Copyright © 2007, European Society of Cardiology
In vivo mechanisms precipitating torsades de pointes in a canine model of drug-induced long-QT1 syndrome
aCenter of Excellence for Cardiovascular Safety Research, Johnson & Johnson Pharmaceutical Research & Development, Beerse, Belgium
bDepartment of Cardiology, Cardiovascular Research Institute Maastricht, Academic Hospital Maastricht, The Netherlands
*Corresponding authors. Dr. Gallacher is to be contacted at Center of Excellence for Cardiovascular Research, Johnson & Johnson Pharmaceutical Research & Development, a Division of Janssen Pharmaceutica N.V., Turnhoutseweg 30, B-2340, Beerse, Belgium. Tel.: +32 14 602846; fax: +32 14 605839. Dr. Volders is to be contacted at Department of Cardiology, Cardiovascular Research Institute Maastricht, Academic Hospital Maastricht, Peter Debyelaan 25, 6229 HX, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands. Tel.: +31 43 3877350; fax: +31 43 3875104. dgallach{at}prdbe.jnj.com p.volders{at}cardio.unimaas.nl
Objective Congenital loss of function and drug-induced inhibition of the slowly-activating delayed-rectifier K+ current (IKs) cause impaired cardiac repolarization. β-Adrenergic-receptor stimulation contributes to sympathetically-induced torsades de pointes (TdP). An in vivo model of long-QT1 (LQT1) syndrome and TdP in a species with IKs characteristics relevant to man is lacking. We investigated the in vivo mechanisms of TdP in a novel canine model of drug-induced LQT1 syndrome.
Methods Adult beagle dogs (n=30; F/M) were anesthetized with lofentanil (0.075 mg/kg i.v.) and etomidate (1.5 mg/kg/hour). ECGs, left- (LV) and right-ventricular (RV) monophasic action potentials (MAPs), and intracavitary pressures were recorded simultaneously. Infusion of the IKs blocker HMR1556 (0.025–0.050 mg/kg/min) mimicked LQT1, and bolus injections of isoproterenol (1.25–5 µg/kg) reproducibly triggered TdP in 94% of dogs (defibrillated if necessary).
Results Isoproterenol evoked paradoxical repolarization prolongation during heart rate accelerations. Beat-to-beat variability [QT, LV MAP duration (MAPD90)] and spatial dispersion of repolarization (Tpeak–Tend interval, endo-minus epicardial MAPD90, LV-RVMAPD90) were significantly increased. Early afterdepolarizations occurred predominantly in the endocardium and not the epicardium. During isoproterenol, secondary systolic contractions (aftercontractions; peak 25±6 mm Hg) arose in the LV (not RV) when TdP ensued. Prevention of TdP by esmolol (1.25 mg/kg), verapamil (0.4 mg/kg) or mexiletine (5 mg/kg) was only successful when repolarization prolongation was contained and aftercontractions remained absent.
Conclusions β-Adrenergic challenges trigger TdP in a reproducible manner in this model of drug-induced LQT1. Paradoxical prolongation and increased temporal and spatial dispersion of repolarization precipitate TdP. Incremental LV systolic aftercontractions precede TdP, suggesting abnormal cellular Ca2+ handling contributes to the arrhythmogenic mechanism.
KEYWORDS Adrenergic (ant)agonists; Calcium (cellular); Ion channels; Long-QT syndrome; Repolarization
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