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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
- Source :
- Cardiovascular toxicology. 20(2)
- Publication Year :
- 2019
-
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.
- Subjects :
- Tachycardia
medicine.medical_specialty
Time Factors
Refractory Period, Electrophysiological
Action Potentials
Rivastigmine
030204 cardiovascular system & hematology
Toxicology
QT interval
Risk Assessment
Afterdepolarization
03 medical and health sciences
0302 clinical medicine
Heart Conduction System
Heart Rate
Internal medicine
medicine
Galantamine
Repolarization
Animals
Donepezil
Molecular Biology
Proarrhythmia
business.industry
Arrhythmias, Cardiac
Isolated Heart Preparation
medicine.disease
Cardiotoxicity
030220 oncology & carcinogenesis
Cardiology
Cholinesterase Inhibitors
Rabbits
medicine.symptom
Cardiology and Cardiovascular Medicine
business
medicine.drug
Subjects
Details
- ISSN :
- 15590259
- Volume :
- 20
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Cardiovascular toxicology
- Accession number :
- edsair.doi.dedup.....ebd6273c54405b68f1d3aab57869679c