Instability and Triangulation of the Action Potential Predict Serious Proarrhythmia, but Action Potential Duration Prolongation Is Antiarrhythmic

Abstract

Background-Prolongation of action potential duration (APD) is considered a major antiarrhythmic mechanism (class III), but paradoxically, it frequently is also proarrhythmic (torsade de pointes). Methods and Results-The cardiac electrophysiological effects of 702 chemicals (class III or HERG channel block) were studied in 1071 rabbit Langendorff-perfused hearts. Temporal instability of APD, triangulation (duration of phase 3 repolarization), reverse use-dependence, and induction of ectopic beats were measured. Instability, triangulation, and reverse use-dependence were found to be important determinants of proarrhythmia. Agents that lengthened the APD by Ͼ50 ms, with induction of instability, triangulation, and reverse use-dependence (nϭ59), induced proarrhythmia (primarily polymorphic ventricular tachycardia); in their absence (nϭ19), the same prolongation of APD induced no proarrhythmia but significant antiarrhythmia (PϽ0.001). Shortening 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, proarrhythmia declined with prolongation of APD, but this effect was not large enough to become antiarrhythmic. Only with agents without instability did prolongation of APD become antiarrhythmic. For 20 selected compounds, it was shown that instability of APD and triangulation observed in vitro were strong predictors of in vivo proarrhythmia (torsade de pointes). Conclusions-Lengthening of APD without instability or triangulation is not proarrhythmic but rather antiarrhythmic.

Techniques for Ventricular Repolarization Instability Assessment From the ECG

“…Evaluation of ECG repolarization adaptation to HR changes will be presented in section III-C1. Another phenomenon is AP variability, measured as fluctuations in the duration of the AP, which has been closely linked to SCD under different conditions [22]. QT variability quantified from the surface ECG can be considered as an approximation to the study of such phenomenon and it will be explored in section III-C2.…”

In silico assessment of drug safety in human heart applied to late sodium current blockers

“…Indeed, changes in QT interval (QT int ), reverse rate-dependence (RRD) of APD prolongation and transmural dispersion of repolarization (TDR) have been also proposed as "torsadogenic" indicators. [22][23][24] Within the past 3 y, computer simulations have been employed in drug development programs with the goal of assessing in silico risk for drug-induced cardiac arrhythmia. [25][26][27][28] However, only Mirams et al 25 and Sarkar et al 29 utilized human AP models, in addition to models of the rabbit and dog ventricular APs.…”

Torsades de Pointes in the Guinea-Pig Heart

“…The low incidence of arrhythmias in guinea-pig hearts appears to be at odds with data obtained from rabbit hearts, where a much higher sensitivity for proarrhythmic drugs is reported [3,13]. What is the underlying mechanism?…”

“…Since TdP is frequently not a direct read-out from the screening models, the determination of proarrhythmic risks is based on surrogate markers. Many such biomarkers for TdP have been proposed, including QT and APD prolongation, reverse-use dependence of drugs, and temporal and spatial dispersion of repolarization duration [3][4][5][6][7][8][9]. Undoubtedly, evaluation of biomarkers for proarrhythmia advanced our knowledge of TdP mechanisms; however, utility of these biomarkers in drug development is still limited as both their specificity and sensitivity is far from optimal.…”