Correction of QT values to allow for increases in heart rate in conscious Beagle dogs in toxicology assessment.
BACKGROUND
Estimation of a direct effect of drugs on the duration of the electrocardiogram (ECG) QT interval can be confused by drug-induced increases in heart rate (HR). The objective of this assessment was to identify a correction formula that adequately corrects QT over a wide range of HRs.


METHODS
Paired recordings of HR and QT interval measurements were obtained from 177 conscious Beagle dogs from both sexes in 9 toxicology studies. ECGs used for this evaluation were collected in either control vehicle-treated dogs, or from dogs prior to the first dose of a daily dosing regimen. Where more than one recording was available per dog, only one was used in the analyses. The assessments were made based on the lowest and highest pre-dose HR for each dog. Correction factors according to [Bazett, H.C. (1920). An analysis of the time relationships or time-relations of electrocardiograms. Heart 7:353-380], [Sagie, A., Larson, M.G., Goldberg, R.J., Bengtson, J.R., & Levy, D. (1992). An improved method for adjusting the QT interval for heart rate (the Framingham heart study). American Journal of Cardiology 70:797-801], [Fridericia, L.S. (1920). Die sytolendauer in elektrokardiogramm bei normalen menschen und bei herzkranken. Acta Medica Scandinavica 53:469-505.], [Todt, H., Krumpl, G., Krejcy, K. & Raberger, G. (1992). Mode of QT correction for heart rate: implications for the detection of inhomogeneous repolarization after myocardial infarction. American Heart Journal 124(3):602-609.] and [Van de Water, A., Verheyen, J., Xhonneux, R., & Reneman, R.S. (1989). An improved method to correct the QT interval of the electrocardiogram for changes in heart rate. Journal of Pharmacological Methods 22:207-217.] were applied to these QT intervals and plotted against HR. Linear regression statistical analyses using a single or multiple (i.e., baseline, sex and study) parameters model was then applied to trend lines.


RESULTS
Although two correction factors ([Todt, H., Krumpl, G., Krejcy, K. & Raberger, G. (1992). Mode of QT correction for heart rate: implications for the detection of inhomogeneous repolarization after myocardial infarction. American Heart Journal 124(3):602-609.] and [Van de Water, A., Verheyen, J., Xhonneux, R., & Reneman, R.S. (1989). An improved method to correct the QT interval of the electrocardiogram for changes in heart rate. Journal of Pharmacological Methods 22:207-217.]) adequately corrected QT for changes in HR [i.e., slope of QTc versus HR not statistically significantly different from zero (p>0.05)] that of Van de Water showed a statistically superior correction. Although the method of analyses accounted for baseline, sex and study it was independently demonstrated that sex did not influence the outcome of the evaluations. Furthermore, higher HRs (i.e., maximum HRs for each dog) were better corrected than the lower HRs. In addition, statistical power analysis applied to these data showed that group sizes of 4-8 could, with 80% chance, detect a 10-5% change, respectively, in appropriately corrected QT.


CONCLUSIONS
Overall, the data suggest that an evaluation of the most appropriate correction factor should be applied to each laboratory using their own data collected by their own method in their particular strain of dog.
Tattersall
Marshall Leslie
ML
Experimental Medicine, AstraZeneca R&D, Charnwood, Loughborough, Leicestershrie LE11 5RH, UK.
Dymond
Michael
M
Hammond
Tim
T
Valentin
Jean-Pierre
JP
D000818:Animals; D001283:Atrioventricular Node / Q000601:surgery; D002036:Bundle of His / Q000601:surgery; D002304:Cardiac Pacing, Artificial; D017115:Catheter Ablation; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions / Q000503:physiopathology*; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006339:Heart Rate / Q000187:drug effects*; D008133:Long QT Syndrome / Q000503:physiopathology*; D008297:Male; D023421:Models, Animal; D012044:Regression Analysis; D015203:Reproducibility of Results; D018675:Toxicity Tests / Q000379:methods