In cardiovascular pharmacology, electrical and mechanical events can be distinguished, and the phrase 'electro-mechanical window' (EMw) describes the temporal difference between these events. We studied whether changes in EMw have potential predictive value for the occurrence of arrhythmias in fentanyl/etomidate-anaesthetized beagle (FEAB) dogs. EXPERIMENTAL APPROACHThe EMw was calculated as differences between the QT interval and QLVPend in FEAB dogs during atrial pacing, treatment with isoprenaline or atropine, body temperature changes and induction of Torsade de Pointes (TdP) in an LQT1 model. KEY RESULTSThe electrical systole (QT interval) was shorter than the duration of the mechanical event (QLVPend), providing a positive EMw. Atrial pacing, atropine or body temperature changes had no major effects on EMw, despite large changes in QT duration. However, b-adrenoceptor stimulation (with isoprenaline) decreased the EMw (from 90 to 5 ms) and in combination with HMR1556, a blocker of the slowly activating potassium current (IKs), induced a large negative EMw (-109 ms) and TdP. Prevention of TdP by atenolol or verapamil was associated with a less negative EMw (-23 to -16 ms). Mexiletine, a poorly effective long QT treatment, did not affect the EMw or prevent TdP induction. CONCLUSIONS AND IMPLICATIONSThe EMw is a marker, other than QT prolongation, of TdP risk in the FEAB model. Therefore, we suggest examining the EMw as a risk marker in cardiovascular safety studies and as a potential biomarker to improve clinical management of long QT syndrome patients, especially in patients with borderline QT prolongation. LINKED ARTICLE

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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 1C) or warmed (42.1 1C). 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 (À14.85±2.08) or heating (À13.12±3.46) protocols. We propose a correction formula to compensate for the influence of Tc changes and standardize the QTcV duration to 37.5 1C: QTcVcT (QTcV corrected for changes in core temperature) ¼ QTcV-14 (37.5 -Tc). Furthermore, cooled dogs were re-warmed (from 34.2 to 40.0 1C) and marked QTcV shortening (À29%) 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 þ ] 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.