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