Mechanisms and models to predict a QTc 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 III 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 ventricular 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Moore
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EN
University of Pennsylvania, Philadelphia 19104.
D000200:Action Potentials / Q000502:physiology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology*; D004195:Disease Models, Animal; D004562:Electrocardiography; D006801:Humans; D008133:Long QT Syndrome / Q000503:physiopathology