Advertisement

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
Article

Abstract

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.

Keywords

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

Notes

Acknowledgements

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.

References

  1. 1.
    El Chemaly, A., Magaud, C., Patri, S., Jayle, C., Guinamard, R., & Bois, P. (2007). The heart rate-lowering agent ivabradine inhibits the pacemaker current I(f) in human atrial myocytes. Journal of Cardiovascular Electrophysiology, 18, 1190–1196.CrossRefGoogle Scholar
  2. 2.
    Ponikowski, P., Voors, A. A., Anker, S. D., Bueno, H., Cleland, J. G., Coats, A. J., et al. (2016). 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) developed with the special contribution of the Heart Failure Association (HFA) of the ESC. European Heart Journal, 37, 2129–2200.CrossRefGoogle Scholar
  3. 3.
    Melgari, D., Brack, K. E., Zhang, C., Zhang, Y., El Harchi, A., Mitcheson, J. S., et al. (2015). hERG potassium channel blockade by the HCN channel inhibitor bradycardic agent ivabradine. Journal of the American Heart Association, 4(4), e001813.CrossRefGoogle Scholar
  4. 4.
    Lees-Miller, J. P., Guo, J., Wang, Y., Perissinotti, L. L., Noskov, S. Y., & Duff, H. J. (2015). Ivabradine prolongs phase 3 of cardiac repolarization and blocks the hERG1 (KCNH2) current over a concentration-range overlapping with that required to block HCN4. Journal of Molecular and Cellular Cardiology, 85, 71–78.CrossRefGoogle Scholar
  5. 5.
    Frommeyer, G., Weller, J., Ellermann, C., Bogeholz, N., Leitz, P., Dechering, D. G., et al. (2017). Ivabradine reduces digitalis-induced ventricular arrhythmias. Basic & Clinical Pharmacology & Toxicology, 121, 526–530.CrossRefGoogle Scholar
  6. 6.
    Frommeyer, G., Weller, J., Ellermann, C., Kaese, S., Kochhauser, S., Lange, P. S., et al. (2017). Antiarrhythmic properties of ivabradine in an experimental model of Short-QT-Syndrome. Clinical and Experimental Pharmacology & Physiology, 44, 941–945.CrossRefGoogle Scholar
  7. 7.
    Frommeyer, G., Sterneberg, M., Dechering, D. G., Ellermann, C., Bogeholz, N., Kochhauser, S., et al. (2017). Effective suppression of atrial fibrillation by ivabradine: Novel target for an established drug? International Journal of Cardiology, 236, 237–243.CrossRefGoogle Scholar
  8. 8.
    Verrier, R. L., Bonatti, R., Silva, A. F., Batatinha, J. A., Nearing, B. D., Liu, G., et al. (2014). If inhibition in the atrioventricular node by ivabradine causes rate-dependent slowing of conduction and reduces ventricular rate during atrial fibrillation. Heart Rhythm, 11, 2288–2296.CrossRefGoogle Scholar
  9. 9.
    Verrier, R. L., Silva, A. F., Bonatti, R., Batatinha, J. A., Nearing, B. D., Liu, G., et al. (2015). Combined actions of ivabradine and ranolazine reduce ventricular rate during atrial fibrillation. Journal of Cardiovascular Electrophysiology, 26, 329–335.CrossRefGoogle Scholar
  10. 10.
    Mengesha, H. G., Weldearegawi, B., Petrucka, P., Bekele, T., Otieno, M. G., & Hailu, A. (2017). Effect of ivabradine on cardiovascular outcomes in patients with stable angina: Meta-analysis of randomized clinical trials. BMC Cardiovascular Disorders, 17, 105.CrossRefGoogle Scholar
  11. 11.
    Frommeyer, G., Clauss, C., Ellermann, C., Bogossian, H., Dechering, D. G., Kochhauser, S., et al. (2017). Antiarrhythmic effect of vernakalant in an experimental model of Long-QT-syndrome. Europace, 19, 866–873.CrossRefGoogle Scholar
  12. 12.
    Frommeyer, G., Garthmann, J., Ellermann, C., Dechering, D. G., Kochhauser, S., Reinke, F., et al. (2017). Broad antiarrhythmic effect of mexiletine in different arrhythmia models. Europace (in press).Google Scholar
  13. 13.
    Frommeyer, G., Milberg, P., Witte, P., Stypmann, J., Koopmann, M., Lucke, M., et al. (2011). A new mechanism preventing proarrhythmia in chronic heart failure: Rapid phase-III repolarization explains the low proarrhythmic potential of amiodarone in contrast to sotalol in a model of pacing-induced heart failure. European Journal of Heart Failure, 13, 1060–1069.CrossRefGoogle Scholar
  14. 14.
    Milberg, P., Frommeyer, G., Kleideiter, A., Fischer, A., Osada, N., Breithardt, G., et al. (2011). Antiarrhythmic effects of free polyunsaturated fatty acids in an experimental model of LQT2 and LQT3 due to suppression of early afterdepolarizations and reduction of spatial and temporal dispersion of repolarization. Heart Rhythm, 8, 1492–1500.CrossRefGoogle Scholar
  15. 15.
    Antzelevitch, C. (2007). Ionic, molecular, and cellular bases of QT-interval prolongation and torsade de pointes. Europace, 9(Suppl 4), iv4–i15.Google Scholar
  16. 16.
    Verduyn, S. C., Vos, M. A., van der Zande, J., Kulcsar, A., & Wellens, H. J. (1997). Further observations to elucidate the role of interventricular dispersion of repolarization and early afterdepolarizations in the genesis of acquired torsade de pointes arrhythmias: A comparison between almokalant and d-sotalol using the dog as its own control. Journal of the American College of Cardiology, 30, 1575–1584.CrossRefGoogle Scholar
  17. 17.
    Thomsen, M. B., Verduyn, S. C., Stengl, M., Beekman, J. D., de Pater, G., van Opstal, J., et al. (2004). Increased short-term variability of repolarization predicts d-sotalol-induced torsades de pointes in dogs. Circulation, 110, 2453–2459.CrossRefGoogle Scholar
  18. 18.
    van Opstal, J. M., Schoenmakers, M., Verduyn, S. C., de Groot, S. H., Leunissen, J. D., van Der Hulst, F. F., et al. (2001). Chronic amiodarone evokes no torsade de pointes arrhythmias despite QT lengthening in an animal model of acquired long-QT syndrome. Circulation, 104, 2722–2727.CrossRefGoogle Scholar
  19. 19.
    Roden, D. M. (1998). Taking the “idio” out of “idiosyncratic”: Predicting torsades de pointes. Pacing and Clinical Electrophysiology, 21, 1029–1034.CrossRefGoogle Scholar
  20. 20.
    Frommeyer, G., Fischer, C., Ellermann, C., Dechering, D. G., Kochhauser, S., Lange, P. S., et al. (2018). Additive proarrhythmic effect of combined treatment with QT-prolonging agents. Cardiovascular Toxicology, 18, 84–90.CrossRefGoogle Scholar

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

Personalised recommendations