REVIEW

Catheter Ablation of Atrial Fibrillation: An Overviewfor Clinicians

Nebojsa Mujovic . Milan Marinkovic . Radoslaw Lenarczyk .

Roland Tilz . Tatjana S. Potpara

Received: June 12, 2017 / Published online: July 21, 2017� The Author(s) 2017. This article is an open access publication

ABSTRACT

Catheter ablation (CA) of atrial fibrillation (AF)is currently one of the most commonly per-formed electrophysiology procedures. Ablationof paroxysmal AF is based on the elimination oftriggers by pulmonary vein isolation (PVI),while different strategies for additional AF sub-strate modification on top of PVI have beenproposed for ablation of persistent AF. Nowa-days, various technologies for AF ablation are

available. The radiofrequency point-by-pointablation navigated by electro-anatomical map-ping system and cryo-balloon technology arecomparable in terms of the efficacy and safety ofthe PVI procedure. Long-term success of AFablation including multiple procedures variesfrom 50 to 80%. Arrhythmia recurrences com-monly occur, mostly due to PV reconnection.The recurrences are particularly common inpatients with non-paroxysmal AF, dilated leftatrium and the ‘‘early recurrence’’ of AF withinthe first 2–3 post-procedural months. In addi-tion, this complex procedure can be accompa-nied by serious complications, such as cardiactamponade, stroke, atrio-esophageal fistula andPV stenosis. Therefore, CA represents a sec-ond-line treatment option after a trial ofantiarrhythmic drug(s). Good candidates for theprocedure are relatively younger patients withsymptomatic and frequent episodes of AF, withno significant structural heart disease and nosignificant left atrial enlargement. Randomizedtrials demonstrated the superiority of ablationcompared to antiarrhythmic drugs in terms ofimproving the quality of life and symptoms inAF patients. However, nonrandomized studiesreported additional clinical benefits from abla-tion over drug therapy in selected AF patients,such as the reduction of the mortality andstroke rates and the recovery of tachyarrhyth-mia-induced cardiomyopathy. Future researchshould enable the creation of more durableablative lesions and the selection of the optimal

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N. Mujovic (&) � M. Marinkovic � T. S. Potpara (&)Cardiology Clinic, Clinical Center of Serbia,Visegradska 26, Belgrade, Serbiae-mail: nmujovic@gmail.com

T. S. Potparae-mail: tatjana.potpara@med.bg.ac.rs

N. Mujovic � T. S. PotparaSchool of Medicine, University of Belgrade, DrSubotica 8, Belgrade, Serbia

R. LenarczykDepartment of Cardiology, Congenital HeartDisease and Electrotherapy, Silesian Centre for HeartDiseases, Silesian Medical University, Zabrze, Poland

R. TilzMedical Clinic II (Cardiology/Angiology/IntensiveCare Medicine), University HospitalSchleswig-Holstein, University Heart Center Lubeck,Zabrze, Poland

Adv Ther (2017) 34:1897–1917

DOI 10.1007/s12325-017-0590-z

lesion set in each patient according to thedegree of atrial remodeling. This could providebetter long-term CA success and expand indi-cations for the procedure, especially among thepatients with non-paroxysmal AF.

Keywords: Atrial fibrillation; Catheterablation; Interventional cardiology; Pulmonaryvein isolation; Stroke; Substrate modification

INTRODUCTION

The incidence and prevalence of atrial fibrilla-tion (AF) are progressively increasing because ofaging of the population, the higher prevalence ofknown AF risk factors in older people and betterstrategies for arrhythmia detection [1]. Thepresence of AF is associated with a 1.5–2-foldincrease in death and heart failure (HF) and5-fold increase in the rates of stroke and systemicthromboembolism [2, 3]. In addition, AF cansignificantly reduce quality of life (QoL) andexercise tolerance because of limiting symptoms[1–3]. Catheter ablation (CA) is superior toantiarrhythmic drug (AAD) therapy in patientswith paroxysmal (PAF) and persistent AF (PeAF)[4]. The number of AF ablation procedures in thelast decade grew exponentially, and indicationsfor the procedure are increasingly expanding;hence, AF-CA has become the most commonlyperformed ablation procedure [5].

However, the success of AF ablation is lim-ited and depends largely on the patient’s clini-cal characteristics [2, 3, 6]. Optimal selection ofpatients for AF-CA is important to avoidexposing the patients with low chances forlong-term sinus rhythm maintenance to aninvasive procedure and to refer those whowould benefit from AF ablation for AF-CA[1–3, 6]. In this article, we present an overviewof the basic technical aspects of the AF-CAprocedure and long-term results of the proce-dure and discuss the optimal selection of AFpatients for CA as well as an adequate follow-upstrategy and drug therapy after this complexprocedure.

This article is based on previously conductedstudies and does not involve any new studies of

human or animal subjects performed by any ofthe authors.

CATHETER ABLATION PROCEDURE

Set of Ablation Lesions

The initiation and maintenance of an AF epi-sode are caused by a complex interaction ofthe arrhythmia triggers, atrial substrate andthe autonomic nervous system activity [2, 3].The triggers are primarily responsible for thePAF, but with progression from paroxysmal topersistent arrhythmia, an atrial substrateassumes a dominant role in sustaining AF[2, 3, 7].

Although the optimal set of ablation lesionshas not been identified yet, it depends primarilyon the clinical type of AF [2, 3]. In patients withPAF, the procedure is directed toward the elimi-nation (isolation) of AF triggers, while in non-PAFpatients many operators proceed with a supple-mentary modification of the AF substrate, on topof trigger elimination, to improve the procedureoutcome [3, 8–13]. For patients with long-stand-ing PeAF, the success of multiple ablation proce-dures based solely on the pulmonary veinisolation (PVI) strategy was less than 50% during a5-year follow-up [14]. However, the STAR AF IIstudy recently failed to demonstrate superiority ofadjuvant ablation strategies compared to PVIalone in patients with PeAF [15]. This multicenterstudy randomized patients to three ablationstrategies: PVI alone, PVI ? complex fractionatedatrial electrogram ablation (CFAE) and PVI ? leftatrial (LA) lines, and after 18 months of follow-up,the rate of freedom from AF (with or withoutAADs) was 59, 49 and 46%, respectively, and afterredo ablation in patients with clinical recurrencethere was still no significant difference in finalarrhythmia outcome [15]. Obviously, using anyset of lesions as a routine ablation strategy willlead to over- or under-treatment in a significantproportion of AF patients. Therefore, the optimalablation strategy should be individually adjustedin each AF patient and determined by the degreeof structural and electrical changes in the atrialmyocardium and not only by the AF clinical type[16–18].

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Targeting the AF Triggers

The arrhythmia triggers originate within thePVs in majority (80–94%) of AF patients[19, 20]. Compared to LA myocytes, cardiomy-ocytes in the PVs have a shorter refractorinessand increased triggered activity, and myocardialstrands at the LA-PV junction form an aniso-tropic mesh with a propensity for micro-reentry

[21]. Figure 1a illustrates a typical electrocar-diographic (ECG) presentation of a highlyactive PV trigger with repetitive short bursts ofatrial ectopic beats in the patient with PAF.

Electrical isolation of the PVs is a corner-stone of AF ablation [2–6, 8–17]. During theevolution of the procedure, the ablation levelwas displaced from the PV ostia to the LA antrato increase the clinical success and reduce the

Fig. 1 a–c Electrocardiograms of a patient with paroxys-mal AF. a Repetitive short-lasting runs of atrial tachycar-dias, i.e., salvos of atrial ectopic beats, commonlyoriginating from the pulmonary veins. These runs of atrialarrhythmia are a trigger for paroxysmal AF (b). After

introduction of a class I antiarrhythmic drug (propafe-none), an AF episode organized to typical atrial flutter (c),implying the presence of a complex atrial arrhythmiasubstrate. AF atrial fibrillation

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risk of PV stenosis [22–24]. The ultimate end-point of AF-CA is electrical isolation of all PVs[2–6, 22–24]. Evaluation of PV electrical activityand identification of residual gaps in the LA-PVconduction during and/or after ablation areperformed by a circular multipolar catheterplaced at the PV ostium, as presented in Fig. 2[23, 24].

Less commonly, identification and elimina-tion of non-PV triggers are required for AFsuppression [3, 20]. The majority of thesenon-PV triggers were found in the superior cavalvein (especially in women and patients withchronic pulmonary disease or sleep apnea orthose undergoing redo PAF ablation procedure),coronary sinus, and crista terminalis or at theposterior LA wall (in elderly and non-PAFpatients), as well as in the left atrial appendage(LAA) (at redo ablation procedures for non-PAF)[25]. It was recently reported that non-PV trig-gers were identified in up to 44% of the patients

with long-standing PeAF, and their presencewas a strong predictor of AF recurrence after aCA procedure [26].

AF Substrate Modification

The process of LA remodeling is associated withchronic inflammation, fibrous degenerativechanges and alteration in atrial electrophysiol-ogy (EP), leading to the development of thesubstrate for non-PAF maintenance [27, 28]. Inpatients with non-PAF and/or a long history ofAF, magnetic resonance imaging (MRI) andintracardiac voltage maps reveal a widespreadscarring most commonly in the thin posteriorand anterior LA walls as well as in the LA sep-tum [16–18, 27, 28]. Different adjuvant strate-gies for AF substrate modification on top of PVIhave been proposed; however, data on theireffectiveness are conflicting, and presently there

Fig. 2 Intracardiac electrogram during a PVI procedure,paper speed 200 mm/s. A circular multipolar mappingcatheter was positioned in the left superior PV. Aftercompletion of PVI, a spontaneous paroxysm of AF wasrecorded on the circular catheter (yellow) within theisolated PV, while stable sinus rhythm was maintained in

the LA (see standard ECG leads, blue, as well as coronarysinus electrograms, green), confirming the exit PV-LAblock after successful ablation. PVI pulmonary veinisolation, AF atrial fibrillation, LA left atrium, ECGelectrocardiogram

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is no consensus whether their application in thefirst-ever AF-CA procedure is justified [2].

The linear LA ablation mimics the surgicalmini-MAZE procedure and consists of twostandard lines: the roof line connecting cranialaspects of upper PVs and the mitral isthmus lineconnecting the lateral mitral annulus and leftinferior PV (Fig. 3a) [10, 11]. Clinical efficacy ofthis approach is based on LA compartmental-ization and prevention of post-PVImacro-reentrant LA tachycardia [29]. Theachievement of a complete and persistent con-duction block across the lines is challenging butcritical to eliminating arrhythmia [30, 31]. LAlinear ablation significantly prolongs the pro-cedure and fluoroscopy times and increases therisk of cardiac perforation [10, 15].

Defragmentation of the LA is based on theelimination of all multicomponent electro-grams of short cycle length (i.e., CFAE), whichpossibly represent the dominant rotors offunctional AF multiple-wavelet circuits [32].Their ablation usually leads to prolongation ofAF cycle length, culminating in conversion intoatrial tachycardia (AT) or sinus rhythm (Fig. 3b)[11, 32]. However, the endpoints of such abla-tion are not clearly defined, resulting in lowintra-procedural reproducibility of CFAE iden-tification and elimination, a limited clinicalsuccess rate and frequent occurrence of iatro-genic ATs [15]. The presence of small rotor-likereentry with fibrillatory conduction in the restof the atrium was identified by conventionalmapping and signal analysis in 15% of patientswith non-PAF, particularly in those with ashorter AF episode and less remodeled atrialsubstrate [33]. These rotors were responsible formaintenance of AF, and their ablation on top ofPVI terminated AF in 75% of the cases [33].Recent studies reported the FIRM (Focal Impulseand Rotor Modulation) ablation strategy, pro-viding more specific identification of AF driversamenable to ablation [7]. Using panoramiccontact mapping with a basket multipolarcatheter within the atria, stable electrical AFrotors and focal sources of AF were reproduciblyidentified [34]. Rotors and focal sources of AFperpetuated within atrial areas of &2 cm2 andtheir selective ablation led to the termination ororganization of AF in 86% of patients with PeAF

or PAF, offering a promising clinical outcome.However, the majority of CFAE sites wereidentified remote from AF sources and were notappropriate targets for ablation [34].

The concept of the LA denervation includesan intentional damage of the LA ganglionatedplexi (GPs) to suppress their influence on the AFtriggers and substrate [3]. Four GPs are locatedapproximately 1–2 cm outside the PV ostia andcan be identified by local endocardial high-fre-quency current stimulation or empiricallyablated at specific anatomical areas, as illus-trated in Fig. 4 [35]. However, the endpoint of‘‘sufficient’’ denervation is not precisely defined,and sometimes it leads to post-procedural sinustachycardia or postural hypotension [36].Moreover, long-term consequences ofparasympathetic denervation after AF ablationare not known. It is well recognized that cardiacdenervation is a marker of higher cardiovasculardeath risk in patients with diabetes and heartfailure and after myocardial infarction [37].

Approximately 20–25% of AF patients alsohave episodes of typical or atypical atrial flutter(AFL) due to the presence of a complex atrialsubstrate and/or a pro-arrhythmic effect of classIC or III AADs prescribed for the prevention ofAF (Fig. 1) [38]. Commonly, the adjuvant abla-tion of these ‘‘organized’’ arrhythmias is a partof the substrate modification procedure toimprove the outcome [3, 38]. Several studieshave demonstrated no clinical benefit of addi-tional ablation for typical or peri-mitral AFLbeyond PVI in these patients, emphasizing thecritical importance of the PV triggers for pre-vention of various atrial tachyarrhythmias[39, 40]. However, in patients with clinicallydocumented or inducible typical AFL, cavotri-cuspid isthmus ablation during the same ses-sion is recommended [2].

Diseased atrial regions exhibiting low-volt-age activity are responsible for slow conduction,contributing to the AF substrate [16]. Severalreports confirmed the feasibility of a tailoredatrial substrate modification based onlow-voltage area ablation or the box isolation of‘‘fibrotic’’ areas (BIFA) (Fig. 4b) [16, 41]. Thisindividualized approach offers identification ofpatient-specific targets for ablation, irrespectiveof AF type [16]. The low-voltage areas were

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Fig. 3 a Standard set of LA lesions commonly deployed inpatients with non-paroxysmal AF, consisting of twocircular ablation lines for isolation of ipsilateral PVscombined with two standard LA lines, i.e., the roof lineconnecting both upper PVs and mitral line connecting thelateral aspect of the mitral annulus with left PVs.

b ‘‘Organization’’ of persistent AF into AT culminatingin termination of the arrhythmia during the extensiveablation of complex fragmented atrial electrograms(CFAEs), i.e., LA defragmentation, due to considerabledebulking of the LA substrate. LA left atrium, AF atrialfibrillation, PV pulmonary vein, AT atrial tachycardia

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identified in 35% and 10% of patients with PeAFand PAF, respectively. The 1-year AF-free sur-vival was significantly better among patientswith low-voltage areas who underwent furthersubstrate modification than in those whoreceived only PVI (70% vs. 27%) [16]. Inanother study, ablation of these areas (in con-junction with PVI) led to termination of PeAF in73% of patients and significantly improved the

rate of 1-year single-procedure arrhythmiafreedom compared to controls who underwentPVI alone [42].

A randomized study reported that empiricaladdition of LAA isolation on top of ‘‘standard’’AF ablation significantly increases the rate offreedom from atrial arrhythmias during the2-year follow-up [43]. Routine LAA isolation inthis study was reported to be safe with no cases

Fig. 4 The GP ablation strategy for substrate modification(a). During left superior GP ablation a transitory slowingof the sinus rate was provoked. After several ablationattempts in this area, the vagally mediated response wasblunted. b The pre-ablation voltage maps in two patientswith paroxysmal AF were compared according to thevoltage-color scale (red and violet represent low and highvoltage, respectively). On the left part, a normal-to-highvoltage map was obtained (violet color dominates),

suggesting absence of significant LA fibrosis. In thisparticular patient the PVI procedure should be sufficientfor AF suppression. However, on the right an example of alow voltage map is presented, suggesting the presence ofprofound LA fibrosis (red is dead) and the progression ofthe AF substrate, probably necessiting the adjuvantsubstrate modification on top of PVI. GP ganglionatedplexi, AF atrial fibrillation, PVI pulmonary vein isolation

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of stroke or embolism after the procedure,although an impaired contractile function ofthe LAA was identified post procedure in morethan 50% of these patients using trans-esophageal echocardiography (TEE) [43]. How-ever, the results of other investigators haverecently aroused concerns regarding LAAthrombogenicity after its inadvertent isolationduring a complex ablation of LA substrate forthe treatment of AF [44]. During the 6-monthfollow-up after the procedure, stroke or transi-tory ischemic attack occurred in 6% of thepatients with isolated LAA, and LAA thrombuswas found in 21% of the remaining patientsdespite oral anticoagulation (OAC) therapy [44].

Ablation Technologies

The PVI can be performed by radiofrequency(RF) current or cryoenergy and by successiveapplication of point-by-point necrotic lesions ora single shot of energy in a circular fashion atthe level of the LA-PV junction [2, 3]. At pre-sent, the choice of technology is a matter ofoperator preference [2, 3].

Point-by-point PVI is performed using RFenergy and a 3.5–4 mm irrigated-tip ablationcatheter [22–25]. An electro-anatomical systemis commonly used, providing a fluoroscopyreduction, better catheter navigation and addi-tional information throughout the proceduresuch as the LA activation and voltage maps[12–16, 22–25, 41, 42]. This technology requiresextensive training of the operator, but enableshim/her to continue with ablation of the sub-strate, non-PV triggers or AFL once the PVI hasbeen completed [9, 10, 12–16, 29–32,35, 38–44]. Recent development of the catheterswith contact-force sensing enabled a more effi-cient tissue heating and the formation of more adurable lesion with better clinical outcome[45, 46]. In addition, to date the RF energysource has been the most widely used technol-ogy for AF ablation; it was introduced earlyfor the procedure, and this technology hasthe longest post-ablation follow-up data[2, 3, 6, 22].

A randomized study recently demonstratednon-inferiority of the cryo-balloon PVI

procedure compared to standard RF point-by-point PVI with respect to clinical success andprocedural safety during the mean follow-up of1.5 years [47]. Although a cryo-balloon enablesfaster and easier PVI compared to RF technol-ogy, it was associated with significantly higherradiation doses because PV angiography toconfirm complete PV occlusion by the balloonis necessary for optimal tissue freezing [47–50].Cryo-balloon technology has a shorter learningcurve and is less operator-dependent than RFablation, ensuring a better reproducibility of theprocedural endpoint especially among lessexperienced electrophysiologists [47–50].Therefore, it could be an attractive option forlow-to-medium volume centers with limitedprevious experience in AF ablation. The pres-ence of unfavorable PV anatomy (i.e., a com-mon trunk of ipsilateral PVs) limits theapplication of this technology and preoperativescreening by computed tomography (CT) orMRI may help in appropriate patient selection[3, 45–47]. In addition, this technology isdesigned only for PVI procedures; if necessary,further ablation of targets other than PVs is notpossible without exchanging the catheters andablation set-up, increasing the cost of the pro-cedure [47–50].

Visually guided laser balloon ablationrequires a short learning curve for the operatorand has several features that facilitate the PVIprocedure [51]. Thus, by changing its diameterthe balloon can accommodate various PV sizesand anatomies. In addition, a thin endoscopeallows direct visualization of targeted atrialstructures during ablation, and titration ofenergy provides creation of optimal lesions atdifferent anatomical sites [51]. A multicenterrandomized study reported comparable12-month clinical success after visually guidedlaser-balloon ablation and standard irrigatedRF ablation of AF (63.5% vs. 63.9%), similarprocedural complication rates (11.8% vs.14.5%) and similar rates of durable PVI lesionsat redo procedures (52.7% vs. 46.4%) [51].Balloon catheters that use RF energy for PVIhave recently become available (hot balloon)or are on the way (multi-electrode RF balloon)[52].

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Complications

Major complications occur in 4.5–6% of the AFablation procedures, more commonly in olderand female patients, patients with a very low orvery high body mass index, those with struc-tural heart disease and those undergoing a redoprocedure, especially if the procedure is per-formed in a low-volume center [22, 53–57].Peri-procedural mortality is 0.01% and mostoften is a related to cardiac tamponade, strokeor atrio-esophageal fistula [2, 22, 25]. The inci-dence of cardiac perforation and tamponade isbetween 0.5% and 3% and decreases with thelearning curve of the operator [3, 53, 54, 57]. Inthe majority of these patients, emergency peri-cardiocentesis and reversal of anticoagulationare sufficient for complete recovery, but urgentsurgical repair may be lifesaving in 15–20% ofthe cases, raising the question of the safety ofthe procedure performed without in-house sur-gical back-up [58]. Importantly, a delayedoccurrence of tamponade, days to weeks afterdischarge, was reported because of a rupture ofthe thinned LA wall following ablation orinflammation in the setting of Dressler’s syn-drome [3, 25, 58]. The reported stroke rate ran-ges between 0.5% and 2% and is the highestduring the procedure and in the first 7–30post-procedural days [3, 22, 25, 53–57]. A strat-egy of uninterrupted OAC throughout theablation procedure significantly reduced theintra-procedural stroke rate compared to‘‘bridging’’ with low-molecular-weight heparin[2]. However, approximately 40% of low- ormedium-volume centers have not implementedthis strategy yet because it differs from localsurgical practice in the case of a hemorrhagicprocedural complication [59]. Systemic throm-boembolism due to AF ablation should be trea-ted by emergency percutaneous intervention orby thrombolytic therapy [3, 25]. Atrio-esopha-geal fistula is a rare complication (0.05%) asso-ciated with high mortality (75%)[2, 3, 25, 53–57]. Several strategies have beenproposed for protecting the esophagus duringan AF-CA procedure, such as pre-procedural orintra-procedural visualization of the esophagus(by barium swallow, 3D mapping system, CT orMRI), active displacement of the esophagus

before RF delivery at the LA posterior wall (byTEE probe or intra-pericardial balloon inser-tion), monitoring of esophageal temperatureduring ablation, limiting the energy output orduration of RF application in the projection ofthe esophagus and esophageal cooling duringthe CA procedure (by irrigation of esophaguswith cool water) [60]. The triad of symptomssuch as sepsis, stroke and dysphagia appearing7–30 days after the AF ablation procedure issuspicious for this complication [24, 61]. Thediagnosis is confirmed by CT, while gastroscopycan be fatal because of insufflation of air intothe esophagus and LA with massive cerebralembolism, and the treatment relies mainly onimmediate surgery [3, 61]. Evolution of the PVIprocedure with more proximal ablation outsidethe PV ostia led to considerable reduction of thePV stenosis rate to less than 1% [21–24, 53–57].It should however be kept in mind that PVstenosis develops gradually and insidiously[3, 25]. The occurrence of pneumonia, hemop-tysis, dyspnea and effort intolerance severalmonths after the ablation procedure indicatesecondary pulmonary hypertension due to PVstenosis [25]. Diagnosis is made by CT or MRI.Percutaneous angioplasty with stenting showedunsatisfactory long-term results with a highrestenosis rate of up to 50% [62].

Success of AF Ablation

Long-term success of percutaneous AF-CA variesconsiderably from 50 to 80% [3, 6]. Estimationof the real AF ablation success is difficultbecause of inconsistency in the definitions ofprocedural success and post-procedural recur-rences, the difference in the intensity ofpost-procedural rhythm monitoring as well asthe analysis of outcomes after single or multipleCA procedures [2, 3]. The academic communityhas defined AF recurrence as the occurrence ofany symptomatic or asymptomatic atrial tach-yarrhythmia after the procedure lasting morethan 30 s [2, 3]. It is obvious that this definitionis arbitrary, and although it allows precise sci-entific communication, it should be understoodin the broader clinical context. For example, ifuncontrolled PeAF in a patient with

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tachycardiomyopathy and congestive HFsymptoms transformed into oligosymptomatic,sporadic attacks of PAF accompanied withcomplete recovery of left ventricular (LV) func-tion after AF ablation, we must underline theconsiderable clinical benefit of the procedurealthough formally it failed since the arrhythmiarecurrence was clearly documented.

Therefore, the clinical success of AF ablationshould be considered in relation to differentoutcomes, such as (1) the rhythm outcome aftera single CA and after multiple ablation proce-dures, (2) the rhythm outcome without AADsand with AADs following ablation, (3) therhythm outcome with respect to the intensityof rhythm monitoring (intermittent vs. con-tinuous) and post-procedural follow-up strategyand (4) the outcome in terms of significantclinical issues other than rhythm control, suchas improvement of LV function and/or QoL,AF-related symptom relief, reduction of mor-tality, etc.

Outcome After Single and Multiple ProceduresLong-term AF ablation success was significantlyimproved after repeated procedures in compar-ison to single AF ablation [6, 13, 63]. In ameta-analysis that included 19 studies and 6167AF patients with mean age ranging from 51 to65 years who were followed between 28 and71 months after multiple AF ablation proce-dures, the AF-freedom rate after a single CAprocedure was 65% at 1 year, 56% at 3 years and51% at 5 years. However, after multiple ablationprocedures AF was successfully suppressed in86% of patients at 12 months, 79% of patientsat 3 years and 78% at 5 years [6].

The rate of freedom from AF after a single CAprocedure was significantly higher in patientswith PAF than in those with PeAF[2, 3, 6, 13, 63]. The single-procedure annualsuccess rate was 67% for PAF and 52% for PeAF[6]. At the end of long-term follow-up ofbetween 3 and 5 years, only 54% of patientswith PAF and 42% with PeAF were arrhythmiafree. However, after multiple procedureslong-term success was similar in patients withPAF or PeAF (79% and 78%, respectively), whilethe number of procedures per patient was sig-nificantly higher in patients with persistent

compared to those with paroxysmal arrhythmia(1.7 vs. 1.4) [6].

AAD Therapy After AblationEven after repeated AF-CA procedures,one-third to one half of patients are still takingAADs [64]. In patients with recurrent arrhyth-mias after ablation, a decision on a re-do pro-cedure is commonly postponed after an AADtrial, although an aggressive approach withearly invasive re-intervention may be justified[65]. In addition, in patients with low expectedprocedural success (i.e., older patients with verydilated LA and non-PAF) and a history of atechnically challenging previous procedure(e.g., difficult vascular or transseptal access orunusual PV anatomy), the clinician may indef-initely continue AAD therapy following theablation regardless of outcome, hoping to pre-vent arrhythmia recurrence and avoid the re-doprocedure [2, 3, 25, 63, 64].

Effectiveness of AADs seems to be increasedafter CA because of significant damage of thearrhythmogenic tissue responsible for the initi-ation and maintenance of AF as well as changesin the autonomic nervous tone after (un)in-tentional ablation of parasympathetic GPs[35, 66–68]. Therefore, the selection of AAD thatwas ineffective before the procedure could havea theoretical justification [67]. Data from arepeated invasive EP study showed that3 months after failed ablation, the LA-PV con-duction delay was significantly more pro-nounced in patients who maintained sinusrhythm on AADs than in ‘‘AAD non-responders’’after the procedure [67]. It has been suggestedthat AADs after AF ablation promote furtherLA-PV conduction slowing until a blockthrough the damaged tissue and occurrence of amore organized recurrent atrial arrhythmia withslower ventricular rate compared to pre-abla-tion AF [66, 68].

Reintroduction of AADs for AF recurrenceafter ablation resulted in successful 5-yeararrhythmia suppression in up to 70% of 125patients with multiple CA procedure failure[69]. During the follow-up of 161 PAF patientsfor almost 5 years after multiple CAs, 68% werefree of AF without AADs, increasing to 80% afterthe re-introduction of AADs in those with

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recurrent AF [63]. In another study 100 patientswith PAF were followed for more than 3 yearsafter multiple ablation procedures [64]. Thesuccess rate was 57% off-AADs and 82% afterre-introduction of AADs [64].

However, another study on 107 patients withPAF and PeAF who were randomly assigned toablation alone or ablation combined with AADs(preferably amiodarone) showed differentresults from the previous reports [66, 70]. Dur-ing a 12-month follow-up, the continuation ofAAD therapy in patients undergoing AF abla-tion did not significantly reduce the rate of AFrecurrence (34% after CA alone vs. 30% after CAcombined with AADs) but significantlyincreased the proportion of asymptomatic AFepisodes among patients with post-ablationarrhythmia recurrence (68% in patients withAADs and 28% in those without AAD afterablation) [70].

Clinical Benefits of AF AblationData accumulated in the last 15 years suggestthat CA, at least in some subsets of AF patients,could have important clinical benefits such asthe reduction of systemic thromboembolismand mortality rate as well as improvement in HFmanagement and QoL [2, 3, 25, 71–76].

Mortality and Thromboembolism Random-ized trials have not demonstrated superiority ofablation compared to medical therapy inreducing mortality and thromboembolicevents, most probably because of the limitedduration of post-procedural follow-up andselection of relatively younger patients with alow prevalence of structural heart disease andlow thromboembolic risk [77]. However, severalnon-randomized studies showed advantages ofCA over medical therapy with respect to sur-vival and stroke prevention in the subgroups of‘‘sicker’’ and older AF patients with significantheart disease, HF and a high CHA2DS2VAScscore [71–76]. These studies included patientswith mean age between 57 and 69 years andmore than one risk factor for thromboem-bolism; more than half of the patients had sig-nificant structural heart or lung disease [71–76].During the mean follow-up of 2.5–4.4 years,significantly lower mortality (3–6% vs. 7–14%)

and thromboembolism rates (2–3% vs. 4–9%)were observed after ablation compared to AADtherapy. Moreover, a stable sinus rhythm afterthe procedure was strongly associated with areduction in mortality [HR 0.14 (95% CI: 0.06 to12.36)], while an AF recurrence was an inde-pendent predictor of vascular thromboembolicevents [HR 2.52 (95% CI: 1.05 to 6.06)] [72, 74].The stroke rate reduction was most prominentamong patients with a high CHA2DS2VAScscore of C2 [HR 0.39 (95% CI: 0.19 to 0.78)][75].

Heart Failure AF and HF share common riskfactors for their development and progression(hypertension, diabetes, coronary and valvulardisease, aging, etc.) [78]. Although the preva-lence of AF increases proportionately to wors-ening of HF, in patients presenting with both AFand HF it is often difficult to determine a causallink between the two [79]. PeAF or frequent PAFepisodes associated with a rapid ventricular ratemay lead to secondary LV systolic dysfunctionand congestive HF, a condition known as‘‘tachycardiomyopathy’’ or tachyarrhyth-mia-induced HF [80]. The recovery of LV sys-tolic function after restoration of sinus rhythmcan last for months after the procedure,depending on the patient age, duration ofpre-ablation AF episode and associated under-lying heart disease. Approximately 10% ofpatients with AF and HF develop pure tachy-cardiomyopathy, and another 25–50% show acertain component of tachycardiomyopathyexacerbating preexisting HF [81].

The use of AADs and rate-controlling agentsin HF is limited because of hypotension, wors-ening of congestive symptoms and possibleventricular pro-arrhythmia [79–81]. Therefore, anon-pharmacological treatment of AF such asCA is a desirable therapeutic option for HFpatients [2, 78–81]. A randomized studydemonstrated significantly better 2-year AF-freesurvival in patients with PeAF, congestive HFand EF \40% who underwent AF ablation(mean 1.4 procedures per patient) than in thosewho were treated with amiodarone (70% vs.34%) [82].

In approximately 70% of AF patients withreduced LV systolic function (ejection fraction,

Adv Ther (2017) 34:1897–1917 1907

EF \50%), a significant average increase of EFfor 12–23% or normalization of EF to C55%can be expected after several months postablation [80, 83]. Maintenance of sinus rhythmafter the procedure was a clinical factor inde-pendently associated with an increase in LV EFfor more than 10% [OR 4.26 (95% CI: 1.69 to10.74)] [84]. In addition, several studies havedemonstrated a significant increase in exercisetolerance and reduction of mitral regurgitationand number of hospitalizations for HF aftersuccessful AF-CA in HF patients [84, 85]. A rateof maintaining stable sinus rhythm in patientswith HF was 48% after the first AF ablationincreasing to 75% after the re-do procedure,while 32% of patients underwent multiple CAprocedures [85].

Quality of Life Improvement Symptomaticand functional improvement of patients isamong the main goals of AF treatment[2, 3, 25, 27]. AF significantly reduces thephysical and mental health components of QoLmeasured by generic and arrhythmia-specificquestionnaires, such as the Short Form-36(SF-36) score and Symptom Check List Fre-quency and Severity (SCL-F and SCL-S) scores[86, 87]. It has been shown that the QoL scorereturned to the pre-procedural level after onlyseveral weeks post ablation, staying at the initiallevel during a long-term follow-up [86]. TheQoL improvement was strikingly higher inpatients who were AF-free than in those withrecurrent arrhythmia after the procedure[86–88]. However, even in patients with AFrecurrence, a significant QoL improvement wasobserved following ablation compared topre-ablation values, possibly because of thehigher proportion of asymptomatic arrhythmiaepisodes, reduction in AF burden, LA denerva-tion, increased AAD effectiveness or placeboeffect post procedure [88].

Rhythm-Monitoring Strategy After AF AblationThere is no consensus on the optimalrhythm-monitoring strategy after AF ablationprocedures [2, 3]. In most cases, the proceduraloutcome is assessed using only clinical fol-low-up and findings of non-invasiverhythm-monitoring systems [2, 3, 89]. These

non-invasive monitoring tools, including astandard 12-lead ECG, Holter, event-recorder,trans-telephonic transmission systems, etc.,strongly depend on patient adherence [89].Moreover, these systems are only capable ofintermittent rhythm monitoring and are com-monly activated by the patient, providingmoderate sensitivity for post-procedural AFdetection in the range from 31 to 71% [89].Although these systems enable clinicians toevaluate the symptoms suggestive of AF relapse,such monitoring strategies can easily overlooksubclinical short-lasting and sporadic AF recur-rences after procedures [90]. The clinical deci-sion on the long-term use of OAC therapy isoften only based on the outcome of ablationprocedures estimated by non-invasiverhythm-monitoring strategies [91]. However,the finding of short-term episodes of atrialtachyarrhythmia has been shown to be stronglyassociated with an increased risk of cryptogenicstroke, thus emphasizing the need for morereliable strategies for routine monitoring afterAF ablation [92].

Implantable cardiac rhythm monitors (ICM)allow continuous rhythm monitoring for sev-eral months to years after the procedure[89, 90, 93]. ICM is armed with specific algo-rithms for automatic AF detection, demon-strating very high accuracy for AF detection of98% [2, 89]. Recently, ICMs were implanted in50 patients 3 months prior to AF ablation, andthese patients were followed for 18 months afterAF-CA [90]. The proportion of asymptomatic AFepisodes increased significantly from 52%before ablation to 79% after ablation, changingthe ratio of asymptomatic to symptomatic AFepisodes from 1.1 before to 3.7 after the proce-dure. In addition, the median duration of AFepisodes was significantly shortened from22 min before to 6 min after ablation [90].Importantly, the ultimate AF recurrence rateafter multiple CA procedures, as estimated onthe basis of post-procedure symptoms, periodic48-h Holter and findings of ICM interrogation,was 58, 56 and 46%, because up to 12% ofpatients experienced exclusively asymptomaticAF recurrences after ablation [90]. Other studiesreported similar findings [93]. These systems arestill not routinely used in this clinical setting,

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likely because of their invasiveness and costs;however, they can be an option for selectedpatients [2].

RECURRENCE OF AF AFTERABLATION

AF recurrences after CA were arbitrarily definedas ‘‘early,’’ ‘‘late’’ and ‘‘very late’’, because thetime course of AF recurrence could implicatethe mechanism as well as clinical significance ofpost-procedure atrial arrhythmia relapse [3].

Early Recurrence of AF

‘‘Early’’ recurrences of AF (ERAF) usually occurduring the first 1–3 months after the AF abla-tion procedure [3]. This vulnerable period afterthe procedure is called the ‘‘blanking period’’,referring to the period of maturation and heal-ing of RF lesions after LA ablation [94]. A highincidence of ERAF during the first weeks postablation was reported, ranging between 30%and 70%, and the ERAF occurrence does notimply immediate re-do ablation [23, 94–96]. Itwas believed that transient LA tissue inflam-mation after RF ablation could be responsiblefor a significant proportion of the ERAF casesbecause in 40–60% of these patients arrhythmiarecurrences gradually disappear in the weeksand months post CA [94–97]. In addition, it hasbeen shown that antiinflammatory therapy(i.e., corticosteroids or colchicine) or AADtherapy during the first days and weeks after AFablation can significantly reduce theERAF occurrence, but with no impact on thelong-term rhythm outcome [94–96]. It is there-fore recommended to continue with AAD ther-apy during the 3-month blanking period afterthe procedure in all patients, hoping to reducethe risk of overt ERAF episodes requiringin-hospital cardioversion [2, 3, 96].

Current guidelines recommended a 3-monthblanking period after AF ablation [3]. However,a recent study called into question the 90-daycutoff value, reporting a strong correlationbetween the timing of ERAF and late AF recur-rence [97]. The 1-year freedom from AF was

62.6, 36.4 and only 7.8% in patients with ERAFoccurrence within the first, second and thirdmonth post-PAF ablation, respectively(P\0.0001), indicating the need for redefiningthe blanking period duration [97]. Otherlong-term follow-up studies after AF ablationconfirmed these findings [98, 99]. During fol-low-up for up to 3 years after ablation, any ERAFoccurrence was a strong and independent pre-dictor of subsequent arrhythmia recurrence[98, 99]. In a recent prospective study, accord-ing to the study protocol all patients underwenta mandatory invasive EP procedure 2 monthsafter the index PVI for PAF [100]. The presenceof a late PV reconnection as well as the numberof reconnected PVs at the repeated EP proceduresignificantly correlated with ERAF occurrencefollowing the index CA [100].

Late and Very Late Recurrence of AF

AF recurrences occurring after the blankingperiod are considered as late recurrences of AF(LRAF) [3]. In repeated EP procedures, a recon-nection of at least one PV was observed in 98%of patients with clinically manifested LRAF[3, 25, 69]. In addition, re-isolation of these PVsled to long-term AF suppression in the majorityof these patients, suggesting a late PV recon-nection post PVI as the main mechanism ofLRAF [25]. So far, various clinical and bio-chemical (pre- and post-procedural) predictorsof LRAF have been identified, such as a historyof non-paroxysmal AF, LA enlargement, hyper-tension, obesity, diabetes mellitus, aging, HF,chronic renal insufficiency, preproceduralamiodarone failure, biochemical markers ofinflammation (a higher preprocedural C-reac-tive protein level, natriuretic peptide level andneutrophil/lymphocyte ratio as well as a lowerpost procedural troponin serum level), MRIfinding of significant atrial fibrosis, increasedthromboembolic score (CHADS2 and CHA2DS2-

VASc), presence of non-PV triggers, ERAFoccurrence post procedure and others[2, 3, 25, 69, 101–109]. In addition, severalintraprocedural strategies were proposed forachieving an enduring PVI lesion, significantlyreducing the LRAF rate (e.g., an optimal contact

Adv Ther (2017) 34:1897–1917 1909

force between the catheter tip and tissue surfaceduring RF ablation, the use of steerable longsheaths and the methods for unmasking andeliminating dormant LA-PV connections postPVI such as adenosine testing or ablation of PVencircling lesions until ‘‘loss of local pace cap-ture’’) [45, 110, 111].

Several studies have shown that the majorityof the LRAFs occurred in the 1st and 2nd yearsafter the procedure, and thereafter only a smallnumber of new-onset AF relapses were docu-mented [25]. Thus, among LRAF patients,arrhythmia recurrences were observed inapproximately 75% of patients in the 1st yearand in 90% of patients up to the end of 2 yearspost procedure [112]. However, other studieshave shown conflicting findings and argueabout the persistency of the long-term AFablation results [99, 102]. In patients who wereAF-free during the 1st year post procedure (andtherefore were considered ‘‘cured’’), a progres-sive increase in the rate of very late AF recur-rence (VLRAF) was identified: 13% after 2 years,35% after 4 years and 55% after 6 years [102].The mechanisms of VLRAF have not beencompletely clarified. Although a PV reconnec-tion was found at the re-do ablation procedurein the majority of patients with VLRAF(69-100%), several observations indicate thatmechanisms other than a simple PV reconnec-tion could be responsible for some VLRAF cases[101–112]. Compared to patients with LRAF,those with VLRAF had a significantly lower rateof AF foci within the LA and PVs (50% vs. 97%and 50% vs. 79%, respectively) and higher rateof AF foci within the right atrium (67% vs. 3%)[112]. In addition, in VLRAF patients,one-third of the AF foci identified at re-doprocedures were the new AF foci, previouslynot ablated during the index procedure, andatrial tachycardia unrelated to the PVs wasidentified in more than a half of VLRAFpatients [104]. Probably the various inherentrisk factors (e.g., hypertension, aging, HF, etc.)promote the bi-atrial cardiomyopathy pro-gression in spite of temporary ‘‘successful’’ AFablation, leading to further arrhythmogenicsubstrate development and re-occurrence ofatrial tachyarrhythmia after several years postCA [99].

Recently, several scoring systems, such asALARMEc, APPLE, BASE-AF2 and MB-LATER,were specifically developed for the prediction ofAF recurrence after ablation [98, 99, 105, 106].All these scores included easily available clinicalvariables, providing better selection of patientsfor invasive procedures (or redo procedures) andoptimal intensity and duration of rhythmmonitoring after the procedure. Of note, thecommon constituents of all of these scores arethree clinical features: pre-ablation history ofnon-paroxysmal AF and LA enlargement andERAF occurrence post ablation[98, 99, 105, 106]. It would be of clinical value ifthe accurate prediction of the long-term proce-dural outcome could inform decisions on theduration of anticoagulant therapy postprocedure.

INDICATION FOR AF ABLATION

During management of AF patients in dailyclinical practice, two questions commonly arise:(1) Who is a good candidate for CA of AF? (2)When in the clinical course of AF does theinvasive procedure becomes medically justifiedfor the patient? An overview of the indicationsfor the AF ablation procedure is listed in Table 1.

The best candidates for CA are relativelyyounger patients with PAF and structurallynormal heart or those with only minimal con-comitant structural heart disease[2, 3, 25, 99–109, 113, 114]. An 85–90% singleCA procedure success rate has been reported inyounger patients with lone AF during the3–5-year follow-up post procedure [113, 114].

The effectiveness of ablation compared tomedical therapy was most pronounced in AFpatients who had already failed AAD therapy[2, 115]. In patients with PAF refractory to atleast one class IC or III drug, changing the AADled to successful AF suppression in \20% ofpatients [115]. However, the long-term effec-tiveness of ablation in this setting approaches70–75% [6]. Although invasive cardiac proce-dures involve life-threatening complications,long-term AAD therapy has been shown to bemore commonly associated with considerableside effects compared to ablation (17% vs. 8%)

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[116]. In addition, a few studies have reportedthat CA can even be considered as the firsttherapeutic option for selected patients withPAF [114].

ANTICOAGULATION THERAPYAFTER ABLATION

There is no consensus about the duration ofOAC therapy after ablation [2, 3]. In accordancewith current recommendations, OAC drugs(vitamin K antagonists or non-vitamin Kantagonist OAC) should be prescribed to allpatients in the first 6 weeks to 3 months afterthe procedure. Thereafter, the indication forOAC should be based on the individual strokerisk (e.g., CHA2DS2-VASc score) irrespective ofthe post-procedural rhythm outcome [2, 3]. Aretrospective study showed an overall strokeincidence of 1.5% during the median follow-upof 18 months after AF ablation, with half of all

events occurring during the first month afterthe procedure [117]. Stroke risk scores such asthe CHADS2, R2CHADS2 and CHA2DS2-VAScscore were independent predictors of throm-boembolic complications post procedure, whileAF recurrence indicated only a non-significanttrend for increased thromboembolic risk. Usingthe CHA2DS2-VASc score additionally stratifiedpatients within the low-risk stratum as catego-rized by the CHADS2 and R2CHADS2 scores,especially in those with documented AF relapseafter ablation [117]. However, controversy existsbecause it has recently been reported that allthromboembolic events after RF-CA of AFoccurred in patients with an arrhythmia recur-rence, with the rate of 4% during a mean fol-low-up of 5 years [91]. Moreover, routinecontinuation of warfarin following CA inpatients with low-to-intermediate thromboem-bolic risk conferred greater hemorrhagic riskthan the benefit from thromboembolic pre-vention [91]. Therefore, more accurate predic-tion and detection of late and very late AFrecurrence after ablation could influence thedecision about the continuation of long-termOAC therapy after the procedure [2, 89–93].

CONCLUSION

Electrical isolation of PVs is the cornerstone ofthe AF-CA procedure. CA is superior to AADtherapy for clinical suppression of AF. Long-termelimination of AF after ablation is achieved in50–80% of patients, but repeated proce-dure(s) are often necessary for a successful out-come. The strongest predictors of AF recurrenceafter CA are a pre-procedural history ofnon-paroxysmal AF, LA enlargement and earlyrecurrence of arrhythmia during the 3-monthpost-procedural blanking period. In patientswith high thromboembolic risk, maintenance ofsinus rhythm after ablation was associated with adecrease in the rates of death and stroke. Inaddition, in patients with heart failure, a signifi-cant recovery of LV systolic function followingsuccessful AF-CA was recorded. The best candi-dates for CA are younger patients with symp-tomatic PAF with no structural heart disease andno significant LA remodeling. In these patients,

Table 1 Selection of patients for AF ablation

Better candidates Worse candidates

Age\70 years Age C70 years

Highly symptomatic Oligosymptomatic or

asymptomatic

LA diameter\45 mm LA diameter C45 mm

Paroxysmal AF (especially

\48 h)

Persistent AF

No other arrhythmia Associated AT or AFL

‘‘Lone’’ AF Structural heart disease

Normal cardiac function Heart failure

Normal BMI Obesity

Normal pulmonary

function

COPD

Normal thyroid function History of thyrotoxicosis

Amiodarone not used History of amiodarone

failure

LA left atrium, AF atrial fibrillation, AT atrial tachycardia,AFL atrial flutter, BMI body mass index, COPD chronicobstructive pulmonary disease

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the QoL improvement and symptomatic reliefwere more pronounced after ablation than withAADs. Because of the 1–5% risk of life-threaten-ing complications, ablation represents a sec-ondary treatment option for selected patientswith AF. Additional technological improvementshould enable the achievement of more durableablative lesions and the identification of anoptimal and individually adjusted lesion set forCA of PeAF. Such advances could significantlyexpand the indication for AF-CA. Also, moreinformation is necessary for determining theoptimal rhythm monitoring and anticoagula-tion strategy after AF ablation.

ACKNOWLEDGEMENTS

Funding. No funding or sponsorship wasreceived for this study or publication of thisarticle.

Authorship. All authors meet the Interna-tional Committee of Medical Journal Editors(ICMJE) criteria for authorship for this manu-script, take responsibility for the integrity of thework as a whole and have given final approvalto the version to be published.

Disclosures. Nebojsa Mujovic, Milan Mar-inkovic, Roland Tilz, Radosław Lenarczyk andTatjana S. Potpara declare that they have noconflict of interest.

Compliance with Ethics Guidelines. Thestudy was conducted in accordance with theDeclaration of Helsinki of 1964 as revised in2013. The study protocol was approved by theInstitutional Review Board of each center. Thisarticle is based on previously conducted studiesand does not involve any new studies of humanor animal subjects performed by any of theauthors.

Open Access. This article is distributedunder the terms of the Creative CommonsAttribution-NonCommercial 4.0 InternationalLicense (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommer-cial use, distribution, and reproduction in any

medium, provided you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons license, andindicate if changes were made.

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