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Atrial Remodeling and Atrial Fibrillation Mechanisms and Implications Stanley Nattel, MD; Brett Burstein, BSc; Dobromir Dobrev, MD A Downloaded from http://circep.ahajournals.org/ by guest on May 13, 2017 trial fibrillation (AF) is the most common arrhythmia in clinical practice. It can occur at any age but is very rare in children and becomes extremely common in the elderly, with a prevalence approaching 20% in patients ⬎85 years of age.1 AF is associated with a wide range of potential complications and contributes significantly to population morbidity and mortality. Present therapeutic approaches to AF have major limitations, including limited efficacy and significant adverse effect liability. These limitations have inspired substantial efforts to improve our understanding of the mechanisms underlying AF, with the premise that improved mechanistic insights will lead to innovative and improved therapeutic approaches.2 Our understanding of AF pathophysiology has advanced significantly over the past 10 to 15 years through an increased awareness of the role of “atrial remodeling.” Any persistent change in atrial structure or function constitutes atrial remodeling. Many forms of atrial remodeling promote the occurrence or maintenance of AF by acting on the fundamental arrhythmia mechanisms illustrated in Figure 1. Both rapid ectopic firing and reentry can maintain AF. Reentry requires a suitable vulnerable substrate, as well as a trigger that acts on the substrate to initiate reentry. Ectopic firing contributes to reentry by providing triggers for reentry induction. Atrial remodeling has the potential to increase the likelihood of ectopic or reentrant activity through a multitude of potential mechanisms. This article reviews the types of atrial remodeling, their underlying pathophysiology, the molecular basis of their occurrence, and finally, their potential therapeutic significance. which (like rapid focal firing) produces fibrillatory activity by virtue of an irregular, fractionated atrial response (Figure 2B). Fibrillatory activity can also be an intrinsic consequence of the AF-maintaining mechanism, when AF is maintained by multiple simultaneous functional reentry circuits (Figure 2C). Atrial Remodeling and Reentry Figure 3 illustrates the fundamental determinants of reentry and the effects of atrial remodeling. Figure 3A shows the initiation of reentry in a schematic circuit. An ectopic beat encounters refractory tissue when propagating in one direction, while able to conduct in faster-recovering tissue in the other direction (“unidirectional block”). For reentry to be maintained (Figure 3B), the impulse must traverse the entire circuit slowly enough for all points to regain excitability, ie, the conduction time has to be greater than the longest refractory period in the circuit. Conduction time is determined by circuit path length and conduction velocity: Long path lengths and slow conduction increase circuit time, which makes it more likely that all points will have recovered excitability early enough to be reactivated by the reentering impulse. The recovery of excitability is governed by the refractory period: Short refractory periods increase the likelihood that tissue will be available for reactivation when the reentering impulse passes through. The “wavelength,” or distance traveled by an impulse in 1 refractory period (given as the product of refractory period and conduction speed), is a useful concept to relate the determinants of reentry. The wavelength approximates the shortest path length for reentry and determines the size of functional reentry circuits. Factors that reduce the atrial wavelength decrease reentry-circuit dimensions, which increases the potential number of simultaneous circuits and augments the probability of AF maintenance. The ways in which atrial remodeling can promote reentry are illustrated at the bottom of Figure 3 (for a detailed description of the underlying physiology, see reference 4). Atrial refractoriness depends on cardiac action potential duration (APD), because the Na⫹ channels that govern cardiomyocyte excitability inactivate when cells are depolarized and require repolarization to ⬇⫺60 mV for channel Physiological Mechanisms by Which Remodeling Promotes AF The mechanisms underlying AF are portrayed schematically in Figure 2. AF can be maintained by rapid focal firing, which may itself be regular but result in fibrillatory activity because of wave breakup in portions of the atrium that fail to follow 1:1 conduction (Figure 2A).3 In addition to their potential role as an AF driver, ectopic foci can contribute to AF by acting on vulnerable reentrant substrates to initiate AF. One form of reentrant AF involves a single, rapidly firing reentrant circuit, From the Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal (S.N., B.B.), Montreal, Quebec, Canada; Department of Pharmacology and Therapeutics, McGill University (S.N., B.B.), Montreal, Quebec, Canada; and Department of Pharmacology and Toxicology (D.D.), Dresden University of Technology, Dresden, Germany. Correspondence to Stanley Nattel, Montreal Heart Institute, 5000 Belanger St E, Montreal, Quebec, Canada H1T 1C8. E-mail [email protected] (Circ Arrhythmia Electrophysiol. 2008;1:62-73.) © 2008 American Heart Association, Inc. Circ Arrhythmia Electrophysiol is available at http://circep.ahajournals.org 62 DOI: 10.1161/CIRCEP.107.754564 Nattel et al Mechanisms and Consequences of Atrial Remodeling Figure 1. General schema representing AF mechanisms and the role of remodeling. Downloaded from http://circep.ahajournals.org/ by guest on May 13, 2017 availability to return (Figure 3C). APD is determined by the balance between inward currents (primarily Ca2⫹, which tends to keep the cell depolarized) and outward currents (primarily K⫹, which tends to repolarize) during the action potential plateau. Atrial remodeling can abbreviate APDs and refractory periods in either way: Sustained rapid atrial activation, as occurs during AF, reduces inward L-type Ca2⫹ current (ICaL) and also enhances outward K⫹ currents.4 These actions are major contributors to clinically relevant AF promotion.5,6 Atrial conduction slowing can result from changes in sarcolemmal (cell membrane) Na⫹ channels, gap junction channels (connexins), or tissue structure (Figure 3D). Normal impulse conduction depends on the balance between the energy for conduction provided by tissue firing (the current “source”) and the dissipation of this energy by the downstream tissue that has to be fired (the current “sink”). The energy source for conduction derives from the large phase 0 Na⫹ current (INa). Energy dissipation is minimized by having good electrical coupling between cardiac cells (provided by low-resistance gap junction channels that connect cell ends in a longitudinal fashion) and a high resistance to lateral current leakage (ensured by a continuous cable-like organization of cardiomyocyte bundles). Atrial tachycardia appears to suppress expression of the atrial-selective connexin-40.7 There is also evidence that atrial tachycardia remodeling (ATR) re- 63 duces INa.8 Congestive heart failure (CHF), a strong promoter of atrial remodeling that facilitates fibrillation, causes atrial tissue fibrosis that interferes with local atrial conduction by disturbing the continuous cable-like arrangement of cardiomyocytes.9,10 Atrial dilation increases the amount of atrial tissue that can accommodate reentry circuits (Figure 3E). Larger atrial size means that more circuits can be accommodated and that long-wavelength circuits that are too large for a normal atrium can be supported. Atrial dimensions are a particularly important determinant of the occurrence of multiple-circuit reentry.11 Atrial enlargement can occur with both atrial tachycardia– and CHF-related remodeling12 and is an important clinical predictor of AF maintenance.13 However, atrial dilation is not essential for the maintenance of CHF-related AF: After full hemodynamic recovery from CHF, fibrosis remains, and sustained AF is still inducible, despite the absence of atrial dilation.10 Atrial Remodeling and Ectopic Activity Figure 4 illustrates the principal mechanisms that generate ectopic activity. The spontaneous firing rate of potentially automatic atrial foci is determined by the slope of phase 4 depolarization, which establishes the time required to reach threshold potential and generate a spontaneous action potential. If the atrial cell firing rate is slower than the sinus node rate, no ectopic activity occurs. When the slope of phase 4 is accelerated, the spontaneous rate increases, and ectopic beats or sustained tachycardias may occur. Increased atrial expression of ion channel subunits that underlie a potentially important contributor to phase 4 depolarization, the “funny current” (I f ), 4 has been observed in both atrial tachycardia–related14 and CHF-related15 remodeling; however, there has been no direct demonstration of enhanced automaticity due to accelerated phase 4 depolarization in AF. Abnormalities in cellular Ca2⫹ handling, particularly Ca2⫹ overload, can cause delayed afterdepolarizations (DADs; Figure 4B), which are spontaneous hump-shaped depolarizations after full cellular repolarization. DADs differ from Figure 2. Principal mechanisms that can produce AF. Reentry involves a vulnerable substrate, which requires a trigger for reentry initiation. Ischemia, inflammation, and dilation make atria more vulnerable to AF. AF that results from any mechanism causes tachycardia-induced remodeling. Even if AF is initially maintained by ectopic activity or single-circuit reentry in a given patient, ATR-induced spatially heterogeneous refractoriness abbreviation creates conditions favorable to multiple-circuit reentry, which may then become the AF-maintaining mechanism. Thus, multiplecircuit reentry may be a final common pathway AF mechanism in many patients. RA indicates right atrium; PVs, pulmonary veins; LA, left atrium; RP, refractory period; and WL, wavelength. 64 Circ Arrhythmia Electrophysiol April 2008 Downloaded from http://circep.ahajournals.org/ by guest on May 13, 2017 Figure 3. Basis for reentry and its promotion by remodeling. A, A premature beat blocks in stillrefractory cardiac tissue but propagates through tissue that has already recovered. B, Conditions for maintenance of reentry. C, Mechanisms involved in shortening refractoriness. D, Mechanisms of remodelinginduced conduction slowing. E, Remodeling-induced atrial dilation promotes AF by increasing circuit path space so that larger reentry circuits can be supported (left) and/or a larger number of circuits can be maintained (right). RP indicates refractory period. spontaneous phase 4 depolarization in both shape and mechanism. When DADs become large enough to reach threshold potential, they cause cell firing, either as the single ectopic beat illustrated in Figure 4B or as a sustained tachycardia. Ca2⫹ enters cells through L-type Ca2⫹ channels with each action potential, so rapid firing rates increase Ca2⫹ entry and can induce DAD-related tachyarrhythmias (so-called triggered activity). CHF promotes atrial DADs16,17 by enhancing cellular Ca2⫹ loading.17 Pulmonary veins may be particularly prone to triggered activity,18 although the evidence for this is controversial.19 Early afterdepolarizations (EADs; Figure 4C) occur when action potentials become abnormally prolonged, which allows ICaL to recover from inactivation and to generate abnormal depolarizations at plateau potentials. Although EADs are most characteristic of Purkinje fiber tissue and long-QT syndrome ventricular tachyarrhythmias,20 EAD-related arrhythmias can also occur at the atrial level.21,22 Investigators have yet to demonstrate a clear role for EAD-related mechanisms in atrial remodeling. Components of Atrial Remodeling Although many processes can alter atrial properties and promote AF, animal models and clinical studies have provided insights into 2 major forms of atrial remodeling: ATR, which occurs with rapid atrial tachyarrhythmias such as AF and atrial flutter, and atrial structural remodeling (ASR), which is associated with CHF and other fibrosis-promoting conditions. Molecular Basis of Atrial Remodeling Atrial Repolarization Abnormalities Figure 4. Basic mechanisms of ectopic impulse generation by (A) enhanced automaticity, (B) DADs, and (C) EADs. The recognition that AF alters atrial electrophysiological properties, promoting AF induction and maintenance, was an important advance in AF pathophysiology.2,23 AF induces electrical remodeling primarily by virtue of a very rapid atrial rate and associated ATR.2,4 Whether AF can produce additional forms of remodeling, particularly when the arrhythmia Nattel et al Mechanisms and Consequences of Atrial Remodeling 65 Figure 5. Mechanisms underlying ATR. Rapid atrial rates increase potentially cytotoxic Ca2⫹ loading. Autoprotective ICaL reductions occur via rapidly developing functional changes (ICaL inactivation) and more slowly developing changes in gene and protein expression. Decreased ICaL reduces Ca2⫹ loading but decreases APD. Diminished APD shortens refractoriness and reduces the wavelength (WL), which allows for smaller and more atrial reentry circuits, thus making AF unlikely to terminate. Atrial tachycardia also increases inward-rectifier currents such as IK1 and IKACh,c, which further reduces APD and promotes AF. RP indicates refractory period; WL, wavelength. Downloaded from http://circep.ahajournals.org/ by guest on May 13, 2017 remains sustained for prolonged periods, remains uncertain.24 Figure 5 summarizes the molecular mechanisms that underlie ATR promotion of reentrant AF. ATR abbreviates atrial refractoriness by decreasing APD, primarily by ICaL downregulation5 but also via increased inward-rectifier K⫹ currents such as the background current IK1 and a constitutively active form of acetylcholine-dependent K⫹ current (IKACh).6,25,26 In addition, ATR impairs atrial contractility, principally by causing Ca2⫹-handling abnormalities,27 which causes atrial dilation12 that further promotes reentry. L-Type Ca2ⴙ Current The abrupt ⬇8-fold increase in atrial rate with the onset of AF substantially increases Ca2⫹ loading. Atrial cardiomyocytes respond by reducing Ca2⫹ influx via ICaL to prevent potentially cytotoxic Ca2⫹ overload, but reduced ICaL decreases APD and wavelength, which favors AF perpetuation (Figure 5). Initially, rapid APD shortening occurs because of functional ICaL inactivation. Sustained AF causes more persistent ICaL decreases, predominantly via downregulation of ICaL poreforming ␣-subunit mRNA28 but possibly also via posttranscriptional mechanisms such as protein dephosphorylation and breakdown.29,30 In addition, intracellular Ca2⫹ handling is altered, which contributes to loss of APD rate dependence and favors reentry-facilitating alternans behavior.31 Some studies at the protein level have confirmed ATR-induced reductions in Cav1.2 ␣-subunit abundance,28,32 whereas others suggest unchanged ␣-subunit protein.29,33,34 Investigators have also detected reduced expression of 1, 2a, 2b, 3, and ␣2␦2 accessory ICaL subunits.29,33,35,36 Decreased expression of the endogenous antioxidant glutathione, the major cellular reducing agent, accompanies enhanced S-nitrosylation.37 Cav1.2 S-nitrosylation is increased in AF, and exogenously applied glutathione partially restores AF-related ICaL reductions.37 Thus, oxidative stress could play an important role in ICaL changes. Recent findings also suggest increased atrial expression of ZnT-1, a protein originally associated with zinc homeostasis, in ATR.38,39 ZnT-1 suppresses ICaL via presently unknown mechanisms.38 Protein kinases attach phosphate groups to proteins, which causes phosphorylation that controls protein function. Altered regulation of ICaL by src-type tyrosine kinases may also cause ICaL dysregulation.34 Inward-Rectifier Kⴙ Currents The cardiomyocyte resting membrane potential is set by background K⫹ conductances, primarily inward rectifiers, and becomes more negative in AF.25,26,40 The main background conductance that controls atrial resting potential is designated IK1 and is formed by Kir2-family subunits, especially Kir2.1. AF increases expression levels of Kir2.1 mRNA25,35 and protein,35 which enlarges IK1. The inward-rectifier K⫹ current IKACh mediates cardiac vagal effects: Acetylcholine released from vagal nerve endings activates IKACh, which causes APD abbreviation and cell-membrane hyperpolarization. Increased vagal activity strongly promotes AF by stabilizing atrial reentrant rotors,41 and clinical AF often begins under vagotonic conditions.42 ATR alters the IKACh system such that agonist-stimulated IKACh (as occurs with vagal activation) is reduced, but agonistindependent (“constitutive”) IKACh (IKACh,c) activity is enhanced.6,26,43,44 IKACh,c enhancement is due to increased singlechannel open probability caused by slowed channel closure.44 mRNA and protein expression of Kir3 subunits underlying IKACh are unchanged in experimental ATR,43,44 whereas in AF patients, they are decreased,26 so increased IKACh,c is not due to increased expression of the underlying ion channel subunits. Inhibition of protein kinase C (PKC) reduces IKACh,c activity, and PKC⑀ protein is upregulated in AF,45 which suggests that increased protein kinase C–mediated phosphorylation is important for AF-induced IKACh,c augmentation. IKACh,c blockade suppresses ATR-induced APD abbreviation and AF promotion,6 which indicates that IKACh,c plays an important role in arrhythmogenesis. The ATP-sensitive inward-rectifier K⫹ current (IKATP) is an important contributor to ischemia-induced electrophysiological abnormalities, and relative ischemia is a potential con- 66 Circ Arrhythmia Electrophysiol April 2008 Downloaded from http://circep.ahajournals.org/ by guest on May 13, 2017 Figure 6. Major profibrotic signaling pathways involved in atrial fibrosis. Interaction between pathways produces positive feedback that is important in fibrosis development. ␣ Indicates integrin receptor ␣- and -subunits; Ang II, angiotensin II; AP-1, activator protein-1; DAG, diacylglycerol; ERK 1/2, extracellular signal-related kinase 1/2; Grb2, growth factor receptor binding protein 2; JAK, Janus kinase; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MEK 1/2, mitogen-activated/ERK kinase 1/2; MMP, matrix metalloproteinase; NF-B, nuclear factor-B; PKC, protein kinase C; PDGFR, PDGF receptor; PIP2, phosphatidylinositol bisphosphate; PLC, phospholipase C; PP2A, protein serine/threonine phosphatase 2A; PTP, phosphotyrosine phosphatase; Shc, src homologous and collagen protein; SMAD, SMA- and MAD-related proteins; SOS, son of sevenless protein; STAT, signal transducers and activators of transcription; TAK1, TGF-1–activated kinase 1; TF, transcription factor; TGF-R, TGF- receptor; IP3, inositol 1,4,5-trisphosphate; and TIMP, tissue inhibitor of matrix metalloproteinase. tributor to ATR. IKATP amplitude is increased under ischemic conditions in cells from AF patients,46 whereas IKATP enhancement by agonists such as rilmakalim is reduced.47 Variable expression changes of the IKATP pore-forming Kir6.2 subunit observed in AF32,48 underscore the complexity of IK,ATP regulation. Voltage-Gated Kⴙ Currents The transient outward K⫹ current (Ito) is consistently decreased in ATR.4 The functional consequences of Ito downregulation are unclear; however, Ito activates quickly and produces an outward-current component that can oppose inward Na⫹ current during the action potential upstroke, so Ito downregulation may facilitate wave propagation by indirectly increasing action potential amplitude. Decreased Ito parallels reductions in both mRNA and protein expression of its pore-forming Kv4.3 subunit.28 Increased calpain-mediated proteolysis may also contribute by degrading Kv4.3 proteins.30,49 The Ca2⫹-dependent protein phosphatase calcineurin suppresses Kv4.3 gene transcription via nuclear factor of activated T-cell (NFAT)– dependent mechanisms,50 and calcineurin activity is increased in AF.51 Reported AF-associated changes in the ultrarapid delayed rectifier IKur have been inconsistent.4 The role of IKur in atrial repolarization depends strongly on action potential morphology and is increased with the short-duration, triangular action potentials that occur in AF.52 Oxidant production is increased in ATR and AF,53,54 and Kv1.5 currents are inhibited by oxidation by S-nitrosylation,55 which may contribute to IKur suppression in AF. The delayed-rectifier currents IKr and IKs are not changed in experimental ATR,5 and information from AF patients is lacking, likely because of difficulties in recording IKr and IKs in human atrial cardiomyocytes isolated by the “chunk” method.56 Atrial Conduction Abnormalities Structural Remodeling and Fibrosis Extensive evidence indicates that structural remodeling, particularly interstitial fibrosis, is an important contributor to the AF substrate.57 The regulatory mechanisms that underlie atrial extracellular matrix remodeling are incompletely understood, and the precise signaling pathways that lead to structural changes may vary in different heart disease paradigms. Several secreted factors are known to be profibrotic. In addition to their individual effects, they often act synergistically.58 Angiotensin II and transforming growth factor-1 (TGF-1) are well-established profibrotic molecules, and recent evidence points to significant roles for platelet-derived growth factor (PDGF) and connective tissue growth factor (CTGF). Figure 6 depicts the interplay of various signaling systems. Angiotensin II Angiotensin II mediates cardiac fibrosis in a variety of cardiac pathologies, including hypertensive heart disease, CHF, myocardial infarction, and cardiomyopathy. Transgenic mice with cardiac-restricted ACE overexpression show marked atrial dilation with focal fibrosis and AF.59 Angiotensin II acts by binding to 2 discrete receptor subtypes, angiotensin type I (AT1R) and type II (AT2R) receptors. The signaling cascades coupled to AT1Rs and AT2Rs are distinct and often have opposing actions. AT1Rs mediate the profibrotic effects of angiotensin II by stimulating fibroblast proliferation, cardiomyocyte hypertrophy, and apoptosis.57 AT1R signaling through the Shc/Grb2/SOS adapter-protein complex activates the small GTPase protein Ras, which initiates mitogen-activated protein kinase phosphorylation cascades that are centrally involved in remodeling.60 The mitogen-activated protein kinases ERK (extracellular signalrelated kinase)-1 and -2, p38, and JNK (c-Jun N-terminal Nattel et al Mechanisms and Consequences of Atrial Remodeling kinase) activate transcription factors (Elk-1, c-jun, and c-fos) that modulate gene expression. In addition, AT1R activation stimulates phospholipase C. Phospholipase C breaks down membrane phosphoinositol bisphosphate (PIP2) into diacylglycerol and inositol 1,4,5-trisphosphate (IP3). Diacylglycerol activates protein kinase C, and IP3 causes intracellular Ca2⫹ release, both of which promote remodeling. Signal transduction also occurs through the JAK/STAT pathway, activating transcription factors such as activator protein-1 and nuclear factor-B. AT2R activation inhibits mitogen-activated protein kinases60 via dephosphorylating actions of phosphotyrosine phosphatase and protein phosphatase 2A and produces antiproliferative and survival-promoting effects that oppose AT1R-mediated changes. The balance between the 2 counterregulatory angiotensin II receptor subtypes (AT1R and AT2R) may have important therapeutic implications. Downloaded from http://circep.ahajournals.org/ by guest on May 13, 2017 Transforming Growth Factor 1 TGF-1 is secreted by both cardiomyocytes and fibroblasts and acts as a primary downstream mediator of angiotensin II effects in both autocrine (influencing the cell that produces angiotensin II/TGF-1) and paracrine (influencing adjacent cells) manners.61 Angiotensin II induces TGF-1 synthesis, which potently stimulates fibroblast activity. In turn, TGF-1 reciprocally enhances the production of angiotensin II and additional profibrotic factors to create positive feedback.61 TGF-1 acts primarily through the SMAD protein (homolog of the Drosophila protein “mothers against decapentaplegic,” or MAD, and the Caenorhabditis. elegans protein, SMA) pathway to stimulate fibroblast activation and collagen deposition.62 Cardiac overexpression of constitutively active TGF-1 causes selective atrial fibrosis, atrial conduction heterogeneity, and AF promotion.63 Platelet-Derived Growth Factor PDGF, a PDGF/vascular endothelial growth factor family member, stimulates fibroblast proliferation and differentiation. Occupation of PDGF receptors causes them to dimerize, which activates a tyrosine kinase that forms part of the PDGF receptor molecule. This tyrosine kinase phosphorylates intracellular domains of the PDGF receptor (autophosphorylation). Autophosphorylation activates PDGF receptors, initiating signaling via mitogen-activated protein kinase, JAK/ STAT, and phospholipase C pathways shared with TGF-1 and angiotensin II. PDGF appears to underlie atrium-selective fibroblast hyperresponsiveness, which may explain why atria are much more susceptible to fibrotic remodeling than ventricles.64 Connective Tissue Growth Factor CTGF is a member of the CCN (cyr61, ctgf, nov) protein family and a major downstream effector of TGF-1 fibrosis promotion. Areas with active myocardial remodeling show coordinate CTGF expression with TGF-1.65 CTGF is upregulated by both angiotensin II66 and TGF-1,67 and it directly activates fibroblasts.66 Profibrotic Signaling in AF Paradigms Atrial angiotensin II expression increases rapidly in tachycardia-induced CHF.68 Renin-angiotensin-aldosterone 67 inhibition by ACE inhibitors,69 AT1R blockers,70 or aldosterone antagonists71 prevents atrial fibrosis and associated AF promotion. Atrial TGF-1 is activated rapidly during tachypacing-induced CHF,72 and TGF-1 inhibition by pirfenidone attenuates remodeling and AF.73 Pathway analysis has implicated CTGF as a potentially important atrial fibrotic mediator.74 There is a delicate balance between matrix metalloproteinases and tissue inhibitors of metalloproteinases in extracellular matrix degradation, and important changes in the tissue inhibitor of metalloproteinases/matrix metalloproteinase system are seen in AF.74 –76 Leukocyte infiltration and increased cell death occur in CHF-induced ASR.72 Oxidant stress is enhanced in AF,53,54 which promotes fibrosis through both cell death and proinflammatory pathways. Rac1 GTPase, a small G-protein NADPH oxidase regulator that increases oxidant stress, is upregulated in AF and produces atrial fibrosis–related AF in mice.77 Statins, which inhibit Rac1 GTPase, prevent ASR, possibly by antioxidant mechanisms.78 Ion Channels Involved in Atrial Conduction Gap Junction Remodeling Relatively little is certain about atrial gap junction remodeling; results reported in the literature vary widely.4 Some of the discrepancies may relate to differences in the duration of AF and the nature of the underlying cardiac pathology.79 Spatially heterogeneous connexin-40 remodeling occurs in the well-established goat AF-remodeling system,7 consistent with clinical evidence for genetically controlled variability in connexin-40 as a determinant of AF predisposition.80,81 Sodium Channel Remodeling INa is reduced in canine ATR, with corresponding decreases in mRNA and protein expression.8,28 However, studies in AF patients have not confirmed INa downregulation.35 Ectopic Impulse Formation Ca2⫹-related triggered activity caused by abnormal Ca2⫹ handling is a strong candidate mechanism to underlie AFgenerating ectopic foci. The main determinants of cellular Ca2⫹ handling are illustrated in Figure 7. Ca2⫹ enters cells principally via Ca2⫹ influx through L-type Ca2⫹ channels. Ca2⫹ entry triggers opening of SR Ca2⫹-release channels (commonly called ryanodine receptors, or RyRs), which causes substantial Ca2⫹-induced Ca2⫹ release. The Ca2⫹ that has entered the cytoplasm during systole is removed in diastole by 2 primary mechanisms: (1) active pumping back into the sarcoplasmic reticulum (SR) via SR Ca2⫹-ATPase (or SERCA), and (2) extrusion across the cell membrane through the Na⫹-Ca2⫹ exchanger (NCX). NCX transfers 3 Na⫹ ions into the cell for every Ca2⫹ ion exported, which yields a net inward (depolarizing) current. SERCA is regulated by the associated protein phospholamban, which inhibits SERCA function. Phospholamban phosphorylation reduces its SERCA-inhibitory capacity and enhances SR Ca2⫹ uptake. The accessory protein FKBP12.6 binds to and stabilizes RyR function, which prevents diastolic RyR reopening. Hyperphosphorylated RyRs lose FKBP12.6 binding, which causes arrhythmogenic diastolic SR Ca2⫹ leak. Any cause of diastol- 68 Circ Arrhythmia Electrophysiol April 2008 Figure 7. Diagram of the cellular Ca2⫹-handling system. CSQ indicates calsequestrin. Downloaded from http://circep.ahajournals.org/ by guest on May 13, 2017 ic Ca2⫹ leak, including cell Ca2⫹ overload and RyR dysfunction due to FKBP12.6 unbinding, increases diastolic [Ca2⫹]i and enhances Ca2⫹ extrusion via NCX-mediated exchange. Enhanced diastolic NCX activity produces a depolarizing current that causes DADs. Calsequestrin is the main SR Ca2⫹-binding protein. Ca2⫹ binding by calsequestrin allows the SR to maintain large Ca2⫹ stores without excessive free Ca2⫹ concentration. Calsequestrin deficiency impairs SR Ca2⫹ binding and function, which promotes Ca2⫹-release events and DADs. Relatively little is known about the molecular basis for abnormal Ca2⫹ handling in AF. The expression levels of calsequestrin, RyRs, and phospholamban are preserved in AF.29,35,82 NCX expression may be upregulated,35,83 which accelerates Ca2⫹ extrusion from the cytoplasm at the expense of larger DAD-generating inward currents produced by electrogenic Ca2⫹ removal. The phosphorylation states of several key Ca2⫹-handling proteins are altered in AF. Protein kinase A (PKA) and Ca2⫹ calmodulin kinase II (CaMKII) hyperphosphorylation of phospholamban,84 along with decreased sarcolipin84,85 (another SERCA inhibitor), enhances SR Ca2⫹ uptake, which reduces diastolic [Ca2⫹]i load at the expense of promoting SR Ca2⫹ overload. Protein kinase A– overexpressing mice have hyperphosphorylated phospholamban and RyRs and develop AF.86 Besides enhanced phosphorylation by kinases, phospholamban and RyR2 hyperphosphorylation may also result from reduced dephosphorylation. Protein phosphatase 1 (PP1) is a key dephosphorylating enzyme. PP1 function is inhibited in AF by increased activity of an endogenous inhibitor, phosphatase inhibitor protein-1 (I-1).87 I-1 is activated by protein kinase A phosphorylation. I-1 protein kinase A phosphorylation is increased 10-fold in AF, to a level that completely inhibits SR-bound PP1 activity.84 IP3 receptor (IP3R2)-mediated SR Ca2⫹ release may amplify Ca2⫹ leak via RyRs to promote atrial arrhythmogenesis,88 and IP3R2 protein expression is increased by ATR.89 IP3R2coupled atrial SR Ca2⫹-release enhancement and related arrhythmogenesis90 may thus be an important contributor to AF-related ectopic activity. Figure 8 summarizes the interplay between various Ca2⫹ homeostasis–related factors in AF. We have already discussed the role of Ca2⫹ loading and associated ionic changes in ATR-induced reentry promotion. Protein hyperphosphorylation due to enhanced I-1, CaMKII, or protein kinase A function,82,84,86 along with decreased SR-bound PP1 activity,84 causes arrhythmogenic dysfunction of RyR/FKBP12.6 and SERCA/phospholamban complexes. Calmodulin and calcineurin are Ca2⫹-regulated proteins that play key roles in remodeling, and nitric oxide and NADPH oxidase control oxidation-state changes that regulate remodeling and Ca2⫹ handling. Both reentry and focal driver mechanisms related to triggered activity contribute to CHF-induced AF.4,16,17 CaMKII-mediated phospholamban hyperphosphorylation contributes to SR Ca2⫹ overload in CHF, causing spontaneous Ca2⫹-release events and DAD-related triggered activity.17 Figure 8. Processes related to Ca2⫹ homeostasis abnormalities that participate in AF promotion. Components that lead to reentry are indicated by stippled fill and italics. PKA indicates protein kinase A; NADPHO, NADPH oxidase; and PLN, phospholamban. Nattel et al Mechanisms and Consequences of Atrial Remodeling Potential Therapeutic Implications Extensive evidence implicates atrial remodeling as an important player in the pathophysiology of AF.2,4 Therefore, atrial remodeling may have significant therapeutic implications. Therapeutic Consequences of ATR Downloaded from http://circep.ahajournals.org/ by guest on May 13, 2017 Implications for Traditional Therapeutic Approaches The changes in ion channel function caused by ATR alter the response to antiarrhythmic drugs, which in general makes AF more drug-resistant.91 A poorer response of more prolonged AF has been shown for both Na⫹ and K⫹ channel52,92,93 blockers. Early detection and termination of AF increases the clinical effectiveness of pharmacological cardioversion.92 However, electrical cardioversion is highly effective in restoring sinus rhythm irrespective of AF duration, and the value of an early termination strategy for electrical cardioversion is unclear. Implantable atrial defibrillators permit rapid detection and termination of AF. A strategy of early cardioversion reduces atrial remodeling,94 prevents atrial dysfunction,95 reduces atrial size,96 and may prolong sinus rhythm maintenance after cardioversion.96,97 However, there is little clinical evidence for the practical value of an early cardioversion strategy.94 Table. 69 ATR Suppression as an Antiarrhythmic Principle ATR is a potentially interesting antiarrhythmic drug target. Both the T-type Ca⫹ channel blocker mibefradil98 and amiodarone99 suppress ATR, whereas ICaL,98 K⫹99, and Na⫹ channel99 blockers are ineffective, and it has been suggested that ATR suppression may contribute to the superior efficacy of amiodarone in AF.99 Bepridil, an L- and T-type Ca2⫹ channel blocker, also suppresses ATR,100 an action that may explain its unusual ability to convert long-standing AF.101 Inflammation and tissue oxidation are believed to be important mediators in atrial remodeling.102 Drugs with antiinflammatory and antioxidant properties, such as glucocorticoids103 and statins,78 suppress ATR and have shown some clinical value in preventing AF recurrence.104,105 ATR suppression may thus prove to be a useful principle as either a primary or adjunct property of new antiarrhythmic drugs. In addition, understanding the ionic basis of ATR may allow for the development of novel ionic targets for antiarrhythmic drug development, such as IKACh,c.6 Therapeutic Consequences of ASR Initial experiments suggested the potential value of angiotensin-production inhibition in the prevention of ASR-related ASR-Targeted Therapies for AF Drug(s) ACE inhibitors AT1R blockers Spironolactone/eplerenone Pirfenidone Statins n-3 PUFAs HSP inducers Action Decrease angiotensin II production Prevent AT1R stimulation Aldosterone antagonists Antifibrotic, antagonizes TGF-1 action HMG-CoA reductase inhibitors, antioxidant and antiinflammatory actions Antioxidant, antiinflammatory actions Augment endogenous HSP production Summary of Findings Experimental Suppressed apoptosis, fibrosis, and AF maintenance in dogs with ventricular tachypacing–induced CHF Clinical Decreased AF in patients with left ventricular dysfunction after myocardial infarction Decreased AF in patients with left ventricular dysfunction Meta-analysis: Prevented AF in patients with left ventricular dysfunction or hypertrophy Experimental Reduced AF promotion and fibrosis in dogs with atrial tachypacing, rapid ventricular response, and tachycardiomyopathy Clinical Meta-analysis: Prevented AF in patients with left ventricular dysfunction or hypertrophy Experimental Decreased atrial ectopy and fibrosis after MI in rats Decreased AF maintenance and fibrosis in dogs with tachypacing-induced CHF Experimental Decreased fibrosis and AF vulnerability in dogs with ventricular tachypacing–induced CHF Experimental Reduced AF promotion and fibrosis in dogs with ventricular tachypacing–induced CHF Clinical Four of 5 clinical trials showed reduced AF incidence Experimental Reduced atrial fibrosis and AF in dogs with ventricular tachypacing–induced CHF Experimental studies Suppressed AF-substrate in dogs with ventricular tachypacing–induced CHF HMG-CoA indicates 3-hydroxy-3-methylglutaryl coenzyme A; PUFAs, polyunsaturated fatty acids; and HSP, heat shock protein. References 68, 69 106 107 108 109 108 110 111 73 112 113 114 115 70 Circ Arrhythmia Electrophysiol April 2008 Downloaded from http://circep.ahajournals.org/ by guest on May 13, 2017 AF69 and received support from clinical trial evidence.106 A variety of elements involved in ASR-inducing signaling have been targeted subsequently in both clinical and experimental studies, as summarized in the Table.68,69,73,106 –115 The interested reader is referred to recent detailed reviews of this approach.57,116 The results to date have been promising, but evidence from randomized prospective, controlled clinical trials will be needed before the precise role of ASR-targeting interventions in clinical AF management can be appreciated. In addition to atrial fibrosis, CHF and many other AFinducing conditions cause atrial dilation. The inhibition of nonselective stretch-sensitive cation channels suppresses AF in a rabbit model of stretch-induced AF,117 which suggests potential additional ionic targets for AF prevention. Finally, abnormal atrial Ca2⫹ handling occurs in CHF17 and other AF paradigms82 and may play an important role in AF-initiating and -maintaining ectopic activity. Compounds such as JTV519, which improve FKBP12.6 binding and stabilization of RyR function,118 may prove to be prototypes for new drugs with efficacy against a variety of arrhythmias, including some forms of AF. 7. 8. 9. 10. 11. 12. 13. 14. Conclusions Considerable progress has been made in understanding the mechanisms underlying atrial remodeling. These insights have potentially important implications for our understanding of the pathophysiology of AF and for the development of new therapeutic approaches. Acknowledgments The authors thank France Thériault for excellent secretarial help. 15. 16. 17. Sources of Funding This study was supported by the Canadian Institutes of Health Research, the Quebec Heart and Stroke Foundation, the German Federal Ministry of Education and Research (Atrial Fibrillation Competence Network grant 01Gi0204), and the Leducq EuropeanNorth American Research Alliance network award (Fondation Leducq). 18. Disclosures 20. Dr Nattel is listed as an inventor on intellectual property belonging to the Montreal Heart Institute: “Statin drugs to treat atrial fibrillation” and “Acetylcholine-dependent current as a novel ionic target for AF.” Dr Dobrev and B. Burstein report no conflicts. 19. 21. 22. References 1. Heeringa J, van der Kuip DA, Hofman A, Kors JA, van Herpen G, Stricker BH, Stijnen T, Lip GY, Witteman JC. Prevalence, incidence and lifetime risk of atrial fibrillation: the Rotterdam study. Eur Heart J. 2006;27:949 –953. 2. Nattel S. New ideas about atrial fibrillation 50 years on. Nature. 2002; 415:219 –226. 3. Berenfeld O, Zaitsev AV, Mironov SF, Pertsov AM, Jalife J. Frequencydependent breakdown of wave propagation into fibrillatory conduction across the pectinate muscle network in the isolated sheep right atrium. Circ Res. 2002;90:1173–1180. 4. Nattel S, Maguy A, Le Bouter S, Yeh YH. Arrhythmogenic ion-channel remodeling in the heart: heart failure, myocardial infarction, and atrial fibrillation. Physiol Rev. 2007;87:425– 456. 5. Yue L, Feng J, Gaspo R, Li G-R, Wang Z, Nattel S. Ionic remodeling underlying action potential changes in a canine model of atrial fibrillation. Circ Res. 1997;81:512–525. 6. Cha TJ, Ehrlich JR, Chartier D, Xiao L, Nattel S. Kir3-based inward rectifier potassium current: potential role in atrial tachycardia 23. 24. 25. 26. remodeling effects on atrial repolarization and arrhythmias. Circulation. 2006;113:1730 –1737. van der Velden HM, Ausma J, Rook MB, Hellemons AJ, van Veen TA, Allessie MA, Jongsma HJ. Gap junctional remodeling in relation to stabilization of atrial fibrillation in the goat. Cardiovasc Res. 2000;46: 476 – 486. Gaspo R, Bosch RF, Bou-Abboud E, Nattel S. Tachycardia-induced changes in Na⫹ current in a chronic dog model of atrial fibrillation. Circ Res. 1997;81:1045–1052. Li D, Fareh S, Leung TK, Nattel S. Promotion of atrial fibrillation by heart failure in dogs: atrial remodeling of a different sort. Circulation. 1999;100:87–95. Shinagawa K, Shi YF, Tardif JC, Leung T-K, Nattel S. Dynamic nature of atrial fibrillation substrate during development and reversal of heart failure in dogs. Circulation. 2002;105:2672–2678. Zou R, Kneller J, Leon LJ, Nattel S. Substrate size as a determinant of fibrillatory activity maintenance in a mathematical model of canine atrium. Am J Physiol (Heart Circ Physiol). 2005;289:H1002–H1012. Shi Y, Ducharme A, Li D, Gaspo R, Nattel S, Tardif JC. Remodeling of atrial dimensions and emptying function in canine models of atrial fibrillation. Cardiovasc Res. 2001;52:217–225. Henry WL, Morganroth J, Pearlman AS, Clark CE, Redwood DR, Itscoitz SB, Epstein SE. Relation between echocardiographically determined left atrial size and atrial fibrillation. Circulation. 1976;53: 273–279. Lai LP, Su MJ, Lin JL, Tsai CH, Lin FY, Chen YS, Hwang JJ, Huang SK, Tseng YZ, Lien WP. Measurement of funny current (If) channel mRNA in human atrial tissue: correlation with left atrial filling pressure and atrial fibrillation. J Cardiovasc Electrophysiol. 1999;10:947–953. Zicha S, Fernández-Velasco M, Lonardo G, L’Heureux N, Nattel S. Sinus node dysfunction and hyperpolarization-activated (HCN) channel subunit remodeling in a canine heart failure model. Cardiovasc Res. 2005;66:472– 481. Stambler BS, Fenelon G, Shepard RK, Clemo HF, Guiraudon CM. Characterization of sustained atrial tachycardia in dogs with rapid ventricular pacing-induced heart failure. J Cardiovasc Electrophysiol. 2003; 14:499 –507. Yeh YH, Wakili R, Qi X, Chartier D, Boknik P, Ravens U, Coutu P, Dobrev D, Nattel S. Calcium handling abnormalities underlying atrial arrhythmogenesis and contractile dysfunction in dogs with congestive heart failure. Circ Arrhythmia Electrophysiol. In press. Chen YJ, Chen SA, Chen YC, Yeh HI, Chan P, Chang MS, Lin CI. Effects of rapid atrial pacing on the arrhythmogenic activity of single cardiomyocytes from pulmonary veins: implication in initiation of atrial fibrillation. Circulation. 2001;104:2849 –2854. Coutu P, Chartier D, Nattel S. Comparison of Ca2⫹-handling properties of canine pulmonary vein and left atrial cardiomyocytes. Am J Physiol (Heart Circ Physiol). 2006;291:H2290 –H2300. Nattel S, Quantz MA. Pharmacological response of quinidine induced early afterdepolarisations in canine cardiac Purkinje fibres: insights into underlying ionic mechanisms. Cardiovasc Res. 1988;22:808 – 817. Satoh T, Zipes DP. Cesium-induced atrial tachycardia degenerating into atrial fibrillation in dogs: atrial torsades de pointes? J Cardiovasc Electrophysiol. 1998;9:970 –975. Burashnikov A, Antzelevitch C. Reinduction of atrial fibrillation immediately after termination of the arrhythmia is mediated by late phase 3 early afterdepolarization-induced triggered activity. Circulation. 2003; 107:2355–2360. Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA. Atrial fibrillation begets atrial fibrillation: a study in awake chronically instrumented goats. Circulation. 1995;92:1954 –1968. Burstein B, Qi XY, Yeh YH, Calderone A, Nattel S. Atrial cardiomyocyte tachycardia alters cardiac fibroblast function: a novel consideration in atrial remodeling. Cardiovasc Res. 2007;76:442– 452. Dobrev D, Graf E, Wettwer E, Himmel HM, Hála O, Doerfel C, Christ T, Schüler S, Ravens U. Molecular basis of downregulation of G-protein-coupled inward rectifying K⫹ current (IK,ACh) in chronic human atrial fibrillation: decrease in GIRK4 mRNA correlates with reduced IK,ACh and muscarinic receptor-mediated shortening of action potentials. Circulation. 2001;104:2551–2557. Dobrev D, Friedrich A, Voigt N, Jost N, Wettwer E, Christ T, Knaut M, Ravens U. The G-protein gated potassium current IK,ACh is constitutively active in patients with chronic atrial fibrillation. Circulation. 2005;112: 3697–3706. Nattel et al Mechanisms and Consequences of Atrial Remodeling Downloaded from http://circep.ahajournals.org/ by guest on May 13, 2017 27. Sun H, Gaspo R, Leblanc N, Nattel S. Cellular mechanisms of atrial contractile dysfunction caused by sustained atrial tachycardia. Circulation. 1998;98:719 –727. 28. Yue L, Melnyk P, Gaspo R, Wang Z, Nattel S. Molecular mechanisms underlying ionic remodeling in a dog model of atrial fibrillation. Circ Res. 1999;84:776 –784. 29. Christ T, Boknik P, Wöhrl S, Wettwer E, Graf EM, Bosch RF, Knaut M, Schmitz W, Ravens U, Dobrev D. Reduced L-type Ca2⫹ current density in chronic human atrial fibrillation is associated with increased activity of protein phosphatases. Circulation. 2004;110:2651–2657. 30. Brundel BJ, Ausma J, van Gelder IC, Van der Want JJ, van Gilst WH, Crijns HJ, Henning RH. Activation of proteolysis by calpains and structural changes in human paroxysmal and persistent atrial fibrillation. Cardiovasc Res. 2002;54:380 –389. 31. Kneller J, Sun H, Leblanc N, Nattel S. Remodeling of Ca2⫹-handling by atrial tachycardia: evidence for a role in loss of rate-adaptation. Cardiovasc Res. 2002;54:416 – 426. 32. Brundel BJ, Van Gelder IC, Henning RH, Tieleman RG, Tuinenburg AE, Wietses M, Grandjean JG, Van Gilst WH, Crijns HJ. Ion channel remodelling is related to intraoperative atrial effective refractory periods in patients with paroxysmal and persistent atrial fibrillation. Circulation. 2001;103:684 – 690. 33. Schotten U, Haase H, Frechen D, Greiser M, Stellbrink C, VazquezJimenez JF, Morano I, Allessie MA, Hanrath P. The L-type Ca2⫹channel subunits alpha1C and beta2 are not downregulated in atrial myocardium of patients with chronic atrial fibrillation. J Mol Cell Cardiol. 2003;35:437– 443. 34. Greiser M, Halaszovich CR, Frechen D, Boknik P, Ravens U, Dobrev D, Lückhoff A, Schotten U. Pharmacological evidence for altered srckinase regulation of ICa,L in patients with chronic atrial fibrillation. Naunyn Schmiedebergs Arch Pharmacol. 2007;375:383–392. 35. Gaborit N, Steenman M, Lamirault G, Le Meur N, Le Bouter S, Lande G, Léger J, Charpentier F, Christ T, Dobrev D, Escande D, Nattel S, Demolombe S. Human atrial ion channel and transporter subunit geneexpression remodeling associated with valvular heart disease and atrial fibrillation. Circulation. 2005;112:471– 481. 36. Bosch RF, Scherer CR, Rüb N, Wöhrl S, Steinmeyer K, Haase H, Busch AE, Seipel L, Kühlkamp V. Molecular mechanisms of early electrical remodeling: transcriptional downregulation of ion channel subunits reduces ICa,L and Ito in rapid atrial pacing in rabbits. J Am Coll Cardiol. 2003;41:858 – 869. 37. Carnes CA, Janssen PM, Ruehr ML, Nakayama H, Nakayama T, Haase H, Bauer JA, Chung MK, Fearon IM, Gillinov AM, Hamlin RL, Van Wagoner DR. Atrial glutathione content, calcium current, and contractility. J Biol Chem. 2007;282:28063–28073. 38. Beharier O, Etzion Y, Katz A, Friedman H, Tenbosh N, Zacharish S, Bereza S, Goshen U, Moran A. Crosstalk between L-type calcium channels and ZnT-1, a new player in rate-dependent cardiac electrical remodeling. Cell Calcium. 2007;42:71– 82. 39. Etzion Y, Ganiel A, Beharier O, Shalev A, Novack V, Volvich L, Abrahamov D, Matsa M, Sahar G, Moran A, Katz A. Correlation between atrial ZnT-1 expression and atrial fibrillation in humans: a pilot study. J Cardiovasc Electrophysiol. 2008;19:157–164. 40. Hara M, Shvilkin A, Rosen MR, Danilo P Jr, Boyden PA. Steady-state and nonsteady-state action potentials in fibrillating canine atrium: abnormal rate adaptation and its possible mechanisms. Cardiovasc Res. 1999;42:455– 469. 41. Kneller J, Zou R, Vigmond EJ, Wang Z, Leon LJ, Nattel S. Cholinergic atrial fibrillation in a computer model of a two-dimensional sheet of canine atrial cells with realistic ionic properties. Circ Res. 2002;90: E73–E87. 42. Yeh Y-H, Lemola K, Nattel S. Vagal atrial fibrillation. Acta Cardiol Sin. 2007;23:1–12. 43. Ehrlich JR, Cha TJ, Zhang L, Chartier D, Villeneuve L, Hébert TE, Nattel S. Characterization of a hyperpolarization-activated timedependent potassium current in canine cardiomyocytes from pulmonary vein myocardial sleeves and left atrium. J Physiol. 2004;557:583–597. 44. Voigt N, Maguay A, Yeh YH, Qi X, Ravens U, Dobrev D, Nattel S. Changes in IK,ACh single channel activity with atrial tachycardia remodeling in canine atrial cardiomyocytes. Cardiovasc Res. 2008;77: 35– 43. 45. Voigt N, Friedrich A, Bock M, Wettwer E, Christ T, Knaut M, Strasser RH, Ravens U, Dobrev D. Differential phosphorylation-dependent regulation of constitutively active and muscarinic receptor-activated IK,ACh 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 71 channels in patients with chronic atrial fibrillation. Cardiovasc Res. 2007;74:426 – 437. Wu G, Huang CX, Tang YH, Jiang H, Wan J, Chen H, Xie Q, Huang ZR. Changes of IK,ATP current density and allosteric modulation during chronic atrial fibrillation. Chin Med J. 2005;118:1161–1166. Balana B, Dobrev D, Wettwer E, Christ T, Knaut M, Ravens U. Decreased ATP-sensitive K⫹ current density during chronic human atrial fibrillation. J Mol Cell Cardiol. 2003;35:1399 –1405. Brundel BJ, Van Gelder IC, Henning RH, Tuinenburg AE, Wietses M, Grandjean JG, Wilde AA, Van Gilst WH, Crijns HJ. Alterations in potassium channel gene expression in atria of patients with persistent and paroxysmal atrial fibrillation: differential regulation of protein and mRNA levels for K⫹ channels. J Am Coll Cardiol. 2001;37:926 –932. Goette A, Arndt M, Rocken C, Staack T, Bechtloff R, Reinhold D, Huth C, Ansorge S, Klein HU, Lendeckel U. Calpains and cytokines in fibrillating human atria. Am J Physiol (Heart Circ Physiol) 2002;283: H264 –H272. Rossow CF, Dilly KW, Santana LF. Differential calcineurin/NFATc3 activity contributes to the Ito transmural gradient in the mouse heart. Circ Res. 2006;98:1306 –1313. Bukowska A, Lendeckel U, Hirte D, Wolke C, Striggow F, Röhnert P, Huth C, Klein HU, Goette A. Activation of the calcineurin signaling pathway induces atrial hypertrophy during atrial fibrillation. Cell Mol Life Sci. 2006;63:333–342. Courtemanche M, Ramirez RJ, Nattel S. Ionic targets for drug therapy and atrial fibrillation-induced electrical remodeling: insights from a mathematical model. Cardiovasc Res. 1999;42:477– 489. Kim YM, Guzik TJ, Zhang YH, Zhang MH, Kattach H, Ratnatunga C, Pillai R, Channon KM, Casadei B. A myocardial Nox2 containing NAD(P)H oxidase contributes to oxidative stress in human atrial fibrillation. Circ Res. 2005;97:629 – 636. Dudley SC Jr, Hoch NE, McCann LA, Honeycutt C, Diamandopoulos L, Fukai T, Harrison DG, Dikalov SI, Langberg J. Atrial fibrillation increases production of superoxide by the left atrium and left atrial appendage: role of the NADPH and xanthine oxidases. Circulation. 2005;112:1266 –1273. Núnez L, Vaquero M, Gómez R, Caballero R, Mateos-Cáceres P, Macaya C, Iriepa I, Gálvez E, López-Farré A, Tamargo J, Delpón E. Nitric oxide blocks hKv1.5 channels by S-nitrosylation and by a cyclic GMP-dependent mechanism. Cardiovasc Res. 2006;72:80 – 89. Yue L, Feng J, Li G-R, Nattel S. Transient outward and delayed rectifier currents in canine atrium: properties and role of isolation methods. Am J Physiol (Heart Circ Physiol): 1996;270:H2157–H2168. Burstein B, Nattel S. Atrial fibrosis: mechanisms and clinical relevance in atrial fibrillation. J Am Coll Cardiol. 2008;51:802– 809. Katz AM. Proliferative signaling and disease progression in heart failure. Circ J. 2002;66:225–231. Xiao HD, Fuchs S, Campbell DJ, Lewis W, Dudley SC Jr, Kasi VS, Hoit BD, Keshelava G, Zhao H, Capecchi MR, Bernstein KE. Mice with cardiac-restricted angiotensin-converting enzyme (ACE) have atrial enlargement, cardiac arrhythmia, and sudden death. Am J Pathol. 2004; 165:1019 –1032. Hunyady L, Catt KJ. Pleiotropic AT1 receptor signaling pathways mediating physiological and pathogenic actions of angiotensin II. Mol Endocrinol. 2006;20:953–970. Rosenkranz S. TGF-beta1 and angiotensin networking in cardiac remodeling. Cardiovasc Res. 2004;63:423– 432. Attisano L, Wrana JL. Signal transduction by the TGF-beta superfamily. Science. 2002;296:1646 –1647. Verheule S, Sato T, Everett T IV, Engle SK, Otten D, Rubart-von der Lohe M, Nakajima HO, Nakajima H, Field LJ, Olgin JE. Increased vulnerability to atrial fibrillation in transgenic mice with selective atrial fibrosis caused by overexpression of TGF-beta1. Circ Res. 2004;94: 1458 –1465. Burstein B, Libby E, Calderone A, Nattel S. Atrial fibroblasts are different from ventricular: a potential contributor to atrial-ventricular remodeling differences? Circulation. 2008;117:1630 –1641. Chuva de Sousa Lopes SM, Feijen A, Korving J, Korchynskyi O, Larsson J, Karlsson S, ten Dijke P, Lyons KM, Goldschmeding R, Doevendans P, Mummery CL. Connective tissue growth factor expression and Smad signaling during mouse heart development and myocardial infarction. Dev Dyn. 2004;231:542–550. Ahmed MS, Øie E, Vinge LE, Yndestad A, Øystein Andersen G, Andersson Y, Attramadal T, Attramadal H. Connective tissue growth 72 67. 68. 69. 70. 71. 72. Downloaded from http://circep.ahajournals.org/ by guest on May 13, 2017 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. Circ Arrhythmia Electrophysiol April 2008 factor: a novel mediator of angiotensin II-stimulated cardiac fibroblast activation in heart failure in rats. J Mol Cell Cardiol. 2004;36:393– 404. Chen MM, Lam A, Abraham JA, Schreiner GF, Joly AH. CTGF expression is induced by TGF- beta in cardiac fibroblasts and cardiac myocytes: a potential role in heart fibrosis. J Mol Cell Cardiol. 2000; 32:1805–1819. Cardin S, Li D, Thorin-Trescases N, Leung TK, Thorin E, Nattel S. Evolution of the atrial fibrillation substrate in experimental congestive heart failure: angiotensin-dependent and -independent pathways. Cardiovasc Res. 2003;60:315–325. Li D, Shinagawa K, Pang L, Leung TK, Cardin S, Wang Z, Nattel S. Effects of angiotensin-converting enzyme inhibition on the development of the atrial fibrillation substrate in dogs with ventricular tachypacinginduced congestive heart failure. Circulation. 2001;104:2608 –2614. Kumagai K, Nakashima H, Urata H, Gondo N, Arakawa K, Saku K. Effects of angiotensin II type 1 receptor antagonist on electrical and structural remodeling in atrial fibrillation. J Am Coll Cardiol. 2003;41: 2197–2204. Shroff SC, Ryu K, Martovitz NL, Hoit BD, Stambler BS. Selective aldosterone blockade suppresses atrial tachyarrhythmias in heart failure. J Cardiovasc Electrophysiol. 2006;17:534 –541. Hanna N, Cardin S, Leung TK, Nattel S. Differences in atrial versus ventricular remodeling in dogs with ventricular tachypacing-induced congestive heart failure. Cardiovasc Res. 2004;63:236 –244. Lee KW, Everett TH IV, Rahmutula D, Guerra JM, Wilson E, Ding C, Olgin JE. Pirfenidone prevents the development of a vulnerable substrate for atrial fibrillation in a canine model of heart failure. Circulation. 2006;114:1703–1712. Cardin S, Libby E, Pelletier P, Le Bouter S, Shiroshita-Takeshita A, Le Meur N, Léger J, Demolombe S, Ponton A, Glass L, Nattel S. Contrasting gene expression profiles in two canine models of atrial fibrillation. Circ Res. 2007;100:425– 433. Nakano Y, Niida S, Dote K, Takenaka S, Hirao H, Miura F, Ishida M, Shingu T, Sueda T, Yoshizumi M, Chayama K. Matrix metalloproteinase-9 contributes to human atrial remodeling during atrial fibrillation. J Am Coll Cardiol. 2004;43:818 – 825. Mukherjee R, Herron AR, Lowry AS, Stroud RE, Stroud MR, Wharton JM, Ikonomidis JS, Crumbley AJ III, Spinale FG, Gold MR. Selective induction of matrix metalloproteinases and tissue inhibitor of metalloproteinases in atrial and ventricular myocardium in patients with atrial fibrillation. Am J Cardiol. 2006;97:532–537. Adam O, Frost G, Custodis F, Sussman MA, Schäfers HJ, Böhm M, Laufs U. Role of Rac1 GTPase activation in atrial fibrillation. J Am Coll Cardiol. 2007;50:359 –367. Shiroshita-Takeshita A, Schram G, Lavoie J, Nattel S. Effect of simvastatin and antioxidant vitamins on atrial fibrillation promotion by atrial-tachycardia remodeling in dogs. Circulation. 2004;110: 2313–2319. Wetzel U, Boldt A, Lauschke J, Weigl J, Schirdewahn P, Dorszewski A, Doll N, Hindricks G, Dhein S, Kottkamp H. Expression of connexins 40 and 43 in human left atrium in atrial fibrillation of different aetiologies. Heart. 2005;91:166 –170. Firouzi M, Ramanna H, Kok B, Jongsma HJ, Koeleman BP, Doevendans PA, Groenewegen WA, Hauer RN. Association of human connexin40 gene polymorphisms with atrial vulnerability as a risk factor for idiopathic atrial fibrillation. Circ Res. 2004;95:e29 – e33. Gollob MH, Jones DL, Krahn AD, Danis L, Gong XQ, Shao Q, Liu X, Veinot JP, Tang AS, Stewart AF, Tesson F, Klein GJ, Yee R, Skanes AC, Guiraudon GM, Ebihara L, Bai D. Somatic mutations in the connexin 40 gene (GJA5) in atrial fibrillation. N Engl J Med. 2006;354: 2677–2688. Vest JA, Wehrens XH, Reiken SR, Lehnart SE, Dobrev D, Chandra P, Danilo P, Ravens U, Rosen MR, Marks AR. Defective cardiac ryanodine receptor regulation during atrial fibrillation. Circulation. 2005;111: 2025–2032. Li D, Melnyk P, Feng J, Wang Z, Petrecca K, Shrier A, Nattel S. Effects of experimental heart failure on atrial cellular and ionic electrophysiology. Circulation. 2000;101:2631–2638. El-Armouche A, Boknik P, Eschenhagen T, Carrier L, Knaut M, Ravens U, Dobrev D. Molecular determinants of altered Ca2⫹ handling in human chronic atrial fibrillation. Circulation. 2006;114:670 – 680. Uemura N, Ohkusa T, Hamano K, Nakagome M, Hori H, Shimizu M, Matsuzaki M, Mochizuki S, Minamisawa S, Ishikawa Y. Downregulation of sarcolipin mRNA expression in chronic atrial fibrillation. Eur J Clin Invest. 2004;34:723–730. 86. Antos CL, Frey N, Marx SO, Reiken S, Gaburjakova M, Richardson JA, Marks AR, Olson EN. Dilated cardiomyopathy and sudden death resulting from constitutive activation of protein kinase A. Circ Res. 2001;89:997–1004. 87. Pathak A, del Monte F, Zhao W, Schultz JE, Lorenz JN, Bodi I, Weiser D, Hahn H, Carr AN, Syed F, Mavila N, Jha L, Qian J, Marreez Y, Chen G, McGraw DW, Heist EK, Guerrero JL, DePaoli-Roach AA, Hajjar RJ, Kranias EG. Enhancement of cardiac function and suppression of heart failure progression by inhibition of protein phosphatase 1. Circ Res. 2005;96:756 –766. 88. Li X, Zima AV, Sheikh F, Blatter LA, Chen J. Endothelin-1-induced arrhythmogenic Ca2⫹ signaling is abolished in atrial myocytes of inositol-1,4,5-trisphosphate(IP3)-receptor type 2-deficient mice. Circ Res. 2005;96:1274 –1281. 89. Zhao ZH, Zhang HC, Xu Y, Zhang P, Li XB, Liu YS, Guo JH. Inositol-1,4,5-trisphosphate and ryanodine-dependent Ca2⫹ signaling in a chronic dog model of atrial fibrillation. Cardiology. 2007;107: 269 –276. 90. Zima AV, Blatter LA. Inositol-1,4,5-trisphosphate-dependent Ca2⫹ signalling in cat atrial excitation-contraction coupling and arrhythmias. J Physiol. 2004;555:607– 615. 91. Nattel S. Atrial electrophysiological remodeling caused by rapid atrial activation: underlying mechanisms and clinical relevance to atrial fibrillation. Cardiovasc Res. 1999;42:298 –308. 92. Tieleman RG, Van Gelder IC, Bosker HA, Kingma T, Wilde AA, Kirchhof CJ, Bennekers JH, Bracke FA, Veeger NJ, Haaksma J, Allessie MA, Crijns HJ. Does flecainide regain its antiarrhythmic activity after electrical cardioversion of persistent atrial fibrillation? Heart Rhythm. 2005;2:223–230. 93. Duytschaever M, Blaauw Y, Allessie M. Consequences of atrial electrical remodeling for the anti-arrhythmic action of class IC and class III drugs. Cardiovasc Res. 2005;67:69 –76. 94. Fynn SP, Todd DM, Hobbs WJ, Armstrong KL, Fitzpatrick AP, Garratt CJ. Clinical evaluation of a policy of early repeated internal cardioversion for recurrence of atrial fibrillation. J Cardiovasc Electrophysiol. 2002;13:135–141. 95. Tse HF, Wang Q, Yu CM, Ayers GM, Lau CP. Time course of recovery of left atrial mechanical dysfunction after cardioversion of spontaneous atrial fibrillation with the implantable atrial defibrillator. Am J Cardiol. 2000;86:1023–1025. 96. Tse HF, Lau CP, Yu CM, Lee KL, Michaud GF, Knight BP, Morady F, Strickberger SA. Effect of the implantable atrial defibrillator on the natural history of atrial fibrillation. J Cardiovasc Electrophysiol. 1999; 10:1200 –1209. 97. Timmermans C, Lévy S, Ayers GM, Jung W, Jordaens L, Rosenqvist M, Thibault B, Camm J, Rodriguez LM, Wellens HJ; Metrix Investigators. Spontaneous episodes of atrial fibrillation after implantation of the Metrix Atrioverter: observations on treated and nontreated episodes. J Am Coll Cardiol. 2000;35:1428 –1433. 98. Fareh S, Bénardeau A, Thibault B, Nattel S. The T-type Ca2⫹ channel blocker mibefradil prevents the development of a substrate for atrial fibrillation by tachycardia-induced atrial remodeling in dogs. Circulation. 1999;100:2191–2197. 99. Shinagawa K, Shiroshita-Takeshita A, Schram G, Nattel S. Effects of antiarrhythmic drugs on fibrillation in the remodeled atrium: insights into the mechanism of the superior efficacy of amiodarone. Circulation. 2003;107:1440 –1446. 100. Nishida K, Fujiki A, Sakamoto T, Iwamoto J, Mizumaki K, Hashimoto N, Inoue H. Bepridil reverses atrial electrical remodeling and L-type calcium channel downregulation in a canine model of persistent atrial tachycardia. J Cardiovasc Electrophysiol. 2007;18:765–772. 101. Fujiki A, Inoue H. Pharmacological cardioversion of long-lasting atrial fibrillation. Circ J. 2007;71:A69 –A74. 102. Neuman RB, Bloom HL, Shukrullah I, Darrow LA, Kleinbaum D, Jones DP, Dudley SC Jr. Oxidative stress markers are associated with persistent atrial fibrillation. Clin Chem. 2007;53:1652–1657. 103. Shiroshita-Takeshita A, Brundel BJJM, Lavoie J, Nattel S. Prednisone prevents atrial fibrillation promotion by atrial tachycardia remodeling in dogs. Cardiovasc Res. 2006;69:865– 875. 104. Issac TT, Dokainish H, Lakkis NM. Role of inflammation in initiation and perpetuation of atrial fibrillation: a systematic review of the published data. J Am Coll Cardiol. 2007;50:2021–2028. 105. Dernellis J, Panaretou M. Relationship between C-reactive protein concentrations during glucocorticoid therapy and recurrent atrial fibrillation. Eur Heart J. 2004;25:1100 –1107. Nattel et al Mechanisms and Consequences of Atrial Remodeling Downloaded from http://circep.ahajournals.org/ by guest on May 13, 2017 106. Pedersen OD, Bagger H, Kober L, Torp-Pedersen C. Trandolapril reduces the incidence of atrial fibrillation after acute myocardial infarction in patients with left ventricular dysfunction. Circulation. 1999;100:376 –380. 107. Vermes E, Tardif JC, Bourassa MG, Racine N, Levesque S, White M, Guerra PG, Ducharme A. Enalapril decreases the incidence of atrial fibrillation in patients with left ventricular dysfunction: insight from the Studies Of Left Ventricular Dysfunction (SOLVD) trials. Circulation. 2003;107:2926 –2931. 108. Healey JS, Baranchuk A, Crystal E, Morillo CA, Garfinkle M, Yusuf S, Connolly SJ. Prevention of atrial fibrillation with angiotensinconverting enzyme inhibitors and angiotensin receptor blockers: a metaanalysis. J Am Coll Cardiol. 2005;45:1832–1839. 109. Kumagai K, Nakashima H, Urata H, Gondo N, Arakawa K, Saku K. Effects of angiotensin II type 1 receptor antagonist on electrical and structural remodeling in atrial fibrillation. J Am Coll Cardiol. 2003;41: 2197–2204. 110. Milliez P, Deangelis N, Rucker-Martin C, Leenhardt A, Vicaut E, Robidel E, Beaufils P, Delcayre C, Hatem SN. Spironolactone reduces fibrosis of dilated atria during heart failure in rats with myocardial infarction. Eur Heart J. 2005;26:2193–2199. 111. Shroff SC, Ryu K, Martovitz NL, Hoit BD, Stambler BS. Selective aldosterone blockade suppresses atrial tachyarrhythmias in heart failure. J Cardiovasc Electrophysiol. 2006;17:534 –541. 73 112. Shiroshita-Takeshita A, Brundel BJ, Burstein B, Leung TK, Mitamura H, Ogawa S, Nattel S. Effects of simvastatin on the development of the atrial fibrillation substrate in dogs with congestive heart failure. Cardiovasc Res. 2007;74:75– 84. 113. Boos CJ, Anderson RA, Lip GY. Is atrial fibrillation an inflammatory disorder? Eur Heart J. 2006;27:136 –149. 114. Sakabe M, Shiroshita-Takeshita A, Maguy A, Dumesnil C, Nigam A, Leung TK, Nattel S. Omega-3 polyunsaturated fatty acids prevent atrial fibrillation associated with heart failure but not atrial tachycardia remodeling. Circulation. 2007;116:2101–1209. 115. Shiroshita-Takeshita A, Sakabe M, Maguy A, Cardin S, Brundel BJ, Nattel S. Heat shock protein induction attenuates atrial remodeling and atrial fibrillation promotion in dogs with ventricular tachycardiomyopathy. Circulation. 2007;116(suppl II):II-251. Abstract. 116. Everett TH IV, Olgin JE. Atrial fibrosis and the mechanisms of atrial fibrillation. Heart Rhythm. 2007;4(suppl 3):S24 –S27. 117. Bode F, Sachs F, Franz MR. Tarantula peptide inhibits atrial fibrillation. Nature. 2001;409:35–36. 118. Lehnart SE. Novel targets for treating heart and muscle disease: stabilizing ryanodine receptors and preventing intracellular calcium leak. Curr Opin Pharmacol. 2007;7:225–232. KEY WORDS antiarrhythmia agents 䡲 ion channels 䡲 remodeling 䡲 arrhythmia 䡲 electrophysiology Atrial Remodeling and Atrial Fibrillation: Mechanisms and Implications Stanley Nattel, Brett Burstein and Dobromir Dobrev Downloaded from http://circep.ahajournals.org/ by guest on May 13, 2017 Circ Arrhythm Electrophysiol. 2008;1:62-73 doi: 10.1161/CIRCEP.107.754564 Circulation: Arrhythmia and Electrophysiology is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2008 American Heart Association, Inc. All rights reserved. Print ISSN: 1941-3149. 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