title: Beat-to-beat variability of repolarization as a new biomarker for proarrhythmia in vivo.
abstract: Pharmacological safety evaluation of (pro) drugs includes cardiac safety assessment of proarrhythmic liability in healthy tissue with emphasis on the rapid component of the delayed rectifier (I(Kr)). The lack of (1) an arrhythmic end point, (2) tests in remodeled, predisposed tissue, and (3) testing chronic drug influence on channel trafficking impairs on the drawn conclusions of these assays regarding drug safety. Moreover, the currently used human ether-à-go-go-related gene assays, action potential duration, prolongation in multicellular preparations, or the QT interval have significant shortcomings in their prediction of an increased risk for drug-induced torsades de pointes arrhythmia. In this review, it will be proposed that beat-to-beat variability of repolarization quantified as short-term variability can (1) discriminate between safe and unsafe drugs even under predisposed and highly arrhythmogenic conditions despite accompanying QT prolongation and (2) identify the individual at risk for subsequent arrhythmic events.
authors.affiliation: Department of Medical Physiology, Division of Heart and Lungs, University Medical Center Utrecht, Yalelaan 50, Utrecht, The Netherlands.
authors.forename: Rosanne
authors.initials: R
authors.lastname: Varkevisser
authors.forename: Sofieke C
authors.initials: SC
authors.lastname: Wijers
authors.forename: Marcel A G
authors.initials: MA
authors.lastname: van der Heyden
authors.forename: Jet D M
authors.initials: JD
authors.lastname: Beekman
authors.forename: Mathias
authors.initials: M
authors.lastname: Meine
authors.forename: Marc A
authors.initials: MA
authors.lastname: Vos
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000032:analysis; D004195:Disease Models, Animal; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D004562:Electrocardiography; D008133:Long QT Syndrome / Q000139:chemically induced*; D011355:Prodrugs / Q000494:pharmacology*; D012307:Risk Factors; D016171:Torsades de Pointes / Q000139:chemically induced*
chemical_list: D015415:Biomarkers; D011355:Prodrugs