doi: 10.1161/01.RES.0000249859.10103.a9
© 2006 American Heart Association, Inc.
Editorials |
The Beat Goes On
Diastolic Noise That Just Won’t Quit
From the Department of Physiology and Cardiovascular Institute, Loyola University Chicago, Stritch School of Medicine, Maywood, Ill.
Correspondence to Donald M. Bers, PhD, Department of Physiology, Loyola University Chicago, Stritch School of Medicine, 2160 South First Avenue, Maywood, IL 60153. E-mail dbers{at}lumc.edu
See related article, pages 979–987
Key Words: cardiac electrophysiology • pacemaker • arrhythmias • sarcoplasmic reticulum Na/Ca exchange • excitation-contraction coupling
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Introduction |
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 Top Introduction How Does the SR...Other Pacemaker MechanismsReferences |
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In this issue Bogdanov et al1 show how late diastolic depolarization in rabbit SA-node pacemaker (SAN) cells may be driven largely by stochastic local SR Ca2+ release events (LCRs), consequent pulses of inward Na/Ca2+ exchange current (INCX) and small jumps in membrane potential (Em). This group has published a comprehensive series of studies (see their reference list) and have made a compelling case for the importance of SR Ca2+ release in SAN pacemaker rate, and response to ß-adrenergic activation. The mechanism is as follows (Figure 1). SAN cells have relatively high basal levels of cAMP and phospholamban phosphorylation,2 resulting in highly active SR Ca2+ uptake. After a prior beat, as SR Ca2+ content rises and the ryanodine receptor (RyR) recovers its triggerability, the high luminal [Ca2+] causes activation of a cluster of RyRs to produce an LCR or Ca2+ spark. The rise in local [Ca2+]i near the Na/Ca2+ exchanger activates Ca2+ extrusion via inward INCX causing depolarization. In particular, these Ca sparks (or LCRs) are known to be very brief stochastic local releases of a bolus of Ca2+, which induce an almost simultaneous bolus of inward INCX (because of the high local submembrane [Ca2+]i near the NCX).3 Note the simultaneous spikes on the RyR release and INCX traces in Figure 2. The high membrane impedance of SAN cells (because of minimal inward rectifier K current IK1)4 allows this brief pulse of inward current to cause a small jump in Em. As more and more of these stochastic events occur during late diastole the diastolic depolarization steepens, bringing Em to the threshold for a regenerative action potential (AP).
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Sympathetic stimulation or ß-adrenergic agonists hasten the heart rate and SAN firing frequency, and this also fits into this Ca2+-centered framework. That is, ß-adrenergic agonists stimulate protein kinase A (PKA) which can phosphorylate phospholamban and stimulate the SR Ca-ATPase such that local SR Ca2+ release events happen sooner during the diastolic interval, thereby accelerating the diastolic depolarization and heart rate. PKA may also enhance RyR gating sensitivity5 (but see also6), which could also favor earlier LCR activity during diastole. PKA also has profound effects on L-type ICa (increasing the amplitude and shifting the Em-dependence to more negative values). This would recruit more ICa earlier during diastole, and again hasten depolarization and heart rate. The increased Ca2+ entry would also enhance SR Ca2+ loading indirectly.
The stochastic nature of the local SR Ca2+ release events was already apparent when this group and others first showed that these events can contribute to pacemaking in atrial pacemaker cells.7–9 However, the stochastic nature of the consequent INCX and depolarization that one would expect had not previously been appreciated experimentally. Here, the novel point made by Bogdanov et al1 is that the late phase of diastolic depolarization in SAN cells (where the LCRs occur) exhibit high variance of the Em recording, which could be consistent with stochastic noise from the LCRs. Moreover, interfering with the LCRs (eg, with ryanodine) was shown to reduce the Em variance in this phase. This is an important test, because one might also expect more stochastic sarcolemmal ion current noise near the threshold of ion channel activation (eg, of T- or L-type ICa), and that could occur at this phase of diastolic depolarization. Thus, this result argues that the Em noise is not likely to be because of sarcolemmal ion channels, but rather by SR Ca2+ release events and consequent INCX. Note that the stochastic behavior that appears to drive the Em noise is still an ion channel, but in this case it is the RyR channel.
Although this Ca-centered view of pacemaker function may not be the whole story (see below), it is also an attractive model because it matches behavior of these Ca2+ transport systems that have been very extensively studied in ventricular myocytes.4 Indeed, this pacemaker pathway is the same as that which is thought to mediate certain triggered arrhythmias. That is, when SR Ca2+ content increases (after a normally activated beat) and reaches the point where the RyR is activated (either because SR Ca2+ load is very high or because the RyR sensitivity is elevated) a spontaneous SR Ca2+ release event can cause a delayed afterdepolarization (DAD) which can trigger an untimely action potential. In ventricular myocytes, the high level of inward rectifier K current (IK1) and normally limited propagation of Ca sparks as waves, limits the ability of INCX (activated by SR Ca2+ release) to trigger an AP under normal conditions. However, in heart failure where NCX expression is elevated and IK1 is downregulated, these events can be more arrhythmogenic.10 Thus, the normal biological SAN pacemaker in the heart and a major mechanism of triggered ventricular arrhythmias may be essentially the same mechanistically.
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How Does the SR Ca2+ Clock Work? |
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TopIntroductionHow Does the SR...Other Pacemaker MechanismsReferences |
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The mathematical model presented1 is a useful extension of this groups previous models2,11 and it incorporates stochastic LCRs, such that one can appreciate the likely scenario in the experiments (small blips of inward INCX). However, the model forces LCRs to behave like they do in the experiments (eg, with respect to frequency, time of appearance after a beat, amplitude, kinetics and spatial spread). Although heuristically useful for predicting the sequelae, it does not provide mechanistic insight about how the SR Ca2+ release events initiate, or how the SR Ca2+ clock works.
So, how does the SR Ca2+ clock work (Figure 1)? First, and most obviously, the SR Ca2+-ATPase refills the SR with Ca2+ after a global SR Ca2+ release, and that rate can be modulated by the phosphorylation of phospholamban by PKA or CaMKII. So, some time is required for Ca2+ to be available for release. It is also now clear that diastolic RyR gating is sensitive to [Ca2+]SR (as well as local [Ca2+]i in the cleft).12,13 This means that as the SR refills the probability of stochastic LCRs or Ca2+ sparks increases, and this relationship is nonlinear (rising steeply as SR Ca2+ content rises). Thus, as the SR refills (especially to a high level), there would be a crescendo of LCR events, ensuring INCX-mediated depolarization toward threshold.
Extensive prior work in myocytes has also shown that the RyR takes time to recover from a prior activation. This is true for the reappearance of Ca2+ sparks, which are temporarily suppressed right after a beat in ventricular myocytes (despite the availability of SR Ca2+), and this also contributes to the process known as postrest potentiation (where higher fractional SR Ca2+ release occurs, despite unaltered SR Ca2+ load and ICa trigger).14,15 This recovery also happens immediately after a wave has occurred in a ventricular myocyte, where releasability of SR Ca2+ recovers with a time constant of a few hundred milliseconds at room temperature.16 Recent work has also suggested that during cardiac Ca2+ alternans (a precursor of more severe arrhythmias), the smaller beat may be, in large part, because of this incomplete RyR recovery during diastole.17 These types of cardiac RyR behavior appear to occur in SAN cells where they may be important in biological pacemaker activity.
In addition, RyR gating can also be modulated by myriad conditions including phosphorylation by both PKA and CaMKII, by redox state and by nitric oxide.4,18 Furthermore, genetic mutations in the cardiac RyR or the intra-SR Ca2+ buffering protein calsequestrin that are associated with catecholaminergic polymorphic ventricular tachycardia (CPVT)19 can also alter RyR sensitivity to both [Ca2+]i and [Ca2+]SR, and in patients with these mutations, the SAN Ca clock could be altered.
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Other Pacemaker Mechanisms |
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TopIntroductionHow Does the SR...Other Pacemaker MechanismsReferences |
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As intriguing as this relatively new Ca2+-related pathway is, there are numerous other ion channel mechanisms that are likely to contribute to the SAN pacemaker. Although Bogdanov and colleagues have presented data which argue strongly that this is the most important determinant of heart rate, other studies have taken an equally strong stand about the primary role of the hyperpolarization-activated cyclic nucleotide-gated (HCN) nonselective cation current, If in SAN pacemaker activity and modulation.20 The issue is not resolved.
Whereas space precludes detailed discussion of other pacemaker mechanisms (gray triangles in Figure 2), I will mention how they are thought to function (without judging primacy). First, there is a time-dependent decay of K conductance (particularly IKr in SAN). As repolarization proceeds this declining K conductance (and declining driving force) causes outward current to decrease (having the net effect of an inward current). Second, repolarization activates the above mentioned If, which activates as an inward Na current at negative Em (despite the nonselective nature of the channel). Third, inward T-type ICa (ICa,T) activates at much more negative Em than L-type ICa (ICa,L) in the diastolic depolarization range, and this ICa,T may also trigger Ca2+ sparks.7 Fourth, in SAN cells there is ICa,L carried by the 
1D isoform (in addition to the dominant cardiac 1C), and this 1D isoform activates at more negative Em.21 Fifth, as [Ca2+]i declines during the previous beat, some of the Ca2+ is removed by inward INCX (which is also hastened by repolarization).3 Sixth, a tiny amount of Na current could become available at the most negative diastolic Em and contribute a very small inward window current.22 Seventh, a Ca2+-activated Cl current (ICl(Ca)) can be activated and could depolarize when Em is below the Cl reversal potential.23 Eighth, a depolarization-activated nonselective cation current, Isustained may also be active in SAN cells during diastole.24 This complex set of membrane currents provides potential mechanistic redundancy with respect to diastolic depolarization. Indeed, these processes overlap temporally even in single pacemaker cells, and may be more important during different phases of diastolic depolarization. Their relative roles may also vary from cell to cell, within the SAN and in other atrial and AV nodal pacemaker cells. Pacemaker function is complex, but understanding how SR Ca2+ cycling can critically influence pacemaker function is an important, relatively new issue. Overall, it will be valuable to continue to work out how all of these pacemaker pathways interact quantitatively.
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Acknowledgments |
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Sources of Funding
National Institutes of Health HL28607 and HL44485 (to F.-R.E.C.). C.A.G. is supported by the California Institute for Regenerative Medicine Training Grant CIRM 00006.
Disclosures
None.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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