Review Atrial remodeling in varying clinical substrates within beating human hearts: Relevance to atrial fibrillation Saurabh Kumar a, b , Andrew W. Teh a, b, c , Caroline Medi a, b, c , Peter M. Kistler c , Joseph B. Morton a, b , Jonathan M. Kalman a, b, * a Department of Cardiology, The Royal Melbourne Hospital, Parkville, Australia b Department of Medicine, University of Melbourne, Parkville, Australia c Department of Cardiology, Alfred Hospital and Baker IDI, Prahran, Australia article info Article history: Available online 16 August 2012 Keywords: Atrial fibrillation Atrial remodeling Pulmonary vein Pulmonary vein remodeling Lone atrial fibrillation Atrial stretch Reverse remodeling abstract Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in human beating hearts. AF initiates self-perpetuating changes in electrophysiology, structure and functional properties of the atria, a phenomenon known as atrial remodeling. Hypertension, heart failure, valvular heart disease, sleep apnea, congenital heart disease are well known risk factors for AF that contribute to the development of atrial substrate. There is some evidence that reversal of atrial remodeling is possible with correction of antecedent conditions, however the timing of the intervention or upstream therapy may be critical. This review will describe the pathophysiology of atrial remodeling as it pertains to AF. We will describe components of remodeling including changes in atrial refractoriness, conduction and atrial structure, in addition to autonomic changes and anatomic factors that predispose to remodeling. We will discuss our current understanding of the electrophysiological changes that contribute to AF persistence. We will describe nature of atrial and pulmonary vein remodeling in the context of different forms of AF, with and without predisposing risk factors. We will describe the nature of remodeling over time following ther- apeutic interventions such as AF ablation in order to show that it does not necessarily improve and may worsen. Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved. Contents 1. Introduction .......................................................................................................................279 2. Atrial electrical remodeling .........................................................................................................279 3. Basic mechanisms behind atrial electrical remodeling ................................................................................. 280 3.1. Mechanisms behind atrial remodeling via altered atrial refractoriness .............................................................. 281 3.1.1. The normal human action potential ..................................................................................... 281 3.1.2. Ionic remodeling associated with atrial repolarization abnormalities ............................. .......................... 281 3.1.3. Role of calcium handling in AF pathogenesis ............................................................................. 282 3.2. Mechanisms behind atrial remodeling via altered atrial conduction ................................................................ 282 4. Atrial structural remodeling: the “second factor” .............................................. ....................................... 282 4.1. Role of atrial fibrosis in structural remodeling .................................................................................... 282 5. Electrophysiologic mechanism for AF stability and persistence .......................................................................... 283 6. Neural and autonomic remodeling ..................................................... ............................................. 284 7. Anatomic factors implicated in AF initiation and maintenance ....................................... .................................. 284 8. Atrial and pulmonary venous remodeling in AF in the absence of structural heart disease .................................................. 284 Abbreviations: AF, atrial fibrillation; AV, atrio-ventricular; APD, action potential duration; ERP, effective refractory period; LA, left atrium; PV, pulmonary vein; RA, right atrium. * Corresponding author. Department of Cardiology, The Royal Melbourne Hospital, Parkville 3050, Australia. Tel.: þ61 3 9349 5400; fax: þ61 3 9349 5411. E-mail address: [email protected](J.M. Kalman). Contents lists available at SciVerse ScienceDirect Progress in Biophysics and Molecular Biology journal homepage: www.elsevier.com/locate/pbiomolbio 0079-6107/$ e see front matter Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.pbiomolbio.2012.07.011 Progress in Biophysics and Molecular Biology 110 (2012) 278e294
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Progress in Biophysics and Molecular Biology 110 (2012) 278e294
Atrial remodeling in varying clinical substrates within beating humanhearts: Relevance to atrial fibrillation
Saurabh Kumar a,b, Andrew W. Teh a,b,c, Caroline Medi a,b,c, Peter M. Kistler c, Joseph B. Morton a,b,Jonathan M. Kalman a,b,*
aDepartment of Cardiology, The Royal Melbourne Hospital, Parkville, AustraliabDepartment of Medicine, University of Melbourne, Parkville, AustraliacDepartment of Cardiology, Alfred Hospital and Baker IDI, Prahran, Australia
Abbreviations: AF, atrial fibrillation; AV, atrio-ventduration; ERP, effective refractory period; LA, left atriright atrium.* Corresponding author. Department of Cardiol
0079-6107/$ e see front matter Crown Copyright � 2http://dx.doi.org/10.1016/j.pbiomolbio.2012.07.011
a b s t r a c t
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in human beating hearts. AFinitiates self-perpetuating changes in electrophysiology, structure and functional properties of the atria,a phenomenon known as atrial remodeling. Hypertension, heart failure, valvular heart disease, sleepapnea, congenital heart disease are well known risk factors for AF that contribute to the development ofatrial substrate. There is some evidence that reversal of atrial remodeling is possible with correction ofantecedent conditions, however the timing of the intervention or upstream therapy may be critical. Thisreview will describe the pathophysiology of atrial remodeling as it pertains to AF. We will describecomponents of remodeling including changes in atrial refractoriness, conduction and atrial structure, inaddition to autonomic changes and anatomic factors that predispose to remodeling. We will discuss ourcurrent understanding of the electrophysiological changes that contribute to AF persistence. We willdescribe nature of atrial and pulmonary vein remodeling in the context of different forms of AF, with andwithout predisposing risk factors. We will describe the nature of remodeling over time following ther-apeutic interventions such as AF ablation in order to show that it does not necessarily improve and mayworsen.
Crown Copyright � 2012 Published by Elsevier Ltd. All rights reserved.
Atrial fibrillation (AF) is the most prevalent cardiacarrhythmia in human beating hearts. The prevalence of AFincreases with age (Wolf et al., 1996). AF is associated withsignificant impairment in quality of life, with a 4e5 fold increasein the risk of stroke, a doubling of risk for dementia, tripling ofthe risk of heart failure and a 40e90% increased risk of mortality(Benjamin et al., 2009). Broadly, three types of AF are recognized:paroxysmal (lasting <7 days and self-terminating), persistent(lasting >7 days and requiring electrical or pharmacologicalreversion) and permanent (cardioversion failed or not attemp-ted). AF is associated with changes in atrial electrophysiology,structure and function, a process termed atrial remodeling.
Paroxysmal AF is triggered by a driver present within cardiacmuscle sleeves inandaround thepulmonaryveins (PVs;Haissaguerreet al., 1998). Rapid activity from the PVs may be due to new impulsesgenerated due to automaticity or triggered activity or frommicro-re-entry due to abnormalities in PV tissue (Schotten et al., 2011).Persistent and permanent forms of AF incorporate more complexelectrical and structural remodeling forming the necessary substratefor AFmaintenance. Inmany cases, AFmay progress fromparoxysmalto persistent to permanent forms through the influence of atrialremodeling caused by the arrhythmia itself and/or progression ofunderlying structural heart disease such as systemic and pulmonaryhypertension, valvular heart disease, congenital heart disease, sinusnodedysfunctionandheart failure. AF-related electrical remodeling ismediated by altered expression and function of cardiac ion channels,a process reversible on AF termination (Nattel et al., 2008). Structuralchanges are responsible for progression of atrial disease andcontribute to AF being permanent (Iwasaki et al., 2011).
2. Atrial electrical remodeling
Progressive longer duration of AF can be sustained with longerdurations of AF induction (either via burst stimulation or rapidatrial pacing) in both the goat and canine models of AF, a conceptreferred to as “AF begets AF” (Wijffels et al., 1995; Morillo et al.,1995; Yue et al., 1997). The increased AF stability is associatedwith a decrease in atrial effective refractory periods (ERPs),increased spatial heterogeneity of ERP and loss of normal ERP rateadaptation (Wijffels et al., 1995; Fareh et al., 1998; Yue et al., 1997).Whilst ERP abbreviation is maximally reduced at 24 h, AF stabilitycontinues to increase over the ensuing weeks (Wijffels et al., 1995;Todd et al., 2004). These findings suggested that another factor,apart from electrical remodeling contributes to AF progression.Structural remodeling is thought to be a “second factor” thought to
contribute to AF progression occurring over a slower time period ofweeks to months and will be discussed in Section 4.
Abnormalities of atrial conduction in AF pathogenesis have beenelucidated by a number of studies. Gaspo et al. (1997) showed thattherewas time-dependent decrease in ERP, conduction velocity andwavelength in a canine model of rapid atrial-pacing. Although ERPshortening occurred maximally within 7 days, conduction velocitydecreased maximally much later at 42 days. Despite ERP changesreaching their peak, the duration of AF episodes continued toincrease in concert with more delayed changes in conduction. Ofnote is that conduction abnormalities in this model might haveoccurred because of moderate left ventricular dysfunction inducedby rapid atrial pacing in the absence of atrio-ventricular block. Laterstudies in a similar model did not confirm changes in conduction(Fareh et al., 1998; Li et al., 1999). On the other hand, studies ina goat model using burst atrial pacing have shown marked slowingin atrial conduction in addition to complex, progressive patterns ofendo-epicardial longitudinal dissociation in the atria resulting inincreasing complexity and stability of AF substrate over time(Eckstein et al., 2011; Verheule et al., 2010).
A number of studies have confirmed that shortened ERPs andconduction abnormalities (prolonged P wave duration, conductiondelays) are a universal feature of patients with AF patientscompared to controls with no AF (Kumagai et al., 1991; Yu et al.,1999; Kojodjojo et al., 2007). Furthermore, in patients with sus-tained atrial arrhythmias who are reverted to sinus rhythm, there isevidence of action potential duration (APD) and ERP shortening,increased ERP heterogeneity, impaired ERP rate adaptation andabnormalities of atrial conduction, which contribute to theheightened susceptibility to AF relapse in the first few weeks aftercardioversion to sinus rhythm (Table 1). Whilst temporal recoveryof ERP occurs early post reversion, abnormalities in conduction takelonger and are often incomplete.
The extent of the contribution of electrical remodeling toprogressionof humanAF is unclear. For example, no differences inAFcycle length were found in instrumented goats that had AF main-tained for 3 weeks vs. those with AF maintained for 6 months(Verheule et al., 2010). The efficacy of pharmacologic cardioversionin thismodel declinedwith increasingduration of AF suggesting thatincreased AF stability was not due to progression of electricalremodeling. Further, the AF cycle length is not shorter in patientswith persistent AF compared to patients with acute paroxysmal AF(Tehet al., 2010).Drugs that prolongAPDmay facilitate cardioversionof AF. Reversal of electrical remodeling alone with anti-arrhythmicdrugs does not explain why the success of chemical cardioversionis highest with recent onset AF but its efficacy is attenuated withlonger durations of AF. ERP abnormalities are expected to reverse
Table 1Human studies of atrial electrical remodeling.
Author Patient population Measures Time point of measures Main findings
Kamalvand et al., 1999 Persistent AF cf. controls ERP; MAPd90 15 min post CV YERP and MAPd90 in AF vs. SR patientsYu et al., 1999 Persistent AF cf. controls ERP, PWD, RA/LA
conduction30 min, 1, 2, 3 and4 d post CV
Immediately post cardioversion: YERP, YERP rateadaptation, Yatrial conduction in AF vs. SR patientsOver 4 d: [ERP and rate adaptation, no change inconduction
Hobbs et al., 2000 Persistent AF undergoingICV, TTM for AF, repeatedICV if AF recurrence
AFCL, couplingintervalsof APBs
Immediately priorto each ICV
[Minimum and mean AFCL with each ICV[AFCL correlated with duration of SR between each ICV[Shortest coupling interval with each ICV[ERP between 1st and 2nd ICV
Manios et al., 2000 Persistent AF cf. controls ERP, MAPd90, PWD 5e20 min, 24 h,1 month post CV
ERP and MAPd90 similar to controls within 24 h in AFpatients; PWD similar to controls at 1 month only
Raitt et al., 2004 Persistent AF ERP, CSNRT, PWD 10 min, 1 h,1 wk post CV
[ERP (recovery in 1 h post CV lateral RA, CS ERPrecovery in 1 week); CSNRT and PWD recoveryat 1 week only
Abbreviations: AFe atrial fibrillation, AFCLe atrial fibrillation cycle length, APBse atrial premature beats, CSe coronary sinus, CSNRTe corrected sinus node recovery time, CVe cardioversion, d e days, ERP e effective refractory period, h e hours, ICV e internal cardioversion, LA e left atrial, MAPd90 e monophasic action potential at 90% repo-larization, min e minutes, PWD e P wave duration, RA e right atrial, SR e sinus rhythm, TTM e trans-telephonic monitoring.
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within 2e3 days of sinus rhythmbut this does not explainwhy thereis persistence of AF vulnerability 2e4 weeks post cardioversionwhen reversal of electrical remodeling would have expected tooccur. This discrepant time course of electrical remodeling and AFvulnerability suggests that other processes apart from electricalremodeling contribute of AF progression (Schotten et al., 2011).
AF can bemaintained by rapid focal firing, whichmay be regularhowever, can manifest as fibrillation because of wave break up in
Fig. 1. Re-entry and atrial remodeling. Tissue entry occurs when a premature beat blocks in othat has already recovered (B). AF is promoted by shortening of refractoriness (C) slowed csupported (E). (Modified from Nattel et al., 2008 with permissions, license number 291286
portions of the atrium that fail to support 1:1 conduction (Nattelet al., 2008). In addition to serving as a focal trigger for parox-ysmal AF, ectopy can act on vulnerable atrial substrate to initiate AF,which is then maintained by multiple simultaneous functional re-entry circuits. Re-entry can be initiated when premature beatblocks in atrial tissue that is still refractory in one direction but isable to propagate through tissue that has already recovered inanother direction (Fig. 1). For re-entry to be maintained, the trav-eling impulse must travel slow enough to allow for all points toregain excitability. Longer path lengths (such as in dilated atria) andslowed conduction will allow sufficient time for this to occur. Short
ne direction (A) and is able to propagate slow enough such that it passes through tissueonduction (D) and remodeling induced atrial dilatation so that re-entry circuits can be0131294.).
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ERPs will increase the likelihood that the tissue is available forre-activation when the impulse passes through. Thus atrialremodeling can promote re-entry by: abbreviation of the APD (orshortened ERP), atrial conduction slowing and atrial dilatation(Nattel et al., 2008). Non-uniform conduction slowing also allowslines of conduction block to occur that can promote re-entry withinthe atria. Longitudinal dissociation consisting of lines of conductionblock running parallel to atrial muscle bundles and betweenendocardial and epicardial muscle bundles can occur (Roberts-Thomson et al., 2008; Allessie et al., 2010).
3.1. Mechanisms behind atrial remodeling via altered atrialrefractoriness
3.1.1. The normal human action potentialThe human APD determines atrial tissue ERP (Fig. 2). APD is
determined by the balance between inward calcium (Ca2þ)currents, which tends to keep the cell depolarized and outwardcurrents potassium (Kþ) currents, which tends to repolarize the cellduring the action potential plateau. The main depolarizing currentsare the rapidly activating and de-activating Naþ-current (INa) andthe L-type Ca2þ current (ICaL). The AP fires when depolarization issufficient to drive resting membrane potential to above thresholdactivating INa and causing the rapid AP upstroke. The AP plateau ismaintained by ICaL. Of the repolarizing currents, the ultra-rapiddelayed rectifier current (IKur) significantly contributes to atrialrepolarization, activating w100 times more rapidly than the rapiddelayed rectifier current (IKr; Schotten et al., 2011). Partial or earlyrepolarization that follows the AP upstroke is mediated by activa-tion of a transient outward Kþ current (Ito) and IKur (Workman et al.,2008). The acetylcholine-activated inward rectifier current IKAChand the inward rectified current, IK1 contribute to terminal repo-larization. IKACh shortens the atrial APD during vagal activity. IK1 is
Fig. 2. The atrial potential and time course of the main ionic currents responsible foreach phase. The main ion currents, their alpha subunit and responsible genes are listedon the right. Depolarizing currents are in gray and repolarising currents in black(modified from Schotten et al., 2011with permissions, license number 2912851112022.).
the main determinant of the resting membrane potential. Othercontributors to the resting membrane potential may include IKACh,Kþ pump current (Ip) and possibly ATP-sensitive Kþ current (IKATP,Workman et al., 2008). Atrial tissue has a lower density of IK1 thanventricular tissue making atrial myocytes more excitable thanventricular myocytes as less depolarizing current is necessary toreach the action potential threshold (Schotten et al., 2011). Mid/laterepolarization results from activation of IKur and the rapid (IKr) andslow (IKs) delayed rectifiers.
The inward NaþeCa2þ exchange current (INCX), is responsible forcellular Ca2þ homeostasis by extruding Ca2þ from the cell inexchange for extracellular Naþ in a 1:3 ionic ratio, generating a netinward movement of positive ions (Greiser et al., 2011; Nattel andDobrev, 2012). The presence of apamin-sensitive Ca2þ-activatedpotassium channels (IKCa), encoded by SK1, SK2 and SK3 genes hasbeen demonstrated. SK channel activity shortens APD, the extent ofwhich is dependent on cytosolic Ca2þ concentration thus providinga mechanism of the interaction between Ca2þ handling and repo-larization (Xu et al., 2003).
Activation of ICaL by membrane depolarization and subsequentinflux of Ca2þ into the cell activates Ca2þ-mediated Ca2þ releasefrom the sarcoplasmic reticulum through Ca2þ release channelscalled Ryanodine Receptors type 2 (RyR2). This causes a cell widetransient increase in Ca2þ current (Iti) which initiates myocytecontraction as free Ca2þ binds to myofilaments. During diastole,Ca2þ levels are restored by the extrusion of Ca2þ into the extra-cellular space by INCX and by Ca2þ reuptake into the sarcoplasmicreticulum via a Ca2þ uptake pump, the sarcoplasmic reticulum Ca2þ
ATPase (SERCA2a; Greiser et al., 2011; Nattel and Dobrev, 2012).
3.1.2. Ionic remodeling associated with atrial repolarizationabnormalities
AF induces electrical remodeling via its rapid atrial rate (“atrialtachycardia remodeling”) inducing changes in the expression andbehavior or ion channels resulting in APD abbreviation and ERPshortening (Nattel et al., 2008; Workman et al., 2008). APD short-ening is mediated by ICaL downregulation, increased IK1 and IKAChcurrents and a decrease in Ito currents (Workman et al., 2008).Rapid atrial rates also cause Ca2þ handling abnormalities, contrib-uting to atrial dilatation and hypocontractility that furtherpromotes re-entry (Nattel et al., 2008).
INa activity is unaltered in human AF whereas ICaL density isw70% lower compared to patients in sinus rhythm (Schotten et al.,2011). The abrupt increase in Ca2þ load in response to an acuteincrease in atrial rate in AF is counteracted acutely by decreasingICaL. This has the effect of decreasing APD, which favors AFperpetuation. Sustained AF causes more persistent ICaL reductionvia down-regulation of pore-forming mRNA and possibly by post-translational mechanisms such as protein de-phosphorylationand breakdown (Nattel et al., 2008).
Of the repolarizing currents, AF increases the expression of Kir2.1 mRNA and its protein that form subunits for IK1 resulting inincreased IK1 activity, contributing significantly to APD shortening(Nattel and Dobrev, 2012). IKACh plays an important role in AFarrhythmogenesis. Vagal activity, which is known to strongly triggerand promote AF, causes APD shortening by acting on IKACh channels.In AF patients, IKACh is constitutively active (i.e. independent of theagonist) due to increased protein kinase-C phosphorylation of thechannel (Nattel et al., 2008). IKATP appears to be important inischemia-induced electrophysiological abnormalities and itsexpression is increased in ischemic conditions in cells of patientswith AF; ischemia is known to be a contributor to atrial tachycardiaremodeling (Nattel et al., 2008). However IKATP changes in AF arecomplex with variable expression reported in AF patients (Nattelet al., 2008). Although Ito is consistently and strongly decreased in
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chronic AF patients, its functional consequences are unclear as itsrapid early activity counteracting inward Naþ current mean thatwhen it is down-regulated it may facilitate wave propagation(Workman et al., 2008; Nattel et al., 2008). AF-associated changes inIKur have also been inconsistent in AF patients, with studiesreporting no change or a decrease in IKur (Workman et al., 2008).
3.1.3. Role of calcium handling in AF pathogenesisThe role of Ca2þ handling changes in the atrial arrhythmogenesis
is the focus of intense investigation and is currently incompletelyunderstood (expertly reviewed by Greiser et al., 2011; Nattel andDobrev, 2012). Changes in Ca2þ handling in atrial myocytes maycontribute to AF initiation and perpetuation but may also develop asa result of AF. Unresolved issues in Ca2þ handling and AF pathogen-esis include changes in expression of ICaL in AF patients vs. controls(reduced ICaL vs. unchanged ICaL), altered sarcoplasmic function(whether there is increased, decreased, or unaltered sarcoplasmicCa2þ load), altered RyR2 function (increased open probability andCa2þ sensitivity of RyR2 vs. reduced expression or sensitivity RyR2)and changes in Ca2þ transients (increased or reduced Ca2þ tran-sients). Further, although ICaL reduction is the hallmark ofAF-inducedelectrical remodeling, data on reduced protein expression andaltered channel regulation is not definitive. Also while INCX upregu-lation is consistently found in AF, its functional significance forsubcellular Ca2þ handling requires furtherwork (Greiser et al., 2011).
Cellular Ca2þ instability may contribute to atrial arrhythmo-genesis by virtue of increased probability of spontaneous Ca2þ
release events (spontaneous Ca2þ sparks and waves) and byenhanced activity of the inward transient current (Iti). SpontaneousCa2þ release events may be pro-arrhythmic by activatingmembranecurrent during periods of repolarization. Enhanced activity of Iti isresponsible for delayed after-depolarizations (Greiser et al., 2011;Nattel and Dobrev, 2012). Congestive heart failure, one of the mostcommon causes of AF, produces atrial cell Ca2þ overload and delayedafter-depolarizations (Nattel et al., 2008). Pulmonary veins may beparticularly prone to triggered activity, although the evidence forthis is controversial (Chen et al., 2001; Coutu et al., 2006). It isimportant to note that these cellular proarrhythmic mechanismshave not been demonstrated in vivo. Most human studies havestudied right atrial appendage tissue which is less arrhythmogenicthan other areas in the right and left atrium (Greiser et al., 2011).
Altered Ca2þ handling has also been implicated in atrialcontractile dysfunction in AF. ICaL downregulation has been shownto occur in concert with progressive loss of atrial contractility(Schotten et al., 2003). Abnormalities of Ca2þ release and intracel-lular Ca2þ wave propagation, impaired coupling between Ca2þ andRyR2, upregulation of INCX are thought to be the main mechanismsof atrial contractile dysfunction. Alterations of sarcoplasmic Ca2þ
load or myofilament function are thought to play a minor role(Greiser et al., 2011; Schotten et al., 2011). Ca2þ dependent calpainactivation can cause myofibrillar degeneration. Ca2þ entry throughnon-selective transient receptor potential (TRP) channels onfibroblasts mediates fibroblast activation, proliferation and differ-entiation in AF. Signaling pathways initiated by Ca2þ overloadduring rapid atrial activation in AF can affect the function of nuclearfactor of activated T-cells (NFAT), which regulates mRNA tran-scription of miR26. miR26 controls the TRP expression on fibro-blasts. This may provide evidence of a link between signaling forelectrical and structural remodeling (Nattel and Dobrev, 2012).
3.2. Mechanisms behind atrial remodeling via altered atrialconduction
Atrial conduction slowing occurs as a result of modulation ofsodium channels (Naþ), gap junctions (known as connexins) and
alterations in tissue structure. Normal cardiac impulse propagationdepends on the current source, which provides the energy forconduction by tissue firing, and the dissipation of this energy bytissue that lies downstream (Fig. 1). The current source is providedby the large phase 0 Naþ current. Energy dissipation is minimizedby virtue of good electrical coupling between cardiac cells anda high resistance to lateral current leakage. Electrical coupling isprovided by low-resistance gap junction channels that connect cellends in a longitudinal fashion. Gap junctions contain trans-memebrane ion-channel proteins called connexins, of which con-nexin 40 and 43 are the most important in atrial tissue. The highresistance to lateral current leakage can be afforded by a continuouscable-like organization of cardiomyocyte bundles (Nattel et al.,2008). This continuous cable-like organization has been shown tobe disrupted in animal models and human studies (discussed inSection 4.1).
Alteration in connexin expression and distribution would beexpected to have a critical influence on cardiac conduction.However, studies have shown divergent results creating uncer-tainty about the nature of connexin perturbations in AF (Kato et al.,2012). Both higher and lower levels and lateralization of connexin40 have been reported (Nao et al., 2003; Polontchouk et al., 2001;Wilhelm et al., 2006; Kostin et al., 2002). The relationshipbetween connexin 40 levels and atrial conduction is also incon-sistent with high levels correlated with slow and complexconduction in some studies, whereas reduction in connexin 40 wasassociated with increased conduction velocity in another study(Kanagaratnam et al., 2004; Beauchamp et al., 2006). Transgenicanimal models have also shown contradictory results with studiesshowing increase or no change in AF susceptibility with connexin40 knockout or even enhanced conduction with connexin 40 loss(Kato et al., 2012).
Atrial structural remodeling promotes atrial tissue fibrosis,which perturbs the continuous cable-like arrangement of atrialcardiomyocytes and slows atrial conduction (Li et al., 1999;Shinagawa et al., 2002). However the contribution of atrialfibrosis as a central mechanism for atrial conduction abnormalitiesis not definitive (see below).
4. Atrial structural remodeling: the “second factor”
In addition to electrical remodeling, increasing duration of AF isassociated with structural remodeling at the macroscopic (atrialdilatation) and microscopic (ultrastructural changes) level. In rapidatrial pacing animal models, there is evidence for progressivestructural alterations such as atrial dilatation, myocyte hypertrophy,sarcomere loss, glycogen accumulation and mitochondrial abnor-malities (Ausma et al., 1997; Morillo et al., 1995; Shi et al., 2001).Increased atrial mass is able to accommodate greater number ofcirculating wavelets, setting up multiple circuit re-entry (Zou et al.,2005). As distinct from electrical remodeling which reverses soonafter reversion to sinus rhythm, the structural changes seen in theatria take longer to recover and recovery is incomplete (Everettet al., 2000; Ausma et al., 2003; Todd et al., 2004).
4.1. Role of atrial fibrosis in structural remodeling
Atrial fibrosis is thought to be a central tenet in the formation ofAF substrate (Spach and Boineau, 1997; Burstein and Nattel, 2008).Atrial fibrosis is evident histological in the atria of patients with AFand those with clinical risk factors for AF (Anne et al., 2005).Structural remodeling due to heart disease and aging is commonlyassociated with fibrosis and increased transverse fiber separation(Spach and Dolber, 1986). Mice with overexpressed TGF-b1 showselective atrial fibrosis and increased AF vulnerability (Verheule
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et al., 2004a). Fibrosis produces progressive electric uncoupling ofside-side connections between parallel orientated muscle bundles,resulting in discontinuous conduction, especially in the transversedirection and at short cycle lengths or short coupled extra-stimuli,facilitating small circuit re-entry (Spach and Boineau, 1997; Spachet al., 2007; Spach and Josephson, 1994). Fibrosis is also thoughtto increase regions of conduction slowing, increase conductionheterogeneity, uni-directional block, and promoting both focal andmacro-re-entry (Burstein and Nattel, 2008). Fibroblasts can coupleelectrically to cardiomyocytes and, when increased in numberectopy (Burstein et al., 2007, 2009). Spatial distribution and degreeof fibrosis plays have an important influence in fibrillatorydynamics, including both the location and variability of wave-frontbreakthroughs (Tanaka et al., 2007).
The mechanisms involved in atrial fibrosis at the molecular andcellular level, include interactions between pro-fibrotic signalingpathways such as angiotensin-II, transforming growth factor b-1(TGF-b1), connective tissue growth factor, platelet-derived growthfactor and their mediators such matrix metalloproteinases andtheir tissue inhibitors (expertly reviewed in Goudis et al., 2012;Nattel et al., 2008).
However there are unresolved issues in the role of atrial fibrosisin the development of AF. The findings of increased fibrosis in AFpatients not uniform across all human studies and atrial fibrosishave been found in patients without a history of AF (Boldt et al.,2004; Saito et al., 2007; Goette et al., 2002). Whether fibrosis wasassociated with AF per se and not the underlying structural abnor-mality is unclear (Anne et al., 2005; Burstein and Nattel, 2008). Notall animal studies have demonstrated increased interstitial fibrosis(Ausma et al., 1997; Li et al., 1999). However, the volume of extra-cellular matrix per myocyte was found to increase in goats duringmonths of AF (Ausma et al., 2003), similar to the pattern observed bySpach et al. during aging (Spach and Boineau, 1997). Verheule et al.(2010) noted that the increased complexity of fibrillatory conduc-tion that was seen with longer duration of AF was accompanied bymyocyte hypertrophy and increased endomyosial fibrosis. Myocytesare organizedwithin bundles separated by perimysial fibrous tissue.Within these bundles, myocytes are separated from each other byendomysial fibrous tissue. Collagenous septa between atrialmyofibrils increase in volume with aging (Koura et al., 2002; Spachand Dolber, 1986), similar to the goat model of rapid atrial pacing inwhich the extracellular volume per myocyte is increased (Ausmaet al., 2003). In contrast to this, the atria of atrial dilatation andheart failure models larger areas of replacement fibrosis are seensecondary to cell damage and tissue death (Boyden and Hoffman,1981; Verheule et al., 2003; Li et al., 1999).
The relationship between atrial fibrosis and atrial conductionabnormalities is also not consistent. Some animal models of atrialdilatation show both atrial fibrosis and conduction abnormalities(Verheule et al., 2004b), whereas others have shown conductiondisturbances in the absence of atrial fibrosis (Neuberger et al.,2005). Rapid atrial pacing alone in dogs caused progressivedecrease in atrial conduction velocity (Gaspo et al., 1997), whereasrapid atrial pacing with a controlled ventricular rate (induced byatrio-ventricular block) did not change atrial conduction (Li et al.,1999; Verheule et al., 2004b). In goats, atrio-ventricular (AV)pacing at high rates was associated with severe atrial structuralchanges whereas AV pacing with controlled ventricular rateshad virtually no changes (Schoonderwoerd et al., 2004). Anne et al.(2007) showed that in the absence of AV pacing with a controlledventricular rate, there is more atrial fibrosis, conduction hetero-geneity and AF persistence compared to AV pacing witha controlled ventricular rate which did not result in atrial fibrosisor AF persistence. An important unresolved question is howdifferent types of fibrosis (large areas of replacement fibrosis vs.
thin strands of interstitial fibrosis) influence atrial conduction(Schotten et al., 2011). Whether there is a threshold of atrialfibrosis above which AF promotion occurs is also unknown(Burstein and Nattel, 2008).
5. Electrophysiologic mechanism for AF stability andpersistence
Perpetuation of AF via the “hierarchical” and “anarchical”mechanisms has been described (Schotten et al., 2011). Hierarchicalorganization implies the arrhythmia being driven by a rapidlocalized source (either focal discharges and small re-entrantcircuits). Examples of hierarchical AF include stable re-entrycircuits (“mother waves”), unstable re-entry circuits (which cansustain AF as long as continuously form and at least one is alwayspresent), and rotors that can be fixed or wandering through theatria (Schotten et al., 2011). In the anarchical AF mechanism,multiple re-entrant wavelets randomly propagate through the atriawith annihilation, blockade and regeneration of new discretewaves. Factors such as shortened ERP, ERP heterogeneity, slowedconduction, increased tissue mass increase the stability of AF in theanarchical model (Schotten et al., 2011).
Sheep and simplified computer models utilizing optical andfrequencymapping have shown that wave propagation during AF isnot completely random (expertly reviewed in Berenfeld, 2010).These studies postulate that rotors are the major organizing centersof AF with a hierarchical distribution of local excitation frequencies,mostly originating from the left atrium (LA), in particular theposterior LA (Skanes et al., 1998; Berenfeld et al., 2000; Mandapatiet al., 2000; Kalifa et al., 2006). Structural remodeling (atrialfibrosis) and ion channel activity (IK1 and IKACh) modulate rotordynamics (Tanaka et al., 2007;Mandapati et al., 2000; Atienza et al.,2006; Voigt et al., 2010; Kalifa et al., 2006). The site of origin of AFbreakthrough waves in normal hearts was in the posterior LA andleft pulmonary venous ostia whereas in the heart failure modelstended to cluster peripherally toward the pulmonary vein ostiacoinciding with areas of histologically determined atrial fibrosis atthese sites (Tanaka et al., 2007). An increasing ratio of myofibro-blasts to myocytes modifies the complexity of spatio-temporalpropagation but reduced re-entry frequency in a cell culturedmonolayer experiment (Zlochiver et al., 2008). Increasing amountof LA fibrosis was associated with lower dominant frequencyduring AF in cardiac surgical patients (Swartz et al., 2009).
Lefteright atrial dominant frequencygradientswere found inpostcardiac surgical AF patients, associated with increased mRNA ex-pressionof IK1 and IKACh channel subunits (Swartz et al., 2009). LAeRAgradient in basal inward rectifier background current was found inparoxysmal AF patients (Voigt et al., 2010). Several studies havecharacterized the spatial distribution of DFs during AF in patients(Lazar et al., 2004; Sahadevan et al., 2004; Sanders et al., 2005).Paroxysmal AF was associated with hierarchical spatial distributionof dominant frequencies highest at the LA and PVs. Temporally andspatially periodic activity emanating from the PV region with regu-larity suggests the critical role of PVs inmaintainingAF inparoxysmalAF patients. By contrast, persistent AF had a more uniform distribu-tion of higher DFs but the highest were not in the PVs.
It is important to note that identifying rotors as drivers for AF isvery difficult with existing mapping techniques. The existence ofrotors in patients with AF has not been demonstrated with acti-vation time mapping. Activation time mapping in humans withpersistent AF has shown progressive longitudinal dissociationconsisting of lines of block running parallel to atrial musculatureresulting in an increase in number of fibrillation waves (Allessieet al., 2010). Lines of interwave conduction block were highlydynamic and shifted in position continuously. Wave boundaries
S. Kumar et al. / Progress in Biophysics and Molecular Biology 110 (2012) 278e294284
were not randomly distributed, but influenced by atrial architec-ture, running parallel to the pectinate muscles in the right atrium.Progressive uncoupling of cardiac myocytes and muscle bundleswas identified as the main mechanism of enhanced AF stability(“longitudinal dissociation”). Epicardial breakthrough wasenhanced in persistent AF patients, hypothesized to be due to moreelectrical dissociation between the epicardial layer and endocardialbundle network (de Groot et al., 2010). In a goat model, progres-sively longer duration of AF was associated with pronounceddissociation of electrical activity between the epicardial layer andthe endocardial bundle network owing to progressive electricaluncoupling between these layers, leading to increasing stabilityand complexity of the AF substrate (Eckstein et al., 2011).
6. Neural and autonomic remodeling
The autonomic nervous system plays a critical role in AF(expertly reviewed by Chou and Chen, 2009). The PVs and PVeLAjunction are richly innervated with autonomic nerves. A dynamicrelationship between the parasympathetic and sympatheticnervous system plays a critical role in the initiation of AF. AF onsetcan be preceded by altered autonomic activity or change in auto-nomic balance rather than increase sympathetic or para-sympathetic drive alone (de Vos et al., 2008; Fioranelli et al., 1999).Studies have reported a primary increase in adrenergic activityfollowed bymarked vagal activity immediately prior to the onset ofparoxysmal AF (Chou and Chen, 2009). Vagal activity enhances theacetylcholine-dependent Kþ channels, shortening APD and stabi-lizing re-entrant rotors (Kneller et al., 2002). Sympathetic stimu-lation increases diastolic Ca2þ leak and promotes delayed afterdepolarization-induced ectopic firing (Dobrev and Nattel, 2011).Gould et al. (2006) demonstrated evidence of heightened atrialsympathetic innervation in right atrial appendage of persistent AFpatients compared to controls undergoing bypass surgery sug-gesting autonomic remodeling as part of the atrial substrate for AFmaintenance. Animal models of rapid atrial pacing and hear failurehave noted AF onset is preceded by simultaneous sympatho-vagaldischarges (Tan et al., 2008). Whilst ablation of extrinsic sym-pathovagal nerves eliminated paroxysmal AF, it did not preventsustained AF suggest that autonomic nerve activity is not the onlyfactor that determines AF maintenance (Tan et al., 2008). Auto-nomic neural remodeling contributes to positive feedback loopsthat are thought to be essential for AF persistence and recurrence;remodeling is of this sort may be the mechanism of how AFmaintains itself in the first few hours (Yu et al., 2011).
7. Anatomic factors implicated in AF initiation andmaintenance
The PVs are critical for both the initiation andmaintenance of AF(Haissaguerre et al., 1998). The PVs have complex fiber orientationthat promotes re-entry with sharp transition from a circumferentialpattern in the endocardium to superioreinferior fiber orientationon the epicardial side (Verheule et al., 2002). Moreover, PVs in AFpatients show more atrial myocardial extensions, with morediscontinuities, hypertrophy and fibrosis of myocytes (Hassinket al., 2003). Abrupt changes in fiber orientation have been impli-cated in conduction delay, zones of conduction block and re-entryaround lines of conduction block between the PVs and LA (Hociniet al., 2002; Arora et al., 2003). Further, unstable re-entry circuitswith entrance and exit at the PVeLA junction have been associatedwith the short ERPs and anisotropic conduction in this region(Kumagai et al., 2004). The roof and posterior LA have complexsubendocardial fiber orientation that favor conduction block, re-entry and wave break (Nishida et al., 2010; Chang et al., 2007;
Tanaka et al., 2007). The septo-pulmonary bundle appears playsa critical role in AF maintenance. Waves propagating from the PVsinto the posterior LA show delay and break at boundaries along theseptopulmonary bundle due to abrupt changes in thickness andfiber direction in this region (Klos et al., 2008). The crista terminalisexhibits conduction slowing that is 10 times slower in the trans-verse direction compared to the longitudinal direction (Saffitz et al.,1994). Anisotropy at the crista is critical for the development ofatrial arrhythmias and in AF (Olgin et al., 1995). Structural remod-eling can readily lead to dissociated conduction patterns in theseareas. A high incidence of fractionated electrograms has been re-ported at this site (Schotten et al., 2011). Bachmann’s bundle is themajor conducting pathway between the left and right atrium,consisting of parallel muscle bundles. After 1 month of AF, a highincidence of complex fractionated electrograms were also noted atthis site (Shan et al., 2004). The pectinate muscles have complexfiber orientation that contribute to wave break up and fibrillatoryactivity and may serve as anchor points for re-entrant circuits(Berenfeld et al., 2002). This area’s complex trabecular networkunderlying a thin epicardial layer can sustain markedly differentendocardial and epicardial activation patterns during AF (Houbenet al., 2004; Eckstein et al., 2011).
8. Atrial and pulmonary venous remodeling in AF in theabsence of structural heart disease
Both rapid PV focal discharges and PVeLA junction re-entry havebeen implicated in arrhythmogenicity of the PVs (Arora et al., 2003;Haissaguerre et al., 1998; Hocini et al., 2002; Chou and Chen, 2009).PV myocytes have been shown to have a larger density of IKs and IKr,lower density of Ito and ICaL. PVs thus have a more depolarizedresting membrane potential, shorter duration action potentials witha slower upstroke velocity, factors implicated in a larger propensityof re-entry but with the absence of automaticity, spontaneous dia-stolic depolarizations or afterdepolarizations (Ehrlich et al., 2003).On the other hand, some studies have shown spontaneous PVactivity with unusual and heterogeneous action potentialmorphologies, and increased early and delayed after-depolariza-tions particularly during sympathetomimetic conditions (Chen andChen, 2006). Abnormalities in PV tissue architecture such as PV fiberorientation promote unidirectional block, slow conduction and re-entry within the PVs (Hocini et al., 2002).
Jais et al. showed that the PVs of patients with paroxysmal AFhave shortened ERPs and conduction abnormalities which contrib-uted to avery favorablemilieu for reentry in or around the veins, thusserving as a substrate for AF maintenance (Table 2, Jais et al., 2002).Rostock et al. demonstrated that the PVs are highly susceptible toelectrical remodeling to a greater extent than the LA with shortepisodes of AF causing immediate shortening of ERPs and conduc-tion slowing, making secondary AF episodes more likely (Table 2,Rostock et al., 2008). There is evidence for progressive electrophys-iological (slowed conduction, shortened ERPs) and structuralremodeling (increased low voltage) in the PVs as AF progresses fromparoxysmal to persistent forms, independent of the presence ofarrhythmia (Table 2, Teh et al., 2011a). These findings suggested anunderlying remodeling process mediated by fibrosis. Fibroticsubstrate could facilitate arrhythmogenesis through heterocellulargap junctional coupling of myofibroblasts with adjacent myocytescausingelectrotonicmodulation of conduction (Miragoli et al., 2006).
Aside the arrhythmia itself, patients with paroxysmal lone AFhave an abnormal atrial substrate characterized by widespread bi-atrial structural abnormalities and conduction slowing that mayexplain progression of AF to the persistent form (Stiles et al., 2009).These changes are accentuated in patients in persistent AF sug-gesting a progressive remodeling process in the absence of
Table 2Human studies of atrial and pulmonary venous remodeling.
Study Patient groups Main findings
Jais et al., 2002 PAF cf. controls Substrate for re-entry in and around PVsAF patients: PV ERPs < LA ERPs, Controls:PV ERPs > LA ERPsPV ERPs (AF) < PV ERPs (controls)[PV conduction delays in AF vs. controls[AF induction from PVs rather thanLA in AF vs. controls
Rostock et al., 2008 Controls with no history of AF (left sided SVT)who had 15 min of AF induced. PV and LAelectrophysiology compared before andafter AF induction
PV susceptible to electrical remodeling togreater extent than LAInduced AF resulted in:YPV ERPs greater than Yin LA ERPs, [conduction delay in PVs (but not LA)[susceptibility to secondary episodes of AF from PVs
Teh et al., 2011a PAF (no AF within 48 h) cf. PeAF cf. controls Progressive electrical and structural remodeling of PVs in AFAF cf. controls had:YERPYConduction, [complex signalsYMean voltage, [% low voltage zonesPeAF cf. PAF had:YConduction, [complex signalsY%low voltage
Stiles et al., 2009 PAF (no AF within 1 wk)cf. controls
Stiles et al., 2010 Paroxsymal AFL (no AFL within 1 wk)cf. controls
Diffuse structural abnormalities and conduction slowing remote from arrhythmiaAFL cf. controls had:Electrical abnormalities e [ERPs, Ylinear conduction, [site-specificconduction delay,[RA conduction time ([fractionated EGMs), [PWD, sinus node dysfunctionStructural abnormalities e YMean voltage, [RA volume
Teh et al., 2011c PAF cf. PeAF cf. controls Progressive LA structural remodeling from PAF to PeAF in absence of structuralheart diseaseAF cf. controls had:YConduction ([complex signals)YMean voltage ([%low voltage zones)More marked changes in PeAF vs. PAF
Abbreviations: AF e atrial fibrillation, AFL e atrial flutter, EGMs e electrograms, ERPs e effective refractory periods, LA e left atrial, PAF e paroxysmal atrial fibrillation, PAFL eparoxysmal atrial flutter, PeAF e persistent AF, PWD e P wave duration, PV e pulmonary veins, RA e right atrial, SVT e supraventricular tachycardia, wk e week.
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structural heart disease (Table 2, Teh et al., 2011c). Similar obser-vations were noted in patients with paroxysmal atrial flutterremote from episodes of arrhythmia who had marked structuralabnormalities and conduction slowing that may explain thefrequent progression of this arrhythmia to (Stiles et al., 2010,Table 2). Of note these structural abnormalities were documentedin the absence of electrical remodeling that may occur with periodsof arrhythmia suggesting that structural abnormalities playa greater role in the progression of the disease.
9. Atrial remodeling associated with clinical AF substrates
Several well known clinical substrates predispose to AFincluding heart failure, valvular heart disease, congenital heartdisease, heart failure, sinus node disease, aging, hypertension andsleep apnea. These will be reviewed in the following sections.
9.1. Atrial remodeling induced by conditions of atrial stretch
Atrial dilatation, a well-known independent risk factor for thedevelopment of AF, promoting atrial electrical remodeling viamechano-electrical feedback (Vaziri et al.,1994; Schotten et al., 2011;Nattel et al., 2008). In addition to predisposing to arrhythmogenesis,atrial dilatation can also be seen as a consequence of AF; hencea positive feedback exists where atrial stretch leads to AF, whichleads to further atrial stretch and self-perpetuation of AF.
9.2. Acute atrial stretch studies
The effect of acute atrial stretch on atrial electrophysiology inanimal studies has shown varying effects on ERP; however thereis evidence of stretch induced conduction slowing and conduc-tion block and increased frequency of atrial arrhythmia(Table 3). Human studies of acute atrial stretch have also yieldedconflicting results with increase, decrease or no effect on atrialERP, but a consistent increase in AF vulnerability (Table 4). Acutestretch has been shown to reduce conduction velocity, increasezones of slowed conduction and conduction block, effectmediated by stretch related effects on ion channels (Kuijperset al., 2007, 2011; Ravelli et al., 2011). The variability inhuman studies may be explained by heterogeneous patientcharacteristics, failure to control for changes in autonomic tone,regional effects of stretch on atrial ERP and competing effects ofstretch on ion channels and APD. Further work is needed toelucidate the effects of acute stretch and its reversal in varioushuman AF substrates.
9.3. Chronic atrial stretch studies
Chronic atrial stretch appears to play a role in the developmentof AF in awide spectrum of clinical conditions, such as heart failure,mitral regurgitation, atrial septal defects, and chronic asynchro-nous ventricular (VVI) pacing.
Table 3Animal studies of acute atrial stretch.
Study Model Mechanism of stretch induction Main findings with acute atrial stretch/[atrialpressure
Kaseda and Zipes, 1988 Whole animal (Canine) Sequential A and V pacing at varying AV intervals(0e280 ms in 20 ms increments)
[LA, RA, interatrial septal ERPs
Satoh and Zipes, 1996 Whole animal (Canine) Simultaneous AV pacing þ saline infusion [ERPs with simultaneous AV pacing associated[atrial pressure (free RA wall [ERPs > thickCT[ERPs); exaggerated [ERP with fluidloading in RA wall cf. thick CT, [AF inducibilityafter fluid load
Sideris et al., 1994 Whole animal (Canine) Rapid saline infusion [ERPs, [conduction time, [AF inducibilityRavelli and Allessie, 1997 Rabbit (Langedorf-perfused) Surgical occlusion modela YRA ERPs, YMAP duration, [LA ERPs at higher
pressures cf. RA with stretch, [AF inducibility;changes reversible within 3 minutes ofpressure normalization
Nazir and Lab, 1996 Guinea pig (Langendorffperfused)
Inflation of fluid-filled intra-atrial balloon catheter YAmplitude and Yduration of MAP at 50%depolarization; [MAP duration at 90%repolarisation associated with EADs; [atrialarrhythmia/premature atrial beats
Eijsbouts et al., 2003 Isolated rabbit hearts Inflation of fluid-filled intra-atrial balloon catheter YConduction velocity, [areas of slow conductionand conduction block, lines of conduction blockwhen pacing low RA rather than CT (similarchanges in LA)
Kalifa et al., 2007 Isolated rabbit hearts Surgical occlusion modela YERPs, [AF inducibility
Abbreviations: A and V pacing e atrial and ventricular pacing, AF e atrial fibrillation, CT e crista terminalis, EADs e early after-depolarizations, ERPs e effective refractoryperiods, LA e left atrial, MAP e monophasic action potential, RA e right atrial.
a Surgical occlusion model of the caval and pulmonary veins and raising the level of an outflow cannula in the pulmonary artery.
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9.3.1. Animal studies of chronic atrial stretchStudies of chronic stretch have shown either no difference or
increased ERP, increased interstitial connective tissue and myocytealterations, increased fibrosis, and heterogeneous conductionslowing (Boyden and Hoffman, 1981; Verheule et al., 2003; Liet al., 1999). Chronic stretch causes LA dilatation, with heteroge-neous remodeling of atrial architecture including myocyte hyper-trophy, fibrosis, and gap junction modulation (Verheule et al.,2003, 2004b; Takeuchi et al., 2006). Mechanical stretch inducescardiac fibroblasts and cardiomyocytes to increase pro-fibroticAngiotensin II, TGF-b1 production and initiation of “A DisintegrinAnd Metalloproteinase” (ADAM)-dependent signaling pathwayinfluencing disintegrin and mettaloproteinase expression resultingin enhanced collagen synthesis (Goudis et al., 2012). EnhancedADAM-dependent disintegrin and metalloproteinase activitysuggests a molecular mechanism that also contributes to the atrialdilation in AF. In addition, mechanical stretch of fibroblasts candirectly modulate myocyte electrical activity, providing a mecha-nism for pro-arrhythmic mechano-electric feedback (Kamkinet al., 2005). It is important to note that chronic atrial stretchcan promote atrial fibrosis in the absence of atrial fibrosis(Neuberger et al., 2005).
Table 4Human studies of acute atrial stretch.
Study Mechanism of stretch induction Main fin
Calkins et al., 1992b AV pacing at 400 ms (AV interval 0) No chanCalkins et al., 1992a AV pacing at 500 ms with AV interval of last 2 beats
varying from 120 ms to 0 msYERPs a
Klein et al., 1990 AV pacing at varying AV intervals (0e360 ms) in SRor during arrhythmia in SVT patients
[RA ERP
Tse et al., 2001 AV pacing at 300 ms AV interval with and withoutautonomic blockade
YRA ERP
Chen et al., 1999 AV pacing at varying intervals (160 ms to 0 ms) inpatients with or without AF
[ERPs, [greater
Antoniou et al., 1997 Saline ([pressure), diuretic (Ypressure) in patientswith lone AF
[AF dur
Ravelli et al., 2011 AV pacing at 450e500 ms AV interval YCondu
Abbreviations: AF e atrial fibrillation, ARPs e absolutely refractory periods, AV e atrial anrhythm, SVT e supraventricular tachycardia.
9.3.2. Human studies of chronic atrial stretchChronic atrial stretch in conditions such as atrioventricular
synchronous pacing, mitral stenosis (MS), mitral regurgitation(MR), chronic heart failure and atrial septal defects have beenassociated with heightened risk of AF. The possible mechanismsbehind this propensity have been studied (Table 5). Sparks et al.demonstrated electrical and structural remodeling of the atriumafter long term AV asynchronous pacing that could be reversedupon re-establishment of synchronous pacing (Sparks et al.,1999a,b). John et al. showed that substrate for AF in patients sub-jected to chronic atrial stretch byMS is related to the structural andassociated widespread and site-specific conduction abnormalities(Table 5). Importantly, while these abnormalities were observedwithin both atria, their extent was greater in the left than the rightatria. Despite an increase in bi-atrial ERP, there was an increasedsusceptibility to develop AF compared to controls, suggesting thatstructural remodeling plays a stronger role in AF progression thanelectrical remodeling consistent with animal studies.
In the presence of volume overload in MR, patients have beenshown to have conduction slowing, conduction heterogeneity,conduction anisotropy and at least one vertical line of functionaldelay between the PVs and posterior LA that facilitated circuitous
dings with acute atrial stretch/[atrial pressure
ge in ERPs, ARP or AF inducibility with or without autonomic blockadend ARPs with and without autonomic blockade
s during SVT
s [AF inducibility, [susceptibility to sustained AF during autonomic blockade
ERP dispersion, [atrial size; [Minimal, maximal ERP dispersion and atrial sizein AF vs. SR patientsation
d ventricular pacing, ERPs e effective refractory period, RA e right atrial, SR e sinus
Table 5Chronic atrial stretch studies.
Study Treatment groups Electrical changes Structural changes
Chronic atrial stretch studiesSparks et al., 1999a VVI pacing for 3 months cf. DDD
pacing 3 monthsVVI pacing restored to DDD pacingafter 3 months
VVI pacing cf. DDD pacing had:Sinus node dysfunctionReturn of ERPs, PWD, sinusnode function after restorationof DDD pacing
VVI pacing cf. DDD pacing had:[Atrial sizeReturn of atrial size after restoration of DDD pacing
Sparks et al., 1999b VVI pacing for 3 months cf. DDDpacing 3 monthsVVI pacing restored to DDD pacingafter 3 months
Not assessed VVI pacing cf. DDD pacing produced:YLAA emptying velocity, YLAA emptying fraction, [SECWith restoration of DDD pacing, all parameters improved tonear baseline
John et al., 2008 MS cf. control [ERPs LA, RAYConduction velocity LA, RA[DPs at CT[Fractionated EGMs at CT[PWD
[LA size[Low voltage areas[Areas of electrical silence (scar)[AF vulnerability
Sanders et al., 2003 CHF cf. controls [ERPs RANo change in ERP heterogeneity[Conduction time RA and CSRegional conduction slowing[Fractionated EGMs at CT,[DPs at CT[PWDSinus node dysfunction
[Low voltage areas[Areas of electrical silence (scar)[AF vulnerability
Morton et al., 2003 ASD patients cf. controlsASD patients pre cf. post repair
[ERPs RA[Conduction delay CT[PWDSinus node dysfunctionAfter ASD closure:Persistent conductionabnormalities CT[ERP distal CS, high septal RA,YERP lateral RA
Roberts-Thomson et al., 2009a ASD patients vs. controls (LA mapping) Unchanged or [ERPs[LA conduction timeLA regional conduction slowing[DPs and fractionated EGMs
Abbreviations:AF e atrial fibrillation, ASD e atrial septal defect, DDD e dual chamber atrio-ventricular pacing (synchronous), CS e coronary sinus, CT e crista terminalis, DP e
double potentials, EGMs e electrograms, ERP e effective refractory period, LA e left arial, LAA e left atrial appendage, PWD e P wave duration, SEC e spontaneous echo-contrast, VVI e single chamber ventricular pacing (asynchronous).
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wavefront propagation (Roberts-Thomson et al., 2009b). Thesechanges were exaggerated in patients with AF. Similarly, patientswith left ventricular dysfunction (compared to those with normalleft ventricular function) had an exaggerated line of conductiondelay, with greater conduction heterogeneity, anisotropy, andlonger total atrial conduction time leading to circuitous wavefrontpropagation in the posterior LA (Roberts-Thomson et al., 2008). Inboth studies, ERP changes were insufficient to explain greaterpropensity to AF, suggesting the criticality of structural andconduction abnormalities in AF perpetuation.
In experimental models of heart failure induced in dogs by rapidventricular pacing, the increased propensity of AF has been asso-ciated with increased conduction heterogeneity with no change inERP or ERP heterogeneity, and dramatic increase in intersititialfibrosis (Li et al., 1999). Sanders et al. showed that substrate for AFin patients with congestive heart failure is predominantly due tothe development of structural abnormalities and conduction delay,rather than changes in atrial ERP as occurs in the remodeling due torapid atrial rates (Table 5, Sanders et al., 2003). Whether treatmentof heart failure reverses the structural abnormalities (and to whatextent) and reduces AF vulnerability is an important question. Therelative contribution of correcting hemodynamic changes andeffect of renin-angiotensin system modulation on these abnor-malities is an important question worthy of future investigation.Differences in extent of structural remodeling at different stages ofheart failure also remain unknown.
Patients with atrial septal defects (ASD) are subject to chronicvolume overload and a propensity toward atrial arrhythmias that is
minimally altered by closure of the ASD (Gatzoulis et al., 1999).Morton et al. (2003) showed that chronic atrial stretch and volumeoverload produces atrial conduction abnormalities, sinus nodedysfunction and atrial dilatation with increased atrial ERPcompared to controls. Upon correction of the volume overload,there was incomplete recovery of atrial size but conductionabnormalities persisted, suggesting persistence of structuralremodeling (Table 5). Roberts-Thomson et al. found identicalchanges in left atrial electrophysiology and electroanatomicmapping in patients with ASDs to that of heart failure (Table 5).Areas of electrical scar were frequently localized to the post LA(Roberts-Thomson et al., 2009a). Whether the structural substrateprogressive over years and explained the heightened risk of latearrhythmias is an important unanswered question.
9.3.3. Role of chronic stretch in AF maintenanceAtrial stretch causes remodeling that predisposes to AF. Hunter
et al. (2012) showed increased LA wall stress results in heteroge-neous focal LA remodeling with areas of lower voltage and elec-trical scar occurring at sites of high wall stress such as the PV ostia,LA appendage ridge, high posterior LA wall and the anterior walland septal regions of the LA. Yoshida et al. (2011) showed a signif-icant correlation between higher LA pressure (higher in persistentvs. paroxysmal AF) and higher dominant frequency at the left atrialappendage, suggesting that atrial stretch may contribute to AFmaintenance by stabilizing high-frequency rotors. Yamazaki et al.(2012) showed that atrial architecture plays a critical role inestablishing the substrate AF maintenance. They described the
S. Kumar et al. / Progress in Biophysics and Molecular Biology 110 (2012) 278e294288
presence meandering atrial scroll waves (transmural rotors arounda filament spanning from the epicardial to the endocardial surface),which were found in normal sheep hearts under acute stretch andpersistent AF sheep hearts. In normal hearts, they meanderedaround regions of sharp transition in myocardial thickness andwere short lived. In persistent AF hearts, they were more numerousand long lasting, stabilizing at the interface of thick and thinmuscle. The authors postulated a mechanism by which atrialarchitecture of the human remodeled atrium may favor AFperpetuation. However the significance of this mechanism inhuman AF perpetuation related to stretch remains unknown.
10. Remodeling associated with sinus node dysfunction andaging
Sinus node disease (SND) is frequently associated with atrialarrhythmias. Sanders et al. found that patients with SND may havewidespread atrial remodeling akin to that of patients subject tochronic atrial stretch with a preponderance of conduction abnor-malities and structural changes that may explain increasedpropensity in AF in these patients (Sanders et al., 2004, Table 6).Why these patients developed such changes in the absence ofchronic stretch is unknown, but it is worthwhile to briefly examinethe nature of atrial remodeling that occurs with aging.
Table 6Atrial remodeling in varying clinical substrates predisposing to AF.
Study Treatment Groups El
Sinus node dysfunctionSanders et al., 2004 SND vs. controls [
[
[
Re[
[
SN
AgingKistler et al., 2004 Aged �60 yrs vs. 31e59 yrs vs. �30 yrs [
NER[
[
Re[
SiTeh et al., 2012 PVs of >50 yrs. Vs. <50 yrs In
N[
Systemic hypertensionMedi et al., 2011 HT vs. normotensive controls [
GRe[
Pulmonary hypertensionMedi et al., 2012 Pulmonary HT vs. controls N
G[
Si
OSADimitri et al., 2012 OSA cf. controls N
[
GRe[
co[
Si
Abbreviations: AF e atrial fibrillation, CT e crista terminalis, DPs e double potentials. Epulmonary veins, PWD e P wave duration, RA e right atrial, SND e sinus node dysfunct
Advancing age is one of the most significant risk factors for thedevelopment of AF. Kistler et al. showed that increased age wasassociated with widespread conduction and structural abnormali-ties, which may explain propensity to AF despite its associationwith increased ERPs (Table 6, Kistler et al., 2004). Teh et al.extended these observations by demonstrating structural remod-eling and conduction slowing in the PVs with increasing agedespite no change in ERPs (Table 6; Teh et al., 2012). The describedchanges are consistent with the development of atrial fibrosis,which has been found in pathological studies of aging. Spach et al.described how fibrosis between muscle bundles with electricaluncoupling of side-side connections in the aging human atriumresulted in conduction anisotropy, forming the necessary substratefor re-entry (Spach and Dolber, 1986; Spach et al., 1982). Aging ratshad greater vulnerability to AF due to conduction slowing andheterogeneous interstititial fibrosis, without differences in ERPcompared to young rats (Hayashi et al., 2002). Aging dogs havedemonstrably greater interstitial fibrosis, fatty infiltrates, laterali-zation of connexins 43 to end-to-end connections between myo-cytes, enhanced conduction anisotropy with extremely slowtransverse “zigezag” conduction patterns and widespread disso-ciated atrial conduction (Koura et al., 2002). Furthermore agingrabbits had increasing tendency to delayed after-depolarizations inthe PVs (Wongcharoen et al., 2007a,b). Recent work by Spach et al.
ectrical changes Structural changes
ERPs RAConduction time RA, CSNumber, [Duration of DPs at CTgional conduction slowingfractionated EGMsPWDcomplex shift
[Low voltage areas[Areas of electrical silence (scar)
ERPs RAo change in ERP rate adaptation orP heterogeneityCT conduction timeDPs and fractionated EGMs at CTgional conduction slowingPWDnus node dysfunction
[Low voltage areas
PVs:o change in ERPs% of complex signals
YMean voltage[% Low voltage areas[Voltage heterogeneity
[Areas of low voltage[Vulnerability to sustained AF
o change ERPslobal conduction slowingDPs and fractionated EGMsnus node dysfunction
YMean voltage[Low voltage areas[Areas of electrical silence (scar)[AF vulnerability
o change ERPsConduction time CT, RAlobal conduction slowinggional conduction slowingNumber and duration ofmplex EGMs CTPWDnus node dysfunction
YAtrial voltage
GMs e electrograms, ERPs e effective refractory periods, HT e hypertension, PV e
ion, yrs e years.
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demonstrated that aging associated variability in arrhythmogenicconduction was mediated by regional alterations in sodiumcurrents affecting repolarization gradients (Spach et al., 2007).Kojodjojo et al. (2006) also demonstrated bi-atrial conductionslowing with increasing age with electroanatomic mapping.
The direct relationship with aging and development of fibrosishas not been definitively proven as a recent study by Platonov et al.,who performed a postmortem histological analysis of importantsites in both atria in patients with paroxysmal, persistent, perma-nent AF and AF free controls and found no correlation between ageand fibrosis at any location. Prevalence of fatty infiltration,inflammatory cell count and fibrosis were higher in AF patients vs.controls and more prevalent in permanent vs. paroxysmal AFpatients (Platonov et al., 2011). Whether the entities of AF, age andfibrosis represent cause, effect or epiphenomenon is an importantquestion that requires further investigation. Whether there areheterogeneities in development of atrial substrate with agingindependent of antecedent conditions and determinants of thisheterogeneity are important areas needing further work. Methodsfor early detection of AF substrate in aging populations may allowtargeted upstream therapies.
11. Atrial remodeling induced by systemic hypertension
Hypertension is the most common treatable risk factor associ-atedwith AF (Haywood et al., 2009). Kim et al. (2011) demonstratedthat elevated afterload for 14e20 weeks in male Wistar ratsresulted in marked LA hypertrophy and fibrosis, reduced conduc-tion velocity, greater inhomogeneity of conduction and higherincidence and duration of pacing-induced AF without a change inERPs. Kistler et al. demonstrated that predominance of atrialstructural remodeling characterized by atrial hypertrophy,increased intercellular collagen deposition, discrete full thicknessendocardial scarring, increased atrial apoptosis associated withmarked atrial conduction slowing, increased heterogeneity ofconduction, and bi-atrial shortening of wavelength in an chronicovine model of hypertension. Hypertensive sheep, compared tocontrols had increased duration of induced AF despite no signifi-cant changes in atrial ERP and preserved rate adaption of refrac-toriness (Kistler et al., 2006). Medi et al. confirmed these findings ina study of patients with systemic hypertension who had extensiveconduction abnormalities, increased number of areas of lowvoltage representing scar and heightened AF vulnerability despiteprolonged ERPs compared to normotensive controls (Table 6, Mediet al., 2011).
In summary, these studies demonstrate that structural, ratherthan electrical remodeling is the predominant mechanism predis-pose to AF in the clinical substrate provided by systemic hyper-tension and importantly, that the nature of this atrial remodeling isprogressive with longer duration of hypertension. An importantquestion for future investigation is characterization of the natureand extent of reverse remodeling with treatment of hypertension.
12. Atrial remodeling induced by obstructive sleep apnea andpulmonary hypertension
Obstructive sleep apnea (OSA) is a known risk factor of AFincreasingly recognized as a potential risk factor for the develop-ment of AF and for greater risk of AF recurrence after cardioversion(Kanagala et al., 2003; Stevenson et al., 2008). A myriad of changesoccur in response to OSA including pulmonary or systemic hyper-tension, catecholamine- and stretch-mediated channel activationand inflammation to create an arrhythmogenic milieu for AF(Stevenson et al., 2008). Dimitri et al. found that marked structuralchanges and conduction abnormalities and absence electrical
remodeling (no change in ERPs) forming the necessary substrate forthe heightened risk of AF in patients with OSA compared to controls(Table 6, Dimitri et al., 2012). Medi et al. showed that pulmonaryhypertension in itself also contributes to the complexity of mech-anisms that increase risk of AF in conditions such as chronic lungdisease, obesity and OSA by studying patients with idiopathicpulmonary hypertension. These patients had significant structuralabnormalities and scar, regional and global conduction slowing andsinus node dysfunction. Despite an increase in ERPs, there was anincreased vulnerability to inducible AF (Table 6, Medi et al., 2012).Thus, as previously noted structural remodeling is the hallmarkof substrate that predisposes to and perpetuates AF in a varietyof clinical conditions. A key question is the characterizationand extent of reverse remodeling with the treatment of theseconditions.
13. Reversal of atrial remodeling
Human studies have demonstrated some reversal of electricalremodeling, particularly ERP normalization, but slower (incom-plete) recovery of conduction (Table 1). Everett et al. showedcomplete reverse electrical remodeling 7e14 days after car-dioversion to sinus rhythm in dogs whowere kept in chronic AF for>8 weeks. However there was no resolution of anatomic andultrastructural abnormalities and vulnerability to AF inductionpersisted despite reverse electrical remodeling (Everett et al.,2000). In another study, atrial electrical and mechanical remodel-ing exhibited divergent patterns of regression such that changes ofERP and contractile function took place more rapidly than those ofconduction velocity and atrial size (Kinebuchi et al., 2005). Reversalof electric remodeling may be slower in the LA than RA (Lee et al.,1999). Structural and gap junction remodeling may persist evenafter 4 months of sinus rhythm (Ausma et al., 2003; Everett et al.,2000). Shinagawa et al. (2002) noted that atrial dimensionsreturned to baseline after 5 weeks of recovery following 4e6 weeksof ventricular tachypacing, sustained AF could still be induced andthere was no recovery heart failure-induced atrial fibrosis or localconduction abnormalities. As previously noted, ASD patients 8months post closure had reversal of ERP, but incomplete reductionsin atrial volume and persistence of conduction abnormalities(Morton et al., 2003).
In conditions of chronic atrial stretch such as asynchronousventricular pacing, reversal of atrial electrical and mechanicalfunction is observed after restoration of synchronous atrio-ventricular pacing (Sparks et al., 1999a,b). Mitral commissur-otomy (MC) can alleviate MS in suitable patients. John et al. (2010)characterized the immediate and late effects of chronic stretchreversal with high-density electrophysiological and electro-anatomical mapping of the atria immediately before and after MCand again �6 months post MC. Acutely after MC, there was therewas marked reduction in LA pressure and volume, improvement inbipolar voltage, increased bi-atrial conduction velocity, reduction inP wave duration and AF susceptibility. Atrial ERP remained unal-tered immediately after MC. Late after reversal of chronic stretch,there was progressive improvement in bipolar voltage withincreased conduction velocity, reduction in fractionated electro-grams, reduction in P wave duration, decrease in atrial ERPs, andreduction in AF susceptibility. That study suggested that chronic-stretch induced atrial substrate may be reversible and that treat-ment of the predisposing condition may be able to modify theunderlying substrate and prevent AF.
Treatment of OSA with continuous positive airway pressure hasbeen shown to reduce right ventricular dimensions, left ventricularmass, bi-atrial volumes and degree of pulmonary hypertension(Colish et al., 2012). Mitral valve repair for mitral regurgitation has
S. Kumar et al. / Progress in Biophysics and Molecular Biology 110 (2012) 278e294290
also been shown to reverse LA remodeling post procedure (Marsanet al., 2011). Thus far, reversal of electrophysiologic and electro-anatomical substrate in these conditions after correction of theunderlying abnormality has not been assessed.
Reversal of LA dilatation has been noted following successfulcatheter ablation for AF (Tops et al., 2011). Teh et al. demonstratedthat despite successful catheter ablation of paroxysmal AF inpatients without structural heart disease and maintenance of sinusrhythm for 6 months, there was progression of atrial substrate. Atbaseline, they had lower regional and global voltage and higherproportion of low-voltage signals, regional and global conductionslowing, an increased proportion of complex signals and prolongedregional ERPs compared to controls without AF (Teh et al., 2011b).After 10 months, when these measurements were repeated, therewas worsening of atrial voltage, further conduction slowing despitereversal of left atrial dilation. Despite the successful of AF ablation,the electrical and electro-anatomic remodeling evident at baselinedoes not reverse and may even worsen. An important question iswhether there were differences in substrate progression in thosewho underwent ablation early vs. later time points. This informa-tion would be critical is determining the optimal time point forintervention.
14. Discussion
As discussed in this review, atrial structural and electricalremodeling is the final common pathway in response to stressorsposed by the presence various clinical conditions that predispose toAF, and in progression of AF from paroxysmal to persistent formswithin human beating hearts. The contribution of electricalremodeling in human AF remains to be definitively establishedbut structural remodeling appears to be critical in the maintenanceof AF.
Recognition of the electrophysiologic and structural changeassociated with different clinical AF substrates suggests that earlyintervention to prevent the onset of these abnormalities may be animportant goal worthy of pursuing. Some interventions directed atreversal of the inciting stimulus, in the case of chronic atrial stretchwith procedures such as mitral commissurotomy, may lead toreversal of components of electrical and structural remodeling.However the lack of reversal in atrial structural abnormalities aftersuccessful catheter ablation for AF suggests that the timing ofintervention is also critical. The role of upstream therapy with anti-remodeling agents such as angiotensin-II receptor antagonists,aldosterone antagonists, statins, omega-3 polyunsaturated fattyacids have not been clearly defined, are the subject of ongoinginvestigation. Current treatment is based on symptoms and type ofAF (paroxysmal, persistent), clearly does not address the presenceand rate of progression of underlying substrate. Methods fordetecting atrial remodeling and its rate of progression need to bedeveloped with the use of biomarkers (e.g. collagen turnoverpeptides) or non-invasive imaging such as MRI. Identification ofpatients at high risk and early stages of remodeling is the key. Theeffect of reversal of antecedent conditions such as hypertension,obesity, sleep apnea on atrial substrate needs to be examined andthe optimal timing of these interventions needs to be determined.The influence of genetic factors in initiation progression of AF islikely to be complex and heterogeneous, and needs to be defined.
Finally, important questions about AF mechanisms remainunanswered and must be addressed. The quantitative and quali-tative relationship between atrial fibrosis and conduction distur-bances needs to be elucidated. The contribution of ectopic focaldischarges or rotors to human persistent AF needs to be explored.This knowledge may improve with the development of morecomplex and detailed mapping techniques. The complex effects of
atrial geometry on AF persistence need to be elucidated. A betterunderstanding of ionic remodeling and molecular pathwaysimplicated in structural remodeling may offer avenues for noveltherapeutic intervention. A better understanding of the factors thatinitiate and maintain AF in specific patient groups is needed inorder to tailor specific therapies. Addressing these research objec-tives is the key in improving our understanding and treatment ofAF, the most common arrhythmia in human beating hearts.
Editors’ note
Please see also related communications in this issue byBerenfeld et al. (2012) and Blazeski et al. (2012).
Acknowledgments
Dr. Kumar is a recipient of a postgraduate research scholarshipco-funded by the National Health and Medical Research Counciland National Heart Foundation of Australia (Scholarship ID622896).
References
Allessie, M.A., de Groot, N.M., Houben, R.P., Schotten, U., Boersma, E., Smeets, J.L.,Crijns, H.J., 2010. Electropathological substrate of long-standing persistent atrialfibrillation in patients with structural heart disease: longitudinal dissociation.Circ. Arrhythm. Electrophysiol. 3, 606e615.
Anne, W., Willems, R., Holemans, P., Beckers, F., Roskams, T., Lenaerts, I., Ector, H.,Heidbuchel, H., 2007. Self-terminating AF depends on electrical remodelingwhile persistent AF depends on additional structural changes in a rapid atriallypaced sheep model. J. Mol. Cell. Cardiol. 43, 148e158.
Anne, W., Willems, R., Roskams, T., Sergeant, P., Herijgers, P., Holemans, P., Ector, H.,Heidbuchel, H., 2005. Matrix metalloproteinases and atrial remodeling inpatients with mitral valve disease and atrial fibrillation. Cardiovasc. Res. 67,655e666.
Antoniou, A., Milonas, D., Kanakakis, J., Rokas, S., Sideris, D.A., 1997. Contractioneexcitation feedback in human atrial fibrillation. Clin. Cardiol. 20, 473e476.
Arora, R., Verheule, S., Scott, L., Navarrete, A., Katari, V., Wilson, E., Vaz, D., Olgin, J.E.,2003. Arrhythmogenic substrate of the pulmonary veins assessed by high-resolution optical mapping. Circulation 107, 1816e1821.
Atienza, F., Almendral, J., Moreno, J., Vaidyanathan, R., Talkachou, A., Kalifa, J.,Arenal, A., Villacastin, J.P., Torrecilla, E.G., Sanchez, A., Ploutz-Snyder, R., Jalife, J.,Berenfeld, O., 2006. Activation of inward rectifier potassium channels acceler-ates atrial fibrillation in humans: evidence for a reentrant mechanism. Circu-lation 114, 2434e2442.
Ausma, J., van der Velden, H.M., Lenders, M.H., van Ankeren, E.P., Jongsma, H.J.,Ramaekers, F.C., Borgers, M., Allessie, M.A., 2003. Reverse structural and gap-junctional remodeling after prolonged atrial fibrillation in the goat. Circula-tion 107, 2051e2058.
Ausma, J., Wijffels, M., Thone, F., Wouters, L., Allessie, M., Borgers, M., 1997. Struc-tural changes of atrial myocardium due to sustained atrial fibrillation in thegoat. Circulation 96, 3157e3163.
Beauchamp, P., Yamada, K.A., Baertschi, A.J., Green, K., Kanter, E.M., Saffitz, J.E.,Kleber, A.G., 2006. Relative contributions of connexins 40 and 43 to atrialimpulse propagation in synthetic strands of neonatal and fetal murine car-diomyocytes. Circ. Res. 99, 1216e1224.
Benjamin, E.J., Chen, P.S., Bild, D.E., Mascette, A.M., Albert, C.M., Alonso, A.,Calkins, H., Connolly, S.J., Curtis, A.B., Darbar, D., Ellinor, P.T., Go, A.S.,Goldschlager, N.F., Heckbert, S.R., Jalife, J., Kerr, C.R., Levy, D., Lloyd-Jones, D.M.,Massie, B.M., Nattel, S., Olgin, J.E., Packer, D.L., Po, S.S., Tsang, T.S., VanWagoner, D.R., Waldo, A.L., Wyse, D.G., 2009. Prevention of atrial fibrillation:report from a national heart, lung, and blood institute workshop. Circulation119, 606e618.
Berenfeld, O., 2010. Ionic and substrate mechanism of atrial fibrillation: rotors andthe exitacion frequency approach. Arch. Cardiol. Mex. 80, 301e314.
Berenfeld, O., Mandapati, R., Dixit, S., Skanes, A.C., Chen, J., Mansour, M., Jalife, J.,2000. Spatially distributed dominant excitation frequencies reveal hiddenorganization in atrial fibrillation in the Langendorff-perfused sheep heart.J. Cardiovasc. Electrophysiol. 11, 869e879.
Berenfeld, O., Zaitsev, A.V., Mironov, S.F., Pertsov, A.M., Jalife, J., 2002. Frequency-dependent breakdown of wave propagation into fibrillatory conduction acrossthe pectinate muscle network in the isolated sheep right atrium. Circ. Res. 90,1173e1180.
Berenfeld, O., Kalifa, J., Yamazaki, M., Filgueiras-Rama, D., 2012. Ectopic and reen-trant activation patterns in the posterior left atrium during stretch-relatedatrial fibrillation. Prog. Biophys. Mol. Biol. 110 (2e3), 269e277.
Blazeski, A., Zhu, R., Hunter, D.W., Weinberg, S.H., Boheler, K.R., Zambidis, E.T.,Tung, L., 2012. Electrophysiological and contractile function of cardiomyocytes
S. Kumar et al. / Progress in Biophysics and Molecular Biology 110 (2012) 278e294 291
derived from human embryonic stem cells. Prog. Biophys. Mol. Biol. 110 (2e3),178e195.
Boldt, A., Wetzel, U., Lauschke, J., Weigl, J., Gummert, J., Hindricks, G., Kottkamp, H.,Dhein, S., 2004. Fibrosis in left atrial tissue of patients with atrial fibrillationwith and without underlying mitral valve disease. Heart 90, 400e405.
Boyden, P.A., Hoffman, B.F., 1981. The effects on atrial electrophysiology andstructure of surgically induced right atrial enlargement in dogs. Circ. Res. 49,1319e1331.
Burstein, B., Nattel, S., 2008. Atrial fibrosis: mechanisms and clinical relevance inatrial fibrillation. J. Am. Coll. Cardiol. 51, 802e809.
Burstein, B., Comtois, P., Michael, G., Nishida, K., Villeneuve, L., Yeh, Y.H., Nattel, S.,2009. Changes in connexin expression and the atrial fibrillation substrate incongestive heart failure. Circ. Res. 105, 1213e1222.
Burstein, B., Qi, X.Y., Yeh, Y.H., Calderone, A., Nattel, S., 2007. Atrial cardiomyocytetachycardia alters cardiac fibroblast function: a novel consideration in atrialremodeling. Cardiovasc. Res. 76, 442e452.
Calkins, H., el-Atassi, R., Kalbfleisch, S., Langberg, J., Morady, F., 1992a. Effects of anacute increase in atrial pressure on atrial refractoriness in humans. Pacing Clin.Electrophysiol. 15, 1674e1680.
Calkins, H., el-Atassi, R., Leon, A., Kalbfleisch, S., Borganelli, M., Langberg, J.,Morady, F., 1992b. Effect of the atrioventricular relationship on atrial refracto-riness in humans. Pacing Clin. Electrophysiol. 15, 771e778.
Chang, S.L., Tai, C.T., Lin, Y.J., Wongcharoen, W., Lo, L.W., Lee, K.T., Chang, S.H.,Tuan, T.C., Chen, Y.J., Hsieh, M.H., Tsao, H.M., Wu, M.H., Sheu, M.H., Chang, C.Y.,Chen, S.A., 2007. The role of left atrial muscular bundles in catheter ablation ofatrial fibrillation. J. Am. Coll. Cardiol. 50, 964e973.
Chen, Y.J., Chen, S.A., 2006. Electrophysiology of pulmonary veins. J. Cardiovasc.Electrophysiol. 17, 220e224.
Chen, Y.J., Chen, S.A., Chen, Y.C., Yeh, H.I., Chan, P., Chang, M.S., Lin, C.I., 2001. Effectsof rapid atrial pacing on the arrhythmogenic activity of single cardiomyocytesfrom pulmonary veins: implication in initiation of atrial fibrillation. Circulation104, 2849e2854.
Chen, Y.J., Tai, C.T., Chiou, C.W., Wen, Z.C., Chan, P., Lee, S.H., Chen, S.A., 1999.Inducibility of atrial fibrillation during atrioventricular pacing with varyingintervals: role of atrial electrophysiology and the autonomic nervous system.J. Cardiovasc. Electrophysiol. 10, 1578e1585.
Chou, C.C., Chen, P.S., 2009. New concepts in atrial fibrillation: neural mechanismsand calcium dynamics. Cardiol. Clin. 27, 35e43. viii.
Colish, J., Walker, J.R., Elmayergi, N., Almutairi, S., Alharbi, F., Lytwyn, M., Francis, A.,Bohonis, S., Zeglinski, M., Kirkpatrick, I.D., Sharma, S., Jassal, D.S., 2012.Obstructive sleep apnea: effects of continuous positive airway pressure oncardiac remodeling as assessed by cardiac biomarkers, echocardiography, andcardiac MRI. Chest 141, 674e681.
Coutu, P., Chartier, D., Nattel, S., 2006. Comparison of Ca2þ-handling properties ofcanine pulmonary vein and left atrial cardiomyocytes. Am. J. Physiol. Heart Circ.Physiol. 291, H2290eH2300.
de Groot, N.M., Houben, R.P., Smeets, J.L., Boersma, E., Schotten, U., Schalij, M.J.,Crijns, H., Allessie, M.A., 2010. Electropathological substrate of longstandingpersistent atrial fibrillation in patients with structural heart disease: epicardialbreakthrough. Circulation 122, 1674e1682.
de Vos, C.B., Nieuwlaat, R., Crijns, H.J., Camm, A.J., LeHeuzey, J.Y., Kirchhof, C.J.,Capucci, A., Breithardt, G., Vardas, P.E., Pisters, R., Tieleman, R.G., 2008. Auto-nomic trigger patterns and anti-arrhythmic treatment of paroxysmal atrialfibrillation: data from the Euro Heart Survey. Eur. Heart J. 29, 632e639.
Dimitri, H., Ng, M., Brooks, A.G., Kuklik, P., Stiles, M.K., Lau, D.H., Antic, N.,Thornton, A., Saint, D.A., McEvoy, D., Antic, R., Kalman, J.M., Sanders, P., 2012.Atrial remodeling in obstructive sleep apnea: implications for atrial fibrillation.Heart Rhythm 9, 321e327.
Dobrev, D., Nattel, S., 2011. New insights into the molecular basis of atrial fibrilla-tion: mechanistic and therapeutic implications. Cardiovasc. Res. 89, 689e691.
Eckstein, J., Maesen, B., Linz, D., Zeemering, S., van Hunnik, A., Verheule, S.,Allessie, M., Schotten, U., 2011. Time course and mechanisms of endo-epicardialelectrical dissociation during atrial fibrillation in the goat. Cardiovasc. Res. 89,816e824.
Ehrlich, J.R., Cha, T.J., Zhang, L., Chartier, D., Melnyk, P., Hohnloser, S.H., Nattel, S.,2003. Cellular electrophysiology of canine pulmonary vein cardiomyocytes:action potential and ionic current properties. J. Physiol. 551, 801e813.
Eijsbouts, S.C., Majidi, M., van Zandvoort, M., Allessie, M.A., 2003. Effects of acuteatrial dilation on heterogeneity in conduction in the isolated rabbit heart.J. Cardiovasc. Electrophysiol. 14, 269e278.
Everett, T.H.t., Li, H., Mangrum, J.M., McRury, I.D., Mitchell, M.A., Redick, J.A.,Haines, D.E., 2000. Electrical, morphological, and ultrastructural remodelingand reverse remodeling in a canine model of chronic atrial fibrillation. Circu-lation 102, 1454e1460.
Fareh, S., Villemaire, C., Nattel, S., 1998. Importance of refractoriness hetero-geneity in the enhanced vulnerability to atrial fibrillation induction causedby tachycardia-induced atrial electrical remodeling. Circulation 98, 2202e2209.
Fioranelli, M., Piccoli, M., Mileto, G.M., Sgreccia, F., Azzolini, P., Risa, M.P.,Francardelli, R.L., Venturini, E., Puglisi, A., 1999. Analysis of heart rate variabilityfive minutes before the onset of paroxysmal atrial fibrillation. Pacing Clin.Electrophysiol. 22, 743e749.
Gaspo, R., Bosch, R.F., Talajic, M., Nattel, S., 1997. Functional mechanisms underlyingtachycardia-induced sustained atrial fibrillation in a chronic dog model.Circulation 96, 4027e4035.
Gatzoulis, M.A., Freeman, M.A., Siu, S.C., Webb, G.D., Harris, L., 1999. Atrialarrhythmia after surgical closure of atrial septal defects in adults. N. Engl. J.Med. 340, 839e846.
Goette, A., Juenemann, G., Peters, B., Klein, H.U., Roessner, A., Huth, C., Rocken, C.,2002. Determinants and consequences of atrial fibrosis in patients undergoingopen heart surgery. Cardiovasc. Res. 54, 390e396.
Goudis, C.A., Kallergis, E.M., Vardas, P.E., 2012. Extracellular matrix alterationsin the atria: insights into the mechanisms and perpetuation of atrialfibrillation. Europace. http://dx.doi.org/10.1093/europace/eur398. EPubahead of print.
Gould, P.A., Yii, M., McLean, C., Finch, S., Marshall, T., Lambert, G.W., Kaye, D.M.,2006. Evidence for increased atrial sympathetic innervation in persistenthuman atrial fibrillation. Pacing Clin. Electrophysiol. 29, 821e829.
Greiser, M., Lederer, W.J., Schotten, U., 2011. Alterations of atrial Ca(2þ) handling ascause and consequence of atrial fibrillation. Cardiovasc. Res. 89, 722e733.
Haissaguerre, M., Jais, P., Shah, D.C., Takahashi, A., Hocini, M., Quiniou, G.,Garrigue, S., Le Mouroux, A., Le Metayer, P., Clementy, J., 1998. Spontaneousinitiation of atrial fibrillation by ectopic beats originating in the pulmonaryveins. N. Engl. J. Med. 339, 659e666.
Hassink, R.J., Aretz, H.T., Ruskin, J., Keane, D., 2003. Morphology of atrial myocar-dium in human pulmonary veins: a postmortem analysis in patients with andwithout atrial fibrillation. J. Am. Coll. Cardiol. 42, 1108e1114.
Hayashi, H., Wang, C., Miyauchi, Y., Omichi, C., Pak, H.N., Zhou, S., Ohara, T.,Mandel, W.J., Lin, S.F., Fishbein, M.C., Chen, P.S., Karagueuzian, H.S., 2002. Aging-related increase to inducible atrial fibrillation in the rat model. J. Cardiovasc.Electrophysiol. 13, 801e808.
Haywood, L.J., Ford, C.E., Crow, R.S., Davis, B.R., Massie, B.M., Einhorn, P.T.,Williard, A., 2009. Atrial fibrillation at baseline and during follow-up in ALLHAT(Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial).J. Am. Coll. Cardiol. 54, 2023e2031.
Hobbs, W.J., Fynn, S., Todd, D.M., Wolfson, P., Galloway, M., Garratt, C.J., 2000.Reversal of atrial electrical remodeling after cardioversion of persistent atrialfibrillation in humans. Circulation 101, 1145e1151.
Hocini, M., Ho, S.Y., Kawara, T., Linnenbank, A.C., Potse, M., Shah, D., Jais, P.,Janse, M.J., Haissaguerre, M., De Bakker, J.M., 2002. Electrical conduction incanine pulmonary veins: electrophysiological and anatomic correlation. Circu-lation 105, 2442e2448.
Houben, R.P., de Groot, N.M., Smeets, J.L., Becker, A.E., Lindemans, F.W.,Allessie, M.A., 2004. S-wave predominance of epicardial electrograms duringatrial fibrillation in humans: indirect evidence for a role of the thin sub-epicardial layer. Heart Rhythm 1, 639e647.
Hunter, R.J., Liu, Y., Lu, Y., Wang, W., Schilling, R.J., 2012. Left atrial wall stressdistribution and its relationship to electrophysiologic remodeling in persistentatrial fibrillation. Circ. Arrhythm. Electrophysiol.. http://dx.doi.org/10.1161/CIR-CEP.111.965541. Epub ahead of print.
Iwasaki, Y.K., Nishida, K., Kato, T., Nattel, S., 2011. Atrial fibrillation pathophysiology:implications for management. Circulation 124, 2264e2274.
Jais, P., Hocini, M., Macle, L., Choi, K.J., Deisenhofer, I., Weerasooriya, R., Shah, D.C.,Garrigue, S., Raybaud, F., Scavee, C., Le Metayer, P., Clementy, J.,Haissaguerre, M., 2002. Distinctive electrophysiological properties of pulmo-nary veins in patients with atrial fibrillation. Circulation 106, 2479e2485.
John, B., Stiles, M.K., Kuklik, P., Brooks, A.G., Chandy, S.T., Kalman, J.M., Sanders, P.,2010. Reverse remodeling of the atria after treatment of chronic stretch inhumans: implications for the atrial fibrillation substrate. J. Am. Coll. Cardiol. 55,1217e1226.
John, B., Stiles, M.K., Kuklik, P., Chandy, S.T., Young, G.D., Mackenzie, L.,Szumowski, L., Joseph, G., Jose, J., Worthley, S.G., Kalman, J.M., Sanders, P., 2008.Electrical remodelling of the left and right atria due to rheumatic mitralstenosis. Eur. Heart J. 29, 2234e2243.
Kalifa, J., Bernard, M., Gout, B., Bril, A., Cozma, D., Laurent, P., Chalvidan, T.,Deharo, J.C., Djiane, P., Cozzone, P., Maixent, J.M., 2007. Anti-arrhythmiceffects of I (Na), I (Kr), and combined I (Kr)eI (CaL) blockade in an experi-mental model of acute stretch-related atrial fibrillation. Cardiovasc. DrugsTher. 21, 47e53.
Kalifa, J., Tanaka, K., Zaitsev, A.V., Warren, M., Vaidyanathan, R., Auerbach, D.,Pandit, S., Vikstrom, K.L., Ploutz-Snyder, R., Talkachou, A., Atienza, F.,Guiraudon, G., Jalife, J., Berenfeld, O., 2006. Mechanisms of wave fractionation atboundaries of high-frequency excitation in the posterior left atrium of theisolated sheep heart during atrial fibrillation. Circulation 113, 626e633.
Kamalvand, K., Tan, K., Lloyd, G., Gill, J., Bucknall, C., Sulke, N., 1999. Alterations inatrial electrophysiology associated with chronic atrial fibrillation in man. Eur.Heart J. 20, 888e895.
Kamkin, A., Kiseleva, I., Lozinsky, I., Scholz, H., 2005. Electrical interaction ofmechanosensitive fibroblasts and myocytes in the heart. Basic Res. Cardiol. 100,337e345.
Kanagala, R., Murali, N.S., Friedman, P.A., Ammash, N.M., Gersh, B.J., Ballman, K.V.,Shamsuzzaman, A.S., Somers, V.K., 2003. Obstructive sleep apnea and therecurrence of atrial fibrillation. Circulation 107, 2589e2594.
Kanagaratnam, P., Cherian, A., Stanbridge, R.D., Glenville, B., Severs, N.J., Peters, N.S.,2004. Relationship between connexins and atrial activation during humanatrial fibrillation. J. Cardiovasc. Electrophysiol. 15, 206e216.
Kaseda, S., Zipes, D.P., 1988. Contractioneexcitation feedback in the atria: a cause ofchanges in refractoriness. J. Am. Coll. Cardiol. 11, 1327e1336.
Kato, T., Iwasaki, Y.K., Nattel, S., 2012. Connexins and atrial fibrillation: filling in thegaps. Circulation 125, 203e206.
S. Kumar et al. / Progress in Biophysics and Molecular Biology 110 (2012) 278e294292
Kim, S.J., Choisy, S.C., Barman, P., Zhang, H., Hancox, J.C., Jones, S.A., James, A.F., 2011.Atrial remodeling and the substrate for atrial fibrillation in rat hearts withelevated afterload. Circ. Arrhythm. Electrophysiol. 4, 761e769.
Kinebuchi, O., Mitamura, H., Shiroshita-Takeshita, A., Kurita, Y., Ohashi, N.,Tanimoto, K., Fukuda, Y., Ieda, M., Sato, T., Hara, M., Takatsuki, S., Ogawa, S.,2005. Temporal patterns of progression and regression of electrical andmechanical remodeling of the atrium. Int. J. Cardiol. 98, 91e98.
Kistler, P.M., Sanders, P., Dodic, M., Spence, S.J., Samuel, C.S., Zhao, C., Charles, J.A.,Edwards, G.A., Kalman, J.M., 2006. Atrial electrical and structural abnormalitiesin an ovine model of chronic blood pressure elevation after prenatal cortico-steroid exposure: implications for development of atrial fibrillation. Eur. Heart J.27, 3045e3056.
Kistler, P.M., Sanders, P., Fynn, S.P., Stevenson, I.H., Spence, S.J., Vohra, J.K.,Sparks, P.B., Kalman, J.M., 2004. Electrophysiologic and electroanatomicchanges in the human atrium associated with age. J. Am. Coll. Cardiol. 44,109e116.
Klein, L.S., Miles, W.M., Zipes, D.P., 1990. Effect of atrioventricular interval duringpacing or reciprocating tachycardia on atrial size, pressure, and refractoryperiod. Contractioneexcitation feedback in human atrium. Circulation 82,60e68.
Klos, M., Calvo, D., Yamazaki, M., Zlochiver, S., Mironov, S., Cabrera, J.A., Sanchez-Quintana, D., Jalife, J., Berenfeld, O., Kalifa, J., 2008. Atrial septopulmonarybundle of the posterior left atrium provides a substrate for atrial fibrillationinitiation in a model of vagally mediated pulmonary vein tachycardia of thestructurally normal heart. Circ. Arrhythm. Electrophysiol. 1, 175e183.
Kneller, J., Zou, R., Vigmond, E.J., Wang, Z., Leon, L.J., Nattel, S., 2002. Cholinergicatrial fibrillation in a computer model of a two-dimensional sheet of canineatrial cells with realistic ionic properties. Circ. Res. 90, E73eE87.
Kojodjojo, P., Kanagaratnam, P., Markides, V., Davies, D.W., Peters, N., 2006. Age-related changes in human left and right atrial conduction. J. Cardiovasc. Elec-trophysiol. 17, 120e127.
Kojodjojo, P., Peters, N.S., Davies, D.W., Kanagaratnam, P., 2007. Characterization ofthe electroanatomical substrate in human atrial fibrillation: the relationshipbetween changes in atrial volume, refractoriness, wavefront propagationvelocities, and AF burden. J. Cardiovasc. Electrophysiol. 18, 269e275.
Kostin, S., Klein, G., Szalay, Z., Hein, S., Bauer, E.P., Schaper, J., 2002. Structuralcorrelate of atrial fibrillation in human patients. Cardiovasc. Res. 54, 361e379.
Koura, T., Hara, M., Takeuchi, S., Ota, K., Okada, Y., Miyoshi, S., Watanabe, A.,Shiraiwa, K., Mitamura, H., Kodama, I., Ogawa, S., 2002. Anisotropic conductionproperties in canine atria analyzed by high-resolution optical mapping: pref-erential direction of conduction block changes from longitudinal to transversewith increasing age. Circulation 105, 2092e2098.
Kuijpers, N.H., Potse, M., van Dam, P.M., ten Eikelder, H.M., Verheule, S.,Prinzen, F.W., Schotten, U., 2011. Mechanoelectrical coupling enhances initiationand affects perpetuation of atrial fibrillation during acute atrial dilation. HeartRhythm 8, 429e436.
Kuijpers, N.H., ten Eikelder, H.M., Bovendeerd, P.H., Verheule, S., Arts, T.,Hilbers, P.A., 2007. Mechanoelectric feedback leads to conduction slowing andblock in acutely dilated atria: a modeling study of cardiac electromechanics.Am. J. Physiol. Heart Circ. Physiol. 292, H2832eH2853.
Kumagai, K., Akimitsu, S., Kawahira, K., Kawanami, F., Yamanouchi, Y., Hiroki, T.,Arakawa, K., 1991. Electrophysiological properties in chronic lone atrial fibril-lation. Circulation 84, 1662e1668.
Kumagai, K., Ogawa, M., Noguchi, H., Yasuda, T., Nakashima, H., Saku, K., 2004.Electrophysiologic properties of pulmonary veins assessed using a multielec-trode basket catheter. J. Am. Coll. Cardiol. 43, 2281e2289.
Lazar, S., Dixit, S., Marchlinski, F.E., Callans, D.J., Gerstenfeld, E.P., 2004. Presence ofleft-to-right atrial frequency gradient in paroxysmal but not persistent atrialfibrillation in humans. Circulation 110, 3181e3186.
Lee, S.H., Lin, F.Y., Yu, W.C., Cheng, J.J., Kuan, P., Hung, C.R., Chang, M.S., Chen, S.A.,1999. Regional differences in the recovery course of tachycardia-inducedchanges of atrial electrophysiological properties. Circulation 99, 1255e1264.
Li, D., Fareh, S., Leung, T.K., Nattel, S., 1999. Promotion of atrial fibrillation by heartfailure in dogs: atrial remodeling of a different sort. Circulation 100, 87e95.
Mandapati, R., Skanes, A., Chen, J., Berenfeld, O., Jalife, J., 2000. Stable micro-reentrant sources as a mechanism of atrial fibrillation in the isolated sheepheart. Circulation 101, 194e199.
Manios, E.G., Kanoupakis, E.M., Chlouverakis, G.I., Kaleboubas, M.D., Mavrakis, H.E.,Vardas, P.E., 2000. Changes in atrial electrical properties following car-dioversion of chronic atrial fibrillation: relation with recurrence. Cardiovasc.Res. 47, 244e253.
Marsan, N.A., Maffessanti, F., Tamborini, G., Gripari, P., Caiani, E., Fusini, L.,Muratori, M., Zanobini, M., Alamanni, F., Pepi, M., 2011. Left atrial reverseremodeling and functional improvement after mitral valve repair in degener-ative mitral regurgitation: a real-time 3-dimensional echocardiography study.Am. Heart J. 161, 314e321.
Medi, C., Kalman, J.M., Ling, L.H., Teh, A.W., Lee, G., Lee, G., Spence, S.J., Kaye, D.M.,Kistler, P.M., 2012. Atrial electrical and structural remodeling associated withlongstanding pulmonary hypertension and right ventricular hypertrophy inhumans. J. Cardiovasc. Electrophysiol.. http://dx.doi.org/10.1111/j.1540-8167.2011.02255.x. Epub ahead of print.
Medi, C., Kalman, J.M., Spence, S.J., Teh, A.W., Lee, G., Bader, I., Kaye, D.M.,Kistler, P.M., 2011. Atrial electrical and structural changes associated withlongstanding hypertension in humans: implications for the substrate for atrialfibrillation. J. Cardiovasc. Electrophysiol. 22, 1317e1324.
Miragoli, M., Gaudesius, G., Rohr, S., 2006. Electrotonic modulation of cardiacimpulse conduction by myofibroblasts. Circ. Res. 98, 801e810.
Morillo, C.A., Klein, G.J., Jones, D.L., Guiraudon, C.M., 1995. Chronic rapid atrialpacing. Structural, functional, and electrophysiological characteristics of a newmodel of sustained atrial fibrillation. Circulation 91, 1588e1595.
Morton, J.B., Sanders, P., Vohra, J.K., Sparks, P.B., Morgan, J.G., Spence, S.J., Grigg, L.E.,Kalman, J.M., 2003. Effect of chronic right atrial stretch on atrial electricalremodeling in patients with an atrial septal defect. Circulation 107, 1775e1782.
Nao, T., Ohkusa, T., Hisamatsu, Y., Inoue, N., Matsumoto, T., Yamada, J., Shimizu, A.,Yoshiga, Y., Yamagata, T., Kobayashi, S., Yano, M., Hamano, K., Matsuzaki, M.,2003. Comparison of expression of connexin in right atrial myocardium inpatients with chronic atrial fibrillation versus those in sinus rhythm. Am. J.Cardiol. 91, 678e683.
Nattel, S., Dobrev, D., 2012. The multidimensional role of calcium in atrial fibrilla-tion pathophysiology: mechanistic insights and therapeutic opportunities. Eur.Heart J.. http://dx.doi.org/10.1093/eurheartj/ehs079. Epub ahead of print.
Nattel, S., Burstein, B., Dobrev, D., 2008. Atrial remodeling and atrial fibrillation:mechanisms and implications. Circ. Arrhythm. Electrophysiol. 1, 62e73.
Nazir, S.A., Lab, M.J., 1996. Mechanoelectric feedback in the atrium of the isolatedguinea-pig heart. Cardiovasc. Res. 32, 112e119.
Neuberger, H.R., Schotten, U., Verheule, S., Eijsbouts, S., Blaauw, Y., van Hunnik, A.,Allessie, M., 2005. Development of a substrate of atrial fibrillation duringchronic atrioventricular block in the goat. Circulation 111, 30e37.
Nishida, K., Sarrazin, J.F., Fujiki, A., Oral, H., Inoue, H., Morady, F., Nattel, S., 2010.Roles of the left atrial roof and pulmonary veins in the anatomic substrate forpersistent atrial fibrillation and ablation in a canine model. J. Am. Coll. Cardiol.56, 1728e1736.
Olgin, J.E., Kalman, J.M., Fitzpatrick, A.P., Lesh, M.D., 1995. Role of right atrialendocardial structures as barriers to conduction during human type I atrialflutter. Activation and entrainment mapping guided by intracardiac echocar-diography. Circulation 92, 1839e1848.
Platonov, P.G., Mitrofanova, L.B., Orshanskaya, V., Ho, S.Y., 2011. Structural abnor-malities in atrial walls are associated with presence and persistency of atrialfibrillation but not with age. J. Am. Coll. Cardiol. 58, 2225e2232.
Polontchouk, L., Haefliger, J.A., Ebelt, B., Schaefer, T., Stuhlmann, D., Mehlhorn, U.,Kuhn-Regnier, F., De Vivie, E.R., Dhein, S., 2001. Effects of chronic atrial fibril-lation on gap junction distribution in human and rat atria. J. Am. Coll. Cardiol.38, 883e891.
Raitt, M.H., Kusumoto, W., Giraud, G., McAnulty, J.H., 2004. Reversal of electricalremodeling after cardioversion of persistent atrial fibrillation. J. Cardiovasc.Electrophysiol. 15, 507e512.
Ravelli, F., Allessie, M., 1997. Effects of atrial dilatation on refractory period andvulnerability to atrial fibrillation in the isolated Langendorff-perfused rabbitheart. Circulation 96, 1686e1695.
Ravelli, F., Mase, M., del Greco, M., Marini, M., Disertori, M., 2011. Acute atrialdilatation slows conduction and increases AF vulnerability in the humanatrium. J. Cardiovasc. Electrophysiol. 22, 394e401.
Roberts-Thomson, K.C., Stevenson, I., Kistler, P.M., Haqqani, H.M., Spence, S.J.,Goldblatt, J.C., Sanders, P., Kalman, J.M., 2009b. The role of chronic atrial stretchand atrial fibrillation on posterior left atrial wall conduction. Heart Rhythm 6,1109e1117.
Roberts-Thomson, K.C., Stevenson, I.H., Kistler, P.M., Haqqani, H.M., Goldblatt, J.C.,Sanders, P., Kalman, J.M., 2008. Anatomically determined functional conductiondelay in the posterior left atrium relationship to structural heart disease. J. Am.Coll. Cardiol. 51, 856e862.
Rostock, T., Steven, D., Lutomsky, B., Servatius, H., Drewitz, I., Klemm, H.,Mullerleile, K., Ventura, R., Meinertz, T., Willems, S., 2008. Atrial fibrillationbegets atrial fibrillation in the pulmonary veins on the impact of atrial fibril-lation on the electrophysiological properties of the pulmonary veins in humans.J. Am. Coll. Cardiol. 51, 2153e2160.
Saffitz, J.E., Kanter, H.L., Green, K.G., Tolley, T.K., Beyer, E.C., 1994. Tissue-specificdeterminants of anisotropic conduction velocity in canine atrial and ventricularmyocardium. Circ. Res. 74, 1065e1070.
Sahadevan, J., Ryu, K., Peltz, L., Khrestian, C.M., Stewart, R.W., Markowitz, A.H.,Waldo, A.L., 2004. Epicardial mapping of chronic atrial fibrillation in patients:preliminary observations. Circulation 110, 3293e3299.
Saito, T., Tamura, K., Uchida, D., Saito, T., Togashi, M., Nitta, T., Sugisaki, Y., 2007.Histopathological features of the resected left atrial appendage as predictors ofrecurrence after surgery for atrial fibrillation in valvular heart disease. Circ. J. 71,70e78.
Sanders, P., Berenfeld, O., Hocini, M., Jais, P., Vaidyanathan, R., Hsu, L.F., Garrigue, S.,Takahashi, Y., Rotter, M., Sacher, F., Scavee, C., Ploutz-Snyder, R., Jalife, J.,Haissaguerre, M., 2005. Spectral analysis identifies sites of high-frequencyactivity maintaining atrial fibrillation in humans. Circulation 112, 789e797.
Sanders, P., Morton, J.B., Davidson, N.C., Spence, S.J., Vohra, J.K., Sparks, P.B.,Kalman, J.M., 2003. Electrical remodeling of the atria in congestive heart failure:electrophysiological and electroanatomic mapping in humans. Circulation 108,1461e1468.
Sanders, P., Morton, J.B., Kistler, P.M., Spence, S.J., Davidson, N.C., Hussin, A.,Vohra, J.K., Sparks, P.B., Kalman, J.M., 2004. Electrophysiological and electro-anatomic characterization of the atria in sinus node disease: evidence of diffuseatrial remodeling. Circulation 109, 1514e1522.
S. Kumar et al. / Progress in Biophysics and Molecular Biology 110 (2012) 278e294 293
Satoh, T., Zipes, D.P., 1996. Unequal atrial stretch in dogs increases dispersion ofrefractoriness conducive to developing atrial fibrillation. J. Cardiovasc. Elec-trophysiol. 7, 833e842.
Schoonderwoerd, B.A., Ausma, J., Crijns, H.J., Van Veldhuisen, D.J., Blaauw, E.H., VanGelder, I.C., 2004. Atrial ultrastructural changes during experimental atrialtachycardia depend on high ventricular rate. J. Cardiovasc. Electrophysiol. 15,1167e1174.
Schotten, U., Duytschaever, M., Ausma, J., Eijsbouts, S., Neuberger, H.R., Allessie, M.,2003. Electrical and contractile remodeling during the first days of atrialfibrillation go hand in hand. Circulation 107, 1433e1439.
Schotten, U., Verheule, S., Kirchhof, P., Goette, A., 2011. Pathophysiologicalmechanisms of atrial fibrillation: a translational appraisal. Physiol. Rev. 91,265e325.
Shan, Z., Van Der Voort, P.H., Blaauw, Y., Duytschaever, M., Allessie, M.A., 2004.Fractionation of electrograms and linking of activation during pharmacologiccardioversion of persistent atrial fibrillation in the goat. J. Cardiovasc. Electro-physiol. 15, 572e580.
Shi, Y., Ducharme, A., Li, D., Gaspo, R., Nattel, S., Tardif, J.C., 2001. Remodeling ofatrial dimensions and emptying function in canine models of atrial fibrillation.Cardiovasc. Res. 52, 217e225.
Shinagawa, K., Shi, Y.F., Tardif, J.C., Leung, T.K., Nattel, S., 2002. Dynamic nature ofatrial fibrillation substrate during development and reversal of heart failure indogs. Circulation 105, 2672e2678.
Sideris, D.A., Toumanidis, S.T., Thodorakis, M., Kostopoulos, K., Tselepatiotis, E.,Langoura, C., Stringli, T., Moulopoulos, S.D., 1994. Some observations on themechanism of pressure related atrial fibrillation. Eur. Heart J. 15, 1585e1589.
Skanes, A.C., Mandapati, R., Berenfeld, O., Davidenko, J.M., Jalife, J., 1998. Spatio-temporal periodicity during atrial fibrillation in the isolated sheep heart.Circulation 98, 1236e1248.
Spach, M.S., Boineau, J.P., 1997. Microfibrosis produces electrical load variations dueto loss of side-to-side cell connections: a major mechanism of structural heartdisease arrhythmias. Pacing Clin. Electrophysiol. 20, 397e413.
Spach, M.S., Dolber, P.C., 1986. Relating extracellular potentials and their derivativesto anisotropic propagation at a microscopic level in human cardiac muscle.Evidence for electrical uncoupling of side-to-side fiber connections withincreasing age. Circ. Res. 58, 356e371.
Spach, M.S., Heidlage, J.F., Dolber, P.C., Barr, R.C., 2007. Mechanism of origin ofconduction disturbances in aging human atrial bundles: experimental andmodel study. Heart Rhythm 4, 175e185.
Spach, M.S., Josephson, M.E., 1994. Initiating reentry: the role of nonuniformanisotropy in small circuits. J. Cardiovasc. Electrophysiol. 5, 182e209.
Spach, M.S., Miller, W.T.r., Dolber, P.C., Kootsey, J.M., Sommer, J.R., Mosher, C.E.J.,1982. The functional role of structural complexities in the propagation ofdepolarization in the atrium of the dog. Cardiac conduction disturbances due todiscontinuities of effective axial resistivity. Circ. Res. 50, 175e191.
Sparks, P.B., Mond, H.G., Vohra, J.K., Jayaprakash, S., Kalman, J.M., 1999a. Electricalremodeling of the atria following loss of atrioventricular synchrony: a long-term study in humans. Circulation 100, 1894e1900.
Sparks, P.B., Mond, H.G., Vohra, J.K., Yapanis, A.G., Grigg, L.E., Kalman, J.M., 1999b.Mechanical remodeling of the left atrium after loss of atrioventricularsynchrony. A long-term study in humans. Circulation 100, 1714e1721.
Stevenson, I.H., Teichtahl, H., Cunnington, D., Ciavarella, S., Gordon, I., Kalman, J.M.,2008. Prevalence of sleep disordered breathing in paroxysmal and persistentatrial fibrillation patients with normal left ventricular function. Eur. Heart J. 29,1662e1669.
Stiles, M.K., John, B., Wong, C.X., Kuklik, P., Brooks, A.G., Lau, D.H., Dimitri, H.,Roberts-Thomson, K.C., Wilson, L., De Sciscio, P., Young, G.D., Sanders, P.,2009. Paroxysmal lone atrial fibrillation is associated with an abnormal atrialsubstrate: characterizing the “second factor”. J. Am. Coll. Cardiol. 53, 1182e1191.
Stiles, M.K., Wong, C.X., John, B., Kuklik, P., Brooks, A.G., Lau, D.H., Dimitri, H.,Wilson, L., Young, G.D., Sanders, P., 2010. Characterization of atrial remod-eling studied remote from episodes of typical atrial flutter. Am. J. Cardiol.106, 528e534.
Swartz, M.F., Fink, G.W., Lutz, C.J., Taffet, S.M., Berenfeld, O., Vikstrom, K.L.,Kasprowicz, K., Bhatta, L., Puskas, F., Kalifa, J., Jalife, J., 2009. Left versus rightatrial difference in dominant frequency, K(þ) channel transcripts, and fibrosisin patients developing atrial fibrillation after cardiac surgery. Heart Rhythm 6,1415e1422.
Takeuchi, S., Akita, T., Takagishi, Y., Watanabe, E., Sasano, C., Honjo, H., Kodama, I.,2006. Disorganization of gap junction distribution in dilated atria of patientswith chronic atrial fibrillation. Circ. J. 70, 575e582.
Tan, A.Y., Zhou, S., Ogawa, M., Song, J., Chu, M., Li, H., Fishbein, M.C., Lin, S.F.,Chen, L.S., Chen, P.S., 2008. Neural mechanisms of paroxysmal atrial fibrilla-tion and paroxysmal atrial tachycardia in ambulatory canines. Circulation 118,916e925.
Tanaka, K., Zlochiver, S., Vikstrom, K.L., Yamazaki, M., Moreno, J., Klos, M.,Zaitsev, A.V., Vaidyanathan, R., Auerbach, D.S., Landas, S., Guiraudon, G., Jalife, J.,Berenfeld, O., Kalifa, J., 2007. Spatial distribution of fibrosis governs fibrillationwave dynamics in the posterior left atrium during heart failure. Circ. Res. 101,839e847.
Teh, A.W., Kalman, J.M., Kistler, P.M., Lee, G., Sutherland, F., Morton, J.B., Vohra, J.K.,Sparks, P.B., 2010. Prevalence of fractionated electrograms in the coronarysinus: comparison between patients with persistent or paroxysmal atrialfibrillation and a control population. Heart Rhythm 7, 1200e1204.
Teh, A.W., Kistler, P.M., Lee, G., Medi, C., Heck, P.M., Spence, S.J., Sparks, P.B.,Morton, J.B., Kalman, J.M., 2011c. Electroanatomic remodeling of the left atriumin paroxysmal and persistent atrial fibrillation patients without structural heartdisease. J. Cardiovasc. Electrophysiol. 23, 232e238.
Todd, D.M., Fynn, S.P., Walden, A.P., Hobbs, W.J., Arya, S., Garratt, C.J., 2004.Repetitive 4-week periods of atrial electrical remodeling promote stability ofatrial fibrillation: time course of a second factor involved in the self-perpetuation of atrial fibrillation. Circulation 109, 1434e1439.
Tops, L.F., Delgado, V., Bertini, M., Marsan, N.A., Den Uijl, D.W., Trines, S.A.,Zeppenfeld, K., Holman, E., Schalij, M.J., Bax, J.J., 2011. Left atrial strain predictsreverse remodeling after catheter ablation for atrial fibrillation. J. Am. Coll.Cardiol. 57, 324e331.
Tse, H.F., Pelosi, F., Oral, H., Knight, B.P., Strickberger, S.A., Morady, F., 2001. Effects ofsimultaneous atrioventricular pacing on atrial refractoriness and atrial fibril-lation inducibility: role of atrial mechanoelectrical feedback. J. Cardiovasc.Electrophysiol. 12, 43e50.
Vaziri, S.M., Larson, M.G., Benjamin, E.J., Levy, D., 1994. Echocardiographic predic-tors of nonrheumatic atrial fibrillation. The Framingham Heart Study. Circula-tion 89, 724e730.
Verheule, S., Sato, T., Everett, T.t., Engle, S.K., Otten, D., Rubart-von der Lohe, M.,Nakajima, H.O., Nakajima, H., Field, L.J., Olgin, J.E., 2004a. Increased vulnerabilityto atrial fibrillation in transgenic mice with selective atrial fibrosis caused byoverexpression of TGF-beta1. Circ. Res. 94, 1458e1465.
Verheule, S., Tuyls, E., van Hunnik, A., Kuiper, M., Schotten, U., Allessie, M., 2010.Fibrillatory conduction in the atrial free walls of goats in persistent andpermanent atrial fibrillation. Circ. Arrhythm. Electrophysiol. 3, 590e599.
Verheule, S., Wilson, E., Banthia, S., Everett, T.H.t., Shanbhag, S., Sih, H.J., Olgin, J.,2004b. Direction-dependent conduction abnormalities in a canine model ofatrial fibrillation due to chronic atrial dilatation. Am. J. Physiol. Heart Circ.Physiol. 287, H634eH644.
Verheule, S., Wilson, E., Everett, T.t., Shanbhag, S., Golden, C., Olgin, J., 2003.Alterations in atrial electrophysiology and tissue structure in a canine model ofchronic atrial dilatation due to mitral regurgitation. Circulation 107, 2615e2622.
Verheule, S., Wilson, E.E., Arora, R., Engle, S.K., Scott, L.R., Olgin, J.E., 2002. Tissuestructure and connexin expression of canine pulmonary veins. Cardiovasc. Res.55, 727e738.
Voigt, N., Trausch, A., Knaut, M., Matschke, K., Varro, A., Van Wagoner, D.R.,Nattel, S., Ravens, U., Dobrev, D., 2010. Left-to-right atrial inward rectifierpotassium current gradients in patients with paroxysmal versus chronic atrialfibrillation. Circ. Arrhythm. Electrophysiol. 3, 472e480.
Wijffels, M.C., Kirchhof, C.J., Dorland, R., Allessie, M.A., 1995. Atrial fibrillation begetsatrial fibrillation. A study in awake chronically instrumented goats. Circulation92, 1954e1968.
Wilhelm, M., Kirste, W., Kuly, S., Amann, K., Neuhuber, W., Weyand, M.,Daniel, W.G., Garlichs, C., 2006. Atrial distribution of connexin 40 and 43 inpatients with intermittent, persistent, and postoperative atrial fibrillation.Heart Lung Circ. 15, 30e37.
Wolf, P.A., Benjamin, E.J., Belanger, A.J., Kannel, W.B., Levy, D., D’Agostino, R.B., 1996.Secular trends in the prevalence of atrial fibrillation: the Framingham study.Am. Heart J. 131, 790e795.
Wongcharoen, W., Chen, Y.C., Chen, Y.J., Lin, C.I., Chen, S.A., 2007b. Effects of agingand ouabain on left atrial arrhythmogenicity. J. Cardiovasc. Electrophysiol. 18,526e531.
Workman, A.J., Kane, K.A., Rankin, A.C., 2008. Cellular bases for human atrialfibrillation. Heart Rhythm 5, S1eS6.
Xu, Y., Tuteja, D., Zhang, Z., Xu, D., Zhang, Y., Rodriguez, J., Nie, L., Tuxson, H.R.,Young, J.N., Glatter, K.A., Vazquez, A.E., Yamoah, E.N., Chiamvimonvat, N., 2003.Molecular identification and functional roles of a Ca(2þ)-activated Kþ channelin human and mouse hearts. J. Biol. Chem. 278, 49085e49094.
Yamazaki, M., Mironov, S., Taravant, C., Brec, J., Vaquero, L.M., Bandaru, K.,Avula, U.M., Honjo, H., Kodama, I., Berenfeld, O., Kalifa, J., 2012. Heterogeneousatrial wall thickness and stretch promote scroll waves anchoring during atrialfibrillation. Cardiovasc. Res. 94, 48e57.
Yoshida, K., Ulfarsson, M., Oral, H., Crawford, T., Good, E., Jongnarangsin, K.,Bogun, F., Pelosi, F., Jalife, J., Morady, F., Chugh, A., 2011. Left atrial pressure anddominant frequency of atrial fibrillation in humans. Heart Rhythm 8, 181e187.
Yu, L., Scherlag, B.J., Sha, Y., Li, S., Sharma, T., Nakagawa, H., Jackman, W.M.,Lazzara, R., Jiang, H., Po, S.S., 2011. Interactions between atrial electricalremodeling and autonomic remodeling: how to break the vicious cycle. HeartRhythm.
S. Kumar et al. / Progress in Biophysics and Molecular Biology 110 (2012) 278e294294
Yu, W.C., Lee, S.H., Tai, C.T., Tsai, C.F., Hsieh, M.H., Chen, C.C., Ding, Y.A.,Chang, M.S., Chen, S.A., 1999. Reversal of atrial electrical remodeling followingcardioversion of long-standing atrial fibrillation in man. Cardiovasc. Res. 42,470e476.
Yue, L., Feng, J., Gaspo, R., Li, G.R., Wang, Z., Nattel, S., 1997. Ionic remodelingunderlying action potential changes in a canine model of atrial fibrillation. Circ.Res. 81, 512e525.
Zlochiver, S., Munoz, V., Vikstrom, K.L., Taffet, S.M., Berenfeld, O., Jalife, J., 2008.Electrotonic myofibroblast-to-myocyte coupling increases propensity to reen-trant arrhythmias in two-dimensional cardiac monolayers. Biophys. J. 95,4469e4480.
Zou, R., Kneller, J., Leon, L.J., Nattel, S., 2005. Substrate size as a determinant offibrillatory activity maintenance in a mathematical model of canine atrium. Am.J. Physiol. Heart Circ. Physiol. 289, H1002eH1012.
