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2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation

Open AccessPublished:May 15, 2017DOI:https://doi.org/10.1016/j.hrthm.2017.05.012

      Keywords

      Abbreviations:

      3D (three-dimensional), AADs (antiarrhythmic drugs), AATAC (Ablation vs Amiodarone for Treatment of Atrial Fibrillation in Patients With Congestive Heart Failure and an Implanted ICD/CRTD), ACE (asymptomatic cerebral emboli), ACT (activated clotting time), ADVICE (Adenosine Following Pulmonary Vein Isolation to Target Dormant Conduction Elimination study), AEF (atrial esophageal fistula), AF (atrial fibrillation), AFACART (Non-Invasive Mapping of Atrial Fibrillation study), AFACT (Atrial Fibrillation Ablation and Autonomic Modulation via Thoracoscopic Surgery study), AFCL (atrial fibrillation cycle length), AFEQT (Atrial Fibrillation Effect on QualiTy-of-Life questionnaire), AFL (atrial flutter), AH (arterial hypertension), ANS (autonomic nervous system), APD (action potential duration), ARREST-AF (Aggressive Risk Factor Reduction Study for Atrial Fibrillation and Implications for the Outcome of Ablation study), ASD (atrial septal defect), ASTA (Arrhythmia-Specific questionnaire in Tachycardia and Arrhythmia), AT (atrial tachycardia), ATA (atrial tachyarrhythmia), ATP (adenosine triphosphate), AV (atrioventricular), AVR (aortic valve replacement), BIFA (box isolation of fibrotic areas), BMI (body mass index), BP (blood pressure), bpm (beats per minute), BSM (body surface mapping), CABANA (Catheter Ablation vs Anti-arrhythmic Drug Therapy for Atrial Fibrillation Trial), CABG (coronary artery bypass grafting), CaMKII (Ca2+/calmodulin-dependent protein kinase II), CB (cryoballoon), CBA (cryoballoon ablation), CF (contact force), CFAE (complex fractionated atrial electrogram), CFS (contact force sensing), CGCI (Catheter Guidance, Control, and Imaging), CHASE-AF (Catheter Ablation of Persistent Atrial Fibrillation study), CI (confidence interval), CMAP (compound motor action potentials), CPAP (continuous positive airway pressure), CPVA (circumferential PV ablation), Cryo-FIRST (Catheter Cryoablation vs Antiarrhythmic Drug as First-Line Therapy of Paroxysmal AF trial), CS (coronary sinus), CSA (central sleep apnea), CT (computed tomography), CV (conduction velocity), DAD (delayed afterdepolarization), DE (delayed enhancement), DECAAF (Delayed Enhancement MRI and Atrial Fibrillation Catheter Ablation study), DF (dominant excitation frequency), DM (diabetes mellitus), DW-MRI (diffusion-weighted magnetic resonance imaging), EAM (electroanatomical mapping), EAST (Early Treatment of Atrial Fibrillation for Stroke Prevention Trial), EAVM (electroanatomical voltage mapping), ECG (electrocardiogram), ECGI (noninvasive electrocardiographic imaging), EF (ejection fraction), ERAF (early recurrence of AF), ERP (effective refractory period), FACM (fibrotic atrial cardiomyopathy), FAP (fractionated atrial potential), FAST (AF Catheter Ablation Versus Surgical Ablation Treatment trial), FDA (U.S. Food and Drug Administration), FIRM (focal impulse and rotor modulation), FLAIR (fluid-attenuated inversion recovery), FTI (force-time integral), GP (ganglionated plexi), HCM (hypertrophic cardiomyopathy), HDF (highest dominant excitation frequency), HF (heart failure), HFS (high-frequency stimulation), HR (hazard ratio), ICE (intracardiac echocardiography), IRGP (inferior right ganglionated plexi), ILR (implantable loop recorder), INR (international normalized ratio), LA (left atrial), LAA (left atrial appendage), LAD (left atrial dimension), LALA (left atrial linear ablation), LEGACY (Long-Term Effect of Goal Directed Weight Management on an Atrial Fibrillation Cohort study), LGE (late gadolinium-enhanced), LI (left inferior), LICU (low-intensity collimated ultrasound), LIPV (left inferior pulmonary vein), LOE (Level of Evidence), Look AHEAD (Action for Health in Diabetes), LS (left superior), LSPV (left superior pulmonary vein), LVEF (left ventricular ejection fraction), MANTRA-PAF (Medical ANtiarrhythmic Treatment or Radiofrequency Ablation in Paroxysmal Atrial Fibrillation), MAP (mean arterial pressure), MLWHF (Minnesota Living with Heart Failure questionnaire), MRI (magnetic resonance imaging), MVRR (mitral valve repair or replacement), NCDR (National Cardiovascular Data Registry), NCX (Na+-Ca2+ exchanger), NOAC (novel oral anticoagulant), NSAID (nonsteroidal anti-inflammatory drug), OAC (oral anticoagulation), OCEAN (Optimal Anticoagulation for Higher Risk Patients Post-Catheter Ablation for Atrial Fibrillation), ODIn-AF (Prevention of Silent Cerebral Thromboembolism by Oral Anticoagulation With Dabigatran After PVI for Atrial Fibrillation trial), OPC (objective performance criteria), OR (odds ratio), OSA (obstructive sleep apnea), PA (peripheral artery), PABA-CHF (Pulmonary Vein Antrum Isolation versus AV Node Ablation with Bi-Ventricular Pacing for Treatment of AF in Patients with Congestive Heart Failure), PAF (paroxysmal AF), PCC (prothrombin complex concentrates), PCWP (pulmonary capillary wedge pressure), PKA (protein kinase A), PN (phrenic nerve), PPIs (proton pump inhibitors), PROTECT AF (WATCHMAN Left Atrial Appendage System for Embolic Protection in Patients With Atrial Fibrillation), PS (phase singularity), PSD (peak skin dose), PV (pulmonary vein), PVAC (pulmonary vein ablation catheter), PVI (pulmonary vein isolation), QALY (quality-adjusted life year), QOL (quality of life), RA (right atrium), RAAFT (First Line Radiofrequency Ablation Versus Antiarrhythmic Drugs for Atrial Fibrillation Treatment), RAAFT-2 (Radiofrequency Ablation versus Antiarrhythmic drugs as First-line Treatment of Paroxysmal AF), RCA (right coronary artery), RCT (randomized controlled trial), RD (risk difference), RE-CIRCUIT (Randomized Evaluation of Dabigatran Etexilate Compared to Warfarin in Pulmonary Vein Ablation: Assessment of an Uninterrupted Periprocedural Anticoagulation Strategy), RF (radiofrequency), RFA (radiofrequency energy ablation), RFC (radiofrequency catheter), RFCA (radiofrequency catheter ablation), RI (right inferior), RIPV (right inferior pulmonary vein), RP (refractory period), RR (relative risk), RS (right superior), RSPV (right superior pulmonary vein), RVSP (right ventricular systolic pressure), SARA (Study of Ablation Versus antiaRrhythmic Drugs in Persistent Atrial Fibrillation), SMART-AF (ThermoCool SmartTouch Catheter for the Treatment of Symptomatic Paroxysmal Atrial Fibrillation), SNP (single nucleotide polymorphism), SPECULATE (Effect of Amiodarone on the Procedure Outcome in Long-standing persistent AF Undergoing PV Antral Isolation), SR (sarcoplasmic reticulum), STAR AF II (Substrate and Trigger Ablation for Reduction of AF Trial Part II), STOP-AF (Sustained Treatment of Paroxysmal Atrial Fibrillation), SVC (superior vena cava), TEE (transesophageal echocardiogram), TIA (transient ischemic attack), VATS (video-assisted thoracoscopic surgery), VKA (vitamin K antagonist), WACA (wide-area circumferential ablation), WL (wavelength)

      Section 1: Introduction

      During the past three decades, catheter and surgical ablation of atrial fibrillation (AF) have evolved from investigational procedures to their current role as effective treatment options for patients with AF. Surgical ablation of AF, using either standard, minimally invasive, or hybrid techniques, is available in most major hospitals throughout the world. Catheter ablation of AF is even more widely available, and is now the most commonly performed catheter ablation procedure.
      In 2007, an initial Consensus Statement on Catheter and Surgical AF Ablation was developed as a joint effort of the Heart Rhythm Society (HRS), the European Heart Rhythm Association (EHRA), and the European Cardiac Arrhythmia Society (ECAS).
      • Calkins H.
      • et al.
      HRS/EHRA/ECAS expert Consensus Statement on catheter and surgical ablation of atrial fibrillation: recommendations for personnel, policy, procedures and follow-up. A report of the Heart Rhythm Society (HRS) Task Force on catheter and surgical ablation of atrial fibrillation.
      The 2007 document was also developed in collaboration with the Society of Thoracic Surgeons (STS) and the American College of Cardiology (ACC). This Consensus Statement on Catheter and Surgical AF Ablation was rewritten in 2012 to reflect the many advances in AF ablation that had occurred in the interim.
      • Calkins H.
      • et al.
      2012 HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design.
      The rate of advancement in the tools, techniques, and outcomes of AF ablation continue to increase as enormous research efforts are focused on the mechanisms, outcomes, and treatment of AF. For this reason, the HRS initiated an effort to rewrite and update this Consensus Statement. Reflecting both the worldwide importance of AF, as well as the worldwide performance of AF ablation, this document is the result of a joint partnership between the HRS, EHRA, ECAS, the Asia Pacific Heart Rhythm Society (APHRS), and the Latin American Society of Cardiac Stimulation and Electrophysiology (Sociedad Latinoamericana de Estimulación Cardíaca y Electrofisiología [SOLAECE]). The purpose of this 2017 Consensus Statement is to provide a state-of-the-art review of the field of catheter and surgical ablation of AF and to report the findings of a writing group, convened by these five international societies. The writing group is charged with defining the indications, techniques, and outcomes of AF ablation procedures. Included within this document are recommendations pertinent to the design of clinical trials in the field of AF ablation and the reporting of outcomes, including definitions relevant to this topic.
      The writing group is composed of 60 experts representing 11 organizations: HRS, EHRA, ECAS, APHRS, SOLAECE, STS, ACC, American Heart Association (AHA), Canadian Heart Rhythm Society (CHRS), Japanese Heart Rhythm Society (JHRS), and Brazilian Society of Cardiac Arrhythmias (Sociedade Brasileira de Arritmias Cardíacas [SOBRAC]). All the members of the writing group, as well as peer reviewers of the document, have provided disclosure statements for all relationships that might be perceived as real or potential conflicts of interest. All author and peer reviewer disclosure information is provided in Appendix A and Appendix B.
      In writing a consensus document, it is recognized that consensus does not mean that there was complete agreement among all the writing group members. Surveys of the entire writing group were used to identify areas of consensus concerning performance of AF ablation procedures and to develop recommendations concerning the indications for catheter and surgical AF ablation. These recommendations were systematically balloted by the 60 writing group members and were approved by a minimum of 80% of these members. The recommendations were also subject to a 1-month public comment period. Each partnering and collaborating organization then officially reviewed, commented on, edited, and endorsed the final document and recommendations.
      The grading system for indication of class of evidence level was adapted based on that used by the ACC and the AHA.
      • Jacobs A.K.
      • Anderson J.L.
      • Halperin J.L.
      The evolution and future of ACC/AHA clinical practice guidelines: a 30-year journey: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
      • Anderson J.L.
      Evolution of the ACC/AHA clinical practice guidelines in perspective: guiding the guidelines.
      It is important to state, however, that this document is not a guideline. The indications for catheter and surgical ablation of AF, as well as recommendations for procedure performance, are presented with a Class and Level of Evidence (LOE) to be consistent with what the reader is familiar with seeing in guideline statements. A Class I recommendation means that the benefits of the AF ablation procedure markedly exceed the risks, and that AF ablation should be performed; a Class IIa recommendation means that the benefits of an AF ablation procedure exceed the risks, and that it is reasonable to perform AF ablation; a Class IIb recommendation means that the benefit of AF ablation is greater or equal to the risks, and that AF ablation may be considered; and a Class III recommendation means that AF ablation is of no proven benefit and is not recommended.
      The writing group reviewed and ranked evidence supporting current recommendations with the weight of evidence ranked as Level A if the data were derived from high-quality evidence from more than one randomized clinical trial, meta-analyses of high-quality randomized clinical trials, or one or more randomized clinical trials corroborated by high-quality registry studies. The writing group ranked available evidence as Level B-R when there was moderate-quality evidence from one or more randomized clinical trials, or meta-analyses of moderate-quality randomized clinical trials. Level B-NR was used to denote moderate-quality evidence from one or more well-designed, well-executed nonrandomized studies, observational studies, or registry studies. This designation was also used to denote moderate-quality evidence from meta-analyses of such studies. Evidence was ranked as Level C-LD when the primary source of the recommendation was randomized or nonrandomized observational or registry studies with limitations of design or execution, meta-analyses of such studies, or physiological or mechanistic studies of human subjects. Level C-EO was defined as expert opinion based on the clinical experience of the writing group.
      Despite a large number of authors, the participation of several societies and professional organizations, and the attempts of the group to reflect the current knowledge in the field adequately, this document is not intended as a guideline. Rather, the group would like to refer to the current guidelines on AF management for the purpose of guiding overall AF management strategies.
      • January C.T.
      • et al.
      2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.
      • Kirchhof P.
      • et al.
      2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS.
      This consensus document is specifically focused on catheter and surgical ablation of AF, and summarizes the opinion of the writing group members based on an extensive literature review as well as their own experience. It is directed to all health care professionals who are involved in the care of patients with AF, particularly those who are caring for patients who are undergoing, or are being considered for, catheter or surgical ablation procedures for AF, and those involved in research in the field of AF ablation. This statement is not intended to recommend or promote catheter or surgical ablation of AF. Rather, the ultimate judgment regarding care of a particular patient must be made by the health care provider and the patient in light of all the circumstances presented by that patient.
      The main objective of this document is to improve patient care by providing a foundation of knowledge for those involved with catheter ablation of AF. A second major objective is to provide recommendations for designing clinical trials and reporting outcomes of clinical trials of AF ablation. It is recognized that this field continues to evolve rapidly. As this document was being prepared, further clinical trials of catheter and surgical ablation of AF were under way.

      Section 2: Definitions, Mechanisms, and Rationale for AF Ablation

       Definition

      AF is a common supraventricular arrhythmia that is characterized by rapid and irregular activation in the atria without discrete P waves on the surface electrocardiogram (ECG). AF can be diagnosed with a surface ECG, an intracardiac atrial electrogram, or both. An arrhythmia that has the ECG characteristics of AF and lasts sufficiently long for a 12-lead ECG to be recorded, or is otherwise documented to last for at least 30 seconds, should be considered to be an AF episode. The 30-second duration was selected based on previous published consensus statements and is used as the minimal duration to define recurrence of AF after catheter ablation.
      • Calkins H.
      • et al.
      HRS/EHRA/ECAS expert Consensus Statement on catheter and surgical ablation of atrial fibrillation: recommendations for personnel, policy, procedures and follow-up. A report of the Heart Rhythm Society (HRS) Task Force on catheter and surgical ablation of atrial fibrillation.
      • Camm A.J.
      • et al.
      Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC).
      This duration of AF has not been linked to a specific outcome of AF. In addition to the duration requirements listed above, the diagnosis of AF requires an ECG or rhythm strip demonstrating: (1) “absolutely” irregular R-R intervals (in the absence of complete atrioventricular [AV] block); (2) no distinct P waves on the surface ECG; and (3) an atrial cycle length (when visible) that is usually less than 200 ms.
      • Calkins H.
      • et al.
      2012 HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design.
      • Camm A.J.
      • et al.
      Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC).
      Although there are several classification systems for AF, for this consensus document, we have adopted in large part the classification system that was presented in the 2014 AHA/ACC/HRS Guideline for the Management of Patients with Atrial Fibrillation.
      • January C.T.
      • et al.
      2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.
      We recommend that this classification system be used for future studies of catheter and surgical ablation of AF. Paroxysmal AF (PAF) is defined as AF that terminates spontaneously or with intervention within 7 days of onset (Table 1); persistent AF is defined as continuous AF that is sustained beyond 7 days; and long-standing persistent AF is defined as continuous AF of greater than 12 months' duration. Early persistent AF is a new term we have defined as continuous AF of more than 7 days' duration but less than 3 months' duration. Within the context of AF ablation and clinical trials of AF ablation, early persistent AF defines a population of patients in whom better outcomes of AF ablation are anticipated as compared with persistent AF of more than 3 months' duration. The term permanent AF is defined as AF in which the presence of the AF is accepted by the patient and physician, and no further attempts will be made to either restore or maintain sinus rhythm. It is important, therefore, to recognize that the term permanent AF represents a therapeutic attitude on the part of a patient and their physician rather than on any inherent pathophysiological attribute of the AF. Such decisions can change as symptoms, the efficacy of therapeutic interventions, and patient and physician preferences evolve. If a rhythm control strategy is recommended after reevaluation, the AF should be redesignated as paroxysmal, persistent, or long-standing persistent AF. Within the context of any rhythm control strategy, including catheter and surgical AF ablation, the term permanent AF is not meaningful and should not be used. Silent AF is defined as asymptomatic AF diagnosed by an opportune ECG or rhythm strip. Paroxysmal, persistent, and long-standing persistent AF can be silent. We recognize that a particular patient might have AF episodes that fall into one or more of these categories; therefore, we recommended that patients be categorized by their most frequent pattern of AF during the 6 months prior to performance of an ablation procedure. Lone AF is a descriptor that has been applied to younger patients without clinical or echocardiographic evidence of cardiac disease. Because the definitions are variable, the term lone AF is potentially confusing, and should not be used to describe populations of patients with AF nor to guide therapeutic decisions.
      • January C.T.
      • et al.
      2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.
      The term chronic AF also has variable definitions and should not be used to describe populations of patients with AF.
      Table 1Atrial fibrillation definitions
      AF episodeAn AF episode is defined as AF that is documented by ECG monitoring or intracardiac electrogram monitoring and has a duration of at least 30 seconds, or if less than 30 seconds, is present throughout the ECG monitoring tracing. The presence of subsequent episodes of AF requires that sinus rhythm be documented by ECG monitoring between AF episodes.
      Chronic AFChronic AF has variable definitions and should not be used to describe populations of AF patients undergoing AF ablation.
      Early persistent AFEarly persistent AF is defined as AF that is sustained beyond 7 days but is less than 3 months in duration.
      Lone AFLone AF is a historical descriptor that is potentially confusing and should not be used to describe populations of patients with AF undergoing AF ablation.
      Long-standing persistent AFLong-standing persistent AF is defined as continuous AF of greater than 12 months’ duration.
      Paroxysmal AFParoxysmal AF is defined as AF that terminates spontaneously or with intervention within 7 days of onset.
      Permanent AFPermanent AF is defined as the presence of AF that is accepted by the patient and physician, and for which no further attempts to restore or maintain sinus rhythm will be undertaken. The term permanent AF represents a therapeutic attitude on the part of the patient and physician rather than an inherent pathophysiological attribute of AF. The term permanent AF should not be used within the context of a rhythm control strategy with antiarrhythmic drug therapy or AF ablation.
      Persistent AFPersistent AF is defined as continuous AF that is sustained beyond 7 days.
      Silent AFSilent AF is defined as asymptomatic AF diagnosed with an opportune ECG or rhythm strip.
      AF = atrial fibrillation; ECG = electrocardiogram.
      The writing group recognizes that these definitions of AF are very broad, and that additional details should be provided when describing a population of patients undergoing AF ablation. With the increased use of implantable loop recorders (ILRs), pacemakers, and implantable cardioverter-defibrillators for rhythm diagnosis, we urge the investigators to specify the duration of time patients have spent in continuous AF prior to an ablation procedure, including the 24-hour AF burden, when data are available. The investigators should also specify whether patients undergoing AF ablation have previously failed pharmacological therapy, electrical cardioversion, catheter and/or surgical ablation. Shown in Table 1 are a series of definitions of AF types that can be used for future trials of AF ablation and in the literature to help standardize reporting of patient populations and outcomes.

       Demographic Profile of Patients with AF and Risk Factors for Development of AF

      AF is an exceedingly common age-related arrhythmia. Among people of European descent, the lifetime risk of developing AF after age 40 is 26% for men and 23% for women.
      • Lloyd-Jones D.M.
      • et al.
      Lifetime risk for development of atrial fibrillation: the Framingham Heart Study.
      There are multiple risk factors for development of AF.
      • January C.T.
      • et al.
      2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.
      • Camm A.J.
      • et al.
      Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC).
      Some of these risk factors are modifiable, including hypertension, obesity, endurance exercise, obstructive sleep apnea (OSA), thyroid disease, and alcohol consumption, whereas many others are not.
      • January C.T.
      • et al.
      2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.
      • Camm A.J.
      • et al.
      Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC).
      • Benjamin E.J.
      • et al.
      Independent risk factors for atrial fibrillation in a population-based cohort: The Framingham Heart Study.
      • Miller J.D.
      • et al.
      Obesity, exercise, obstructive sleep apnea, and modifiable atherosclerotic cardiovascular disease risk factors in atrial fibrillation.
      • EHRA Scientific Committee Task Force
      • et al.
      European Heart Rhythm Association (EHRA)/European Association of Cardiovascular Prevention and Rehabilitation (EACPR) position paper on how to prevent atrial fibrillation endorsed by the Heart Rhythm Society (HRS) and Asia Pacific Heart Rhythm Society (APHRS).
      Nonmodifiable risk factors include age, sex, family history, race, tall stature, and other types of heart and valvular disease.
      • January C.T.
      • et al.
      2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.
      • Camm A.J.
      • et al.
      Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC).
      Among the many risk factors for development of AF, age is perhaps the most powerful.
      • Lloyd-Jones D.M.
      • et al.
      Lifetime risk for development of atrial fibrillation: the Framingham Heart Study.
      • Benjamin E.J.
      • et al.
      Independent risk factors for atrial fibrillation in a population-based cohort: The Framingham Heart Study.
      The relative risks (RRs) of AF development associated with a number of risk factors are provided in a recent systematic review.
      • Allan V.
      • et al.
      Are cardiovascular risk factors also associated with the incidence of atrial fibrillation? A systematic review and field synopsis of 23 factors in 32 population-based cohorts of 20 million participants.
      It is rare to develop AF prior to age 50; and by age 80, approximately 10% of individuals are diagnosed with AF. The precise pathophysiological basis of this link between AF and age is not completely understood; however, age-related fibrosis likely plays a key role.
      • Benjamin E.J.
      • et al.
      Independent risk factors for atrial fibrillation in a population-based cohort: The Framingham Heart Study.
      AF risk factors have also been shown to be of value in predicting progression of paroxysmal to persistent AF.
      • de Vos C.B.
      • et al.
      Progression from paroxysmal to persistent atrial fibrillation clinical correlates and prognosis.
      It is notable that many of the risk factors that have been associated with development of AF also contribute to AF progression, recurrences of AF following ablation, and complications associated with AF (e.g., stroke).

       Natural History of AF

      The concept of “AF begets AF” remains a cornerstone in the understanding of the natural history of AF progression.
      • Wijffels M.C.
      • et al.
      Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats.
      Increasing AF burden is associated with progressive atrial remodeling and the development of atrial fibrosis, which can contribute to the long-term persistence of AF.
      • Walters T.E.
      • et al.
      Progression of atrial remodeling in patients with high-burden atrial fibrillation: Implications for early ablative intervention.
      A wealth of experimental data exist regarding structural and functional atrial changes that contribute to the development, maintenance, and progression of AF. In contrast, considerably less data exist regarding the natural history of AF.
      • Wakili R.
      • et al.
      Recent advances in the molecular pathophysiology of atrial fibrillation.
      • Heijman J.
      • et al.
      Cellular and molecular electrophysiology of atrial fibrillation initiation, maintenance, and progression.
      This is in large part related to the difficulty in accurately assessing the underlying burden of AF in individuals and large populations. Thus, estimates of the prevalence of clinical AF subtypes and their progression have evolved with the changes in population characteristics, associated comorbidities, and development of modern arrhythmia monitoring technology. For example, the rate of progression appears to be very low in individuals with an initial diagnosis of AF who are younger than 60 years of age and who have no concomitant heart disease. Among 97 individuals followed over three decades, 21% had an isolated AF event without further recurrence, 58% had recurrent AF, and 22% developed persistent AF.
      • Kopecky S.L.
      • et al.
      The natural history of lone atrial fibrillation. A population-based study over three decades.
      Other longitudinal studies have demonstrated a much higher rate of AF progression. One recent study examined the rate of progression to persistent AF among 1219 paroxysmal patients with AF.
      • de Vos C.B.
      • et al.
      Progression from paroxysmal to persistent atrial fibrillation clinical correlates and prognosis.
      Progression to persistent AF was observed in 15% of the patients over 12 months of follow-up. Predictors of progression included age, hypertension, prior transient ischemic attack (TIA) or stroke, and chronic obstructive pulmonary disease. Similar results were reported in another recent study that examined AF progression while waiting for an AF ablation procedure.
      • Kochhauser S.
      • et al.
      Predictors for progression of atrial fibrillation in patients awaiting atrial fibrillation ablation.
      Among 564 patients with PAF, 11% progressed to persistent AF during a 10-month follow-up period. In this study, heart failure (HF) and a left atrial (LA) diameter >45 mm were predictive of progression. These findings raise the possibility that the clinical progression of AF could be driven by the development of associated comorbidities as opposed to the arrhythmia itself. Moreover, recent studies using pacemaker-documented AF burden have demonstrated a more complex natural history of the arrhythmia, with persistent AF reverting to paroxysmal forms, without intervention.
      • Sugihara C.
      • et al.
      The development of AF over time in patients with permanent pacemakers: objective assessment with pacemaker diagnostics demonstrates distinct patterns of AF.
      This highlights our incomplete understanding of the natural history of clinical AF and the need for larger studies focusing on the accurate assessment of AF progression and regression.

       Genetic Contribution to AF

      It is now well recognized that AF is heritable.
      • Fox C.S.
      • et al.
      Parental atrial fibrillation as a risk factor for atrial fibrillation in offspring.
      • Arnar D.O.
      • et al.
      Familial aggregation of atrial fibrillation in Iceland.
      • Lubitz S.A.
      • et al.
      Association between familial atrial fibrillation and risk of new-onset atrial fibrillation.
      Individuals having a first-degree relative with AF have approximately a 40% increased risk for development of AF after accounting for established clinical AF risk factors.
      • Lubitz S.A.
      • et al.
      Association between familial atrial fibrillation and risk of new-onset atrial fibrillation.
      In the last decade, great progress has been made in identifying the genetic determinants of AF. Although studies of families with AF have led to the identification of mutations in a series of ion channels and molecules, these mutations are typically family-specific, rare, and do not explain a significant portion of the heritability of AF.
      • Christophersen I.E.
      • Ellinor P.T.
      Genetics of atrial fibrillation: from families to genomes.
      Therefore, population-based or genome-wide studies have been used to identify many AF risk loci.
      • Gudbjartsson D.F.
      • et al.
      Variants conferring risk of atrial fibrillation on chromosome 4q25.
      • Benjamin E.J.
      • et al.
      Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry.
      • Gudbjartsson D.F.
      • et al.
      A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke.
      • Ellinor P.T.
      • et al.
      Common variants in KCNN3 are associated with lone atrial fibrillation.
      • Ellinor P.T.
      • et al.
      Meta-analysis identifies six new susceptibility loci for atrial fibrillation.
      • Sinner M.F.
      • et al.
      Integrating genetic, transcriptional, and functional analyses to identify 5 novel genes for atrial fibrillation.
      The genes at these loci encode transcription factors and ion channels, and many are without a clear relation to AF at the present time.
      There is interest in trying to use genetics to predict the onset of AF, to stratify the risk of AF outcomes such as stroke and HF, and to identify the response to treatments including antiarrhythmic medications or catheter ablation procedures. Interestingly, a genetic risk score consisting of the top 12 loci for AF can be used to identify as much as a 5-fold gradient in the risk of AF or those at greatest risk for a stroke.
      • Lubitz S.A.
      • et al.
      Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese.
      • Tada H.
      • et al.
      Twelve-single nucleotide polymorphism genetic risk score identifies individuals at increased risk for future atrial fibrillation and stroke.
      However, similar to other common diseases, the genetic risk for AF provides minimal additional predictive value after considering basic clinical risk factors such as age and sex.
      • Everett B.M.
      • et al.
      Novel genetic markers improve measures of atrial fibrillation risk prediction.
      • Lubitz S.A.
      • et al.
      Genetic risk prediction of atrial fibrillation.
      Future studies will be directed at using a comprehensive panel of genetic variants to identify those at greatest risk for AF, and also to predict stroke risk and outcomes to AF therapy, including AF ablation.
      • Hucker W.J.
      • et al.
      Atrial fibrillation genetics: is there a practical clinical value now or in the future?.
      Whether genetic testing will ultimately prove to be an important clinical marker of AF risk will become clear over time. An alternative and/or complementary strategy, which might be easier for clinicians to employ, will be the use of a clinical risk score.

       Genetic Determinants of Ablation Outcome

      Because many genetic determinants of AF have been identified, a logical question would be to ask whether genetics can help predict the outcome of an ablation procedure.
      • Hucker W.J.
      • et al.
      Atrial fibrillation genetics: is there a practical clinical value now or in the future?.
      At the present time, however, whether genetics will help predict outcomes remains an unanswered question. Although there have been a number of studies exploring the relation between a genetic variant or single nucleotide polymorphism (SNP) and AF ablation outcome, these studies have been challenged by small sample sizes, testing of a limited number of SNPs, and variable endpoints.
      One recent study pooled ablation data from three different sites consisting of 991 individuals of European ancestry.
      • Shoemaker M.B.
      • et al.
      Common genetic variants and response to atrial fibrillation ablation.
      They tested representative SNPs at the top three loci (PITX2, ZFHX3, and KCNN3) identified for AF in genome-wide association studies and related these SNPs to ablation outcome. The primary finding was that an SNP, rs2200733, at the chromosome 4q25 or the PITX2 locus for AF was associated with a 1.4-fold increased risk of late AF recurrence. In contrast, another recent study found differing results in a large Korean population of 1068 individuals undergoing catheter ablation for AF.
      • Choi E.K.
      • et al.
      Korean Atrial Fibrillation (AF) Network: genetic variants for AF do not predict ablation success.
      This second study tested a similar set of SNPs, representing the PITX2, ZFHX3, and KCNN3 loci, yet they did not observe any long-term difference in AF recurrence after an ablation.
      It is possible that the different outcomes noted in these two studies are due to a racial difference in the genetic influence on ablation outcome, although future studies will be necessary to resolve this issue. Larger, prospective, multiethnic studies that test a comprehensive number of SNPs will be necessary before genetic data can be considered clinically useful when considering AF ablation procedures.

       Significance of AF

      AF is an important arrhythmia for many reasons. First, it is common: current estimates reveal that more than 33 million individuals worldwide have AF.
      • Chugh S.S.
      • et al.
      Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study.
      In the United States alone, it is estimated that between 3 and 5 million people have AF, and that by 2050 this number will exceed 8 million.
      • Colilla S.
      • et al.
      Estimates of current and future incidence and prevalence of atrial fibrillation in the U.S. adult population.
      Second, AF increases risk of stroke by an average of 5-fold.
      • Kannel W.B.
      • et al.
      Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: population-based estimates.
      AF-related strokes are more severe than those not related to AF.
      • Miller P.S.
      • Andersson F.L.
      • Kalra L.
      Are cost benefits of anticoagulation for stroke prevention in atrial fibrillation underestimated?.
      Third, AF increases mortality, and has been linked to an increased risk of sudden death.
      • Miyasaka Y.
      • et al.
      Mortality trends in patients diagnosed with first atrial fibrillation: a 21-year community-based study.
      • Chen L.Y.
      • Benditt D.G.
      • Alonso A.
      Atrial fibrillation and its association with sudden cardiac death.
      Consistent with these prior studies, a recent Framingham study reported that those with recurrent or sustained AF had a higher multivariable-adjusted mortality compared with those with an isolated AF episode.
      • Lubitz S.A.
      • et al.
      Atrial fibrillation patterns and risks of subsequent stroke, HF, or death in the community.
      Fourth, AF increases the risk of HF.
      • Wang T.J.
      • et al.
      Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: the Framingham Heart Study.
      Fifth, recent studies have linked AF with the development of dementia.
      • Jacobs V.
      • et al.
      Atrial fibrillation and dementia.
      Finally, AF causes a wide variety of symptoms, including fatigue and reduced exercise tolerance, and significantly impairs quality of life (QOL).
      • Dorian P.
      • et al.
      The impairment of health-related quality of life in patients with intermittent atrial fibrillation: implications for the assessment of investigational therapy.
      It is notable that asymptomatic status is associated with similar (or worse) prognosis compared with symptomatic status.
      • Boriani G.
      • et al.
      Asymptomatic atrial fibrillation: clinical correlates, management, and outcomes in the EORP-AF Pilot General Registry.
      AF is also important when considered in terms of use of health care resources and cost. In the United States, AF accounts for more than 450,000 hospitalizations yearly and has contributed to more than 99,000 deaths.
      • Kim M.H.
      • et al.
      Estimation of total incremental health care costs in patients with atrial fibrillation in the United States.
      • Go A.S.
      • et al.
      Executive summary: heart disease and stroke statistics–2014 update: a report from the American Heart Association.
      AF has been reported to increase annual health care costs by $8700 per patient, resulting in a $26 billion annual increase in U.S. health care costs. Although studies have not been performed to address the question of whether AF control with catheter ablation impacts the morbidity and mortality associated with AF, it is notable that emerging data have revealed that persistent forms of AF are associated with a significant increase in thromboembolism and death compared with PAF.
      • Ganesan A.N.
      • et al.
      The impact of atrial fibrillation type on the risk of thromboembolism, mortality, and bleeding: a systematic review and meta-analysis.
      The morbidity and mortality associated with AF provide a rationale to maintain sinus rhythm. Given the anticipated enormous public health impact of AF, proven interventions to reduce the risk of stroke, HF, cognitive impairment, and mortality are direly needed. Large, prospective, multicenter, randomized clinical trials will help address whether sinus rhythm achieved with ablation techniques lowers morbidity and mortality compared with rate control alone or treatment with antiarrhythmic therapy. These studies will also best define the patient population that will derive the most benefit. Until the results of these types of clinical trials are available, it must be recognized that the only proven benefit of AF ablation remains the reduction of symptoms and an improvement in QOL.

       Relationship Between Presence and Type of AF and Symptoms

      During the past 15 years, multiple studies have investigated the impact of rate vs rhythm control on stroke risk and mortality.
      • Van Gelder I.C.
      • et al.
      A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation.
      • Wyse D.G.
      • et al.
      A comparison of rate control and rhythm control in patients with atrial fibrillation.
      • Carlsson J.
      • et al.
      Randomized trial of rate-control versus rhythm-control in persistent atrial fibrillation: the Strategies of Treatment of Atrial Fibrillation (STAF) study.
      • Roy D.
      • et al.
      Rhythm control versus rate control for atrial fibrillation and HF.
      These studies have demonstrated no difference in these endpoints. When interpreting the results of these studies, it is important to keep in mind the population of patients who were enrolled, the approach used for rhythm control, and the duration of follow-up. These studies enrolled predominantly elderly, minimally symptomatic patients with AF in whom either a rate or rhythm control strategy would be acceptable; the mean duration of follow-up was less than 4 years. The primary indication for catheter ablation is to reduce patient symptoms and improve QOL. Therefore, prior to undergoing catheter ablation, it is important to confirm that the patient's symptoms (palpitations, fatigue, or effort intolerance) result from AF and to assess their severity. In some patients with PAF, arrhythmia-monitoring tools (e.g., transtelephonic monitoring, Holter) are useful to establish the correlation between symptoms and rhythm. In patients with persistent AF who initially appear to be asymptomatic, a reassessment of symptoms after restoration of sinus rhythm with cardioversion often reveals that the patient does in fact feel better when in sinus rhythm. Because of this observation, many experienced clinicians routinely recommend cardioversion with a reassessment of symptoms in apparently asymptomatic patients with persistent AF. If the patient is ultimately demonstrated to be symptomatic, a rhythm control strategy becomes an attractive therapeutic approach. Conversely, if there is no change in symptoms postrestoration of sinus rhythm, a rate control strategy could be preferable.
      Several AF ablation studies evaluated the relationship between patient characteristics and the presence of AF symptoms.
      • Hindricks G.
      • et al.
      Perception of atrial fibrillation before and after radiofrequency catheter ablation: relevance of asymptomatic arrhythmia recurrence.
      • Vasamreddy C.R.
      • et al.
      Symptomatic and asymptomatic atrial fibrillation in patients undergoing radiofrequency catheter ablation.
      • Verma A.
      • et al.
      Discerning the incidence of symptomatic and asymptomatic episodes of atrial fibrillation before and after catheter ablation (DISCERN AF): a prospective, multicenter study.
      It is well recognized that patients' perception of AF varies widely. One of the first studies to examine AF symptoms prior to and following ablation found that among 114 patients who underwent 7-day Holters prior to and following ablation, 38% of the patients had only symptomatic AF episodes, 57% had both symptomatic and asymptomatic episodes, and 5% of the patients had only asymptomatic episodes. Following the ablation, the percentage of patients with only asymptomatic episodes of AF increased to 37%.
      • Hindricks G.
      • et al.
      Perception of atrial fibrillation before and after radiofrequency catheter ablation: relevance of asymptomatic arrhythmia recurrence.
      Asymptomatic AF is more frequent in men than in women.
      • Boriani G.
      • et al.
      Asymptomatic atrial fibrillation: clinical correlates, management, and outcomes in the EORP-AF Pilot General Registry.
      • Rienstra M.
      • et al.
      Asymptomatic persistent atrial fibrillation and outcome: results of the RACE study.
      • Siontis K.C.
      • et al.
      Typical, atypical, and asymptomatic presentations of new-onset atrial fibrillation in the community: Characteristics and prognostic implications.
      In two prospective registries and in one recent retrospective study, older age was associated with asymptomatic AF.
      • Boriani G.
      • et al.
      Asymptomatic atrial fibrillation: clinical correlates, management, and outcomes in the EORP-AF Pilot General Registry.
      • Siontis K.C.
      • et al.
      Typical, atypical, and asymptomatic presentations of new-onset atrial fibrillation in the community: Characteristics and prognostic implications.
      • Reynolds M.R.
      • et al.
      Influence of age, sex, and atrial fibrillation recurrence on quality of life outcomes in a population of patients with new-onset atrial fibrillation: the Fibrillation Registry Assessing Costs, Therapies, Adverse events and Lifestyle (FRACTAL) study.
      Inconsistent results have been reported for the association between asymptomatic AF and cardiac and noncardiac comorbidities.
      • Boriani G.
      • et al.
      Asymptomatic atrial fibrillation: clinical correlates, management, and outcomes in the EORP-AF Pilot General Registry.
      • Rienstra M.
      • et al.
      Asymptomatic persistent atrial fibrillation and outcome: results of the RACE study.
      • Siontis K.C.
      • et al.
      Typical, atypical, and asymptomatic presentations of new-onset atrial fibrillation in the community: Characteristics and prognostic implications.
      Although any type of AF can be asymptomatic, asymptomatic AF is more common in patients with continuous persistent AF.
      • Boriani G.
      • et al.
      Asymptomatic atrial fibrillation: clinical correlates, management, and outcomes in the EORP-AF Pilot General Registry.
      In approximately half of the patients with highly symptomatic AF referred for catheter ablation, asymptomatic episodes are also present.