Differentiating electrophysiological effects and cardiac safety of drugs based on the electrocardiogram: a blinded validation

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.

Objective: To conduct a blinded in vitro assessment of the ionic mechanisms for drug-induced ECG changes.

Methods and results: Fourteen cardiac and noncardiac drugs with known effects on cardiac ion channels were selected by the study sponsor, and were tested in the rabbit left ventricular 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 effects of I(Kr), I(Ks), I(Ca,L), I(Na) blocker, and I(KATP) opener on QRS, QT, and T(p-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 I(Kr), I(Ks), I(Ca,L), I(Na), and I(KATP). Among ECG parameters, T(p-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 left ventricular wedge preparation. Change in T(p-e) provides the most relevant information.