Use and abuse of QT and TRIaD in cardiac safety research: importance of study design and conduct.
Triangulation, reverse use dependence, instability and dispersion of ventricular repolarization (TRIaD), together with the cardiac wavelength (lambda), are powerful proarrhythmic predictors. QT interval prolongation as such is not, as it provides false positives as well as false negatives. This has been established in various preclinical experiments on isolated tissues, perfused hearts and experimental animals, as well as in the clinic. Numerous risk factors including female gender, low serum potassium and magnesium, bradycardia and genetic predisposition, further promote arrhythmogenesis. Reliable quantitative preclinical cardiac safety studies using any experimental approach always require (1) rigorous adherence to Good Laboratory Practices (GLP), (2) collection of data only after complete drug equilibration has been established, (3) adequate resolution, (4) analysis based upon suitably powered statistical tests, (5) a sufficient number of experiments and (6) validated experimental protocols. Genesis of data not in accord with such standards and reported in an incorrect fashion confounds the significance of preclinical results for eventual clinical studies and elicits confusion regarding important drug effects. In this context, establishing a preclinical research consortium is suggested. This to assure: (1) the use of standardized experimental protocols and animal models; (2) data analysis with appropriately powered statistical tests; (3) correct testing and reporting and (4) elimination of some of the errors and abuses outlined in this paper.
Hondeghem
Luc M
LM
Catholic University Leuven, Westlaan 85, B-8400 OOSTENDE, Belgium. Luc.Hondeghem@ScreenQT.com
D000200:Action Potentials; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000503:physiopathology; D003627:Data Interpretation, Statistical; D004353:Drug Evaluation, Preclinical / Q000379:methods* / Q000592:standards; D019983:Guideline Adherence; D017408:Guidelines as Topic; D006329:Heart Conduction System / Q000187:drug effects* / Q000503:physiopathology; D006801:Humans; D007700:Kinetics; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology; D023421:Models, Animal; D012015:Reference Standards; D015203:Reproducibility of Results; D012107:Research Design / Q000592:standards; D018570:Risk Assessment; D012307:Risk Factors; D018675:Toxicity Tests / Q000592:standards