Cisapride-Induced Transmural Dispersion of Repolarization and Torsade de Pointes in the Canine Left Ventricular Wedge Preparation During Epicardial Stimulation

Abstract

Background-Cisapride, a gastrointestinal prokinetic agent, was recently withdrawn from the market because of its propensity to induce torsade de pointes (TdP) arrhythmias. The present study examines the electrophysiological actions of cisapride in the isolated arterially perfused canine left ventricular wedge preparation. Methods and Results-Transmembrane action potentials from epicardial and M regions and a pseudo-ECG were simultaneously recorded. Cisapride (0.1 to 5 mol/L) was added to the coronary perfusate. Cisapride prolonged the QT interval and increased transmural dispersion of repolarization (TDR) at relatively low but not at high concentrations. TdP could be induced with programmed electrical stimulation only at a low concentration of drug (0.2 mol/L), when TDR was maximally prolonged. Moreover, TdP could only be induced during epicardial (but not endocardial) activation of the wedge, which was found to augment TDR. At higher concentrations of cisapride, QT was further prolonged, TDR was diminished, and TdP could no longer be induced. T peak -T end interval and T peak -T end area provided reasonable electrocardiographic indices of TDR. Conclusion-Our data (1) demonstrate a biphasic concentration/response relationship for the effect of cisapride to induce long-QT syndrome and TdP, (2) show the value of the left ventricular wedge preparation in identifying drugs that pose an arrhythmic risk, (3) support the hypothesis that risk for development of TdP is related to the increase in TDR rather than to prolongation of the QT interval, and (4) indicate that epicardial activation of the left ventricle, as occurs during biventricular pacing, can facilitate the development of TdP under long-QT conditions.

Role of spatial dispersion of repolarization in inherited and acquired sudden cardiac death syndromes

“…The available data support the hypothesis that TDR, rather than QT prolongation, underlies the principal substrate for the development of TdP (9,11,27,46,54). Our working hypothesis for the development of long QT syndrome-related TdP presumes the presence of electrical heterogeneity in the form of TDR under baseline conditions and the amplification of TDR by agents that reduce net repolarizing current via a reduction in I Kr or I Ks or augmentation of I Ca or late I Na (Fig.…”

The proarrhythmic effect of cardiac resynchronization therapy: An issue that should be borne in mind

“…Epicardial pacing involves a non-physiological activation sequence in which the vector of the transmural propagation is reversed, resulting in delayed endocardial depolarization and earlier epicardial depolarization. 24 Experimental studies have shown that epicardial-endocardial conduction time is significantly longer than endocardial-epicardial conduction time, due to a zone of myocardial wall between the deep subendocardium and mid-myocardial layers. 25,26 The resulting increased dispersion of repolarization prolongs QT The proarrhythmic effect of cardiac resynchronization therapy: An issue that should be borne in mind 309.e5…”

Transmural Dispersion of Repolarization Determines Scroll Wave Behavior During Ventricular Tachyarrhythmias - A Simulation Study -

“…4 Diego et al demonstrated that the risk for TdP induction was related to the increase in TDR, rather than in the QT interval. 7 Scroll wave re-entry is the active source of excitation that sustains ventricular tachyarrhythmias. However, the role of TDR during scroll wave re-entry is not well understood.…”