Arrhythmogenic mechanisms of QT prolonging drugs: Is QT prolongation really the problem?

Torsade de Pointes (TdP) is an atypical ventricular arrhythmias associated with the acquired and congenital forms of the long QT syndrome. The substrate for the arrhythmia develops as a consequence of the amplification of electrical heterogeneities intrinsic to the ventricular myocardium. These heterogeneities exist because of differences in the time course of repolarization of the three predominant cell types that make up the ventricular myocardium, giving rise to transmural voltage gradients and a dispersion of repolarization responsible for the inscription of the electrocardiographic T wave. A wide variety of drugs are capable of reducing net repolarizing current and thus amplifying the intrinsic spatial dispersion of repolarization, so as to create the substrate for the development of re-entry. The result is a prolongation of the QT interval, abnormal T waves, and development of polymorphic re-entrant ventricular tachycardia displaying characteristics of TO. Recent studies demonstrate that prolongation of the QT interval is not the sole determinant of the potential of a drug to cause TdP; agents that do not increase transmural dispersion of repolarization have little or no potential to induce the arrhythmia despite their ability to prolong the QT interval. Moreover, drugs such as sodium pentobarbital, which reduce transmural dispersion of repolarization, can diminish the likelihood of TdP, despite their ability to prolong the QT interval.