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)

摘要

Introduction: 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 0.01. μM. Digoxin (1 and 5. μM), encainide (5 and 20. μM) and propoxyphene (10 and 100. μM) markedly reduced both iCEB and λ, predicting their ability to induce non-TdP-like VT/VF. At 10. μM, both NS1643 and levcromakalim significantly decreased λ and iCEB, which was preceded with presence of non-TdP-like VT/VF. Isoprenaline (0.05 to 0.5. μM) 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. Discussion: 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.