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

<jats:p> 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<jats:sup>2+</jats:sup> wave (CaW) vs. L-type Ca current ( I<jats:sub>Ca,L</jats:sub>), still remains controversial. In the present study, we simultaneously recorded action potentials (APs) and intracellular Ca<jats:sup>2+</jats:sup> images in isolated rabbit ventricular myocytes and systematically compared the properties of EADs in the following two pharmacological models: 1) hydrogen peroxide (H<jats:sub>2</jats:sub>O<jats:sub>2</jats:sub>; 200 μM); 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<jats:sub>Ca,L</jats:sub>, 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<jats:sub>2</jats:sub>O<jats:sub>2</jats:sub> model, but persisted in the Iso + BayK model. We postulate that, although CaWs and reactivation of I<jats:sub>Ca,L</jats:sub> may act synergistically in either case, reactivation of I<jats:sub>Ca,L</jats:sub> plays a predominant role in EAD genesis under oxidative stress (H<jats:sub>2</jats:sub>O<jats:sub>2</jats:sub> model), while spontaneous CaWs are a predominant cause for EADs under Ca<jats:sup>2+</jats:sup> overload condition (Iso + BayK model). </jats:p>