THE QT INTERVAL IN THE DOG ECG: IMPORTANCE IN PRECLINICAL TOXICOLOGY AND RELATIONSHIP TO HEART RATE

Abstract

The significance for toxicology of QT-interval changes, their relationship to heart rate (HR), and the formulas used to correct the QT interval for HR are discussed. A number of drugs belonging to different therapeutic classes produce increases in QT-interval duration, and this change has been associated with ventricular arrhythmias in humans and, on some occasions, in animals. Investigation of changes in QT intervals in toxicity studies in dogs is therefore of potential value. Changes in the QT interval are inversely correlated with changes in HR; that is, they are positively correlated with changes in the interval RR. This relationship results from complex interactions among physiological mechanisms regulating cardiovascular function. Because of this relationship, direct effects of compounds on the QT interval should be distinguished from indirect effects on HR. The direct effect can be assessed on the basis of QT values corrected for HR (QTc). Various equations have been proposed to describe the relationship between HR (or RR) and QT intervals, and correction formulas have been derived. The most frequently used is the formula of Bazett (a square root relationship), which was established in humans and applied to dogs in a number of experiments. However,in dogs this formula results in an inversion of the relationship between QT and RR and is therefore not acceptable for use in this species. Other authors have proposed correction formulas based on a linear relationship, and they have found that it better fits their experimental data for dogs. Some authors proposed correction formulas based on a logarithmic relationship between QT and HR or RR. These formulas have been applied to our historical data, and we have found that they do not perfectly correct QT values (QTc still correlated to RR), although they are better than Bazett's formula. Using our historical data, we have established and compared correction formulas and found that the one based on a linear relationship between the QT interval and the HR best fits our experimental data. However, there is no universal formula for QTc calculation in dogs, and each laboratory should have its own formula, based on the analysis of data obtained from the strain used in its own experimental conditions.