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

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Abstract

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.

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Acknowledgements

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

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Authors and Affiliations

  1. Department of Cardiology II (Electrophysiology), University Hospital Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany

    Christian Ellermann, Alix Coenen, Philipp Niehues, Patrick Leitz, Simon Kochhäuser, Dirk G. Dechering, Lars Eckardt & Gerrit Frommeyer

  2. Clinic of Exotic Pets, Reptiles, Exotic and Feral Birds, University of Hanover, Bünteweg 9, 30559, Hanover, Germany

    Michael Fehr

  3. Klinik für Kardiologie II - Rhythmologie, Universitätsklinikum Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany

    Christian Ellermann

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  1. Christian Ellermann
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  2. Alix Coenen
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Correspondence to Christian Ellermann.

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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.

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Ellermann, C., Coenen, A., Niehues, P. et al. Proarrhythmic Effect of Acetylcholine-Esterase Inhibitors Used in the Treatment of Alzheimer’s Disease: Benefit of Rivastigmine in an Experimental Whole-Heart Model. Cardiovasc Toxicol 20, 168–175 (2020). https://doi.org/10.1007/s12012-019-09543-8

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