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Yin and yang of the cardiac pacemaker clock system in health and disease

  • Victor A. Maltsev
    Affiliations
    Laboratory of Cardiovascular Science, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, Maryland
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  • Edward G. Lakatta
    Correspondence
    Address reprint requests and correspondence: Dr. Edward G. Lakatta, National Institute on Aging, Gerontology Research Center, 5600 Nathan Shock Drive, Baltimore, Maryland 21224-6825
    Affiliations
    Laboratory of Cardiovascular Science, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, Maryland
    Search for articles by this author
Published:November 09, 2009DOI:https://doi.org/10.1016/j.hrthm.2009.11.001
      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
      • Joung B.
      • Tang L.
      • Maruyama M.
      • et al.
      Intracellular calcium dynamics and acceleration of sinus rhythm by beta-adrenergic stimulation.
      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
      • Joung B.
      • Lin S.F.
      • Chen Z.
      • et al.
      Mechanisms of sinoatrial node dysfunction in a canine model of pacing-induced atrial fibrillation.
      combined their method with measurements of expression of Ca2+ cycling proteins to explore the mechanisms of SA node dysfunction in AF.
      Voltage-gated sarcolemmal ion currents are the proximal cause of an action potential (AP) as originally described by Hodgkin and Huxley
      • Hodgkin A.L.
      • Huxley A.F.
      A quantitative description of membrane current and its application to conduction and excitation in nerve.
      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.
      • Wilders R.
      Computer modelling of the sinoatrial node.
      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+.
      • Lakatta E.G.
      • Capogrossi M.C.
      • Kort A.A.
      • et al.
      Spontaneous myocardial calcium oscillations: overview with emphasis on ryanodine and caffeine.
      Although a potential role of the Ca2+ cycling in normal function of cardiac pacemaker cells had been envisioned
      • Rapp P.E.
      • Berridge M.J.
      Oscillations in calcium-cyclic AMP control loops form the basis of pacemaker activity and other high frequency biological rhythms.
      • Tsien R.W.
      • Kass R.S.
      • Weingart R.
      Cellular and subcellular mechanisms of cardiac pacemaker oscillations.
      and experimentally demonstrated
      • Rubenstein D.S.
      • Lipsius S.L.
      Mechanisms of automaticity in subsidiary pacemakers from cat right atrium.
      • Rigg L.
      • Terrar D.A.
      Possible role of calcium release from the sarcoplasmic reticulum in pacemaking in guinea-pig sino-atrial node.
      • Li J.
      • Qu J.
      • Nathan R.D.
      Ionic basis of ryanodine's negative chronotropic effect on pacemaker cells isolated from the sinoatrial node.
      • Ju Y.K.
      • Allen D.G.
      Intracellular calcium and Na+-Ca2+ exchange current in isolated toad pacemaker cells.
      long ago, recent extensive studies (during the last decade) have discovered the spatiotemporal characteristics of the SR Ca2+ cycling and its interactions with the M clock (see review by Maltsev et al
      • Maltsev V.A.
      • Lakatta E.G.
      Dynamic interactions of an intracellular Ca2+ clock and membrane ion channel clock underlie robust initiation and regulation of cardiac pacemaker function.
      ). Confocal measurements in isolated pacemaker cells detect localized submembrane Ca2+ releases (LCRs) generated by the SR via ryanodine receptors (RyRs) during the late diastolic depolarization.
      • Huser J.
      • Blatter L.A.
      • Lipsius S.L.
      Intracellular Ca2+ release contributes to automaticity in cat atrial pacemaker cells.
      • Bogdanov K.Y.
      • Vinogradova T.M.
      • Lakatta E.G.
      Sinoatrial nodal cell ryanodine receptor and Na+-Ca2+ exchanger: molecular partners in pacemaker regulation.
      The integrated Ca2+ signal of these multiple LCRs during diastolic depolarization represents diastolic Ca2+ release (Figure 3 in Maltsev et al
      • Maltsev V.A.
      • Vinogradova T.M.
      • Bogdanov K.Y.
      • et al.
      Diastolic calcium release controls the beating rate of rabbit sinoatrial node cells: numerical modeling of the coupling process.
      ) that was observed by Joung et al
      • Joung B.
      • Tang L.
      • Maruyama M.
      • et al.
      Intracellular calcium dynamics and acceleration of sinus rhythm by beta-adrenergic stimulation.
      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,
      • Vinogradova T.M.
      • Zhou Y.Y.
      • Maltsev V.
      • et al.
      Rhythmic ryanodine receptor Ca2+ releases during diastolic depolarization of sinoatrial pacemaker cells do not require membrane depolarization.
      in detergent-permeabilized SANC,
      • Vinogradova T.M.
      • Lyashkov A.E.
      • Zhu W.
      • et al.
      High basal protein kinase A-dependent phosphorylation drives rhythmic internal Ca2+ store oscillations and spontaneous beating of cardiac pacemaker cells.
      and in silico (when membrane currents set to zero).
      • Maltsev V.A.
      • Lakatta E.G.
      Synergism of coupled subsarcolemmal Ca2+ clocks and sarcolemmal voltage clocks confers robust and flexible pacemaker function in a novel pacemaker cell model.
      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
      • Maltsev V.A.
      • Lakatta E.G.
      Dynamic interactions of an intracellular Ca2+ clock and membrane ion channel clock underlie robust initiation and regulation of cardiac pacemaker function.
      and Lakatta et al
      • Lakatta E.G.
      • Vinogradova T.
      • Lyashkov A.
      • et al.
      The integration of spontaneous intracellular Ca2+ cycling and surface membrane ion channel activation entrains normal automaticity in cells of the heart's pacemaker.
      ). 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
      • Maltsev V.A.
      • Lakatta E.G.
      Dynamic interactions of an intracellular Ca2+ clock and membrane ion channel clock underlie robust initiation and regulation of cardiac pacemaker function.
      and demonstrated in a numerical study that predicts LDCAE.
      • Maltsev V.A.
      • Lakatta E.G.
      Synergism of coupled subsarcolemmal Ca2+ clocks and sarcolemmal voltage clocks confers robust and flexible pacemaker function in a novel pacemaker cell model.
      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.
      • Maltsev V.A.
      • Lakatta E.G.
      Dynamic interactions of an intracellular Ca2+ clock and membrane ion channel clock underlie robust initiation and regulation of cardiac pacemaker function.
      In the context of the concept of a coupled clock system, the finding of the study by Joung et al
      • Joung B.
      • Lin S.F.
      • Chen Z.
      • et al.
      Mechanisms of sinoatrial node dysfunction in a canine model of pacing-induced atrial fibrillation.
      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
      • Yeh Y.H.
      • Burstein B.
      • Qi X.Y.
      • et al.
      Funny current downregulation and sinus node dysfunction associated with atrial tachyarrhythmia: a molecular basis for tachycardia-bradycardia syndrome.
      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
      • Joung B.
      • Lin S.F.
      • Chen Z.
      • et al.
      Mechanisms of sinoatrial node dysfunction in a canine model of pacing-induced atrial fibrillation.
      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
      • Maltsev V.A.
      • Lakatta E.G.
      Synergism of coupled subsarcolemmal Ca2+ clocks and sarcolemmal voltage clocks confers robust and flexible pacemaker function in a novel pacemaker cell model.
      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
      • Yeh Y.H.
      • Burstein B.
      • Qi X.Y.
      • et al.
      Funny current downregulation and sinus node dysfunction associated with atrial tachyarrhythmia: a molecular basis for tachycardia-bradycardia syndrome.
      ). 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.
      Figure thumbnail gr1
      Figure 1The combined impairment of M clock and Ca2+ clock in AF can result in generation of irregular action potentials by SA node cells. Simulations by a recent numerical model of rabbit SANC
      • Maltsev V.A.
      • Lakatta E.G.
      Synergism of coupled subsarcolemmal Ca2+ clocks and sarcolemmal voltage clocks confers robust and flexible pacemaker function in a novel pacemaker cell model.
      illustrate spontaneous action potentials (top traces), funny current (If, middle traces), and Ca2+ release flux from junctional SR (bottom panels) in control (A), 50% reduction in If conductance (B), no Ca2+ release (C), and 50% reduction in If conductance combined with no Ca2+ release (D). The original model
      • Maltsev V.A.
      • Lakatta E.G.
      Synergism of coupled subsarcolemmal Ca2+ clocks and sarcolemmal voltage clocks confers robust and flexible pacemaker function in a novel pacemaker cell model.
      was slightly modified to increase basal If conductance to 0.23625 nS/pF. See text for details. AF = atrial fibrillation; M clock = membrane clock; SA = sinoatrial; SANC = sinoatrial node cell; SR = sarcoplasmic reticulum.
      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
      • Joung B.
      • Lin S.F.
      • Chen Z.
      • et al.
      Mechanisms of sinoatrial node dysfunction in a canine model of pacing-induced atrial fibrillation.
      ) is regulated, the nature and kinetics of the molecular dysregulation in AF, and whether, in particular, changes in RyRs and AF are concomitantly reversed by cessation of chronic pacing.
      In summary, the study by Joung et al
      • Joung B.
      • Lin S.F.
      • Chen Z.
      • et al.
      Mechanisms of sinoatrial node dysfunction in a canine model of pacing-induced atrial fibrillation.
      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
      • Joung B.
      • Tang L.
      • Maruyama M.
      • et al.
      Intracellular calcium dynamics and acceleration of sinus rhythm by beta-adrenergic stimulation.
      • Joung B.
      • Lin S.F.
      • Chen Z.
      • et al.
      Mechanisms of sinoatrial node dysfunction in a canine model of pacing-induced atrial fibrillation.
      and Yeh et al
      • Yeh Y.H.
      • Burstein B.
      • Qi X.Y.
      • et al.
      Funny current downregulation and sinus node dysfunction associated with atrial tachyarrhythmia: a molecular basis for tachycardia-bradycardia syndrome.
      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.

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