The Electro-Mechanical window: A risk marker for Torsade de Pointes in a canine model of drug induced arrhythmias

Abstract

BACKGROUND AND PURPOSE 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 APPROACH The EMw was calculated as differences between the QT interval and QLVP end 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 RESULTS The electrical systole (QT interval) was shorter than the duration of the mechanical event (QLVP end), providing a positive EMw. Atrial pacing, atropine or body temperature changes had no major effects on EMw, despite large changes in QT duration. However, β-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 (I Ks), 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 IMPLICATIONS The 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 This article is commented on by Vargas, pp. 1441-1443 of this issue. To view this commentary visit © 2010 Johnson & Johnson Pharmaceutical Research and Development. British Journal of Pharmacology © 2010 The British Pharmacological Society.