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Cytosolic Ca2+ triggers early afterdepolarizations and torsade de pointes in rabbit hearts with type 2 long QT syndrome

By Bum-Rak Choi, Francis Burton and Guy Salama

Abstract

The role of intracellular Ca2+ (Cai2+) in triggering early afterdepolarizations (EADs), the origins of EADs and the mechanisms underlying Torsade de Pointes (TdP) were investigated in a model of long QT syndrome (Type 2). Perfused rabbit hearts were stained with RH327 and Rhod-2/AM to simultaneously map membrane potential (Vm) and Cai2+ with two photodiode arrays. The IKr blocker E4031 (0.5 μM) together with 50% reduction of [K+]o and [Mg2+]o elicited long action potentials (APs), Vm oscillations on AP plateaux (EADs) then ventricular tachycardia (VT). Cryoablation of both ventricular chambers eliminated Purkinje fibres as sources of EADs. E4031 prolonged APs (0.28 to 2.3 s), reversed repolarization sequences (base→apex) and enhanced repolarization gradients (30 to 230 ms, n = 12) indicating a heterogeneous distribution of IKr. At low [K+]o and [Mg2+]o, E4031 elicited spontaneous Cai2+ and Vm spikes or EADs (3.5 ± 1.9 Hz) during the AP plateau (n = 6). EADs fired ‘out-of-phase’ from several sites, propagated, collided then evolved to TdP. Phase maps (Cai2+ vs. Vm) had counterclockwise trajectories shaped like a ‘boomerang’ during an AP and like ellipses during EADs, with Vm preceding Cai2+ by 9.2 ± 1.4 (n = 6) and 7.2 ± 0.6 ms (n = 5/6), respectively. After cryoablation, EADs from surviving epicardium (∼1 mm) fired at the same frequency (3.4 ± 0.35 Hz, n = 6) as controls. At the origins of EADs, Cai2+ preceded Vm and phase maps traced clockwise ellipses. Away from EAD origins, Vm coincided with or preceded Cai2+. In conclusion, overload elicits EADs originating from either ventricular or Purkinje fibres and ‘out-of-phase’ EAD activity from multiple sites generates TdP, evident in pseudo-ECGs

Topics: Original Articles
Publisher: Blackwell Science Inc
OAI identifier: oai:pubmedcentral.nih.gov:2290501
Provided by: PubMed Central
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