THE PRESENT AND FUTURE JACCCOUNCIL PERSPECTIVES
Atrial Fibrillation
JACC Council Perspectives
Mina K. Chung, MD,aMarwan Refaat, MD,bWin-Kuang Shen, MD,cValentina Kutyifa, PHD,dYong-Mei Cha, MD,e Luigi Di Biase, MD,fAdrian Baranchuk, MD,gRachel Lampert, MD,hAndrea Natale, MD,iJohn Fisher, MD,f Dhanunjaya R. Lakkireddy, MBBS,jon behalf of the ACC Electrophysiology Section Leadership Council
ABSTRACT
Atrialfibrillation (AF) is an increasingly prevalent arrhythmia; its pathophysiology and progression are well studied.
Stroke and bleeding risk models have been created and validated. Decision tools for stroke prophylaxis are evolving, with better options at hand. Utilization of various diagnostic tools offer insight into AF burden and thromboembolic risk. Rate control, rhythm control, and stroke prophylaxis are the cornerstones of AF therapy. Although antiarrhythmic drugs are useful, AF ablation has become a primary therapeutic strategy. Pulmonary vein isolation is the cornerstone of AF ablation, and methods to improve ablation safety and efficacy continue to progress. Ablation of nonpulmonary vein sites is increasingly being recognized as an important strategy for treating nonparoxysmal AF. Several new ablation techniques and technologies and stroke prophylaxis are being explored. This is a contemporary review on the prevalence, pathophysiology, risk prediction, prophylaxis, treatment options, new insights for optimizing treatment outcomes, and emerging concepts of AF. (J Am Coll Cardiol 2020;75:1689–713) © 2020 Published by Elsevier on behalf of the American College of Cardiology Foundation.
A
trialfibrillation (AF) is an increasingly prev- alent arrhythmia with significant health and socioeconomic impact. Therapeutic op- tions have expanded tremendously. This review summarizes current knowledge on the pathophysi- ology, prevention, and management of AF, including epidemiology, pathophysiology, predic- tive models for AF stroke risk, gaps in knowledge,and future directions for AF prevention and treat- ment (Central Illustration).
EPIDEMIOLOGY AND RISK FACTORS
GENERAL INCIDENCE AND PREVALENCE. AF affects w33 million people worldwide and>3 million in the United States (1); its incidence in the United States is
ISSN 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2020.02.025
The views expressed in this paper by the American College of Cardiology’s (ACC’s) Electrophysiology Section Leadership Council do not necessarily reflect the views of theJournal of the American College of Cardiologyor the ACC.
From theaCleveland Clinic, Cleveland, Ohio;bAmerican University of Beirut, Beirut, Lebanon;cMayo Clinic, Scottsdale, Arizona;
dState University of New York Rochester, Rochester, New York;eMayo Clinic, Rochester, Minnesota;fMontefiore Medical Center, Bronx, New York;gUniversity of Ottawa, Toronto, Ontario, Canada;hUniversity of Connecticut, New Haven, Connecticut;iTexas Cardiac Arrhythmia Institute, Austin, Texas; and thejKansas City Heart Rhythm Institute and Research Foundation, Overland Park, Kansas. Dr. Kutyifa has received research grants from Boston Scientific, ZOLL, and Biotronik; and has received consultant fees from Biotronik and ZOLL. Dr. Di Biase has served as a consultant to Medtronic, Biotronik, BWI, and Boston Scientific; and has received speaker/travel honoraria from Biosense Webster, St. Jude Medical (now Abbott), Boston Scientific, Medtronic, Biotronik, Pfizer, and Bristol-Myers Squibb. Dr. Baranchuk has received grants from Medtronic, Abbot, and Bayer; and has received honoraria from Medtronic, Abbot, Bayer, Pfizer, and Bristol-Myers Squibb. Dr. Lampert has received modest consulting honoraria and significant research grants from Medtronic; has received a significant research grant from St. Jude/Abbott; and has received a modest research grant (in kind) from Amgen. Dr. Natale has received consulting fees and honoraria from Medtronic, Boston Scientific, BWI, Baylis, and Abbott. Dr. Fisher has served as a consultant for Medtronic. Dr. Lakkireddy has served as a consultant for Abbott, Biotronik, BWI, Atricure, Northeast Scientific, Acutus, and Lifetech. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Manuscript received September 16, 2019; revised manuscript received February 7, 2020, accepted February 13, 2020.
Listen to this manuscript’s audio summary by Editor-in-Chief Dr. Valentin Fuster on JACC.org.
predicted to double from 1.2 to 2.6 million cases from 2010 to 2030, with an increase in prevalence from 5.2 million to 12.1 million (2) (Figure 1). The Framingham study (3) noted an increasing incidence and preva- lence of AF, but with trends toward improved survival, perhaps attributable to improved awareness and better treatment of AF and its causes. In contrast, a large United Kingdom study (4) reported increases in both AF incidence (mainly in patients age
>75 years) and global AF-associated mortal- ity from 1990 to 2010. Interestingly, in the Framingham study, obesity and diabetes increased, whereas smoking, moderate- heavy alcohol use, and hypertension decreased over time with little change in the associated hazards for AF (3). These epide- miological studies highlight the need for greater public awareness, screening and treatment for AF, and effective interventions to control modi- fiable risk factors.
RISK FACTORS FOR AF. Potentially modifiable AF risk factors include hypertension, coronary artery disease, valvular heart disease, heart failure, car- diomyopathy, diabetes mellitus, obesity, sleep ap- nea, hyperthyroidism, excessive alcohol, drugs, and extreme exertion (Figure 2). Less or nonmodifiable risk factors associated with AF include older age, lean body mass, height, and family history of AF.
Many of these conditions can lead to progressive alterations in atrial wall stress, pressure, and size with extracellular and cellular changes that increase susceptibility to AF. Evidence suggests genetic, nongenetic, environmental, and/or other stressor mechanisms may promote AF. The impact on AF of targeting reversible risk factors is a critical area in need of further study.
IMPACT OF AF ON OUTCOMES AND ECONOMICS.
Associated with ischemic, nonischemic, hypertro- phic, and infiltrative cardiomyopathies, AF is a major risk factor for new-onset heart failure with reduced or preserved ventricular dysfunction, stroke, dementia, and mortality. AF has significant economic impact:
data from 2001 suggested hospitalization costs for nonvalvular AF in the United States were $6.65 billion with outpatient costs of $1.53 billion and $235 million for drugs (5). Given the increasing prevalence of AF with aging of the population, as well as its marginal cost impact on comorbid conditions, such as heart failure or stroke, and advances in and cost of ablation therapies since then, the current economic impact is likely significantly higher (6).
AF PATHOPHYSIOLOGY AND GAPS FOR FUTURE STUDY
Despite significant progress, our understanding of AF pathophysiology remains suboptimal. As a result, most pharmacological and ablation strategies remain empirical.
TRIGGERS, ROTORS, AND SUBSTRATES FOR AF.
Achieving electrical isolation of triggers arising from the pulmonary vein (PV) ostia or antra has become the cornerstone of AF ablation since the report by Haissaguerre et al. (7) more than 20 years ago. Suc- cessful ablation requires isolation of all PV ostia, yet there remains a ceiling of 80% to 90% success even in lone paroxysmal AF, with much lower success rates for more persistent forms of AF or with structural heart disease. Ablation strategies for persistent AF remain controversial. Whether additional substrate ablation beyond pulmonary vein isolation (PVI) should be performed at initial ablation remains under active study. Targeted substrates have included the ligament of Marshall, superior vena cava, left atrial appendage (LAA), complex fractionated electrograms, and presumed areas of scar indicated by low ampli- tude electrograms or magnetic resonance imaging.
Mapping to identify atrial sites that give rise to ablatable rotors has yielded variable results (8).
Clinically, ablation ranges from point ablation to PV ostial ablation, to linear ablation connecting PVs or the mitral valve isthmus isolating the posterior wall or LAA, and to rotors. Work continues to determine the true nature or existence of rotors as a meaningful cause of AF and target for ablation.
The durability of PVI has also been problematic with a continuing incidence of late AF recurrence, sometimes occurring years after initially successful
HIGHLIGHTS
AF is a cardiovascular pandemic with a complex pathophysiology and contrib- utes to significant patient morbidity and mortality.
Emphasis is on early detection and intervention for stroke prophylaxis and disease progression.
Significant progress has been made in paroxysmal AF, but better understanding is needed on substrate progression, evo- lution of non-PV triggers, and a compre- hensive approach to multisystem risk factor modification.
A B B R E V I A T I O N S A N D A C R O N Y M S
AAD= antiarrhythmic drug AF= atrialfibrillation AI= ablation index DOAC= direct oral anticoagulant
ECG= electrocardiogram LA= left atrium LAA= left atrial appendage LAAC= left atrial appendage closure
LOE= level of evidence PV= pulmonary vein PVI= pulmonary vein isolation SVC= superior vena cava TIA= transient ischemic attack
ablation. AF recurrence after PVI has been attributed to non-PV triggers, recovery across ablation lines, or additional arrhythmogenicfibrotic substrates. Addi- tional study to improve the durability of ablation lines and PVI is needed.
AF AS A MANIFESTATION OF ATRIAL MYOPATHY.
AF may also represent a secondary manifestation of a progressive atrial cardiomyopathy (6,9) and may help to explain why some stroke events in patients with implanted devices fail to demonstrate a temporal relationship to preceding AF episodes. Whether AF itself or an atrial myopathy is primary or secondary remains a conundrum, but the predominant factors may evolve with disease progression. As AF burden progresses from paroxysmal to persistent and long- standing persistent AF, the role of PV triggers may reduce and that of non-PV triggers and atrial myopathic substrate may increase. The natural his- tory of AF can be variable (9). In some patients, fibrosis and cardiomyopathic changes appear to lead to AF; in others, paroxysmal AF progresses to an apparent atrial myopathy, and yet others have de- cades of paroxysmal AF without apparent progression
(9). Rapid progression of substrate seems to be more common in women with evidence of significant atrial scarring (10). Environmental or other occult factors, such as obstructive sleep apnea, obesity, alcohol, hypertension, other lifestyle stresses, or degenerative myoneuropathic mechanisms (11), may also contribute to the course of AF progression.
ROLE OF ATRIAL SCAR OR FIBROSIS. Atrialfibrosis or scarring is associated with increased risk of AF (6).
However, effective ablation forms atrial scars that electrically isolate the PVs or create lines of block that limit re-entrant activation. If AF is generated within the PVs, then PVI might prevent progressive changes in atrial tissue. In contrast, if AF results from a pro- gressive or preceding atrialfibrotic cardiomyopathy, then early ablation may be less critical or successful.
Whether ablation to homogenize scarred areas in the atria is beneficial is also under study. Subepicardial adipose tissue can undergo fibrotic transformation, perhaps mediated by lymphocytes (12), and may promote AF. Prevention of such fibrotic trans- formation may also be a reasonable direction for further research.
CENTRAL ILLUSTRATION Management of AF
Stroke Management
• Improved AF diagnostics-smart watches/monitors
• DOACs/Warfarin-efforts to improve compliance
• LAA exclusion-
epicardial/endocardial tools
Rhythm Control
• Antiarrhythmic drugs • Need improved safety and efficacy
• Ablation
• Trigger-PV and non-PV sources (LAA, PW, SVC.LoM) • Re-entry & substrate modification • Adjunctive strategies • Novel energy sources and catheters
• ↓ collateral damage while ↑ ablation efficacy • Adjunctive AF surgery
Secondary Prevention
• Aggressive integrated weight- loss programs
• Treat hypertension
• OSA - uncover, treat and improve compliance
• Heart failure RX
• Yoga/acupuncture
• Minimize alcohol consumption
• Stop smoking Access to Care
• Facilitate early and easy access to care
• Training physicians in
comprehensive AF Rx strategies
• Core curriculum advances in GME programs
Disease Awareness
• Grassroots level public awareness campaign
• Efforts from professional and patient advocacy
organizations
• Inter-societal collaboration
AF Management
Primary Prevention
• Risk factor management
• RAAS modulation
• Ideal body weight target
• Prophylactic PVI in high-risk patients while undergoing open-heart procedures
Chung, M.K. et al. J Am Coll Cardiol. 2020;75(14):1689–713.
Multiprolonged approach to AF management that stresses the role of disease awareness, access to care, prevention, and more targeted rhythm/rate control along with stroke management. AF¼atrialfibrillation; DOAC¼direct oral anticoagulantl; LAA¼left atrial appendage; OSA¼obsructive sleep apnea; PV¼pulmonary vein;
PVI¼pulmonary vein isolation; PW¼posterior wall; RAAS¼renin angiotensin activation system; SVC¼superior vena cava.
FIGURE 1 Probabilistic Range of Projected AF Prevalence
18.0 16.0 14.0 12.0 10.0 8.0 6.0 4.0 2.0 20.0
AF Prevalence (Millions)
0.0 2010
2029 2028 2027 2026 2025 20232024 2022 2021 2020 2019 2018 2017 2016 2015 2014 2013 2012 2011
2030
14%
12%
10%
8%
6%
4%
2%
16%
Prevalence of AF
0%
2007 2006 2005 2004 2003 2002
Year 2001 2000 1999 1998 1997
Male 60-69 Female 60-69
Male 80+
Female 80+
Male 20-59 Female 20-59
Male 70-79 Female 70-79
Blue dashed lineis the upper 10% likelihood estimate, thegray dotted lineis the lower 10% likelihood estimate, and thered solid lineis the base atrialfibrillation (AF) prevalence estimate with logarithmic incidence growth rate projection.
INFLAMMATION AND OXIDATIVE STRESS.Inflam- mation and oxidative stress have been associated with AF, particularly after cardiac surgery. Several inflammatory markers, including C-reactive protein, tumor necrosis factor, and interleukin-2, -6, and -8, have been associated with AF (13). Inflammation may also promote a prothrombotic state in AF through endothelial activation/damage, production of tissue factor from monocytes, increased platelet activation, and increased expression of fibrinogen (13). Low- grade systemic inflammation associated with obesity may affect the myocardium and contribute to the pathogenesis of obesity-associated AF. Recently both
“conventional” and human immunodeficiency vi- ruses have been associated with and implicated as potential causes of AF (14). Future investigations aimed at mitigating inflammatory, oxidative, or possibly even infectious stress appear appropriate.
ABNORMAL PROTEOSTASIS. Deposits of protein ag- gregates as amyloid have been documented by Congo red staining in human aged atria and are immunore- active for atrial natriuretic peptide (15). Atrial amy- loid is associated with persistent AF independent of age (15). Heat shock proteins (16) play a protective role in the heart, mitigating protein aggregation and
the negative remodeling effects of AF. Transition from paroxysmal to persistent AF is accompanied by a reduction in heat shock proteins (16). It is not yet known how to prevent the exhaustion of heat shock proteins or favor their production in patients with AF, but preclinical studies are ongoing.
NEURAL MECHANISMS/CARDIAC NERVE SPROUTING.
Neural mechanisms, including autonomic factors, have been associated with AF, with episodes occur- ring with excitement, stimulants, vagal stimulation, or medications such as digitalis. Ganglionated plexi are abundant in the atria, especially near PV ostia.
Plexi ablation remains a controversial strategy. Het- erogeneous sympathetic innervation occurs in con- ditions such as sick sinus syndrome and possibly ventricular pacing. Rapid atrial pacing also induces nerve sprouting, more pronounced in the left than right atrium (17), suggesting 1 pathophysiolog- ical basis for the concept that “AF begets AF.”
Autonomic interventions are the target of continuing studies.
GENETICS AND AF. Genetic abnormalities and chan- nelopathies have been associated with familial AF (18,19). However, the fact that common AF can be
FIGURE 2 Potential Modifiable and Nonmodifiable Risk Factors for AF
Atrial Fibrillation
Reversible Risk Factors
Non-reversible Risk Factors
Diabetes Mellitus
Alcohol Drugs Hyper-
thyroidism
Obesity
Heart Failure / Cardiomyo-
pathy Hypertension
Sleep Apnea Coronary
Artery Disease Valvular
Heart Disease Cardiac
Surgery
AF Risk Genotypes
Older
Age Height
Family History of
AF
Thefigure highlights various modifiable and nonmodifiable risk factors that are relevant to atrialfibrillation (AF). This provides a unique opportunity to influence the primary and secondary prevention pathways in managing patients with AF or at risk for AF.
heritable (20,21) is confirmed by genome-wide asso- ciation studies that have identified over 100 loci associated with AF risk (Figure 3) (22,23). Top variants are on chromosome 4q25, nearPITX2, a gene involved with PV formation and suppression of a left atrium
(LA) sinus node program (24–26). The exact biological pathways involving these loci and their direct con- nections to AF, panels of potential screens for genetic testing, and new genome-based personalized thera- pies for AF remain under investigation.
FIGURE 3 Genome-Wide Association Studies of AF
520
–log10 (p Value) 30
20
10
0
1 2 3 4 5 6 7
Chromosome
8 9 10 12 14 16 18 21
A
500 400 300 200 100 25
Association (–log10 (p Value)) 30
5 15 20
10
0 1 2 3 4 5 6 7
Genomic Position
8 9 10 12 14 16 18 19 17 15 13 11
22 21 X
B
Known Loci Novel Loci
(A)Manhattan plot of combined-ancestry genome-wide association study (GWAS) meta-analyses (61).(B)Large atrialfibrillation (AF) GWAS reporting over 100 associated loci. PITX2 and ZFHX3 stand out to be potential influencers in increasing the risk of AF. Several new chro- mosomes and loci are being currently investigated.
PREDICTION MODELS FOR AF
PREDICTION OF RISK FOR AF. Prediction models for assessing AF risk in the general population are important for targeting primary prevention strate- gies. Although developed for thromboembolic risk prediction in AF, CHADS2 (congestive heart failure, hypertension, age 75 years, diabetes mellitus, prior stroke or transient ischemic attack) score $2 and CHA2DS2-VASc (congestive heart failure, hyperten- sion, age$75 years, diabetes mellitus, prior stroke or transient ischemic attack, vascular disease, age 65 to 74 years, female) score$3 have been independently associated with increased risk of subsequent new- onset AF in patients presenting with symptoms or signs suggestive of cardiac arrhythmia but no docu- mented AF (27). Both scores are significant predictors of post-cardiac surgery AF. The most recent scoring system is the CHARGE-AF (Cohorts for Heart and Aging Research in Genomic Epidemiology—Atrial Fibrillation) model (Table 1) (28), which was validated in 2 additional cohorts and demonstrated excellent discrimination, but overestimated the risk of AF, requiring recalibration (29,30). The CHARGE-AF risk score appears superior to CHA2DS2-VASc in predicting risk of AF (31). Electrocardiogram (ECG)-derived var- iables, including PR interval, P-wave duration, area and terminal force, and left ventricular (LV) hyper- trophy, in the CHARGE-AF score added only marginal predictive value beyond clinical variables. Other predictors of AF risk include echocardiographic LA diameter (32), tissue Doppler imaging–derived atrial conduction time for post-operative or new-onset AF (33), multidetector computed tomography estimation of periatrial epicardial adipose tissue for new-onset AF in coronary artery disease patients (34), frequent atrial ectopy (>76/day) for new-onset AF at 10-year follow-up (35), and >32 beats/h with >90% speci- ficity for predicting AF at 15 years in the Cardiovas- cular Health Study (36).
The HATCH score (Table 2) predicts progression from paroxysmal to persistent AF (37) and also new- onset AF after atrialflutter ablation (38).
CHADS2 (Table 3), CHA2DS2-VASc (Table 4), and R2CHADS2have been utilized to predict AF recurrence after catheter ablation, but with only modest predic- tive value (39). Late gadolinium enhancement mag- netic resonance imaging is used in some centers to triage AF patients prior to ablation. Extensive late gadolinium enhancement ($30% LA wall enhance- ment), indicating LA wall structural remodeling, predicts high recurrence rates after catheter ablation (40). However, whether outcomes are improved by use of these predictive models to either stratify
candidacy for ablation or to determine ablation stra- tegies remains to be demonstrated.
AF AND STROKE: COMPLEXITIES OF PREDICTION, MONITORING, AND DECISION MAKING
PREDICTION OF STROKE AND BLEEDING RISKS.
Prediction of thromboembolic risk from AF, coupled with prediction scores for bleeding risk from anti- coagulation, forms the basis of anticoagulation stra- tegies to reduce stroke risk in AF patients. CHADS2
(Table 3) and CHA2DS2-VASc (Table 4) scores were originally developed to predict risk of stroke in AF patients (41–43). CHA2DS2-VASc, the most commonly used risk stratification score, has high accuracy/
specificity for low or intermediate risk, but low specificity for high risk (44). Bleeding risk prediction models for AF patients include HAS-BLED (Hyper- tension, Abnormal liver or renal function, Stroke, Bleeding, Labile INRs, Elderly (>65 years), Drugs or ETOH) (Table 5), HEMORR2HAGES (Hepatic or Renal Disease, Ethanol Abuse, Malignancy History, Older than age 75, Reduced platelet count or function, Rebleeding risk, Hypertension, Anemia, Genetic
TABLE 1 CHARGE-AF Scoring System for Prediction of Risk for AF
Coefficientper Increment
Age 0.508 x (per 5 yrs)
Height 0.248 x (per 10 cm)
Weight 0.115 x (per 15 kg)
Systolic BP 0.197 x (per 20 mm Hg)
Diastolic BP 0.101 x (per 10 mm Hg)
Current smoker 0.359
Antihypertensive medication 0.349
Diabetes 0.237
Congestive heart failure 0.701
Myocardial infarction 0.496
LVH by electrocardiogram PR interval (<120 vs. 120–199 ms) PR interval (>199 vs. 120–199 ms)
BP¼blood pressure; LVH¼left ventricular hypertrophy.
TABLE 2 HATCH Score for Prediction of Progression From Paroxysmal to More Persistent AF and Prediction of New AF After Atrial Flutter Ablation
H Hypertension 1
A Age$75 yrs 1
T Transient ischemic attack or stroke 2
C Chronic obstructive pulmonary disease 1
H Heart failure 2
AF¼atrialfibrillation.
factors [CYP2C9 single nucleotide polymorphisms], Excessive fall risk, Stroke history), ATRIA (anemia, severe renal disease, Age 75 or older, Any prior hemorrhage diagnosis, Hypertension history), and ORBIT (Outcomes Registry for Better Informed Treatment). HAS-BLED has significantly better pre- dictive ability for clinically relevant bleeding and equal predictive ability for major bleeding compared with other bleeding risk scores (45).
The SAMe-TT2R2 (Sex, Age [above or below 60], medical history [2 or more from - hypertension, dia- betes mellitus, coronary artery disease, peripheral artery disease, congestive heart failure, pulmonary disease, hepatic disease or renal disease], Treatment [medication interaction], Tobacco use, Race [non- caucasian]) scoring system helps decision making regarding oral anticoagulation. Patients with low SAMe-TT2R2score (0 to 1) usually do well on warfarin, whereas those with scores >1 may benefit from additional interventions or direct oral anticoagulants (DOACs) to achieve acceptable anticoagulation con- trol (46). Future development of additional or expanded patient decision tools for anticoagulation decision making may be helpful and should include consideration of the risk of thromboembolism versus bleeding, warfarin versus DOACs, and potentially also nonpharmacological therapies, such as LAA exclusion.
Various biomarkers have been tested as predictors of clinical outcomes in patients with AF. N-terminal fragment B-type natriuretic peptide and high
sensitivity cardiac troponin have been independently associated with risk of stroke in AF (47). Combined with age and clinical history, this combination has been touted as superior to the CHA2DS2-VASc score as a predictor of clinical outcomes, particularly stroke (47). Further progress is expected in this area.
SCREENING AND MONITORING DEVICES IN THE DETECTION OF AF. Opportunistic screening for AF is recommended by pulse taking or ECG rhythm strip in patients>65 years of age (Class I, Level of Evidence [LOE]: B), and systematic ECG screening may be considered for patients age>75 years or those at high stroke risk (Class IIb, LOE: B) (48). In patients with transient ischemic attack (TIA) or ischemic stroke, screening for AF is recommended by short-term ECG monitoring followed by continuous ECG monitoring for at least 72 h (48). In stroke patients, long-term noninvasive ECG monitors or implantable cardiac monitors should be considered to document silent AF. In patients with cryptogenic stroke or TIA, there is an incremental yield of prolonged electrocardio- graphic monitoring. AF detection rate was 2.2% with a 24-h Holter monitor and was 7.4% with 1-week, 11.6%
with 2-week, 12.3% with 3-week, and 14.8% with 4-week event recorders (49). Rates of AF detection at 3 years with an implantable cardiac monitor was 30.0% compared with 3.0% in the control arm of the CRYSTAL AF (Cryptogenic Stroke and Underlying Atrial Fibrillation) trial (50).
AF BURDEN AND THROMBOEMBOLISM.More advanced AF burden is associated with thromboembolism and worse prognosis (37). In the prospective observational TRENDS (Relationship Between Daily Tachyar- rhythmia Burden From Implantable Device Di- agnostics and Stroke Risk) study of 2,486 patients with a cardiac device (mean follow-up 1.4 years), there was a trend toward higher rate of thromboem- bolism (2.4%/year) with daily atrial tachycardia/AF burden$5.5 h, (hazard ratio [HR]: 2.2) compared with patients without such burden (51). AF episodes>24 h had an adjusted HR of 3.1 for thromboembolism in a prospective registry of 725 patients with dual-chamber pacemakers (median follow-up 22 months) (52).
SUBCLINICAL AF DETECTED BY CARDIAC IMPLANTABLE ELECTRICAL DEVICES.The detection of asymptomatic AF in patients with implanted pacemakers, de- fibrillators, or loop recorders raises the question of what AF burden is associated with higher risk of thromboembolism. Atrial high rate episodes lasting
>5 min are associated with risk of silent ischemic brain lesions in both the overall population and pa- tients without prior history of AF or stroke/TIA (53).
In 2,580 patients with pacemakers or defibrillators
TABLE 3 CHADS2Score for Prediction of Stroke in Atrial Fibrillation Patients
C Congestive heart failure 1
H Hypertension (>140/90 mm Hg) 1
A Age$75 yrs 1
D Diabetes mellitus 1
S2 Prior TIA or stroke 2
TIA¼transient ischemic attack.
TABLE 4 CHA2DS2-VASc Score for Prediction of Stroke in Atrial Fibrillation Patients
C Congestive heart failure 1
H Hypertension (>140/90 mm Hg) 1
A Age$75 yrs 2
D Diabetes mellitus 1
S2 Prior TIA or stroke 2
V Vascular disease (MI, aortic plaque, and so on) 1
A Age 65–74 yrs 1
Sc Sex category (female¼1 point) 1
MI¼myocardial infarction; TIA¼transient ischemic attack.
monitored for 3 months, subclinical atrial tachyar- rhythmia was detected in 10.1% at 3 months and independently associated with a 2.5-fold increased risk of ischemic stroke or systemic embolism (54).
In another study, subclinical AF on an implanted monitor was detected frequently in patients$65 years of age attending cardiovascular or neurology clinics (34.4%/year), although detection was not more common among patients with a prior stroke (55). Given the frequent detection of subclini- cal AF with long-term monitoring, authors urged caution in assuming AF causality after cryptogenic stroke (55). Nevertheless, Camm et al. (56) recom- mended consideration of anticoagulation in men with CHA2DS2-VASc$2 and in women with CHA2DS2-VASc score$3 with no history of ischemic stroke or AF and without clinical AF on 12-lead ECG or rhythm strip or Holter, if atrial high rate episodes on an implanted device exceeds 24 h. A determination of whether anticoagulation is useful in patients with subclinical AF awaits completion of ongoing clinical trials (ARTESiA [Apixaban for the Reduction of Thrombo- Embolism in Patients With Device-Detected Sub- Clinical Atrial Fibrillation] and NOAH-AF NET 6 [Non-vitamin K antagonist Oral anticoagulants in patients with Atrial High rate episodes] (57,58).
TEMPORAL RELATIONSHIP BETWEEN ATRIAL MYOPATHY AF AND THROMBOEMBOLISM. Implan- ted device data for 20 patients with ischemic stroke or systemic embolism in the TRENDS populations showed that the majority of ischemic stroke or sys- temic embolism did not occur in temporal proximity to recent atrial tachycardia/AF episodes (59), implying that thrombogenesis in patients with implantable devices may involve mechanisms other than cardioembolism due to atrial tachyarrhythmias.
Thromboembolic risk likely involves a complex interplay of atrial arrhythmia, atrial myopathy, stasis, endothelial damage or dysfunction related to comorbidities, and abnormal hemostasis. Atrial high- rate episodes may be a marker rather than the cause of embolic events, and stasis caused by AF is not the lone cause of thrombogenesis. Large randomized
trials like AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management) and RACE (Rate Control versus Electrical Cardioversion for Atrial Fibrillation) reported that risk of thromboem- bolism persisted even in AF patients who maintained sinus rhythm, although this may have been at least in part due to unrecognized asymptomatic AF (60).
Although there is an independent correlation be- tween atrial fibrosis and stroke (61), the relative contribution of atrial myopathy to thrombogenesis remains unclear. Recent studies hypothesize that the underlying atrial myopathy that causes AF can also affect thrombosis risk by modulating the atrial blood flow and/or the hemostatic profile, thereby increasing thromboembolic risk even in the absence of AF. Ef- forts to improve our understanding of the role of atrial myopathy in thrombogenesis might enhance risk stratification of stroke currently assessed by the clinical risk factors alone.
STRATEGIES FOR PRIMARY AND SECONDARY PREVENTION OF AF
Primary prevention of AF, aimed at preventing the onset of AF, has focused primarily on reversing the modifiable risk factors for AF (43). Secondary pre- vention of AF is aimed at reduction in AF burden and prevention of progression of AF to more persistent forms.
UPSTREAM TARGETS FOR PREVENTION OF AF. Up- stream therapies for AF refer to use of non–ion- channel drugs targeting atrial substrate or specific mechanisms of AF (62) (Figure 4). Studies have focused on anti-inflammatory agents, antioxidants, drugs targeting the renin-angiotensin-aldosterone system, and omega-3 polyunsaturated fatty acids.
To date, although retrospective and secondary ana- lyses of AF outcomes from randomized studies showed initial promise, the few randomized controlled studies performed have in general failed to establish AF-specific indications for these drugs outside of conditions for which they are already established. Exceptions may be steroid and statin therapy, which have shown promising results in preventing post-operative AF. Vitamin C (63) and omega-3 fatty acids (64) have shown mixed results, and the recently reported REDUCE-IT (Reduction of Cardiovascular Events with EPA-Intervention Trial) of a purified form of omega-3 fatty acids reported a higher rate of AF (65). Evidence for angiotensin- converting enzyme inhibitors and angiotensin re- ceptor blockers has been limited to secondary end- points or post hoc analysis, and suggests that they may reduce AF in patients with heart failure
TABLE 5 HAS-BLED Score for Prediction of Bleeding Risk
H Hypertension 1
A Abnormal liver or renal function 1 point each
S Stroke 1
B Bleeding 1
L Labile INRs 1
E Elderly (>65) 1
D Drugs or ETOH 1 point each
ETOH¼ethyl alcohol; INR¼international normalized ratio.
(66), LV dysfunction (66), post-myocardial infarction (67), hypertension with LV hypertrophy (68), or cardiovascular risk factors (69), although no differ- ences in AF were seen in studies enrolling patients
with hypertension only (70,71). Novel therapies tar- geting upstream pathways, such as proteostasis, metabolic stress, mitochondrial function, and fibrosis pathways, are being studied, mostly in
FIGURE 4 Targetable Upstream Pathways Predisposing to AF and AF Progression and Potential Drug Candidates
Patterns of Atrial Structural Remodeling 20
16 12 8 4 24
AT/AF Hours/Day 0
Day 20
16 12 8 4 24
AT/AF Hours/Day 0 20 16 12 8 4 24
AT/AF Hours/Day 0 50 4030 20 10 60
AT/AF Minutes/Day
Patterns of AF Burden
0
Atrial Fibrillation
• Steroids
• NSAIDs
• Statins
• Soluble epoxide hydrolase inhibitor
• Omega-3 polyunsaturated fatty acids
• Anti-oxidants
• Ascorbic acid (vitamin C)
• Vitamin E
• Carotenoids
• Omega-3 polyunsaturated fatty acids
• N-acetylcysteine
• Statins
• Angiotensin-converting enzyme (ACE) inhibitors
• Angiotensin receptor blockers (ARBs)
• Mineralocorticoid receptor antagonists (MRAs) - eplerenone
• Galectin-3 (Gal-3) inhibitors
• TGF-β inhibitors - Pirfenidone
• Geranylgeranyl acetone (GGA, teprenone)
• BGP-15
• 4-phenylbutyric acid (4-PBA, buphenyl)
• Rapamycin
• Histone deacetylase 6 (HDAC6) inhibitors - ricolinostat, tubastatin-A
• AMPK activators (Metformin, Resveratrol)
• PPARγ activators:
thiazolidinediones (TZDs) - pioglitazone
• Inhibitors of fatty acid oxidation - ranolazine, trimetazidine Inflammation Oxidative Stress Fibrosis Proteostasis Metabolic Stress
Thisfigure shows a comprehensive list of pathways that can be influenced for a potential therapeutic intervention. Various strategies impacting at a molecular level is at display. AF¼atrialfibrillation; AMPK¼AMP-activated protein kinase; AT¼atrial tachyarrhythmia; BGP-15¼O-(3-piperidino-2-hydroxy-1-propyl)nicotinic amidoxime;
NSAID¼nonsteroidal anti-inflammatory drug; PPAR¼peroxisome proliferator-activated receptor; TGF¼transforming growth factor.
cellular or animal models. At this time human data are lacking.
LIFESTYLE/RISK FACTOR MODIFICATION. Physical inactivity, obesity, smoking, alcohol consumption, and psychological stress can contribute to AF.
Although long-term, high-intensity vigorous endur- ance exercise, such as in marathoners or Nordic cross- country skiers, can increase the AF risk presumably due to atrial remodeling, elevated LA pressure, sinus bradycardia, and genetic predisposition, moderate exercise appears protective (72,73). A training pro- gram with $2 metabolic equivalents gained was linked to a 10% reduction in AF for each metabolic equivalent gained, highlighting the importance of cardiorespiratory fitness and training programs as powerful prevention tools (74). Lifestyle/risk factor modification studies in AF (LEGACY [Long-Term Ef- fect of Goal-Directed Weight Management in an Atrial Fibrillation Cohort: A Long-Term Follow-Up Study]
[75], CARDIO-FIT (Impact of CARDIOrespiratory FITness on Arrhythmia Recurrence in Obese
Individuals with Atrial Fibrillation) [74], and ARREST-AF (Aggressive Risk Factor Reduction Study for Atrial Fibrillation and Implications for the Outcome of Ablation) [76]), including weight loss and exercise, show very significant reductions in AF burden (Figure 5) (77). Yoga has similarly been sug- gested as a possible way to reduce AF occurrence; the YOGA My Heart study described a lower burden of both symptomatic and asymptomatic AF episodes (78). Substance use may be targetable for AF. Obser- vational studies strongly suggest higher AF preva- lence with alcohol use. Compared with nondrinkers, each drink/day increased AF risk by 8%, with up to a 47% increase for 5 drinks/day (79). As alcohol use has been reported by over 50% of Americans (80), focusing on alcohol use might be effective in reducing AF burden in the general population. Smoking has been associated with a 32% to 51% higher AF risk in the ARIC (Atherosclerosis Risk In Communities) (81) and Rotterdam studies (82). The ARIC study further suggested a trend toward a lower incidence of AF
FIGURE 5 Risk Factor Management and Lifestyle Modification in the LEGACY, ARREST-AF, and CARDIO-FIT Trials
Smoking cessation & alcohol abstinence (or reduction to 30 g per week)
Aggressive Risk Factor Management
• Educate for permanent lifestyle change
• Diet plan
• Initial target:
>10% weight loss
• Final target:
BMI <27 kg/m2
• Avoid weight fluctuation
• Exercise:
30 min for 3 - 4x per week
• Increase up to 250 minutes per week
• Initial lifestyle measures
• At 3 months:
Start statins if LDL >100 mg/dl
• Add fibrates if TG >230 mg/dl
• Start fibrates if TG >500 mg/dl
• Overnight sleep study
• CPAP if AHI ≥30;
or ≥20/h with resistant hypertension or daytime somnolence
• Check adherence:
regular CPAP machine data download
• Home BP diary:
2- 3x daily
• Reduce salt
• Start ACEI or ARB
• Target
<130/80 mm Hg (at rest) and <200/100 mm Hg (at peak exercise)
• Glucose tolerance test
• Lifestyle measures
• At 3 months:
Metformin if HbA1c >6.5%
• Diabetes clinic or endocrine review Weight
Management and Exercise
Hyperlipidemia Obstructive Sleep
Apnea Hypertension Diabetes
Thisfigure shows a comprehensive list of all clinically modifiable risk factors that can potentially affect AF patients. The role of risk factor modification has been well studied in the mentioned studies. ACEI¼angiotensin-converting enzyme inhibitor; AF¼atrialfibrillation; AHI¼apnea–hypopnea index; ARB¼angiotensin receptor blocker; ARREST-AF¼Aggressive Risk Factor Reduction Study for Atrial Fibrillation and Implications for the Outcome of Ablation; BMI¼body mass index; BP¼blood pressure; CARDIO-FIT¼Impact of CARDIOrespiratory FITness on Arrhythmia Recurrence in Obese Individuals with Atrial Fibrillation; CPAP¼continuous positive air pressure; LEGACY¼Long-Term Effect of Goal-Directed Weight Management in an Atrial Fibrillation Cohort: A Long-Term Follow-Up Study; LDL¼low-density lipoprotein; TG¼triglycerides. Reproduced with permission from Lau et al. (77).
after smoking cessation. However, the impact of smoking cessation on risk of AF has not been pro- spectively studied. Caffeine appears benign up to several cups of coffee per day (83).
Psychological stress may contribute to AF. Ten- sion, anger, and hostility are associated with 24%, 20%, and 30% higher AF risk (84). Reducing negative emotions and stress might reduce AF risk, especially in high-risk individuals (85).
Although lifestyle factors clearly contribute to the development of AF, preventive methods are scarce.
In the future, preventive methods aimed at high-risk individuals as well as targeting the general popula- tion might reduce AF burden and should be a priority.
CURRENT RECOMMENDATIONS ON PREVENTION.
As drugs targeting upstream pathways have not been demonstrated to reverse AF substrate, these thera- pies are not recommended for secondary prevention of AF in the absence of another indication (43). AF management guidelines recommend an angiotensin- converting enzyme inhibitor or angiotensin receptor blocker for primary prevention of new-onset AF as reasonable in patients with heart failure and reduced ventricular function (Class IIa, LOE: B) and may be considered in the setting of hypertension (Class IIb, LOE: B) (43). Statin therapy was also considered reasonable for primary prevention of post-operative AF after coronary artery surgery (Class IIb, LOE: B) (43). In contrast, lifestyle modifications to address the modifiable risk factors for AF remain potential targets (86). Weight loss combined with risk factor modifi- cation is recommended for overweight and obese patients with AF (Class I, LOE: B-R) (87).
THE FUTURE OF POTENTIAL UPSTREAM TARGETS AND AGENTS.Significant gaps remain in our under- standing of the genomic, structural, and electro- physiological connections that promote AF development and progression, as well as the mecha- nisms by which genetic variants cause AF. The ex- plosion of genomics, transcriptomics, and other
“omics” data in AF should be leveraged to provide more logical selection of upstream targets for study and to facilitate better stratification of molecular or clinical AF phenotypes that could drive personalized targeting of preventive therapies.
USING GENETICS TO TARGET AF THERAPY
AF “ABLATOGENOMICS.” As AF has been strongly associated with over 100 genetic loci (23,88), personalized genomics-based treatment could potentially guide AF therapy. Results of top AF risk loci in ablative therapies have been mixed (89–91).
This variability highlights the complexity of the un- derlying pathophysiological mechanisms of AF as well as challenges in using genetic information to stratify AF treatments. However, studies based on large cohorts of patients might provide strong evidentiary bases for future genome-based therapy for AF. A genetics substudy of the CABANA (Catheter ABlation vs. ANtiarrhythmic Drug Therapy in Atrial Fibrillation) trial may provide another large cohort for study.
POTENTIAL FOR GENE THERAPY IN AF.With ongoing advances in gene transfer, vector delivery, and AF target gene selection, gene therapy might be antici- pated to affect AF treatment in the future. Electro- poration has yet to be applied to AF gene delivery, although it is being studied for AF ablation. Epicardial gene painting, a novel method of vector delivery, might be suitable for the treatment of post-operative AF applied to the PVs (92). Although significant challenges remain, post-operative AF may be thefirst area targeted for AF gene therapy. This evolving area will continue to benefit from the rapid pace of dis- coveries that elucidate new molecular targets for AF.
TREATMENT
Following the initial assessment of patients with AF, treatment strategies need to be developed with 2 major goals: 1) preventing thromboembolism; and 2) symptom control with either a rhythm control or rate control strategy.
THROMBOEMBOLISM AND STROKE PREVENTION.
The LAA is the most common site of thrombus for- mation and subsequent systemic thromboemboliza- tion in patients with AF. Why the LAA becomes thrombogenic and arrhythmogenic remains unclear.
A complex interplay of pathophysiological factors could potentially affect the LAA in AF (Figure 6).
STROKE PREVENTION, ORAL ANTICOAGULATION, AND ANTIPLATELET STRATEGIES. Oral anti- coagulation therapy (OAT) (vitamin K antagonists [VKAs] or DOACs) remains thefirst-line treatment for stroke prevention in AF (43,48). CHADS2 and CHA2DS2-VASc are the 2 most commonly used stroke risk stratification models for patients with non- valvular AF. Current guidelines recommend using oral anticoagulation for CHA2DS2-VASc $2. More recent evidence shows a benefit of starting anti- coagulation even if 1 risk factor for stroke is present, that is, men with CHA2DS2-VASc score of 1 and women with CHA2DS2-VASc of 2 (93,94).
Earlier clinical trials evaluated antiplatelet thera- pies for stroke prevention in AF. In a meta-analysis,
aspirin (ASA) compared with placebo was associated with a 19% risk reduction for primary prevention of stroke (95). The ACTIVE-W (Atrialfibrillation Clopi- dogrel Trial with Irbesartan for prevention of Vascular Events) and ACTIVE-A studies showed that adjusted- dose warfarin is superior to clopidogrel plus ASA, and clopidogrel plus ASA is superior to ASA alone for stroke prevention (96,97). ASA therapy alone is often used for patients with low risk of stroke, that is, men with CHA2DS2-VASc score of 0 and women with CHA2DS2-VASc of 1.
Risk of bleeding continues to be a major limitation for all forms of OAT. A meta-analysis of major trials showed that DOACs outperformed warfarin in mini- mizing systemic thromboembolism, mortality, and intracranial bleeding with a slightly higher risk of gastrointestinal (GI) bleeding (98). A total of 50% of patients who have indications for OAT do not get it because of GI bleeding (99). In a study of whether DOACs would prevent major systemic thromboem- bolism in VKA-ineligible patients (100), a significant proportion of patients had recurrence of major bleeding while on DOACs. The use of octreotide was
associated with no recurrence of GI bleeding in 70%
of patients who were continued on OAT despite a history of GI bleeding while on OAT (101). This strat- egy might be helpful for patients with high risk of bleeding as a bridge to a more definitive LAA exclu- sion strategy. Empiric anticoagulation after crypto- genic stroke is not recommended even though a significant percentage will eventually have AF (102).
The most recent European and U.S. guidelines indi- cate a preference for DOACs in the absence of con- traindications (Class Ia). The use of ASA in low-risk patients is not recommended in the guidelines.
A number of special circumstances should be mentioned while discussing anticoagulation in AF:
1. Mounting evidence suggests that withholding anticoagulation with warfarin or DOACs is not required for catheter ablation of AF (103,104).
2. In AF patients undergoing PCI, triple therapy with ASA, P2Y12inhibitors, and anticoagulation has been associated with a higher risk of bleeding (105). In patients on anticoagulation and undergoing PCI, clopidogrel without ASA was associated with
FIGURE 6 Why Does the LAA Turn Pathologic in AF?
• Dilatation
• Patchy fibrosis
• Loss of contractility
• Endothelial changes
• Inflammation
• Stasis
• Altered platelet function
• ↑ wall stress
• Activation of de Bakker cells – focal triggers
• Re-entry due to patchy fibrosis
Arrhythmic substrate Upregulation of
RAAS Activation of Virchow’s triad Complex morphology
with higher arborization index (Non-chicken wing
morphology) Loss of booster/
reservoir function Smoke, sludge and
thrombus
AF/ AT/PAC HFpEF
HTN Age Genetics
Obesity OSA HFrEF
VHD
AF
Interplay of various risk factors in thrombogenicity and arrhythmogenesis of left atrial appendage in AF. Anatomic, histopathological, and physiological changes in the LAA resulting in loss of booster and reservoir function, activation of prothrombogenic state, and up-regulation of renin-angiotensin activation system combined with a complex of LAA morphology causes, sludging, smoke, and thrombus. Increased wall stress and activation of the de Bakker cells can initiate focal triggers, and patchy scar can result in re-entry, ultimately making the LAA arrhythmogenic. AF¼atrialfibrillation; AT¼atrial tachycardia; HFpEF¼heart failure with preserved ejection fraction; HFrEF¼heart failure with reduced ejection fraction; HTN¼hypertension; LAA¼left atrial appendage; OSA¼obstructive sleep apnea; PAC¼premature atrial contraction; RAAS¼renin angiotensin activation system; VHD¼valvular heart disease.
reduction in bleeding risk without increase in thrombotic events (106). Recently the PIONEER AF (Prevention of Bleeding in Patients with Atrial Fibrillation Undergoing PCI) trial showed low-dose rivaroxaban þ P2Y12 inhibitors or very low dose rivaroxaban along with dual antiplatelet therapy was associated with lower bleeding risk than triple therapy (107).
3. Interruption of OAC in the periprocedural period for noncardiac surgery should be individualized to the risk of thrombosis and bleeding. For patients with high thrombotic risk (e.g., mechanical pros- thetic valves), bridging is recommended (43), but in lower-risk patients, brief periods off of anti- coagulation appears safe based on the BRIDGE (Effectiveness of Bridging Anticoagulation for Surgery) (108) and BRUISE CONTROL-2 (A ran- domized controlled trial of continued versus interrupted direct oral anti-coagulant at the time of device surgery) (109). In patients who developed intracranial hemorrhage while on OAT, optimal timing for resumption of OAT is uncertain (110).
However, a recent large observational registry showed reintroduction of OAT was associated with reductions in all-cause mortality and ischemic
strokes (111). In AF patients with embolic stroke, OAT can be resumed as early as 24 to 48 h or after 1 to 2 weeks depending on the size of the infarct (112). With the availability of LAA closure devices, this patient population will be treated differently and data will continue to evolve.
MANAGEMENT OF BLEEDING IN PATIENTS ON OAT.
Once hemostasis is achieved, patients on VKA can receive prothrombin complex concentrate, fresh frozen plasma, vitamin K, or a combination depend- ing on the clinical situation. For DOACs, the U.S. Food and Drug Administration recently approved 2 reversal agents: idarucizumab, a monoclonal antibody that binds to dabigatran and is excreted renally, and andexanet, which is a modified recombinant deriva- tive of factor Xa that acts as a decoy receptor with a higher affinity to Xa inhibitors, including rivarox- aban, apixaban, and edoxaban, and binds the drug in the vascular system preferentially (113).
LEFT ATRIAL APPENDAGE CLOSURE. Utilization of percutaneous catheter-based endocardial and epicardial left atrial appendage closure (LAAC) tech- niques is increasing (Figure 7). Endocardial occlusion devices include the WATCHMAN (Boston Scientific,
FIGURE 7 Epicardial and Endocardial Left Atrial Appendage Closure Devices
Ultraseal Cardia
Pfm Pfm Medical
Watchman
Amulet
Lariat
Atriclip
LAmbre Lifetech Scientific
Sideris Patch Custom Medical Devices
Endocardial LAA Occluders Epicardial LAA Excluders
PLAATO Appriva Medical
WaveCrest Biosense Webster
Occlutech Occlutech
Other Endocardial LAA Occluders
Thisfigure illustrates various currently available left atrial appendage (LAA) closure devices in the market in different parts of the world. They can be primarily categorized into endocardial occluders and epicardial excluders. Amongst the endocardial occluders, Watchman and Amulet are more popular. Lariat is a suture ligation system and Atriclip is a cotton wrapped Nitinol clip deployed epicardially. There are various other less popular LAA occluder devices mostly available in the European market.
Natick, Massachusetts), Amplatzer Cardiac Plug/
Amulet (Abbott, Golden Valley, Minnesota), and many other occluders in use in different parts of the world. In warfarin-eligible nonvalvular AF patients, PROTECT-AF (WATCHMAN left atrial appendage system for Embolic Protection in Patients With Atrial Fibrillation) and PREVAIL-AF (Prospective Random- ized Evaluation of Watchman Left Atrial Appendage Closure Device in Patients with Atrial Fibrillation Versus Long-Term Warfarin Therapy) showed cumu- lative advantage of LAA occlusion over warfarin for major bleeding and death combined (114,115). Lariat suture ligation (SentreHEART Inc., Redwood City, California), used clinically through a 501K approval for tissue closure, requires endocardial transseptal and epicardial access. Although with initial safety concerns, the Lariat procedure performed similarly to WATCHMAN with use of a micropuncture pericardial access needle, peri-procedural drain, and colchicine (116). Atriclip, an epicardial surgical closure device, is used in both open and minimally invasive approaches with good safety and closure efficacy (117). Epicardial- based exclusion by Lariat electrically isolates the LAA, and may reduce AF burden and improve neurohormonal modulation (118) and LA reservoir and conduit functions (119,120). The aMAZE (LAA Ligation Adjunctive to PVI for Persistent or Long- standing Persistent Atrial Fibrillation;NCT02513797) trial is currently evaluating the adjunctive role of LAA ligation in AF ablation for nonparoxysmal AF after the promising results shown by the LAALA-AF (Left Atrial Appendage Ligation and Ablation for Persistent Atrial Fibrillation) registry (121).
Patient selection for LAAC is not clear based on the current evidence. The only available randomized tri- als on LAAC enrolled patients who could tolerate anticoagulation. In real-life, patients needing LAAC are at high risk of bleeding on OAC or have contra- indications to it. More recently, data from observa- tional studies like the EWOLUTION (Evaluating Real- Life Clinical Outcomes in Atrial Fibrillation Patients Receiving the Watchman Left Atrial Appendage Closure Technology), Multicenter Canadian trial, and the ASAP (ASA Plavix Feasibility Study with WATCHMAN Left Atrial Appendage Closure Technol- ogy) registry included patients with contraindications to anticoagulation. Strategies like octreotide bridging (101), shortened dual antiplatelet therapy, low-dose DOAC, or single antiplatelet regimens offer promise in patients who need post-LAAC anticoagulation and cannot tolerate it secondary to high bleeding risk.
With approved access to LAAC devices, enrollment in randomized trials evaluating the efficacy of LAAC in OAC-contraindicated patients would be difficult, as is
being demonstrated by the ongoing ASAP-TOO (Assessment of Watchman Device in Patients Un- suitable for Oral Anticoagulation) study. Currently, the role of DOACs compared with LAAC remains clear, but is being addressed by ongoing clinical trials (PRAGUE-17 [Left Atrial Appendage Closure vs. Novel Anticoagulation Agents in Atrial Fibrillation];
NCT02426944).
THERAPEUTIC STRATEGIES.R a t e v e r s u s r h y t h m c o n t r o l r e v i s i t e d .Two large randomized trials, AFFIRM (122) and RACE (60), specifically evaluated the outcomes of rate versus rhythm control in AF patients. AFFIRM (n ¼4,060 recurrent AF) found a trend toward a decrease in the primary endpoint of all-cause mortality in the rate control arm (HR: 0.87;
p ¼0.08), whereas no differences in cardiac death, arrhythmic death, or stroke were evident between the groups. A subsequent analysis suggested that any beneficial effects of antiarrhythmic drugs (AADs) might have been offset by their adverse effects, such that if an effective method for maintaining sinus rhythm with fewer adverse effects were available, it might be beneficial. RACE (n¼522 persistent AF) also found a trend toward a lower risk with rate control of the primary endpoint of cardiovascular death, admission for heart failure, thromboembolic event, severe bleeding, pacemaker implantation, or severe side effects from AADs, with an HR of 0.73 (p¼0.11), indicating a 27% risk reduction of events (60); quality of life was similar (123). These trials are fundamen- tally limited by the rhythm-control groups achieving low rhythm control at follow-up and large pro- portions of patients in rate-control groups achieving sinus rhythm, confounding interpretation. Both trials were conducted before PVI became a standard AF strategy and enrolled relatively older subjects (mean age 70 and 68 years, respectively). Some patient subsets (e.g., younger age, highly symptomatic, or with heart failure) may benefit from rhythm control as a bridge to definitive ablative therapy. Conversely, a rate-control strategy might be reasonable in signif- icantly older and frail patients, especially if they are asymptomatic with normal LV function.
Catheter-based ablation therapy for rhythm control may allow selected patients to discontinue OAT and/or AADs. The CABANA trial randomized patients to catheter ablation versus AAD therapy and demon- strated no significant difference in the primary endpoint of all-cause mortality, disabling stroke, serious bleeding, or cardiac arrest during 5-year follow-up in an intention-to-treat analysis. The sec- ondary endpoint of death and cardiovascular hospi- talization was significantly reduced in the ablation
group (51.7% vs. 58.1%), primarily due to a lower incidence of hospitalizations for AAD titration, toxicity, and pacemaker implantation (124).
RATE CONTROL STRATEGIES.The choice of therapy for rate control is typically based on hemodynamic status, AF duration, degree of symptoms, presence of heart failure, and other underlying diseases (43).
Beta-blockers are commonly used with good effi- cacy and favorable risk profile followed by non- dihydropyridine calcium-channel blockers, digoxin, and amiodarone. Intravenous administration of beta- blockers or nondihydropyridine calcium-channel blockers is highly effective in patients with acute symptoms if there is no pre-excitation present.
RATE CONTROL DRUGS. Rate control therapy needs to be chosen and titrated on an individual basis based on LV ejection fraction and comorbidities. Following initiation of therapy, continued follow-up is advised to optimize therapy and discontinue or adjust therapy due to side effects, if needed.
Beta-adrenergic blockers are the most commonly used rate control agents (122). In heart failure pa- tients, carvedilol was more effective for rate control when used in combination with digoxin, and was associated with improvement in symptom score, and LV function.
Nondihydropyridine calcium-channel blockers,such as diltiazem and verapamil, are effective in both acute and chronic AF management. They provide immediate rate control in acute settings, reduce resting and exercise heart rates, and improve exercise tolerance with chronic use. They are often used in combination with beta-blockers, but should be avoi- ded in patients with heart failure and manifest pre- excitation.
Digoxin is often used as a second-line chronic therapy to further reduce ventricular rate, although its effect is slow, and it is ineffective at controlling rate during exercise. Digoxin is primarily recom- mended in combination with beta-blockers or non- dihydropyridine calcium-channel blockers to improve ventricular rate control during exercise. Digoxin level and dose adjustments are recommended especially in the elderly and patients with kidney impairment. A large recent meta-analysis of the use of digoxin in AF patients showed that increased serum levels of digi- talis are associated with arrhythmias and increased mortality (125).
Target heart rates for rate control are generally#80 beats/min at rest and#110 beats/min during exercise (122). However, the RACE-II trial enrolled 614 per- manent AF patients with mostly normal LV function and suggested that lenient rate control with a resting
heart rate<110 beats/min is noninferior to strict rate control for the composite outcome of death from cardiovascular causes, hospitalization for heart fail- ure, stroke, systemic embolism, bleeding, and life-threatening arrhythmic events (126). Current American Heart Association/American College of Cardiology/Heart Rhythm Society guidelines suggest lenient heart rate control to be reasonable in asymp- tomatic AF patients with preserved LV function (Class IIb, LOE: B) (43).
ATRIOVENTRICULAR NODE ABLATION.Atrioven- tricular (AV) node ablation can be considered for tachycardia-induced cardiomyopathy when rate or rhythm control is not achieved using medical ther- apy. AV node ablation improves symptoms, quality of life, and health care utilization but it does not obviate the need for anticoagulation, it obligates pacemaker dependence, and in a proportion of patients, right ventricular pacing can cause pacing-induced cardio- myopathy. In patients with severely reduced LV ejection fraction, implantation of a cardiac resynch- ronization therapy system is indicated along with AV node ablation (127). Similarly, in patients with prior implanted pacemakers, AV node ablation, right ven- tricular pacing, LV dysfunction, and moderate to se- vere symptoms of heart failure, an upgrade to cardiac resynchronization therapy might be reasonable.
However, AV node ablation with biventricular pacing was not superior to PVI in reducing the symptoms of patients with AF and heart failure with reduced ejection fraction (#40%). The CASTLE-AF (Catheter Ablation vs. Standard Conventional Treatment in Patients with LV Dysfunction and AF) trial showed a mortality benefit of catheter ablation based rhythm control (128) with a significantly lower primary com- posite endpoint of all-cause mortality and heart fail- ure hospitalization than the medical therapy group (44.6% vs. 28.5%; HR: 0.62; p¼0.007).
PHARMACOLOGICAL RHYTHM CONTROL STRATEGIES.
When administered early and in appropriate doses, AADs increase the likelihood of sinus rhythm con- version to 90% (129). AADs act on the cardiac ion channels altering the channel structure, dynamics, or gating process through alteration of excitability, effective refractory period, conduction, or abnormal automaticity. Commonly used AADs are based on the Singh Vaughan classification.
Selection of antiarrhythmic drugs for long-term AF management is based on underlying heart disease, drug properties and side-effect profiles, and safety in the presence of structural heart disease. Only amio- darone and dofetilide have been shown not to in- crease mortality in patients with heart failure (130,131).
Structurally normal heart: Flecainide, prop- afenone, sotalol, dofetilide, dronedarone, amio- darone (second line).
Coronary artery disease: Sotalol (first line, beta- blockade activity), dofetilide, dronedarone, amio- darone (second line).
Congestive heart failure: Amiodarone, dofetilide.
Hypertension with no severe LV hypertrophy: fle- cainide and propafenone (first line, they do not prolong the QTc interval), amiodarone, dofetilide, or sotalol (second line).
Severe LV hypertrophy (>15 mm): Flecainide, propafenone, dofetilide, and sotalol are usually avoided.
NONPHARMACOLOGICAL RHYTHM CONTROL STRATEGIES:
ABLATION THERAPY.AF substrate may evolve with progression from paroxysmal to more persistent AF (Figure 8). Consequently, different ablation techniques have been utilized for different types of AF.
ABLATION IN PAROXYSMAL AF. Catheter ablation for symptomatic paroxysmal AF is recommended if AF is refractory or intolerant to at least 1 Class I or III AAD (Class I, LOE: A) and is reasonable prior to initi- ation of antiarrhythmic therapy with a Class I or III AAD (Class IIa, LOE: B-R) (132). In paroxysmal AF, electrical isolation of the PVs is the cornerstone of ablation technique by creation of circumferential le- sions around the right and the left PV antrum.
Achievement of electrical isolation requires, at a minimum, assessment and demonstration of PV
entrance and exit block (Class I, LOE: B-R). Moni- toring for PV reconnection for 20 min following initial PV isolation is reasonable (Class IIa, LOE: B-R).
Administration of adenosine 20 min following initial PVI using radiofrequency (RF) energy with re- ablation if PV reconnection (Class IIb, LOE: B-R), use of a pace-capture (pacing along the ablation line) ablation strategy (10 mA at 2 ms) (Class IIb, LOE: B-R), and demonstration of exit block (Class IIb, LOE: B-NR) (61) may be considered to enhance success of RF PVI.
DIFFERENCES IN OUTCOMES WITH VARIOUS ABLATION SYSTEMS.RF energy and cryoablation are the 2 most commonly used methods of AF ablation. Cryoablation is comparable to RF in its primary efficacy and safety but is limited to PVI (133). PVI using the balloon-based laser HeartLight endoscopic ablation system (EAS) (CardioFocus, Marlborough, Massachusetts) is a newer technique reported to have a similar safety and efficacy profile as RF ablation with greater PVI dura- bility (134). Modifications to the balloon have improved compliance, produced a much wider arc of ablation, and improved procedural times and efficacy (132). Several other newer ablation systems are currently available.
DURABILITY OF PVI. Durable PVI depends on full- thickness gap-free ablation. Studies show that when gaps exceed 10 mm, AF recurrence increases. Force sensing improves the efficacy of PVI when ablation is performed at optimal contact force. SMART AF (THERMOCOOL SMARTTOUCH Catheter for the Treatment of Symptomatic Atrial Fibrillation) and
FIGURE 8 Progression of Paroxysmal to Persistent AF
Evolution of Atrial Fibrillation Substrate Early Persistent
Paroxysmal
Focal Pulmonary Vein Triggers AF Drivers
• ‘Anatomical’ Substrate
• Non-PV triggers (LAA/CS/PW/RA/SVC/IVC/CT)
• Scar interaction/ Reentry
• ?Rotors ?Anchors?Areas of interest
Longstanding Persistent
Thisfigure shows the evolution of the atrial substrate and the relative role of pulmonary vein (PV) triggers and non-PV triggers from left atrial appendage (LAA), coronary sinus (CS), posterior wall (PW), superior vena cava (SVC), inferior vena cava (IVC), rotors, and re-entry. Non-PV triggers become increasingly important as atrialfibrillation (AF) progresses from the paroxysmal to nonparoxysmal state. CT¼crista terminalis; RA¼right atrium.
