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


METHODS
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.


RESULTS
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.


CONCLUSIONS
It is clear that QTc prolongation is a more robust predictor of torsadogenicity than Tp-Te in the male guinea pig heart.
Roche
Brian M
BM
QTest Laboratories, Inc., 6456 Fiesta Drive, Columbus, Ohio 43235, USA. broche@qtestlabs.com
Kijtawornrat
Anusak
A
Hamlin
Robert L
RL
Hamlin
David M
DM
D000818:Animals; D002317:Cardiovascular Agents / Q000009:adverse effects* / Q000145:classification; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D022062:Electrophysiologic Techniques, Cardiac; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology; D008297:Male; D009924:Organ Culture Techniques; D010477:Perfusion; D011237:Predictive Value of Tests; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000503:physiopathology; D015262:Xenobiotics / Q000009:adverse effects* / Q000145:classification
D002317:Cardiovascular Agents; D015262:Xenobiotics