Relationship between prolongation of QTc and prolongation of the peak of T (Tp) to the end of T (Te)

• Published in: Journal of pharmacological and toxicological methods 2005-07, Vol.52 (1), p.178-181
• Main Authors: Roche, Brian M., Kijtawornrat, Anusak, Hamlin, Robert L., Hamlin, David M.
• Format: Article
• Language: English
• Subjects: Animals; Cardiovascular Agents - adverse effects; Cardiovascular Agents - classification; Drug Evaluation, Preclinical - methods; Electrophysiologic Techniques, Cardiac; Fridericia; Guinea Pigs; Heart; Heart - drug effects; Heart - physiopathology; Heterogeneity; Long QT Syndrome - chemically induced; Long QT Syndrome - physiopathology; M fibers; Male; Methods; Organ Culture Techniques; Perfusion; Predictive Value of Tests; QTc; Repolarization; Torsade de pointes; Torsades de Pointes - chemically induced; Torsades de Pointes - physiopathology; Tp–Te; Xenobiotics - adverse effects; Xenobiotics - classification
• ISSN: 1056-8719; 1873-488X
• DOI: 10.1016/j.vascn.2005.03.004

Lengthening of ventricular repolarization is known to be a risk factor for development of torsade de pointes, a form of ventricular tachycardia thought to be initiated by an early after depolarization and to be sustained by a novel reentrant mechanism precipitated, putatively, by heterogeneity of repolarization among ventricular myocytes. While prolongation of QT and QTc are good predictors of torsdogenic potential, the duration from the peak to the end of the T wave (Tp–Te) is thought to be a more accurate reflection of heterogeneity of ventricular repolarization. This study, conducted on Langendorff guinea pig hearts, was designed to compare lengthening of QTc with lengthening of Tp–Te for 16 test articles known to be and 7 known not to be torsadogenic. Bipolar, transventricular electrograms, recorded from 83 guinea pig hearts perfused according to methods of Langendorff, were exposed to escalating concentrations of test articles. RR, QT, QTc and Tp–Te were measured. QTc was calculated by the method of Fridericia. Data was analyzed using a mixed model ANOVA where least squared means ( t-test) was used for comparing males vs. females and for concentration levels for each parameter studied. QTc lengthened in 16 of 16 test articles known to be torsadogenic and did not lengthen in 7 of 7 test articles known not to be torsadogenic—sensitivity and specificity of 1.0. In 9 out of 16 torsadogenic test compounds, the Tp–Te interval increased parallel with QTc. In 7 test compounds known not to be torsadogenic, two test compounds increased Tp–Te. It is clear that QTc prolongation is a more robust predictor of torsadogenicity than Tp–Te in the male guinea pig heart.