European Journal of Internal Medicine 20 (2009) 672–681

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European Journal of Internal Medicine

j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e j i m

Review article

Atrial fibrillation: Mechanistic insights and treatment options

Sunil T. Mathew a,⁎, Jigar Patel b, Satheesh Joseph c
a
Cardiovascular Section, University of Oklahoma Health Sciences Center, University of Oklahoma School of Medicine, Oklahoma City, OK, USA
b
Department of Internal Medicine, University of Oklahoma Health Sciences Center, University of Oklahoma School of Medicine, Oklahoma City, OK, USA
c
Brookhaven Heart, 100 Hospital Rd., Suite 120, East Patchogue, NY 11772, USA

a r t i c l e i n f o a b s t r a c t

Article history: Atrial fibrillation (AF) remains the most common clinically encountered arrhythmia. Unlike supraventricular
Received 19 December 2008 arrhythmias that use a defined mechanism, AF involves a wide spectrum of arrhythmias from lone AF to
Received in revised form 23 June 2009 paroxysmal to chronic AF. AF is an arrhythmia that may develop in several ways. Mechanical remodeling
Accepted 22 July 2009
manifests as decreased atrial contractility and increased atrial compliance which leads to a stretch of the
Available online 27 September 2009
atrial myocardium. Atrial remodeling may also increase in atrial fibrosis which can slow conduction velocity
and can shorten the refractory period in atria with long-standing AF. It is still unclear whether initiation of AF
Keywords:
Arrhythmia activates direct inflammatory effects or whether the presence of a pre-existing systemic inflammatory state
Atrial fibrillation promotes further persistence of AF.
Arrhythmia mechanism Currently, the patient population undergoing AF ablation has greatly expanded. Patients are older and have
Arrhythmia treatment larger left atrial size and are more likely to have persistent/permanent AF. It is likely that AF comprises a
spectrum of disease with no single mechanism adequate enough to comprehensively explain AF and its
variability. The management of patients with AF involves elements of anticoagulation, rate control and
rhythm control and such treatment strategies are not necessarily mutually exclusive of each other.
© 2009 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

1. Introduction possible mechanisms which may be interrelated. This paper reviews

Atrial fibrillation (AF) is the most common clinically encountered
arrhythmia [1]. The arrhythmia is associated with heart failure, se-
nescence, and numerous diseases related to senescence and has an
incidence of more than 2.3 million in the United States. However, the
mechanisms underlying AF are only partially understood and recent
epidemiologic data indicate that AF prevalence is not explained by age
alone [2]. Furthermore, additional risk markers such as obesity [3,4],
obstructive sleep apnea [5,6], anger and hostility [7], and long-term
alcohol consumption [8–10] only partially account for the increase in
AF. Multiple AF descriptors have developed in light of such wide-
spread prevalence of the arrhythmia. Various descriptors such as lone
AF, paroxysmal AF, and chronic AF had been previously used some-
what indiscriminately. Recently however a consensus classification
scheme has been proposed to simplify its description with respect to
its clinical relevance (Fig. 1).
Although significant progress in understanding the mechanism of
this arrhythmia has been accomplished with the advent of catheter
ablation, the pathophysiology of AF is complex and likely has many
⁎ Corresponding author. Fax: + 1 866 384 0496.
E-mail address: stmathew@gmail.com (S.T. Mathew).
this clinically widespread arrhythmia. Both traditional and more
contemporary theories responsible for AF as well as standard and
evolving treatment modalities are also reviewed herein.
2. Basic science insights on atrial fibrillation mechanism(s)
2.1. Rotors and wavelets
Several theories attempt to explain different aspects of such
mechanism(s), however a unifying theory remains lacking. Three
major theories are often included in this constituency, including
(a) the random reentry model; (b) the single or multiple rapidly firing
ectopic foci; and (c) the multiple reentrant model.
2.1.1. Random reentry
Moe and Abildskov's hypothesis [11] of random reentry has been
one of the prevailing concepts. Its basis centers on multiple wandering
atrial reentrant wavelets colliding with each other to either self-
terminate or produce daughter wavelets which sustain atrial excita-
tion. Theories describing the genesis of AF typically have originated
from animal models describing these random atrial reentry wavelets.
Canine models have demonstrated that these AF pathways are vagally
mediated and are determined by a critical amount of atrial refrac-
toriness and excitability, not on atrial anatomy [11–14].

0953-6205/$ – see front matter © 2009 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.ejim.2009.07.011
 S.T. Mathew et al. / European Journal of Internal Medicine 20 (2009) 672–681 673

2.2. Modulating factors

Other basic mechanisms include those that modulate arrhythmo-

genesis [22] which often occur in conjunction with those mechanisms
that are thought to initiate or perpetuate AF. These modulation factors
can further be described as potentially modifiable or non-modifiable
(i.e. age or genetics). As discussed below, there are many modifiable
modulating factors that may maintain or inhibit AF. The major
modulating factors such as endocrine activity, pulmonary vein and
atrial function, are typically more familiar to the practicing clinician
and will be described. Those less prevalent clinically, such as mechan-
ical and electrical atrial remodeling and inflammatory processes will
also be reviewed, as well as the advanced concept of AF modulation by
the autonomic nervous system. Wyse and Gersh have proposed
schematics to illustrate the presumed relationship among modulation
factors to AF (Fig. 2) as well as how these relate to a trigger and/or
substrate as a fundamental mechanism(s) thought to initiate and
sustain AF (Fig. 3). Entities thought to be AF “triggers” are more
associated with initiating AF and may be more predominant in the
mechanism of paroxysmal AF. Alternatively, those described as
“substrates” are more likely associated with influencing persistent AF.

2.2.1. Mechanical and electrical atrial remodeling

Fig. 1. Updated atrial fibrillation classification schema. Our understanding of AF was broadened by the recognition that
(Adapted from Estes NA 3rd, Halperin JL, Calkins H, et al. J Am Coll Cardiol. 2008 Feb once AF initiated, atrial electrophysiological properties changed and a
26;51(8):865–84.) lower threshold induced the arrhythmia. This process explained AF
propagation by a process known as electrical remodeling [24]. The
primary stimulus needed to induce electrical remodeling was an
estimated tenfold increase in the atrial rate caused by AF [25]. Similar
2.1.2. Multiple foci changes were also produced by any form of sufficiently rapid atrial
Somewhat in contrast to the random reentry model, another tachycardia [25].
theory suggests single or multiple rapidly firing ectopic foci. This is not The cellular basis for the observed changes from AF mediated
as widely acknowledged, based in part from studies supporting tachycardia is thought to be due to changes in calcium (Ca2+) loading.
verification of the multiple reentrant concept by Allessie et al. [15,16]. Ca2+ enters the cells through inward L-type Ca2+ current (ICa 2+) and
with each action potential, there is a substantial increase in cellular
2.1.3. Multiple reentry Ca2+ loading in the presence of the arrhythmia [26]. The ensuing
Though multiple reentrant theory appeared to best explain adaptive responses that occur decrease Ca2+ loading by reducing ICa2+,
persistent AF [12,14], there still lacks a general inability of these but at the expense of a shorter action potential duration, which
principal theories to fully describe AF and this further underscores increases the propensity for atrial fibrillation [25,26]. These AF in-
both the difficulty in understanding this arrhythmia. duced electrophysiological changes promote a vicious cycle of ar-
rhythmia that enhances the ability of the disorder to sustain itself, and
2.1.4. New data also create an increasing vulnerability to relapse [24,27–29] (often
Contemporary investigations have only continued to add complex- described as “AF begets AF”) [24].
ity. For example, the initiation of AF from anatomic substrates in the
area around the pulmonary veins [17] question the random reentry
hypothesis and have resurrected prior theories such as the single
source of stable reentry. An attempt at understanding the various
putative mechanisms is required in order to adequately utilize some
of the state-of-the-art therapies that are now available.
Jalife and colleagues, using optical mapping studies on an ovine
model, demonstrated that a primary localized generator (or rotor)
comprising either an ectopic focus or single small reentry circuit
[18,19] in the atria is responsible for AF initiation. In this model, a
functional, anatomic reentry occurs with spiral waves rotating around
reentrant circuits of about one centimeter diameter and is thought to
be the likely source of AF [20,21]. They have also shown that these
dominant rotors that drive AF consistently arise from the left atrium
with passive activation of the right atrium [18,19]. While such studies
have shown that in some cases the relative roles of focal reentry and
abnormal automaticity in the pulmonary vein region may be more
relevant, it is still unclear whether significant rotors exist in humans
and what their location may be. There is also ambiguity as to the
differences between the apparently disparate concepts of multiple
Fig. 2. Schematic illustrating the numerous “modulating factors” that influence and may
wavelet reentry and the primary rotor model: some have hypothe- contribute to the pathogenesis of atrial fibrillation.
sized that it is possible that they may have more similarities than (Wyse DG, Gersh BJ. Atrial fibrillation: a perspective: thinking inside and outside the
differences [22,23]. box. Circulation 2004 Jun 29;109(25):3089–95.)
674 S.T. Mathew et al. / European Journal of Internal Medicine 20 (2009) 672–681
Fig. 3. Schematic illustrating how modulating factors relate to the various mechanisms
thought to invoke reentry.AF initiation and perpetuation are illustrated as well as how
AF can produce modulating factors that further perpetuate it or produce manifestations
of AF.
(Wyse DG, Gersh BJ. Atrial fibrillation: a perspective: thinking inside and outside the
box. Circulation 2004 Jun 29;109(25):3089–95.)
Although it is well established that the perpetuation of AF causes
electrical remodeling, AF's links to contractile and structural remodel-
ing remain controversial. Mechanical remodeling is thought to com-
prise both contractile and structural remodeling of the atria as a result
of AF. Whereas electrical and contractile atrial remodeling may be
reversible after the cessation of AF, structural remodeling is less likely
to revert [22,30]. Electrical remodeling and constant changes in the
L-type Ca2+ channels are both thought to be the primary cause for
contractile remodeling. Mechanical remodeling manifests as de-
creased atrial contractility and increased atrial compliance which
causes the atrial myocardium to stretch. Such decreased atrial
contractility acts as a stimulus for structural remodeling due to the
remodeled enlarged atria. This abnormal atrium now becomes an
electro-anatomical substrate for AF by allowing more intra-atrial
circuits to potentially perpetuate due to a reduction in wavelength
(shortening of refractoriness and slowing of conduction) and an
increase in non-uniform atrial tissue [30]. Thus, the remodeled atria
with its enlarged chambers act as AF substrate as it promotes the
Fig. 4. Illustration of the potential interplay of electrical, contractile and structural
feedback loops of atrial remodeling on AF. Increased atrial myocardial stretch is
hypothesized to act as a stimulus for structural remodeling of the atria. The resulting
enlarged atria allow intra-atrial circuits of small size, due to a reduction in wavelength
(shortening of refractoriness and slowing of conduction) and increased non-uniform
tissue anisotropy (zigzag conduction).
(Allessie M, Ausma J, Schotten U. Electrical, contractile and structural remodeling
during atrial fibrillation. Cardiovasc Res 2002 May;54(2):230–46.)
development of smaller sized intra-atrial circuits [30]. The size of the
atrial reentry circuits depends on the circuit's wavelength: those
with a short wavelength (or smaller atrial circuits) will maintain
several reentry circuits and thereby promote the continuation of AF
(Fig. 4) [28,30]. Larger atria are more likely than smaller atria to
promote smaller intra-atrial circuits [30].
2.2.2. Inflammation/fibrosis
Atrial remodeling may also increase in atrial fibrosis. This process can
slow conduction velocity and may change the atrial refractory period
with long-standing AF [31,32]. It is still unclear whether initiation of AF
activates direct inflammatory effects or whether the presence of a pre-
existing systemic inflammatory state promotes further persistence of AF
[33]. One of the first studies comparing inflammatory markers to atrial
remodeling was reported by Frustaci et al. [34]. Nakamura et al. [35]
confirmed this association by showing that atrial biopsies from patients
with lone AF had higher amounts of atrial fibrosis, inflammatory
infiltrates, and myocyte necrosis compared to those with sinus rhythm.
Canine models with sustained AF demonstrated active atrial perimyo-
carditis with inflammatory infiltrates, lipid degeneration, and fibrosis
[36]. Furthermore, not only have increased C-reactive protein (CRP)
levels been demonstrated as early as within the first 24-hours of the
onset of AF [37], patients with persistent AF have also shown markedly
increased CRP levels when compared to patients with paroxysmal AF
(independent of other risk factors) [38]. This suggests that inflammation
may also promote the persistence of AF.
Corollaries to these observations came from a positive effect of
corticosteroid treatment in a randomized study of 216 patients un-
dergoing coronary or valvular heart surgery [39]. The study demon-
strated that a single dose of dexamethasone was associated with a
decreased incidence of new-onset AF in the first 3 days post-surgery.
Recently, a similar multi-centered randomized study corroborated
this by showing that the use of intravenous hydrocortisone reduced
the incidence of AF after cardiac surgery among 241 consecutive
patients without prior AF or flutter [40]. The pleiotropic effects of
HMG-CoA reductase inhibitors have also been shown in studies which
Fig. 5. Illustration of the possible role of oxidative stress and inflammation contributing
to electrical remodeling in AF. [ICaL — L-type Ca2+ current; APD — action potential
duration; AERP — atrial effective refractory period; CV — conduction velocity.]
(Korantzopoulos P, Kolettis T, Siogas K, Goudevenos J. Atrial fibrillation and electrical
remodeling: the potential role of inflammation and oxidative stress. Med Sci Monit
2003;9(9):RA225-9.)
 S.T. Mathew et al. / European Journal of Internal Medicine 20 (2009) 672–681
investigated the association between statin use and incidence of AF.
The most compelling data come from Kumagai et al. [36] which
utilized atorvastatin on AF in a canine pericarditis model. The ator-
vastatin group had lower C-reactive protein levels, less pronounced
fibrosis in the atrial myocardium, and a shorter duration of AF. Fibrosis
and inflammation are thought to change the anatomical and
electrophysiological substrate of the atria [28] and it is thought that
the interplay of inflammation may not only be a response to AF but
also an integral part of it [41]. Inflammation and fibrosis in AF merits
further study (Fig. 5) [42] since recovery from electrical remodeling
by conventional pharmacotherapy remains inadequate.
2.2.3. Endocrine activity
Using a multivariable model based on data from the Framingham
Heart Study (with adjustment for age and other AF risk factors), the
odds ratio of AF with diabetes was 1.4 for men and 1.6 for women [43].
Kato et al. hypothesized that endocrine mediated disorders such as
diabetes mellitus may promote the development of atrial fibrosis
leading to a predisposition to AF. Using a rat model, they found that
structural remodeling of the atrium characterized by diffuse inter-
stitial fibrosis is a major substrate for diabetes related AF [44]. Another
well-known clinical endocrine modulating factor is the association of
AF with hyperthyroidism whereby changes in thyroid hormone
concentration directly affects the initiation or inhibition of AF [22].
There is also growing evidence to suggest a role for the renin–
angiotensin system (RAS) in the pathogenesis of AF. Inhibition of RAS
with captopril or candesartan, yields a reduction in atrial tachycardia
associated electrical remodeling in dogs subjected to rapid atrial
pacing for a relatively short duration. Among dogs subjected to pacing
for a longer duration (i.e. 1–5 weeks), RAS inhibition did not appear to
alter atrial remodeling during the relatively early stages of electrical
remodeling [45,46]. The role of RAS in atrial remodeling to sustain AF
in humans is less clear. Angiotensin II infusion in human subjects has
not been shown to shorten the atrial refractory period [42] and may
not have a significant acute effect on human atrial electrical re-
modeling. It may, however, facilitate the role of structural remodeling
and fibrosis of atrial tissue, which suggests a link between RAS and
remodeling of atrial tissue [42]. This may be consistent with clinical
data demonstrating the effectiveness of a RAS blockade in preventing
new-onset or recurrent AF among those with hypertension and left
ventricular hypertrophy, congestive heart failure, and those under-
going electrical cardioversion for AF [47,48]. However, more clinical
and experimental animal studies are needed in order to define the
role of RAS inhibition in patients with AF.
2.2.4. Pulmonary veins and atrial function
Haissaguerre et al. demonstrated that premature depolarizations
originating from the pulmonary veins could contribute to the gen-
eration of AF [17]. They showed that the pulmonary vein foci may
initiate AF by originating as a rapid atrial tachycardia. Subsequent
studies have shown that AF originating from pulmonary vein foci may
then degenerate as a consequence of atrial remodeling which acts to
maintain AF by promoting multiple reentry circuits [49,50]. Other
studies have also shown this activity and implicate the pulmonary
veins in both the initiation as well as maintenance of AF [51,52].
The pulmonary vein-left atrial junction has also become a target
for morphological studies in both animal and human hearts in
describing AF arrhythmogenicity. The multilayer left atrial myocar-
dium extend in a variable arrangement and distance into each PV
resulting in a complex three-dimensional fiber orientation [53,54]].
These pulmonary vein-left atrial muscle sleeves consist of specialized
conduction cells similar to those found in the sinus node [55]. The
transition zones of these myocardial extensions were thickest at the
venoatrial junction (mean 1.1 mm) and became thinner moving
distally [56]. Their thickness is variable with the inferior walls of the
superior veins. In contrast, the superior walls of the inferior veins have
675
a thicker myocardial extension [55]]. Such observations from the area
of the pulmonary veins with the passive activation of the right atrium
[18,19] have lessened the dominance of the multiple wavelet
hypothesis and renewed interest in concepts of fibrillatory conduction
and a dominant rotor as primary drivers of AF [57]. These observations
have provided further pathophysiological insight and have also
helped expand therapy options for current cutting edge pulmonary
vein ablation procedures.
2.2.5. Autonomics
The anatomy of the sympathetic and parasympathetic innervation of
the sinus and AV nodes is intricate and each component of the autonomic
nervous system follows a different course [58]. Parasympathetic neurons
extend to the heart through the vagus nerves and the ones destined to
innervate the sinus node terminate in the pulmonary vein fat pad,
whereas those that predominantly innervate the AV node terminate in the
inferior vena cava–inferior left atrial fat pad [59]]. Parasympathetic
denervation by surgical dissection of the fat pads does not influence
sympathetic control of sinus rate and AV-nodal conduction [57]].
The electrophysiologic properties of atrial cells are moderated
differently by parasympathetic and sympathetic influences. For
example, vagal mediated influences favor atrial macroreentry phe-
nomena and sympathetic influences favor abnormal automaticity and
triggered activity [60]. In normal hearts, vagal influences predomi-
nate, which partially explains why the clinical pattern of vagally
mediated paroxysmal AF is often found in young males with no
detectable heart disease. These patients usually have an ECG pattern of
atrial flutter alternating with fibrillation [61]. The vagal effect is to shorten
both the action potential and refractory period. This is recognized to occur
heterogeneously within the atrial wall, suggesting that such inhomo-
geneity may contribute to a reentry mechanism rather than hyperexcit-
ability [62]]. Conversely, AF mediated by the sympathetic nervous system
is observed in the presence of most any heart disease, of which the first
effect is often to provoke a vagal withdrawal [59]].
Although studies have demonstrated that the rate of arrhythmo-
genicity near the pulmonary vein can be greatly accelerated by
adrenergic stimulation [63], little is known about the impact of base-
line autonomic tone and the development of new-onset AF in the
general population. Despite epidemiological evidence from the
Framingham Heart Study subjects suggesting that baseline autonomic
dysregulation reflected by altered heart rate variability (HRV) is
associated with risk of AF, the association did not persist after
adjusting for potential confounders. Much of the apparent association
between HRV and AF in the Framingham cohort was believed to be
mediated by traditional risk factors [64].
Tomita et al. [65] demonstrated a relationship between the time of
paroxysmal AF onset and autonomic tone both before and after
paroxysmal AF and found that the autonomic nervous system plays an
important role in both the initiation and termination of paroxysmal
AF. They also found that the onset of paroxysmal AF influences the
autonomic tone at the initiation as well as during termination of
paroxysmal AF [65]. However, the role of autonomic tone in the
initiation of paroxysmal atrial flutter has not been reported.
These epidemiologic and clinical observations between AF and the
autonomic nervous system gain further credibility with basic science
associations. For example, the novel Class III antiarrhythmic agent,
NIP-142, shows a link between the autonomic impact on AF in a canine
model of atrial fibrillation and flutter. As a primary potassium channel
blocker, NIP-142 prolonged atrial refractoriness and was effective in
treating atrial flutter and vagally-induced AF [66]. Such studies are
important as they add insight into the autonomic component of the
arrhythmia. This understanding forms the basis for some of the
emerging therapies aimed at targeting the autonomic nervous system
for the treatment of refractory AF. Coumel has suggested that in order to
confirm vagally derived initiation of AF, the minutes and hours pre-
ceding AF onset need to be recorded in order to demonstrate the
676 S.T. Mathew et al. / European Journal of Internal Medicine 20 (2009) 672–681
relationship between arrhythmia onset and heart rate changes [60]. The
well-known mechanism of ectopic foci located in the left atrium or the
pulmonary veins [17] is compatible with vagal or adrenergic profiles.
Such ectopic foci may form the arrhythmia trigger and vagally derived
arrhythmias are often sensitive to focal ablation [67].
3. Clinical science and treatment issues
Although there has been much insight regarding the pathophysiolo-
gical triggers of AF, an understanding of its mechanisms is still inadequate
[56]. This manifests by less than optimal treatment of this arrhythmia
despite the development of novel catheter-based ablation therapy and
pharmacotherapy. Though these techniques may in time lead to a cure for
the disorder in some patients, focal atrial ablation or pulmonary vein
isolation is not currently universally effective [68]]. Currently, two
fundamental strategies dominate treatment options: (i) ventricular rate
control; and (ii) restoration of sinus rhythm to obtain rhythm control.
3.1. Treatment insights from clinical trials: rate or rhythm control
AF management involves three facets: rate control; prevention of
thromboembolism; and the restoration of sinus rhythm. The data
available on the clinical relationship between sinus node dysfunction
and AF suggest that the sinoatrial (SA) node is probably passive during
AF. Diseases often affect both the SA node and atria simultaneously
which can contribute to persistent AF. This is different from instances
where abnormal SA node dysfunction contributes to AF maintenance
[28]. Theoretically, the basis for restoration of normal sinus rhythm was
believed to have several benefits over rate control. These potential
advantages include improved cardiac output from the restoration of
atrial systolic function which yields improvement in quality of life;
greater exercise capacity; lower risk of stroke; the possibility of stopping
anticoagulation with maintenance of sinus rhythm; and the theoretical
benefits of potentially reversing atrial structural or electrical remodeling
[28]. Even in light of these potential advantages, it appears that rhythm
control is nearly equivocal to rate control for mortality benefit.
Several trials have analyzed the restoration of normal sinus rhythm
and demonstrated that not only did rhythm control offer no added
morbidity and mortality benefit, the quality of life measures did not
differ significantly during follow-up. Such trials included RACE (RAte
Control versus Electrical conversion) [69], AFFIRM (Atrial Fibrillation
Follow-up of Rhythm Management) [70], PIAF (Pharmacological
Intervention in Atrial Fibrillation) [71], STAF (Strategies of Treatment
of Atrial Fibrillation) [72], and HOT-CAFE (How to Treat Chronic Atrial
Fibrillation) [73] (the study parameters and key findings are
summarized in Table 1). In summary, these studies showed that a
rate-control strategy was at least as effective as rhythm control and
that antithrombotic therapy is important even when a rhythm-control
strategy is employed. Though an important caveat to this was that the
trials were problematic because of the inability to maintain sinus
rhythm in a large percentage of the sinus-rhythm arm suggesting that
the antiarrythmics used proved essentially inadequate for the job and
no superiority of sinus control could be demonstrated.
Regardless of how the rate- or rhythm-control strategy is dealt
with, attention must also be directed to antithrombotic therapy for
prevention of thromboembolism [74]]. In a meta-analysis, the Atrial
Fibrillation Investigators [75] reported that warfarin reduced the risk
of death by 33% and that warfarin is the only pharmacologic therapy
that has been reported to improve survival in AF.
Many patients with AF who are thought to be low risk for AF
associated stroke do not substantially benefit from anticoagulation.
These patients can be reliably identified using the CHADS2 stroke risk
stratification scheme (an acronym for Congestive heart failure,
Hypertension, Age ≥ 75 years, Diabetes and prior Stroke/or transient
ischemic attack (with S2 to indicate stroke with a weight of 2 points)).
Ischemic stroke risk is estimated with the CHADS2 score (one point
for each disease state and 2 points for prior strokes or transient
ischemic attacks) [69] (see Tables 2 and 3). Anticoagulation with
warfarin is recommended for patients with valvular atrial fibrillation
or a CHADS2 score ≥ 2 (INR 2–3 and 2.5–3.5 for patients with me-
chanical valves), unless contraindicated or there is an annual major
bleeding risk exceeds 3% [76]. Aspirin or warfarin may be used when
the CHADS2 score = 1. Aspirin, 81–325 mg daily, is recommended in
patients with a CHADS2 score of 0, or if warfarin is contraindicated.
Current recommendations include continued anticoagulation with
warfarin in patients with sufficient thromboembolic risk whether
they have persistent or paroxysmal atrial fibrillation [74,77].
Differing patient selection criteria, endpoints and therapeutic inter-
ventions in many of the above studies limit the applicability of the findings
to all AF populations. For example, AFFIRM, RACE and HOT-CAFE did not
evaluate a single drug or type of treatment. Another criticism was that
these trials were not comparisons of sinus rhythm and AF, but rather
comparisons of the strategy of rate control to that of rhythm control where
the success rate of the rhythm-control strategy was relatively poor [78].
Up to 35% of rhythm-control patients in AFFIRM were actually using rate-
control drugs by the end of the study. In subanalyses, many patients in the
rate-control arm were spontaneously in sinus rhythm by the end of the
study period. The same number was 10% in STAF and RACE to 35% in
AFFIRM which suggests that by switching analysis according to the
patient's actual rhythm, the benefit of sinus rhythm over AF becomes
obvious [77]]. This is consistent with population-based studies such as
SOLVD, DIAMOND and CHF-STAT which have long shown the negative
prognostic impact of AF on survival [79]. With the exception of the PIAF
trial, antithrombotic therapy was discontinued in some patients who were
assigned to the rhythm-control groups. Withholding antithrombotic
therapy is one possible explanation for the higher rate of non-
cardiovascular mortality observed in the rhythm-control arm of AFFIRM.
The majority of strokes in RACE occurred while receiving inadequate
anticoagulation therapy. In RACE, 21 of the 35 thromboembolic
complications occurred under rhythm control. Six patients had the
event after cessation of oral anticoagulant therapy, with five of them in
apparent sinus rhythm. Asymptomatic episodes of AF may add to
continued stroke risk in rhythm-control patients who are believed to be
in persistent sinus rhythm [80]]. Such thromboembolic complications
despite apparent sinus rhythm contribute to the benefits of warfarin and
its ability to reduce the risk of death by a third [75,81]].
Younger patients who have greater cumulative risk for developing
sequelae of chamber remodeling were underrepresented in these trials.
The mean age was 70 years in AFFIRM and 68 years in the RACE study. In
excluding the younger subgroup, the results of these studies may not be
representative for the full spectrum of AF patients. This younger
symptomatic subgroup is thought to represent at least one third of all AF
patients [82]. With AFFIRM, there was a trend toward a benefit of
rhythm control for patients younger than 65 years which indicated an
improved outcome in cases of maintained sinus rhythm [70]. In PIAF,
where the mean age was slightly younger (60–61 years), exercise
tolerance was better with a rhythm-control strategy. A follow-up
analysis of outcomes in AFFIRM [79] showed that the presence of sinus
rhythm was associated with reduced mortality (47% reduction, 99% CI
28–61; p ≤ 0.0001). The benefits of sinus-rhythm maintenance over
time have yet to be carefully evaluated [83] and the optimum resting
heart rate or heart rate during exercise remains undefined for patients
with permanent AF despite retrospective nonrandomized data of
AFFIRM and the AFFIRM-RACE cooperation [84–87].
4. Additional management options
While the cornerstone of long-term AF management is usually
anticoagulation with rate and/or rhythm control, there are several
additional treatment options. The following section will touch on
many of the major management options available and describe some
of the benefits and disadvantages of each.
 S.T. Mathew et al. / European Journal of Internal Medicine 20 (2009) 672–681 677

Table 1
Randomized trials comparing rate versus rhythm control for atrial fibrillation.

Trial N Mean Hypotheses
age
PIAF (Pharmacological Intervention 252 61 There is equivalency
in Atrial Fibrillation) between rate-control
versus rhythm-control
strategies for AF
STAF (Strategies of Treatment of 200 66 There is equivalency
Atrial Fibrillation) between rate-control
versus rhythm-control
strategies for AF
AFFIRM (Atrial Fibrillation Follow-up 4060 70 There is noninferiority
of Rhythm Management) of rate control versus
rhythm control in
patients with AF
RACE (RAte Control versus 522 68 There is noninferiority
Electrical conversion) of rate control to
rhythm control with
regard to morbidity
and mortality
HOT-CAFE (HOw to Treat Chronic 206 61 There is equivalency
Atrial Fibrillation) between rate-control
versus rhythm-control
strategies for AF
Rate-control Rhythm- Primary endpoint Outcome and key p-value
regimen control findings
regimen
Diltiazem Amiodarone or Elimination of Both groups showed 0.317
cardioversion palpitations, dyspnea, similar improvement in
shortness of breath approximately 60% of
and dizzy spells patients after 3 weeks of
treatment in both arms.
NSR maintained: 56% of
rhythm-control versus 10%
of rate-control points
β-blockers; Cardioversion; Composite of: death, No mortality difference NS
nondihydropyridine or amiodarone; stroke or TIA, between two groups.
calcium blockers; sotalol resuscitation from Rhythm points
digoxin; or cardiac arrest, and hospitalized significantly
cardioversion; or peripheral emboli more/for longer periods.
ablation and/or 70% of rhythm-control
pacemaker points successfully
implantation cardioverted, but NSR
maintained in only 23% at
3 years (versus 9% of points
in rate-control group)
β-blockers; Amiodarone, Overall or all-cause No significant difference in 0.08
nondihydropyridine disopyramide, mortality all-cause mortality
calcium blockers; flecainide, • Mortality: rhythm
digoxin; or moricizine, control, 23.8%; rate
combinations of procainamide, control, 21.3%
these drugs propafenone, • More adverse drug
quinidine, reactions in rhythm-
sotalol, and control points
combinations • 63% of rhythm-control
points in NSR; 80% of
rate-control points
with adequate HR
control at 5 years
Digitalis; or Sotalol; or Composite of Composite endpoint reached 0.11
nondihydropyridine flecainide; or cardiovascular death, in 17.2% of patients in rate-
calcium-channel propafenone; hospitalization for control arm and 22.6% in
blockers; or a β- or amiodarone heart failure, rhythm-control arm
blockers, alone or in thromboembolic • 39% of rhythm-control
combination complications, severe points in NSR versus
hemorrhage, 10% in rate-control group
pacemaker • Thromboembolic
implantation, or severe complications more
drug side effects likely in rhythm group
• Pacemaker implantation
more likely in rhythm
group
β-blockers; Propafenone Composite of No significant differences 0.71
nondihydropyridine disopyramide, cardiovascular death, between rate- and rhythm-
calcium blockers; sotalol, or thromboembolic control points. No
digoxin; or a amiodarone complications or thromboembolic
combination of these intracranial or other complications observed in
drugs; or major hemorrhage points left in AF; 3 ischemic
cardioversion; or strokes reported in rhythm-
ablation control arm (2 due to
cardioversion, 1 to late AF
recurrence)

4.1. Pacing and atrioventricular nodal ablation
Among AF patients who are refractory to rate-control objectives,
the “ablate and pace” strategy offers symptomatic relief, but is
considered a therapy of last resort because of the potential negative
effects of long-term right ventricular (RV)-pacing. A meta-analysis
of trials of AV-node ablation and pacing demonstrated symptom
and exercise tolerance improvement and has provided support for
this modality [88]. Procedural shortcomings include complication
rates associated with the pacemaker insertion or the ablation; per-
manent pacemaker dependence; and a small risk of sudden death
in the early post-ablation period [89]. Furthermore, small rando-
mized trials of the procedure versus rate-slowing drug therapy did
not show a significant benefit on endpoints of exercise tolerance,
symptomatic improvement or improvement of LV function [90–92].
Other small clinical studies have shown a trend toward a benefit of
reducing the frequency of AF, using various alternative pacing
algorithms such as right atrial septal pacing; low interatrial septal
pacing; and Bachmann's bundle pacing [93–95]. Some evidence
additionally suggests a better outcome with biventricular pacing in
patients with pre-existing LV-dysfunction [96]. However, AV-nodal
ablation and permanent pacing is only warranted in patients who
have failed rate-control pharmacotherapy and remain highly symp-
tomatic from AF.
678 S.T. Mathew et al. / European Journal of Internal Medicine 20 (2009) 672–681
Table 2
CHADS2 scoring system for AF.
From: Gage, BF, Waterman, AD, Shannon, W, Boechler M, Rich MW, Radford MJ.
Validation of clinical classification schemes for predicting stroke: results from the
National Registry of Atrial Fibrillation. JAMA 2001;285:2864–2870.
Risk factor CHADS2 score (points)
Congestive heart failure (EF b 35%) 1
Hypertension (systolic N 160 mm Hg) 1
Age greater than 75 years 1 patient population undergoing AF ablation has expanded significantly.
Diabetes 1 Patients are older and have larger left atrial size and are more likely to
Stroke (prior cerebral ischemia: CVA or TIA) 2 have persistent AF often having been subjected to fewer prior
CHADS2 is an acronym derived from the stated risk factors and the scoring of 2 for prior
stroke or TIA. The CHADS2 score is calculated by totaling the scores for each risk factor
present.
Abbreviations: CHF, congestive heart failure; EF, ejection fraction; TIA, transient ischemic
attack.
4.2. Surgical intervention
The goal of AF surgical management is to make atrial incisions at
critical locations that create barriers to conduction and prevent
persistent AF preserving sinus node and atrial transport functions
[71]. The surgical “maze” or “cut-and-sew” technique has evolved
tremendously since its inception over 25 years ago. The objective is to
ensure that these transmural incisions isolate the pulmonary veins,
while also connecting these incisions to additional surgical incisions
around the mitral valve annulus, in order to create electrical barriers
within the atria to prevent macroentrant rhythms—atrial flutter or AF—
from becoming persistent [97]. Success rates [98] from 70% to nearly 95%
over 15 years of follow-up have been reported in patients undergoing
mitral valve surgery [99]. Despite its reasonably high success rate, the
surgical maze is not routinely performed other than for patients
undergoing cardiac surgery because of the requirement of cardiopul-
monary bypass. Several less invasive variations are under investigation,
including thoracoscopic and catheter-based epicardial techniques [93].
If the efficacy and safety of these surgical adaptations approach that of
the percutaneous ablative techniques, they may become acceptable
alternatives for a larger proportion of patients with AF.
4.3. Percutaneous intervention
In most AF patients (94%), the AF focus was in ≥1 of the pulmonary
veins (PVs) which was a landmark observation by Haissaguerre et al.
[17]. Extra-PV sites may trigger AF, but is thought to occur in only a
minority of patients: no more than 6% to 10% [46]. This facilitated
recognition of the pathophysiological role played by these “muscle
sleeves”; or extensions of myocardium within the PV in the initiation
of AF. Dominant rotors of AF are localized primarily in the junction
between the left atrium (LA) and PVs, have been demonstrated by
several subsequent investigations [77,100–102]. A recent study has
also demonstrated that the PV-LA region has heterogeneous electro-
physiological properties capable of sustaining reentry (micro or
macro) [103]. Since PV isolation was first described for treating AF in
Table 3
Risk of stroke by CHADS2 score.
From: Gage, BF, Waterman, AD, Shannon, W, Boechler M, Rich MW, Radford MJ.
Validation of clinical classification schemes for predicting stroke: results from the
National Registry of Atrial Fibrillation. JAMA 2001;285:2864–2870.
CHADS2 score Adjusted stroke rate (per 100 person-years)
0 1.9
1 2.8
2 4.0
3 5.9
4 8.5
5 12.5
6 18.2
1998, percutaneous procedures have evolved to replicate and
improve on surgical maze techniques. The former is done by making
continuous endocardial lesions to encircle the pulmonary veins with
the goal of contemporary AF ablation to electrically “disconnect” the
PVs from the rest of the atrium by ablating around the origin of the
veins. These percutaneous procedures are often considered for
patients who have failed antiarrhythmic drug therapy. The current,
antiarrhythmic agents [104].
Although PV isolation results in a long-term clinically satisfactory
outcome in an estimated 60–85% [95,105–108] of patients with
paroxysmal AF, it is clearly not the ideal approach in all AF patients
[98,109]. Histological studies have shown that complex atrial
anatomy has marked variations in atrial wall thickness [110,111].
Adjacent structures of the atrial wall may vary in depth by several
millimeters, so applying the same degree of energy at two contiguous
spots can result in excessive heating in one spot and non-transmural
heating in the other. Consequently, complete conduction block via
radiofrequency application may not always be achieved [112].
Potential complications of catheter ablation for AF include systemic
thromboembolism, PV stenosis, pericardial effusion, cardiac tampo-
nade, and phrenic nerve paralysis [113–115]]. Packer et al. [116] have
suggested that although the short-term safety of newer ablation
techniques has improved, several serious complications remain a
reality with long-term safety and ablation efficacy rates are still not
clearly defined. Finally, unavoidable procedure-related complications
may occur and general skepticism tends to arise which further
highlight the need for the development of less complex therapies.
4.4. Targeting ganglionated plexi
Coumel first described adrenergically and vagally derived AF in
patients [60]. Patterson et al. noted that combined parasympathetic
and sympathetic nerve stimulation modulate firing in canine
pulmonary veins [117]. The human heart contains a variety of
morphologically distinct nerve terminals concentrated at the gang-
lionated plexi (GP). They are distributed more widely than has been
described in experimental animals [118]. Other similar arrhythmo-
genic foci which may trigger AF have been found in the superior vena
cava, the right and left atria, the coronary sinus, and the ligament of
Marshall [50]. Focal atrial ablation has a low success rate in patients
with persistent AF and particularly in patients with the vagotonic type
of paroxysmal AF. An approach that involves ablation within the left
atrium is likely to yield better results in these subgroups, as well as
those subgroups with paroxysmal AF that do not respond to focal
atrial ablation [81,102]. Multivariate analysis indicated that there
were only two independent predictors of recurrent AF after
pulmonary vein isolation: persistent AF at the time of pulmonary
vein isolation and the vagotonic variety of paroxysmal AF. These
results tend to show that the pulmonary veins play a less important
role in the generation of persistent/permanent AF and in the initiation
or maintenance of vagotonic paroxysmal AF than in paroxysmal AF
that is either random or adrenergic in onset [107]. Little is known
about the impact of baseline autonomic tone and the development of
new-onset AF in a population-based cohort. Inferences from recent
reports have been that stimulation of the GP situated at the PV-atrial
junctions can convert PV focal firing into AF [119] or initiate
paroxysmal AF and can provide a basis for potential therapy [120].
Radiofrequency ablation of the GP can also prevent AF inducibility
[121]. The role of the intrinsic cardiac autonomic nervous system in
the genesis and perpetuation of AF was further emphasized by several
recent clinical reports. This approach centered on ablation of the GP
located in proximity to the PV-atrial junction and resulted in a high
success rate in eliminating symptomatic AF of the vagotonic variety
 S.T. Mathew et al. / European Journal of Internal Medicine 20 (2009) 672–681
[122–124]. The involvement of local cardiac autonomic elements
requires further investigation and it remains to be determined
whether targeting the GPs clinically will result in significantly higher
AF ablation success rates.
4.5. Pharmacologic therapy
Pharmacotherapy remains an essential component in the manage-
ment of AF since invasive procedures are currently not globally
efficacious nor can they be performed on all patients with AF.
Available antiarrhythmic drugs are only modestly effective in
suppressing AF. Drug therapy leading to sinus-rhythm maintenance
may be a marker of improved outcome or less serious disease. Or it
may indicate that, while the ability of treatment to maintain sinus
rhythm is inherently beneficial, such benefit may come at the expense
of toxic effects and poor efficacy [27]. It is uncommon for patients to
have complete suppression of AF. Successful therapy is often gauged
by reduction in frequency severity and duration of episodes.
Most antiarrhythmic drugs used for AF were never designed to
target the atria but rather developed for ventricular arrhythmias
which partially explains their toxicity limitations predominantly
related to prolonged QT. Recently, a meta-analysis of over 11,000
patients reported that Class IA, IC, and III drugs are effective in
maintaining sinus rhythm but also reported an increase in adverse
effects, as well as an increase in mortality with Class IA drugs [125].
Specifically, several Class IA (disopyramide phosphate, quinidine
sulfate), Class IC (flecainide acetate, propafenone hydrochloride), and
Class III (amiodarone, dofetilide, sotalol hydrochloride) drugs sig-
nificantly reduced recurrence of atrial fibrillation, but they also had
associated increased withdrawals due to adverse effects. Pooled
analysis of Class IA drugs were associated with increased mortality
compared with controls and with the exception of amiodarone and
propafenone, each showed an increased propensity toward arrhythmia
[125]. Investigational drugs with potentially improved efficacy and
safety profiles are under development. Some of these novel agents are
non-selective ion channel blocking drugs or analogs to amiodarone.
Other such experimental drugs are designed to target specific ion
channels to provide atrial antiarrhythmic effects without ventricular
arrhythmias by preferential action on the atria (inhibition of the ITO
channel) or via selective action on the atria (inhibition of IKUR currents)
[126]. Combined pharmacologic and nonpharmacologic strategies may
ultimately replace current approaches to the treatment of AF.
5. Conclusion
Unlike other supraventricular arrhythmias, AF is more complex. AF is
an arrhythmia that may develop in several ways but our basic insight
into its mechanism remains too limited to allow reliable classification.
Mechanisms operating in AF derived from different animal and
experimental models are often different in genesis and perpetuation
from clinical models involving humans [127]. It is likely that AF
comprises a spectrum of diseases with no single mechanism adequate
enough to comprehensively explain the variability of AF. A unifying
conclusion may be that the AF mechanism is multifactorial and we
cannot be certain about such mechanism of AF in most individual
patients. Despite the treatment implications evidenced in clinical trials,
it would be an oversimplification to assume that rate control should be
the management approach for all patients. The management of patients
with AF involves elements of anticoagulation, rate control and rhythm
control and such treatment strategies are not necessarily mutually
exclusive of each other. The development of novel drugs allows for
improved efficacy, atrial selectivity and reduced toxicity. Evolving
technological improvement in ablative procedural devices and the
incorporation of real time three-dimensional imaging modalities may
also improve chances of the termination long-term arrhythmia
[14,27,126]. It is hoped that continued research and improved
679
electrophysiological instrumentation may contribute to better insight
into AF mechanisms for purposes of more effective therapies.
6. Learning points
• Significant progress in understanding the mechanism of this
arrhythmia has been accomplished with the advent of catheter
ablation, the pathophysiology of AF is complex and likely has many
possible mechanisms which may be interrelated. This paper reviews
this clinically widespread arrhythmia. Both traditional and more
contemporary theories responsible for AF as well as standard and
evolving treatment modalities are also reviewed herein.
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