Instability and triangulation of the action potential predict serious proarrhythmia, but action potential duration prolongation is antiarrhythmic

Background-Prolongation of action potential duration (APD) is considered a major antiarrhythmic mechanism (class m), but paradoxically, it frequently is also proarrhythmic (torsade de pointes). Methods and Results-The cardiac electrophysiological effects of 702 chemica ls (class III or HERG channel block) were studied in 1071 rabbit Langendorf f-perfused hearts. Temporal instability of APD, triangulation (duration of phase 3 repolarization), reverse use-dependence, and induction of ectopic b eats were measured. Instability, triangulation, and reverse use-dependence were found to be important determinants of proanhythmia. Agents that length ened the APD by >50 ms, with induction of instability, triangulation, and r everse use-dependence (n=59), induced proarrhythmia (primarily polymorphic ventricular tachycardia); in their absence (n=19), the same prolongation of APD induced no proarrhythmia but significant antiarrhythmia (P<0.001). Sho rtening of APD, when accompanied by instability and triangulation, was also markedly proarrhythmic (primarily monomorphic ventricular tachycardia). In experiments in which instability and triangulation were present, proarrhyt hmia declined with prolongation of APD, but this effect was not large enoug h to become antiarrhythmic. Only with agents without instability did prolon gation of APD become antiarrhythmic. For 20 selected compounds, it was show n that instability of APD and triangulation observed in vitro were strong p redictors of in vivo proarrhythmia (torsade de pointes). Conclusions-Lengthening of APD without instability or triangulation is not proarrhythmic but rather antiarrhythmic.