Calmodulin inhibitor W-7 unmasks a novel electrocardiographic parameter that predicts initiation of torsade de pointes

Background - We have shown that the calmodulin inhibitor W-7 suppresses torsade de pointes (TdP) without shortening the QT interval, which is consistent with other findings that QT prolongation, per se, is insufficient to generate TdP. ECGs were analyzed from a well-characterized animal model of TdP to identify more reliable predictors of this life-threatening ventricular arrhythmia. Methods and Results - TdP was induced using methoxamine and clofilium in 12 of 14 rabbits pretreated with vehicle control, whereas pretreatment with W-7 (50 μmol/kg), an inhibitor of the intracellular Ca²⁺-binding protein calmodulin, significantly suppressed TdP induction (1 of 11 rabbits with TdP, P<0.001). W-7 did not affect heart rate, increases in QT intervals, or dispersion compared with measurements in vehicle-treated control animals. However, a progressive and significant increase in the ratio of U-wave to T-wave amplitude (UTA) occurred before TdP onset in control animals, and this was prevented by W-7. Conclusions - Selective suppression of TdP inducibility by W-7, without shortening the duration of cardiac repolarization, allowed identification of the UTA ratio as a new electrocardiographic index for predicting TdP onset. These findings are consistent with the idea that prolonged repolarization is not the proximate cause of arrhythmia initiation, and they suggest that an increased UTA ratio reflects activation of intracellular Ca²⁺/calmodulin-dependent processes that are required for triggering TdP in this model.