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Cardiac arrhythmias in general, and atrial fibrillation (AF) in particular, are important global health problems. Despite extensive studies, arrhythmia mechanisms remain unclear. The problem is complicated because heart function is affected by a complex integration of numerous biochemical and biophysical processes within and among cardiac cells. Interactions within the sinoatrial (SA) node, the heart's primary pacemaker that initiates and regulates the cardiac rhythm, result in one such critical unsolved complexity. Joung et al
have recently applied a method of simultaneous recording of intracellular Ca2+ and membrane potential to approach the riddle of complex/intimate interactions between electrophysiology and intracellular Ca2+signaling within cells comprising the SA node. In this issue of Heart Rhythm, Joung et al
based on voltage clamp data. In silico, the ensemble, or system, of the sarcolemmal electrogenic molecules (ion channels and transporters) of cardiac pacemaker cells can generate rhythmic APs, e.g., in 12 SA node cell (SANC) numerical models.
Therefore, this system of ion currents can be envisioned as a membrane voltage oscillator or membrane clock (M clock). The classical perspective on cardiac pacemaker cell function is that the M clock is the ultimate cardiac pacemaker clock, i.e., its function is not only necessary, but also sufficient to drive normal automaticity. However, in addition to an M clock, cardiac pacemaker cells have another intrinsic oscillatory subsystem that resides within the cell: the sarcoplasmic reticulum (SR) pumps and periodically releases Ca2+.
as late diastolic Ca2+ elevation (LDCAE) in the primary region (i.e., impulse-initiating part) of the isolated intact dog SA node. The spontaneous Ca2+ releases are referred to as an intracellular Ca2+ clock because their occurrence is periodic during voltage clamp,
In nature, i.e., in spontaneously firing SANC, in contrast to in silico or skinned or voltage-clamped cells, Ca2+ and M clocks do not exist in isolation of each other. Numerous and complex interactions via membrane voltage, submembrane Ca2+, and protein phosphorylation occur between the 2 subsystem clocks (M clock and Ca2+ clock), and the subsystems become mutually entrained, forming the full pacemaker cell system or the master pacemaker clock (reviews in Maltsev et al
). The 2 interacting clock subsystems do not just simply coexist within the pacemaker system, but their interaction confers robustness and flexibility to the cardiac pacemaker function as discussed in a recent review
Specifically, the presence of the Ca2+ clock extends the failsafe variations of membrane clock parameters, such as L-type Ca2+ current (ICaL) conductance and, vice versa, the presence of some membrane components, such as funny current (If), increases the failsafe variations of Ca2+ clock parameters, such as the Ca2+ pumping rate.
that RyR2 are down-regulated and LDCAE are absent in their experimental AF model, can be interpreted to indicate that the Ca2+ clock subsystem is impaired in AF, resulting probably in decreased robustness and flexibility of the pacemaker system. In other words, the impairment of diastolic Ca2+ releases shifts the operation of SANC likely toward less safe (i.e., susceptible to arrhythmia) operation.
But what about SANC M clock changes in AF? A recent study by Yeh et al
has identified that major electrophysiological changes of SANC in experimentally induced AF in dogs include a 50% reduction in If conductance and a 33% reduction in slow delayed rectifier K+ current (IKs). Their numerical simulations showed that IKs change had almost no effect on SANC rhythm (<1% cycle length change) and the If change resulted in a cycle length increase of ∼9%. But a change of this magnitude seems to be a relatively moderate effect, i.e. far from trouble. However, taking into account that the robustness of the coupled clock system had been compromised by Ca2+ clock impairment, identified by Joung et al
and discussed above, is it possible that this If change could be critical for SANC function? We believe that the answer to this question is not trivial, and presently can be approached only by numerical integration of changes of both Ca2+ and M clocks. Accordingly, we used our recently developed prototype model of interacting Ca2+ clock and M clock in rabbit SANC
and performed numerical simulations to illustrate that it is indeed possible, at least at the level of a single pacemaker cell (Figure 1). The 50% reduction in If conductance produced a moderate rate reduction of the simulated AP firing rate (i.e., similar to numerical modeling by Yeh et al
). The absence of Ca2+ release, with If remaining intact, however, substantially slowed the rate by ∼40%, but AP firing still remained rhythmic (Figure 1C). However, when the impaired Ca2+ release was combined with the impaired If function, the spontaneous beating became irregular.
These simple first-order estimates illustrate that: (1) interactions of subsystem clocks are crucial to the generation of spontaneous APs of a normal rate and rhythm, and (2) when both the M clock and the Ca2+ clock are impaired in AF (or in any other experimental or pathological conditions), uncoupling of the M clock and the Ca2+ clock can push the master pacemaker clock toward its limits of failsafe operation.
Specific, detailed mechanisms of the system changes in AF and their numerical integration, specifically in the canine SANC and SA node (and, ultimately, in the human SA node), however, merit further study. These additional mechanisms include characterization and integration of components of protein kinase A and Ca2+/calmodulin-dependent protein kinase-dependent phosphorylation (e.g., phosphorylation of phospholamban, SERCA, RyR, L-type Ca2+ channels), sarcolemmal ion exchangers (e.g., Na+/Ca2+ exchanger and Na+/K+ pump), ion channel kinetics, intracellular contacts (e.g., via connexins), and mechanical factors, i.e., strain. An additional important requirement is a further improvement of both selectivity and spatiotemporal resolution of LDCAE recording within the SA node. Such improvements will permit a determination of whether LDCAE exists during basal beating in large animals like canines as is the case for rabbit and mouse, as well as whether LDCAE can propagate within the SA node. Another intriguing question is how expression of sarcolemmal electrogenic molecules (ion channels and transporters) and Ca2+ cycling proteins (especially RyR as found by Joung et al
in this issue of Heart Rhythm suggests that rhythm disturbances in canine experimental AF are caused, at least in part, by a failure of Ca2+ clock function, specifically its release from SR via RyR2. However, the extent to which this mechanism contributes to AF requires further study of integration of changes in Ca2+ cycling proteins, their phosphorylation status, and changes in sarcolemmal electrogenic molecules. We believe that an important lesson from the recent reports by Joung et al
and our simple simulations (Figure 1) is that to be informative, future studies of cardiac pacemaker function, either normal or abnormal, must include integration of the 2 mutually entrained subsystems, the Ca2+ clock and the membrane clock, the yin and yang of cardiac pacemaker cell function.
Intracellular calcium dynamics and acceleration of sinus rhythm by beta-adrenergic stimulation.