MECHANISMS AND MODELS TO PREDICT A QT(C) EFFECT

Prolongation of the QT interval with consequent ventricular tachyarrhythmias may arise in the context of bradycardia (pause dependent) or may reflect sympathetic imbalances (adrenergic dependent). The normal repolarization process of ventricular myocardial cells is not entirely synchronous; some cells recover early and some later, resulting in a normal heterogeneity in refractoriness among ventricular cells during the inscription of the T wave. If the normal heterogeneity in ventricular repolarization is increased, as can occur following administration of some class IA and class II antiarrhythmic agents, then the QT interval will be prolonged. All-or-none action potentials can be evoked only in cells that have repolarized to a critical membrane potential of about -60 mV. Thus, the late-recovering cells (which terminate the T wave) may still be refractory and incapable of generating propagated action potentials while the early-recovering cells (which initiate the T wave) are fully excitable. In normal hearts, the period between repolarization of the earliest and the latest cells is insufficient to allow even very premature ventricular beats that occur early during the T wave (R-on-T phenomenon) to precipitate a sustained tachyarrhythmia. When the recovery process among vetricular cells becomes more inhomogeneous, however, as in the prolonged QT syndrome, the accompanying increased heterogeneity in ventricular repolarization and refractoriness can lead to the development of malignant ventricular arrhythmias, including torsades de pointes. Any drug that increases the dispersion of the repolarization process may prolong the QT interval and raise the potential for arrhythmias. QT prolongation and ventricular arrhythmias may also stem from the presence of early afterdepolarizations (EADs). The occurrence of EADs at the plateau level as well as near repolarization membrane levels leads to inhomogeneities in recovery and refractoriness. Accordingly, the accompanying increase in QT interval and dispersion of refractoriness can lead to the development of malignant arrhythmias. A rise in adrenergic tone and sympathetic tone imbalance has also been implicated in congenital and other prolonged QT syndromes. The contribution of sympathetic imbalance to QT prolongation and arrhythmias has been demonstrated in a number of animal models. In humans, sympathetic imbalance plays a particularly important role in the congenital prolonged QT syndromes.