Estimation of Proarrhythmic Hazards by QT Prolongation/Shortening: QT Obsession?

Abstract

QT prolongation is frequently associated with proarrhythmia, including torsade de pointes (TdP). At the same time, prolongation of action potential duration (APD) is widely recognized as a primary antiarrhythmic mechanism. This paradox results from linking an accidental association (APD prolongation) to the cause of proarrhythmia: triangulation, reverse use dependence, and instability of the cardiac action potential, which result in dispersion (TRIaD). Thus, prolongation of APD can occur without TRIaD (antiarrhythmic) or with TRIaD (proarrhythmic). Human ether-à-go-go related gene (hERG) blockers are more often than not associated with TRIaD and proarrhythmia. When associated with prolongation of APD, their average proarrhythmia does increase and is frequently TdP. But, when associated with APD shortening, proarrhythmia increases more steeply and frequently becomes ventricular fibrillation. For hERG blockers that change the APD little or not at all, proarrhythmia increases with increasing TRIaD, while TRIaD reduction can lead to antiarrhythmic action. In the absence of TRIaD, prolongation of the APD becomes increasingly antiarrhythmic. In conclusion, (a) rejection of drugs that lengthen the APD without TRIaD may unnecessarily withhold safe and valuable therapeutic agents from needy patients; (b) acceptance of drugs that shorten the APD but possess TRIaD may result in proarrhythmic agents. These will not be stopped by QT prolongation tests, even when thorough. Thus, banning drugs solely on the QT interval is counterproductive.