QT and JT dispersion in the drug-induced long QT syndrome in anaesthetized rabbits is accurately detected by a three-lead surface ECG measurement.
BACKGROUND
QT dispersion (QTd) can be measured from three leads of the ECG in patients with myocardial ischemia. However, whether QT and JT dispersion (QTd, JTd) can be calculated from a three-lead of the ECG in drug-induced long QT syndrome (LQTS) in animals remains elusive. Therefore, we determined to what extent a three-lead measurement of the surface ECG accurately detects dispersion of QT and JT in comparison with multi-lead assessments in anaesthetized rabbits, challenged with methoxamine and additionally infused intravenously with solvent or dofetilide.


METHODS
Using several ECG leads in anaesthetized rabbits challenged intravenously with an alpha(1)-adrenoceptor agonist methoxamine, we assessed the QT and JT interval, as well as QT and JT dispersion, at baseline and in response to solvent or dofetilide (0.02 or 0.04 mg/kg/min iv for 60 min), an I(Kr) blocker. For that purpose, we recorded and analyzed the surface ECG and assessed QT and JT dispersion by four methods: (1) 12-lead ECG; (2) six precordial leads (V1-V6); (3) three leads most likely to contribute to the dispersion (aVF, V1, and V4); (4) three quasi-orthogonal leads (aVF, I, and V2). QT and JT dispersion were significantly lower in 6- and 3-lead measurements than in 12-lead measurement, both at baseline and during infusion of solvent or dofetilide. At 5 and 10 min of infusion, dofetilide at 0.02 or 0.04 mg/kg/min iv markedly increased QT and JT dispersion by 100% to 500% in all four ECG lead combinations. This dose regimen of dofetilide markedly prolonged QT and JT intervals in lead II, and was associated with high incidences of polymorphous ventricular tachycardia (PVT: 30% at 0.02 mg/kg/min; 100% at 0.04 mg/kg/min) and of ventricular fibrillation (VF: 17% with 0.02 mg/kg/min; 58% with 0.04 mg/kg/min).


CONCLUSIONS
Our present study shows that the measurement of QT and JT dispersion in three surface ECG leads only (aVF, I, V2 or aVF, V1 V4), instead of 12 ECG leads, is an appropriate approach to assess drug-induced heterogeneity or dispersion of ventricular repolarization in anaesthetized rabbits, both at baseline and during arrhythmogenic sensitization with methoxamine and challenged with dofetilide.
Center of Excellence for Cardiovascular Research, Johnson & Johnson Pharmaceutical Research and Development, a division of Janssen Pharmaceutica N.V., Turnhoutseweg 30, B-2340 Beerse, Belgium. hlu@prdbe.jnj.com
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Van Ammel
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Vlaminckx
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De Clerck
D000316:Adrenergic alpha-Agonists / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects / Q000295:instrumentation* / Q000379:methods*; D005260:Female; D007275:Injections, Intravenous; D008133:Long QT Syndrome / Q000139:chemically induced / Q000503:physiopathology*; D008729:Methoxamine / Q000008:administration & dosage / Q000494:pharmacology; D010627:Phenethylamines / Q000008:administration & dosage / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology; D011817:Rabbits; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology; D017180:Tachycardia, Ventricular / Q000139:chemically induced / Q000503:physiopathology*
D000316:Adrenergic alpha-Agonists; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D013449:Sulfonamides; D008729:Methoxamine; C063533:dofetilide