title: Assessment of efficacy of proarrhythmia biomarkers in isolated rabbit hearts with attenuated repolarization reserve.
abstract: Isolated hearts with reduced repolarization reserve would be suitable for assessing the proarrhythmic liability of drugs. However, it is not known which proarrhythmia biomarkers indicate the increased susceptibility to torsades de pointes arrhythmia (TdP) in such experimental setting. Thus, we estimated the efficacy of proarrhythmia biomarkers in isolated hearts with attenuated repolarization reserve. Langendorff-perfused rabbit hearts were used. Repolarization reserve was reduced by concomitant inhibition of the rapid (IKr) and slow (IKs) delayed rectifier potassium currents by dofetilide and HMR-1556, respectively. Rate corrected QT (QTc) interval and beat-to-beat variability of the QT interval measured in sinus rhythm or irrespective of rhythm even during arrhythmias (sinus and absolute QT variability, respectively) were tested. QTc failed to predict increased proarrhythmic risk. Sinus QT variability indicated proarrhythmic liability when low concentration of dofetilide was used. However, when arrhythmias compromised sinus variability measurement during coperfusion of catecholamines and elevated concentration of dofetilide, only absolute QT variability indicated increased proarrhythmic risk. Absolute QT variability parameters seem to be the most practical and sensitive biomarkers of proarrhythmic liability in rabbit hearts with reduced repolarization reserve. Absolute QT variability parameters could serve as surrogates for torsades de pointes in drug-safety investigations in isolated rabbit hearts with attenuated repolarization reserve.
authors.affiliation: *Gedeon Richter Plc., Budapest, Hungary; †Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary; ‡Department of Electrical Engineering and Cybernetics, Kecskemét College, Kecskemét, Hungary; §Division of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Szeged, Hungary; and ¶Second Department of Medicine and Cardiology Centre, Faculty of Medicine, University of Szeged, Szeged, Hungary.
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Orosz
authors.forename: Annamária
authors.initials: A
authors.lastname: Sarusi
authors.forename: Norbert
authors.initials: N
authors.lastname: Csík
authors.forename: Julius Gy
authors.initials: JG
authors.lastname: Papp
authors.forename: András
authors.initials: A
authors.lastname: Varró
authors.forename: Sándor
authors.initials: S
authors.lastname: Farkas
authors.forename: Tamás
authors.initials: T
authors.lastname: Forster
authors.forename: Attila S
authors.initials: AS
authors.lastname: Farkas
authors.forename: András
authors.initials: A
authors.lastname: Farkas
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000503:physiopathology; D015415:Biomarkers / Q000378:metabolism; D002839:Chromans / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D005260:Female; D010627:Phenethylamines / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*; D011817:Rabbits; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000503:physiopathology
chemical_list: D015415:Biomarkers; D002839:Chromans; C420023:HMR 1556; D010627:Phenethylamines; D013449:Sulfonamides; C063533:dofetilide