Abstract 11220: Electrotonic Interactions Contribute to the Genesis of Phase-3 Early Afterdepolarizations and Triggered Activity in Acquired Long QT Syndrome
Introduction: Both phase-2 and phase-3 early afterdepolarizations (EADs) occur in long QT syndromes, with the latter proposed to be generated by spontaneous sarcoplasmic reticulum (SR) Ca release. However, direct evidence is lacking.
Objective: To determine whether phase-3 EADs are a genuine cellular level phenomenon, or a consequence of “prolonged repolarization-dependent reexcitation” mediated by electrotonic interaction.
Methods and Results: Cai and membrane voltage (Vm) were simultaneously mapped in cryoablated Langendorff-perfused rabbit ventricles (n=16). E-4031 (an I Kr blocker) combined with reduced extracellular K and Mg prolonged action potential duration (APD) heterogeneously and induced phase-2 and phase-3 EADs. No spontaneous SR Ca release was associated with phase-3 EADs. The site of origin of 47 triggered activity (TA) episodes including 18 ventricular tachycardias (2 monomorphic, 13 polymorphic, 3 Torsades de Pointes) was determined. Phase-2 EADs directly induced TA in 12 episodes (26%), while phase-3 EADs induced TAs in 35 episodes (74%). Not all phase-3 EADs were accompanied by phase-2 EADs, but when present, phase-2 EADs accentuated APD heterogeneity, leading to a high Vm gradient at the boundary between long and short APD regions. Phase-3 EADs and TAs emerged from this boundary, with the amplitude of phase-3 EADs correlating with the Vm gradient (r=0.898, P<0.001). Retrograde electrotonic interaction from induced TAs contributed to maintenance of high Vm gradients during ventricular tachycardias. Computer simulations showed that phase-3 EADs could be either intrinsically by reduced I K1 secondary to low extracellular K concentration, or extrinsically by purely electrotonic effects between regions with heterogeneous repolarization. Both promoted TA from the boundary zone.
Conclusions: Phase-3 EADs do not require spontaneous SR Ca release, and can be generated both by intrinsic (reduced I K1) and extrinsic (electrotonic) mechanisms. Both mechanisms contribute importantly to ventricular arrhythmogenesis in the setting of acquired long QT syndrome due to I Kr blockade.
- © 2010 by American Heart Association, Inc.