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(Circulation Research. 2002;90:14.)
© 2002 American Heart Association, Inc.

Editorials

Calcium and Cardiac Rhythms

Physiological and Pathophysiological

Donald M. Bers

From the Department of Physiology, Loyola University Chicago, Stritch School of Medicine, Maywood, Ill.

Correspondence to Donald M. Bers, Department of Physiology, Loyola University Chicago, Stritch School of Medicine, 2160 S First Ave, Maywood, IL 60153. E-mail dbers{at}lumc.edu

Key Words: cardiac electrophysiology • pacemaker • arrhythmias • sarcoplasmic reticulum Na⁺-Ca²⁺ exchange • excitation-contraction coupling

Calcium plays two pivotal roles in cardiac excitation-contraction (E-C) coupling.¹ Ca²⁺ drives myofilament activation and carries or regulates ionic currents that are responsible for normal electrical rhythms² as well as life-threatening arrhythmias.³ In this editorial, I will focus on Ca²⁺ and pacemaker activity and arrhythmogenesis.

Ca²⁺ entry via Ca²⁺ current (I_Ca) triggers sarcoplasmic reticulum (SR) Ca²⁺ release via ryanodine receptors (RyRs), and relaxation is driven by Ca²⁺ transport by the SR Ca²⁺-ATPase and Na⁺-Ca²⁺ exchange. Two I_Ca types occur in cardiac myocytes: L-type (I_Ca,L) activated at E_m>-40 mV and T-type (I_Ca,T) activated at E_m>-60 mV (near the pacemaker range). Inward I_Ca,T and I_Ca,L can contribute importantly to both normal and abnormal cardiac depolarization. I_Ca,L is crucial in E-C coupling in all cardiac myocytes. I_Ca,T is absent in most ventricular myocytes but is present in neonatal ventricular myocytes, some atrial myocytes, and in conducting and pacemaker cells. ß-Adrenergic receptors (ß-ARs) and cAMP-dependent protein kinase (PKA) increase I_Ca,L amplitude and shift activation to more negative E_m (closer to the pacemaker range). Parasympathetic stimulation of the heart (via muscarinic receptors) can offset the ß-AR effect. Withdrawal of muscarinic activation can also cause a rebound overshoot in I_Ca,L and may contribute directly to postvagal tachycardia.^4,5 I_Ca,L is rapidly inactivated by local [Ca²⁺] at the inner channel mouth (mediated by calmodulin associated with the channel).^6,7 As [Ca²⁺]_i declines, I_Ca,L can recover partially from inactivation, even at depolarized E_m.⁸ This can allow I_Ca,L reactivation before the action potential (AP) fully repolarizes, inducing early afterdepolarizations (EADs).

Resting myocytes exhibit spontaneous, localized SR Ca²⁺ release events (Ca²⁺ sparks),⁹ attributed to clusters of 6 to 20 RyRs localized at a single sarcolemmal-SR junction.¹ During normal E-C coupling, Ca²⁺ entry via I_Ca,L triggers SR Ca²⁺ release (as sparks), but the temporal synchronization by the AP obscures individual Ca²⁺ sparks. Diastolic Ca²⁺ spark probability is increased by elevation of either local [Ca²⁺]_i or intra-SR Ca²⁺ content. When cellular Ca²⁺ load is high, Ca²⁺ spark frequency and amplitude are high. At sufficiently high SR Ca²⁺ load, waves of Ca²⁺-induced Ca²⁺ release propagate in myocytes. SR Ca²⁺ release can activate ionic currents that contribute to normal pacemaker activity, delayed afterdepolarizations (DADs), and triggered arrhythmias.

Na⁺-Ca²⁺ exchange produces inward or outward current (I_Na/Ca) depending on E_m, [Ca²⁺], and [Na⁺]. Depolarization favors Ca²⁺ influx (outward I_Na/Ca), but as [Ca²⁺]_i rises and E_m repolarizes, Ca²⁺ efflux (inward I_Na/Ca) is more strongly favored. Moreover, high submembrane [Ca²⁺]_i during I_Ca and SR Ca²⁺ release drives Ca²⁺ extrusion via I_Na/Ca at an earlier time during the AP than would be expected from the global Ca²⁺ transient.¹⁰ Inward I_Na/Ca, activated by high [Ca²⁺]_i, can contribute to both normal pacemaker activity and arrhythmogenesis.

Ca²⁺-Activated Currents: How Ca²⁺ Signals Change E_m

Three Ca²⁺-activated currents have been reported in cardiac myocytes: I_Na/Ca, Ca²⁺-activated Cl^- current (I_Cl(Ca)), and nonselective current (I_NS(Ca)).^11,12 I_Na/Ca is important in all cardiac myocytes, both as a Ca²⁺ transporter and as inward I_Na/Ca involved with pacemaker activity and arrhythmogenic transient inward current (I_ti). I_Cl(Ca) occurs in many types of cardiac myocytes and has a low Ca²⁺ sensitivity, such that it is only activated by high local [Ca²⁺]_i.¹³ The Cl^- reversal potential is generally near -55 mV. Thus, I_Cl(Ca) would be depolarizing at E_m=-80 mV, have little effect around E_m=-55 mV, and be a repolarizing outward current at positive E_m during the AP. This allows I_Cl(Ca) to contribute to the early AP repolarizing notch (Ca²⁺-activated transient outward current) and possibly to arrhythmogenic depolarizations. I_NS(Ca) would reverse near 0 mV, so like I_Cl(Ca), it could contribute to both repolarization and depolarization. However, there is less compelling evidence for any functional contribution of I_NS(Ca) in cardiac myocytes.

Ca²⁺-activated K⁺ channels (I_K(Ca)) are present in many cell types but not in cardiac myocytes. Early work implicated I_K(Ca) as part of the transient outward current (I_to). However, it is now clear that I_to is caused by I_Cl(Ca) (Ca²⁺-sensitive component) and several time- and E_m-dependent K⁺ channels (mainly coded by Kv4.2/4.3 and Kv1.4 genes).¹⁴ Thus, the main Ca²⁺-activated currents in heart cells are I_Na/Ca and I_Cl(Ca), which can contribute to both depolarization or repolarization.

Extracellular [Ca²⁺] ([Ca²⁺]_o) can also modify the gating of all E_m-dependent ion channels by reducing surface potential.¹ High [Ca²⁺]_o shifts channel activation to more positive E_m, which typically reduces excitability. Conversely, low [Ca²⁺]_o shifts activation to more negative E_m, increasing excitability. Elevated [Ca²⁺]_i can also, in principle, increase excitability, but this effect has been less well documented experimentally. These effects can shift the gating of Na⁺ and Ca²⁺ channels as much as 20 mV and thus effect excitability. Thus any inward current is more likely to activate I_Na or I_Ca when [Ca²⁺]_o is low.

Ca²⁺ and Normal Pacemaker Activity

Cells in the sinoatrial (SA) node and latent pacemakers in the atria, atrioventricular (AV) node, and Purkinje cells all exhibit spontaneous pacemaker activity. There is a normal hierarchy, where the fastest intrinsic pacemaker (SA node, 60 to 80/min) drives the whole heart. However, if SA-node firing frequency slows or conduction through the heart is blocked, other regions can take over (AV node 40 to 60/min; His-Purkinje system 20 to 30/min). This creates a functional fail-safe for activating the heart. There are also multiple cellular mechanisms involved in normal pacemaker activity (Figure 1) and these vary in different cells. This creates another type of mechanistic redundancy, such that complete failure of one channel type is unlikely to prevent pacemaker activity altogether. All of these pacemaker cells have relatively low levels of inward rectifier K⁺ current (I_K1) compared with ventricular myocytes. I_K1 is largely responsible for stabilizing the resting E_m near the K⁺ equilibrium potential (E_K-90 mV). Low I_K1 causes the more positive diastolic E_m in SA- and AV-node cells and gives pacemaker cells high input impedance, such that small inward currents can cause relatively large depolarization.

View larger version (31K): [in this window] [in a new window]   Figure 1. Ionic currents involved in cardiac pacemaker activity. Several currents increase and/or decrease during the diastolic depolarization in cardiac myocytes (indicated by triangular shapes). See text for details and abbreviations.

Pacemaker depolarization can be caused by either increasing inward current or decreasing outward current (Figure 1). An example of the latter is a time-dependent decrease in delayed outward K⁺ current (I_K). This can contribute to early pacemaker depolarization, especially in nodal cells where E_m does not get very negative (so I_K turns off slowly). The so-called pacemaker current (I_f) is a nonselective inward current (carried mostly by Na⁺), activated during repolarization, and formed by hyperpolarization-activated cyclic nucleotide gated channels (HCN1, 2, and 4).¹⁵ The activation E_m range for I_f is progressively more negative going from SA-node to Purkinje cells to ventricular myocytes, and cAMP shifts the activation to more positive E_m. Controversy continues as to the quantitative role of I_f in SA-node pacemaking,^16–18 mainly because I_f activation can be very slow at pacemaker E_m in SA node. Nevertheless, this inward current undoubtedly contributes to pacemaker activity and especially so in Purkinje cells that have more negative diastolic E_m. The cAMP response also makes them a more likely contributor to sympathetic-induced chronotropy and enhanced automaticity. Although there is typically very little I_Na available in atrial and nodal pacemaker cells (at the usual diastolic E_m), I_Na might make a tiny contribution to pacemaker depolarization.¹⁹ There is also a sustained nonselective inward current (I_sustained) in some SA- and AV-nodal cells.¹⁸ I_sustained activates at -65 mV (or more positive E_m) and inactivates only weakly, such that it may contribute during much of the pacemaker depolarization in these cells.

Both I_Ca,T and I_Ca,L can participate in pacemaker activity. The activation E_m for I_Ca,T is right in the range of the pacemaker potential, such that as depolarization proceeds, I_Ca,T is progressively activated and inactivated. Indeed, blocking I_Ca,T with µmol/L Ni²⁺ can slow pacemaker rates in SA-node and latent atrial pacemakers.^20,21 The Ca²⁺ that enters via I_Ca,T can also trigger local SR Ca²⁺ release, especially apparent in latent atrial pacemaker cells where broad subsarcolemmal SR junctions occur.²² This released Ca²⁺ activates inward I_Na/Ca, which drives further depolarization. This may be particularly relevant late in diastolic depolarization. Inward I_Na/Ca can also contribute to early depolarization because repolarization and high [Ca²⁺]_i stimulate inward I_Na/Ca.

Ca²⁺ sparks can also create an intrinsic rhythmicity, dependent on properties of the SR Ca²⁺-ATPase and RyR. That is, after a local SR Ca²⁺ release (spark), a finite time is required for local [Ca²⁺]_i decline and reuptake into the SR (creating the driving force for another Ca²⁺ spark). In addition, the RyR requires some recovery time after an initial release (Figure 1). Thus, Ca²⁺ spark frequency recovers gradually after an SR Ca²⁺ release.^23,24 Indeed, with cellular Ca²⁺ overload, myocytes can exhibit regular, stable Ca²⁺ oscillations that are independent of E_m (provided that Ca²⁺ extrusion via Na⁺-Ca²⁺ exchange is blocked). ß-AR activation stimulates SR Ca²⁺ uptake (by PKA-dependent phosphorylation of phospholamban), and this can increase the resting Ca²⁺ spark frequency, increasing diastolic depolarization rate.

In this issue of Circulation Research, Vinogradova et al² show that this Ca²⁺ spark-I_Na/Ca system is very important for the basal rate of rabbit SA-nodal cells as well as the response to ß-AR stimulation. They also indicated that by comparison, changes in I_Ca,L, I_Ca,T, and I_f are less important to the isoproterenol-induced increase in SA-node cell firing. They conclude that the late diastolic Ca²⁺ sparks are triggered by SR properties (rather than by I_Ca,T). The balance and timing of these various contributors to pacemaker activity is likely to vary in different cells and conditions, with different currents being more or less dominant in different cell types (eg, SA-node, latent atrial pacemakers, and Purkinje cells). This scenario also creates a multiplicity of regulatory targets (including cAMP/PKA effects on I_f, I_Ca,L, SR Ca²⁺ transport, and delayed rectifier I_K). It should also be noted that a spontaneous diastolic SR Ca²⁺ release normally activates inward I_Na/Ca and Ca²⁺ extrusion. This may be a physiological part of pacemaker activity (and can serve to reduce Ca²⁺ overload), but it also creates arrhythmogenic I_ti or delayed afterdepolarizations (DADs) in ventricular myocytes. Although we know several key contributors to cardiac pacemaking, there is likely to be tremendous heterogeneity, making absolute pronouncements of dominant mechanisms a continuing challenge.

Ca²⁺ and Triggered Cardiac Arrhythmias

Ventricular tachycardia (VT) is an immediate precursor of ventricular fibrillation and a major cause of sudden death in heart failure (HF). Three-dimensional mapping studies indicate that most VT in human HF initiates by nonreentrant mechanisms, especially in nonischemic HF.²⁵ Triggered arrhythmias (DADs and EADs) are major initiators of VT. EADs are secondary depolarizations that occur before full AP repolarization (Figure 2). EADs are more common with long AP durations, during bradycardia and in patients with long-QT syndrome, where congenital mutations in specific ion channels have been directly implicated.²⁶ In HF, there are reductions in K⁺ channel expression (I_to, I_K1, and perhaps I_K) and more slowly inactivating I_Na, and these cause AP prolongation.^27,28 The smaller Ca²⁺ transients in HF may also cause less complete I_Ca inactivation during the early phases of the AP. These factors combine to increase the likelihood of reactivation of inward I_Ca,L late in the AP (a most likely cause of EADs).^29,30

View larger version (36K): [in this window] [in a new window]   Figure 2. Factors contributing to triggered arrhythmias in heart failure.

DADs initiate after repolarization and are caused by SR Ca²⁺ release and consequent Ca²⁺-activated I_ti. They are associated with cellular Ca²⁺ overload and are more common at normal or high heart rates and especially with ß-AR activation. This makes sense because ß-AR activation increases I_Ca,L and SR Ca²⁺ uptake. This tends to load the SR with Ca²⁺, overcoming the low SR Ca²⁺ load typical in HF (which contributes to the poor contractile function).^3,31 In HF, Na⁺-Ca²⁺ exchange is increased and I_K1 is decreased. This means that a given SR Ca²⁺ release in HF will produce more I_ti (more inward I_Na/Ca). Ventricular I_ti and DADs are due almost entirely to I_Na/Ca (versus I_Cl(Ca) or I_NS(Ca)).³ Further, any given I_ti will produce a greater DAD because there is less I_K1 to stabilize resting E_m. Thus, only half as much SR Ca²⁺ release is required in HF to cause a DAD that reaches the threshold to trigger an arrhythmogenic AP.³ Indeed, this arrhythmogenic mechanism in ventricle is similar to the pacemaker mechanism in SA node described by Vinogradova et al.² Thus, I_Ca and I_Na/Ca are centrally important in the genesis of life-threatening arrhythmias as well as in normal pacemaker activity in the heart.

In conclusion, there are multiple ways in which Ca²⁺ alters cellular cardiac rhythms (normal and abnormal). Traditionally, there has been some segregation between investigation of cardiac rhythms/arrhythmias, myocyte Ca²⁺ regulation, and cardiac mechanics. These perspectives must be merged to develop a modern, comprehensive understanding of how the heart works.

Footnotes

The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

References

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