A new method to calculate the beat-to-beat instability of QT duration in drug-induced long QT in anesthetized dogs.
BACKGROUND
Instability of QT duration is a marker to predict Torsade de Pointes (TdP) associated with both congenital and drug-induced long QT syndrome. We describe a new method for the quantification of instability of repolarization.


METHODS
Female, adult beagle dogs anesthetized with a potent morphinomimetic were treated with either solvent (n=7) or dofetilide (n=7). Poincaré plots with QT(n) versus QT(n+1) were constructed to visualize the beat-to-beat variation in QT intervals from the lead II ECG. Short-term instability (STI), long-term instability (LTI) and total instability (TI) were quantified by calculating the distances of 30 consecutive data-points from the x and y-coordinate to the "centre of gravity" of the data cluster. Dofetilide at 0.0025 to 0.04 mg/kg i.v. (plasma concentrations of 4+/-0.6 to 41+/-2.7 ng/ml), dose-dependently prolonged QT and QTcV (at 0.04 mg/kg i.v.: QT: 280+/-ms versus 236+/-5 ms with solvent; p<0.05 and QTcV: 290+/-9 ms versus 252+/-4 ms with solvent; p<0.05). Concomitantly, the compound induced an increase in the instability parameters in a similar dose-dependent manner (at 0.04 mg/kg i.v.: TI: 6.8+/-0.9 ms versus 1.7+/-0.3 ms; p<0.05, LTI: 3.6+/-0.5 ms versus 1.0+/-0.2 ms; p<0.05 and STI: 4.2+/-0.6 ms versus 1.0+/-0.2 ms; p<0.05). The increases induced by dofetilide were associated with a high incidence of early afterdepolarizations (EADs) in the endocardial monophasic action potential (in 6 out of the 7 compound-treated animals versus 0 out of the 7 solvent animals; p<0.05).


CONCLUSIONS
Quantification of beat-to-beat QT instability by our method clearly detects changes in short-term, long-term and total instability induced by dofetilide, already at pre-arrhythmic doses. Dofetilide administration to anesthetized dogs prolongs ventricular repolarization, concomitantly increases beat-to-beat QT instability and induces early after depolarizations (EADs). As such, the use of these parameters in this in vivo model shows clear potential for risk identification in cardiovascular safety assessment.
van der Linde
H
H
Center of Excellence for Cardiovascular Safety Research, Johnson and Johnson Pharmaceutical Research and Development, B-2340 Beerse, Belgium.
Van de Water
A
A
Loots
W
W
Van Deuren
B
B
Lu
H R
HR
Van Ammel
K
K
Peeters
M
M
Gallacher
D J
DJ
D000758:Anesthesia; D000818:Animals; D002317:Cardiovascular Agents / Q000009:adverse effects / Q000145:classification; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005260:Female; D007275:Injections, Intravenous; D008133:Long QT Syndrome / Q000139:chemically induced / Q000503:physiopathology*; D008955:Models, Cardiovascular; D009200:Myocardial Contraction; D010627:Phenethylamines / Q000009:adverse effects; D026902:Potassium Channel Blockers / Q000009:adverse effects; D013449:Sulfonamides / Q000009:adverse effects; D016171:Torsades de Pointes / Q000139:chemically induced / Q000503:physiopathology*
D002317:Cardiovascular Agents; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D013449:Sulfonamides; C063533:dofetilide