Received May 16, 2002
Accepted after revision June 13, 2002

Cytosolic Ca²⁺ triggers early afterdepolarizations and Torsade de Pointes in rabbit hearts with long QT syndrome, LQT2

¹ University of Pittsburgh, School of Medicine, Department of Cell Biology and Physiology, Pittsburgh, PA 15261, USA
² Department of Cell Biology and Physiology, University of Pittsburgh, School of Medicine, S314 Biomedical Science Tower, 3400 Terrace Street, Pittsburgh, PA 15261, USA

^* To whom correspondence should be addressed.

The role of intracellular Ca²⁺ (Ca²⁺_i) 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 (V_m) and Ca²⁺_i with two photodiode arrays. The I_Kr blocker E4031 (0.5 µM) plus 50 % reduction of [K⁺]_o and [Mg²⁺]_o elicited long action potentials (APs), V_m 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 (baseå[%%%]apex) and enhanced repolarization gradients (30 to 230 ms, n = 12) indicating a heterogeneous distribution of I_Kr. At low [K⁺]_o and [Mg²⁺]_o, E4031 elicited spontaneous Ca²⁺_iand V_m 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 (Ca²⁺_ivs. V_m) had counterclockwise trajectories shaped like a 'boomerang' during an AP and like ellipses during EADs, with V_m preceding Ca²⁺_iby 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, Ca²⁺_ipreceded V_m and phase maps traced clockwise ellipses. Away from EAD origins, V_m coincided with or preceded Ca²⁺_i. 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-EKGs.

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