Atrial Structure and Function and its Implications for Current and Emerging Treatments for Atrial Fibrillation

PR O G RE S S I N C ARDI O V A S CU L A R D I S EA S E S XX ( 2 0 1 5) XXX – XXX

Available online at www.sciencedirect.com

ScienceDirect www.onlinepcd.com

Atrial Structure and Function and its Implications for Current and Emerging Treatments for Atrial Fibrillation Sandeep Prabhua, b, c, d , Alex J.A. McLellana, b, c, d , Tomos E. Waltersa, c, d , Meenal Sharmaa , Alex Voskoboinika , Peter M. Kistlera, b, d,⁎ a

Department of Cardiovascular Medicine, Alfred Hospital, VIC, Australia Baker IDI Heart and Diabetes Institute, VIC, Australia c Cardiology Department, Royal Melbourne Hospital, VIC, Australia d Faculty of Medicine, Dentistry, and Health Sciences, University of Melbourne, VIC, Australia b

A R T I C LE I N F O

AB ST R A C T

Keywords:

Left atrial (LA) structure and function are intimately related to the clinical phenotypes of

Atrial fibrillation

atrial fibrillation (AF), and have direct implications for the success or otherwise of various

Left atrium

therapeutic strategies. In conjunction with intrinsic structural characteristics of the LA,

Electrical remodelling

pathological remodelling to a large extent dictates the clinical course of AF. Remodelling is a

Structural remodelling

product of the physiological and structural plasticity of the LA in disease states (including

Ablation

AF itself), and manifests as electrical, physical and structural changes that promote the

Novel therapies

substrate necessary for AF maintenance. The degree of remodelling impacts upon the

Catheter ablation

efficacy of pharmacological, non-pharmacological and interventional treatments for AF.

Atrial fibrosis

Evolving therapies seek to specifically target these processes although presently, several remain in the development phase. Catheter ablation (CA) is now firmly established as a highly effective treatment for AF, although increasing its efficacy in the remodelled LA of more severe AF phenotypes remains an ongoing challenge. © 2015 Elsevier Inc. All rights reserved.

Atrial fibrillation (AF) is one of few cardiovascular (CV) conditions increasing in incidence across the world1 conferring a considerable health, social and economic burden worldwide.2 The treatment options for patients with AF have recently improved with the establishment of catheter ablation (CA) as a mainstream management option for a growing number of patients. In contrast, pharmacological treatments have been notably slow to develop and with the mainstay of therapy changing modestly only in recent times. The key to understanding the role and limitations of AF treatments is to appreciate the interplay of physiological and structural remodelling processes that occur in the setting of AF. This

review seeks to examine the implications of left atrial (LA) structure and remodelling on current and evolving treatments for AF. In particular, we will focus on the treatment implications of electrical remodelling, intrinsic anatomical factors and structural remodelling on AF management.

LA remodelling The LA is a complex entity displaying a considerable degree of physiological, electrical and anatomical plasticity in disease states. “Remodelling” refers to electrical and structural alterations to the atrial tissue leading to impairment of normal atrial

⁎ Address reprint requests to Prof Peter M. Kistler, MBBS, PhD, Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, Victoria, Australia 3004. E-mail address: [email protected] (P.M. Kistler). http://dx.doi.org/10.1016/j.pcad.2015.08.004 0033-0620/© 2015 Elsevier Inc. All rights reserved.

Please cite this article as: Prabhu S, et al. Atrial Structure and Function and its Implications for Current and Emerging Treatments for Atrial Fibrillation. Prog Cardiovasc Dis (2015), http://dx.doi.org/10.1016/j.pcad.2015.08.004

2

P R O GRE S S I N CA RDI O VAS CU L AR D I SE AS E S XX ( 2 0 15 ) XXX– X XX

Abbreviations and Acronyms 3D = 3 dimensional ACE = angiotensin converting enzyme AF = atrial fibrillation APD = action potential duration AV = atrio-ventricular CA = catheter ablation CRP = C-reactive protein CT = computer tomography CV = cardio-vascular ERP = effective refractory period HF = heart failure HTN = hypertension ITO = transient outward current (potassium) IKur = ultra-rapid delayed rectifier current ICaL = L-type Ca2+ current IKr = rapid delayed rectifier current IKs = slow delayed rectifier current IK1 = inward rectifier current IKAch = acetylcholine-activated inward rectifier current LA = left atrial, left atrium, left atria LAA = left atrial appendage LV = left ventricle, left ventricular

function. Many disease processes lead to atrial remodelling, including hypertension (HTN), valvular heart disease (VHD) and cardiomyopathy, however, remodelling in the setting of AF is of particular interest as its occurrence appears to directly impact upon disease progression and the effectiveness of treatments. Electrical remodelling encompasses the electrophysiological changes promoting AF development and maintenance. These occur via changes in: ion channel function, intracellular calcium handling, autonomic activity and intercellular electrical conduction. Structural remodelling refers to alteration in atrial tissue composition (primarily by fibrosis) generally heralding irreversible microscopic (and often macroscopic) changes and a more severe disease phenotype. Both processes are intimately related and include overlapping disease pathways.

MiRNA = micro-ribonucleic acid MRI = magnetic resonance imaging MMP = matrix-metallo proteases

Electrical remodelling in AF and implication for treatments

NAC = N-acetyl cysteine NF-κ-B = nuclear factor kappa light-chain-enhancer of activated B cells NSR = normal sinus rhythm PDGF = platelet derived growth factor PPAR = peroxisome proliferator-activated receptor

Mechanisms of electrical remodelling The mechanisms of electrical remodelling in AF are multifaceted. Electrical remodelling facilitates all three arrhythmia mechanisms: enhanced automaticity,

triggered activity and re-entry.3 Enhanced automaticity and triggered activity promote spontaneous rapid depolarisations of atrial myocytes. Re-entry is facilitated by processes which shorten atrial effective refractory period (ERP), reduce action potential duration (APD) and slow conduction velocity.4 These changes increase the period of potential excitability (excitable gap) facilitating conditions favourable for AF.5 Understanding the ionic currents involved in the normal atrial action potential is crucial to understating atrial function in AF and the potential sites for pharmacological intervention. Fig 1 provides a summary of the electrical remodelling processes occurring in AF, including summarising normal ion channel activity. Analysis of isolated human atrial myocytes demonstrates that AF leads to a reduction ICaL and Ito density, largely in response to increased intracellular calcium at rapid rates, promoting reduced APD and reduced rate response of atrial repolarisation. The inward rectifier IK1 current and IAch both display increased activity in AF at hyperpolarising potentials. These increase the excitability of atrial myocytes, promoting AF.6,7 Alterations in intracellular calcium handling have an important role in AF development and maintenance (Panel B). These result in increased intracellular Ca2+ from spontaneous sarcoplasmic reticular release of calcium via reduced ICaL activity and via RyR2 and SERCA2a altered function8 promoting triggered activity through early and delayed afterdepolarisations,7 abnormal electric–mechanical coupling9 and in ultra-structural changes and inflammatory cell and fibroblast modulation — providing an important mechanistic link between electrical and structural remodelling in AF.8

Sodium channel blockade Flecanide is a class 1C antiarrhythmic medication which initially was thought to have primary activity against fast acting sodium channels and the rapid IKr current,10 resulting in reduced conduction velocity and prolongation of APD. More recently the drug’s activity on reducing intracellular calcium load has been appreciated, which also suppresses several pro-inflammatory pathways likely impacting upon structural remodelling — perhaps explaining flecanide’s long term efficacy in AF control.11 Flecanide in AF has been evaluated in clinical trials as a short term reversion agent12 and a long term antiarrhythmic.13,14 In 3.5%–5% of cases, slowed conduction can facilitate organisation of AF to atrial flutter with the potential for 1:1 atrio-ventricular (AV) conduction and extremely rare and unstable ventricular rates.15 Furthermore, its poor specificity for atrial activity and ventricular effects has limited its use particularly in those with structural heart disease. The Cardiac Arrhythmia Suppression Trial (CAST) study identified increased mortality in patients with prior myocardial infarction and left ventricular (LV dysfunction).16 In heart failure (HF), flecanide has marked negative inotropic effects. Although flecanide remains an efficacious medication for use in AF, its lack of selectivity curtails its use in certain groups. Given the proarrhythmic potential for non-selective sodium channel blockade, efforts have been made to specifically target the atrium. AZD 1035 is a compound displaying predominately atrial sodium channel blockade. Studies

Please cite this article as: Prabhu S, et al. Atrial Structure and Function and its Implications for Current and Emerging Treatments for Atrial Fibrillation. Prog Cardiovasc Dis (2015), http://dx.doi.org/10.1016/j.pcad.2015.08.004

PR O G RE S S I N C ARDI O V A S CU L A R D I S EA S E S XX ( 2 0 1 5) XXX – XXX

PUFA = poly-unsaturated fatty acids

demonstrate that AZD1305 is able to prolong APD in the PV = pulmonary vein atria by prolonging PVI = pulmonary vein isolation initial depolarisation rate, and the post poRAAS = renin–angiotensin–aldotential refractory sterone system period.17 AZD 1035 (R)AGE = (receptor) for advanced has successfully comglycalation end-products pleted phase I safety trials. Ranolazine is RFA = radio frequency ablation already approved as RMP = resting membrane an anti-anginal agent potential with demonstrated and IKr blocking I Na ROS = reactive oxygen species capability in the caRyR2 = ryanodine receptor 2 nine model. In particular, preferential SERCA = sarcoplasmic reticulum activity upon the pulCa2+ ATP-ase monary vein (PV) tisSP = septo-pulmonary bundle sue in canine models TGF-β1 = transforming growth may explain its antifactor arrhythmic effect in preventing PV triggers TIA = transient ischaemic attack from initiating AF.18 The RAFFAELLO trial assessed the safety and efficacy of ranolazine and found some clinical benefit at higher doses although an adequately powered clinical trial is needed to clarify this.19 Recently the beneficial effect of AF suppression of combined ranolazine and dronedarone therapy was demonstrated in human trials with up to 70% reduction in AF burden in 45%–69% of patients over 12 weeks,20 suggesting a synergistic effect of both agents by optimising atrial targeting of sodium channels.21

Potassium channel blockade The IKur current is exclusively expressed in the atrial myocardium making it an attractive pharmacological target for selective atrial antiarrhythmic activity avoiding potentially proarrhythmic ventricular effects.22 A novel compound AVE0118, initially thought to have selective IKur blocking action, demonstrated AF suppression in animal models.23 The thienopyrimidine XEN-D0101 has shown more promise. Ford et al. inhibited IKur with high selectivity, and moderate activity on Ito (at higher doses). In vitro analysis demonstrated significant prolongation of APD. In healthy volunteers, there was no observable QT prolongation, suggesting negligible ventricular activity. XEN-D0101, and its related compound XEN-D0103 have progressed to Phase 1b. IKAch has potent APD abbreviating effects and is known to become constitutively active in the setting of AF.23 Similar to IKur, IKAch is predominately expressed in atrial tissue minimising ventricular effects when therapeutically targeted. Tertiapin Q (isolated from the venom of the European honey bee) is a highly selective antagonist of IAch and has demonstrated increased APD and suppression of AF in canine models.24 Several related small molecules selectively targeting IAch have been identified.25 NTC-801 displays efficacy for AF termination in rapidly paced

3

canines that is superior to flecanide and dofetilide. This compound and related compound AZD-2927 have progressed to phase II clinical trials in Japan and Europe.

Multi-channel active agents Vernakalant is a pyrrolidine compound with activity against multiple ion channels across the action potential. It predominantly acts on IKur and INa, explaining its relative atrial selectivity. Whilst IKur is expressed almost exclusively in atrial tissues, the rapid atrial depolarisation results in atrial tissue being relatively more depolarised than ventricular tissue, promoting predominantly atrial INa activity. Its activity on IKr (albeit 100 times less potent than flecanide) explains why some ventricular effects are noted, particularly in the setting of LV dysfunction and structural heart disease. It is approved for use in Europe as an intravenous acute pharmacological cardioversion agent. Its rapid onset (mean time to cardioversion of 8–14 min) makes it logistically attractive as an alternative to cardioversion. Its efficacy at rapid cardioversion in several clinical trials in conjunction with an acceptable safety profile has seen it incorporated into European AF guidelines.26 Micro-RNAs (MiRNAs) are a recently characterised novel class of short (roughly 19–25 nucleotides in length) non-coding RNA capable of mediating a myriad of intracellular processes primarily by posttranscriptional modification of gene expression. Thousands of MiRNAs have been characterised and some have been implicated in both electrical and structural remodelling associated with AF. Gaborit et al. demonstrated that the degree of upregulation of IKr activity in AF was disproportionally higher than the degree of upregulation of its coding mRNA, implicating a significant role of post transcriptional modification (regulated by miRNA) in driving potassium current phenotype. MiRNA328 has been implicated in reducing the expression of ICaL through post-transcriptional processes in the canine model,27 and has also shown to be overexpressed in patients with documented AF.28 Other miRNAs are also being evaluated and may have an exciting role in the future not only as therapeutic targets, but also as biomarkers of disease severity.29

Calcium handling in AF Diastolic calcium efflux from the sarcoplasmic reticulum is of critical importance in the ionic pathophysiology of AF (Fig 1 - Panel B). The compound JK519 promotes the binding of calstabin 2 to PKA-phosphorylated RyR2 and attenuates this diastolic leak and reduces calcium cellular overload.30 This drug is currently the focus of phase II investigative clinical trial and may have a broader role in remodelling processes given the strong overlap of calcium handling pathways in electrical and early structural remodelling.31

Neural mediated electrical remodelling Autonomic cardiac inputs are well described and originate both centrally (extrinsic) and locally (intrinsic), contain both cholinergic and adrenergic inputs and have been recently expertly reviewed by Chen et al.23 Extrinsic inputs arise from the medulla (vagal nerve) or the paravertebral ganglia (superior cervical, middle cervical and cervicothoracic or stellate ganglion). Broadly,

Please cite this article as: Prabhu S, et al. Atrial Structure and Function and its Implications for Current and Emerging Treatments for Atrial Fibrillation. Prog Cardiovasc Dis (2015), http://dx.doi.org/10.1016/j.pcad.2015.08.004

4

P R O GRE S S I N CA RDI O VAS CU L AR D I SE AS E S XX ( 2 0 15 ) XXX– X XX

parasympathetic and sympathetic inputs are mediated via the vagal nerve and stellate ganglion respectively, although considerable overlap exists.32 Intrinsic parasympathetic and sympathetic neural inputs are heavily co-localised with up to 30% having dual adrenocholanergic properties — making selective targeting of autonomic activity by localised ablation difficult. By far most intrinsic cardiac nerve complexes are located in the atria, often congregating in known arrhythmogenic ‘hot spots’ such as the PV/LA junction and have been heavily implicated in arrhythmogenesis.33 The mechanisms by which autonomic inputs promote atrial arrhythmia have been well explored and are shown in Fig 1. Kharche et al. recently evaluated the role of chronic β-blockade on electrical remodelling associated with AF in human atrial myocyte and computerised modelling. In addition to the acute neutrally medicated effects, long-term β blockade counteracted electrical remodelling by reducing the IK1 and ITO repolarising currents, resulting in APD prolongation and increased ERP. Thus whilst β-blocker therapy is clinically widely used in AF, its role in electrical remodelling has only recently been appreciated.

Remodelling and atrial conduction The large INa current, which provides electrical propagation, is generally unaffected by electrical remodelling. However, the intercellular transmission of conduction relies on the efficient, low resistant electrical coupling, which occurs via gap junctions, namely connexin 40 and 43 (the most prevalent in atrial tissue). These are located predominately in the intercalated discs, which promote longitudinal conduction over transverse conduction. Thus atrial conduction is anisotropic rather than uniform. Electrical remodelling has been implicated in processes resulting in slowed and heterogeneous conduction promoting conditions favourable for re-entry (Fig 1). Recently a murine model with a loss of function mutations in connexin 40, adapted from mutations described in humans with AF, demonstrated a predisposition to sustained AF.34 In addition to gap junction function, disruption of normal myofilament architecture by structural remodelling processes also promotes slowed conduction. The experimental peptide rotigaptide (ZP123) is a selective gap junction modifier, which enables increased inter-cellular ion transmission facilitating increased conduction velocity. A small peptide, GAP134, demonstrated improved conduction and reduced AF induction in in-vitro and canine models, in addition to a favourable pharmacokinetic profile with high oral bioavailability. This drug has successfully completed Phase I trial development. Gene therapy is another experimental treatment utilising connexin activity to improve atrial conduction and reduce AF. Igarahi et al. utilised adenoviruses expressing connexin 40 or 43 as gene transfer vectors to increase gap junction expression following epicardial painting in a swine model. In transfected swine with AF, connexin 43 and 40 were maintained at sinus rhythm levels with preserved atrial conduction and reduced AF.

Clinical importance of electrical remodelling in AF treatment Although electrical remodelling almost always regresses in the absence of ongoing tachycardia stimulus, AF sustainabil

ity persists, highlighting the role of structural remodelling in maintaining AF.35 The Flec-SL trial randomised patients with persistent AF post successful cardioversion to no therapy, 4 weeks (short term) or 6 months (long term) of flecanide. Given the reversibility of electrical remodelling, antiarrhythmic therapy beyond an initial 4 week period was hypothesised to have little impact upon prevention of recurrence. In fact, whilst both treatment groups were superior to no therapy, long-term therapy had significantly less recurrence highlighting the likely role of factors other than electrical remodelling in AF. 13

Anatomical considerations and implications for AF treatments Before exploring the crucial role of structural remodelling it is worth appreciating the structural aspects of the LA, and its implications on AF development and treatment. The advent of CA for AF, which by its very nature requires an intimate navigation around the LA endocardium, has significantly advanced our anatomical and electrophysiological understanding of LA structure and function. Nonetheless, despite this detailed biological characterisation of the LA, significant debate still exists about the fundamental mechanisms driving and sustaining AF in various clinical phenotypes.

PV isolation (PVI)/AF ablation Given that CA is an established treatment for AF with efficacy consistently superior to medical therapy, 36,37 an overview of the procedure is warranted. The cornerstone of the AF ablation is electrical isolation of the PVs by the targeted deployment of radiofrequency (essentially heat energy) ablation (RFA) lesions around the PV Ostia; CA is performed percutaneously via endovascular catheters. An ablation catheter and multi-electrode catheter are placed in the LA via fluoroscopically (and often ultrasound) guided transeptal puncture. Catheter location and navigation are guided by three dimensional (3D) mapping systems capable of visually displaying the catheters in a computerised 3D atrial shell generated by surface contact information in pre-procedural computed tomography (CT) or magnetic resonance imaging (MRI). This facilitates catheter manipulation with minimal need for X ray. A circular multi-polar catheter is advanced into each PV to monitor PV electrical activity to ensure that electrical dissociation is achieved following ablation. Recently cryo-tipped inflatable balloons have been utilised to rapidly deliver circumferential hypothermic injury around the PV ostia to facilitate more rapid PVI, with similar efficacy to radiofrequency energy although with a different adverse effect profile.38 Significant variations in practice may occur based on institution or operator preference. In addition to PVI, further lesions or lines of block may be delivered for the purposes of additional substrate modification (in persistent AF), or in the process of mapping and ablating other atrial macro-re-entrant or focal tachyarrythmias — although the optimal approach here remains the focus of considerable debate.

Please cite this article as: Prabhu S, et al. Atrial Structure and Function and its Implications for Current and Emerging Treatments for Atrial Fibrillation. Prog Cardiovasc Dis (2015), http://dx.doi.org/10.1016/j.pcad.2015.08.004

PR O G RE S S I N C ARDI O V A S CU L A R D I S EA S E S XX ( 2 0 1 5) XXX – XXX

5

Fig 1 – The interplay of processes contributing to electrical remodelling in AF. Panel A: Ionic remodelling. The bar graph indicates the ionic currents active during the atrial myocyte action potential. Green bars indicate inward current, red bars outward current. Panels B and C highlight the processes in calcium processing and inter-cell electrical coupling respectively. The green boxes highlight the various pharmacological strategies and their site of action against electrical remodelling. Abbreviations: APD = action potential duration, ERP = effective refractory period, RMP = resting membrane potential, TO = transient outward, IKur = ultra-rapid delayed rectifier current, ICaL = L-type Ca2+ current, IKr = rapid delayed rectifier current, IKs = slow delayed rectifier current, IK1 = inward rectifier current, IKAch = acetylcholine-activated inward rectifier current, RyR2 = ryanadine receptor 2, SERCA = sarcoplasmic reticulum clacium-ATP-ase.

LA and PV anatomy relevant to AF ablation (Fig 2) The PVs have been shown to play a crucial role in the development of ectopic foci capable of initiating AF in the susceptible atrium.39,40 Post mortem studies of patients both with and without a history of AF showed more atrial myocardial extensions into the PVs, which were also more likely to be discontinuous in patients with AF.41 Interestingly, the length of extensions appeared greater in the upper PVs compared to the lower veins consistent with the finding that these veins are more likely to trigger AF.40 Furthermore, the pulmonary veins were associated with intercellular fibrosis and myocyte hypertrophy, each extending a variable distance both proximally and distally from the pulmonary vein ostia.41 In addition the sharp transition in fibre orientation in the vicinity of the pulmonary veins may intrinsically promote conditions for re-entry by virtue of high tissue anisotropy.42 The dense neural inputs in the region of the PV/LA junction and their contribution to arrhythmogenesis in AF have been described above. These intrinsic anatomical and structural features promote rapid electrical and structural remodelling even in the settings of considerably modest AF burdens (such as ‘lone’ AF).43–45 Myocardial fibres along the intervenous ridges may be associated with epicardial connections

facilitating PV–LA connections across an apparent circumferential line of block.46 In addition, the left lateral ridge [also known as the LA appendage (LAA/PV ridge)] which divides the anterior region of the left PVs and the LAA, has been well described as a highly arrhythmogenic region. The oblique vein of Marshall runs along the epicardial region of the ridge and carries with it a myriad of autonomic neural bundles with important implications for arryhthmogenesis. Furthermore, dense muscular connections between the upper ridge and left superior PVs may be important conduits for PV triggers to initiate AF.47 Beyond the PVs, the septo-pulmonary bundle provides another substrate for AF by virtue of sudden alterations in atrial thickness particularly along its boundaries.48 These anatomical challenges impact the approach to AF ablation. Given the degree of arrhythmogenic substrates in close proximity to the PV/LA ostia, a significant development in AF ablation strategy is the delivery of a progressively wider (or more antral) circumferential ablation line in order to encompass a larger proportion of this potentially arrhythmogenic substrate, as well as minimising the potential for PV stenosis — a recognised complication of ostial (also termed segmental) PV ablation. However, results have been somewhat mixed. A recent meta-analysis of ostial versus wide

Please cite this article as: Prabhu S, et al. Atrial Structure and Function and its Implications for Current and Emerging Treatments for Atrial Fibrillation. Prog Cardiovasc Dis (2015), http://dx.doi.org/10.1016/j.pcad.2015.08.004

6

P R O GRE S S I N CA RDI O VAS CU L AR D I SE AS E S XX ( 2 0 15 ) XXX– X XX

circumferential ablation strategies showed a markedly improved freedom from AF recurrence in the wide ablation group.49 A recent multicentre study by our group has demonstrated that pulmonary veins requiring ablation along the intervenous ridge to achieve isolation were often associated with higher AF recurrence post ablation.50 Anatomical variations in PV anatomy may also have important implications for long term procedural success.51 PV reconnection is the most common cause for recurrent AF post ablation and is regarded as the ‘Achilles heel’ of AF ablation. Gaps in the ablation line facilitating PV/LA reconnection may be due to: (1) inadequate (sub-transmural) lesion formation,52 (2) pseudo-block at the time of isolation presumably due to temporary peri-lesional oedema inactivating viable tissues capable of facilitating conduction52 or (3) as a consequence of tissue remodelling.53 A relatively recent development in AF ablation is the use of intravenous bolus doses of adenosine to unmask dormant conduction in the PVs in order to identify acute reconnection. This technique utilises unique electrophysiological properties of the PVs and ablated atrial tissue to transiently establish conduction so that residual gaps can be identified and targeted for further ablation. Initial data regarding the routine use of adenosine during AF ablation following acute PVI have been mixed. Initially, the identification of dormant PV conduction predicted a greater likelihood of recurrence even when eliminated with further ablation.54 However, a recently published prospective randomised trial concluded that elimination of dormant conduction identified with adenosine conferred an overall 14% improvement in procedural success.55 This result suggests that routine adenosine usage may have a role in standard AF ablation practice.

LAA structure and function and thromboembolic implications The importance of appropriate thromboembolic prophylaxis in patients with AF who meet current guideline based criteria cannot be over emphasised. Crucially, it should be considered separate to the attempts to control or otherwise manage rhythm as multiple studies have consistently shown that a significant stroke rate exists for patients with one or more stroke risk factors (as identified by the CHA2DS2-VASc score 56) regardless of a rate or rhythm control strategy. 57 Echocardiographic measures of LAA function have been commonly used to evaluate for thrombus, and features such as LV dysfunction, LA dimensions and LAA flow velocity have correlated with thrombus detection but their value over standard clinical risk factors is unclear.58 In a novel approach, Di Biase and colleagues recently evaluated the thrombogenic implications of LAA structure and morphology in predicting thromboembolic events in patients with AF undergoing AF ablation. Utilising CT and MRI assessment of LAA morphology, LAA anatomy was classified into 4 types based on appearance: cactus, chicken wing, windsock, and cauliflower. The chicken wing morphology was associated with the lowest incidence of stroke/TIA with the other morphologies carrying 4–8 fold increased thrombo-emboli risk.59

Structural remodelling (Fig 3) Structural remodelling refers to alterations in the tissue architecture of the LA at both a cellular and macroscopic level the hallmark of which is atrial fibrosis, however inflammation and LA mechanical factors also play a role.

Atrial fibrosis Whilst the association of atrial fibrosis and AF (and particularly more established forms of AF) is well established, opinions differ regarding the direct causal relationship between atrial fibrosis and AF.60 Atrial fibrosis promotes the development of AF by causing alterations to the electrical properties, such as heterogeneous conduction slowing,61 and creating a substrate capable of sustaining re-entry and more likely to develop and sustain AF.62–64 Other studies suggest that AF itself can precipitate atrial fibrosis as demonstrated by rapid atrial pacing canine models,65 and the presence of atrial fibrosis at autopsy in patients with structural heart disease and yet no AF.66 These discrepancies in findings complicate our understanding of structural remodelling and its implications for AF management. In addition, the relationship (causal or otherwise) of fibrosis quantity, type and distribution to various AF phenotypes remains unclear.65

Mechanisms of atrial fibrosis and implications for treatment Angiotensin (Ang) II and renin–angiotensin–aldosterone system (RAAS). Ang II mediates profibrotic changes via several mechanisms including alteration of gap junctions,67 the promotion of collagen deposition68 and the development of reactive oxygen species and free radical mediated cell injury and fibrosis in murine models. Ang II is also implicated in electrical remodelling, promoting increased density of calcium channels through a variety of intracellular signalling pathways. Murine models with overexpression of angiotensin converting enzyme (ACE) and increased levels of angiotensin II (Ang II) demonstrate areas of focal atrial fibrosis, atrial dilatation, myocyte apoptosis and hypertrophy and slowed conduction.69 The promising effects of RAAS blockade in vitro and in animal models of fibrosis have not directly translated to compelling clinical use solely for the treatment of AF.69 A meta-analysis of 14 randomised trials including over 90,000 patients investigated the role of RAAS inhibition in preventing new onset AF; Ang II receptor blockade demonstrated a significant benefit (RR = 0.78, p = 0.009), although no benefit was evident for ACE inhibitor or aldosterone antagonist therapy. The benefit was most notable in those with HF, suggesting that in part the benefit may be the result of favourable ventricular remodelling rather than a true anti-fibrotic effect.70 The Losartan Intervention for Endpoint Reduction study evaluated outcomes in patients with HTN treated with losartan or atenolol and found reduced incidence (RR = 0.67, p < 0.001) of new-onset AF despite equivalent blood pressure reduction in patients in the losartan arm, although again ventricular reverse remodelling may have played a role.71 The ANTIPAF and J-RHYTHM trials evaluated the effects

Please cite this article as: Prabhu S, et al. Atrial Structure and Function and its Implications for Current and Emerging Treatments for Atrial Fibrillation. Prog Cardiovasc Dis (2015), http://dx.doi.org/10.1016/j.pcad.2015.08.004

PR O G RE S S I N C ARDI O V A S CU L A R D I S EA S E S XX ( 2 0 1 5) XXX – XXX

of olmesartan and candesartan, respectively, on AF burden in patients with no structural heart disease, and found no significant benefit in atrial remodelling or AF reduction.72,73 Aldosterone antagonists are alternative approaches to RAAS inhibition by counteracting aldosterone, which has wide ranging pro-fibrotic and pro-remodelling properties.74 Aldosterone levels are increased in humans with AF.75 The beneficial effects on atrial fibrosis and electrical remodelling have been demonstrated in animal models of tachycardia-induced remodelling.76,77 In the EMPHASIS-HF study-evaluating patients with mild HF, randomisation to elperenone was associated with reduced incidence of new onset AF (2.7% vs 4.5%, HR = 0.58, p = 0.034).78 A non-randomised study evaluating the effects of eplerenone in 106 patients with long standing persistent AF (continuous AF duration for greater than 1 year) undergoing ablation found that eplerenone use significantly improved freedom from AF in long term follow-up.75 We await the outcome of further clinical studies to further understand the role of routine aldosterone antagonist use in the AF patient population.

Transforming growth factor-beta 1 (TGF-β1). TGF-β1 is primarily a down stream mediator of Ang II activity and promotes fibrotic remodelling by stimulating collagen production, although other mediators such as matrix metalloprotease (MMP)-2, MMP-9, plasmin and other oxygen reactive species have also been known to promote TGF-β1 release. In the heart it promotes myocyte hypertrophy and extra cellular matrix deposition.79 In cardiac remodelling, the atrial specificity of its activity is quite marked. A transgenic murine model overexpressing TGF-β1 demonstrated atrial specific fibrosis and increased propensity to AF.64,80 Pirfenidone is an orally active anti-fibrotic agent known to suppress the production of TGF-β1, in addition to a number of other pro-fibrotic pathways,81 with demonstrated clinical efficacy in pulmonary fibrosis.82 Pirfenidone has shown a reduction in multiple pro-fibrotic and inflammatory mediators in rat and canine models in addition to reduced LA fibrosis, increased conduction velocity and reduced AF vulnerability.83 Tranilast is another antifibrotic agent capable of suppressing TGF-β1 activity. Animal models have demonstrated a suppression of atrial remodelling and AF inducibility.84,85 To date no clinical data utilising these drugs for AF in humans have been published. Platelet derived growth factor (PDGF). PDGF is an important mitogen for mesenchymal cells (such as fibroblasts and smooth muscle cells) implicating it in processes involved in structural atrial remodelling.86 In-vitro analysis also demonstrated a role in electrical remodelling by reducing the density of ICaL. In both models, the fibrotic and electrical remodelling effects were reversed in the presence of a blocking monoclonal antibody.87 Whilst biological agents capable of selectively targeting isoforms of PDGF exist for use in varying neoplastic conditions, to date their potential clinical role in AF treatment has not been explored. Peroxisome proliferator-activated receptor (PPAR-γ).

Recently the role of PPAR-γ activation in atrial fibrosis has been appreciated as an important down regulator of several

7

pro-inflammatory and pro-fibrotic pathways by inhibition of transcription factors which act via interaction with nuclear factor kappa light-chain-enhancer of activated B cells (NF-κB) in macrophages and neutrophils. PPAR-γ activation is also involved in increasing the expression of molecules involved in anti-oxidant processes.88 Pioglitazone is a clinically available agonist of the PPAR-γ receptor and has been investigated in animal models89,90 in which it suppresses the activity of TGF-β1 and other mediators implicated in atrial fibrosis. Recently the related drug rosiglitazone was shown to have effects on atrial remodelling on AF development in a diabetic rabbit model.91 Lin et al. demonstrated that circulating levels of the endogenous agonist of PPAR-γ receptor agonist (PPAR-γ receptor protein) are decreased in elderly patients with AF compared to aged matched controls. Gu et al. investigated the effects of pioglitazone in 150 non-randomised patients with AF and type 2 diabetes undergoing AF ablation. Patients receiving pioglitazone had significantly higher single procedural long-term freedom from AF (86% vs 70%, p = 0.034) and much lower rates of repeat AF ablation.92 Further studies are required to evaluate the routine use of pioglitazone in the AF population.

Inflammation and oxidative stress in atrial structural remodelling Recently, the role of inflammation in AF has been increasingly appreciated and investigated. Several systemic markers of inflammation, such as interleukin (IL)-2, IL-6, IL-8, monocyte chemoattractant protein (MCP)-1, C-reactive protein (CRP) and tumor necrosis factor-α have been associated with pro-inflammatory activities of leukocytes. A bilateral causative relationship exists between AF and inflammation. Goldstein et al. found that AF was inducible in a sterile canine pericarditis model displaying atrial inflammation, which attenuated with steroid treatment of the inflammation.93 Clinically, post-operative cardiac patients who developed AF were more likely to have elevated CRP levels.94 In a longitudinal cohort study, the presence of elevated inflammatory mediators independently predicted the incidence of AF over a 14 year follow-up period.95 Marcus et al. demonstrated a reduction in pre-procedural IL-6 and CRP levels post atrial flutter ablation, suggesting that the arrhythmia was driving the inflammatory process. Statins have a recognised anti-inflammatory role independent of their cholesterol lowering ability.96 A recent meta-analysis examining 20 randomised studies involving 23,577 patients found that statin therapy significantly reduced rates of AF (OR = 0.34, 95% CI:0.18–0.64, p < 0.001), although this benefit was limited to simvastatin and atorvastatin, with no benefit shown with pravastatin or rosuvastatin. An increased magnitude of benefit was noted in the secondary prevention population rather than the primary prevention population.97 The Oxidative Stress Injury and Effect of Statins (PAFRIOSIES) trial is a prospective randomised trial aiming to test the hypothesis that statins prevent AF recurrences (ClinicalTrials.gov Identifier: NCT00321802). Four clinical trials investigating the prevention of post-operative AF with atorvastatin showed a benefit in the reduction of early postoperative AF.98,99

Please cite this article as: Prabhu S, et al. Atrial Structure and Function and its Implications for Current and Emerging Treatments for Atrial Fibrillation. Prog Cardiovasc Dis (2015), http://dx.doi.org/10.1016/j.pcad.2015.08.004

8

P R O GRE S S I N CA RDI O VAS CU L AR D I SE AS E S XX ( 2 0 15 ) XXX– X XX

Fig 2 – The interplay of factors impacting upon the overall procedural success of AF ablation. Abbreviations: HF = heart failure, SP = septo-pulmonary, LAA = left atrial appendage, PV = pulmonary vein, LA = left atrium.

Receptor for advanced glycalation end products (RAGE) The RAGE axis mediates a complex array of pro-oxidation and pro-inflammatory pathways in the hyperglycaemic environment when advanced glycalation end products (AGEs) accumulate and stimulate RAGE receptors. These mechanisms have been implicated in the pathogenesis of AF by promoting atrial fibrosis by the generation of IL-6 and TNF-α, in addition to other roles.100 Furthermore, AGE/RAGE interaction leads to activation of the transcription factor NF-κB which may mediate cell apoptosis — a process inhibited by N-acetyl cysteine (NAC).101 In this regard, NAC has been evaluated as a therapeutic option for the prevention of AF in the post cardiac surgery setting, where post-operative inflammation is thought to be a key driver AF. A recent meta-analysis including 10 studies and 1026 patients concluded that prophylactic NAC significantly reduced post-operative AF (OR = 0.56, 95%CI: 0.40–0.77, p < 0.001) and was somewhat surprisingly associated with a lower all cause mortality.102 The role of NAC beyond the postoperative population is yet to be evaluated.

Oxidative stress Oxidative stress is an important pathway implicated in both structural and electrical remodelling in AF.103 Oxidative stress refers to the generation of reactive oxygen species, which mediate a multitude of downstream inflammatory processes. In AF, there is increased activity in the enzymes implicated in ROS generation. Downstream effects are complex and incompletely understood, but are known to affect calcium handling and TGF-β1.104 Antioxidant treatments such as poly unsaturated fatty acids such as omega 3 fatty acids had initially shown some promise in the prevention of post operative AF,105 however, subsequent larger trials have failed to demonstrate a

benefit.106,107 Other potential therapies targeting this pathway are being investigated.104

Atrial stretch Mechanism of remodelling associated with chronic atrial stretch Atrial stretch and dilation are adaptive processes by the LA to haemodynamic stressors such as AF, HTN, VHD, LV dysfunction or other structural lesions which may induce elevated cardiac filling pressure. Physical processes that contribute to atrial stretch trigger a constellation of remodelling mechanisms, leading to structural and electrical remodelling of the LA (Fig 3). First, atrial dilatation is an obvious consequence of atrial stretch due to increased wall tension. However, animal models suggest that the degree and rapidity of atrial dilatation are related more to the presence of LV dysfunction or rapid ventricular rates rather than rapid atrial pacing alone.108 Alterations in calcium handling appear to be the primary consequence of atrial stretch.109 Second, myocyte hypertrophy occurs in response to atrial stretch largely driven by RAAS mediators, as localised stretch increases the production of local ACE110 and can facilitate activity of Ang II type 1 receptor in the absence of Ang II. In stretch remodelling associated with LV remodelling, systemic activation of the RAAS is likely to also play a role. Third, stretch can induce atrial fibrosis possibly mediated by plasma endothelin 1 (ET-1), which is known to upregulate MMP2 activity, promoting collagen deposition.111 Last, atrial stretch can induce remodelling by activation of pro-inflammatory pathways and by facilitating oxidative stress, both of which can promote fibrosis as described previously. Given the multitude of overlapping processes contributing to atrial electrical and structural remodelling, Sanders et al. investigated the contribution of atrial stretch to these processes by electrophysiologically evaluating the left atrium

Please cite this article as: Prabhu S, et al. Atrial Structure and Function and its Implications for Current and Emerging Treatments for Atrial Fibrillation. Prog Cardiovasc Dis (2015), http://dx.doi.org/10.1016/j.pcad.2015.08.004

PR O G RE S S I N C ARDI O V A S CU L A R D I S EA S E S XX ( 2 0 1 5) XXX – XXX

9

Fig 3 – The complex interplay of physiological processed involved in structural remodelling in AF. Abbreviations: ACE = angiotensin converting enzyme, PUFA = poly-unsaturated fatty acids, (R)AGE = (Receptor) for advanced glycalation end-products, PPAR = peroxisome proliferator-activated receptor, TGF = transforming growth factor, NF-Kappa-B = nuclear factor kappa light-chain-enhancer of activated B cells.

in the dilated atria in 21 patients pre and post percutaneous balloon mitral commissurotomy for severe mitral stenosis. They identified progressive improvements in P wave duration, conduction velocity, global voltage and atrial ERP, highlighting the contribution and reversibility of atrial stretch to atrial remodelling.112 LA diameter, a traditional albeit crude measurement of LA size, has been shown to correlate with AF recurrence in large population cohort studies. In a post hoc analysis of the AFFIRM trial, LA diameter > 4.1 cm predicted recurrence in a cohort of patients with mixed treatment strategies (i.e., both rate and rhythm control).113 A similar analysis looking specifically at the post-cardioversion population suggested that LA diameter > 4.5 cm was predictive of requiring > 2 cardioversion attempts, however the sensitivity and specificity of this measure were poor, suggesting that the clinical utility of this measurement was low.114 A LA volume index (LAVI) < 30 mL/m2 has also been shown to correlate with increased AF recurrence post cardioversion.115 Older studies had suggested that in the setting of amiodarone therapy, LA dimensions may not significantly predict AF outcomes. However, these studies may have preferentially selected patients prone to recurrence, and assessments of LA dimensions at that stage (with primarily M-mode echocardiography) were likely crude at best.116 Apart from predicting AF, LA diameter has been independently associated with ischaemic stroke in women, and increased all cause mortality in all patients, including those without AF, although whether this represents an

independent risk factor or merely non-diagnosed subclinical AF remains unclear.117 Several studies have shown a predictive value of LA size on outcomes post CA. A meta-analysis of 22 studies and 3750 patients found that LA diameter as measured by echocardiography predicted single procedure success in a predominately paroxysmal patient population.118 Von Bary et al. evaluated the predictive potential of LA dimensions as measured by other non-invasive imaging techniques such as CT and MRI, often routine pre-procedural imaging. These modalities offer a detailed 3D assessment of atrial volume and reasonable correlation with each other, while echocardiography may underestimate LA volume.119 Additionally, LA volume did not necessarily predict recurrence post AF ablation, although it did predict progression to persistent AF in those patients who did develop recurrence.120 Amin et al. evaluated the correlation between CT derived LA volume and the outcomes in patients with persistent AF undergoing AF ablation. Patients with persistent AF had larger LA volumes at baseline, and LA volume appeared predictive of recurrence at 12 months but this did not reach statistical significance.121 The strong overlap between LA size and the concurrent presence of other remodelling processes, to a degree, may explain this finding. Furthermore, the ‘multiple wavelet’ hypothesis of AF mechanisms (which is not universally accepted) suggests that a critical mass of atrial tissue is required to sustain AF. Atrial dilatation makes this more likely by increasing the endocardial surface area, promoting multiple wavelets in the setting of appropriate AF triggers.122 Further prospective randomised

Please cite this article as: Prabhu S, et al. Atrial Structure and Function and its Implications for Current and Emerging Treatments for Atrial Fibrillation. Prog Cardiovasc Dis (2015), http://dx.doi.org/10.1016/j.pcad.2015.08.004

10

P R O GRE S S I N CA RDI O VAS CU L AR D I SE AS E S XX ( 2 0 15 ) XXX– X XX

Fig 4 – The interplay of factors impacting upon thrombogenesis in AF. Images adapted with permission from Di Biase et al. (2012) JACC 60(6); 531–8.

Implications of structural remodelling in AF treatment

enhancement of the atrial wall by cardiac MRI, can predict stroke,128 LAA thrombus, and spontaneous echo contrast129 despite the location of fibrosis well beyond the LAA, suggesting that the role of LA remodelling in thrombogenesis is incompletely understood.

Thromboembolic complications of AF

Limitations in detecting structural remodelling

The contribution of these inflammatory and fibrotic processes to creating the prothrombotic environment of AF has also been appreciated (Fig 4). Elevated inflammatory markers in patients with chronic AF have been independently associated with stroke risk.123 Inflammatory processes may promote thrombogenesis by promoting endothelial dysfunction, and platelet activation which can promote thrombosis, and the release of other inflammatory mediators.124 Inflammatory cells, through the action of various cytokines and chemokines, mediate thrombus development via direct stimulation of coagulation factors.125 Soluble CD40 ligand (SCD40L) from activated platelets is a potent mediator of thrombotic processes and has been independently associated with increased stroke risk,126 and remains elevated for weeks following cardioversion, highlighting the importance of adequate anticoagulation in the pericardioversion period. The LAA is primarily the location of thrombosis in AF, although interatrial septal thrombus has been described in valvular AF.127 Interestingly, the relatively widespread distribution of structural remodelling processes seems contradictory to the relatively location specific formation of thrombus in AF. Indeed, recent evidence suggests that atrial fibrosis as estimated by late gadolinium

A significant limitation to our understanding is the poor capacity to characterise the degree and distribution of atrial fibrosis in the living substrate. Current techniques to image atrial fibrosis utilise MRI and include late gadolinium enhancement of the atrial wall and T1 mapping. Whilst the former allows spatial identification of fibrosis and correlates well with voltage mapping,130 it is limited by image quality, uncertain reproducibility131,132 and a high degree of operator dependence,133 due to the thinness and hence limited resolution of the atrial wall. T1 mapping has been correlated with atrial scar detected by voltage mapping129 and to clinical outcomes following AF ablation,134 however, it is limited in spatial resolution – requiring a regional assessment of atrial areas – and has yet to be validated histologically. Both essentially assume the presence of fibrosis based on extra-cellular volume expansion. Targeted or molecular imaging seeks to directly target areas of fibrosis by facilitating the direct binding of contrast agent (gadolinium or positron emission tomographic tracer) to areas of fibrosis. This technique has been demonstrated in animal ventricular models135 and its role in detecting atrial fibrosis and remodelling is a subject of ongoing research.

studies need to be performed to evaluate the predictive potential of LA dimensions in AF ablation.

Please cite this article as: Prabhu S, et al. Atrial Structure and Function and its Implications for Current and Emerging Treatments for Atrial Fibrillation. Prog Cardiovasc Dis (2015), http://dx.doi.org/10.1016/j.pcad.2015.08.004

PR O G RE S S I N C ARDI O V A S CU L A R D I S EA S E S XX ( 2 0 1 5) XXX – XXX

Direct incorporation of spatial fibrosis data into exiting 3D mapping systems may help guide ablation procedures and improve outcome in the future.

Structural remodelling and AF ablation Structural remodelling has procedural implications which impact outcomes for AF ablations. These are particularly relevant in persistent AF ablation, in which the atrial substrate beyond the pulmonary veins is implicated in sustaining AF. Existing substrate modification strategies have shown mixed results, and consistently poorer long term outcomes compared with ablation of paroxysmal AF.136 A recent multi-centre randomised controlled trial (STAR2-AF) examining long term outcomes of the three ablative strategies found no difference in freedom from AF compared to PVI alone.137 The optimal approach to substrate modification in persistent AF remains unknown.

Structural remodelling in AF and LV dysfunction The population of patients with concurrent AF and LV dysfunction warrants special consideration with respect to LA structural remodelling, as hidden prevalence of arrhythmia mediated cardiomyopathy in this patient population is increasingly appreciated. In large part, this clinical situation arises from the inter-related causal relationship between the two conditions — with the pathophysiology of each condition capable of driving the other (Fig 2). LV dysfunction is associated with significant atrial remodelling, even in the absence of documented AF, in both animal138 and human models,139 with evidence of both electrical and structural remodelling. However, there is significant evidence that AF in itself can cause HF through various mechanisms including tachycardia, irregular ventricular contraction, loss of atrial contractile function and tachycardia induced valvular dysfunction.140 Experiences in humans with focal atrial tachycardia, which is often readily amenable to curative ablation, show progressive reverse remodelling of LV and LA dimensions after restoration of normal sinus rhythm (NSR).141 Unfortunately, given the significant overlap in the prevalence of both conditions (estimated at 20%–35%)140 a significant proportion of patients will present with both conditions and the value of rhythm control in this patient group can be difficult to determine. Recently, the superior efficacy of AF ablation over amiodarone (the most effective medical rhythm control agent) as a tool for the long-term maintenance of NSR in 203 patients with LV dysfunction has been shown in a large prospective international randomised trial with 70% compared to 34% freedom from AF at 3 years in the ablation arm compared to the amiodarone arm.142 In this regard, several prospective single centre studies have demonstrated improvements in LV ejection fraction in patients with LV dysfunction and HF,143,144 including demonstrating an improvement in LA dimensions in those patients who maintained NSR.145 Evidence from animal models suggests that this improvement may be driven by improvement in LV end diastolic pressure as LV function improves, with a positive feedback mechanism driving LA reverse remodelling.146 Identifying the optimal patient population with AF and LV dysfunction remains an unmet challenge in this area, although the advent of new imaging technologies may have a role.

11

Structural remodelling and the impact of risk factor modification Recently, attention has returned to risk factor modification in AF and its effect on atrial structure and function. The Aggressive Risk Factor Reduction Study for Atrial Fibrillation and Implications for the Outcome of Ablation (ARREST-AF Cohort Study)147 highlighted the importance of concurrent risk factor modification in the post ablation setting. In particular, The Long-Term Effect of Goal-Directed Weight Management in an Atrial Fibrillation Cohort A Long-Term Follow-Up Study (LEGACY) looked at the role of aggressive weight loss in patients with AF and BMI >27 kg/m2. Weight reduction resulted in improved AF control and a startling reduction in LA size in a dose dependent manner with a greater than 10% reduction from baseline body weight incurring the most benefit. These trials reinforce the critical role of aggressive risk factor control, especially weight reduction, in controlling AF with measurable impact upon LA structure and function.148

Conclusion Atrial structure and function have direct implications for the management of AF. Electrical remodelling results in a multitude of complex physiological changes, which create conditions favourable to AF development and sustainment. The identification of key molecular pathways improves our understanding of AF mechanisms, and may also provide opportunities for the development of novel pharmacological therapies, of which more are sorely needed. Intrinsic anatomical aspects of the LA have an increasingly appreciated impact upon CA as it evolves as a mainstream treatment for AF. Structural remodelling heralds a more advanced and complex process involving fibrosis and inflammation and may potentiate permanent changes to atrial structure, complicating the effectiveness of existing treatments, both pharmacological and interventional. Nonetheless, evolving treatments may have a role in this regard in the future. The importance of concurrent risk factor management and non-pharmacological non-interventional strategies has recently been re-emphasised, and should continue to have a central place in the overall management approach to AF.

Statement of Conflict of Interest The authors have no conflicts of interest to disclose.

Acknowledgments Drs Sandeep Prabhu, Alex JA McLellan and Tomos E Walters receive funding from Australian National Health and Medical Research Council (NHMRC) and National Heart Foundation of Australia. Drs Sandeep Prabhu and Alex JA McLellan also receive funding from the Baker IDI Heart and Diabetes Research Institute. Professor M Kistler is supported by practitioner fellowships from the NHMRC. Drs Meenal Sharma and Alex Voskoboinik have no disclosures. This research is supported in part by the Victorian Government’s Operational Infrastructure Funding. All authors have reported no financial relationships to disclose.

Please cite this article as: Prabhu S, et al. Atrial Structure and Function and its Implications for Current and Emerging Treatments for Atrial Fibrillation. Prog Cardiovasc Dis (2015), http://dx.doi.org/10.1016/j.pcad.2015.08.004

12

P R O GRE S S I N CA RDI O VAS CU L AR D I SE AS E S XX ( 2 0 15 ) XXX– X XX

REFERENCES

1. Chugh SS, Havmoeller R, Narayanan K, et al. Worldwide epidemiology of atrial fibrillation: a global burden of disease 2010 study. Circulation. 2014;129:837-847. 2. Wolowacz SE, Samuel M, Brennan VK, Jasso-Mosqueda JG, Van Gelder IC. The cost of illness of atrial fibrillation: a systematic review of the recent literature. Europace. 2011;13:1375-1385. 3. Wakili R, Voigt N, Kaab S, Dobrev D, Nattel S. Recent advances in the molecular pathophysiology of atrial fibrillation. J Clin Invest. 2011;121:2955-2968. 4. Krogh-Madsen T, Abbott GW, Christini DJ. Effects of electrical and structural remodeling on atrial fibrillation maintenance: a simulation study. PLoS Comput Biol. 2012;8:e1002390. 5. Nattel S, Burstein B, Dobrev D. Atrial remodeling and atrial fibrillation: mechanisms and implications. Circ Arrhythm Electrophysiol. 2008;1:62-73. 6. Bosch RF, Zeng X, Grammer JB, Popovic K, Mewis C, Kühlkamp V. Ionic mechanisms of electrical remodeling in human atrial fibrillation. Cardiovasc Res. 1999;44:121-131. 7. Grandi E, Pandit SV, Voigt N, et al. Human atrial action potential and Ca2 + model: sinus rhythm and chronic atrial fibrillation. Circ Res. 2011;109:1055-1066. 8. Nattel S, Dobrev D. The multidimensional role of calcium in atrial fibrillation pathophysiology: mechanistic insights and therapeutic opportunities. Eur Heart J. 2012;33:1870-1877. 9. Schotten U. Electrical and contractile remodeling during the first days of atrial fibrillation go hand in hand. Circulation. 2003;107:1433-1439. 10. Wang Z, Pagé P, Nattel S. Mechanism of flecainide's antiarrhythmic action in experimental atrial fibrillation. Circ Res. 1992;71:271-287. 11. Iwai T, Tanonaka K, Inoue R, et al. Sodium accumulation during ischemia induces mitochondrial damage in perfused rat hearts. Cardiovasc Res. 2002;55:141-149. 12. Alp N, Bell J, Shahi M. Randomised double blind trial of oral versus intravenous flecainide for the cardioversion of acute atrial fibrillation. Heart. 2000;84:37-40. 13. Kirchhof P, Andresen D, Bosch R, et al. Short-term versus long-term antiarrhythmic drug treatment after cardioversion of atrial fibrillation (FLEC-SL): a prospective, randomised, open-label, blinded endpoint assessment trial. Lancet. 2012;380:238-246. 14. Gulizia M, Mangiameli S, Orazi S, et al. A randomized comparison of amiodarone and class IC antiarrhythmic drugs to treat atrial fibrillation in patients paced for sinus node disease: the Prevention Investigation and Treatment: A Group for Observation and Research on Atrial Arrhythmias (PITAGORA) trial. Am Heart J. 2008;155:100-107. [107 e101]. 15. Falk RH. Proarrhythmia in patients treated for atrial fibrillation or flutter. Ann Intern Med. 1992;117:141-150. 16. Greene HL, Roden DM, Katz RJ, Woosley RL, Salerno DM, Henthorn RW. The cardiac arrhythmia suppression trial: first cast … then cast-ii. J Am Coll Cardiol. 1992;19:894-898. 17. Burashnikov A, Zygmunt AC, Di Diego JM, Linhardt G, Carlsson L, Antzelevitch C. Azd1305 exerts atrial predominant electrophysiological actions and is effective in suppressing atrial fibrillation and preventing its reinduction in the dog. J Cardiovasc Pharmacol. 2010;56:80-90. 18. Sicouri S, Glass A, Belardinelli L, Antzelevitch C. Antiarrhythmic effects of ranolazine in canine pulmonary vein sleeve preparations. Heart Rhythm. 2008;5:1019-1026. 19. De Ferrari GM, Maier LS, Mont L, et al. Ranolazine in the treatment of atrial fibrillation: results of the dose-ranging RAFFAELLO (Ranolazine in Atrial Fibrillation Following An ELectrical CardiOversion) study. Heart Rhythm. 2015;12: 872-878.

20. Kowey PR, Reiffel JA, John Camm A, et al. Lb03–05: the effect of the combination of ranolazine and low dose dronedarone on atrial fibrillation burden in patients with paroxysmal atrial fibrillation (HARMONY trial). Heart Rhythm 35th Annual Scientific Sessions presented 10th May 2014; 2014. 21. Burashnikov A, Sicouri S, Di Diego JM, Belardinelli L, Antzelevitch C. Synergistic effect of the combination of ranolazine and dronedarone to suppress atrial fibrillation. J Am Coll Cardiol. 2010;56:1216-1224. 22. Carlsson L, Duker G, Jacobson I. New pharmacological targets and treatments for atrial fibrillation. Trends Pharmacol Sci. 2010;31:364-371. 23. Chen PS, Chen LS, Fishbein MC, Lin SF, Nattel S. Role of the autonomic nervous system in atrial fibrillation: pathophysiology and therapy. Circ Res. 2014;114:1500-1515. 24. Cha TJ, Ehrlich JR, Chartier D, Qi XY, Xiao L, Nattel S. Kir3-based inward rectifier potassium current: potential role in atrial tachycardia remodeling effects on atrial repolarization and arrhythmias. Circulation. 2006;113:1730-1737. 25. Tanaka H, Hashimoto N. A multiple ion channel blocker, NIP-142, for the treatment of atrial fibrillation. Cardiovasc Drug Rev. 2007;25:342-356. 26. Savelieva I, Graydon R, Camm AJ. Pharmacological cardioversion of atrial fibrillation with vernakalant: evidence in support of the ESC guidelines. Europace. 2014;16:162-173. 27. Lu Y, Zhang Y, Wang N, et al. Microrna-328 contributes to adverse electrical remodeling in atrial fibrillation. Circulation. 2010;122:2378-2387. 28. McManus DD, Lin H, Tanriverdi K, et al. Relations between circulating micrornas and atrial fibrillation: data from the Framingham offspring study. Heart Rhythm. 2014;11:663-669. 29. Maan A, Mansour M, McManus DD, et al. Novel therapeutic targets in the management of atrial fibrillation. Am J Cardiovasc Drugs. 2014;14:403-421. 30. Sacherer M, Sedej S, Wakula P, et al. JTV519 (K201) reduces sarcoplasmic reticulum Ca(2)(+) leak and improves diastolic function in vitro in murine and human non-failing myocardium. Br J Pharmacol. 2012;167:493-504. 31. Dincer UD. Cardiac ryanodine receptor in metabolic syndrome: is JTV519 (K201) future therapy? Diabetes Metab Syndr Obes. 2012;5:89-99. 32. Onkka P, Maskoun W, Rhee KS, et al. Sympathetic nerve fibers and ganglia in canine cervical vagus nerves: localization and quantitation. Heart Rhythm. 2013;10:585-591. 33. Tan AY, Li H, Wachsmann-Hogiu S, Chen LS, Chen PS, Fishbein MC. Autonomic innervation and segmental muscular disconnections at the human pulmonary vein-atrial junction: implications for catheter ablation of atrial-pulmonary vein junction. J Am Coll Cardiol. 2006;48: 132-143. 34. Lubkemeier I, Andrie R, Lickfett L, et al. The connexin40a96s mutation from a patient with atrial fibrillation causes decreased atrial conduction velocities and sustained episodes of induced atrial fibrillation in mice. J Mol Cell Cardiol. 2013;65:19-32. 35. Wijffels MCEF, Kirchhof CJHJ, Dorland R, Allessie MA. Atrial fibrillation begets atrial fibrillation: a study in awake chronically instrumented goats. Circulation. 1995;92: 1954-1968. 36. Noheria A, Kumar A, Wylie Jr JV, Josephson ME. Catheter ablation vs antiarrhythmic drug therapy for atrial fibrillation: a systematic review. Arch Intern Med. 2008;168: 581-586. 37. Shi LZ, Heng R, Liu SM, Leng FY. Effect of catheter ablation versus antiarrhythmic drugs on atrial fibrillation: a meta-analysis of randomized controlled trials. Exp Ther Med. 2015;10:816-822.

Please cite this article as: Prabhu S, et al. Atrial Structure and Function and its Implications for Current and Emerging Treatments for Atrial Fibrillation. Prog Cardiovasc Dis (2015), http://dx.doi.org/10.1016/j.pcad.2015.08.004

PR O G RE S S I N C ARDI O V A S CU L A R D I S EA S E S XX ( 2 0 1 5) XXX – XXX

38. Bhat T, Baydoun H, Asti D, et al. Major complications of cryoballoon catheter ablation for atrial fibrillation and their management. Expert Rev Cardiovasc Ther. 2014;12:1111-1118. 39. Rostock T, Steven D, Lutomsky B, et al. Atrial fibrillation begets atrial fibrillation in the pulmonary veins on the impact of atrial fibrillation on the electrophysiological properties of the pulmonary veins in humans. J Am Coll Cardiol. 2008;51:2153-2160. 40. Haïssaguerre M, Jaïs P, Shah DC, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med. 1998;339:659-666. 41. Hassink RJ, Aretz HT, Ruskin J, Keane D. Morphology of atrial myocardium in human pulmonary veins. J Am Coll Cardiol. 2003;42:1108-1114. 42. Aslanidi OV, Colman MA, Varela M, et al. Heterogeneous and anisotropic integrative model of pulmonary veins: computational study of arrhythmogenic substrate for atrial fibrillation. Interface Focus. 2013;3:20120069. 43. Hafid KA, Xin HC, Xi W, Yan ZQ, Bo Y. Difference between electrical remodelling after pulmonary veins and right atrium appendage pacing. Europace. 2007;9:608-612. 44. Jaïs P, Hocini M, Macle L, et al. Distinctive electrophysiological properties of pulmonary veins in patients with atrial fibrillation. Circulation. 2002;106:2479-2485. 45. Stiles MK, John B, Wong CX, et al. Paroxysmal lone atrial fibrillation is associated with an abnormal atrial substrate: characterizing the "second factor". J Am Coll Cardiol. 2009;53: 1182-1191. 46. McLellan AJA, Ling L-H, Azzopardi S, et al. A minimal or maximal ablation strategy to achieve pulmonary vein isolation for paroxysmal atrial fibrillation: a prospective multi-centre randomized controlled trial (the Minimax study). 2015. 47. Cabrera JA, Ho SY, Climent V, Sanchez-Quintana D. The architecture of the left lateral atrial wall: a particular anatomic region with implications for ablation of atrial fibrillation. Eur Heart J. 2008;29:356-362. 48. Klos M, Calvo D, Yamazaki M, et al. Atrial septopulmonary bundle of the posterior left atrium provides a substrate for atrial fibrillation initiation in a model of vagally mediated pulmonary vein tachycardia of the structurally normal heart. Circ Arrhythm Electrophysiol. 2008;1:175-183. 49. Proietti R, Santangeli P, Di Biase L, et al. Comparative effectiveness of wide antral versus ostial pulmonary vein isolation: a systematic review and meta-analysis. Circ Arrhythm Electrophysiol. 2014;7:39-45. 50. Cabrera JA, Ho SY, Climent V, Fuertes B, Murillo M, Sánchez-Quintana D. Morphological evidence of muscular connections between contiguous pulmonary venous orifices: relevance of the interpulmonary isthmus for catheter ablation in atrial fibrillation. Heart Rhythm. 2009;6:1192-1198. 51. McLellan AJA, Ling L-h, Ruggiero D, et al. Pulmonary vein isolation: the impact of pulmonary venous anatomy on long-term outcome of catheter ablation for paroxysmal atrial fibrillation. Heart Rhythm. 2014;6:549-556. 52. Kowalski M, Grimes MM, Perez FJ, et al. Histopathologic characterization of chronic radiofrequency ablation lesions for pulmonary vein isolation. J Am Coll Cardiol. 2012;59: 930-938. 53. McGarry TJ, Narayan SM. The anatomical basis of pulmonary vein reconnection after ablation for atrial fibrillation: wounds that never felt a scar? J Am Coll Cardiol. 2012;59:939-941. 54. McLellan AJ, Kumar S, Smith C, Morton JB, Kalman JM, Kistler PM. The role of adenosine following pulmonary vein isolation in patients undergoing catheter ablation for atrial

55.

56.

57. 58.

59.

60.

61.

62.

63.

64.

65.

66.

67.

68.

69.

70.

71.

13

fibrillation: a systematic review. J Cardiovasc Electrophysiol. 2013;24:742-751. Macle L, Khairy P, Weerasooriya R, et al. Lb01–02— adenosine-guided pulmonary vein isolation for the treatment of atrial fibrillation: results of the prospective multicenter randomized advice trial. Late breaking clinical trials I presented 8th May 2015Heart Rhythm 35th Annual Scientific Sessions; 2014. Lip GYH, Halperin JL. Improving stroke risk stratification in atrial fibrillation. The American Journal of Medicine. 2010;123: 484-488. Lip GY, Lane DA. Stroke prevention in atrial fibrillation: a systematic review. JAMA. 2015;313:1950-1962. Ayirala S, Kumar S, O'Sullivan DM, Silverman DI. Echocardiographic predictors of left atrial appendage thrombus formation. J Am Soc Echocardiogr. 2011;24:499-505. Di Biase L, Santangeli P, Anselmino M, et al. Does the left atrial appendage morphology correlate with the risk of stroke in patients with atrial fibrillation? Results from a multicenter study. J Am Coll Cardiol. 2012;60:531-538. Kumar S, Teh AW, Medi C, Kistler PM, Morton JB, Kalman JM. Atrial remodeling in varying clinical substrates within beating human hearts: relevance to atrial fibrillation. Prog Biophys Mol Biol. 2012;110:278-294. Krul SP, Berger WR, Smit NW, et al. Atrial fibrosis and conduction slowing in the left atrial appendage of patients undergoing thoracoscopic surgical pulmonary vein isolation for atrial fibrillation. Circ Arrhythm Electrophysiol. 2015;8: 288-295. Kottkamp H. Human atrial fibrillation substrate: towards a specific fibrotic atrial cardiomyopathy. Eur Heart J. 2013;34: 2731-2738. Luo MH, Li YS, Yang KP. Fibrosis of collagen I and remodeling of connexin 43 in atrial myocardium of patients with atrial fibrillation. Cardiology. 2007;107:248-253. Verheule S, Sato T, Everett Tt, et al. Increased vulnerability to atrial fibrillation in transgenic mice with selective atrial fibrosis caused by overexpression of TGF-beta1. Circ Res. 2004;94:1458-1465. Burstein B, Nattel S. Atrial fibrosis: mechanisms and clinical relevance in atrial fibrillation. J Am Coll Cardiol. 2008;51: 802-809. de Oliveira IM, Oliveira BD, Scanavacca MI, Gutierrez PS. Fibrosis, myocardial crossings, disconnections, abrupt turns, and epicardial reflections: do they play an actual role in human permanent atrial fibrillation? A controlled necropsy study. Cardiovasc Pathol. 2013;22:65-69. Schorb W, Conrad KM, Singer HA, Dostal DE, Baker KM. Angiotensin II is a potent stimulator of map-kinase activity in neonatal rat cardiac fibroblasts. J Mol Cell Cardiol. 1995;27: 1151-1160. Okada M, Yamawaki H, Hara Y. Angiotensin II enhances interleukin-1beta-induced MMP-9 secretion in adult rat cardiac fibroblasts. J Vet Med Sci. 2010;72:735-739. Ehrlich JR, Hohnloser SH, Nattel S. Role of angiotensin system and effects of its inhibition in atrial fibrillation: clinical and experimental evidence. Eur Heart J. 2006;27: 512-518. Khatib R, Joseph P, Briel M, Yusuf S, Healey J. Blockade of the renin–angiotensin–aldosterone system (RAAS) for primary prevention of non-valvular atrial fibrillation: a systematic review and meta analysis of randomized controlled trials. Int J Cardiol. 2013;165:17-24. Nattel S. Can losartan prevent new-onset atrial fibrillation in hypertensive patients more effectively than atenolol? Nat Clin Pract Cardiovasc Med. 2005;2:332-333.

Please cite this article as: Prabhu S, et al. Atrial Structure and Function and its Implications for Current and Emerging Treatments for Atrial Fibrillation. Prog Cardiovasc Dis (2015), http://dx.doi.org/10.1016/j.pcad.2015.08.004

14

P R O GRE S S I N CA RDI O VAS CU L AR D I SE AS E S XX ( 2 0 15 ) XXX– X XX

72. Goette A, Schon N, Kirchhof P, et al. Angiotensin II-antagonist in paroxysmal atrial fibrillation (ANTIPAF) trial. Circ Arrhythm Electrophysiol. 2012;5:43-51. 73. Yamashita T, Inoue H, Okumura K, et al. Randomized trial of angiotensin II-receptor blocker vs. dihydropiridine calcium channel blocker in the treatment of paroxysmal atrial fibrillation with hypertension (J-RHYTHM II study). Europace. 2011;13:473-479. 74. Korantzopoulos P, Goudevenos JA. Aldosterone signaling in atrial fibrillation another piece in the puzzle of atrial remodeling. J Am Coll Cardiol. 2010;55:771-773. 75. Ito Y, Yamasaki H, Naruse Y, et al. Effect of eplerenone on maintenance of sinus rhythm after catheter ablation in patients with long-standing persistent atrial fibrillation. Am J Cardiol. 2013;111:1012-1018. 76. Shroff SC, Ryu K, Martovitz NL, Hoit BD, Stambler BS. Selective aldosterone blockade suppresses atrial tachyarrhythmias in heart failure. J Cardiovasc Electrophysiol. 2006;17: 534-541. 77. Zhao J, Li J, Li W, et al. Effects of spironolactone on atrial structural remodelling in a canine model of atrial fibrillation produced by prolonged atrial pacing. Br J Pharmacol. 2010;159: 1584-1594. 78. Swedberg K, Zannad F, McMurray JJ, et al. Eplerenone and atrial fibrillation in mild systolic heart failure: results from the EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization And Survival Study in Heart Failure) study. J Am Coll Cardiol. 2012;59:1598-1603. 79. Dobaczewski M, Chen W, Frangogiannis NG. Transforming growth factor (TGF)-beta signaling in cardiac remodeling. J Mol Cell Cardiol. 2011;51:600-606. 80. Nakajima H, Nakajima HO, Salcher O, et al. Atrial but not ventricular fibrosis in mice expressing a mutant transforming growth factor-1 transgene in the heart. Circ Res. 2000;86:571-579. 81. Macias-Barragan J, Sandoval-Rodriguez A, Navarro-Partida J, Armendariz-Borunda J. The multifaceted role of pirfenidone and its novel targets. Fibrogenesis Tissue Repair. 2010;3:16. 82. King TE, Bradford WZ, Castro-Bernardini S, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:2083-2092. 83. Ma J, Ma S, Ding C. Gw25-e2383 pirfenidone prevents atrial fibrillation in atrial fibrosis rats. J Am Coll Cardiol. 2014;64. 84. Thanigaimani S, Lau DH, Brooks AG, et al. Abstract 18013: tranilast prevents hypertensive atrial electrical and structural remodeling independent of systolic blood pressure level: a comparative study with blood pressure lowering therapies. Circulation. 2014;130:A18013. 85. Nakatani Y, Nishida K, Sakabe M, et al. Tranilast prevents atrial remodeling and development of atrial fibrillation in a canine model of atrial tachycardia and left ventricular dysfunction. J Am Coll Cardiol. 2013;61:582-588. 86. Liao CH, Akazawa H, Tamagawa M, et al. Cardiac mast cells cause atrial fibrillation through pdgf-a-mediated fibrosis in pressure-overloaded mouse hearts. J Clin Invest. 2010;120: 242-253. 87. Musa H, Kaur K, O'Connell R, et al. Inhibition of platelet-derived growth factor-AB signaling prevents electromechanical remodeling of adult atrial myocytes that contact myofibroblasts. Heart Rhythm. 2013;10:1044-1051. 88. Xu D, Murakoshi N, Igarashi M, et al. Ppar-gamma activator pioglitazone prevents age-related atrial fibrillation susceptibility by improving antioxidant capacity and reducing apoptosis in a rat model. J Cardiovasc Electrophysiol. 2012;23: 209-217. 89. Shimano M, Tsuji Y, Inden Y, et al. Pioglitazone, a peroxisome proliferator-activated receptor-gamma activator,

90.

91.

92.

93.

94.

95.

96.

97.

98.

99.

100.

101.

102.

103.

104.

105.

106.

attenuates atrial fibrosis and atrial fibrillation promotion in rabbits with congestive heart failure. Heart Rhythm. 2008;5: 451-459. Takahashi N, Kume O, Wakisaka O, et al. Novel strategy to prevent atrial fibrosis and fibrillation. Circ J. 2012;76: 2318-2326. Liu T, Zhao H, Li J, Korantzopoulos P, Li G. Rosiglitazone attenuates atrial structural remodeling and atrial fibrillation promotion in alloxan-induced diabetic rabbits. Cardiovasc Ther. 2014;32:178-183. Gu J, Liu X, Wang X, et al. Beneficial effect of pioglitazone on the outcome of catheter ablation in patients with paroxysmal atrial fibrillation and type 2 diabetes mellitus. Europace. 2011;13:1256-1261. Goldstein RN, Ryu K, Khrestian C, van Wagoner DR, Waldo AL. Prednisone prevents inducible atrial flutter in the canine sterile pericarditis model. J Cardiovasc Electrophysiol. 2008;19: 74-81. Lo B, Fijnheer R, Nierich AP, Bruins P, Kalkman CJ. C-reactive protein is a risk indicator for atrial fibrillation after myocardial revascularization. Ann Thorac Surg. 2005;79:1530-1535. Conen D, Ridker PM, Everett BM, et al. A multimarker approach to assess the influence of inflammation on the incidence of atrial fibrillation in women. Eur Heart J. 2010;31: 1730-1736. Antonopoulos AS, Margaritis M, Lee R, Channon K, Antoniades C. Statins as anti-inflammatory agents in atherogenesis: molecular mechanisms and lessons from the recent clinical trials. Curr Pharm Des. 2012;18:1519-1530. Fang WT, Li HJ, Zhang H, Jiang S. The role of statin therapy in the prevention of atrial fibrillation: a meta-analysis of randomized controlled trials. Br J Clin Pharmacol. 2012;74:744-756. Lertsburapa K, White CM, Kluger J, Faheem O, Hammond J, Coleman CI. Preoperative statins for the prevention of atrial fibrillation after cardiothoracic surgery. J Thorac Cardiovasc Surg. 2008;135:405-411. Patti G, Chello M, Candura D, et al. Randomized trial of atorvastatin for reduction of postoperative atrial fibrillation in patients undergoing cardiac surgery: Results of the armyda-3 (atorvastatin for reduction of myocardial dysrhythmia after cardiac surgery) study. Circulation. 2006;114: 1455-1461. Kato T, Yamashita T, Sekiguchi A, et al. Ages-rage system mediates atrial structural remodeling in the diabetic rat. J Cardiovasc Electrophysiol. 2008;19:415-420. Yamagishi S, Inagaki Y, Okamoto T, et al. Advanced glycation end product-induced apoptosis and overexpression of vascular endothelial growth factor and monocyte chemoattractant protein-1 in human-cultured mesangial cells. J Bio Chem. 2002;277:20309-20315. Liu X-H, Xu C-Y, Fan G-H. Efficacy of n-acetylcysteine in preventing atrial fibrillation after cardiac surgery: a meta-analysis of published randomized controlled trials. BMC Cardiovasc Disord. 2014;14:52-60. Korantzopoulos P, Kolettis T, Siogas K, Goudevenos J. Atrial fibrillation and electrical remodeling: the potential role of inflammation and oxidative stress. Med Sci Monit. 2003;9: RA225-229. Woods CE, Olgin J. Atrial fibrillation therapy now and in the future: drugs, biologicals, and ablation. Circ Res. 2014;114: 1532-1546. Calo L, Bianconi L, Colivicchi F, et al. N-3 fatty acids for the prevention of atrial fibrillation after coronary artery bypass surgery: A randomized, controlled trial. J Am Coll Cardiol. 2005;45:1723-1728. Mozaffarian D, Marchioli R, Macchia A, et al. Fish oil and postoperative atrial fibrillation: the Omega-3 Fatty Acids for

Please cite this article as: Prabhu S, et al. Atrial Structure and Function and its Implications for Current and Emerging Treatments for Atrial Fibrillation. Prog Cardiovasc Dis (2015), http://dx.doi.org/10.1016/j.pcad.2015.08.004

PR O G RE S S I N C ARDI O V A S CU L A R D I S EA S E S XX ( 2 0 1 5) XXX – XXX

107.

108.

109.

110.

111.

112.

113.

114.

115.

116.

117.

118.

119.

120.

121.

122.

Prevention of Post-operative Atrial Fibrillation (OPERA) randomized trial. JAMA. 2012;308:2001-2011. Macchia A, Grancelli H, Varini S, et al. Omega-3 fatty acids for the prevention of recurrent symptomatic atrial fibrillation: results of the forward (randomized trial to assess efficacy of PUFA for the maintenance of sinus rhythm in persistent atrial fibrillation) trial. J Am Coll Cardiol. 2013;61:463-468. Schoonderwoerd BA, Ausma J, Crijns HJGM, et al. Atrial ultrastructural changes during experimental atrial tachycardia depend on high ventricular rate. J Cardiovasc Electrophysiol. 2004;15:1167-1174. Leistad E, Aksnes G, Verburg E, Christensen G. Atrial contractile dysfunction after short-term atrial fibrillation is reduced by verapamil but increased by BAY K8644. Circulation. 1996;93:1747-1754. Liang F, Gardner DG. Autocrine/paracrine determinants of strain-activated brain natriuretic peptide gene expression in cultured cardiac myocytes. J Biol Chem. 1998;273:14612-14619. Mayyas F, Niebauer M, Zurick A, et al. Association of left atrial endothelin-1 with atrial rhythm, size, and fibrosis in patients with structural heart disease. Circ Arrhythm Electrophysiol. 2010;3:369-379. John B, Stiles MK, Kuklik P, et al. Reverse remodeling of the atria after treatment of chronic stretch in humans: implications for the atrial fibrillation substrate. J Am Coll Cardiol. 2010;55:1217-1226. Olshansky B, Heller EN, Mitchell LB, et al. Are transthoracic echocardiographic parameters associated with atrial fibrillation recurrence or stroke? Results from the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study. J Am Coll Cardiol. 2005;45:2026-2033. Raitt MH, Volgman AS, Zoble RG, et al. Prediction of the recurrence of atrial fibrillation after cardioversion in the atrial fibrillation follow-up investigation of rhythm management (affirm) study. Am Heart J. 2006;151:390-396. Akdemir B, Altekin RE, Kucuk M, et al. The significance of the left atrial volume index in cardioversion success and its relationship with recurrence in patients with non-valvular atrial fibrillation subjected to electrical cardioversion: A study on diagnostic accuracy. Anadolu Kardiyol Derg. 2013;13:18-25. Gold RL, Haffajee CI, Charos G, Sloan K, Baker S, Alpert JS. Amiodarone for refractory atrial fibrillation. Am J Cardiol. 1986;57:124-127. Bouzas-Mosquera A, Broullon FJ, Alvarez-Garcia N, et al. Left atrial size and risk for all-cause mortality and ischemic stroke. CMAJ. 2011;183:E657-664. Zhuang J, Wang Y, Tang K, et al. Association between left atrial size and atrial fibrillation recurrence after single circumferential pulmonary vein isolation: a systematic review and meta-analysis of observational studies. Europace. 2012;14:638-645. Boyd AC, Thomas L. Left atrial volumes: two-dimensional, three-dimensional, cardiac magnetic resonance and computed tomography measurements. Curr Opin Cardiol. 2014;29: 408-416. von Bary C, Dornia C, Eissnert C, et al. Predictive value of left atrial volume measured by non-invasive cardiac imaging in the treatment of paroxysmal atrial fibrillation. J Interv Card Electrophysiol. 2012;34:181-188. Amin V, Finkel J, Halpern E, Frisch DR. Impact of left atrial volume on outcomes of pulmonary vein isolation in patients with non-paroxysmal (persistent) and paroxysmal atrial fibrillation. Am J Cardiol. 2013;112:966-970. Qu Z. Critical mass hypothesis revisited: role of dynamical wave stability in spontaneous termination of cardiac fibrillation. Am J Physiol Heart Circ Physiol. 2006;290:H255-H263.

15

123. Conway DS, Buggins P, Hughes E, Lip GY. Relationship of interleukin-6 and c-reactive protein to the prothrombotic state in chronic atrial fibrillation. J Am Coll Cardiol. 2004;43: 2075-2082. 124. Kamath S, Blann AD, Chin BSP, et al. A study of platelet activation in atrial fibrillation and the effects of antithrombotic therapy. Eur Heart J. 2002;23:1788-1795. 125. Guo Y, Lip GY, Apostolakis S. Inflammation in atrial fibrillation. J Am Coll Cardiol. 2012;60:2263-2270. 126. Ferro D, Loffredo L, Polimeni L, et al. Soluble cd40 ligand predicts ischemic stroke and myocardial infarction in patients with nonvalvular atrial fibrillation. Aterioscler Throm Vasc Biol. 2007;27:2763-2768. 127. Gurudevan SV, Shah H, Tolstrup K, Siegel R, Krishnan SC. Septal thrombus in the left atrium: is the left atrial septal pouch the culprit? J Am Coll Cardiol Img. 2010;3:1284-1286. 128. Mahnkopf C, Mitlacher M, Brachmann J. The degree of left atrial fibrosis as a potential risk factor for stroke: lessons learned from cardiac MRI. J Am Coll Cardiol. 2015;65:A1180. 129. Beinart R, Khurram IM, Liu S, et al. Cardiac magnetic resonance T1 mapping of left atrial myocardium. Heart Rhythm. 2013;10:1325-1331. 130. Ravanelli D, EC dal Piaz, Centonze M, et al. A novel skeleton based quantification and 3-D volumetric visualization of left atrium fibrosis using late gadolinium enhancement magnetic resonance imaging. IEEE Trans Med Imaging. 2014;33:566-576. 131. Bois JP, Glockner J, Sheldon S, et al. Left atrial delayed enhancement by MRI is not associated with occurrence or type of atrial fibrillation: a single-center experience. J Am Coll Cardiol. 2013;61:E403. 132. Sramko M, Peichl P, Wichterle D, et al. Clinical value of assessment of left atrial late gadolinium enhancement in patients undergoing ablation of atrial fibrillation. Int J Cardiol. 2015;179:351-357. 133. Vijayakumar S, Kholmovski EG, Haslam MM, Burgon N, Marrouche NF. Dependence of image quality of late gadolinium enhancement MRI of left atrium on number of patients imaged: results of multi-center trial DECAAF. J Cardiovasc Magn Reson. 2014;16:P146. 134. McLellan A, Ling L, Ellims A, et al. Diffuse atrial fibrosis measured by T1 mapping on cardiac MRI predicts success of atrial fibrillation ablation. Heart Lung Circ. 2013;22. 135. de Haas HJ, Arbustini E, Fuster V, Kramer CM, Narula J. Molecular imaging of the cardiac extracellular matrix. Circ Res. 2014;114:903-915. 136. Scherr D, Khairy P, Miyazaki S, et al. Five-year outcome of catheter ablation of persistent atrial fibrillation using termination of atrial fibrillation as a procedural endpoint. Circ Arrhythm Electrophysiol. 2014;8:18-24. 137. Verma A, Jiang CY, Betts TR, et al. Approaches to catheter ablation for persistent atrial fibrillation. N Engl J Med. 2015;372:1812-1822. 138. O'Brien DW, Fu Y, Parker HR, et al. Differential morphometric and ultrastructural remodelling in the left atrium and left ventricle in rapid ventricular pacing-induced heart failure. Can J Cardiol. 2000;16:1411-1419. 139. Sanders P, Morton JB, Davidson NC, et al. Electrical remodeling of the atria in congestive heart failure: electrophysiological and electroanatomic mapping in humans. Circulation. 2003;108:1461-1468. 140. Anter E, Jessup M, Callans DJ. Atrial fibrillation and heart failure: treatment considerations for a dual epidemic. Circulation. 2009;119:2516-2525. 141. Peters KG, Kienzle MG. Severe cardiomyopathy due to chronic rapidly conducted atrial fibrillation: complete recovery after restoration of sinus rhythm. Am J Med. 1988;85:242-244.

Please cite this article as: Prabhu S, et al. Atrial Structure and Function and its Implications for Current and Emerging Treatments for Atrial Fibrillation. Prog Cardiovasc Dis (2015), http://dx.doi.org/10.1016/j.pcad.2015.08.004

16

P R O GRE S S I N CA RDI O VAS CU L AR D I SE AS E S XX ( 2 0 15 ) XXX– X XX

142. Di Biase Luigi, Mohanty Prasant, Mohanty Sanghamitra, et al. Ablation vs. amiodarone for treatment of atrial fibrillation in patients with congestive heart failure and an implanted ICD/CRTD (AATAC-AF in heart failure). [Internet]ClinicalTrials.gov. Bethesda (MD): National Librbary of Medicine (US). 2015. [[cited 2015 Jun 9). Available from: http://clinicaltrials.gov/show/NCT00729911 NLM Identifier:NCT00729911. 2015]. 143. Anselmino M, Matta M, D'Ascenzo F, et al. Catheter ablation of atrial fibrillation in patients with left ventricular systolic dysfunction: A systematic review and meta-analysis. Circ Arrhythm Electrophysiol. 2014;7:1011-1018. 144. Hunter RJ, Berriman TJ, Diab I, et al. A randomized controlled trial of catheter ablation versus medical treatment of atrial fibrillation in heart failure (the CAMTAF trial). Circ Arrhythm Electrophysiol. 2014;7:31-38.

145. Efremidis M, Sideris A, Xydonas S, et al. Ablation of atrial fibrillation in patients with heart failure: Reversal of atrial and ventricular remodelling. Hellenic J Cardiol. 2007;48: 19-25. 146. De Jong AM, Van Gelder IC, Vreeswijk-Baudoin I, Cannon MV, Van Gilst WH, Maass AH. Atrial remodeling is directly related to enddiastolic left ventricular pressure in a mouse model of ventricular pressure overload. Plos One. 2013;8, e72651. 147. Pathak RK, Middeldorp ME, Lau DH, et al. Aggressive risk factor reduction study for atrial fibrillation and implications for the outcome of ablation: the ARREST-AF cohort study. J Am Coll Cardiol. 2014;64:2222-2231. 148. Pathak RK, Middeldorp ME, Meredith M, et al. Long-term effect of goal-directed weight management in an atrial fibrillation cohort: a long-term follow-up study (LEGACY). J Am Coll Cardiol. 2015;65:2159-2169.

Please cite this article as: Prabhu S, et al. Atrial Structure and Function and its Implications for Current and Emerging Treatments for Atrial Fibrillation. Prog Cardiovasc Dis (2015), http://dx.doi.org/10.1016/j.pcad.2015.08.004