Proarrhythmic Effect of Acetylcholine-Esterase Inhibitors Used in the Treatment of Alzheimer’s Disease: Benefit of Rivastigmine in an Experimental Whole-Heart Model

  • Christian EllermannEmail author
  • Alix Coenen
  • Philipp Niehues
  • Patrick Leitz
  • Simon Kochhäuser
  • Dirk G. Dechering
  • Michael Fehr
  • Lars Eckardt
  • Gerrit Frommeyer


Several studies suggest QT prolongation and torsade de pointes with acetylcholine-esterase inhibitors. We therefore examined the electrophysiologic profile of donepezil, rivastigmine, and galantamine in a sensitive whole-heart model of proarrhythmia. 34 rabbit hearts were isolated and retrogradely perfused employing the Langendorff setup. Hearts were treated either with donepezil, rivastigmine, or galantamine in rising concentrations and electrophysiologic studies were performed. In the presence of donepezil and galantamine, spatial dispersion of repolarization was amplified. Cardiac repolarization (QT interval and action potential duration) was prolonged with donepezil but not with galantamine. Remarkably, both drugs induced triggered activity (early afterdepolarizations and torsade de pointes tachycardia). Despite a pronounced prolongation of repolarization with rivastigmine, no increase in spatial dispersion of repolarization and thus no triggered activity was observed. In the present study, donepezil and galantamine provoked triggered activity, whereas rivastigmine did not have proarrhythmic effects. Spatial dispersion of repolarization but not duration of cardiac repolarization was associated with increased risk of drug-induced proarrhythmia with acetylcholine-esterase inhibitors. Consequently, QT interval duration might be insufficient to estimate the risk of proarrhythmia with acetylcholine-esterase inhibitors. Our findings emphasize the need for further electrocardiographic risk predictors.


Acetylcholine-esterase inhibitors Torsade de pointes Sudden cardiac death Galantamine Donepezil Rivastigmine 



This study was supported by the Hans-and-Gertie Fischer Foundation and by the German Cardiac Society (to G.F.).

Compliance with Ethical Standards

Conflict of interest

All other authors declare that they have no conflicts of interest.

Ethical Approval

All applicable international, national, and institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution at which the studies were conducted.


  1. 1.
    Prince, M., Bryce, R., Albanese, E., Wimo, A., Ribeiro, W., & Ferri, C. P. (2013). The global prevalence of dementia: A systematic review and metaanalysis. Alzheimers Dementia, 9(63–75), e2.Google Scholar
  2. 2.
    Hort, J., Obrien, J., Gainotti, G., et al. (2010). EFNS guidelines for the diagnosis and management of Alzheimer’s disease. European Journal of Neurology, 17, 1236–1248.CrossRefGoogle Scholar
  3. 3.
    Kumar, A., & Singh, A. (2015). A review on Alzheimer’s disease pathophysiology and its management: An update. Pharmacological Reports, 67, 195–203.CrossRefGoogle Scholar
  4. 4.
    Schwartz, P. J., & Woosley, R. L. (2016). Predicting the unpredictable: drug-induced QT prolongation and torsades de pointes. Journal of the American College of Cardiology, 67, 1639–1650.CrossRefGoogle Scholar
  5. 5.
    Martens, E., Sinner, M. F., Siebermair, J., et al. (2014). Incidence of sudden cardiac death in Germany: Results from an emergency medical service registry in Lower Saxony. Europace, 16, 1752–1758.CrossRefGoogle Scholar
  6. 6.
    Straus, S. M., Sturkenboom, M. C., GlS, Bleumink, et al. (2005). Non-cardiac QTc-prolonging drugs and the risk of sudden cardiac death. European Heart Journal, 26(19), 2007–2012.CrossRefGoogle Scholar
  7. 7.
    Nordström, P., Religa, D., Wimo, A., Winblad, B., & Eriksdotter, M. (2013). The use of cholinesterase inhibitors and the risk of myocardial infarction and death: a nationwide cohort study in subjects with Alzheimer’s disease. European Heart Journal, 34, 2585–2591.CrossRefGoogle Scholar
  8. 8.
    Keller, G. A., Ponte, M. L., & Di Girolamo, G. (2010). Other drugs acting on nervous system associated with QT-interval prolongation. Current Drug Safety, 5, 105–111.CrossRefGoogle Scholar
  9. 9.
    Birks, J. S. (2006). Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database of Systematic Reviews. Scholar
  10. 10.
    Howes, L. G. (2014). Cardiovascular effects of drugs used to treat Alzheimer’s disease. Drug Safety, 37, 391–395.CrossRefGoogle Scholar
  11. 11.
    Takaya, T., Okamoto, M., Yodoi, K., et al. (2009). Torsades de Pointes with QT prolongation related to donepezil use. Journal of Cardiology, 54, 507–511.CrossRefGoogle Scholar
  12. 12.
    Kröger, E., Berkers, M., Carmichael, P.-H., Souverein, P., van Marum, R., & Egberts, T. (2012). Use of rivastigmine or galantamine and risk of adverse cardiac events: A database study from the Netherlands. The American Journal of Geriatric Pharmacotherapy, 10, 373–380.CrossRefGoogle Scholar
  13. 13.
    Jackobson, G., Carmel, N. N., Lotan, D., Kremer, A., & Justo, D. (2018). Reckless administration of QT interval-prolonging agents in elderly patients with drug-induced torsade de pointes. Zeitschrift fur Gerontologie und Geriatrie, 51, 41–47.CrossRefGoogle Scholar
  14. 14.
    Frommeyer, G., & Eckardt, L. (2016). Drug-induced proarrhythmia: Risk factors and electrophysiological mechanisms. Nature Reviews Cardiology, 13, 36.CrossRefGoogle Scholar
  15. 15.
    Frommeyer, G., Clauss, C., Ellermann, C., et al. (2017). Antiarrhythmic effect of vernakalant in an experimental model of Long-QT-syndrome. Europace, 19, 866–873.CrossRefGoogle Scholar
  16. 16.
    Ellermann, C., Wolfes, J., Kochhäuser, S., et al. (2017). Divergent antiarrhythmic effects of resveratrol and piceatannol in a whole-heart model of long QT syndrome. International Journal of Cardiology, 243, 233–238.CrossRefGoogle Scholar
  17. 17.
    Milberg, P., Fink, M., Pott, C., et al. (2012). Blockade of ICa suppresses early afterdepolarizations and reduces transmural dispersion of repolarization in a whole heart model of chronic heart failure. British Journal of Pharmacology, 166, 557–568.CrossRefGoogle Scholar
  18. 18.
    Leitch, A., McGinness, P., & Wallbridge, D. (2007). Calculate the QT interval in patients taking drugs for dementia. BMJ, 335, 557.CrossRefGoogle Scholar
  19. 19.
    Vigneault, P., Bourgault, S., Kaddar, N., et al. (2012). Galantamine (Reminyl®) delays cardiac ventricular repolarization and prolongs the QT interval by blocking the HERG current. European Journal of Pharmacology, 681, 68–74.CrossRefGoogle Scholar
  20. 20.
    Edwards, A. G., & Louch, W. E. (2017). Species-dependent mechanisms of cardiac arrhythmia: A cellular focus. Clinical Medicine Insights: Cardiology, 11, 1179546816686061.Google Scholar
  21. 21.
    Lu, Z., Kamiya, K., Opthof, T., Yasui, K., & Kodama, I. (2001). Density and kinetics of I Kr and I Ks in guinea pig and rabbit ventricular myocytes explain different efficacy of I Ks blockade at high heart rate in guinea pig and rabbit: implications for arrhythmogenesis in humans. Circulation, 104, 951–956.CrossRefGoogle Scholar
  22. 22.
    Frommeyer, G., Brücher, B., von der Ahe, H., et al. (2016). Low proarrhythmic potential of citalopram and escitalopram in contrast to haloperidol in an experimental whole-heart model. European Journal of Pharmacology, 788, 192–199.CrossRefGoogle Scholar
  23. 23.
    Ellermann, C., Sterneberg, M., Kochhäuser, S., et al. (2018). Antiarrhythmic effect of antazoline in experimental models of acquired short-and long-QT-syndromes. Europace, 20, 1699–1706.CrossRefGoogle Scholar
  24. 24.
    Frommeyer, G., Ellermann, C., Dechering, D. G., et al. (2016). Ranolazine and vernakalant prevent ventricular arrhythmias in an experimental whole-heart model of short QT syndrome. Journal of Cardiovascular Electrophysiology, 27, 1214–1219.CrossRefGoogle Scholar
  25. 25.
    Kaese, S., Frommeyer, G., Verheule, S., et al. (2013). The ECG in cardiovascular-relevant animal models of electrophysiology. Herzschrittmacherther + Elektrophysiologie, 24, 84–91.CrossRefGoogle Scholar
  26. 26.
    Kang, C., Brennan, J., Kuzmiak-Glancy, S., Garrott, K., Kay, M., & Efimov, I. (2016). Technical advances in studying cardiac electrophysiology—Role of rabbit models. Progress in Biophysics and Molecular Biology, 121, 97–109.CrossRefGoogle Scholar
  27. 27.
    Ebert, S. N., Liu, X.-K., & Woosley, R. L. (1998). Female gender as a risk factor for drug-induced cardiac arrhythmias: evaluation of clinical and experimental evidence. Journal of Women’s Health, 7, 547–557.CrossRefGoogle Scholar
  28. 28.
    Antzelevitch, C. (2005). Role of transmural dispersion of repolarization in the genesis of drug-induced torsades de pointes. Heart Rhythm, 2, S9–S15.CrossRefGoogle Scholar
  29. 29.
    Antzelevitch, C. (2007). Ionic, molecular, and cellular bases of QT-interval prolongation and torsade de pointes. Europace, 9, iv4–iv15.CrossRefGoogle Scholar
  30. 30.
    Grossberg, G. T. (2003). Cholinesterase inhibitors for the treatment of Alzheimer’s disease: Getting on and staying on. Current Therapeutic Research, 64, 216–235.CrossRefGoogle Scholar
  31. 31.
    Doan, J., Zakrzewski-Jakubiak, H., Roy, J., Turgeon, J., & Tannenbaum, C. (2013). Prevalence and risk of potential cytochrome p450–mediated drug-drug interactions in older hospitalized patients with polypharmacy. Annals of Pharmacotherapy, 47, 324–332.CrossRefGoogle Scholar
  32. 32.
    Nobili, A., Licata, G., Salerno, F., et al. (2011). Polypharmacy, length of hospital stay, and in-hospital mortality among elderly patients in internal medicine wards. The REPOSI study. European Journal of Clinical Pharmacology, 67, 507–519.CrossRefGoogle Scholar
  33. 33.
    Mallet, L., Spinewine, A., & Huang, A. (2007). The challenge of managing drug interactions in elderly people. Lancet, 370, 185–191.CrossRefGoogle Scholar
  34. 34.
    Frommeyer, G., Fischer, C., Ellermann, C., et al. (2018). Additive proarrhythmic effect of combined treatment with QT-prolonging agents. Cardiovascular Toxicology, 18, 84–90.CrossRefGoogle Scholar
  35. 35.
    Alonge, O., Iqbal, F. M., & Cifonelli, E. (2018). Collapse in the elderly: Rivastigmine-induced heart block and a literature review of the pharmacology of acetylcholinesterase inhibitors used in Alzheimer’s disease. BMJ Case Report. Scholar
  36. 36.
    Hondeghem, L. M., & Hoffmann, P. (2003). Blinded test in isolated female rabbit heart reliably identifies action potential duration prolongation and proarrhythmic drugs: Importance of triangulation, reverse use dependence, and instability. Journal of Cardiovascular Pharmacology, 41, 14–24.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Cardiology II (Electrophysiology)University Hospital MünsterMünsterGermany
  2. 2.Clinic of Exotic Pets, Reptiles, Exotic and Feral BirdsUniversity of HanoverHanoverGermany
  3. 3.Klinik für Kardiologie II - RhythmologieUniversitätsklinikum MünsterMünsterGermany

Personalised recommendations