Cardiac pacemaker cell failure with preserved I_f, I_CaL, and I_Kr: A lesson about pacemaker function learned from ischemia-induced bradycardia

The study by Du and Nathan in this issue of Journal of Molecular and Cellular Cardiology [1] suggests that simulated ischemia-induced bradycardia in rabbit SANC is caused, at least in part, by a failure (i.e., reduction) of two ion currents I_CaT and I_NCX. However, the extent to which each of these reductions contributes to bradycardia was not determined. Since previous studies demonstrated a minor role of I_CaT in normal pacemaker function of rabbit SANC, the reduction in I_NCX rather than that in I_CaT is likely the major mechanism in the simulated ischemia-induced bradycardia. The finding that other major currents, I_CaL, I_f, and I_Kr, contributing to the diastolic depolarization, do not fail under ischemic-like conditions, whereas NCX does, suggests that the latter is critical to the normal pacemaker function. This idea is in line with direct, recent demonstrations in other studies of rabbit SANC [17,18] of the key role of NCX in normal pacemaker function. Furthermore, because NCX is activated by intracellular Ca²⁺, a broad interpretation of the results of this study is that pacemaker failure during simulated ischemia is not caused solely by ion channel failure, but also by altered SR Ca²⁺ cycling and/or a compromised intracellular Ca²⁺ integration with the membrane excitation due to the deficiency of NCX function. This interpretation supports the novel hypothesis [6,7] that normal cardiac pacemaker function requires functional integration of internal Ca²⁺ cycling with membrane-delimited electrogenic proteins. According to this Ca²⁺ integrated pacemaker concept, spontaneous local Ca²⁺ releases emerging during the late DD activate an ensemble of local inward NCX currents; this accelerates DD and ignites I_CaL to generate an AP (Fig. 1A). This DD acceleration is clearly demonstrated in the Du and Nathan's recordings of spontaneous APs, and it is the late, non-linear DD part (associated with normal SANC operation) that does fail under ischemia-like conditions (Fig. 1B). While previous experiments demonstrated that ischemia interferes with the SR Ca²⁺ cycling in different cardiac cell types, unfortunately Ca²⁺ measurements were not performed in this study. A direct evaluation of local spontaneous Ca²⁺ releases during the late DD of SANC in future studies of ischemia-induced bradycardia merits consideration.