QTc prolongation as a surrogate for drug-induced arrhythmias: fact or fallacy?

QTc prolongation is commonly used as a surrogate for drug-induced torsade de pointes (TdP) because it is frequently associated with TdP. However, TdP can also occur in the absence of QTc prolongation or even when QTc is shortened. In the absence of disturbances of lambda-TRIaD (lambda: cardiac wavelength, Triangulation, Reverse use dependence, Instability and Dispersion; TRIaD) QTc prolongation can be antiarrhythmic. In the presence of disturbances of lambda-TRIaD, QTc prolongation still reduces proarrhythmia but frequently cannot overcome the proarrhythmic effect induced by lambda-TRIaD disturbances. Safety evaluation focused upon QTc prolongation (antiarrhythmic parameter) instead of disturbances of lambda-TRIaD (proarrhythmic parameters), is scientifically incorrect. Such evaluation can impede the development of highly valuable drugs, while not recognizing agents that disturb lambda-TRIaD and hereby endanger patient safety. It must be concluded that the century old proposal by Lewis that prolongation of action potential duration and refractory period can be antiarrhythmic is still correct, provided it is not contaminated by disturbances of lambda-TRIaD.