann, and Julian Wolfes, and Dirk Puckhaber, and Nils Bögeholz, and Patrick Leitz, and Philipp S Lange, and Lars Eckardt, and Gerrit Frommeyer
June 1985, The American journal of cardiology,
Christian Ellermann, and Julian Wolfes, and Dirk Puckhaber, and Nils Bögeholz, and Patrick Leitz, and Philipp S Lange, and Lars Eckardt, and Gerrit Frommeyer
January 1976, Heart & lung : the journal of critical care,
Christian Ellermann, and Julian Wolfes, and Dirk Puckhaber, and Nils Bögeholz, and Patrick Leitz, and Philipp S Lange, and Lars Eckardt, and Gerrit Frommeyer
May 2000, Cardiology clinics,
Christian Ellermann, and Julian Wolfes, and Dirk Puckhaber, and Nils Bögeholz, and Patrick Leitz, and Philipp S Lange, and Lars Eckardt, and Gerrit Frommeyer
August 2008, Cardiology clinics,
Christian Ellermann, and Julian Wolfes, and Dirk Puckhaber, and Nils Bögeholz, and Patrick Leitz, and Philipp S Lange, and Lars Eckardt, and Gerrit Frommeyer
January 1984, Cardiology,
Christian Ellermann, and Julian Wolfes, and Dirk Puckhaber, and Nils Bögeholz, and Patrick Leitz, and Philipp S Lange, and Lars Eckardt, and Gerrit Frommeyer
October 1995, Minerva cardioangiologica,
Christian Ellermann, and Julian Wolfes, and Dirk Puckhaber, and Nils Bögeholz, and Patrick Leitz, and Philipp S Lange, and Lars Eckardt, and Gerrit Frommeyer
February 1984, The American journal of cardiology,
Christian Ellermann, and Julian Wolfes, and Dirk Puckhaber, and Nils Bögeholz, and Patrick Leitz, and Philipp S Lange, and Lars Eckardt, and Gerrit Frommeyer
December 2017, Basic & clinical pharmacology & toxicology,
Copied contents to your clipboard!