Synchronized Cardiac Impulses Emerge From Heterogeneous Local Calcium Signals Within and Among Cells of Pacemaker Tissue

Rostislav Bychkov, Magdalena Juhaszova, Kenta Tsutsui, Christopher Coletta, Michael D. Stern, Victor A. Maltsev, Edward G. Lakatta

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


Objectives: This study sought to identify subcellular Ca2+ signals within and among cells comprising the sinoatrial node (SAN) tissue. Background: The current paradigm of SAN impulse generation: 1) is that full-scale action potentials (APs) of a common frequency are initiated at 1 site and are conducted within the SAN along smooth isochrones; and 2) does not feature fine details of Ca2+ signaling present in isolated SAN cells, in which small subcellular, subthreshold local Ca2+ releases (LCRs) self-organize to generate cell-wide APs. Methods: Immunolabeling was combined with a novel technique to detect the occurrence of LCRs and AP-induced Ca2+ transients (APCTs) in individual pixels (chronopix) across the entire mouse SAN images. Results: At high magnification, Ca2+ signals appeared markedly heterogeneous in space, amplitude, frequency, and phase among cells comprising an HCN4+/CX43 cell meshwork. The signaling exhibited several distinguishable patterns of LCR/APCT interactions within and among cells. Rhythmic APCTs that were apparently conducted within the meshwork were transferred to a truly conducting HCN4/CX43+ network of striated cells via narrow functional interfaces where different cell types intertwine, that is, the SAN anatomic/functional unit. At low magnification, the earliest APCT of each cycle occurred within a small area of the HCN4 meshwork, and subsequent APCT appearance throughout SAN pixels was discontinuous and asynchronous. Conclusions: The study has discovered a novel, microscopic Ca2+ signaling paradigm of SAN operation that has escaped detection using low-resolution, macroscopic tissue isochrones employed in prior studies: synchronized APs emerge from heterogeneous subcellular subthreshold Ca2+ signals, resembling multiscale complex processes of impulse generation within clusters of neurons in neuronal networks.

Original languageEnglish (US)
Pages (from-to)907-931
Number of pages25
JournalJACC: Clinical Electrophysiology
Issue number8
StatePublished - Aug 2020
Externally publishedYes


  • calcium
  • conduction
  • pacemaker
  • rhythm
  • sinoatrial node

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


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