Update On Atrial Fibrillation

The Egyptian Heart Journal (2014) 66, 193216
H O S T E D BY
Egyptian Society of Cardiology
The Egyptian Heart Journal

www.elsevier.com/locate/ehj
www.sciencedirect.com
REVIEW
Update on atrial brillation

Mohammad Shenasa
a
b
a,b,*
, Hossein Shenasa
a,b
, Mona Soleimanieh
Heart & Rhythm Medical Group, San Jose, CA, USA

Department of Cardiovascular Services, OConnor Hospital, San Jose, CA, USA
Received 12 March 2014; accepted 23 March 2014

Available online 21 May 2014
KEYWORDS
Atrial brillation;
Catheter ablation;
Heart failure;
Hypertension;
Obstructive sleep apnea;
Stroke
Abstract Atrial brillation (AF) is the most common sustained arrhythmia encountered in clinical
practices with signicant morbidity, mortality and socioeconomic burden. Its prevalence and incidence are on the rise due to an increase in population age. AF has complex electrophysiological
mechanisms, etiology and natural history and thus management is a challenge. More than 80%
of cases in AF are related to an underlying structural heart disease. Stroke and congestive heart failure remain the most signicant complications of AF. Depending on the patients symptoms, duration and type of AF, structural heart disease and non-cardiac comorbidities, several management
options are currently available. Asymptomatic AF carries similar risks as symptomatic AF. Rate
control approach in majority of cases especially elderly patients is reasonable. Novel anticoagulation agents have shifted the paradigm in stroke prevention and management in patients with AF.
Catheter ablation of paroxysmal AF in patients with no to minimal structural heart disease who
have failed at least one antiarrhythmic agent appears reasonable.
2014 Production and hosting by Elsevier B.V. on behalf of Egyptian Society of Cardiology.
Contents
1.
2.
3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Clinical presentation of atrial brillation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Classication of atrial brillation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1. Atrial brillation and quality of life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2. Recent epidemiological observations of atrial brillation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.3. Etiologies of atrial brillation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.4. Pathophysiology and mechanisms of atrial brillation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.5. Diagnosis and detection of atrial brillation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.6. Inammation, brosis and atrial brillation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.7. Atrial brillation progression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
* Corresponding author at: Heart & Rhythm Medical Group, 105 N.

Bascom Ave Suite 204, San Jose, CA, USA. Tel.: +1 (408) 918 9400;
fax: +1 (408) 286 2922.
E-mail address: mohammad.shenasa@gmail.com (M. Shenasa).
Peer review under responsibility of Egyptian Society of Cardiology.
1110-2608 2014 Production and hosting by Elsevier B.V. on behalf of Egyptian Society of Cardiology.
http://dx.doi.org/10.1016/j.ehj.2014.03.004
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17.
M. Shenasa et al.
3.8. Biomarkers of atrial brillation (see Table 1). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.9. Hypertension and atrial brillation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Heart failure and atrial brillation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1. Atrial brillation in patients with decreased left ventricular dysfunction. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Atrial brillation in patients with diastolic dysfunction (AF with preserved LV systolic function) . . . . . . . . . . . . . . .
5.1. Atrial brillation and type II diabetes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2. Atrial brillation and hypertrophic cardiomyopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.3. Atrial brillation and stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.4. Post-operative atrial brillation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.5. Atrial brillation in athletes and during endurance exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.6. Genetics of atrial brillation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.7. Novel risk factors in atrial brillation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.8. Atrial brillation and obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.9. Atrial brillation and obstructive sleep apnea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Atrial brillation and kidney disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Management of atrial brillation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.1. Acute management of atrial brillation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.2. Drug therapy for atrial brillation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.3. Pharmacologic therapy for rhythm control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Pharmacological therapy for rate control. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.1. Rate versus rhythm control strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.2. Arguements in favor of rhythm control approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.3. Arguements against rhythm control approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.4. Argues in favor of rate control approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.5. Anticoagulation in atrial brillation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Catheter ablation of atrial brillation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9.1. Pulmonary veins and atrial brillation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9.2. Current status and results of atrial brillation ablation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9.3. Perioperative anticoagulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9.4. Strategies for catheter ablation of atrial brillation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9.5. Rotor ablation in patients with AF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9.6. Techniques for atrial brillation ablation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Cryoballoon ablation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Results of catheter ablation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11.1. Outcomes of catheter ablation of atrial brillation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Imaging before and during AF ablation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Complication of catheter ablation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Ablate and PACE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14.1. Left atrial appendage (LAA) closure for stroke prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14.2. Uncertainties in catheter ablation of AF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14.3. Should catheter ablation be the rst line therapy for patients with AF? . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14.4. Denition of successful procedure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14.5. Duration of post ablation monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14.6. Procedural end points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14.7. Cost of catheter ablation of atrial brillation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Future directions in catheter ablation of atrial brillation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
15.1. Concepts to consider in the future management of AF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Future opportunities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
16.1. Future trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conict of Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction
Atrial brillation (AF) is the most common sustained arrhythmia worldwide with a current prevalence of 2.76.1 million in
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the United States and Europe with an estimated increase of

15.9 million in 2050.1 We rst discuss selected topics on
etiologies followed by current management options and future
directions.
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lar heart disease. AF may present as rapid palpitations,
chest pain, and shortness of breath, dizziness, light-headedness and rarely syncope where rapid ventricular response is
present. Diminished exercise capacity (malaise and fatigue)
and symptoms of transient ischemic attack and stroke are
among other symptoms. AF impacts exercise capacity in
patients with HF either with preserved or reduced systolic
function.2
On the other hand many episodes of AF remain unnoticed
silent and are often detected during routine physical examination or upon admissions to the hospital for other causes
such as HF and stroke.
3. Classication of atrial brillation
Figure 1 Different types of AF according to its duration. ( CV:

Cardioversion) Camm J, Kirchhof P, Lip GYH, et al. Guidelines
for management of atrial brillation. Eur Heart J 2010;31:2369
2429.
2. Clinical presentation of atrial brillation

AF is generally diagnosed by an electrocardiogram and is
characterized by absence of P-wave, with brillatory waves
usually <200 ms with absolutely irregularly irregular heart
rate. Symptoms of AF depend mainly on the rate, irregularity, and underlying structural heart disease, such as heart
failure (HF) and coronary artery disease (CAD) and valvu-
AF is classied into four categories based on its duration as

shown in Fig. 1 below.
(1) First detected or diagnosed AF independent of its duration, and presence or absence of any symptoms.
(2) Paroxysmal AF: Episodes lasting less than 2448 h that
terminate spontaneously but may also last up to
7 days. After this period the rate of spontaneous termination is low and anticoagulation is warranted. Episodes that are longer than 30 seconds are considered
as recurrences. This duration is considered in trials
for drug efcacy.
(3) Persistent AF: Episodes lasting longer than 7 days that
require termination by either direct electrical cardioversion or pharmacological intervention.
Figure 2 (AD) Panel A: AF with rapid ventricular response. Panel B: Atrial utter with 2:1 AV conduction. Panel C: Sustained
AVNRT with conversion to sinus rhythm and reinitiation of AF in panel D.
196
M. Shenasa et al.
Figure 3 Illustrates the different etiologies of AF. Many of them maybe interconnected. Modied from Shenasa et al. Individualized
therapy in patients with atrial brillation: new look at atrial brillation, Europace 2012.
Table 1 Risk factors and markers for AF. Modied from Shenasa et al. Atrial brillation in different clinical substrates. In Shenasa M,
Camm JA, editors. Management of atrial brillation: a practical approach. Oxford University Press, in publication.
Traditional risk factors
Novel risk factors
Age, male sex

Hypertension/diabetes mellitus
Alcohol consumption
Clinical conditions
Left ventricular hypertrophy
Myocardial infarction/heart failure
Valvular heart disease
Thyroid disease
Prior cardiac surgery/post-cardiac surgery
Congenital heart disease
Cardiomyopathies
Inherited channelopathies
Autonomic imbalance
Reduced vascular compliance

Increased arterial stiness
Atherosclerosis
Prolonged QRS duration
Insulin resistance
P-wave dispersion
Environmental factors (air pollution, etc.) Low birth weight
Excess vitamin D
Inammatory markers
Atrial brosis
Neurohormones
Antiarrhythmic agents
Genetic variants
Extreme exercise
Pulse pressure
Inammation
Thyroid stimulation hormone, T3, T4
Obstructive sleep apnea
ANP
Obesity/metabolic syndrome
Hs-CRP
Smoking
Interleukin-6
Chronic kidney disease
Angiotensin II
Markers for brosis
Echocardiographic predictors of AF: - LV fractional
shortening- Mitral annular calcication- Left atrial
enlargment- LVH ( LV wall thickness)
Electrolyte imbalance
Markers
Pulmonary disease
(4) Long-lasting persistent AF: Episodes lasting longer than

one year. This denition is created for cases where a
rhythm control strategy is recommended mostly to consider catheter ablation of AF.
(5) Permanent AF: Episodes when patients and their physician accept to maintain AF, or when restoring sinus
rhythm is not attempted or failed and rate control is
the chosen strategy over rhythm control.
(6) Lone AF: Dened as AF in patients below age 60 with
no clinically detectable structural cardiovascular disease,
which could be paroxysmal, persistent, or permanent.
(7) AF Burden: Dened as the proportion of time patients
are in AF.
AF maybe associated with other arrhythmias, the most

common ones being atrial utter, atrial tachycardia. Less frequently AV nodal reentrant tachycardia (AVNRT) and accessory pathway tachycardia are associated with AF. These
arrhythmias may coexist with AF as seen in Fig. 2AD (same
patient).
Furthermore, ventricular tachycardia and AF may be seen
in the same patients especially those with advanced HF.
3.1. Atrial brillation and quality of life
It is shown that patients with AF have poorer quality of life
compared to healthy individuals.3
197
Remodeling in Atrial Fibrillation

action potential duration
refractory
period
electrical
AP D
C a++-influx
contractility
size of reentry
number of reentries
AF
stretch
contractile
structural
dilatation
RAS activation
conduction
dis order
c omplianc e
fibrosis
loss of a-wave
ECG
LA pressure a
normal
dilated
V
Courtesy of Kb S,
Figure 4
Interplay between the electrical, mechanical and structural remodeling pathways in AF. Courtesy of Stephan Kaab.
Figure 5 Illustrates the interplay of different pathophysiological processes in AF. (MI : myocardial infarction, LV: left ventricular, AF:
atrial brillation) Courtesy of Ali Sovari MD.
3.2. Recent epidemiological observations of atrial brillation

The lifetime risk of developing AF after age 40 is one in four and
will increase with advanced age.1 Essentially, AF is an agedeveloped disease, occurring in 10% of patients at the age of
90. AF is more common in Caucasians than AfricanAmericans
and Hispanics.4 Subclinical silent or asymptomatic AF has
become more recognizable and recent observations suggest it
carries the same risk of stroke as symptomatic AF. AF is one
of the most common arrhythmias for emergency room visits
and hospitalizations and accounts for most of AF related costs.
Health outcomes: Incident of AF increases the risk of all

causes as well as cardiovascular mortality by 1.52 fold and
the risk is even higher in women (5-fold).1 AF has a diverse etiology as shown in Fig. 3.
3.3. Etiologies of atrial brillation
AF has a very diverse and often multiple etiologies, such as
hypertension, coronary disease, HF, thyrotoxicosis, acute
myocardial infarction as shown in Fig. 3. Some recently recognized etiologies and risk factors such as obesity; obstruc-
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Figure 6 Relationship between magnitude of atrial brosis and types of AF as detected by delayed-enhanced MRI. Courtesy of Nassir
Marrouche. (MRI: Magnetic resonance imaging, AF: Atrial brilation)
tive sleep apnea and impaired renal function are also related
to AF.
Hypertension is the most common cause of AF is followed
by HF, valvular heart disease, left ventricular hypertrophy
(LVH), left atrial enlargement, CAD and diabetes. Less common etiologies are hyperthyroid state and alcohol use.
Recently, novel etiologies such as obesity, obstructive sleep
apnea (OSA), impaired renal function and smoking have
emerged. A variety of traditional and novel risk factors and
markers are shown below in Table 1.
3.4. Pathophysiology and mechanisms of atrial brillation

Since the initial description by Gordon Moe.5 that multiple
reentrant wavelets are present during computer simulations
and experimental models of AF, multiple mechanisms some
of which maybe present simultaneously have been proposed
and can be classied as follows:6
(A) Single source:

a. Automatic focus from either pulmonary veins (PVs)
or atrial tissues.
b. Mother wave.
c. Fixed rotor.
d. Moving rotor.
(B) Multiple sources:
1)
Multiple foci.
2)
Unstable circuits.
3)
Multiple wavelengths.
4)
Focus + multiple wave lengths.
It is now well established that AF begets AF and cellular
and ionic remodeling (electrical, mechanical and neuro hormonal) plays a signicant role in initiation and progression
of AF (Fig. 4).
With the landmark report by Haisseguerre et al.7 rapid
depolarization from PVs that can initiate and perpetrate AF
Figure 7 Panel A: Demonstrates the interplay between AF and

HF cycle and Panel B HFAF cycle. (AF, atrial brillation; ANP,
atrial natriuretic peptide; BNP, brain natriuretic peptide; EDP,
end diastolic pressure; LAP, left atrial pressure; HF, heart failure;
LVD, left ventricular dilation). Courtesy of Alfred Bove.
has led investigators to better understand mechanism(s) of

AF and develop novel therapeutic approaches to AF. The
mechanism by which PV res and triggers AF is poorly understood, but it may be related to genetic factors, stretch, neuro-

hormonal and autonomic inuences. Non-pulmonary thoracic
veins such as coronary sinus, superior and inferior vena cava
and vein of Marshall can but less often, be a source of
abnormal ring and triggers of AF. Autonomic innervation
to the heart particularly in the atria as well as intrinsic
neural pelxi in the atria, as well as direct sympathetic and parasympathetic activity can play a signicant role in the pathogenesis of AF.
3.5. Diagnosis and detection of atrial brillation
First step in diagnosis of AF is by rhythm documentation,
either by electrocardiogram (ECG), rhythm strips or long-term
electrocardiography, such as Holter monitor or event recorders. Recently, many episodes of AF asymptomatic so-called
silent have been documented by interrogation of implantable pacemakers, implantable cardioverter debrillators or
loop recorders. Importantly the stroke risk of asymptomatic
AF remains the same or even higher than symptomatic ones
(see section on Stroke and AF).8 The varieties of AF monitoring and detection devices that are currently available include
event recorders, smart phones, etc.
3.6. Inammation, brosis and atrial brillation
Several studies have elaborated on the role of inammation
and subsequently brosis as an integral part of the
pathophysiology of AF.9 A complex cascade of inammatory
processes and oxidative stress leading to brosis and subsequently AF is depicted in Fig. 5.6
Briey, AF is clearly associated with increased levels of
inammatory markers and atrial biopsies in patients with
AF have also conrmed the presence of inammation. There
is evidence supporting a link between inammation and AF,
and some of the drug therapies, such as the angiotensin-converting-enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), steroids, sh oils, and vitamin C, that might be
efcacious in the prevention of AF by modulating inammatory pathways. However, randomized trial and longitudinal
studies are needed to conrm the direct relationship between
AF and inammation.
199
Table 2
Risk scheme for CHADS2 and CHADS2-VASc.
CHADS2
C
H
A
D
S2
Congestive HF
Hypertension
Age P75 yrs
Diabetes
Stroke
1
1
1
1
2
point
point
point
point
points
CHADS2-VASc
C
H
A
D
S2
V
A
Sc
Congestive HF
Hypertension
Age P75 yrs
Diabetes
Stroke
Vascular disease
Age P65 yrs
Sex category, female
1
1
2
1
2
1
1
1
point
point
points
point
points
points
points
points
The left atrial (LA) anatomy, structure, function and electrophysiology is different than the right atrial (RA). Fibroblasts migrate selectively to the LA secreting collagen,
pectin and are not excitable. Fibroblasts produce atrial brosis and inhomogeneity, which are a good substrate for
arrhythmias.
Recent reports by Marrouche et al., demonstrated that the
magnitude of atrial brosis correlates with increased risk of
AF as well as progression from paroxysmal to persistent and
permanent. Furthermore, the presence of increased brosis will
lower the success rate of catheter ablation as well as an
increase in the risk of recurrence of AF. Marrouche et al., categorized the magnitude of atrial brosis to Utah 14. Utah 1
has 05% brosis, Utah II >520%, Utah III >2035%
and IV >35% (Ref. 8). Kottkamp recently proposed brotic
atrial cardiomyopathy as the substrate for AF.10 Fig. 6 shows
the relationship between magnitude of atrial brosis and types
of AF as detected by delayed-enhanced MRI.
3.7. Atrial brillation progression
In majority of cases AF may initially present as paroxysmal
form and may progress to persistent and eventually become
Figure 8 Example of atrial tachycardia from interrogation of an implantable device in a patient who was recurrent episodes of
asymptomatic (silent) AF.
200
permanent. The rate of progression is variable and depends on
many factors including magnitude of atrial remodeling, associated structural heart disease and their progression.11 It is
unknown why in some patients it takes a few months for paroxysmal AF to become permanent and others 30 years.
3.8. Biomarkers of atrial brillation (see Table 1)
Certain pathophysiological markers are used to assess the risk
of AF and its progression as well as the response to therapy
and interventions. The most common biomarkers that are used
in clinical practice are B-type natriuretic peptide (BNP) and Creactive protein (CRP), which predict the high risk of incident
AF, and its progression. However, most of our biomarkers are
nonspecic and overlap with other cardiac and non-cardiac
conditions making their clinical utility marginal. It maybe that
in the future the biomarker scores integrated with other risk
score systems to better select high risk individuals, but to date
their clinical appreciation is limited. Other biomarkers like
interleukin-6 and tissue necrosis factors have been reported
and are currently under investigation in large trials.
3.9. Hypertension and atrial brillation
Hypertension is the most common risk factor for AF and is
present in 7080% of patients with AF. Hypertension causes
left ventricular hypertrophy (LVH), diastolic dysfunction, left
atrial hypertrophy and brosis, all of which promote AF.
Long-term longitudinal studies from Framingham Heart
Study1 and Womens Health Study revealed both high systolic
and diastolic BP increase the risk of developing AF.12 Almost
one-third of AF patients with hypertension remain asymptomatic. A combination of hypertension and AF is present in 72%
of stroke patients and 82% of patients with chronic kidney disease, 77% of those with diabetes, 73% of those with CAD,
71% of patients with HF, and 62% with metabolic syndrome.
In addition, hypertension is seen in 4990% of AF trials.13
LVH alone is an independent risk factor of AF recurrences.
4. Heart failure and atrial brillation
4.1. Atrial brillation in patients with decreased left ventricular
dysfunction
AF is the most common dysrhythmia in patients with HF and
there exists signicant association between AF and HF. Both
conditions share many risk factors. AF and HF are two important emerging epidemics in medicine.14 AF causes HF and HF
causes AF (HF begets AF and AF begets HF).
The AFHF cycle: There exists a complex interaction and
relationship between the two diseases. Data from Framingham
study demonstrated that AF and HF often coexist and that
both often have an adverse effect on each other irrespective
of which comes rst (chicken or the egg). Data from multiple
longitudinal studies suggest AF increases the risk of HF by
23 fold, and HF also increases the likelihood of AF and promotes AF from paroxysmal to permanent. About one-third of
patients with HF will develop AF (Fig. 7). The incidence of AF
in patients with HF increases according to the severity of HF
and yet remains diverse. Furthermore, the prevalence of AF in
M. Shenasa et al.
HF increases according to the New York Heart Association
(NYHA) Class ranging from 4% in NYHA Class I to almost
50% in NYHA Class VI. Furthermore, HF poses a signicant
risk of proarrhythmia in patients treated with antiarrhythmic
agents for AF. A recent trial on the use of dronedarone in
high-risk patients with AF (i.e. those with HF and reduced systolic function) revealed the unexpected deleterious effect with
increased mortality in patients who received dronedarone compared to a placebo.15
5. Atrial brillation in patients with diastolic dysfunction (AF
with preserved LV systolic function)
Diastolic dysfunction is now recognized as an independent risk
factor for incident AF. In patients with diastolic dysfunction,
the most common ndings are left atrial enlargement,
increased left atrial afterload and preload as well as increased
atrial wall stress and brosis, as they all promote occurrence of
AF.16 Diastolic dysfunctions share many etiologies with AF
such as hypertension, cardiomyopathies, diabetes.
5.1. Atrial brillation and type II diabetes
Type II diabetes is an independent risk factor for developing
AF. Diabetes has been found in 20% of patients with AF
and patients with diabetes have approximately 40% greater
risk of developing AF. The exact mechanism and relationship
between diabetes type II and AF are not fully understood
however it is postulated to be due to atrial patchy amyloid
in the atrium leading to atrial remodeling and brosis which
promotes AF.
5.2. Atrial brillation and hypertrophic cardiomyopathy
Hypertrophic Cardiomyopathy (HCM) is an independent risk
factor for AF and is the most common arrhythmia in patients
with HCM with a prevalence of 22%. As such patients with
HCM carry a 46 fold higher risk of developing AF compared
to the general population.17 AF poses an adverse outcome
effect in patients with AF and once AF occurs in patients with
HCM the prognosis is poor. Most patients with HCM have
signicant hypertrophy, diastolic dysfunction and left atrial
enlargement all of which promote occurrence of AF. Management of AF in patients with HCM is a challenge.
5.3. Atrial brillation and stroke
AF is found in about 25% of patients admitted with ischemic
stroke and it increases the risk of stroke by 36 fold. Stroke is
the most devastating complication of AF and causes death,
neurological decits, longer hospitalization and disability.
Multiple studies have demonstrated the relationship between
AF and stroke. The Stroke Prevention in Atrial Fibrillation
Study (SPAF III) data showed that up to 45% of the patients
enrolled had ECG documentation of AF.18 Stroke can occur
as the rst manifestation of AF. A recent study by Healy
et al.,19 demonstrated that the patient with asymptomatic
silent AF and atrial tachyarrhythmias detected during interrogation of permanent pacemakers and ICDs revealed higher
incidence (50%) of stroke than those without silent AF.
201
Fig. 8 illustrates an example of asymptomatic atrial tachycardia. Another similar study (TRENDS) provided similar data
and conclusions.20 Based on the STROKESTOP trial it is
recommended that patients with silent AF should be screened
for the risk of stroke.21
Several stroke risk prediction scores have been proposed.
The most widely accepted predictor is CHADS2 (Congestive
Heart Failure (CHF), hypertension, age, diabetes, stroke/transient ischemic attack). Recently CHADS2-VASC score has
been introduced which additionally includes age >65 years,
vascular disease and female sex. CHADS2 has been validated
by several studies and CHADS2-VASC is more popular in
Europe. There is a stepwise approach increase in risk of
stroke as the CHADS2 or CHADS2-VASC score increases22
(Table 2).
A simplied approach for real world cases is based on a
patients age being over 65 years and presence of any of the
stroke risk factors (CHF, hypertension, diabetes, previous
stroke/transient ischemic attack, vascular disease and female
sex), anticoagulation is recommended. Otherwise no treatment
or aspirin is the recommended management.
than 50% of patients experience one episode of post-op AF.

The majority of post-op AF converts to sinus rhythm spontaneously in the rst 2448 h, however if it takes longer than
48 hours it increases the risk of stroke and prolongs hospitalization and its related costs. Risk factors and predictors for
post-op AF include older age, male gender, pervious history
of AF, history of previous cardiac surgery, concomitant valve
surgery, LV dysfunction and impaired renal function. In the
postoperative period volume overload, hyper/hypotension,
inammation, post pericardiotomy syndrome are among the
common risk factors for AF.
Post-operative AF affects both early and late mortality
after isolated CABG. Most of the complications are related
to stroke therefore post-operative surveillance and long-term
management with antiarrhythmic agents and antithrombotic
management is warranted.
Preoperative treatments with beta-blockers have been
shown to effectively reduce the risk of AF since inammation
plays a signicant role in the genesis of post op AF. Colchicine
as well as statins is effective in prevention of this
arrhythmia.23,24.
5.4. Post-operative atrial brillation
5.5. Atrial brillation in athletes and during endurance exercise
AF is the most common arrhythmia after cardiac surgery and

occurs approximately in 2050% of patients depending on the
type of surgery. AF occurs in 3040% of patients post
coronary artery bypass graft (CABG) and up to 6070% of
patients with combined CABG and valve surgery. Almost,
60% of episodes of AF happen in day 23 of post op and more
AF is the most common arrhythmia seen in athletes. The incidence of AF in this population depending on the type of sport
ranges from 5 to 10% and is most common in marathon runners, cyclists and cross country skiers. The mechanism(s) of
endurance exercised AF is not fully understood but maybe
related to left atrial enlargement, inammation, remodeling
Figure 9 Indications for electrical and pharmacological cardioversion, and choice of antiarrhythmic drugs for pharmacological
cardioversion in patients with recent-onset AF. Adopted from Camm JA, Lip GYH, De Caterina R, et al. 2012 Focused update of the ESC
Guidelines for the management of atrial brillation. Eur Heart J 2012;33:27102747.
202
M. Shenasa et al.
Figure 10 A and B demonstrates a simplied approach with antiarrhythmic therapy for rhythm control in patients with normal LV
systolic function (Panel A) and reduced LV systolic function (Panel B).
and brosis. As well as left ventricular hypertrophy, enhanced

vagal tone and sinus bradycardia, which is a physiological
response to exercise. Aside from restriction of endurance exercise management of AF in athletes remains the same as others,
however current guidelines recommend to rule out the presence of associated conditions such as WolffParkinsonWhite
syndrome, HCM and ARVD/C.25 History, physical examination, ECG and treadmill test should be part of the workup.26
5.6. Genetics of atrial brillation
Lone AF and those occurring in patients 60 years or younger
have a genetic background and it is important to screen
families with a history of AF in young population. Familial
AF is now a known entity and is often associated with

other inherited channelopathies such as Brugada syndrome,
Long and Short QT syndrome and other sodium-channel
mutations.
The most common type of genetic AF is linked to chromosome 4q25.27 In addition, several other genes identied have
been to be linked to AF such as KCNQ1, KCNE2, SCN5A
and others.
Giustetto et al.28 recently reported on the prevalence of AF
in large patient population with Brugada syndrome. The
results revealed that the prevalence with AF and Flutter is
higher than the general population of the same age. Patients
who developed AF and utter after the diagnosis of Brugada
ECG are younger, have a greater prevalence of spontaneous
type 1 Brugada ECG and more often experience cardiac arrest.
203
Figure 11 Illustrates the ESC guidelines for rate control approach in patients with AF. Camm JA, Lip GYH, De Caterina R, et al. 2012
Focused update of the ESC guidelines for the management of atrial brillation. Eur Heart J 2012;33:27102747.
The prognosis is worse in this patient population compared to

those with Brugada Syndrome without AF and Flutter. At
present genetic testing is not recommended.
5.7. Novel risk factors in atrial brillation
Several novel risk factors have emerged in relation to AF as
seen in Table 1.
5.8. Atrial brillation and obesity
Obesity carries a high risk of developing AF, as it shares multiple etiologies with other comorbidities such as hypertension,
diastolic dysfunction, diabetes type 2, sleep apnea and metabolic syndrome. Obesity adversely affects the response of AF
to antiarrhythmic agents and catheter ablation. Therefore
aggressive lifestyle modications should be discussed with the
patient to potentially reduce the risk of AF.29
5.9. Atrial brillation and obstructive sleep apnea

Obstructive sleep apnea (OSA) is a recognized independent
risk factor for AF. In particular nocturnal AF of either paroxysmal or persistent type is often detected in patients with OSA.
Thus patients with signicant OSA should be screened for the
risk of AF and likewise patients with nocturnal AF should be
screened for possible sleep apnea. Appropriate management of
OSA will decrease the incidence of AF. OSA signicantly
decreases the efcacy of antiarrhythmic agents as well as radiofrequency ablation of AF.30
6. Atrial brillation and kidney disease
Impaired renal function is now recognized among novel risk
factors for incident AF and progression of this arrhythmia.
Chronic kidney disease may be found in about 35% of patients
with AF.31 Patients with end stage renal disease and on kidney
204
M. Shenasa et al.
Table 3 Comparison of warfarin to novel oral anticoagulants. Adopted and modied from Cairn JA. Canadian Journal of
Cardiology 2013;29:11651172.
Feature
Warfarin
Dabigatran
Rivaroxaban
Apixaban
Mechanism
Prodrug
Dose regiment
Administration
AF dose (mg)
Food eect
Food interaction
Bioavailability (%)
tmax (h)
T (h)
Substrate CYP
Substrate P-gp
Renal clearance
Protein binding (%)
Monitoring
AF trial complete
Inhibits synthesis: II, VII, IX, X

No
Oral
OD
INR 23
Yes
Many
98
72120
2060
2C9, 3A4
No
No
99
INR
Phase III (19891992)
Direct IIa inhibitor

Yes
Oral
BID
150, 110, 75
Delays absorption
No
6.5
0.52
1117
No
Yes
85
35
No
Phase III (2010)
Direct Xa inhibitor
No
Oral
OD
20, 15
Delays absorption
No
80100
24
513
3A4, 2J2
Yes
33
9095
No
Phase III (2010)
Dirext Xa inhibitor
No
Oral
BID
5, 25
No
No
50
34
513
3A4
Yes
27
8793
No
Phase III (2011)
dialysis are at highest risk for developing AF. On the other

hand newly diagnosed AF doubles the mortality in patients
with end stage renal disease and those on dialysis. Furthermore, chronic kidney disease is now emerging as an independent risk factor for occurrence of AF and stroke.32,33
With increasing use of novel oral anticoagulant (NOAC)
agents, caution should be practiced to the use of these agents
as some of them have signicant renal clearance such as
Dabigatran.
7. Management of atrial brillation
The goals of AF management are:
1. Prevention of recurrences and maintenance of sinus
rhythm.
2. Prevention of AF complications: most importantly stroke
prevention including risk stratication for stroke.
3. Prevention of HF.
4. Improving quality of life.
5. Improving survival.
6. Anticoagulation in AF.
7.1. Acute management of atrial brillation
Figure 12 Recommendation from ESC Guidelines on AF for the

choice of anticoagulation in AF. (NOAC : novel oral anticoagulant , VKA : vitamin K antagonist) Camm JA, Lip GYH, De
Caterina R, et al. 2012 Focused update of the ESC Guidelines for
the management of atrial brillation. Eur Heart J 2012;33:2710
2747. With permission.
A majority of patients with acute AF present to hospitals

(emergency rooms). Acute management of AF depends on
the severity of symptoms, which often present as rapid palpitations, increasing shortness of breath, chest pain, light headedness, and rarely syncope. If the patient is hemodynamically
compromised, direct current cardioversion is the safest. If
patients are stable enough pharmacological cardioversion is
done with intravenous Procainamide, Flecainide, Ibutilide,
Vernakalant or Amiodarone depending on the availability of
these drugs34 Fig. 9.
7.2. Drug therapy for atrial brillation
Long-term management of AF should be individualized and
evidence based. Selection should be based according to the
Figure 13
205
A histogram of published articles between 2000 and 2013 in the English language.
Figure 14A Electroanatomical mapping of the left atrium in a posterioranterior projection illustrates left atrium and pulmonary veins.
Each red dot denotes one ablation lesion for isolation of PVs. CS, coronary sinus; LIPV, left inferior pulmonary vein; LSPV, left superior
pulmonary vein; Posterior LA, Posterior left atrium; RIPV, right inferior pulmonary vein; RSPV, right superior pulmonary vein.
underlying structural heart disease. Although most trials on antiarrhythmic drugs for AF remain unsatisfactory, antiarrhythmic
therapy remains the mainstay of AF management. Two strategies
of rate control versus rhythm control have been discussed in
length elsewhere. 35 Current evidence suggests that rate control
even lenient rate control is not inferior to rhythm control.
7.3. Pharmacologic therapy for rhythm control

In patients with paroxysmal AF with no structural heart disease and normal LV function, Class I C agents may be used
safely. In patients with congestive HF, Amiodarone is more
effective than Sotalol, but has more non-cardiac side effects.36
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M. Shenasa et al.
Figure 14B Electroanatomical mapping (EMA) and computerized tomography (CT) of the left pulmonary veins. LAA, left atrial
appendage. Abbreviations same as Fig. 14A above.
Dofetilide can be used in patients with reduced LV ejection

fraction37 (Fig. 10).
8. Pharmacological therapy for rate control
of beta-blockers and digoxin have been found to be most

effective.34
In certain young active individuals who remain symptomatic rhythm control is preferred over rate control.34
8.2. Arguements in favor of rhythm control approach
The selection of pharmacological agents is dictated by a

patients type of AF, underlying structural heart disease most
importantly degree and left ventricular dysfunction and coronary artery disease34 Fig. 11.
8.1. Rate versus rhythm control strategies
The rate control strategies became popular after the large
scale AFFIRM Trial: Atrial brillation follow up investigation of rhythm management3840 was published. The
AFFIRM study included 4060 patients, 65 years and older
with AF and were randomized into rate or rhythm control
strategies. Follow up included stroke, heart failure, hospitalization and death. The study found slightly higher trends
toward increased mortality in patients with rhythm control
compared to rate control (p = 0.08). This may have been
due to adverse effect of antiarrhythmic therapy that has offset the benet of sinus rhythm. In a similar trial of rate control versus electrical cardioversion (RACE Trial), there was
no signicant difference between rate versus rhythm control
strategy.41
From these controlled randomized trials it can be concluded
that in older and less active individuals who make the majority
cases of AF, a rate control strategy with appropriate stroke risk
stratication and anticoagulation therapy is acceptable.
A variety of rate control agents are available including
calcium antagonist, beta-blockers and digoxin. Combinations
Maintenance of sinus rhythm has been associated with improvement in quality of life, left ventricular ejection fraction improved
exercise capacity and left atrial size.42 Furthermore patients who
undergo catheter ablation and maintain sinus rhythm have signicantly reduced the rate of progression to permanent AF.
8.3. Arguements against rhythm control approach
1. Rhythm control management is often difcult to achieve.
2. Antiarrhythmic drugs have a signicant side effect including proarrhythmic effect.
3. Antiarrhythmic agents are potentially contraindicated in a
large number of patients.
4. Associated structural heart disease and risk factors modulate and reduce the response to antiarrhythmic agents and
under certain conditions have a negative effect such as
HF and cardiomyopathies.
5. No evidence that maintaining sinus rhythm will improve
survival.
6. Due to the high incidence of silent AF anticoagulation
needs to be continued.
8.4. Argues in favor of rate control approach

1. Rate control agents are safe and do not produce
proarrhythmia.
207
bundle and coronary sinus.
Figure 15 (AC) From our laboratory illustrates a case of AF as detected in intracardiac electrograms from HIS bundle and coronary
sinus electrodes.
208
M. Shenasa et al.
Figure 16 Ablation at the carvo-tricuspid isthmus that abolishes atrial utter in the same patient as Figs. 14A and 14B. The red dots
denote the site of RF ablation.
Figure 17B 2014 AHA/ACC/HRS Guideline for the Management of Patients with AF: Executive Summary. January CT,
Wann S, Alpert JA, et al. J Am College Cardiol 2014.
3. In patients with CHF large randomized trials have not

shown superiority of rhythm control over rate control in
terms of mortality and hospitalization (Ref. University of
Ottawa pg1156, FALK).
Figure 17A ESC guidelines for catheter ablation of AF. Camm
JA, Lip GYH, De Caterina R, et al. 2012 Focused update of the
ESC Guidelines for the management of atrial brillation. Eur Heart
J 2012;33:27102747. With permission.
2. Rate control even lenient rate control approach is not inferior to rate control.
8.5. Anticoagulation in atrial brillation

In view of the recent experience with NOAC we only summarized the comparison of the three new NOACs with Warfarin.
Oral anticoagulation either with Warfarin or NOACs is recommended for most patients with AF. Stroke risk scores are

more useful for small portion of patients in which oral anticoagulation may not be necessary. Table 3 shows the pertinent
clinical and pharmacological prole of the three NOACs compared to Warfarin.43
The recommendation from ESC Guidelines on AF for
choice of anticoagulants in AF is shown in Fig. 12.
9. Catheter ablation of atrial brillation
Since the landmark report of Haissaguerre et al.44 on successful ablation of triggers from pulmonary veins that eliminated
paroxysmal AF was published, a plethora of reports have
emerged (Fig. 13).
9.1. Pulmonary veins and atrial brillation
Electrical activity arises from pulmonary veins (PVs) that triggers AF and ablation of these triggers eliminates recurrences of
AF. Many reports have conrmed these observations and PV
isolation (PVI) is now the corner stone of catheter ablation of
AF. Although PV triggers are common they are not exclusive,
as other sources of AF triggers exist.45 Further it has been
demonstrated that left atrial tissue extends 13 cm like a
sleeve into the PVs and carries the same structural and electrical properties.46
The reason then why everyone does not get AF and only
certain individuals develop AF remains elusive of certain
electrical and neurohormonal changes such as stretch,
increased left atrial pressure, may promote trigger activity
in PVs. It is also assumed that there may be an electrical
block between PVs and left atrium under normal conditions.
Once the repeated ring from PVs enters the left atrium
the substrate initiates AF in a multiple macro-reentrant
circuit either of single or multiple rotors (see mechanism).
Thus elimination of triggers will abolish recurrences of AF
in about 60% of the patients. Failure in the remaining
patients and recurrences is most likely due to incomplete
PVI and presence of the so-called gaps that often necessitate
redo procedures.
9.2. Current status and results of atrial brillation ablation
Today catheter ablation of paroxysmal AF is commonly preformed generally after a failure of at least one antiarrhythmic
Figure 18
209
agent. In 2012 about 50,000 procedures were performed in the
United States. On average the short-term success rate in high
volume experienced centers is about 60% for the rst procedure and 71% after multiple procedures. 1535% of patients
undergo a redo procedure.47
PVI remains the cornerstone of AF ablation, which is often
effective in 5060% of patients with paroxysmal AF
(Figs. 14A and 14B).
Substrate modication, i.e., left atrial and other sources are
often necessary in cases of persistent and long-lasting persistent AF. In more complex cases extensive substrate modication including rooine, posterior left atrial wall ablation;
ablation around the left atrial appendage may be needed.
Fig. 15AC is from our laboratory illustrates a case of AF
as detected in intracardiac electrograms from His bundle and
coronary sinus electrodes. Occasionally after termination of
AF, atrial utter emerges may necessitate ablation at the
carvo-tricuspid isthmus as shown in Fig. 16. Extensive ablation to the left atrium in some cases produces left atrial tachycardia/utter at the mitral isthmus that also may require
ablation of that region.
Several randomized trials have compared catheter ablation
with antiarrhythmic agents in a randomized fashion. All the
reported trials were designed to include symptomatic patients
with paroxysmal, persistent and long lasting persistent AF
who have failed at least one antiarrhythmic agent. All these trials have shown superiority of catheter ablation over antiarrhythmic therapy in terms of symptom relief, recurrences,
quality of life and outcome issues.
Experimental and clinical reports suggest that neural pelxi
that lie over the junction of PVs and left atrium may serve
as a source of inducing and maintain AF. High frequency stimulation of neural plexi in both animals and humans demonstrated to induce AF and thus attempts to ablate neural
plexi have resulted in the elimination of AF. To date there
are no randomized trials comparing PVI with neural plexi
ablation in patients with AF.48
Thus, catheter ablation of AF in patients with paroxysmal
type with no to minimal structural heart disease may now be
considered as rst line therapy and is considered reasonable
in patients with paroxysmal and persistent AF.33 Fig. 17A
shows the ESC guidelines and Fig. 17B illustrates the American College of Cardiology, American Heart Association and
Heart Rhythm Society 2014.
(A) Depicts circular mapping and ablation catheter. (B) Cryoballoon ablation catheter. Image courtesy of Medtronic, Inc.
210
M. Shenasa et al.
Figure 19
CT angio and Fly Thru of the LA and Pulmonary Veins. (LA : left Atrium).
9.3. Perioperative anticoagulation

Based on the Meta-analysis results, 9 studies with 27,402
patients, undergoing uninterrupted anticoagulation therapy
with Warfarin have signicantly reduced the risk of thromboembolic complication without an increased risk of bleeding.49
9.4. Strategies for catheter ablation of atrial brillation
Different approaches for catheter ablation of AF have been
used in different centers as summarized below.
1) Anatomical approach: PV isolation, roof-lines, box
lines.
2) Substrate based approach.
Electrogram based.
Electrogram fractionation (Complex Fractionated
Atrial Electrograms (CFAE)).50
Neural Plexi.48
9.6. Techniques for atrial brillation ablation

1. Radiofrequency ablation.
According to the initial report of Haissaguerre et al.,44 the
triggers were within the PVs and radiofrequency (RF) currents
were delivered within the PVs have eliminated AF. However,
follow up reports showed PV stenosis have developed with
signicant symptoms that in some patient interventions were
needed to correct it by stenting. Currently, PVI around the
antrum is a common practice.
10. Cryoballoon ablation
This balloon based ablation system freezes the antrum of the
PVs. The cryoballoon ablation isolates PVs by freezing them
at 80. A few randomized trials have compared RF ablation
with cryoballoon ablation techniques as seen in Fig. 18A and B.
11. Results of catheter ablation
3) Etiology and mechanism based approach.

The Bordeaux group rst reported on a stepwise approach that
is currently adopted in many centers. In this approach the procedure begins with PVI and according to the termination or extent
of underlying atrial remodeling a roof line followed by mitral isthmus line, followed by anterior mitral isthmus line and inferior and
posterior lateral lines that completes the left atrial box.5153
9.5. Rotor ablation in patients with AF
Evidence from patients with AF and from experimental studies
has suggested that single or multiple rotors maybe operated in
AF and elimination of rotors have terminated the AF in these
models. Recently, Narayan et al.54 have demonstrated single
rotors in human AF and ablation of these rotors have eliminated AF without additional ablation of the PV and other
sites. A randomized trial is currently under investigation.
The best results of PVI are obtained in patients with paroxysmal AF with no structural heart disease. The acute success
rate is about 57% (5060%). The success rate of multiple
procedures without antiarrhythmic agents is at best 71%
(6577%) and multiple procedures with antiarrhythmic
agents are 77% (7381%).47 The immediate 3 months are
considered a blanking period as many asymptomatic recurrences have been detected. Weerasooriya et al.55 reported
on the long-term results after multiple catheter ablation procedures of AF having shown that the sinus rhythm maintained at 1, 2, and 5 years was 87%, 81% and 63%.
However after a single procedure 40%, 37% and 29% at
1, 2 and 5 years were reported.55 The associated comorbidities such as hypertension, diastolic dysfunction, heart failure,
obstructive sleep apnea, obesity and impaired renal function
have shown to lower the success rate of catheter ablation of
AF and increase recurrences.

11.1. Outcomes of catheter ablation of atrial brillation
Catheter ablation of AF is taken with much enthusiasm and the
ablationists promoting that the long term outcomes of AF ablation are superior to antiarrhythmic therapy. However, there are
no large randomized trials to show that the catheter ablation is
superior to medical management in terms of reduction of mortality, stroke, hospitalization, and improvement in heart failure.
Only the MANTRA trial demonstrates that after 2 years the
quality of life was better compared to antiarrhythmic therapy.
A very recent trial comparing antiarrhythmic therapy to radiofrequency ablation of AF as rst line therapy just published
showed a lower rate of recurrent paroxysmal AF in patients
who underwent catheter ablation of AF.56,57. It is hoped that
with early intervention and maintenance of sinus rhythm, atrial
remodeling is minimized and improves the burden of AF. At
present no data has demonstrated that maintaining sinus
rhythm with catheter ablation will reduce the death rate related
to AF. Recently Mont et al.58 reported on catheter ablation vs.
antiarrhythmic drug treatment of persistent AF: a multicenter,
randomized, controlled trial (SARA study). The results revealed
that catheter ablation was superior to medical therapy in maintaining sinus rhythm in patients with persistent AF during a 12month follow up. The shortcoming of this trial was that the trial
was terminated prematurely due to low patient recruitment and
the primary endpoint of the study was only recurrences of AF
24 h after ablation.
Dagres et al.,59 reported on a meta-analysis of randomized
trial that there were no mortality benets of catheter ablation
over drug therapy. Similarly two Canadian trials of AF-CHF60
and the RAAFT study (rst line radiofrequency ablation versus antiarrhythmic drugs for atrial brillation treatment) did
not show mortality benet of catheter ablation.
12. Imaging before and during AF ablation
(1) Preprocedure imaging includes transthoracic echocardiogram, cardiac computerized tomography (CT) to
evaluate left atria and PVs geometry and its branch as
seen in Fig. 19.
(2) Intraprocedural imaging includes magnetic resonance
imaging (MRI) to evaluate the degree of brosis, intracardiac echocardiography (ICE), electroanatomical
mapping, magnetic resonance imaging and direct visualization of ablation lesion (currently under investigation).
13. Complication of catheter ablation

Catheter ablation of AF is now an established procedure and
has a low incidence of procedural complications in experienced
and high volume centers. Two worldwide surveys by Cappato
et al. have reported on the safety and complication of catheter
ablation of AF, initially in 200561 and again in 2010.62 Gupta
et al.63 recently reported a systemic review of 192 studies with a
total of 83,236 patients with periprocedural complication rate
of 2.63.2% in catheter ablation of AF.
The most common acute complications include vascular
complications including atriovenous stula, femoral pseudoaneurysm, stroke and TIA. PV stenosis (less often seen as PV iso-
211
lation is preformed at the antrum of PVs), tamponade,
pericardial effusion, phrenic nerve injury, pneumothorax/hemothorax, sepsis and valve damage. However, the most devastating
complications are death, stroke and atrioespohageual stula.
The predictors of complications are related to the operators
experience, low volume centers and extent of other
comorbidities.63
Two recent reports on complications of catheter ablation of
AF have been published.64,65 The most common complication
of cryoballoon procedure is phrenic nerve palsy, which often
resolves spontaneously however occasionally permanent damage may occur. Lee et al. recently reported a low risk of major
complications in 500 consecutive patients who underwent PVI
only for paroxysmal AF.66 Therefore overall catheter ablation
of AF appears to be safe and effective in a selected patient
population.
14. Ablate and PACE
In patients who are not appropriate candidates of AF ablation
and adequate rate control with pharmacological agents cannot
be achieved, AV-nodal ablation and pacemaker implantation
maybe considered. In this group those with heart failure may
benet from biventricular devices.6769
14.1. Left atrial appendage (LAA) closure for stroke prevention
In patients who are not a candidates for antithrombotic
agents and are at risk for stroke, left atrial appendage
(LAA) closure either surgically or with implantation of
devices appears reasonable. Currently, several devices are
under investigation and the most commonly used is the
Watchman device.70 The PROTECT-AF trial was designed
to prospectively evaluate the safety and efcacy of the
Watchman device in 59 centers. A total of 707 patients with
CHADS2 score of >1 were enrolled and in 89.5% of
patients successful implantation was achieved. The trial concluded that the LAA closure was not inferior to systemic
anticoagulation to Warfarin.71 Other devices such as the
Lariat (SentreHeart, Inc.) is a percutaneous suture ligation
for LAA closure is also under investigation.70,72
14.2. Uncertainties in catheter ablation of AF
When catheter ablation was initially introduced for more discrete cases such accessory pathways and AV nodal reentrant
tachycardias.
There existed a large experience in electrophysiology
studies dening the characteristics of tachycardia circuits as
well as experience obtained from surgical cases. Thus it
was the best of times; and it was the age of wisdom. However in AF ablation, it was the worst of the times; it was the
age of foolishness.73 Thus in the former scenario, the procedure was more successful (90%) with a very low complication rate. However in case of AF after the Haisseguerre
and colleagues landmark report Spontaneous initiation of
atrial brillation by ectopic beats originating in the pulmonary veins, many centers have begun to perform the procedure without scientic background in a more complex and
heterogeneous substrate.7
212
M. Shenasa et al.
Figure 20 Opportunities and challenges for future AF. AF, atrial brillation; AA, antiarrhythmic therapy; SHD, structural heart
disease; HF, heart failure; CRT, cardiac resynchronization therapy; NOAC, novel oral anticoagulants; LAA, left atrial appendage; CHF,
chronic heart failure; NOAC, novel oral anticoagulants; Echo, echocardiography; CT, computerized tomography; MRI, magnetic
resonance imaging.
Figure 21
Final common pathways of diverse etiologies of inammation, brosis and remodeling lead to AF.

14.3. Should catheter ablation be the rst line therapy for
patients with AF?
Controversies continue surrounding whether catheter ablation
should be offered as rst line therapy in patients with paroxysmal AF. Few studies have prospectively and in a randomized
fashion have assessed the outcome of catheter ablation of
AF as the rst line therapy. The available data indicate that
the efcacy of catheter ablation as a rst line therapy is at least
equivalent74 or better56 than the rst line antiarrhythmic drug
therapy. Quality of life appears to be better in the ablation
group compared with antiarrhythmic therapy. Thus current
evidence supports the position of European Society of Cardiology, AF guidelines, as rst line therapy in symptomatic paroxysmal AF appears reasonable in experienced centers.
14.4. Denition of successful procedure
The Heart Rhythm Society consensus on AF published in 2012
dened success as freedom from any symptomatic or asymptomatic AF of any type, atrial tachycardia or utter longer
than 30 s, 12 months after the procedures. However for practical purpose a signicant reduction in AF burden as well as signicant reduction in symptomatic AF is considered a clinical
success. The limitation of these denitions is however the
uncertainty of duration of monitoring post ablation.
14.5. Duration of post ablation monitoring
It has been recognized that during the rst 3 months post AF
ablation there are signicant short and long term AF
recurrences. Therefore this period is arbitrarily designed as
blanking period which may be due to the signicant amount
of tissue damage and edema that promotes AF.
14.6. Procedural end points
At present there is no uniform agreement on what is accepted as
end points of catheter ablation. These uncertainties are due in
part to the following issues: (1) AF types, i.e., paroxysmal, persistent and long lasting persistent. (2) Ablation protocols, i.e.,
PVI only or additional ablation. (3) Ablation techniques i.e.
radiofrequency, cyroablation, laser, etc. (4) Immediate post
ablation protocol, i.e., burst pacing, isoproterenol infusion,
adenosinetriphosphate administration etc. (5) Duration and
methods of rhythm monitoring.
14.7. Cost of catheter ablation of atrial brillation
Catheter ablation is an expensive procedure with the initial
cost and 5 year follow up totaling a sum of $30,00035,000
per patient in the United States.55,79 McKenna et al.76 report
the cost of catheter ablation in United Kingdom to be
7700 - 7900 pound while Canada having a cost of $16,278.7577
15. Future directions in catheter ablation of atrial brillation
Due to relatively high recurrence rates even after the blanking
period and the need for repeated procedure, newer ablation technologies are sought. Endoscopic navigation and visualization of
213
the target tissue and ablation effect on the atria are under investigation. Preliminary reports have examined the feasibility of
this method in experimental animal and the rst 200 patients.78
(1) Recent reports revealed that case done in community
hospitals with low volume procedures had higher complication rates of about 6.2%. Whereas procedures
that are performed in high volume centers with experienced operators had lower complication rates
(3.9%).6164
(2) Direct vision during catheter ablation to better identify
the target tissue and its effect on the atrial tissue.78,79
(3) Since radiation during the procedure is an important
issue to the patient, operator and cath lab staff,
newer technologies are emerging to use ionized radiation free techniques such as magnetic resonance
guided EP study and ablation. Preliminary results
are favorable however; no long-term results are
available.
15.1. Concepts to consider in the future management of AF
Selective ion channel blockers.
Multi-channel blockade (like Amiodarone, Dronedarone
and Ranolazine).
Atrial channel selective (usually relative).
Substrate based mapping and ablation.
Gap junction conduction.
Fibrosis.
Inammation.
Future AF management should focus on personalized risk
factors that better predict the best approach (pharmacological
or nonpharmacological), identify risk and biomarkers as well
as better understanding of genetic, environmental interaction
with such complex arrhythmias. At the same time improvement in AF detection tools and imaging techniques of both
the heart and brain to better understand the pathophysiology
of AF, i.e., system biology. Furthermore, the burden of
brosis should be on the future agenda.
16. Future opportunities
(1) Noninvasive characterization of AF and its types maybe
useful in the identication of patient proles.
(2) At present there are no uniform protocols for catheter ablation of AF and it remains empirical. Hopefully the future trials will provide insights to design
uniform protocols. This inconsistency maybe imparted
due to the complexity of substrate and presence of
evolving underlying heart disease such as HF, hypertension. As such there remain many unanswered
questions like endpoints, follow-ups and denition
of success, etc.
(3) Atrial selective antiarrhythmic and upstream therapy
will continue to expand.
(4) Results and technology of catheter ablation of AF will
expand.
(5) The design of future trials should attempt to answer
some of the following questions::
1. What is the best method and duration of rhythm
monitoring post ablation?
214
M. Shenasa et al.
2. Comparative effectiveness of various ablation
approaches in paroxysmal and persistent AF, i.e.,
PVI only versus PVI and substrate modication
and neuraplexi ablation, rotor ablation, etc.
3. Can anticoagulation be discontinued in some
patients if they maintain sinus rhythm?
4. Best outcome measures, AF recurrences, hospitalization, stroke, death and quality of life.
5. Cost-effectiveness of catheter ablation.
16.1. Future trials

(1) Catheter ablation vs. anti-arrhythmic drug therapy for
atrial brillation trial (CABANA).80
(2) Early treatment of atrial brillation for stroke prevention trial (EAST).81
(3) Rate vs. catheter ablation rhythm control in patients
with heart failure and high-burden atrial brillation
(RAFT-AF).82,83
(4) First line radiofrequency ablation vs. antiarrhythmic
drugs for atrial brillation treatment (The RAAFT
Study).84
(5) Delayed-Enhancement MRI Determinant of Successful
Radiofrequency Catheter Ablation of Atrial Fibrillation
(DECAAF)85
17. Summary
In summary AF prevalence and incidence are increasing by age.
Aggressive risk stratication and preventive measures should be
part of management. The management should focus on four
strategies: (1) Prevention of arrhythmia and progression from
paroxysmal to persistent and permanent forms, (2) stroke
risk assessment and prevention of embolic complications, (3)
arrhythmia management according to the guidelines and patient
underlying structural heart disease, and (4) treatment of the
underlying causes.
Our current biomarkers for AF are nonspecic, however
a multimarker approach may improve their sensitivity.
Improved detection methods of AF especially after antiarrhythmic therapy and ablative procedures are important.
Overall, trials to date have failed to show that rhythm control approach is superior to rate control approach in allcomposite measures, although some trials have shown that
patients who maintained sinus rhythm reported improved
quality of life.
According to the recent evidence based and guidelines catheter ablation of AF seems reasonable in patients with paroxysmal AF with no to minimal structural heart disease who have
failed at least one antiarrhythmic agent. Aggressive risk modication of comorbidities such as obesity sleep apnea, impaired
renal function. is necessary and should be an integral part of
AF management. Finally, Berti et al. proposed a multidisciplinary nurse-coordinated AF program to improve detection
management and outcome of patients with AF. This approach
will begin with comprehensive risk assessment, patient education, patient centered medical care and evaluation of management outcome.86
As AF is an evolving disease we will witness a signicant
paradigm shift in understanding the pathophysiology and
management of AF. Fig. 20 demonstrates the opportunities

and challenges for future AF.
Finally, all AF patients are not the same and AF is not a
disease it is a symptom like fever, syncope, etc. Management
should be etiology based rather than mechanism based. Prevention should be the rst line of therapy. As inammation,
brosis and remodeling are the nal common pathway of
diverse etiologies, innovative therapies should focus on brosis
and inammation as shown in Fig. 21.
Conict of Interest
None.
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Update On Atrial Fibrillation

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Update On Atrial Fibrillation

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The Egyptian Heart Journal (2014) 66, 193216

Egyptian Society of Cardiology

The Egyptian Heart Journal

Update on atrial brillation

Heart & Rhythm Medical Group, San Jose, CA, USA

Received 12 March 2014; accepted 23 March 2014

* Corresponding author at: Heart & Rhythm Medical Group, 105 N.

the United States and Europe with an estimated increase of

Update on atrial brillation

Figure 1 Different types of AF according to its duration. ( CV:

2. Clinical presentation of atrial brillation

AF is classied into four categories based on its duration as

Novel risk factors

Age, male sex

Reduced vascular compliance

(4) Long-lasting persistent AF: Episodes lasting longer than

AF maybe associated with other arrhythmias, the most

Update on atrial brillation

Remodeling in Atrial Fibrillation

3.2. Recent epidemiological observations of atrial brillation

Health outcomes: Incident of AF increases the risk of all

3.4. Pathophysiology and mechanisms of atrial brillation

(A) Single source:

Figure 7 Panel A: Demonstrates the interplay between AF and

has led investigators to better understand mechanism(s) of

Update on atrial brillation

Risk scheme for CHADS2 and CHADS2-VASc.

Update on atrial brillation

than 50% of patients experience one episode of post-op AF.

5.4. Post-operative atrial brillation

5.5. Atrial brillation in athletes and during endurance exercise

AF is the most common arrhythmia after cardiac surgery and

and brosis. As well as left ventricular hypertrophy, enhanced

AF is now a known entity and is often associated with

Update on atrial brillation

The prognosis is worse in this patient population compared to

5.9. Atrial brillation and obstructive sleep apnea

Inhibits synthesis: II, VII, IX, X

Direct IIa inhibitor

dialysis are at highest risk for developing AF. On the other

Figure 12 Recommendation from ESC Guidelines on AF for the

A majority of patients with acute AF present to hospitals

Update on atrial brillation

7.3. Pharmacologic therapy for rhythm control

Dofetilide can be used in patients with reduced LV ejection

of beta-blockers and digoxin have been found to be most

The selection of pharmacological agents is dictated by a

8.4. Argues in favor of rate control approach

Update on atrial brillation

bundle and coronary sinus.

3. In patients with CHF large randomized trials have not

8.5. Anticoagulation in atrial brillation

Update on atrial brillation

9.3. Perioperative anticoagulation

9.6. Techniques for atrial brillation ablation

3) Etiology and mechanism based approach.

Update on atrial brillation

13. Complication of catheter ablation

Update on atrial brillation

16.1. Future trials

management of AF. Fig. 20 demonstrates the opportunities

Update on atrial brillation

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