Cardiac pacemaker cell failure with preserved If, ICaL, and IKr: A lesson about pacemaker function learned from ischemia-induced bradycardia

Victor A. Maltsev, Edward G. Lakatta

Research output: Contribution to journalEditorialpeer-review

Abstract

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 ICaT and INCX. However, the extent to which each of these reductions contributes to bradycardia was not determined. Since previous studies demonstrated a minor role of ICaT in normal pacemaker function of rabbit SANC, the reduction in INCX rather than that in ICaT is likely the major mechanism in the simulated ischemia-induced bradycardia. The finding that other major currents, ICaL, If, and IKr, 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 ICaL 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.

Original languageEnglish (US)
Pages (from-to)289-294
Number of pages6
JournalJournal of Molecular and Cellular Cardiology
Volume42
Issue number2
DOIs
StatePublished - Feb 2007

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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