A new preclinical biomarker for risk of Torsades de Pointes: drug-induced reduction of the cardiac electromechanical window.
Evaluation of new therapeutic agents for their potential to cause QT interval prolongation and drug-induced ventricular arrhythmia, like Torsades de Pointes (TdP), is a critical activity during drug development. The QT interval has been used as a surrogate biomarker to assess ventricular repolarization effects caused by drug-induced blockade of cardiac repolarizing currents, mainly IKr, but is imperfect in predicting proarrhythmia. Evidence suggests that left ventricular mechanical dysfunction may also contribute to ventricular arrhythmias; thus, electrical and mechanical alterations may have a role in drug-induced TdP. The electromechanical window (EMw) represents the time difference between the end of electrical systole (i.e. the QT interval) and the completion of ventricular relaxation (i.e. the QLVPend interval), and appears to be a new potential biomarker for TdP risk. A reduction in the EMw (to negative values) has now been shown to be associated with the onset of TdP in an anaesthetized dog model of long QT1 syndrome. Therefore, the EMw represents a novel indicator of TdP risk that may add predictive value beyond assay of drug-induced QT interval prolongation.
Vargas
Hugo M
HM
Department of Investigative Toxicology, Amgen Inc., Thousand Oaks, CA 91320, USA. hvargas@amgen.com
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000503:physiopathology; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D064420:Drug-Related Side Effects and Adverse Reactions; D004562:Electrocardiography / Q000187:drug effects; D006321:Heart / Q000503:physiopathology; D006352:Heart Ventricles / Q000503:physiopathology; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology; D012306:Risk; D018570:Risk Assessment; D013599:Systole / Q000187:drug effects; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000503:physiopathology; D016277:Ventricular Function, Left / Q000502:physiology