Drug-induced QT prolongation and proarrhythmia: an inevitable link?

One of the most feared potential adverse effects of many drugs is life threatening or fatal arrhythmia--particularly torsade de pointes (TdP) ventricular tachycardia in conjunction with QT prolongation. To fully understand the implications of QT prolongation, it is essential to have an understanding of the ion currents that comprise repolarization and their relation to electrophysiological abnormalities associated with TdP. Also, the QT interval is subject to patient-specific and sometimes idiosyncratic variability. The following questions are addressed: How close is the relationship between QT prolongation and proarrhythmia? How accurately do QT-interval measurements reflect cardiac repolarization? How representative is a single QT measurement with respect to the QT response to a drug? The presumed relationship between the QT interval and myocardial repolarization will be deconstructed, demonstrating that most of the important aspects of repolarization, and subsequent arrhythmogenesis, cannot be understood only through the simple numerical measurement of the QT interval. Repolarization reserve is also discussed. Suggestions for refining the understanding of drug-induced QT prolongation, TdP, and shortcomings of some current definitions are outlined. We speculate on possible future developments in understanding this relationship.