title: A new biomarker--index of cardiac electrophysiological balance (iCEB)--plays an important role in drug-induced cardiac arrhythmias: beyond QT-prolongation and Torsades de Pointes (TdPs).
abstract: BACKGROUND
  In the present study, we investigated whether a new biomarker - index of cardiac electrophysiological balance (iCEB=QT/QRS) - could predict drug-induced cardiac arrhythmias (CAs), including ventricular tachycardia/ventricular fibrillation (VT/VF) and Torsades de Pointes (TdPs).
  
  
  METHODS
  The rabbit left ventricular arterially-perfused-wedge was used to investigate whether the simple iCEB measured from the ECG is reflective of the more difficult measurement of λ (effective refractory period×conduction velocity) for predicting CAs induced by a number of drugs.
  
  
  RESULTS
  Dofetilide concentration-dependently increased iCEB and λ, predicting potential risk of drug-induced incidence of early afterdepolarizations (EADs) starting at 0.01μM. Digoxin (1 and 5μM), encainide (5 and 20μM) and propoxyphene (10 and 100μM) markedly reduced both iCEB and λ, predicting their ability to induce non-TdP-like VT/VF. At 10μM, both NS1643 and levcromakalim significantly decreased λ and iCEB, which was preceded with presence of non-TdP-like VT/VF. Isoprenaline (0.05 to 0.5μM) significantly reduced both λ and iCEB, which was associated with a high incidence of non-TdP-like VT/VF in most preparations. Other biomarkers (i.e. transmural dispersion of T-wave and instability of the QT interval) predicted only dofetilide-induced long QT and EADs, but did not predict drug-induced risk of non-TdP-like VT/VF.
  
  
  CONCLUSIONS
  Our data from 7 reference drugs of known pro-arrhythmic effects suggests that 1) this non-invasive iCEB predicts potential risk of drug-induced CAs beyond long QT and TdP; 2) iCEB is more useful than the current biomarkers (i.e. transmural dispersion and instability) in predicting potential risks for drug-induced non-TdP-like VT/VF.
authors: Janssen Research and Development, Janssen Pharmaceutica NV, Belgium. Electronic address: hlu@its.jnj.com.
authors: Hua Rong
authors: HR
authors: Lu
authors: Main Line Health Heart Center and Lankenau Institute for Medical Research, Wynnewood, PA, USA.
authors: Gan-Xin
authors: GX
authors: Yan
authors: Janssen Research and Development, Janssen Pharmaceutica NV, Belgium.
authors: David J
authors: DJ
authors: Gallacher
mesh_terms: D000818:Animals; D054316:Biomarkers, Pharmacological; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D005260:Female; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology; D008133:Long QT Syndrome / Q000139:chemically induced / Q000503:physiopathology; D008297:Male; D011817:Rabbits; D017180:Tachycardia, Ventricular / Q000139:chemically induced* / Q000503:physiopathology; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000503:physiopathology; D014693:Ventricular Fibrillation / Q000139:chemically induced* / Q000503:physiopathology
chemical_list: D054316:Biomarkers, Pharmacological
keywords: BCL; Basic cycle lengths; CAST; CPMP; CV; Cardiac Arrhythmia Suppression Trial; DMSO; Drug-induced arrhythmias; E14; EAD; ECG; ERP; I(Kr); I(Ks); I(Na); ICH; ICH Harmonized Tripartite Guideline E14: The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs; MAP; QRS; QT; T wave peak-Twave end (measurement of transmural dispersion); TDR; TdPs; TdPs: Torsades de Pointes; The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use; Torsades de Pointes; Tp-Te; VF; VT; VT/VF: ventricular tachycardia/fibrillation; committee for proprietary medicinal products; conduction velocity; dimethyl sulphoxide; early afterdepolarization; effective refractory period; electrocardiogram; hERG; human ether-à-go-go-related gene; iCEB; iCEB (index of Cardiac Electrophysiological Balance); index of Cardiac Electrophysiological Balance; lambda; maximal transmural dispersion of repolarization; monophasic action potential; sodium current; the rapidly activating delayed rectifier potassium current; the slowly activating component of delayed rectifier potassium current; ventricular fibrillation; ventricular tachycardia; λ