Revisiting the ionic mechanisms of early afterdepolarizations in cardiomyocytes: Predominant by Ca waves or Ca currents?

Zhenghang Zhao, Hairuo Wen, Nadezhda Fefelova, Charelle Allen, Akemichi Baba, Toshio Matsuda, Lai Hua Xie

Research output: Contribution to journalArticlepeer-review

75 Scopus citations


Early afterdepolarizations (EADs) have been implicated in severe cardiac arrhythmias and sudden cardiac deaths. However, the mechanism(s) for EAD genesis, especially regarding the relative contribution of Ca 2+ wave (CaW) vs. L-type Ca current (I Ca,L), still remains controversial. In the present study, we simultaneously recorded action potentials (APs) and intracellular Ca 2+ images in isolated rabbit ventricular myocytes and systematically compared the properties of EADs in the following two pharmacological models: 1) hydrogen peroxide (H 2O 2; 200 μ M); and 2) isoproterenol (100 nM) and BayK 8644 (50 nM) (Iso + BayK). We assessed the rate dependency of EADs, the temporal relationship between EADs and corresponding CaWs, the distribution of EADs over voltage, and the effects of blockers of I Ca,L, Na/Ca exchangers,and ryanodine receptors. The most convincing evidence came from the AP-clamp experiment, in which the cell membrane clamp was switched from current clamp to voltage clamp using a normal AP waveform without EAD; CaWs disappeared in the H 2O 2 model, but persisted in the Iso + BayK model. We postulate that, although CaWs and reactivation of I Ca,L may act synergistically in either case, reactivation of I Ca,L plays a predominant role in EAD genesis under oxidative stress (H 2O 2 model), while spontaneous CaWs are a predominant cause for EADs under Ca 2+ overload condition (Iso + BayK model).

Original languageAmerican English
Pages (from-to)H1636-H1644
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Issue number8
StatePublished - Apr 15 2012

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


  • Ca wave
  • L-type Ca current
  • Na/Ca exchanger
  • Reactive oxygen species
  • β-adrenergic stimulation


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