JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
14, 2020
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VOL. 75, NO.
ª 2020 PUBLISHED BY ELSEVIER ON BEHALF OF THE
AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
THE PRESENT AND FUTURE
JACC COUNCIL PERSPECTIVES
Atrial Fibrillation
JACC Council Perspectives
Mina K. Chung, MD,a Marwan Refaat, MD,b Win-Kuang Shen, MD,c Valentina Kutyifa, PHD,d Yong-Mei Cha, MD,e
Luigi Di Biase, MD,f Adrian Baranchuk, MD,g Rachel Lampert, MD,h Andrea Natale, MD,i John Fisher, MD,f
Dhanunjaya R. Lakkireddy, MBBS,j on behalf of the ACC Electrophysiology Section Leadership Council
ABSTRACT
Atrial fibrillation (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 trial fibrillation (AF) is an increasingly prev-
alent arrhythmia with significant health
and socioeconomic impact. Therapeutic op-
tions have expanded tremendously. This review
and future directions for AF prevention and treat-
ment (Central Illustration).
EPIDEMIOLOGY AND RISK FACTORS
summarizes current knowledge on the pathophysi-
ology, prevention, and management of AF, GENERAL INCIDENCE AND PREVALENCE. AF affects
including epidemiology, pathophysiology, predic- w33 million people worldwide and >3 million in the
tive models for AF stroke risk, gaps in knowledge, United States (1); its incidence in the United States is
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 the Journal of the American College of Cardiology or the ACC.
From the aCleveland Clinic, Cleveland, Ohio; bAmerican University of Beirut, Beirut, Lebanon; cMayo Clinic, Scottsdale, Arizona;
d
State 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 the jKansas 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.
ISSN 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2020.02.025
1690 Chung et al.
Atrial Fibrillation
ABBREVIATIONS predicted to double from 1.2 to 2.6 million
AND ACRONYMS
cases from 2010 to 2030, with an increase in
prevalence from 5.2 million to 12.1 million
AAD = antiarrhythmic drug
(2) (Figure 1). The Framingham study (3)
AF = atrial fibrillation
noted an increasing incidence and preva-
AI = ablation index
lence of AF, but with trends toward
DOAC = direct oral improved survival, perhaps attributable to
anticoagulant
improved awareness and better treatment of
ECG = electrocardiogram
AF and its causes. In contrast, a large United
LA = left atrium
Kingdom study (4) reported increases in
LAA = left atrial appendage both AF incidence (mainly in patients age
LAAC = left atrial appendage >75 years) and global AF-associated mortal-
closure
ity from 1990 to 2010. Interestingly, in the
LOE = level of evidence
Framingham study, obesity and diabetes
PV = pulmonary vein increased, whereas smoking, moderate-
PVI = pulmonary vein isolation heavy alcohol use, and hypertension
SVC = superior vena cava decreased over time with little change in the
TIA = transient ischemic attack 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).
JACC VOL. 75, NO. 14, 2020
APRIL 14, 2020:1689–713
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.
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
JACC VOL. 75, NO. 14, 2020 Chung et al. 1691
APRIL 14, 2020:1689–713 Atrial Fibrillation

C ENTR AL I LL U STRA T I O N Management of AF

Stroke Management Access to Care Primary Prevention

• Improved AF diagnostics-smart • Facilitate early and easy access • Risk factor management
watches/monitors to care • RAAS modulation
• DOACs/Warfarin-efforts to • Training physicians in • Ideal body weight target
improve compliance comprehensive AF Rx strategies • Prophylactic PVI in high-risk
• LAA exclusion- • Core curriculum advances in patients while undergoing
epicardial/endocardial tools GME programs open-heart procedures

Rhythm Control Secondary Prevention

• Antiarrhythmic drugs
AF Management • Aggressive integrated weight-
• Need improved safety and loss programs
efficacy • Treat hypertension
• Ablation • OSA - uncover, treat and
• Trigger-PV and non-PV Disease Awareness improve compliance
sources (LAA, PW, SVC.LoM) • Heart failure RX
• Grassroots level public
• Re-entry & substrate • Yoga/acupuncture
awareness campaign
modification • Minimize alcohol
• Efforts from professional and
• Adjunctive strategies consumption
patient advocacy
• Novel energy sources and • Stop smoking
organizations
catheters
• Inter-societal collaboration
• ↓ collateral damage while
↑ ablation efficacy
• Adjunctive AF surgery

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. AF ¼ atrial fibrillation; DOAC ¼ direct oral anticoagulantl; LAA ¼ left atrial appendage; OSA ¼ obsructive sleep apnea; PV ¼ pulmonary vein;
PVI ¼ pulmonary vein isolation; PW ¼ posterior wall; RAAS ¼ renin angiotensin activation system; SVC ¼ superior vena cava.

ablation. AF recurrence after PVI has been attributed
to non-PV triggers, recovery across ablation lines, or
additional arrhythmogenic fibrotic 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. Atrial fibrosis
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 atrial fibrotic 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.
1692 Chung et al. JACC VOL. 75, NO. 14, 2020

Atrial Fibrillation APRIL 14, 2020:1689–713

F I G U R E 1 Probabilistic Range of Projected AF Prevalence

20.0

18.0

16.0
AF Prevalence (Millions)

14.0

12.0

10.0

8.0

6.0

4.0

2.0

0.0
10

20

30
20 9

20 9
12

20 3

20 8

22

20 3

20 8
24
20 1
20 1

14

16

20 6
20 5

20 5
20 7

20 7
2
1

2
1

2
1

2
1

2
2
1

2
20

20

20
20
20

20

20

20
16%

14%

12%
Prevalence of AF

10%

8%

6%

4%

2%

0%
1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007
Year

Male 20-59 Male 60-69 Male 70-79 Male 80+

Female 20-59 Female 60-69 Female 70-79 Female 80+

Blue dashed line is the upper 10% likelihood estimate, the gray dotted line is the lower 10% likelihood estimate, and the red solid line is
the base atrial fibrillation (AF) prevalence estimate with logarithmic incidence growth rate projection.
JACC VOL. 75, NO. 14, 2020 Chung et al. 1693
APRIL 14, 2020:1689–713 Atrial Fibrillation

F I G U R E 2 Potential Modifiable and Nonmodifiable Risk Factors for AF

Reversible Risk Factors

Valvular Coronary
Cardiac Sleep
Heart Artery
Surgery Apnea
Disease Disease

Non-reversible Risk Factors

Family
AF Risk
History of
Genotypes
AF Heart
Atrial Diabetes
Hypertension Obesity
Failure /
Fibrillation Mellitus Cardiomyo-
pathy
Older
Height
Age

Hyper-
Alcohol Drugs
thyroidism

The figure highlights various modifiable and nonmodifiable risk factors that are relevant to atrial fibrillation (AF). This provides a unique opportunity to influence the
primary and secondary prevention pathways in managing patients with AF or at risk for AF.

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
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Atrial Fibrillation APRIL 14, 2020:1689–713

F I G U R E 3 Genome-Wide Association Studies of AF

520

30
–log10 (p Value)

20

10

0
1 2 3 4 5 6 7 8 9 10 12 14 16 18 21
Chromosome

B
500
400
300
Association (–log10 (p Value))

200
100
30

25

20

15

10

0
1 2 3 4 5 6 7 8 9 10 12 14 16 18 22
11 13 15 17 19 21 X
Genomic Position
Known Loci Novel Loci

(A) Manhattan plot of combined-ancestry genome-wide association study (GWAS) meta-analyses (61). (B) Large atrial fibrillation (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.

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, near PITX2, 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.
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PREDICTION MODELS FOR AF

T A B L E 1 CHARGE-AF Scoring System for Prediction of
Risk for AF
PREDICTION OF RISK FOR AF. Prediction models for
Coefficient  per Increment
assessing AF risk in the general population are
Age 0.508 x (per 5 yrs)
important for targeting primary prevention strate-
Height 0.248 x (per 10 cm)
gies. Although developed for thromboembolic risk
Weight 0.115 x (per 15 kg)
prediction in AF, CHADS 2 (congestive heart failure, Systolic BP 0.197 x (per 20 mm Hg)
hypertension, age 75 years, diabetes mellitus, prior Diastolic BP 0.101 x (per 10 mm Hg)
stroke or transient ischemic attack) score $2 and Current smoker 0.359
CHA2 DS2-VASc (congestive heart failure, hyperten- Antihypertensive medication 0.349

sion, age $75 years, diabetes mellitus, prior stroke or Diabetes 0.237
Congestive heart failure 0.701
transient ischemic attack, vascular disease, age 65 to
Myocardial infarction 0.496
74 years, female) score $3 have been independently
LVH by electrocardiogram
associated with increased risk of subsequent new- PR interval (<120 vs. 120–199 ms)
onset AF in patients presenting with symptoms or PR interval (>199 vs. 120–199 ms)
signs suggestive of cardiac arrhythmia but no docu-
mented AF (27). Both scores are significant predictors BP ¼ blood pressure; LVH ¼ left ventricular hypertrophy.

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 CHA2DS 2-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 atrial flutter ablation (38).
CHADS2 (Table 3), CHA 2DS2-VASc (Table 4), and
R 2CHADS 2 have been utilized to predict AF recurrence
after catheter ablation, but with only modest predic-
tive value (39). Late gadolinium enhancement mag-
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). CHA 2DS2-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), HEMORR 2HAGES (Hepatic or Renal
Disease, Ethanol Abuse, Malignancy History, Older
than age 75, Reduced platelet count or function,
Rebleeding risk, Hypertension, Anemia, Genetic
T A B L E 2 HATCH Score for Prediction of Progression From
Paroxysmal to More Persistent AF and Prediction of New AF After
Atrial Flutter Ablation

netic resonance imaging is used in some centers to H Hypertension 1

triage AF patients prior to ablation. Extensive late A Age $75 yrs 1
gadolinium enhancement ($30% LA wall enhance- T Transient ischemic attack or stroke 2

ment), indicating LA wall structural remodeling, C Chronic obstructive pulmonary disease 1

H Heart failure 2
predicts high recurrence rates after catheter ablation
(40). However, whether outcomes are improved by AF ¼ atrial fibrillation.
use of these predictive models to either stratify
1696 Chung et al.
Atrial Fibrillation
T A B L E 3 CHADS 2 Score for Prediction of Stroke in
Atrial Fibrillation Patients
C Congestive heart failure
H Hypertension (>140/90 mm Hg)
A Age $75 yrs
D Diabetes mellitus
S2 Prior TIA or stroke
TIA ¼ transient ischemic attack.
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-TT 2R 2 (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-TT 2R 2 score (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
exclusion.
Various biomarkers have been tested as predictors
of clinical outcomes in patients with AF. N-terminal
fragment B-type natriuretic peptide
T A B L E 4 CHA 2 DS 2 -VASc Score for Prediction of Stroke in
Atrial Fibrillation Patients
C Congestive heart failure
H Hypertension (>140/90 mm Hg)
A Age $75 yrs
D Diabetes mellitus
S2 Prior TIA or stroke
V Vascular disease (MI, aortic plaque, and so on)
A Age 65–74 yrs
Sc Sex category (female ¼ 1 point)
MI ¼ myocardial infarction; TIA ¼ transient ischemic attack.
JACC VOL. 75, NO. 14, 2020
APRIL 14, 2020:1689–713
sensitivity cardiac troponin have been independently
associated with risk of stroke in AF (47). Combined
with age and clinical history, this combination has
1
1
been touted as superior to the CHA 2 DS2-VASc score as
1 a predictor of clinical outcomes, particularly stroke
1 (47). Further progress is expected in this area.
2
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),
as LAA 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
and high 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
1
ELECTRICAL DEVICES. The detection of asymptomatic
1
2 AF in patients with implanted pacemakers, de-
1 fibrillators, or loop recorders raises the question of
2 what AF burden is associated with higher risk of
1 thromboembolism. Atrial high rate episodes lasting
1 >5 min are associated with risk of silent ischemic
1
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
JACC VOL. 75, NO. 14, 2020
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T A B L E 5 HAS-BLED Score for Prediction of Bleeding Risk
H Hypertension
A Abnormal liver or renal function
S Stroke
B Bleeding
L Labile INRs
E Elderly (>65)
D Drugs or ETOH
ETOH ¼ ethyl alcohol; INR ¼ international normalized ratio.
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
implanted monitor was detected
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
CHA2 DS2-VASc $2 and in women with CHA 2DS2-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
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
implying that thrombogenesis in
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
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
Chung et al. 1697
Atrial Fibrillation
trials like AFFIRM (Atrial Fibrillation Follow-up
Investigation of Rhythm Management) and RACE
1
(Rate Control versus Electrical Cardioversion for
1 point each
Atrial Fibrillation) reported that risk of thromboem-
1
1 bolism persisted even in AF patients who maintained
1 sinus rhythm, although this may have been at least in
1 part due to unrecognized asymptomatic AF (60).
1 point each 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-
AF on an forts to improve our understanding of the role of
frequently in 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-
ATRIAL 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
episodes (59), therapy, which have shown promising results in
patients with 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
related to 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
1698 Chung et al. JACC VOL. 75, NO. 14, 2020

Atrial Fibrillation APRIL 14, 2020:1689–713

F I G U R E 4 Targetable Upstream Pathways Predisposing to AF and AF Progression and Potential Drug Candidates

Inflammation Oxidative Stress Fibrosis Proteostasis Metabolic Stress

• Steroids • Anti-oxidants • Angiotensin-converting • Geranylgeranyl • AMPK activators

• NSAIDs • Ascorbic acid enzyme (ACE) acetone (GGA, (Metformin,
• Statins (vitamin C) inhibitors teprenone) Resveratrol)
• Soluble epoxide • Vitamin E • Angiotensin receptor • BGP-15 • PPARγ activators:
hydrolase • Carotenoids blockers (ARBs) • 4-phenylbutyric acid thiazolidinediones
inhibitor • Omega-3 • Mineralocorticoid (4-PBA, buphenyl) (TZDs) - pioglitazone
• Omega-3 polyunsaturated receptor antagonists • Rapamycin • Inhibitors of fatty acid
polyunsaturated fatty acids (MRAs) - eplerenone • Histone deacetylase 6 oxidation - ranolazine,
fatty acids • N-acetylcysteine • Galectin-3 (Gal-3) (HDAC6) inhibitors - trimetazidine
• Statins inhibitors ricolinostat,
• TGF-β inhibitors - tubastatin-A
Pirfenidone

Atrial Fibrillation
Patterns of AF Burden
60
Minutes/Day

50
40
AT/AF

30
20
10
0

24
20
Hours/Day

16
AT/AF

12
8
4
0

24
20
Hours/Day

16
AT/AF

12
8
4
0

24
20
Hours/Day

16
AT/AF

12
8
4
0
Day
Patterns of Atrial Structural Remodeling

This figure 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. AF ¼ atrial fibrillation; AMPK ¼ AMP-activated protein kinase; AT ¼ atrial tachyarrhythmia; BGP-15 ¼ O-(3-piperidino-2-hydroxy-1-propyl)nicotinic amidoxime;
NSAID ¼ nonsteroidal anti-inflammatory drug; PPAR ¼ peroxisome proliferator-activated receptor; TGF ¼ transforming growth factor.

(66), LV dysfunction (66), post-myocardial infarction with hypertension only (70,71). Novel therapies tar-
(67), hypertension with LV hypertrophy (68), or geting upstream pathways, such as proteostasis,
cardiovascular risk factors (69), although no differ- metabolic stress, mitochondrial function, and
ences in AF were seen in studies enrolling patients fibrosis pathways, are being studied, mostly in
JACC VOL. 75, NO. 14, 2020 Chung et al. 1699
APRIL 14, 2020:1689–713 Atrial Fibrillation

F I G U R E 5 Risk Factor Management and Lifestyle Modification in the LEGACY, ARREST-AF, and CARDIO-FIT Trials

Aggressive Risk Factor Management

Weight
Obstructive Sleep
Management Hyperlipidemia Hypertension Diabetes
Apnea
and Exercise

• Educate for • Initial lifestyle • Overnight sleep • Home BP diary: • Glucose tolerance
permanent measures study 2- 3x daily test
lifestyle change • At 3 months: • CPAP if AHI ≥30; • Reduce salt • Lifestyle measures
• Diet plan Start statins if or ≥20/h with • Start ACEI or ARB • At 3 months:
• Initial target: LDL >100 mg/dl resistant • Target Metformin if
>10% weight • Add fibrates if hypertension or <130/80 mm Hg HbA1c >6.5%
loss TG >230 mg/dl daytime somnolence (at rest) and • Diabetes clinic
• Final target: • Start fibrates if • Check adherence: <200/100 mm Hg or endocrine review
BMI <27 kg/m2 TG >500 mg/dl regular CPAP (at peak exercise)
• Avoid weight machine data
fluctuation download
• Exercise:
30 min for
3 - 4x per week
• Increase up to
250 minutes
per week

Smoking cessation & alcohol abstinence (or reduction to 30 g per week)

This figure 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. ACEI ¼ angiotensin-converting enzyme inhibitor; AF ¼ atrial fibrillation; AHI ¼ apnea–hypopnea index; ARB ¼ angiotensin receptor
blocker; ARREST-AF ¼ Aggressive Risk Factor Reduction Study for Atrial Fibrillation and Implications for the Outcome of Ablation; BMI ¼ body mass index; BP ¼ blood
pressure; CARDIO-FIT ¼ Impact of CARDIOrespiratory FITness on Arrhythmia Recurrence in Obese Individuals with Atrial Fibrillation; CPAP ¼ continuous positive air
pressure; LEGACY ¼ Long-Term Effect of Goal-Directed Weight Management in an Atrial Fibrillation Cohort: A Long-Term Follow-Up Study; LDL ¼ low-density
lipoprotein; TG ¼ triglycerides. Reproduced with permission from Lau et al. (77).

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
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
Obese suggested a trend toward a lower incidence of AF
1700 Chung et al.
Atrial Fibrillation
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
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
personalized genomics-based treatment
potentially guide AF therapy. Results of top AF risk
loci in ablative therapies have been mixed (89–91).
JACC VOL. 75, NO. 14, 2020
APRIL 14, 2020:1689–713
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 the first
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
AF
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 the first-line treatment for
stroke prevention in AF (43,48). CHADS 2 and
CHA 2DS2-VASc are the 2 most commonly used stroke
risk stratification models for patients with non-
valvular AF. Current guidelines recommend using
oral anticoagulation for CHA2DS 2-VASc $2. More
recent evidence shows a benefit of starting anti-
coagulation even if 1 risk factor for stroke is present,
(23,88), that is, men with CHA2DS2-VASc score of 1 and
could women with CHA 2 DS2-VASc of 2 (93,94).
Earlier clinical trials evaluated antiplatelet thera-
pies for stroke prevention in AF. In a meta-analysis,
JACC VOL. 75, NO. 14, 2020 Chung et al. 1701
APRIL 14, 2020:1689–713 Atrial Fibrillation

F I G U R E 6 Why Does the LAA Turn Pathologic in AF?

Obesity • Dilatation Loss of booster/

• Patchy fibrosis reservoir function Smoke,
OSA • Loss of contractility sludge and
• Endothelial changes Complex morphology thrombus
HFrEF • Inflammation with higher
• Stasis arborization index
VHD
• Altered platelet function (Non-chicken wing
morphology)

Activation of
Virchow’s triad
AF
Upregulation of
RAAS
HFpEF

HTN • ↑ wall stress AF/ AT/PAC

• Activation of de Bakker
Age cells – focal triggers
• Re-entry due to patchy Arrhythmic
Genetics fibrosis substrate

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. AF ¼ atrial fibrillation; AT ¼ atrial tachycardia; HFpEF ¼ heart failure with preserved ejection fraction; HFrEF ¼ heart
failure with reduced ejection fraction; HTN ¼ hypertension; LAA ¼ left atrial appendage; OSA ¼ obstructive sleep apnea; PAC ¼ premature
atrial contraction; RAAS ¼ renin angiotensin activation system; VHD ¼ valvular heart disease.

aspirin (ASA) compared with placebo was associated
with a 19% risk reduction for primary prevention of
stroke (95). The ACTIVE-W (Atrial fibrillation 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 CHA 2DS 2-VASc score of 0 and women with
CHA2 DS2-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, P2Y12 inhibitors, 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
1702 Chung et al.
Atrial Fibrillation
F I G U R E 7 Epicardial and Endocardial Left Atrial Appendage Closure Devices
Endocardial LAA Occluders Epicardial LAA Excluders
Watchman
Amulet
This figure 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.
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
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APRIL 14, 2020:1689–713
Other Endocardial LAA Occluders
PLAATO WaveCrest Occlutech
Appriva Medical Biosense Webster Occlutech
Lariat
LAmbre Sideris Patch
Lifetech Scientific Custom Medical Devices
Atriclip
Ultraseal Pfm
Cardia Pfm Medical
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,
JACC VOL. 75, NO. 14, 2020
APRIL 14, 2020:1689–713
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
Chung et al. 1703
Atrial Fibrillation
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 ¼ 4,060 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 ¼ 0.08), 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 (n ¼ 522 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 (p ¼ 0.11),
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
1704 Chung et al.
Atrial Fibrillation
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
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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; p ¼ 0.007).
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).
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F I G U R E 8 Progression of Paroxysmal to Persistent AF
Evolution of Atrial Fibrillation Substrate
Paroxysmal
Focal Pulmonary Vein Triggers
AF Drivers
This figure 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 atrial fibrillation (AF) progresses from the paroxysmal to nonparoxysmal state. CT ¼ crista terminalis; RA ¼ right atrium.

Structurally normal heart: Flecainide,
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
Chung et al. 1705
Atrial Fibrillation
Early Persistent Longstanding Persistent
• ‘Anatomical’ Substrate
• Non-PV triggers (LAA/CS/PW/RA/SVC/IVC/CT)
• Scar interaction/ Reentry
• ?Rotors ?Anchors?Areas of interest
prop- 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
1706 Chung et al.
Atrial Fibrillation
TOCCASTAR (TactiCath Contact Force Ablation Cath-
eter Study for Atrial Fibrillation) demonstrated that
ablation at optimal force (when $90% of the lesions
were >10 g) and when time in contact force range
exceeded 80%, success rates improved. General
anesthesia, jet ventilation, steerable sheaths, and
touch up ablation with adenosine challenge have also
been found to be useful in improving the durability of
RF PVI. Ablation index (AI) is a novel lesion quality
marker that utilizes contact force, time, and power in
a weighted formula; optimal AI can correlate with
greater success rates (target AI 400 on the posterior
wall and 550 on the anterior wall) (135).
LOW-VOLTAGE AREAS AND PREDICTION OF
AF-FREE SURVIVAL AFTER PVI. Low-voltage areas
(LVAs) with electrogram amplitudes <0.5 mV are
frequently observed in patients with AF and may
predict AF recurrence after catheter ablation. Pre-
dictors of LA substrate were identified and a DR-
FLASH risk score was developed (based on diabetes
mellitus, renal dysfunction, persistent form of AF, LA
diameter >45 mm, age >65 years, female sex, and
hypertension). The DR-FLASH score may be useful to
identify patients who may require extensive sub-
strate modification instead of PVI alone (136).
ABLATION IN NONPAROXYSMAL AF
COMPLEXITY OF PLANNING THE ABLATION.
Although PVI has been shown to be a very effective
ablation technique in patients with paroxysmal AF,
patients with persistent and long-standing AF often
require ablation of non-PV triggers.
THE EFFECT OF SCAR IN THE LA. The DECAAF
(Delayed-Enhancement MRI [DE-MRI] Determinant of
Successful Radiofrequency Catheter Ablation of Atrial
Fibrillation) trial has shown high recurrence after AF
ablation in patients with increased scar in the LA
(137). An advanced substrate with significant scarring
is likely to have low AF-free survival after
AF ablation.
EVOLUTION OF THE ABLATION STRATEGY: PVI
ALONE VERSUS PVI PLUS STRATEGIES. Among pa-
tients with persistent AF, the STAR AF II (Substrate
and Trigger Ablation for Reduction of Atrial Fibrilla-
tion) trial found no reduction in the rate of recurrent
AF when either linear ablation or ablation of complex
fractionated electrograms was performed in addition
to PVI (138).
WHICH OF THE PVI PLUS STRATEGIES HAVE A TRUE AND
MEANINGFUL IMPACT? N o n - P V f o c a l t r i g g e r s . Non-
PV atrial triggers may include the posterior wall of the
LA, the superior vena cava (SVC), including persistent
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left SVC, the inferior vena cava, the crista terminalis,
the fossa ovalis, the coronary sinus, behind the
Eustachian ridge, along the vein or ligament of
Marshall, and adjacent to the AV valve annuli.
Furthermore, re-entrant circuits maintaining AF may
be located within the right and left atria.
Administration of isoproterenol in incremental
doses of up to 20 mg/min and/or cardioversion of
induced and spontaneous AF, can help identify PV
and non-PV triggers (139). Ablation of the vein of
Marshall can be achieved with RF or via retrograde
ethanol injection.
Complex fractionated atrial electrograms. Available data
on complex fractionated atrial electrogram (CFAE)
ablation are conflicting (140,141) and could be
because CFAEs are nonspecific indicators of target
sites, CFAE definition is nonstandard and subjective,
and the contribution of CFAE to rhythm control re-
mains unclear.
E m p i r i c l i n e a r a b l a t i o n . The most common sites of
linear ablation are the LA “roof” connecting the su-
perior aspects of the left and right upper PVI lesions,
the region of tissue between the mitral valve and the
left inferior PV (the mitral isthmus), and anteriorly
between the roof line near the left or right circum-
ferential lesion and the mitral annulus. Although this
technique showed significant improvement in suc-
cess rates if combined with PVI, compared with PVI
alone, in patients with drug refractory paroxysmal AF
(142), its role remains controversial in patients with
nonparoxysmal AF (143). Empiric lines are frequently
proarrhythmic, as most of them are incomplete with
wide gaps making post-AF ablation intra-atrial re-
entrant tachycardia a major problem.
L A A e x c l u s i o n a n d o t h e r s t r a t e g i e s . The LAA has
been found to be an important source of AF triggers
and re-entry. Targeting the LAA either endocardially
or epicardially and isolating it from the LA may be a
useful adjunct to PVI and other additional ablation
strategies, but the effect on thromboembolism needs
to be assessed. LAA isolation (BELIEF [Effect of
Empirical Left Atrial Appendage Isolation on Long-
term Procedure Outcome in Patients with Persistent
or Long-standing Persistent Atrial Fibrillation Un-
dergoing Catheter Ablation] trial) and LAA exclusion
(LAALA AF Registry) have been reported to show
improved success rates for nonparoxysmal AF abla-
tion (121,144). The ongoing aMAZE (Percutaneous
alternative to the Maze procedure for the treatment of
persistent or long-standing persistent atrial fibrilla-
tion) trial aims to assess the benefit of epicardial LAA
exclusion by suture ligation in non-paroxysmal AF
ablation (145).
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CONTACT FORCE SENSING ABLATION
A constant challenge in catheter ablation is opti-
mizing electrode–tissue contact to create predictable
and reliable lesions. Contact force at the catheter tip
can be directly measured or estimated based on local
impedance. Efficacy and safety of contact force
catheter for the treatment of paroxysmal AF were
demonstrated in both nonrandomized (146) and ran-
domized studies (147).
ABLATION STRATEGIES IN VALVULAR AND
STRUCTURAL HEART DISEASE WITH AF
Concomitant open surgical ablation of AF (such as
with mitral valve surgery) is recommended for
symptomatic AF (Class I, LOE: B-NR). Concomitant
closed surgical ablation of AF (such as with CABG and
AVR) is recommended for symptomatic AF refractory
or intolerant to at least one Class I or III antiar-
rhythmic (Class I, LOE: B-NR) and is reasonable for
symptomatic AF prior to initiation of antiarrhythmic
therapy with a Class I or III antiarrhythmic medica-
tion (Class IIa, LOE: B-NR) (132). Stand-alone surgical
ablation can be considered for patients who have
failed $1 catheter ablation, are intolerant or re-
fractory to AAD, and prefer a surgical approach after
review of its safety and efficacy for paroxysmal (Class
IIb, LOE: B-NR), persistent, and long-standing AF
(Class IIb, LOE: C-EO) (132). In patients with symp-
tomatic paroxysmal or persistent AF with LVEF
#35% and an implantable cardioverter-defibrillator,
catheter ablation has been shown to be associated
with higher efficacy compared with conventional
drug treatment, with a 38% reduction in all-cause
mortality and a significant decline in heart failure
hospitalizations (128).
NONTRADITIONAL MAPPING AND ABLATION OF
AF. Various techniques using noninvasive external
and invasive intracardiac mapping of nontraditional
targets have been relatively disappointing. The
effectiveness of noninvasive mapping of AF as per-
formed using the CardioInsight ECUVUE Vest (Med-
tronic, Minneapolis Minnesota) is yet to
determined (146). A small series of AF ablation tar-
geting areas of spatiotemporal dispersion (a potential
visually recognizable electric footprint for AF drivers)
has shown initial promise (147). Similarly, focal im-
pulse and rotor modulation–guided ablation has
shown some initial promise in nonrandomized
studies, but subsequent studies have been disap-
pointing and did not show any additional benefit
(149,150). External beam photonic cardiac ablation
has been successfully reported (151). Sharma et al.
Chung et al. 1707
Atrial Fibrillation
showed marked voltage reduction to <0.05 mV in the
PV–LA junction in a swine model using noninvasive
stereotactic radiosurgery (CyberHeart, Mountain
View, California) (152). With successful reports of VT
ablation using noninvasive cardiac radiation in
humans (153), this technology will likely be tested for
AF in the future. Remote navigation may yield suc-
cessful AF ablation with decreased operator fluoros-
copy time. This can be achieved via the robot-assisted
Sensei system (Hansen Medical, Mountain View,
California) or a magnetic system (Niobe, Stereotaxis,
St. Louis, Missouri), consisting of 2 magnets creating
a magnetic field (0.08-T) inside of the patient’s chest
and a computer-controlled catheter advancer system
(Cardiodrive unit, Stereotaxis) used for navigation.
This has found a niche use by a reasonable group of
operators around the world.
ABLATION COMPLICATIONS: PREVENTION,
EARLY IDENTIFICATION, AND MANAGEMENT
Complications related to AF ablation include vascular
injuries, pericardial effusion, cardiac tamponade,
acute coronary artery occlusion and stenosis, mitral
valve trauma and curvilinear catheter entrapment, air
embolism, stroke, TIA, silent microembolism, atrial
esophageal fistula, atrial pericardial fistula, PV ste-
nosis, gastric hypomotility, vagal nerve injury,
phrenic nerve palsy, stiff LA syndrome, radiation
injury, persistent sinus tachycardia, and death.
Although the overall complications associated with
AF ablation are relatively low and most can be
managed successfully, lifelong disability or death can
occur. Experienced operators, a well-trained proce-
dural team, simpler techniques, and advancing tech-
nology will undoubtedly continue to lower
complications. Periprocedural preparation, early
recognition, and effective intervention are also criti-
cally important to reduce additional unwanted con-
sequences should complications occur. Here, we
provide a brief update on selected complications of
which the understanding of pathophysiological
mechanisms, prevention, and management of such
be complications continue to evolve.
PHRENIC NERVE INJURY. Phrenic nerve (PN) injury is
a common complication related to cryoballoon abla-
tion (148), although it can occur with other energy
delivery technologies when ablation is near the
anatomic location of the right or left PN. Whereas
transient PN palsy has been reported with an inci-
dence of 3.5% to 11.2%, permanent PN palsy (no or
reduced PN function for 12 months or longer after
ablation) has been estimated to be <0.5% (149,150).
Left PN injury is uncommon but can occur, with
1708 Chung et al.
Atrial Fibrillation
ablation near the roof of the LAA. Use of larger cry-
oballoons and real time intracardiac ultrasound
visualization, pre-ablation mapping of the PN, and/or
monitoring of compound motor action potentials
from the diaphragm and diaphragmatic movement
while pacing the PN from the SVC or subclavian vein
during CBA are often routine during SVC or right PV
ablation. Direct monitoring of compound motor ac-
tion potentials may provide early detection and
reduce PN injury.
ATRIAL-ESOPHAGEAL INJURY. Several esophageal
injuries, such as erythema, erosion, or ulcer, have
been reported after AF ablation. Most lesions resolve
after proton pump inhibitor treatment. Esophageal
perforation, atrial pericardial fistula, and atrial-
esophageal fistula (AEF) are rare (#0.1%) but often
lethal. Due to the delayed nature of AEF occurrence (2
to 4 weeks after ablation) and often nonspecific
symptoms prior to acute deterioration, a heightened
vigilance of patient’s symptoms and signs resulting in
early diagnosis and intervention may reduce further
morbidity or mortality. Fever and general malaise are
earlier signs followed by acute onset of neurological
deficits and hematemesis. Chest CT scan is a
preferred diagnostic modality. Barium swallow can
outline the fistula, although sensitivity is low.
Endoscopy with air insufflation should be avoided if
AEF is suspected due to the risk of air embolism.
Several approaches have been proposed to reduce
serious atrial-esophageal injuries and AEF: 1) reduced
RF power (#25 W) and duration of delivery at a single
location (#15 to 20 s) during ablation on the posterior
wall or directly over the trajectory of the esophagus;
2) real-time temperature monitoring in the esophagus
(stop power delivery when temperature exceeds 38 to

39 C or when esophageal temperature starts to rise
 
>1 C from baseline during RF or <20 C when using
cryoballoon ablation); 3) move the esophagus away
from the ablation site by various tools (151,152); and 4)
use of proton pump inhibitor and sucralfate for 2 to
4 weeks after the procedure. Once AEF is confirmed,
immediate surgical repair is the treatment of choice.
Esophageal deviation with endoluminal deviators
seem to be effective and safe. A recent non-
randomized multicenter experience with Esosure
(NorthEast Scientific, Danbury, Connecticut) showed
that the esophagus can be safely deviated resulting in
improved acute and long-term PVI. However, there
has been no endoscopic data to rule out iatrogenic
trauma and its ability to minimize esophageal injury
from direct and indirect causes (153). A randomized
trial is on the way to assess the anatomic impact on
the esophagus with the deviators.
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VAGAL NERVE INJURY. Injury to the anterior
esophageal plexus (formed from branches of vagal
and visceral branches of sympathetic trunk) can occur
during AF ablation due to its anatomical proximity to
the posterior LA wall. Symptoms of nausea, vomiting,
abdominal pain, and bloating can occur a few hours to
weeks after the ablation procedure. Gastric symptoms
can occur in 10% to 15% of patients and can last up to
several weeks or longer (154). Vagal nerve injury can
manifest in as many as 70% of the patients with AF
ablation, although most are asymptomatic (154).
Esophageogastric manometry, gastric emptying
study, and pancreatic polypeptide level can help
assess the injury pattern to the vagus nerve. After the
diagnosis is confirmed, small meals with low fat and
fiber content are recommended. Metoclopramide can
be used on a short-term basis to promote gastric
motility. Whether vagal plexus injury can be reduced
by esophageal deviation is not clear.
STIFF LEFT ATRIUM SYNDROME. This is a clinical
syndrome characterized by signs of right heart failure
after LA ablation or surgical Maze procedure in the
presence of preserved LV function, new or worsening
pulmonary hypertension (mean PA pressure
>25 mm Hg at rest or >30 mm Hg during exercise),
and large V-wave on pulmonary capillary wedge
pressure ($10 mm Hg without significant mitral valve
disease or pulmonary valve stenosis) (155). The inci-
dence of stiff LA syndrome is estimated to be in the
range of 1% to 8% (156–159). An LA stiffness (expan-
sion) index was recently proposed by using invasive
pressure measurements and cardiac magnetic reso-
nance imagingdetermined LA volumes to assess the
degree of LA dysfunction (160). Reproducibility,
applicability in a routine clinical setting, and how it
may be used to assess the natural history of stiff LA
syndrome require further investigation. Prevention
requires a fine balance between the pursuit of rhythm
control and the aggressiveness of LA ablation. Treat-
ment is similar to treating right HF. Most patients
respond to diuretic agents and pre-load reduction.
AF ABLATION IN SELECTED POPULATIONS. In a
select group of patients, the evidence for AF ablation
stems from observational studies. These selected
populations include older patients ($75 years of age),
younger patients (#45 years of age), high-level ath-
letes, hypertrophic cardiomyopathy, heart failure,
and tachy-brady syndrome. The guiding principles in
ablation indications and techniques in these selected
patient populations are similar to the general AF
population at large. The potential greater benefit
from restoring and maintaining sinus rhythm in
these patients must be weighed against higher
JACC VOL. 75, NO. 14, 2020 Chung et al. 1709
APRIL 14, 2020:1689–713 Atrial Fibrillation

procedure-related risk and AF recurrence in these
special groups.
SURGICAL ABLATION. Surgical intervention for AF is
most frequently performed when patients are un-
dergoing elective mitral valve
concomitant open LA or with CABG or aortic valve
surgery. A standalone surgical AF procedure can be
performed in patients who have failed at least 1
attempt at catheter ablation. Advancements in thor-
acoscopic surgery and continuing exploration of
autonomic modulation by epicardial ganglion plexus
ablation will likely advance surgical AF ablation. With
the increasing trends of surgery becoming less inva-
sive, interventional EP procedures being more com-
plex and invasive, and technological advances in
hybrid operating rooms, a hybrid epicardial (surgical)
and endocardial (interventional
approach is evolving in selected centers (161). Given
the current challenges in treating patients with
persistent and long-standing persistent AF, such
hybrid approaches will likely evolve, although well-
designed randomized clinical trials will be needed to
optimize clinical practice.
FUTURE DIRECTIONS
AF is a complex cardiovascular disease. Much is
known, but much more remains to be discovered.
Although there has not emerged a “unifying hy-
pothesis” that explains all causes for AF, AF appears
to be a “final common pathway” resulting from the
influence of varied genetic, environmental, cellular
surgery with a stress, and lifestyle factors. Difficulties in predicting
the consequences of AF and its therapies and the
limitations of current therapies make it imperative
to study and improve preventive and therapeutic
strategies. We face questions as to the best ap-
proaches for reduction of thromboembolic compli-
cations with efficacy and safety of these strategies
requiring intensive risk/benefit decision making.
Similarly, antiarrhythmic drugs are limited in effi-
cacy and often have significant side effect profiles
that have hampered development. A hope is that
basic and translational research will lead to more
EP) ablation effective and safe therapeutic options, including
pharmacological and nonpharmacological ablative
approaches.
ADDRESS FOR CORRESPONDENCE: Dr. Dhanunjaya
R. Lakkireddy, University of Missouri Columbia, The
Kansas City Heart Rhythm Institute (KCHRI) at HCA
MidWest, Overland Park Regional Medical Center,
12200, West 106th Street, Overland Park,
Kansas 66215. E-mail: dhanunjaya.lakkireddy@
hcahealthcare.com. Twitter: @DJ_Lakkireddy.

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KEY WORDS atrial fibrillation, future,
present