Calcium and Cardiac Rhythms
2002; Lippincott Williams & Wilkins; Volume: 90; Issue: 1 Linguagem: Galês
10.1161/res.90.1.14
ISSN1524-4571
Autores Tópico(s)Neuroscience and Neuropharmacology Research
ResumoHomeCirculation ResearchVol. 90, No. 1Calcium and Cardiac Rhythms Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBCalcium and Cardiac RhythmsPhysiological and Pathophysiological Donald M. Bers Donald M. BersDonald M. Bers From the Department of Physiology, Loyola University Chicago, Stritch School of Medicine, Maywood, Ill. Originally published3 Apr 2018https://doi.org/10.1161/res.90.1.14Circulation Research. 2002;90:14–17Calcium 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 (ICa) 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 ICa types occur in cardiac myocytes: L-type (ICa,L) activated at Em>−40 mV and T-type (ICa,T) activated at Em>−60 mV (near the pacemaker range). Inward ICa,T and ICa,L can contribute importantly to both normal and abnormal cardiac depolarization. ICa,L is crucial in E-C coupling in all cardiac myocytes. ICa,T is absent in most ventricular myocytes but is present in neonatal ventricular myocytes, some atrial myocytes, and in conducting and pacemaker cells. β-Adrenergic receptors (β-ARs) and cAMP-dependent protein kinase (PKA) increase ICa,L amplitude and shift activation to more negative Em (closer to the pacemaker range). Parasympathetic stimulation of the heart (via muscarinic receptors) can offset the β-AR effect. Withdrawal of muscarinic activation can also cause a rebound overshoot in ICa,L and may contribute directly to postvagal tachycardia.4,5ICa,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, ICa,L can recover partially from inactivation, even at depolarized Em.8 This can allow ICa,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 ICa,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 (INa/Ca) depending on Em, [Ca2+], and [Na+]. Depolarization favors Ca2+ influx (outward INa/Ca), but as [Ca2+]i rises and Em repolarizes, Ca2+ efflux (inward INa/Ca) is more strongly favored. Moreover, high submembrane [Ca2+]i during ICa and SR Ca2+ release drives Ca2+ extrusion via INa/Ca at an earlier time during the AP than would be expected from the global Ca2+ transient.10 Inward INa/Ca, activated by high [Ca2+]i, can contribute to both normal pacemaker activity and arrhythmogenesis.Ca2+-Activated Currents: How Ca2+ Signals Change EmThree Ca2+-activated currents have been reported in cardiac myocytes: INa/Ca, Ca2+-activated Cl− current (ICl(Ca)), and nonselective current (INS(Ca)).11,12INa/Ca is important in all cardiac myocytes, both as a Ca2+ transporter and as inward INa/Ca involved with pacemaker activity and arrhythmogenic transient inward current (Iti). ICl(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, ICl(Ca) would be depolarizing at Em=−80 mV, have little effect around Em=−55 mV, and be a repolarizing outward current at positive Em during the AP. This allows ICl(Ca) to contribute to the early AP repolarizing notch (Ca2+-activated transient outward current) and possibly to arrhythmogenic depolarizations. INS(Ca) would reverse near 0 mV, so like ICl(Ca), it could contribute to both repolarization and depolarization. However, there is less compelling evidence for any functional contribution of INS(Ca) in cardiac myocytes.Ca2+-activated K+ channels (IK(Ca)) are present in many cell types but not in cardiac myocytes. Early work implicated IK(Ca) as part of the transient outward current (Ito). However, it is now clear that Ito is caused by ICl(Ca) (Ca2+-sensitive component) and several time- and Em-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 INa/Ca and ICl(Ca), which can contribute to both depolarization or repolarization.Extracellular [Ca2+] ([Ca2+]o) can also modify the gating of all Em-dependent ion channels by reducing surface potential.1 High [Ca2+]o shifts channel activation to more positive Em, which typically reduces excitability. Conversely, low [Ca2+]o shifts activation to more negative Em, 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 INa or ICa when [Ca2+]o is low.Ca2+ and Normal Pacemaker ActivityCells 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 (IK1) compared with ventricular myocytes. IK1 is largely responsible for stabilizing the resting Em near the K+ equilibrium potential (EK≈−90 mV). Low IK1 causes the more positive diastolic Em in SA- and AV-node cells and gives pacemaker cells high input impedance, such that small inward currents can cause relatively large depolarization. Download figureDownload PowerPointFigure 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 (IK). This can contribute to early pacemaker depolarization, especially in nodal cells where Em does not get very negative (so IK turns off slowly). The so-called pacemaker current (If) 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 Em range for If is progressively more negative going from SA-node to Purkinje cells to ventricular myocytes, and cAMP shifts the activation to more positive Em. Controversy continues as to the quantitative role of If in SA-node pacemaking,16–18 mainly because If activation can be very slow at pacemaker Em in SA node. Nevertheless, this inward current undoubtedly contributes to pacemaker activity and especially so in Purkinje cells that have more negative diastolic Em. The cAMP response also makes them a more likely contributor to sympathetic-induced chronotropy and enhanced automaticity. Although there is typically very little INa available in atrial and nodal pacemaker cells (at the usual diastolic Em), INa might make a tiny contribution to pacemaker depolarization.19 There is also a sustained nonselective inward current (Isustained) in some SA- and AV-nodal cells.18Isustained activates at −65 mV (or more positive Em) and inactivates only weakly, such that it may contribute during much of the pacemaker depolarization in these cells.Both ICa,T and ICa,L can participate in pacemaker activity. The activation Em for ICa,T is right in the range of the pacemaker potential, such that as depolarization proceeds, ICa,T is progressively activated and inactivated. Indeed, blocking ICa,T with μmol/L Ni2+ can slow pacemaker rates in SA-node and latent atrial pacemakers.20,21 The Ca2+ that enters via ICa,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 INa/Ca, which drives further depolarization. This may be particularly relevant late in diastolic depolarization. Inward INa/Ca can also contribute to early depolarization because repolarization and high [Ca2+]i stimulate inward INa/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 Em (provided that Ca2+ extrusion via Na+-Ca2+ exchange is blocked). β-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-INa/Ca system is very important for the basal rate of rabbit SA-nodal cells as well as the response to β-AR stimulation. They also indicated that by comparison, changes in ICa,L, ICa,T, and If 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 ICa,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 If, ICa,L, SR Ca2+ transport, and delayed rectifier IK). It should also be noted that a spontaneous diastolic SR Ca2+ release normally activates inward INa/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 Iti 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 ArrhythmiasVentricular 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 (Ito, IK1, and perhaps IK) and more slowly inactivating INa, and these cause AP prolongation.27,28 The smaller Ca2+ transients in HF may also cause less complete ICa inactivation during the early phases of the AP. These factors combine to increase the likelihood of reactivation of inward ICa,L late in the AP (a most likely cause of EADs).29,30Download figureDownload PowerPointFigure 2. Factors contributing to triggered arrhythmias in heart failure.DADs initiate after repolarization and are caused by SR Ca2+ release and consequent Ca2+-activated Iti. They are associated with cellular Ca2+ overload and are more common at normal or high heart rates and especially with β-AR activation. This makes sense because β-AR activation increases ICa,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 IK1 is decreased. This means that a given SR Ca2+ release in HF will produce more Iti (more inward INa/Ca). Ventricular Iti and DADs are due almost entirely to INa/Ca (versus ICl(Ca) or INS(Ca)).3 Further, any given Iti will produce a greater DAD because there is less IK1 to stabilize resting Em. 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, ICa and INa/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.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.FootnotesCorrespondence to Donald M. 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