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Published on: December 11, 2017
The canine model with chronic, complete atrio-ventricular block
Avram Oros1, Jet D M Beekman, Marc A Vos
1Department of Medical Physiology, Division Heart and Lungs, UMC Utrecht, Yalelaan 50, 3584 CM Utrecht, The Netherlands.
Abstract:
Proarrhythmic susceptibility to drug-induced Torsades de Pointes is restricted to individuals with a predisposed phenotype characterized by a reduced repolarization reserve. Additional factors are often involved in a further impairment of repolarization, possibly culminating with dangerous ventricular polymorphic tachyarrhythmias. Drugs that block repolarizing currents represent such an additional hit. The dog model with chronic, complete atrio-ventricular block has been used frequently for proarrhythmic drug screening. The ventricular remodeling seen after ablation of the AV node enhances the susceptibility for repolarization-dependent arrhythmias. In this review, we 1) describe the cellular and molecular basis of ventricular remodeling, 2) validate the CAVB dog as a drug screening model and 3) introduce a new surrogate predictive proarrhythmic parameter: beat-to-beat variability of repolarization.
Insights
Drug-induced Torsades de Pointes risk is linked to reduced repolarization reserve. A chronic atrio-ventricular block (CAVB) dog model shows promise for screening drugs affecting repolarization and predicting arrhythmias using beat-to-beat variability.
Area of Science:
- Cardiology
- Pharmacology
- Electrophysiology
Background:
- Drug-induced Torsades de Pointes (TdP) risk is associated with a reduced repolarization reserve.
- Impaired repolarization, often due to blocking drugs, can lead to dangerous ventricular arrhythmias.
- Ventricular remodeling after atrio-ventricular node ablation increases susceptibility to repolarization-dependent arrhythmias.
Purpose of the Study:
- To describe the cellular and molecular basis of ventricular remodeling.
- To validate the chronic, complete atrio-ventricular block (CAVB) dog model for proarrhythmic drug screening.
- To introduce beat-to-beat variability of repolarization as a novel predictive parameter.
Main Methods:
- Review of literature on cellular and molecular mechanisms of ventricular remodeling.
- Validation of the CAVB dog model in proarrhythmic drug screening.
- Introduction and discussion of beat-to-beat variability of repolarization as a predictive tool.
Main Results:
- Ventricular remodeling contributes to increased susceptibility to arrhythmias.
- The CAVB dog model effectively mimics conditions relevant for proarrhythmic drug screening.
- Beat-to-beat variability of repolarization shows potential as a surrogate predictive parameter for arrhythmias.
Conclusions:
- Understanding ventricular remodeling is crucial for assessing proarrhythmic risk.
- The CAVB dog model is a valuable tool for evaluating drug-induced arrhythmias.
- Beat-to-beat variability of repolarization offers a promising new method for predicting proarrhythmic events.
