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

Abstract

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 Ca²⁺ 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 Ca²⁺ images in isolated rabbit ventricular myocytes and systematically compared the properties of EADs in the following two pharmacological models: 1) hydrogen peroxide (H₂O₂; 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_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 H₂O₂ 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 (H₂O₂ model), while spontaneous CaWs are a predominant cause for EADs under Ca²⁺ overload condition (Iso + BayK model).