Article

Ion Channel Remodelling in Atrial Fibrillation

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Abstract

Atrial fibrillation (AF) is the most common arrhythmia and is associated with substantial cardiovascular morbidity and mortality, with stroke being the most critical complication. Present drugs used for the therapy of AF (antiarrhythmics and anticoagulants) have major limitations, including incomplete efficacy, risks of life-threatening proarrhythmic events and bleeding complications. Non-pharmacological ablation procedures are efficient and apparently safe, but the very large size of the patient population allows ablation treatment of only a small number of patients. These limitations largely result from limited knowledge about the underlying mechanisms of AF and there is a hope that a better understanding of the molecular basis of AF may lead to the discovery of safer and more effective therapeutic targets. This article reviews the current knowledge about AF-related ion-channel remodelling and discusses how these alterations might affect the efficacy of antiarrhythmic drugs.

Keywords

Atrial fibrillation, remodelling, ion channels, mechanisms,

Disclosure:The authors have no conflicts of interest to declare.

Received:

Accepted:

DOI:https://doi.org/10.15420/ecr.2011.7.2.97

Acknowledgements:The authors’ research is supported by the Deutsche Forschungsgemeinschaft (Do769/1-1-3), the German Federal Ministry of Education and Research through the Atrial Fibrillation Competence Network (01Gi0204), the European-North American Atrial Fibrillation Research Alliance (ENAFRA) network grant of Fondation Leducq (07CVD03) and the European Network for Translational Research in Atrial Fibrillation (EUTRAF) FP7 programme grant of the European Union (No 261057).

Correspondence Details:Dobromir Dobrev, Division of Experimental Cardiology, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany. E: dobromir.dobrev@medma.uni-heidelberg.de

Copyright Statement:

The copyright in this work belongs to Radcliffe Medical Media. Only articles clearly marked with the CC BY-NC logo are published with the Creative Commons by Attribution Licence. The CC BY-NC option was not available for Radcliffe journals before 1 January 2019. Articles marked ‘Open Access’ but not marked ‘CC BY-NC’ are made freely accessible at the time of publication but are subject to standard copyright law regarding reproduction and distribution. Permission is required for reuse of this content.

Atrial fibrillation (AF) is common and is associated with significant cardiovascular morbidity and mortality, with stroke being the most critical complication.1,2 Drugs presently used for AF therapy have major limitations, including incomplete efficacy and risks of life-threatening proarrhythmic events (antiarrhythmic drugs) and bleeding complications (anticoagulants).3 Non-pharmacological ablation procedures are efficient and apparently safe, but only a small number of patients can be treated.4–6 These limitations largely result from the limited knowledge about the underlying mechanisms of AF. There is a hope that a better understanding of the molecular basis of AF may uncover safer and more effective therapeutic targets. In this article, current knowledge about AF-related ion-channel remodelling is reviewed and how such remodelling might affect the efficacy of antiarrhythmic drugs is discussed.

Fundamental Atrial Fibrillation Mechanisms

The mechanisms underlying AF induction and maintenance are incompletely understood, but it is generally accepted that re-entry is the major mechanism of AF maintenance. Re-entry induction requires an appropriate vulnerable substrate, as well as a trigger that initiates re-entry within the substrate (see Figure 1).

Single-circuit re-entry can maintain AF by functioning as a rapid driver that induces fibrillatory conduction. Multiple-circuit re-entry involves coexisting functional re-entry-circuits that maintain fibrillatory activity because the rate of new-circuit formation exceeds the rate of circuit extinction, continuously maintaining AF episodes. The likelihood of re-entry is determined by the tissue properties of conduction and refractoriness (for detailed discussion see7,8), with slow conduction and short refractoriness making persistence of re-entry more likely.

Another mechanism potentially involved in AF is ectopic activity, which is governed by factors controlling the occurrence of afterdepolarisations, primarily Ca2+-handling abnormalities that can cause delayed afterdepolarisations (see Figure 1). Ectopic activity can also result from excessive action potential duration (APD) prolongation, which produces early afterdepolarisations. It remains to be shown whether early afterdepolarisations contribute to AF pathophysiology.

Prolonged episodes of AF alter atrial properties (‘atrial remodelling’) promoting AF maintenance (see Figure 1).9 Changes in atrial structure or function that constitute atrial remodelling are key elements in the AF-substrate.7,10 Remodelling increases the likelihood of ectopic firing or re-entry, thereby promoting AF initiation and/or maintenance. Ion-channel remodelling shortens the effective refractory period (ERP) by reducing APD.7,10,11 Spatially heterogeneous ERP abbreviation promotes the conduction block and wave break underlying fibrillatory conduction and APD shortening contributes to AF-related atrial contractile dysfunction.12–16 APD, and thus ERP, is determined by the balance between inward currents that depolarise and outward currents that repolarise cardiac myocytes (see Figure 2).

Studies in animal models and in patients with chronic AF have shown that the following are major contributors to APD shortening:17–24

  • decreased L-type Ca2+ current (ICa,L; reduced depolarisation power);
  • increased inward rectifier K+ current (IK1; enhanced repolarisation power); and
  • constitutively-active acetylcholine-independent K+ current (IK,ACh,c enhanced repolarisation power).

Initially the resulting shortening of APD helps to compensate for initial Ca2+ overload (see Figure 1), but this occurs at the expense of decreased ERP, which favours re-entry.7,25 The shorter refractoriness together with an unchanged sodium current (INa) may promote the induction of high-frequency sources (rotors). These undergo complex, spatially distributed conduction block patterns with wavefront fractionation manifesting as ‘fibrillatory conduction’ that maintains AF.26

Long-term AF causes profound alterations in atrial structure (cardiomyocyte hypertrophy, glycogen accumulation and interstitial fibrosis).27,28 These lead to inhomogeneous conduction slowing that promotes the development of anatomically-fixed re-entry circuits. Atrial remodelling is clinically important as it explains the transition of paroxysmal to persistent AF,9 the larger resistance of persistent AF to treatment29,30 and higher AF recurrence rate in the first days after cardioversion.31

Ion-channel Remodelling in Atrial Fibrillation

As introduced above, the AF-related shortening of the APD can be attributed to decreased inward currents, enhanced outward K+ currents or a combination of both. Depolarising inward INa and ICa,L currents are balanced by a diversity of repolarising K+ outward currents (see Figure 2). The main human atrial repolarising K+ currents include:

  • the transient outward current, Ito;
  • the ultra-rapidly activating delayed rectifier current, IKur;
  • the rapid (IKr) and the slow (IKs) activating delayed rectifier currents; and
  • the three inward rectifier currents, IK1, IK,ACh and ATP-sensitive IK,ATP.

There is also evidence for the existence and role of Ca2+-dependent small conductance potassium channels (SK channels) and transient receptor potential channels in shaping the human atrial AP (see below). Whether and how they contribute to remodelling in AF is currently unknown.

The molecular mechanisms leading to the repolarisation changes in AF are only partially understood. Increased atrial rate causes cellular Ca2+ loading,32 which alters cellular Ca2+ signalling leading to functional ICa,L inactivation, which attenuates initial Ca2+ overload.33 Persistent AF produces sustained Ca2+ loading that is offset by the decreased function of ICa,L and by increased Ca2+ extrusion via the Na+-Ca2+- exchanger. These compensatory changes limit cytotoxic Ca2+ influx but cause further ERP abbreviation, favouring multiple circuit re-entry (see Figure 1).8,10,25 The increase in intracellular Ca2+ is likely a primary signal for altered gene expression34 and regulation of ion channels.

Molecular Changes of INa

Sodium current (INa) density is reduced in a canine model of atrial tachycardia remodelling (ATR), with corresponding decreases in channel mRNA and protein expression.17 Such changes could contribute to the atrial conduction slowing seen in AF. Despite this theory, Gaborit et al. did not find evidence of atrial INa changes at the genomic level in AF patients.35 Data obtained in atrial myocytes from AF patients showed either unchanged36 or only slightly reduced37 INa amplitude.

Molecular Determinants of ICa,L Alterations

Reduced ICa,L density is a consistent finding in animal models of ATR and patients with AF.17–19,38 In control cardiomyocytes, inhibition of ICa,L with calcium-channel inhibitors mimics the APD abbreviation in ATR and AF.17–19 Reduced ICa,L was therefore initially considered as the only determinant of refractoriness shortening in ATR and AF. Subsequent studies, however, indicated important contributions of increased IK1 along with constitutively active IK,ACh.21–24,39–41 The molecular basis of decreased ICa,L in ATR and AF is complex and likely depends partly on underlying heart disease.

Transcriptional down-regulation of the Cav1.2 subunit, due to initial Ca2+ overload, is one potential mechanism of reduced ICa,L density.34,42,43 Direct measurements demonstrated that rapid pacing quickly increases cardiomyocyte intracellular Ca2+.32In addition to this, recent in vitro studies of tachypaced dog atrial cardiomyocytes directly confirmed that Ca2+ influx via ICa,L itself and the related Ca2+ overload are major determinants of the transcriptional down-regulation of ICa,L. Here, Ca2+-calmodulin/calcineurin-related mechanisms were implicated in modification of transcription.34 Some subsequent studies at the mRNA and protein level confirmed the reductions in Cav1.2 subunit abundance,35,44 whereas other reports found no change in protein amount or dihydropyridine receptor density in AF,19,45,46 suggesting the existence of alternative mechanisms.

There is evidence for increased Ca2+-channel dephosphorylation by increased activity of type-1 (PP1) and type-2A (PP2A) serine/ threonine protein phosphatases in AF19,46,47 that is expected to reduce the open probability, potentially explaining the decreased ICa,L amplitude. Defective regulation of ICa,L by inhibitory src-type tyrosine kinases may also participate in ICa,L dysregulation.46 S-nitrosylation of the Cav1.2 subunit is increased in AF and exogenously applied glutathione partially restores the AF-related ICa,L reduction.48 Thus, oxidative stress could play an important role in ICa,L changes.

Finally, some, but not all, investigations detected decreased expression of accessory β1, β2a, β2b, α2δ2 subunits.19,35,38,45,49 These may also contribute to the reduction of ICa,L.

Mechanisms of Altered Voltage-gated K+-currents

Ito amplitude is consistently reduced in animals with ATR and in AF patients.10,17,38,43,50 The functional consequences of impaired Ito are unclear, but reduced Ito might facilitate wave propagation by indirectly increasing the upstroke velocity of the atrial AP.

In ATR and AF, reductions in Ito are paralleled by decreases in both mRNA and protein expression of the pore-forming Kv4.3 subunit,43,50,51 with calpain-mediated proteolysis likely contributing to decreased Kv4.3 protein levels.52,53 CaMKII activity is enhanced in ATR15 and in AF patients.54,55 CaMKII accelerates Ito inactivation, but the higher PP1 and PP2A activity in AF19,46,47 could offset the enhanced CaMKII effect. Ca2+-dependent protein phosphatases, such as calcineurin, may suppress Kv4.3 gene transcription via a nuclear factor of activated T-lymphocyte-dependent mechanism56 because calcineurin activity is increased in AF.57

Results about the function of the ultra-rapid delayed-rectifier IKur are discrepant, showing either unchanged or reduced IKur function in AF.50 The contribution of IKur to atrial repolarisation depends on AP morphology and is increased with short-duration triangular APs, as occur in AF. For this reason, IKur may contribute more strongly to atrial repolarisation in AF cardiomyocytes.58,59

Decreased39,51,60 or unchanged36,61,62 current amplitude and unaltered mRNA or reduced protein levels of the pore-forming Kv1.5 subunit are reported.42,61,63,64 The inconsistent results regarding IKur function might result from variations in expression and posttranslational modifications of the principal channel α-subunit Kv1.5, including protein degradation due to increased proteolysis by calpains.53 Intracellular redox state is shifted to increased oxidant production in ATR and AF65,66 and Kv1.5 currents are inhibited by S-nitrosylation.67 Variations in underlying cardiac diseases35and/or concomitant medication may contribute to some of the inconsistencies in various clinical studies.50

The delayed-rectifier currents IKr and IKs are not changed in experimental ATR17 and information from AF patients is very limited, probably because of difficulties recording proper IKr and IKs in human atrial myocytes isolated with the ‘chunk’ method. Initial molecular studies in AF patients have reported decreased mRNA and protein abundance of the HERG-subunit of IKr and varying expression changes in the α-subunit (KvLQT1) of IKs, along with increased mRNA and protein levels of the β-subunit minK.35,50,63 One recent study detected higher IKs amplitude in left and right atrial myocytes of chronic AF patients and suggested enhanced IKs as an additional contributor to AF-related APD abbreviation.68 The function of atrial IKr during AF is still unknown.

Molecular Basis of Altered Inward Rectifier K+-current Function

The cardiomyocyte resting membrane potential is set primarily by background inward rectifier K+ conductances. The resting membrane potential is more negative in AF,21–24,41,69,70 which is consistent with the increased amplitude of inward rectifier K+-current, IK1, in both dogs with ATR and AF patients.20–24,40,41,69,71

Increased Kir2.1 mRNA21,35,72 and protein levels35,72 contribute to enhanced IK1 in clinical AF. In dogs with ATR of up to six weeks duration, however, Kir2.1 remains stable.43 This suggests that increased Kir2.1 mRNA is likely to be a consequence of longstanding ATR or underlying clinical conditions in AF patients. Single-channel studies show that increased whole-cell IK1 may result from the enhanced open probability in AF.22 The underlying molecular mechanisms remain to be determined. Despite this, channel phosphorylation reduces IK1 amplitude73 and channel dephosphorylation due to increased phosphatase activity of PP1 and PP2A19,46,47 could contribute to the increased IK1 activity in AF. MicroRNA-1 reciprocally regulates the Kir2.1 subunit expression of IK1 in coronary artery disease, contributing to arrhythmogenesis.74 MicroRNA-1 levels are greatly reduced in human AF, possibly contributing to up-regulation of Kir2.1 subunits, leading to increased IK1.72

Increased vagal activity strongly promotes AF by stabilising atrial re-entrant rotors and initiation of clinical AF is more likely under vagotonic conditions.75 Acetylcholine released from vagal nerve endings stimulates cardiac muscarinic receptors (M-receptors) that activate IK,ACh, which produces highly arrhythmogenic, spatially heterogeneous decreases in atrial ERP. In knock-out mice lacking IK,ACh, M-receptor stimulation does not induce AF.76 Besides activation by M-receptors, atrial IK,ACh is also stimulated by adenosine77 and sphingosine-1 phosphate78 receptors. The activation of IK,ACh in response to receptor stimulation is reduced, however, in ATR and AF patients.20,21,69

Recent work suggests that the reduced receptor-mediated IK,ACh activation is related to a loss of channel control by cardiac receptors. This leads to increased agonist-independent constitutive IK,ACh, both in dogs with ATR20,23,40 and in patients with chronic, but not paroxysmal, AF.22,24,41 Blockade of constitutive IK,ACh suppresses APD abbreviation and AF promotion in ATR preparations,23 indicating that constitutive IK,ACh contributes to ATR-induced atrial arrhythmogenesis.

Agonist-independent constitutive IK,ACh results from the enhanced open probability due to the increased frequency of channel openings.22,40 mRNA and protein expression of Kir3.1 and Kir3.4 subunits are unchanged in experimental ATR.40 In AF patients, however, the mRNA and protein levels of both subunits are decreased.21,35,41,42,63

In atrial myocardium, IK,ACh is localised in a macromolecular complex including catalytic subunits of PKA, PKC, CaMKII, PP1 and PP2A.79 Altered composition of this complex in AF may lead to abnormal phosphorylation-dependent IK,ACh regulation. Blockade of PKC reduces, whereas inhibition of protein phosphatases increases, constitutive IK,ACh activity80 and the abundance of PKCε protein is enhanced in AF.24 This clearly suggests that PKC-hyperphosphorylation of IK,ACh may underlie the AF-related development of agonist-independent constitutive IK,ACh activity.81

ATP-sensitive inward rectifier K+ currents (IK,ATP) are important contributors to ischemia-induced changes in cardiac electrophysiology and atrial ischaemia is likely to occur, particularly in persistent AF. IK,ATP amplitude is higher in myocytes from AF patients under ischaemic conditions,82 whereas IK,ATP activation in response to agonists like rilmakalim is strongly limited.83

Data about expression of the pore-forming Kir6.2 subunit are inconsistent.42,63 They suggest a complex and perhaps clinical condition-dependent regulation of IK,ATP in AF.

Remodelling of Ion Channels Involved in Atrial Conduction

Ventricular expression and function of the major cardiac connexin, connexin-43, is reduced by structural remodelling (gap junctional remodelling) and these changes correlate with pro-arrhythmic conduction slowing.84 Phosphorylation of connexins by different kinases determines connexin trafficking, gap junction assembly and channel-gating properties. Dephosphorylation and redistribution to lateral cell borders are prominent and important determinants of cardiac conduction disturbances.84,85

Relatively little is known about gap junctional remodelling in the atria, with discrepant results in the literature showing unchanged, increased and decreased connexin isoform expression.10,35,86 It is possible that the specific connexin alteration depends on the time course, underlying cardiac pathology and animal model used.87,88 Spatially heterogeneous connexin-40 remodelling is observed in the well-controlled goat AF-remodelling system.89 This is consistent with the extensive clinical evidence pointing to disturbances in connexin-40 as a basis for genetic AF predisposition.90–92

Remodelling of Other Plasmalemmal Ion Channels

Canonical transient receptor potential channels contribute to abnormal Ca2+ signalling in hypertrophy (for recent review see93) and are potentially involved in arrhythmias.94 Type-1 and type-3 transient receptor-potential channels are expressed in the human atrium of patients with diseased hearts. Transient receptor potential channel 3 protein expression is higher in animals with sustained AF and in AF patients.95 This suggests transient receptor potential channel 3 proteins as potential novel contributors to AF-related ion-channel remodelling.

In a recent genome-wide association study, a single nucleotide polymorphism that lies within the gene encoding a specific small conductance K+ channel (SK3) was associated with lone AF.96 Human atria express three different SK channel subunits (SK1–3).97 Overexpression of SK2 channels in mice shortens atrial AP,98 whereas SK2 knock-out prolongs APD and induces early afterdepolarisations.99 SK channels appear to contribute to pacing-induced shortening of APD in rabbit pulmonary veins.98 Although SK2 and SK3 channels are potential novel contributors to AF-related ion-channel remodelling, their precise roles in atrial remodelling require further extensive examination and validation.

Remodelling of Ion Channels and Transporters that Contribute to Atrial Ectopic Activity

Multiple studies have shown that abnormal SR Ca2+ handling may play a central role in the initiation and/or maintenance of AF in humans.100–107 Defective Ca2+ handling was shown to predispose to spontaneous sarcoplasmic reticulum (SR) Ca2+ release events in atrial myocytes from patients with chronic AF.100–103 SR Ca2+ load is not increased in chronic AF patients,100,103,105 suggesting that these spontaneous SR Ca2+ releases most likely occurred because of alterations in ryanodine receptor channels (RyR2) and the resulting increase in diastolic SR Ca2+ leak. Phosphorylation of RyR2 at Ser2808 (or Ser2809, depending on the species)101 by PKA and at Ser2814 (or Ser2815 depending on species)54,103,108 by CaMKII is higher in dogs with pacing-induced chronic AF and patients with chronic AF. These posttranslational alterations increase the sensitivity of RyR2 to cytosolic Ca2+ and enhance the open probability,101 providing a possible molecular mechanism for aberrant RyR2 function in AF.

It is very likely that enhanced RyR2 activity plays a role in AF pathogenesis, as mice with a gain-of-function mutation in RyR2 or knock-out of the RyR2-inhibitory FKBP12.6 subunit exhibit an increased susceptibility to pacing-induced AF.54,109 Using these mice models it was demonstrated that increased SR Ca2+ leak in atrial myocytes can promote triggered activity and atrial arrhythmias.

Altered RyR2 function in chronic AF is accompanied by an increase in Na+-Ca2+-exchanger expression and function.12,47,103,105,110 This suggests that diastolic SR Ca2+ leak can be amplified by the Na+-Ca2+-exchanger, thereby triggering delayed afterdepolarisations and subsequent ectopic focal discharges or facilitating micro-re-entry circuits promoting AF maintenance. In addition to this, IP3 receptor (IP3R2)-mediated SR Ca2+ release may also facilitate SR Ca2+ leak via RyRs, which promotes atrial arrhythmogenesis,111 and protein expression of IP3R2 is increased in a model of ATR.112 IP3R2-coupled amplification of atrial SR Ca2+ release events and related arrhythmogenesis may thus be an important contributor to AF-related ectopic activity.

Therapeutic Consequences of Ion-channel Remodelling

The changes in ion-channel function caused by AF alter the response to antiarrhythmic drugs, principally making AF more drug-resistant.113 A poorer response of more prolonged AF has been shown for both Na+- and K+-channel blockers.29,30,58

Early detection and termination of AF increases the clinical effectiveness of pharmacological cardioversion.30 A strategy of early cardioversion:

  • reduces atrial remodelling;114 
  • prevents atrial dysfunction;115 
  • reduces atrial size; and116
  • may prolong sinus-rhythm maintenance in the post-cardioversion period.116,117

Despite this, there is little evidence from clinical trials for the therapeutic value of an early cardioversion strategy.114

Ion-channel remodelling provides a potential antiarrhythmic drug target. Both the T-type Ca+-channel blocker mibefradil118 and amiodarone119 suppress APD abbreviation as an index of ion-channel remodelling. ICa,L118,120 K+-channel and Na+-channel blockers, however, are mostly ineffective.119 It has been assumed that prevention of ion-channel remodelling (suppression of ICa,L reduction) may contribute to amiodarone’s superior efficacy in AF.119 Bepridil, a L- and T-type Ca2+-channel blocker, also suppresses ion-channel remodelling indices, an action that may explain bepridil’s unusual ability to convert long-standing AF.121

Drugs targeting atrial-selective channels such as IKur and constitutive IK,ACh provide a promising approach because they do not affect ventricular repolarisation.33 However, due to the remodelling effectiveness of IKur blockers (e.g. AVE0118) is reduced in patients with chronic AF.59

Increased inward rectifier K+ currents, such as constitutive IK,ACh, are more effective at stabilising and accelerating AF-sustaining rotors than reduction of ICa,L.122 Selective inhibition of IK,ACh with the IK,ACh-blocker tertiapin prolongs APD in ATR-remodelled canine preparations and suppresses tachyarrhythmias.23 AVE0118 and flecainide both inhibit constitutive IK,ACh in chronic AF patients,41 an effect that might contribute to their effectiveness in terminating AF. However, although IK,ACh pore-channel blockers effectively terminate AF, they could also have off-target effects in the brain, gastrointestinal and urinary tracts. Despite this, targeting the pathology-specific molecular mechanisms of constitutive IK,ACh may be an effective and safe anti-AF approach that does not interfere with physiological cholinergic agonist-stimulated IK,ACh function.

There is emerging evidence of increased diastolic SR Ca2+ leak through RyR2 channels and enhanced Na+-Ca2+-exchanger function. This may cause delayed after depolarisations and triggered activity contributing to AF maintenance. Such effects suggest that the development of new drugs specifically targeting arrhythmogenic diastolic SR Ca2+ leak might offer unique therapeutic opportunities to reduce atrial arrhythmogenesis by normalising SR Ca2+ handling (for detailed discussions see33,106,123).

Inflammation and tissue oxidation are believed to be important mediators in atrial remodelling.124 Drugs with anti-inflammatory and antioxidant properties, such as glucocorticoids125 and statins,126 suppress atrial electrical remodelling, and have shown some clinical value in preventing AF recurrence.127,128 Suppression of ion-channel remodelling may thus prove to be a useful principle, as either a primary or adjunct property of new antiarrhythmic drugs.

Conclusions

The past decade has provided important insights into key determinants of ion-channel remodelling in both experimental paradigms and clinical AF. Despite major advances, understanding about the underlying molecular mechanisms leading to and perpetuating ion-channel remodelling during AF is very limited. Better knowledge and deeper insights into the molecular mechanisms underlying AF may help to identify new and atrial-selective drug targets for the improved treatment of AF.

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