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


METHODS
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.


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 (-109ms) and TdP. Prevention of TdP by atenolol or verapamil was associated with a less negative EMw (-23 to -16ms). Mexiletine, a poorly effective long QT treatment, did not affect the EMw or prevent TdP induction.


CONCLUSIONS
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.
Center of Excellence for Cardiovascular Safety Research and Mechanistic Pharmacology, Johnson & Johnson Pharmaceutical Research and Development, Division of Janssen Pharmaceutica NV, Beerse, Belgium. hvdlinde@its.jnj.com
H J
HJ
van der Linde
B
B
Van Deuren
Y
Y
Somers
B
B
Loenders
R
R
Towart
D J
DJ
Gallacher
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000503:physiopathology; D001285:Atropine / Q000494:pharmacology; D001831:Body Temperature; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D064420:Drug-Related Side Effects and Adverse Reactions; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006321:Heart / Q000503:physiopathology; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology; D008297:Male; D013599:Systole / Q000187:drug effects; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000503:physiopathology; D016277:Ventricular Function, Left / Q000502:physiology*
D000318:Adrenergic beta-Agonists; D000889:Anti-Arrhythmia Agents; D001285:Atropine; D007545:Isoproterenol