OBJECTIVE: Congenital loss of function and drug-induced inhibition of the slowly-activating delayed-rectifier K(+) current (I(Ks)) cause impaired cardiac repolarization. beta-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 I(Ks) 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 I(Ks) blocker HMR1556 (0.025-0.050 mg/kg/min) mimicked LQT1, and bolus injections of isoproterenol (1.25-5 microg/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 (MAPD(90))] and spatial dispersion of repolarization (T(peak)-T(end) interval, endo-minus epicardial MAPD(90), LV-RVMAPD(90)) 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: beta-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 Ca(2+) handling contributes to the arrhythmogenic mechanism.
OBJECTIVE: Congenital loss of function and drug-induced inhibition of the slowly-activating delayed-rectifier K(+) current (I(Ks)) cause impaired cardiac repolarization. beta-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 I(Ks) 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 I(Ks) blocker HMR1556 (0.025-0.050 mg/kg/min) mimicked LQT1, and bolus injections of isoproterenol (1.25-5 microg/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 (MAPD(90))] and spatial dispersion of repolarization (T(peak)-T(end) interval, endo-minus epicardial MAPD(90), LV-RVMAPD(90)) 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: beta-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 Ca(2+) handling contributes to the arrhythmogenic mechanism.
Authors: Courtney M Campbell; Jonathan D Campbell; Christopher H Thompson; Eleonora Savio Galimberti; Dawood Darbar; Carlos G Vanoye; Alfred L George Journal: Circ Arrhythm Electrophysiol Date: 2013-09-04
Authors: Natalia DeMaria; Ahmed Selmi; Samuel Kashtan; Xiaojuan Xia; Matthew Wang; Wojciech Zareba; Jean-Philippe Couderc; David S Auerbach Journal: Auton Neurosci Date: 2020-09-06 Impact factor: 3.145
Authors: David K Jones; Fang Liu; Ravi Vaidyanathan; L Lee Eckhardt; Matthew C Trudeau; Gail A Robertson Journal: Proc Natl Acad Sci U S A Date: 2014-12-01 Impact factor: 11.205