Skip Navigation LinksHome > August 2012 - Volume 60 - Issue 2 > Transmural Dispersion of Repolarization as a Preclinical Mar...
Journal of Cardiovascular Pharmacology:
doi: 10.1097/FJC.0b013e3182597f67
Original Article

Transmural Dispersion of Repolarization as a Preclinical Marker of Drug-induced Proarrhythmia

Said, Tamer H. MD*; Wilson, Lance D. MD*; Jeyaraj, Darwin MD*; Fossa, Anthony A. PhD; Rosenbaum, David S. MD*

Collapse Box

Abstract

Abstract: Torsade de Pointes (TdP) proarrhythmia is a major complication of therapeutic drugs that block the delayed rectifier current. QT interval prolongation, the principal marker used to screen drugs for proarrhythmia, is both insensitive and nonspecific. Consequently, better screening methods are needed. Drug-induced transmural dispersion of repolarization (TDR) is mechanistically linked to TdP. Therefore, we hypothesized that drug-induced enhancement of TDR is more predictive of proarrhythmia than QT interval. High-resolution transmural optical action potential mapping was performed in canine wedge preparations (n = 19) at baseline and after perfusion with 4 different QT prolonging drugs at clinically relevant concentrations. Two proarrhythmic drugs in patients (bepridil and E4031) were compared with 2 nonproarrhythmic drugs (risperidone and verapamil). Both groups prolonged the QT (all P < 0.02), least with the proarrhythmic drug bepridil, reaffirming that QT is a poor predictor of TdP. In contrast, TDR was enhanced only by proarrhythmic drugs (P < 0.03). Increased TDR was due to a preferential prolongation of midmyocardial cell, relative to epicardial cell, APD, whereas nonproarrhythmic drugs similarly prolonged both cell types. In contrast to QT prolongation, augmentation of TDR was induced by proarrhythmic but not nonproarrhythmic drugs, suggesting TDR is a superior preclinical marker of proarrhythmic risk during drug development.

© 2012 Lippincott Williams & Wilkins, Inc.

Follow Us!

Login

Search for Similar Articles
You may search for similar articles that contain these same keywords or you may modify the keyword list to augment your search.