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

Zhao Z, Wen H, Fefelova N, Allen C, Baba A, Matsuda T, Xie LH. Revisiting the ionic mechanisms of early afterdepolarizations in cardiomyocytes: predominant by Ca waves or Ca currents? Am J Physiol Heart Circ Physiol 302: H1636-H1644, 2012. First published February 3, 2012; doi: 10.1152/ajpheart.00742.2011.-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,I-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 mu 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 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).