| Abnormal prolongation of QT interval, Long QT syndrome (LQTS), has been associated with polymorphic ventricular tachycardia called Torsades de Pointes (TdP). Suggested mechanisms underlying TdP are that abnormal depolarization during action potential (AP) plateau, called early afterdepolarization (EAD), may trigger reentrant arrhythmias with enhanced dispersion of repolarization (DR).;The aims were to investigate the role of [Ca 2+]i and/or DR in the initiation and maintenance of EADs and TdPs. A new technique was developed to measure APs and [ Ca2+]i simultaneously from 252 sites of epicardium of rabbit and guinea pig hearts using two 16 x 16 photodiode arrays.;Hearts were perfused with IKr and IKs blockers (E4031 and chromanol respectively) to induce long QT. APD prolongation by E4031 and chromanol suggests IKr is more abundant at the apex while IKs is more at the base. EADs occurred during a 2 min perfusion with E4031 and low [K+]o and [Mg2+]o, and elicited EADs that propagated across the heart. At sites that fired EADs, [Ca2+]i elevation precede voltage depolarization, implying that [Ca 2+]i elevation induces Ca 2+-dependent depolarizing currents. During TdPs, activation maps show repetitive firing of EADs from several foci, supporting that multifocal activity produces the undulating ECG pattern.;The spatio-temporal organization of VF/VT was investigated from normal and E4031 perfused hearts. The spatial distribution of VF/VT frequencies and activation intervals were highly correlated to the spatial distribution of APDs measured in normal hearts and in hearts with enhanced DR by E4031. These findings show that the local APDs influence VF/VT dynamics.;In conclusion, in an animal model of long QT, the prolonged AP produces anomalies in Ca2+ handling which may trigger EADs and maintain TdP. In VF/VT induced by burst pacing, the cellular electrical properties that determine APDs are heterogeneously distributed in the heart producing spatio-temporal heterogeneities of VF/VT frequencies. |
