Ivabradine Reduces Digitalis‐induced Ventricular Arrhythmias

Abstract

The I channel inhibitor ivabradine is recommended for treatment of heart failure but also affects potassium currents and thereby prolongs ventricular repolarization. The aim of this study was to examine the electrophysiological effects of ivabradine on digitalis-induced ventricular arrhythmias. Thirteen rabbit hearts were isolated and Langendorff-perfused. After obtaining baseline data, the digitalis glycoside ouabain was infused (0.2 μM). Monophasic action potentials and ECG showed a significant abbreviation of QT interval (-34 ms, p < 0.05) and action potential duration (APD ; -27 ms, p < 0.05). The shortening of ventricular repolarization was accompanied by a reduction in effective refractory period (ERP; -27 ms, p < 0.05). Thereafter, hearts were additionally treated with ivabradine (5 μM). Of note, this did not exert significant effects on QT interval (-4 ms, p = ns) or APD (-15 ms, p = ns) but resulted in an increase in ERP (+17 ms, p < 0.05). This led to a significant increase in post-repolarization refractoriness (PRR, +32 ms, p < 0.01) as compared with sole ouabain treatment. Under baseline conditions, ventricular fibrillation (VF) was inducible by a standardized pacing protocol including programmed stimulation and burst stimulation in four of 13 hearts (31%; 15 episodes). After application of 0.2 μM ouabain, eight of 13 hearts were inducible (62%, 49 episodes). Additional infusion of 5 μM ivabradine led to a significant suppression of VF. Only four episodes could be induced in two of 13 hearts (15%). In this study, ivabradine reduced digitalis-induced ventricular arrhythmias. Ivabradine did not affect ventricular repolarization in the presence of digitalis treatment but demonstrated potent anti-arrhythmic properties based on an increase in both ERP and PRR. The study further characterizes the beneficial electrophysiological profile of ivabradine.

The Hyperpolarization-Activated Cyclic-Nucleotide-Gated Channel Blocker Ivabradine Does Not Prevent Arrhythmias in Catecholaminergic Polymorphic Ventricular Tachycardia

“…The bradycardic features of ivabradine raise the question of whether it could be effective in ventricular arrhythmias. Recently, ivabradine was found to decrease digitalis-induced ventricular arrhythmias and short QT-induced arrhythmic features in Langendorff-perfused rabbit heart preparations (Frommeyer et al, 2017a;Frommeyer et al, 2017b). Along with this rationale, we asked in the present work whether ivabradine could prevent the ventricular arrhythmias found in cellular and animal models of CPVT2.…”

“…Moreover, it was shown that ivabradine blocks the recombinant hERG current over a range of concentrations overlapping with those required to block HCN4 (Melgari et al, 2015). Because of its concurrent inhibitory action on If and IKr currents, ivabradine was suggested to be a potential antiarrhythmic drug thanks to an increase in both the effective refractory period and the post-repolarization refractoriness (Frommeyer et al, 2017a;Frommeyer et al, 2017b). The bradycardic features of ivabradine raise the question of whether it could be effective in ventricular arrhythmias.…”

“…Recently, the pacemaker channel inhibitor ivabradine was found to decrease digitalis-induced ventricular arrhythmias and short QT-induced arrhythmic features in Langendorff-perfused rabbit heart preparations (Frommeyer et al, 2017a;Frommeyer et al, 2017b). Ivabradine is usually prescribed to treat stable angina pectoris and in association with b-blockers to cure heart failure with left ventricular systolic dysfunction (Koruth et al, 2017).…”

Ventricular arrhythmia suppression with ivabradine in a patient with catecholaminergic polymorphic ventricular tachycardia refractory to nadolol, flecainide, and sympathectomy

“…Ivabradine is known to prolong ventricular repolarization and alter electrical restitution properties of the myocardium in both in vitro cellular models and perfused guinea pig hearts via inhibition of hERG/I Kr channels 14,15 and has been shown to mitigate digitalis‐induced ventricular arrhythmias 16 . Similar beneficial effects on ventricular arrhythmogenesis have been noted in humans with heart failure (LVEF < 35%) where ivabradine markedly decreased dobutamine‐induced ectopy 17 .…”

Effect of Ivabradine on Cardiac Ventricular Arrhythmias: Friend or Foe?

“…Ivabradine reduced inducible VA in a Langendorff-perfused rabbit heart in the model of short-QT syndrome induced by a potassium channel opener, pinacidil [ 66 ] as well as digitalis-induced VA in the same rabbit model [ 67 ], while it was proarrhythmic in a model of long QT syndrome [ 68 ].…”