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 2I), but paradoxically, it frequently is also proarrhythmic (torsade de pointes).


RESULTS
The cardiac electrophysiological effects of 702 chemicals (class 2I 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 >50 ms, with induction of instability, triangulation, and reverse 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). 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.
Hondeghem
L M
LM
Department of Pharmacology, Leuven, Belgium. luchondeghem@yahoo.com
Carlsson
L
L
Duker
G
G
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000175:diagnosis* / Q000503:physiopathology*; D001794:Blood Pressure / Q000187:drug effects; D002317:Cardiovascular Agents / Q000494:pharmacology; D027682:Cation Transport Proteins; D004353:Drug Evaluation, Preclinical; D004562:Electrocardiography / Q000187:drug effects; D051638:Ether-A-Go-Go Potassium Channels; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011237:Predictive Value of Tests; D011817:Rabbits; D016171:Torsades de Pointes / Q000139:chemically induced / Q000175:diagnosis / Q000503:physiopathology
D000889:Anti-Arrhythmia Agents; D002317:Cardiovascular Agents; D027682:Cation Transport Proteins; D051638:Ether-A-Go-Go Potassium Channels; C092509:KCNH6 protein, human; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated