Role of transmural dispersion of repolarization in the genesis of drug-induced torsades de pointes.
Torsades de pointes (TdP) is a potentially lethal arrhythmia that develops as a consequence of 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 inscription of the ECG T wave. 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 the intrinsic spatial dispersion of repolarization, thus creating the substrate for the development of reentry. The result is prolongation of the QT interval, abnormal T waves, and development of polymorphic reentrant ventricular tachycardia displaying characteristics of TdP. Prolongation of the QT interval apparently is not the sole determinant of a drug's potential to cause TdP. Agents that do not increase transmural dispersion of repolarization have little or no potential to induce TdP despite any ability to prolong the QT interval. In addition, drugs such as amiodarone and sodium pentobarbital can cause large QT prolongations but, by reducing transmural dispersion of repolarization, may reduce the likelihood of TdP. Arterially perfused wedge preparations of canine left ventricle can be used to explore the role of transmural dispersion of repolarization in the genesis of TdP. The purpose of this article is to review recent advances that have improved our understanding of these mechanisms, particularly the role of transmural dispersion of repolarization, in the genesis of drug-induced TdP and to examine how these advances can guide us toward the development of safer and more effective drugs.
Antzelevitch
Charles
C
Masonic Medical Research Laboratory, 2150 Bleeker Street, Utica, NY 13501, USA. ca@mmrl.edu
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000009:adverse effects; D004562:Electrocardiography; D006329:Heart Conduction System / Q000503:physiopathology*; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced / Q000188:drug therapy; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000188:drug therapy / Q000503:physiopathology
D000889:Anti-Arrhythmia Agents