The effect of changes in core body temperature on the QT interval in beagle dogs: a previously ignored phenomenon, with a method for correction.
OBJECTIVE
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.


METHODS
Anaesthetized beagle dogs were artificially cooled (34.2 degrees C) or warmed (42.1 degrees 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.


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 degrees 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 degrees 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
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.
van der Linde
H J
HJ
Division of Janssen Pharmaceutica NV, Center of Excellence for Cardiovascular Safety Research, Johnson & Johnson Pharmaceutical Research and Development, Beerse, Belgium. hvdlinde@prdbe.jnj.com
Van Deuren
B
B
Teisman
A
A
Towart
R
R
Gallacher
D J
DJ
D000818:Animals; D001831:Body Temperature / Q000502:physiology*; D004285:Dogs; D004562:Electrocardiography; D005260:Female; D005334:Fever / Q000378:metabolism; D006339:Heart Rate / Q000502:physiology; D006801:Humans; D007035:Hypothermia / Q000378:metabolism; D008297:Male; D010805:Physical Conditioning, Animal / Q000502:physiology*; D011188:Potassium / Q000097:blood*
D011188:Potassium