Cardiovascular Toxicology

, Volume 19, Issue 2, pp 129–135 | Cite as

Ivabradine Aggravates the Proarrhythmic Risk in Experimental Models of Long QT Syndrome

  • Gerrit FrommeyerEmail author
  • Jan Weller
  • Christian Ellermann
  • Patrick Leitz
  • Simon Kochhäuser
  • Philipp S. Lange
  • Dirk G. Dechering
  • Lars Eckardt


Ivabradine has recently been demonstrated to have antiarrhythmic properties in atrial fibrillation. The aim of the present study was to assess the electrophysiologic profile of ivabradine in an experimental whole-heart model of long-QT-syndrome. In 12 isolated rabbit hearts long-QT-2-syndrome (LQT2) was simulated by infusion of d,l-sotalol (100 µM). 12 rabbit hearts were treated with veratridine (0.5 µM) to mimic long-QT-3-syndrome (LQT3). Sotalol induced a significant prolongation of QT-interval (+ 40 ms, p < 0.01) and action potential duration (APD, + 20 ms, p < 0.01). Similar results were obtained in veratridine-treated hearts (QT-interval: +52 ms, p < 0.01; APD: + 41 ms, p < 0.01). Of note, both sotalol (+ 26 ms, p < 0.01) and veratridine (+ 42 ms, p < 0.01) significantly increased spatial dispersion of repolarisation. Additional infusion of ivabradine (5 µM) did not change these parameters in sotalol-pretreated hearts but resulted in a further significant increase of QT-interval (+ 26 ms, p < 0.05) and APD (+ 49 ms, p < 0.05) in veratridine-treated hearts. Lowering of potassium concentration in bradycardic AV-blocked hearts resulted in the occurrence of early afterdepolarizations (EAD) or polymorphic ventricular tachycardias (VT) resembling torsade de pointes in 6 of 12 sotalol-treated hearts (56 episodes) and 6 of 12 veratridine-treated hearts (73 episodes). Additional infusion of ivabradine increased occurrence of polymorphic VT. Ivabradine treatment resulted in occurrence of EAD and polymorphic VT in 9 of 12 sotalol-treated hearts (212 episodes), and 8 of 12 veratridine-treated hearts (155 episodes). Treatment with ivabradine in experimental models of LQT2 and LQT3 increases proarrhythmia. A distinct interaction with potassium currents most likely represents a major underlying mechanism. These results imply that ivabradine should be employed with caution in the presence of QT-prolongation.


Ivabradine Long-QT-syndrome Sudden cardiac death Dispersion of repolarization 



This study was supported by the German Cardiac Society and the Hans und Gertie-Fischer Foundation.

Compliance with Ethical Standards

Conflict of interest

All authors declare to have no conflict of interest related to this study.


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Gerrit Frommeyer
    • 1
    Email author
  • Jan Weller
    • 1
  • Christian Ellermann
    • 1
  • Patrick Leitz
    • 1
  • Simon Kochhäuser
    • 1
  • Philipp S. Lange
    • 1
  • Dirk G. Dechering
    • 1
  • Lars Eckardt
    • 1
  1. 1.Division of Electrophysiology, Department of Cardiovascular MedicineUniversity of MünsterMünsterGermany

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