Genesis of phase 3 early afterdepolarizations and triggered activity in acquired long-QT syndrome

Mitsunori Maruyama, Shien Fong Lin, Yuanfang Xie, Su Kiat Chua, Boyoung Joung, Seongwook Han, Tetsuji Shinohara, Mark J. Shen, Zhilin Qu, James N. Weiss, Peng Sheng Chen

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Abstract

Background-Both phase 2 and phase 3 early afterdepolarizations (EADs) occur in long-QT syndromes, but their respective roles in generating arrhythmias in intact cardiac tissue are incompletely understood. Methods and Results-Intracellular Ca (Cai) and membrane voltage (Vm) were optically mapped in a quasi 2-dimensional model of cryoablated Langendorff-perfused rabbit ventricles (n=16). E-4031 (an IKr blocker) combined with reduced extracellular K ([K+]o) and Mg ([Mg2+]o) prolonged action potential duration heterogeneously and induced phase 2 and phase 3 EADs. Whereas phase 2 EADs were Cai-dependent, phase 3 EADs were not. The origins of 47 triggered activity episodes were attributed to phase 2 EADs in 12 episodes (26%) and phase 3 EADs in 35 episodes (74%). When phase 2 EADs accompanied phase 3 EADs, they accentuated action potential duration heterogeneity, creating a large Vm gradient across the boundary between long and short action potential duration regions from which triggered activity emerged. The amplitude of phase 3 EADs correlated with the Vm gradient (r=0.898, P<0.001). Computer simulation studies showed that coupling of cells with heterogeneous repolarization could extrinsically generate phase 3 EADs via electrotonic current flow. Alternatively, reduced IK1 caused by low [K+]o could generate intrinsic phase 3 EADs capable of inducing triggered activity at the boundary zone. Conclusions-Phase 3 EADs can be extrinsic as the result of electrotonic current across steep repolarization gradients or intrinsic as the result of low IK1 and do not require spontaneous sarcoplasmic reticulum Ca release. Reduction of IK1 by low [K+]o strongly promotes ventricular arrhythmias mediated by phase 3 EADs in acquired long-QT syndrome caused by IKr blockade.

Original languageEnglish
Pages (from-to)103-111
Number of pages9
JournalCirculation: Arrhythmia and Electrophysiology
Volume4
Issue number1
DOIs
Publication statusPublished - 2011 Feb 1

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Maruyama, M., Lin, S. F., Xie, Y., Chua, S. K., Joung, B., Han, S., Shinohara, T., Shen, M. J., Qu, Z., Weiss, J. N., & Chen, P. S. (2011). Genesis of phase 3 early afterdepolarizations and triggered activity in acquired long-QT syndrome. Circulation: Arrhythmia and Electrophysiology, 4(1), 103-111. https://doi.org/10.1161/CIRCEP.110.959064