Journal
PHARMACOLOGY & THERAPEUTICS
Volume 119, Issue 2, Pages 168-178Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.pharmthera.2008.03.006
Keywords
hypertrophy and electrical remodeling; ventricular arrhythmias and sudden cardiac death; drug-induced Torsades de Pointes; acquired long-QT syndrome; beat-to-beat variability of repolarization
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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 I) 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. (C) 2008 Elsevier Inc. All rights reserved.
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