From two competing oscillators to one coupled-clock pacemaker cell system

Abstract

At the beginning of this century, debates regarding “what are the main control mechanisms that ignite the action potential (AP) in heart pacemaker cells” dominated the electrophysiology field. The original theory which prevailed for over 50 years had advocated that the ensemble of surface membrane ion channels (i.e., “M-clock”) is sufficient to ignite rhythmic APs. However, more recent experimental evidence in a variety of mammals has shown that the sarcoplasmic reticulum (SR) acts as a “Ca2+-clock” rhythmically discharges diastolic local Ca2+ releases (LCRs) beneath the cell surface membrane. LCRs activate an inward current (likely that of the Na+/Ca2+ exchanger) that prompts the surface membrane “M-clock” to ignite an AP. Theoretical and experimental evidence has mounted to indicate that this clock “crosstalk” operates on a beat-to-beat basis and determines both the AP firing rate and rhythm. Our review is focused on the evolution of experimental definition and numerical modeling of the coupled-clock concept, on how mechanisms intrinsic to pacemaker cell determine both the heart rate and rhythm, and on future directions to develop further the coupled-clock pacemaker cell concept.

A Singular Role of IK1 Promoting the Development of Cardiac Automaticity during Cardiomyocyte Differentiation by IK1 –Induced Activation of Pacemaker Current

“…One limitation is that our current study focused on regulating cellular automaticity by the sarcolemmal currents of I K1 -induced I f activation but didn’t include the influence of intracellular Ca 2+ transients, which coordinates together with sarcolemmal ion currents to control cellular automaticity 49,50 . Recently, Vaidyanathan et al found that upregulated I K1 could enhance the amplitude of Ca 2+ transients in iPSC-CMs 51 ; therefore, the automaticity development promoted by I K1 -induced I f activation might be also mediated partially through intracellular Ca 2+ transients.…”

Advances in the management of heart failure: the role of ivabradine

“…This process activates a current generated by the sodium–calcium exchanger, which contributes to diastolic depolarization (“calcium clock”), ultimately triggering action potential firing 42. Although there is debate whether one of these “clock” mechanisms is the key initiator of diastolic depolarization and cardiac pacemaking,43 a close interplay between both concepts (“coupled clock”) seems to be crucial for proper rhythm generation in pacemaker cells 44…”

Cardiac Purkinje fibers and arrhythmias; The GK Moe Award Lecture 2015

“…Involvement of intracellular Ca 2+ cycling in Ca 2+ wave formation and resultant DADs in Purkinje cells was also discussed 17 but the role of intracellular Ca 2+ cycling in pacemaker function of both normal canine Purkinje and SAN cells remains uncertain. Is there an interdependence of I f and Ca 2+ cycling (so called membrane and Ca 2+ clocks 19 ) in these pacemakers of the heart?…”