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Differentiating Electrophysiological Effects and Cardiac Safety of Drugs Based on the Electrocardiogram: A Blinded Validation

Tengxian, Liu and Traebert, Martin and Ju, Haisong and Suter, Willi and Donglin, Guo and Hoffmann, Peter and Peter R., Kowey and Gan-Xin, Yan (2012) Differentiating Electrophysiological Effects and Cardiac Safety of Drugs Based on the Electrocardiogram: A Blinded Validation. Circulation: Arrhythmia and Electrophysiology.

Abstract

Background: The ventricular components (QRS and QT) on the electrocardiogram (ECG) depend on the properties of ventricular action potentials that can be modulated by drugs via specific ion channels. However, the correlation of ECG ventricular waveforms with underlying ion actions is not well established and has been extensively debated. We conducted a blinded in vitro assessment of the ionic mechanisms for drug-induced ECG changes.
Methods and Results: 14 cardiac and non-cardiac drugs with known effects on cardiac ion channels were selected by the study sponsor, and were tested in the rabbit left ventricular (LV) wedge preparation with recording of the ECG and contractility. The investigators who performed the experiments and analyzed the data were blinded to names, concentrations and molecular weights of the drugs. The compounds were prepared by the sponsor and sent to the investigators as 56 stock solutions. The effect of IKr, IKs, ICa,L, INa blocker and IKATP opener on QRS, QT and Tp-e, were evaluated. Disclosure of the names and concentrations after completion of the study revealed that there were highly correlated ECG changes with underlying ionic mechanisms and proarrhythmic potential of drugs that respectively target IKr, IKs, ICa,L, INa and IKATP. Among ECG parameters, Tp-e was more useful in differentiating drugs’ actions.
Conclusions: Specific electrophysiological action and the consequent proarrhythmic potential of a drug can be accurately determined by analysis of drug-induced changes in ECG in the rabbit LV wedge preparation. Change in Tp-e provides the most relevant information.

Item Type: Article
Keywords: QT, Tp-e, Tp-e/QT ratio, proarrhythmias, ionic channels, IKr, IKs, ICa,L, INa and IKATP
Date Deposited: 28 Apr 2016 23:45
Last Modified: 28 Apr 2016 23:45
URI: https://oak.novartis.com/id/eprint/6884

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