Abstract
Background and purpose:Body core temperature (Tc) changes affect the QT interval, but correction for this has not been systematically investigated. It may be important to correct QT intervals for drug-induced changes in Tc.Experimental approach:Anaesthetized beagle dogs were artificially cooled (34.2 °C) or warmed (42.1 °C). The relationship between corrected QT intervals (QTcV; QT interval corrected according to the Van de Water formula) and Tc was analysed. This relationship was also examined in conscious dogs where Tc was increased by exercise.Key results:When QTcV intervals were plotted against changes in Tc, linear correlations were observed in all individual dogs. The slopes did not significantly differ between cooling (−14.85±2.08) or heating (−13.12±3.46) protocols. We propose a correction formula to compensate for the influence of Tc changes and standardize the QTcV duration to 37.5 °C: QTcVcT (QTcV corrected for changes in core temperature)=QTcV–14 (37.5 – Tc). Furthermore, cooled dogs were re-warmed (from 34.2 to 40.0 °C) and marked QTcV shortening (−29%) was induced. After Tc correction, using the above formula, this decrease was abolished. In these re-warmed dogs, we observed significant increases in T-wave amplitude and in serum [K+] levels. No arrhythmias or increase in pro-arrhythmic biomarkers were observed. In exercising dogs, the above formula completely compensated QTcV for the temperature increase.Conclusions and implications:This study shows the importance of correcting QTcV intervals for changes in Tc, to avoid misleading interpretations of apparent QTcV interval changes. We recommend that all ICH S7A, conscious animal safety studies should routinely measure core body temperature and correct QTcV appropriately, if body temperature and heart rate changes are observed.
Highlights
The QT interval of the ECG is an indirect measurement of the time taken for the ventricles to depolarize and repolarize
The underlying mechanisms of QT interval changes associated with hypo- and hyperthermia are not fully understood, it is known that serum potassium concentrations can increase during hyperthermia in different species (Spurr and Barlow, 1959; Sprung et al, 1991), and during malignant hyperthermia in humans (Wappler et al, 2000)
The aim of the present study was to explore the changes of QT interval (QTcV interval; QT interval corrected according to the Van de Water formula), under controlled hypothermic and hyperthermic conditions in anaesthetized dogs, and to propose a mathematical formula to correct the QTcV interval for changes in body temperature
Summary
The QT interval of the ECG is an indirect measurement of the time taken for the ventricles to depolarize and repolarize. The underlying mechanisms of QT interval changes associated with hypo- and hyperthermia are not fully understood, it is known that serum potassium concentrations can increase during hyperthermia in different species (Spurr and Barlow, 1959; Sprung et al, 1991), and during malignant hyperthermia in humans (Wappler et al, 2000) What role these electrolyte alterations have on cardiac repolarization during temperature change is unknown, as action potential durations are increased in in vitro studies—using tissue from guinea-pigs (Lathrop et al, 1998), rabbits (unpublished data) and pigs (Roscher et al, 2001), where electrolyte levels are controlled through perfusion of physiological salt solutions. British Journal of Pharmacology (2008) 154, 1474–1481; doi:10.1038/bjp.2008.265; published online 23 June 2008
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