The canine model with chronic, complete atrio-ventricular block.
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.
Oros
Avram
A
Department of Medical Physiology, Division Heart and Lungs, UMC Utrecht, Yalelaan 50, 3584 CM Utrecht, The Netherlands.
Beekman
Jet D M
JD
Vos
Marc A
MA
D000818:Animals; D054537:Atrioventricular Block / Q000503:physiopathology; D004195:Disease Models, Animal; D004285:Dogs; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D010641:Phenotype; D012307:Risk Factors; D016171:Torsades de Pointes / Q000139:chemically induced*; D018675:Toxicity Tests / Q000379:methods; D020257:Ventricular Remodeling