Calmodulin Inhibitor W-7 Unmasks a Novel Electrocardiographic Parameter That Predicts Initiation of Torsade de Pointes

Abstract

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 mol/kg), an inhibitor of the intracellular Ca 2ϩ -binding protein calmodulin, significantly suppressed TdP induction (1 of 11 rabbits with TdP, PϽ0.001). 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 Ca 2ϩ /calmodulin-dependent processes that are required for triggering TdP in this model.

Role of Gap Junction Channel in the Development of Beat-to-Beat Action Potential Repolarization Variability and Arrhythmias

“…In these experiments the increased SBVR better predicted the development of TdP arrhythmia than repolarization prolongation alone [3,4,19,20]. Hinterseer et al published similar findings in selected human patients [21] and it is also known that the successful antiarrhythmic treatment does not need to be accompanied by QT interval shortening [22,23]. These results question the association between QT prolongation and the arrhythmia development.…”

Effects of Sarcolemmal Ca2+ Entry, Ryanodine Function, and Kinase Inhibitors on a Rabbit Model of Heart Failure

“…W-7: Increased activity of calmodulin after prolongation of repolarization has been implicated as a cause of afterdepolarizations in many studies, and the calmodulin antagonist W-7 has been demonstrated to prevent TdP initiated by coadministration of methoxamine and clofilium in anesthetized rabbit. 15,16) Unexpectedly, our results show that W-7 expedites the onset of TdP and can not protect dofetilide-induced TdP in conscious rabbits with heart failure. It might be possible that the altered kinetics of calmodulin in heart failure are different from those in normal hearts, which in turn may have consequences for the induction of VPD and TdP.…”

“…The doses of dofetilide and pretreated compounds were chosen based on the findings of previous publications. 5,7,[14][15][16][17]20) Statistics: Values are expressed as the mean ± SEM and n indicates the number of animals. Student's t test and one-way analysis of variance (ANOVA) were applied when appropriate.…”

“…8,13) Many studies have demonstrated that a PKA inhibitor (H-8), calmodulin antagonist (W-7), and CaMKII inhibitor (KN-93) can suppress EADs and attenuate arrhythmias. [14][15][16] This evidence implies that PKA inhibition, CaMKII inhibition, and calmodulin antagonism could prevent TdP and therefore might be useful as novel antiarrhythmic drugs. However, these modalities have not been evaluated in a systematic manner in a uniform preparation.…”

Beat-to-Beat Variability in Field Potential Duration in Human Embryonic Stem Cell-Derived Cardiomyocyte Clusters for Assessment of Arrhythmogenic Risk, and a Case Study of Its Application

“…In this hES-CMC system, we record the field potential duration (FPD)-as QT-like intervals-of clusters treated with a compound; we then calculate the corrected FPD (FPDc) and examine whether or not the compound prolongs FPDc. However, there have been reports that the QT interval is not a good surrogate marker of TdP and ventricular fibrillation [9][10][11][12][13][14][15][16][17][18]; the beat-to-beat variability of QT or QTc is suggested to be a better parameter [14,15]. It would therefore be of interest to investigate whether short-term variability in FPDc (STV FPDc ), as beat-to-beat variability, is increased along with FPDc prolongation in hES-CMCs treated with torsadogenic agents.…”