TRIad: foundation for proarrhythmia (triangulation, reverse use dependence and instability).

There exist both safe and dangerous prolongations of the QT interval. Proarrhythmia can be induced by triangulation of the cardiac action potential, reverse use dependence and instability, a set of three features termed TRIad. TRIad leads to dispersion (spatial, transmural and temporal), stalling of fast repolarization or even early after-depolarization (EAD). EAD can progress to Torsade de Pointes (TdP) especially in the presence of prolonged APD; as the QT interval shortens (e.g. by reverse use-dependence), the cardiac wavelength shortens and TdP can progress to ventricular fibrillation (VF). In the absence of TRIad and QT prolongation, chemicals exhibit on average neither pro- nor anti-arrhythmia. However, QT prolongation in the absence of TRIad becomes antiarrhythmic. Furthermore, this desirable effect increases as TRIad components are replaced by squaring of the action potential, use-dependent prolongation of APD and stabilization of the action potential. It is concluded that proarrhythmic characteristics of drugs can readily be recognized and that hope exists for an effective and safe class III antiarrhythmic agent after all.