Ionic, molecular, and cellular bases of QT-interval prolongation and torsade de pointes.
Torsade de pointes (TdP) is a life-threatening arrhythmia that develops as a consequence of a reduction in the repolarization reserve of cardiac cells leading to amplification of electrical heterogeneities in the ventricular myocardium as well as to the development of early after depolarization-induced triggered activity. Electrical heterogeneities within the ventricles are due to 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 that contributes to the inscription of the electrocardiographic T wave. A number of non-antiarrhythmic drugs and antiarrhythmic agents with class III actions and/or the various mutations and cardiomyopathies associated with the long QT syndrome reduce net repolarizing current and amplify spatial dispersion of repolarization, thus creating the substrate for re-entry. This results in a prolongation of the QT interval, abnormal T waves, and development of TdP. Agents that prolong the QT interval but do not cause an increase in transmural dispersion of repolarization (TDR) do not induce TdP, suggesting that QT prolongation is not the sole or optimal determinant for arrhythmogenesis. This article reviews recent advances in our understanding of these mechanisms, particularly the role of TDR in the genesis of drug-induced TdP, and examines how these may guide us towards development of safer drugs.
Antzelevitch
Charles
C
Masonic Medical Research Laboratory, 2150 Bleecker Street, Utica, NY 13501, USA. ca@mmrl.edu
D000200:Action Potentials / Q000502:physiology; D006329:Heart Conduction System / Q000503:physiopathology; D006801:Humans; D007473:Ion Channels / Q000502:physiology; D008133:Long QT Syndrome / Q000209:etiology* / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000502:physiology; D016171:Torsades de Pointes / Q000209:etiology* / Q000503:physiopathology
D007473:Ion Channels