Statistical analysis of QT interval as a function of changes in RR interval in the conscious dog.
BACKGROUND
The duration of cardiac ventricular depolarization and repolarization is represented as the QT interval. QT prolongation has been associated with the occurrence of arrhythmias. Both cardiovascular as well as noncardiovascular agents have caused QT prolongation and sudden death in humans. Changes in heart rate (HR) play a major, though not exclusive, role in QT variation. Considerable debate has centered on how to normalize QT for variations in HR (QTc).


METHODS
The most common approaches use Bazett's (QTc = QT/(square root)RR) or Fridericia's (QTc = QT/(cube root)) formulas to fit the data and establish a single coefficient to analyze QT with respect to its relationship to RR, where RR= 60/HR. These single-coefficient models do not adequately describe the QT functional relationship with RR for the dog. Therefore, any calculation of QTc for the dog is misleading and can result in a false-positive indication or mask the potential hazards of a high QT. Other investigators have proposed multicoefficient exponential regression analyses to best fit the QT-RR relationship.


CONCLUSIONS
Data presented here from dogs under resting conditions and during pharmacological maneuvers (E-4031 or cisapride intravenous infusion) support the use of such a model. In order to fully characterize drug-induced changes in the QT-RR relationship, our approach includes a statistical comparison of the regression curves for an overall effect, and quantitates the incidence and magnitude of points exceeding the upper 95% confidence interval ('outliers') to assess the degree of heterogeneity of ventricular repolarization.
Raunig
D
D
Department of General Pharmacology, Pfizer Inc. Global Research and Development, Groton, CT 06340, USA.
Depasquale
M J
MJ
Huang
C H
CH
Winslow
R
R
Fossa
A A
AA
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000494:pharmacology; D020117:Cisapride / Q000008:administration & dosage / Q000494:pharmacology; D003243:Consciousness / Q000502:physiology; D003627:Data Interpretation, Statistical; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000662:veterinary*; D006329:Heart Conduction System / Q000187:drug effects / Q000502:physiology*; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology*; D007262:Infusions, Intravenous / Q000662:veterinary; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology
D000889:Anti-Arrhythmia Agents; D010880:Piperidines; D011725:Pyridines; D017366:Serotonin Receptor Agonists; C063968:E 4031; D020117:Cisapride