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Arrhythmogenic Ion-Channel Remodeling in the Heart: Heart Failure, Myocardial Infarction, and Atrial Fibrillation

Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada

ABSTRACT

I. INTRODUCTION

A. Channel Function as a Regulated Phenomenon

B. Regional Considerations

II. REMODELING OF IONIC CURRENTS ASSOCIATED WITH CARDIAC DISEASE: CONGESTIVE HEART FAILURE

A. Significance and Arrhythmic Consequences

B. Alterations in K+ Currents

1. Ion-current changes

2. Molecular basis

3. Arrhythmic consequences

C. Alterations in Ca2+ Currents and Cellular Ca2+ Handling

1. Changes in Ca2+ currents

2. Changes in Ca2+-handling proteins

3. Functional consequences

D. Alterations in Na+ Current

1. Na+ current changes

2. Functional consequences

E. Changes in Connexin Function

1. Cell-coupling and connexin changes

2. Functional consequences

F. Hyperpolarization-Activated, Cyclic Nucleotide-Gated Nonselective Cation Channels

1. Changes in hyperpolarization-activated nonselective cation currents and corresponding subunits

2. Functional consequences

III. REMODELING OF IONIC CURRENTS ASSOCIATED WITH CARDIAC DISEASE: MYOCARDIAL INFARCTION

A. Significance and Arrhythmic Consequences

B. Alterations in K+ Currents

1. Changed K+ current function in surviving border-zone cells

2. Changes in K+ currents in normal zones of hearts with prior myocardial infarction

C. Alterations in Ca2+ Currents and Cellular Ca2+ Handling

1. Changes in Ca2+ current

2. Changes in cellular Ca2+ handling

D. Alterations in Na+ Current

1. Na+ current changes

2. Functional consequences

E. Changes in Connexin Function

IV. REMODELING OF IONIC CURRENTS ASSOCIATED WITH ATRIAL FIBRILLATION

A. Significance and Arrhythmic Consequences

B. Alterations in K+ Currents

1. Changes in voltage-dependent K+ currents

2. Changes in inward-rectifier K+ currents

C. Alterations in Ca2+ Currents and Cellular Ca2+ Handling

1. Changes in L-type Ca2+ current and molecular basis

2. Changes in cellular Ca2+ handling

D. Alterations in Na+ Current

E. Changes in Connexin Function

V. A COMPARISON OF IONIC REMODELING IN VARIOUS ARRHYTHMOGENIC PARADIGMS

VI. MECHANISMS UNDERLYING THE DEVELOPMENT OF REMODELING

A. Factors Modulating Ion-Channel Transcription

B. Altered Regulation of Ion-Channel and Transporter Function

C. Altered Transport and Assembly Into Macromolecular Complexes

VII. THERAPEUTIC IMPLICATIONS OF IONIC CURRENT AND TRANSPORTER REMODELING

A. Remodeling-Induced Modification of the Response to Therapeutic Interventions

1. Heart failure-induced remodeling

2. Postmyocardial infarction remodeling

3. AF-related remodeling

B. Ionic Remodeling as a Target for Novel Therapeutic Approaches

1. Heart failure-induced remodeling

2. Postmyocardial infarction remodeling

3. AF-related remodeling

VIII. CONCLUSIONS

GRANTS

ACKNOWLEDGMENTS

REFERENCES

	ABSTRACT

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	I. INTRODUCTION

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The cardiac action potential represents cardiac transmembrane potential (measured at the inside of the cell) as a function of time. The action potential is a key determinant of cardiac electrical activity and is shaped by underlying ionic currents and transporters [for detailed reviews, see Nerbonne and Kass (219) and/or Schram et al. (280)]. A schematic representation of a cardiac action potential and the principal currents involved in its various phases are shown in Figure 1A. The phases of the cardiac action potential are designated by the numbers 0 through 4, beginning with initial depolarization (phase 0) to the return to the resting state (phase 4). The cellular resting potential is set by the resting K⁺ conductance, which is normally large in non-nodal tissue (working atrial and ventricular muscle, specialized ventricular conducting tissue composed of Purkinje fiber cells) because of a high resting permeability through inward-rectifier current (I_K1) channels. The substantial resting I_K1 conductance fixes the resting potential of non-nodal cardiac muscle near the K⁺ equilibrium potential of about –80 to –90 mV. Upon activation, cells are depolarized by the rapid entry of Na⁺ through Na⁺ channels, generating a large inward-flowing (depolarizing) Na⁺ current (I_Na). The maximum rate of voltage upstroke during phase 0 of the action potential, dV/dt_max, is determined by (and closely correlated with) the size of the depolarizing I_Na. After a brief rapid repolarization phase (phase 1) due to K⁺ egress through a rapidly activating and inactivating transient outward current (I_to) K⁺ channel, cardiac cells enter a plateau phase (phase 2) during which there is a balance between inward currents (Ca²⁺ through the L-type Ca²⁺ current, I_CaL) and outward K⁺ currents. During this phase there is progressive time-dependent activation of delayed-rectifier currents, particularly the rapid delayed-rectifier I_Kr, which finally terminate the action potential with an appropriate delay by producing rapid phase 3 repolarization. Nodal-type cells in the sinoatrial node (also called the sinus node) and atrioventricular node maintain a more primitive phenotype, with a smaller resting K⁺ conductance producing less negative resting potentials (further from the K⁺ equilibrium potential) and a slow action potential upstroke generated by Ca²⁺ entry through the L-type Ca²⁺ channel. Typical examples of action potentials from various cardiac regions are illustrated in Figure 1B, along with a schematic diagram to show the normal pattern of electrical activation of the heart.

View larger version (31K): [in this window] [in a new window]   FIG. 1. Generation of cardiac electrical activity. A: schematic cardiac action potential with the various phases and principal corresponding ionic currents indicated. The horizontal lines at the bottom indicate schematically the portions of the action potential during which each current flows. B, left: the cardiac impulse is initiated by spontaneous regular firing of the sinoatrial (SA) node. It then spreads to the atria to cause them to fire and contract, and from the atria arrives at the atrioventricular (AV) node. The AV node is normally the only conducting pathway between the atria and ventricles, which are otherwise separated by nonconducting fibrous tissue. After a delay in the AV node to provide time for the ventricles to fill before they contract, the impulse spreads via the specialized Purkinje fiber ventricular conducting system to activate the ventricles. Right: typical action potentials (APs) corresponding to the tissues shown at left. The short vertical lines indicate the time of onset of activity in the SA node for one beat (for reference purposes). NCX, Na+-Ca2+ exchanger.

Various forms of cardiac disease and rhythm disturbances result in altered cardiac ion channel and transporter function. These alterations appear in many instances to be part of the homeostatic adaptive response to the primary abnormality (213), but often result in secondary cardiac dysfunction, including excessively rapid cardiac rhythms ("tachyarrhythmias"). Over the past 20 years, an enormous amount has been learned about the biophysical nature of arrhythmogenic ion-channel remodeling, as well as of its pathophysiological consequences and molecular basis. We review the available information with respect to three selected paradigms of conceptual and clinical importance: congestive heart failure, myocardial infarction, and atrial fibrillation (AF).

A. Channel Function as a Regulated Phenomenon

The classical notion of ion-channel function viewed ion-channel properties as essentially fixed in the absence of tissue damage; however, our understanding has evolved to appreciate that ion-channel properties are regulated and responsive to changes in ionic fluxes, neurohumoral environment, and hemodynamic state (212). It is logical that ion-channel function be regulated, because physiological action potential properties require fine balances among a wide range of currents. This would seem to necessitate some form(s) of feedback control on ion-channel production and function in relationship to action potential waveforms, frequency of activation, and cellular metabolism. How such mechanisms, designed to maintain physiological function under a broad range of normal conditions, come into play in the face of disease processes that are often associated with aging-related pathology remains to be clarified. A variety of mechanisms, including modulation of gene transcription, mRNA processing, mRNA translation, protein processing, subunit assembly, membrane transport, assembly into macromolecular complexes, and posttranslational regulation, have the capacity to mediate the remodeling of ion-channel expression and function (264). Although we know a great deal about the functional consequences of such processes, we are only beginning to learn about the fundamental mechanisms controlling their occurrence. Our ability to control remodeling-induced changes will ultimately depend on our understanding of how they come about; however, because remodeling may be part of an adaptive physiological program, any therapeutic manipulation will need to take into consideration the potentially negative consequences of interfering with homeostatic paradigms.

B. Regional Considerations

The various regions of the heart have highly specialized electrical functions, determined by a defined complement of ion channels and transporters (for detailed reviews of regional ion-channel expression properties and their relationship to electrophysiological function and arrhythmias, see Refs. 211, 219, and 280). Regional functional specialization is typified in part by characteristic action potential waveforms in various cardiac regions, as illustrated in Figure 1B. Emerging information is clarifying the molecular bases for the specificity of regional ion-channel complement patterns (116, 185, 193, 280). The principal arrhythmic consequences of ion-channel remodeling are related to these specialized functions and their underlying molecular/biophysical basis.

	II. REMODELING OF IONIC CURRENTS ASSOCIATED WITH CARDIAC DISEASE: CONGESTIVE HEART FAILURE

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A. Significance and Arrhythmic Consequences

Heart failure is a syndrome caused by significant impairments in cardiac function. Sudden death, generally due to arrhythmic causes, is responsible for up to 50% of deaths among patients with cardiac failure (153). Cardiac dysfunction is the single most useful clinical predictor of the mortality-preventing effectiveness of implantable ventricular cardioverter/defibrillator devices, which automatically terminate ventricular tachyarrhythmias by giving an appropriately adjusted shock to the heart (201). This finding highlights the importance of ventricular tachyarrhythmias in heart failure patients, all of whom have impaired cardiac function. In addition to ventricular tachyarrhythmias, patients with heart failure experience a variety of other significant rhythm abnormalities. Atrial arrhythmias, particularly atrial fibrillation, are very common in heart failure and can contribute substantially to morbidity and mortality (82). Sinoatrial node function is abnormal in clinical and experimental heart failure (230, 273, 371), causing slow heart rhythms, "bradycardias," that may produce weakness, syncope, cardiac dysfunction, or circulatory collapse requiring artificial pacemaker implantation.

Many of the arrhythmic consequences associated with cardiac failure are due to disease-induced remodeling of ion-channel and ion-transport function that may initially be adaptive in nature. For example, the increases in ventricular APD that are typical of heart failure can improve contraction strength (270) and thereby support the weakened heart. The sinus bradycardia caused by remodeling due to cardiac failure may improve mechanical efficiency and have protective value (134). However, these adaptive responses, which presumably are intended to deal with physiological stresses, may have maladaptive consequences when invoked by chronic diseases associated with aging like heart failure, leading to arrhythmic syndromes and in some instances ultimately impairing contractile function (213). Specific heart failure-induced changes in ion-handling function and their significance are discussed below. The associated arrhythmia mechanisms, including enhanced automaticity, early and delayed afterdepolarizations, and reentry, are illustrated along with the major predisposing ion current modifications induced by heart failure in Figure 2.

View larger version (21K): [in this window] [in a new window]   FIG. 2. Schematic summary of arrhythmia mechanisms in congestive heart failure (CHF). A: abnormalities in spontaneous pacemaking function (automaticity). Reductions in the nonselective cation current If and its underlying HCN subunit contribute to impaired SA node function and bradycardia in CHF. Increases in atrial and ventricular If may contribute to ectopic beat formation in CHF. B: repolarization impairment and early afterdepolarizations (EADs). CHF-induced reductions in repolarizing K+ currents (including IK1, IKs, and Ito) and increases in depolarizing plateau currents (like late INa, INaL) impair repolarization, prolong the APD, and promote formation of arrhythmogenic EADs. C: delayed afterdepolarizations (DADs). DADs are formed when cytoplasmic Ca2+ released by an abnormal diastolic SR Ca2+ discharge is exchanged for extracellular Na+ via the Na+-Ca2+ exchanger (NCX). Since NCX removes only 1 Ca2+ for every 3 Na+ entering, it causes a net flow of positive ions to enter and depolarize the cell. If the DAD is large enough to raise the membrane voltage to threshold, an extrasystole is induced, a phenomenon known as triggered activity (TA). In CHF, DADs and TA are favored by 1) increased NCX function; 2) Ca2+ release channel (CaRC) phosphorylation, which increases the likelihood of abnormal diastolic Ca2+ release; and 3) reduced IK1, which increases diastolic membrane resistance and increases the voltage deflection caused by a given depolarizing current (see Fig. 4). D: reentrant activity. Reentry requires an impulse to block in one of two potential conducting pathways (unidirectional block), and then to return and reenter through the previously inexcitable zone. Reentry is favored by premature impulses (which can find one path refractory when the other can conduct, thereby triggering reentry), by variability in refractoriness (which provides the differences allowing for only one path to be activated) and by slow conduction, which allows enough time for the previously refractory pathway to recover by the time the returning impulse (stippled line) gets back to the site where it previously blocked. Factors favoring reentry in CHF include premature impulses arising from the mechanisms shown in A–C, refractoriness heterogeneity due to spatially variable APD increases, and slowed conduction caused by reduced connexin expression, decreased connexin phosphorylation, and reduced phase 0 INa. For a more detailed discussion of these mechanisms, see Reference 211.

A consistent feature of action potentials recorded in ventricular myocytes from subjects with cardiac dysfunction is APD prolongation (6, 134, 171, 226). Early afterdepolarizations are frequently observed in relation to impaired repolarization (134, 171, 172, 226). Early afterdepolarizations are an important arrhythmia mechanism associated with delayed repolarization and are particularly prone to produce a specific form of ventricular tachyarrhythmia called Torsades des Pointes (85). K⁺ currents play a key role in shaping the cardiac action potential, and remodeling-induced changes in K⁺ currents are important contributors to repolarization abnormalities associated with heart failure. Some of the changes in heart failure mimic congenital ion channelopathies that cause long QT syndromes, and congestive heart failure can be viewed as a form of acquired long QT syndrome (55).

1. Ion-current changes

Studies addressing K⁺ current alterations in various models of cardiac failure are listed in Table 1. A variety of animal models have been used, with the most common involving rapid ventricular pacing (ventricular tachypacing) to produce an arrhythmic cardiomyopathy that parallels the clinical syndrome of tachycardiomyopathy associated with sudden death due to ventricular tachyarrhythmias (220). Twelve studies have assessed ventricular ion channels and one each changes in atrial, sinoatrial node, and Purkinje fiber cells from the specialized ventricular conducting system. The most consistent finding is a decreased Ca²⁺-independent I_to, observed in all studies and all tissues other than the sinus node. In ventricular myocytes, seven studies show a decrease in the inward-rectifier current I_K1, but two other studies (268, 318) do not. In addition, the one study that has been performed on atrial cardiomyocytes (170) did not find any I_K1 change with congestive heart failure. The variability in findings regarding I_K1 is likely due, at least in part, to differences in the severity and duration of cardiac dysfunction. Most investigators have found no change in I_Kr, but Tsuji et al. (318) reported decreased I_Kr in ventricular-tachypaced rabbits. Of note, the current-voltage relation for I_Kr in the latter study was similar to that of I_Ks, with a half-activation potential of the order of +20 mV, whereas I_Kr typically activates 30–40 mV more negatively than I_Ks, at –20 to –10 mV (275). Since I_Kr was defined by E-4031-sensitive current in the Tsuji study, it is possible that I_Ks rundown during E-4031 superfusion contributed significantly to the current differences between pre- and postdrug values. A subsequent study in the same model recorded I_Kr and I_Ks with more typical relative voltage dependencies, and noted no heart failure-induced change in I_Kr (319). Six studies found that heart failure decreases I_Ks in ventricular, atrial, and sinoatrial node cells; the only study that did not report I_Ks change was in Purkinje fibers (117), which require isolation by a "chunk" method that can artifactually suppress delayed-rectifier currents (363).

The molecular basis of changes in K⁺ current function associated with heart failure has been examined by several groups over the past 7 years (Table 2). Downregulation of transcript expression clearly plays a major role. Transcripts encoding I_to subunits, in particular Kv4.3, have been found to be reduced in heart failure by six studies. Protein expression changes are consistent with the mRNA data. The -subunit KChIP2, which is critical for the formation of functional I_to channels (219), was found to be unaltered at the mRNA level by heart failure in two studies (8, 373) and downregulated in one (265); however, in all three studies KChIP2 protein expression was unaltered. Thus the evidence argues against a significant role for KChIP2 in heart failure-induced I_to downregulation. Three studies showed mRNA expression of Kir2.1, which encodes the principal cardiac I_K1 subunit (337), to be unchanged in heart failure (8, 141, 337), whereas two studies (28, 265) showed it to be decreased. One study that noted decreased Kir2.1 mRNA expression found Kir2.1 protein levels to be unchanged (265). Thus the basis of I_K1 suppression in congestive heart failure remains unclear, and the explanation may not simply involve decreased production of protein corresponding to the principal subunit. The results for the principal I_Kr subunit ERG have been consistent, with four studies noting unaltered mRNA levels. There is much more variability in results for the I_Ks subunits KvLQT1 and minK in studies of heart failure; one investigation showed a decrease, three no change, and one increased mRNA expression. Similar discrepancies exist in studies of I_Ks-related subunit protein expression. Thus posttranscriptional and posttranslational mechanisms may be important in heart failure-related I_Ks downregulation, a result that would not be surprising in view of the important regulation of I_Ks function by associated proteins in macromolecular complexes (187).

The downregulation of K⁺ currents can promote the occurrence of arrhythmogenic early afterdepolarizations, either by directly prolonging APD in the voltage range at which I_CaL reactivation generates afterdepolarizations (217, 334), or by reducing "repolarization reserve" (262), as illustrated in Figure 3. Repolarization reserve refers to the ability of cardiomyocytes to compensate for the loss of a repolarizing current by recruiting other outward currents, thereby minimizing the repolarization deficit. Loss of repolarization reserve can result in imperceptible repolarization changes at baseline because of remaining compensatory mechanisms, but greatly exaggerated repolarization abnormalities when a major compensating component is lost. Thus cardiac failure itself may not greatly prolong ventricular or Purkinje cell APD, but may result in exaggerated responses and tachyarrhythmias upon exposure to I_Kr blockers (117, 319). An additional, indirect consequence of heart failure-induced K⁺ current downregulation is the promoting effect of I_K1 decreases on the occurrence of delayed afterdepolarizations. The large background I_K1 conductance produces a very small resting membrane resistance. When I_K1 is reduced, membrane resistance increases, causing a much bigger voltage deflection for a given quantity of depolarizing membrane current (Fig. 4). Pogwizd et al. (246) have shown this to be an important mechanism for the promotion of afterdepolarization-induced arrhythmias in a rabbit heart failure model.

View larger version (17K): [in this window] [in a new window]   FIG. 3. The importance of repolarization reserve. A: normal action potential, along with a schematic diagram of corresponding rapid (IKr) and slow (IKs) delayed-rectifier current. For the normal action potential (AP), IKr is much larger than IKs. B: when IKs is reduced by 90%, the effect is very small because 1) baseline IKs for the normal AP is small and 2) IKr increases to compensate. C: when IKr is reduced by 90%, APD is prolonged, but because the longer AP leaves more time for activation of IKs, APD prolongation is limited. D: when IKs is now also reduced by 90%, the compensation is lost and APD increases substantially. Note that the APD-prolonging effect of blocking IKs when repolarization reserve is reduced by decreased IKr (compare D with C) is much greater than when repolarization reserve is intact (compare B with A). Similarly, the APD-prolonging effect of IKr inhibition is much greater when IKs is reduced (compare D with B) than when IKs is intact (compare C with A).

View larger version (12K): [in this window] [in a new window]   FIG. 4. Role of congestive heart failure (CHF)-induced IK1 reduction and consequent membrane resistance increase in delayed aftedepolarization promotion. A: the myocardial diastolic membrane resistance is determined by the normally high resting conductance (g) to K+ through IK1, which keeps the resistance very low. If an abnormal depolarizing diastolic current arises [e.g., generated by Na+-Ca2+ exchange (NCX) of abnormally released Ca2+], the resulting voltage deflection (V), given mathematically by the product of membrane resistance R and current amplitude I, will be small. B: if IK1 is reduced as in CHF, the membrane resistance increases and the voltage deflection caused by the same NCX-generated current will be greatly increased, potentially causing the cell to depolarize to threshold and fire an ectopic beat.

Cardiac failure has major effects on cellular Ca²⁺ handling. Some of the principal components of the Ca²⁺ handling system and associated abnormalities described in heart failure are illustrated in Figure 5. For a detailed discussion of cellular Ca²⁺ handling and coupled events, the interested reader is referred to some excellent recent reviews (19, 20). In brief, Ca²⁺ enters cardiomyocytes via a variety of Ca²⁺ conductances, of which that carrying L-type Ca²⁺ current (I_CaL) is the most prominent, with a potential but still controversial contribution of reverse-mode function of the Na⁺-Ca²⁺ exchanger, NCX (164). The voltage-dependent transsarcolemmal entry of Ca²⁺ triggers the release of additional Ca²⁺ from sarcoplasmic reticulum Ca²⁺ stores through closely coupled sarcoplasmic reticulum Ca²⁺ release channels. This process is commonly called Ca²⁺-induced Ca²⁺ release. The magnitude of Ca²⁺-induced Ca²⁺ release is governed by a number of factors, including sarcoplasmic reticulum Ca²⁺ content and the function of Ca²⁺ release channels. Ca²⁺ release channel function is regulated by phosphorylation, which depends particularly on key intracellular phosphorylating enzymes like protein kinase A and Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), as well as a variety of phosphatases which cause dephosphorylation. Sarcoplasmic reticulum Ca²⁺ content depends on cellular Ca²⁺ entry, particularly via I_CaL, Ca²⁺ removal from the cell (particularly via the sarcolemmal Ca²⁺ pump and forward-mode Na⁺-Ca²⁺ exchange) and Ca²⁺ pumping into the sarcoplasmic reticulum by the Ca²⁺-ATPase Ca²⁺ pump (the principal cardiac form of which is SERCA2a).

View larger version (62K): [in this window] [in a new window]   FIG. 5. Normal Ca2+ handling and Ca2+-handling remodeling in congestive heart failure (CHF). Left: normal Ca2+ handling. Ca2+ entering through the L-type Ca2+ current (ICaL) causes a triggered release of SR Ca2+ through the Ca2+ release channel (CaRC). CaRC function is stabilized by binding to calstabin (FKB12.6). When the cell repolarizes, cytoplasmic Ca2+ that has accumulated because of Ca2+ entry through ICaL and consequent SR release is removed from the cytoplasm by two main processes: Ca2+ extrusion via Na+-Ca2+ exchange (NCX) and Ca2+ uptake into the SR by the SR Ca2+-ATPase (SERCA). SERCA function is regulated by phospholamban. Right: changes in Ca2+ handling with CHF. CaRCs are hyperphosphorylated by -adrenergic controlled protein kinase A (PKA) and/or by Ca2+/calmodulin kinase II (CaMKII). CaRC hyperphosphorylation dissociates FKB12.6, destabilizing the CaRC and causing abnormal diastolic Ca2+ leak from the SR. NCX activity is enhanced, promoting delayed afterdepolarization formation and reducing intracellular Ca2+ stores by extruding more Ca2+ out of the cell. SERCA function is reduced, both by reduced SERCA expression and by the action of protein phosphatase-1 (PP1)-mediated dephosphorylation of phospholamban. Decreased SERCA function further impairs SR Ca2+ stores and reduces contractility.

Studies of I_CaL have produced varying results, with some showing a decrease (170, 203, 232) and others no change (21, 122, 142, 171, 194). These apparently discrepant results are likely due to two opposing heart failure-induced changes in I_CaL. The membrane density of I_CaL channels is reduced by cardiac failure (53, 122, 203). However, channel phosphorylation is increased, leading to reduced response to phosphorylating interventions (53, 232) and causing increased single-channel open probability (281) that compensates for the reductions in channel density.

2. Changes in Ca²⁺-handling proteins

Heart failure causes very significant changes in Ca²⁺-handling proteins. The results of relevant studies are summarized in Table 3. Na⁺-Ca²⁺ exchange is enhanced by cardiac failure, and most studies show increases in Na⁺-Ca²⁺ exchanger mRNA and protein expression. Decreases in SERCA2a function are also commonly observed, and most studies have shown decreases in corresponding mRNA. Studies of SERCA2a protein expression have provided discrepant results (Table 3): of five studies performed before 1998, three showed SERCA2a protein to be unchanged and two showed a decrease; however, six studies performed subsequently consistently show decreased SERCA2a protein expression. Phospholamban is a small regulatory peptide that controls sarcoplasmic reticulum Ca²⁺-ATPase function: dephosphorylated phospholamban inhibits SERCA2a function by decreasing its affinity for Ca²⁺, whereas phospholamban phosphorylation removes this inhibition. Phospholamban expression appears unchanged in heart failure; however, phospholamban phosphorylation is decreased, possibly because of increased phosphatase activity and expression (113, 132), leading to reduced SERCA2a function (272, 283). Mishra et al. (198) found reduced Ca²⁺/calmodulin kinase function in experimental heart failure, along with reduced phospholamban phosphorylation at both protein kinase A (Ser-16) and CaMKII (Thr-17) sites.

Ca²⁺ release channels are found in macromolecular complexes along with protein kinase A, CaMKII, various phosphatases, and calstabin. Ca²⁺ release channel phosphorylation leads to calstabin dissociation (188). There is evidence for increased Ca²⁺ release channel phosphorylation by protein kinase A in heart failure (4, 188), with a potentially important role in progression of the condition (339). It has been suggested that protein kinase A phosphorylation destabilizes Ca²⁺ release channels by causing calstabin dissociation, thereby reducing sarcoplasmic reticulum Ca²⁺ stores via increased diastolic Ca²⁺ leak and producing triggered arrhythmias due to abnormal diastolic Ca²⁺ discharge (167). However, the precise role of protein kinase A phosphorylation of Ca²⁺ release channels in heart failure is controversial. Some studies failed to find increased protein kinase A hyperphosphorylation of Ca²⁺ release channels in experimental models of cardiac dysfunction (140, 221). Other investigators were unable to show significant effects of protein kinase A phosphorylation on Ca²⁺ release channel function (174, 298) and suggested that effects on phospholamban may be of greater importance for protein kinase A actions on Ca²⁺ release events (174). Whether heart failure causes protein kinase A hyperphosphorylation of Ca²⁺ release channels has been contested (347, 349), as has the ability of such phosphorylation to dissociate calstabin (348). There is evidence that abnormal Ca²⁺ uptake, rather than changed Ca²⁺ release channel function, may be crucial for sarcoplasmic reticulum Ca²⁺ handling abnormalities in heart failure (140). In at least one study, CaMKII-induced hyperphosphorylation was quantitatively and functionally more important in heart failure-induced sarcoplasmic reticulum Ca²⁺ release channel dysfunction than that caused by protein kinase A, and produced important sarcoplasmic reticulum diastolic Ca²⁺ leaks (4). The deltaC isoform of CaMKII is particularly overexpressed in pressure overload-induced cardiac dysfunction, and targeted overexpression of this isoform leads to a cardiomyopathic phenotype with Ca²⁺ release channel hyperphosphorylation that precedes any signs of heart failure (366). Thus the weight of evidence suggests that CaMKII modulation of the Ca²⁺ release channel-calstabin interaction is particularly important for Ca²⁺-handling abnormalities and triggered arrhythmias in heart failure.

3. Functional consequences

The changes in Ca²⁺ handling caused by heart failure have important implications for cardiac function and arrhythmogenesis. The cytoplasmic Ca²⁺ content increases resulting from Ca²⁺ entry through I_CaL and subsequent sarcoplasmic reticulum Ca²⁺ release are handled by two principal mechanisms: 1) Ca²⁺ exchange for Na⁺ across the sarcolemma to the extracellular space and 2) SERCA2a-mediated transport back into the sarcoplasmic reticulum. Decreased SERCA2a activity and increased Na⁺-Ca²⁺ exchange favor net Ca²⁺ efflux from the sarcoplasmic reticulum towards the extracellular space. This efflux reduces cellular Ca²⁺ stores and consequently decreases contractile function. Increased diastolic Ca²⁺ loss from the sarcoplasmic reticulum because of leaky Ca²⁺ release channels, resulting from hyperphosphorylation and decreased calstabin expression, further contributes to reducing Ca²⁺ stores and impairs contractility. In cardiomyocytes from dogs with heart failure, Na⁺-Ca²⁺ exchange inhibition normalizes the systolic Ca²⁺ transient and sarcoplasmic reticulum Ca²⁺ load (125). Similarly, increasing SERCA2a function by adenoviral gene transfer of a dominant-negative construct of phospholamban improves SR Ca²⁺ stores and reverses contractile dysfunction (374). CaMKII overexpression by recombinant adenovirus infection into adult rabbit cardiomyocytes increases diastolic Ca²⁺ leak and reduces sarcoplasmic reticulum Ca²⁺ stores, but without suppressing contractility, suggesting active compensatory mechanisms (157). Enhanced calstabin binding improves function in heart failure, but only in wild-type, not calstabin-knockout, mice (338). Thus a variety of innovative interventions that restore more normal Ca²⁺ homeostasis show promise for heart failure therapy.

Triggered activity related to delayed afterdepolarizations caused by spontaneous diastolic Ca²⁺ release is an important mechanism underlying ventricular tachyarrhythmias caused by cardiac failure (246, 332). Delayed afterdepolarizations occur in congestive heart failure despite reduced cell Ca²⁺ stores because of a number of features of cardiac failure-induced ion transport remodeling (4, 245, 246). 1) Hyperphosphorylated Ca²⁺ release channels are prone to spontaneous diastolic Ca²⁺ release. 2) For any given level of Ca²⁺ release, enhanced Na⁺-Ca²⁺ exchange function increases the depolarizing current resulting from electrogenic Ca²⁺ extrusion, with three Na⁺ (total charge +3) transported into the cell for every Ca²⁺ ion (charge +2) transported out. 3) I_K1 downregulation increases membrane resistance, resulting in a larger depolarization for a given inward current (Fig. 4).

D. Alterations in Na⁺ Current

1. Na⁺ current changes

I_Na is responsible for rapid initial (phase 0) action potential depolarization (280) and provides the electrical energy for electrical impulse propagation. As such, it is a key determinant of cardiac conduction speed. In addition, appropriate I_Na inactivation is essential for effective action potential repolarization; abnormalities in I_Na inactivation produce large inward Na⁺ currents during the cardiac action potential plateau, causing repolarization failure, early afterdepolarizations, and life-threatening ventricular tachyarrhythmias (209). A variety of Na⁺ channel abnormalities have been demonstrated in heart failure. Several studies suggest that peak I_Na is reduced (161, 321, 324, 372). Possible underlying mechanisms include posttranscriptional reductions in the cardiac I_Na -subunit protein Nav1.5 (372) and posttranslational mechanisms (161, 321) such as deficient Nav1.5 glycosylation (321).

Additional data point to abnormalities in I_Na inactivation. Inactivation deficiencies result in an abnormally large late component of I_Na, which flows during the action potential plateau in failing human (183, 323, 324) and animal (321, 324) hearts. These abnormalities cause APD prolongation and early afterdepolarizations (321, 323). Single-channel studies show that both a bursting mode and scattered late openings are responsible for late I_Na (322).

2. Functional consequences

Since I_Na is a major determinant of cardiac conduction velocity, I_Na reductions contribute to conduction slowing in failing hearts. Slowed intracardiac conduction favors reentry (211) and contributes to dyssynergic and inefficient cardiac contraction. In addition, I_Na inactivation failure promotes arrhythmogenic early afterdepolarizations. The relative importance of I_Na dysfunction compared with other cardiac failure-related abnormalities causing conduction slowing (like connexin dysfunction and tissue fibrosis) and early afterdepolarizations (like K⁺ channel abnormalities) is unclear.

E. Changes in Connexin Function

1. Cell-coupling and connexin changes

Conduction abnormalities are a common feature of cardiomyopathies, both clinical (149) and experimental (163). The underlying mechanisms have been a subject of intense investigation. In 1999, De Mello (66) described a decline in cell-to-cell coupling in cardiomyopathic hamsters. Subsequent studies showed substantial abnormalities in the expression, distribution, and regulation of the connexin proteins that effect electrical continuity between cardiomyocytes. The expression of the principal ventricular connexin isoform, connexin43, is downregulated by heart failure (5, 7, 78, 158, 243). Heart failure activates the mitogen-activated protein kinase C-Jun NH₂-terminal kinase (JNK), which downregulates connexin43 (239). In addition to decreasing connexin43 expression, heart failure causes phosphorylation changes that impair connexin43 function. Increased tyrosine phosphorylation by c-Src tyrosine kinase in cardiomyopathic hearts can impair connexin43 function (314), and more recent work points to defects in connexin43 phosphorylation (5, 7). Connexin43 dephosphorylation is due to increased colocalization with protein phosphatase-2, and impairments in cellular coupling can be improved by the phosphatase inhibitor okadaic acid (5). Changes in connexin43 expression may be regionally determined and aggravated by dyssynchronous contraction (243, 297). Increased heterogeneity of connexin43 expression is associated with an increased likelihood of ventricular tachyarrhythmias (152). Other connexins, including connexin45 (353) and connexin40 (78), are upregulated in failing hearts, possibly as a compensation for connexin43 downregulation. However, the functional importance of connexin40/45 upregulation in failing hearts is uncertain because neither is importantly expressed in the ventricles.

2. Functional consequences

Decreased connexin43 expression and phosphorylation contribute to conduction slowing in the failing heart (5, 7). Such conduction abnormalities in turn contribute to mechanical dysfunction and adverse ventricular remodeling (297), producing a deleterious positive feedback system: cardiac failure causes connexin dysfunction, which produces conduction abnormalities that result in dyssynchronous contraction, which further worsens the state of the failing heart. Conduction abnormalities also predispose to the generation of reentrant arrhythmias. In addition, cellular uncoupling enhances APD heterogeneity (243), which favors the occurrence of reentry.

F. Hyperpolarization-Activated, Cyclic Nucleotide-Gated Nonselective Cation Channels

1. Changes in hyperpolarization-activated nonselective cation currents and corresponding subunits

Hyperpolarization-activated, cyclic nucleotide-gated (HCN) subunits encode the relatively nonselective cation channel I_f, which plays an important role in cardiac pacemaking (67, 300). Sinus node function is impaired in both clinical (273) and experimental (230, 371) heart failure. Downregulation of I_f causes the sinus node pacemaker dysfunction seen in failing rabbit hearts (331). Sinus node dysfunction in dogs with heart failure is associated with mRNA and protein downregulation of both HCN4 and HCN2 (371), suggesting that HCN subunit remodeling decreases I_f and impairs pacemaking. In contrast, HCN subunits are upregulated in failing atria (371), in which increased I_f function may contribute to heart failure-related arrhythmic activity from abnormal (ectopic) foci (127).

2. Functional consequences

Clinically significant sinus node dysfunction is common in patients with heart failure and may contribute to cardiac decompensation (9). Heart failure patients have an increased risk of bradycardia requiring artificial pacemaker implantation. When a pacemaker is needed, the pacing lead is usually installed in the right ventricle (because of ready access via peripheral veins), producing a dyssynchronous cardiac contraction pattern with left ventricular contraction lagging behind. Dyssynchronous contraction may cause adverse ventricular remodeling (297). Biventricular pacing, which is technically more complicated to install and more expensive, may be required to optimize cardiac function and prognosis in heart failure patients (50). Increased I_f in nonpacemaking tissues of heart failure patients may induce arrhythmias by causing abnormal impulse generation, which may be suppressible by recently introduced I_f blocking drugs (27).

	III. REMODELING OF IONIC CURRENTS ASSOCIATED WITH CARDIAC DISEASE: MYOCARDIAL INFARCTION

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A. Significance and Arrhythmic Consequences

Myocardial infarction refers to the death of cardiac tissue, most often caused by critical decreases in coronary artery blood flow induced by obstructive coronary artery disease. Prior myocardial infarction is an important risk factor for sudden cardiac death (144), due primarily to ventricular tachyarrhythmias. There is a very extensive experimental literature regarding ventricular arrhythmia mechanisms in myocardial infarction; for a detailed review, see Janse and Wit (135). Several mechanisms, including reentry and triggered activity due to early and delayed afterdepolarizations, contribute to ventricular tachyarrhythmia induction (63, 135, 253). Remodeling of ion-channel and transport processes cause important changes in cellular electrical activity and impulse propagation over days and weeks following acute infarction. Within the infarct zone itself, most ventricular cardiomyocytes die, leaving a surviving subendocardial Purkinje fiber layer with prolonged action potentials and enhanced automaticity (95, 296). Surviving cardiomyocytes in the viable border zone adjacent to a prior infarction have signs of reduced excitability: reduced action potential amplitude and dV/dt_max (181), along with postrepolarization refractoriness (44). Marked abnormalities of activation include very slow and sometimes discontinuous conduction (63, 99, 293). Features like electrotonic potentials and a decreased space constant suggest abnormal cell-to-cell coupling (294). These abnormalities cause severe conduction disturbances that strongly promote reentry. A particularly important arrhythmia mechanism is anisotropic reentry in the peri-infarction border zone (68, 192, 261). Acute myocardial infarction causes longer term (remodeling) changes over days to weeks, as well as important very early (within minutes to hours) functionally based ion-channel abnormalities caused by intracellular acidosis, K⁺ loss, and membrane breakdown. In this review, we deal with only the longer term remodeling changes. Figure 6 illustrates how different forms of ion-channel remodeling contribute to anisotropic reentry in the presence of a healed myocardial infarction.

View larger version (35K): [in this window] [in a new window]   FIG. 6. Contributors to anisotropic reentry in myocardial infarction (MI). A principal mechanism underlying potentially lethal ventricular tachyarrhythmias post-MI is anisotropic reentry, represented schematically by the black activation map in the central part of the figure [From Peters et al. (237).] The numbers indicated on the map are times of electrical activation, and the curved lines (isochrones) indicate zones of tissue activated within 10 ms of each other. Crowded isochrones denote very slow conduction. Thicker black lines show lines of functional conduction block parallel to fiber orientation, due to the impaired transverse conduction (increased anisotropy) post-MI. The impulse travels slowly in two parallel streams (thick arrows) around the lines of block, which come together to conduct through the central corridor (thinner arrows) of the reentrant pathway. The ways in which ion-channel remodeling post-MI lead to this arrhythmia mechanism are indicated by the red points, organized into groups of dysfunction categories (blue underlined headings). Increased tissue anisotropy, which causes the unidirectional block needed for reentry initiation, arises because of connexin downregulation, reduced gap junction number and size, fewer side-to-side connections, and tissue fibrosis around muscle bundles. Unidirectional block is also favored by refractoriness heterogeneity due to spatially heterogeneous K+ channel downregulation coupled with postrepolarization refractoriness. Slowed conduction, which allows enough time for the proximal part of the central corridor to recover excitability when the reentering impulse returns, is caused by connexin downregulation, INa decreases, and reduced ICaL (ICaL is particularly important for conduction in conditions of impaired coupling). Finally, the ectopic complexes needed to engage spatially variable refractoriness and initiate reentry are provided by early afterdepolarizations (EADs) promoted by K+ current downregulation and delayed afterdepolarizations (DADs) caused by spontaneous diastolic Ca2+ releases from the SR.

Myocardial infarction causes substantial changes in K⁺ current expression, density, and function. Key sources of postinfarction arrhythmias are situated in border-zone cells, including the often-spared epicardial rim, the lateral margins, and subendocardial Purkinje fibers nourished by left ventricular cavity blood (135). Alterations in border-zone tissues have been studied almost exclusively in large-animal models (dogs or cats). Studies in smaller-animal models (rats and rabbits) have examined changes in cells remote from the infarction, which reflect the effects of cardiac hypertrophy and/or failure caused by a loss of cardiac tissue in the necrotic infarct zone rather than infarction per se.

1. Changed K⁺ current function in surviving border-zone cells

Increased border-zone cell APD, particularly in subendocardial Purkinje cells (95), causes early afterdepolarizations and related arrhythmias (110). A variety of K⁺ currents are downregulated in border-zone cells. Background K⁺ conductance is reduced in surviving canine subendocardial Purkinje fibers (31), due to reduced I_K1 and altered delayed-rectifier currents (240). Border-zone left ventricular cardiomyocytes show reduced I_to (181). I_to decreases are most prominent within days of acute infarction and tend to resolve over the subsequent 2 months (74). Delayed-rectifier currents are also reduced in border-zone cardiomyocytes (75, 139, 361). Both I_Kr and I_Ks decrease (139). The expression of subunits encoding I_Kr (ERG) and I_Ks (KvLQT1 and minK) is downregulated in 2-day postinfarction border-zone cells. ERG and KvLQT1 expression normalizes by day 5, whereas minK remains suppressed. Persistent decreases in minK with normalized KvLQT1 expression may underlie unusual delayed-rectifier currents with very rapid activation (75, 139), resembling currents produced by the expression of KvLQT1 in the absence of minK (18, 274). Overall, the multiple forms of K⁺-channel dysfunction postinfarction impair repolarization and lead to early afterdepolarizations.

2. Changes in K⁺ currents in normal zones of hearts with prior myocardial infarction

APD increases and ventricular arrhythmias are features of normal-zone tissues from postinfarction rat (130, 145, 146, 235, 253) and rabbit (179) hearts. Both reentry associated with spatial refractoriness heterogeneity and triggered activity are involved (179, 253). Decreases in I_to, I_K1, and total delayed-rectifier current (I_K) occur in rabbit hearts (179). In rats, I_to decreases correlate most closely with downregulation of Kv4.2 subunits (106, 130, 145, 146, 235, 359). Metabolic disturbances contribute to postinfarction I_to decreases in rats (267, 269). There may be compensatory upregulation of Kv1.4 subunits (145, 146), although downregulation of Kv1.4 has also been reported (106). Decreases in rat I_K correlate with downregulation of the putative -subunit Kv2.1 (130, 131). The effects of postinfarction remodeling on spatial dispersion of electrophysiological properties in noninfarcted tissues are controversial, with one study showing increases in dispersion (131) and another decreased spatial heterogeneity (145).

C. Alterations in Ca²⁺ Currents and Cellular Ca²⁺ Handling

Changes in Ca²⁺ handling contribute importantly to arrhythmogenesis postinfarction. Changes may be due to the infarct per se, and be restricted to the border zone, or may occur broadly in noninfarcted myocardium and be related to myocardial hypertrophy and/or failure. In this section, we limit ourselves to studies of Ca²⁺ handling in border-zone cells.

1. Changes in Ca²⁺ current

I_CaL is diminished in border-zone cells of dogs (2, 74), sheep (150), cats (241), and rabbits (178). I_CaL kinetic properties also change, with slowed recovery (74) and hyperpolarizing shifts in inactivation voltage dependence (241). The I_CaL response to dihydropyridine agonists (252) and tyrosine kinase inhibitors (351) is preserved in the border zone. T-type Ca²⁺ current (I_CaT) varies over time, being unchanged 5 days postinfarction (2) and increasing thereafter (74). In surviving subendocardial Purkinje cells, both I_CaL and I_CaT are reduced (34).

2. Changes in cellular Ca²⁺ handling

Ca²⁺ transients in border-zone cells are decreased in amplitude and show slowed recovery and decay (150, 176). SERCA2A is downregulated (150). The diminished and slowed Ca²⁺ transients are due to impaired spatial coordination of quantal Ca²⁺ releases, or sparks (178). Na⁺-Ca²⁺ exchange function is unaltered, and action potential abnormalities are not responsible for Ca²⁺ handling abnormalities (251). Surviving subendocardial Purkinje cells show marked abnormalities in subcellular Ca²⁺ release events, with spontaneous and spatiotemporally nonuniform microreleases that can trigger arrhythmic episodes (32). Drugs that suppress Ca²⁺ microreleases by either inhibiting sarcoplasmic reticulum Ca²⁺ release channels or inositol trisphosphate receptors may constitute a novel antiarrhythmic approach postinfarction (33).

D. Alterations in Na⁺ Current

1. Na⁺ current changes

Surviving border-zone tissue is characterized by reduced phase 0 amplitude and upstroke velocity (dV/dt_max), suggestive of reduced I_Na (95, 293). These abnormalities in excitability favor unidirectional block and reentry (135). Isolated border-zone cardiomyocytes also have reduced dV/dt_max (181) and marked abnormalities in I_Na, including reduced current density, accelerated inactivation, and slowed reactivation (250). I_Na changes are related to abnormal cell-membrane localization of I_Na (Nav1.5) -subunit protein (16). Computer simulations suggest that both I_Na and I_CaL abnormalities contribute to conduction abnormalities in the reentry circuit (16), in keeping with the key role of I_CaL in the context of reduced coupling (286). Protein kinase A activators partially improve I_Na in peri-infarct zone cells, and the response to phosphatase inhibitors suggests that I_Na is hyperphosphorylated (15). In late postinfarction rat cardiomyocytes, changes in I_Na properties and in ion-channel subunit expression suggest the appearance of atypical I_Na isoforms (12, 129); these changes may be due to generalized cardiac hypertrophy/dysfunction rather than infarction per se.

2. Functional consequences

Oxidative stress in postinfarction tissues produces reactive intermediates (especially E2-isoketals) that alter I_Na in a fashion similar to arrhythmogenic Nav1.5 subunit mutations and potentiate the effects of Na⁺ channel-blocking drugs (96). The I_Na blocker lidocaine differentially affects peri-infarct zone cardiomyocytes (249). These differential effects may contribute to the tendency of I_Na blockers to cause malignant ventricular tachyarrhythmias postinfarction (216, 256). These paradoxical "proarrhythmic" effects of I_Na-blocking antiarrhythmic drugs on myocardial infarction tissues contribute to a mortality-enhancing potential (47).

E. Changes in Connexin Function

Cells in the surviving peri-infarct zone have prepotentials and notches on phase 0 upstrokes, reduced space constants, and discontinuous propagation due to abnormal cell-to-cell coupling (99, 294, 295). Marked changes in gap junction organization and connexin43 distribution occur within healed myocardial infarctions in human (236), canine (236, 237), and rat (190, 191) models. Gap junction changes precede the formation of the infarct scar and are thus a primary phenomenon unrelated to physical cell separation by scar tissue (236). Postinfarction remodeling of gap junction distribution in rats is linked to desmosome and adherens junction alterations, with temporary intracellular junctional complexes formed as a component of complex remodeling of cell-to-cell and cell-to-extracellular matrix interactions (190). In healed myocardial infarctions from dogs, there are smaller and fewer gap junctions, with a decreased proportion of side-to-side versus end-to-end connections (236). Decreased side-to-side intercellular coupling contributes to transverse conduction block (perpendicular to fiber orientation) and anisotropic reentry (358). In hearts with inducible ventricular tachyarrhythmias, connexin43 disorganization extends through the full thickness of surviving myocardium at sites corresponding to the central common pathways of figure-8 reentrant circuits (237). Thus coupling abnormalities due to connexin changes are central to ventricular arrhythmogenesis postinfarction.

	IV. REMODELING OF IONIC CURRENTS ASSOCIATED WITH ATRIAL FIBRILLATION

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A. Significance and Arrhythmic Consequences

AF, which causes very rapid and highly irregular atrial firing, is the most common sustained arrhythmia in the developed world, with an age-dependent prevalence exceeding 10% in elderly populations (1, 316), and is a significant source of cardiovascular morbidity and mortality (215). AF results from a variety of conditions that cause ion-channel remodeling, including congestive heart failure and acute myocardial infarction, with features discussed in detail elsewhere in this review. In addition, however, AF itself causes ionic current remodeling, which plays a significant role in AF pathophysiology. AF alters atrial electrophysiological properties in a way that favors AF occurrence (this auto-perpetuation phenomenon has been called "AF begets AF"), both by increasing AF sustainability and by enhancing atrial vulnerability to AF induction by premature atrial beats (10, 71, 218, 342). The primary factor in AF-induced remodeling is the rapid atrial rate: any sufficiently rapid atrial tachycardia produces remodeling virtually indistinguishable from that caused by AF itself (303, 343). This form of remodeling, often called atrial tachycardia remodeling, is studied in experimental animals by rapidly pacing ("tachypacing") the atria for days or weeks. The principal mechanisms by which atrial tachycardia remodeling promotes AF involve facilitation of atrial reentry, via regionally heterogeneous atrial refractoriness abbreviation and abnormalities in atrial conduction properties (90, 101, 200, 342). In addition, there is evidence of enhanced focal atrial driver activity (200), possibly related to triggered activity associated with Ca²⁺-handling abnormalities (333, 370). Figure 7 illustrates the role of ion-channel and transporter remodeling in atrial tachycardia remodeling. Conceptually, the atria adapt to AF in ways that enable them to maintain rapid atrial firing with minimal metabolic cost, but at the expense of making AF more likely to be sustained.

View larger version (32K): [in this window] [in a new window]   FIG. 7. Pathophysiology of AF promotion by atrial tachycardia remodeling (ATR). The ATR-induced changes in atrial-cardiomyocyte electrophysiology that result in AF promotion are indicated in red, with control-cell properties depicted in black. ATR creates a substrate for multiple circuit reentry; for a detailed review, see Nattel et al. (214). The reentry substrate is favored by decreases in refractory period (RP) and conduction velocity (CV). The minimum size of a functional reentry circuit is given by the wavelength (WL), or product of RP and CV. The shorter the WL, the larger the number of reentry circuits that can be maintained simultaneously. When the WL is reduced, the atria move from the condition shown at the left of the black inset, in which very few circ