Drug-induced Torsades de pointes: Insights from a canine model of chronic atrioventricular block.

Abstract

Torsades de pointes is a potentially fatal ventricular arrhythmia that can arise when a patient receives medicines that adversely antagonize the potassium current governed by the Kv11.1 ion channel. Several drugs across numerous therapeutic classes, including antiarrhythmic drugs, can trigger this arrhythmia in susceptible individuals. Consequently, interest in the preclinical screening of medications, identification of at-risk patients, and the development of reliable arrhythmia biomarkers has significantly increased. Animal models of torsades de pointes are rare; however, the canine model of chronic atrioventricular block (CAVB) has become pivotal in understanding the underlying mechanisms involved in this type of arrhythmia. Cardiac hypertrophy, prolonged repolarization, and a marked propensity for drug-induced torsades de pointes are the hallmarks of this model. This review provides an overview of drug-induced torsades de pointes mechanisms and explores the pathophysiological changes observed in dogs with CAVB. The primary focus is the beat-to-beat variability of repolarization duration (BVR), measured as temporal fluctuations in the QT interval, which has emerged as a robust biomarker for the risk of torsades de pointes. This review evaluates the current evidence supporting BVR as a predictive tool for drug-induced arrhythmia, underscoring its potential utility in preclinical safety assessments.