Journal of the American College of Cardiology
© 2000 by the American College of Cardiology
Published by Elsevier Science Inc.
Vol. 35, No. 6, 2000
ISSN 0735-1097/00/$20.00
PII S0735-1097(00)00589-1
EDITORIAL
Mechanisms of Atrial
Fibrillation: Is a Cure at Hand?
Melvin M. Scheinman, MD, FACC
San Francisco, California
The mechanisms of atrial fibrillation relate to the presence of random reentry involving
multiple interatrial circuits. Triggers for development of atrial fibrillation include rapidly
discharging atrial foci (mainly from pulmonary veins) or degeneration of atrial flutter or atrial
tachycardia into fibrillation. Therapy for control of atrial fibrillation includes drugs, atrial
pacing for those with sinus node dysfunction, or ablation of the atrioventricular junction.
Therapeutic maneuvers for cure of atrial fibrillation include surgical or radiofrequency
catheter induced linear lesions to reduce the atrial tissue and prevent the requisite number of
reentrant wavelets. We need a much better understanding of basic mechanisms before a true
cure is at hand. (J Am Coll Cardiol 2000;35:1687–92) © 2000 by the American College of
Cardiology
Atrial fibrillation (AFib) is the most common sustained
clinical cardiac arrhythmia, afflicting some 4% of people age
ⱖ60 years (1). Recent laboratory and clinical observations
have greatly enhanced our understanding of the mechanisms
of this arrhythmia, and are now beginning to bear fruit in
the clinical arena.
Older studies of this arrhythmia concentrated on induction by acetylcholine or vagal stimulation or use of topical
aconitine application to the atrium (2,3), emphasizing a
focal mechanism. Others, however, attributed AFib to
reentry (4,5). The modern era of our understanding of this
arrhythmia begins with the hypothesis of Moe (6), suggesting that AFib is the result of multiple atrial random
reentrant waves. He showed, using a computer model, that
such meandering waves could result in a sustained arrhythmia. Before this conceptual breakthrough, reentry in cardiac
muscle was explained largely on the basis of fixed anatomic
circuits (i.e., tachycardia rotating around an infarct scar or
natural barriers).
Anatomic reentry can be described as a fixed circuit with
propagation around a nonconducting barrier (7). The circuit
can be divided into the depolarized area, which is called the
wavelength of the tachycardia, and is determined by the
average conduction velocity multiplied by the refractory
period. The portion of the circuit that is not refractory is
referred to as the excitable gap. Reentry persists as long as
the wavelength of the tachycardia is less than the tachycardia path length.
The next conceptual breakthrough occurred with the
understanding that reentry in cardiac tissue could be funcFrom the Department of Medicine and the Cardiovascular Research Institute,
University of California, San Francisco, California.
Manuscript received October 1, 1999; revised manuscript received November 18,
1999, accepted January 13, 2000.
tionally determined. Functional reentry does not require
anatomically determined obstacles, but its initiation and
persistence is dependent on basic heterogeneities of cardiac
tissue. At least two mechanisms are responsible for functional reentry. Allessie et al. (8) described a leading edge
type of reentry occurring in a rabbit atrium, characterized by
the “tail” wave front being closely pursued by the “head” so
that no excitable gap is present. The leading edge circuit is
maintained by centripetal activation, rendering the central
region refractory.
Another type of functional reentry involves generation of
spiral waves, which have been shown to circulate through
either atrial or ventricular tissue. In spiral wave propagation,
the safety margin for conduction is least at points of
maximal curvature (9 –11). Spiral or meandering waves may
become stationary by anchoring around anatomic obstacles
(i.e., pulmonary or systemic veins) and would, thus, become
manifest on surface electrocardiogram (ECG) recordings as
monomorphic arrhythmias (i.e., flutter). By contrast, nonstationary spiral waves would assume the typical characteristics of AFib (12,13).
Gordon Moe’s original multiple wavelet hypothesis was
ultimately substantiated by Allessie et al. in both experimental as well as clinical studies. In the canine heart, for
example, it was demonstrated that four to six circulating
wavelets were necessary for maintenance of AFib (14).
Smaller numbers of wavelets tend to coalesce and restore
sinus rhythm. Several principles emerged from these observations. Maintenance of AFib depends on adequate atrial
mass to encompass sufficient wavelets to perpetuate the
arrhythmia. In addition, conditions that decrease atrial
refractoriness (hence resulting in a decrease in tachycardia
wavelength) would tend to perpetuate AFib (15). These
important concepts will be revisited when we consider
newer therapeutic options.
1688
Scheinman
AFib, Mechanism and Treatment
Abbreviations and Acronyms
AFib ⫽ atrial fibrillation
AV ⫽ atrioventricular
ECG ⫽ electrocardiogram
Another important concept generated by Allessie’s group
is the idea that atrial fibrillation per se may act to produce
both electrophysiologic and anatomic remodeling, which,
apart from any preexisting structural atrial abnormalities,
may result in more ready initiation as well as perpetuation of
AFib. Wijffels et al. (16), for example, found that persistence of AFib produced several important electrophysiologic
changes, resulting in both shortening of atrial refractoriness
as well as disturbance of the normal rate responsiveness to
overdrive atrial pacing. Normally, atrial overdrive pacing
results in shortening of refractoriness in response to increased rate. In animals with persistent AFib who are
reverted to sinus rhythm, overdrive pacing may show either
no change or increased atrial refractoriness in response to
overdrive pacing.
How do these concepts help to explain clinical AFib?
Konnigs et al. (17) provided detailed atrial mapping in
patients with the Wolff-Parkinson-White syndrome who
required cardiac surgery. Atrial fibrillation was induced and
recordings obtained from high density electrodes placed
over the right atrium. They described three types of AFib
patterns. Type I was characterized as a single dominant
wave front, while type III was more akin to that predicted
from the multiple wavelet hypothesis. In type III, flutter
wavelets were observed to collide and extinguish, or wavelet
may summate and augment conduction. Other wavelets
encounter areas of block with production of “daughter”
wavelets. Another type of circuit described in type III
fibrillation involved waves that return to the point of origin,
indicative of a leading edge circuit. Type II flutter often was
found to be intermediate between the other types.
POSSIBLE EXPLANATION OF TYPE I AFIB
The close relationship between AFib and flutter was studied
extensively by Waldo et al. (18,19). They showed this
relationship in both the canine pericarditis model and
postoperative cardiac patients (20). More recently, they
showed that flutter circuits may circulate around the pulmonary veins and produce AFib with simultaneous maintenance of the originating flutter circuit. Termination of
atrial fibrillation was followed by reinitiation from the
original flutter circuit (21). In addition, Ikeda et al. (12)
showed that meandering wave fronts had a greater tendency
to become stationary when the core surrounded a larger hole
(i.e., pulmonary or systemic vein). A larger hole was
associated with a greater propensity for anchoring spiral
waves because of a lesser angle of curvature and a greater
source to sink the safety margin of conduction. Meandering
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May 2000:1687–92
waves tended, on the other hand, to detach themselves from
smaller orifices because of a lesser safety margin for wave
propagation around the smaller orifice.
The strong relationship between atrial flutter and fibrillation is supported by our own clinical observations that
typical clockwise or counterclockwise flutter may assume
atypical patterns (22,23). Atrial fibrillation may evolve from
these atypical patterns and appear to result from one or
more breaks in the crista terminalis (23,24). The cause of
breakdown of functional barriers is not clear. Rapid atrial
rates have been shown to produce alternation of atrial action
potential duration (25). In ventricular muscle, these alternations may be either concordant or discordant (26). Introduction of premature complexes in ventricular rhythms
showing discordant action potential duration may produce
ventricular fibrillation. Similar patterns have recently been
described in atrial muscle (27).
One may logically consider the pathogenesis of AFib as
requiring specific triggers, a suitable substrate and modifying factors. An important trigger is the development of focal
automatic atrial rhythms. Rapid rates from these foci may
result in AFib by means of the mechanisms discussed above.
Focal atrial tachycardia producing AFib has been verified in
the clinic, and the majority of these foci originate from the
pulmonary veins (28). Another trigger may result from atrial
flutter (especially rapid atypical forms) as discussed above.
Not only atrial flutter, but actually any supraventricular
arrhythmia, may serve to trigger AFib (29,30). It is appreciated that rapid atrial rates serve to increase inhomogeneity
of the refractory period and thereby increase atrial vulnerability to AFib (31). In addition, rapid rates decrease atrial
wave length, and they also make the atria more vulnerable to
fibrillation.
The appropriate substrate involves, first, an adequate
atrial mass capable of encompassing the necessary numbers
of wavelets required to maintain AFib. This explains why
this arrhythmia is rarely observed in species with small atria
or even in human neonates. Additional anatomic factors
appear to be related to the complex architecture of the
atrium, which has prominent muscle ridges (which may
produce areas of anisotropic conduction) as well as the
orifices of systemic and pulmonary veins. Furthermore, in
patients with cardiac disease, atrial areas with heterogeneous
electrophysiologic properties may act as an appropriate
substrate for maintenance of atrial fibrillation.
A variety of modifying factors appear to be of importance
in the initiation and maintenance of AFib. It has long been
appreciated that intense vagal stimulation produces AFib in
animals (32). A likely explanation appears to be related to
the action of acetylcholine in shortening the atrial action
potential duration, which would encourage a greater number of atrial wavelets because each wavelet would be associated with a decreased wavelength. Similar considerations
apply to AFib, which may be induced by intravenous
adenosine (33). The very elegant and important work from
Allessie’s (16) laboratory has shown that persistent AFib
Scheinman
AFib, Mechanism and Treatment
JACC Vol. 35, No. 6, 2000
May 2000:1687–92
may result in modification of atrial electrophysiology as well
as atrial anatomy, which may favor the perpetuation of
AFib. These findings have led to the concept that AFib
begets atrial fibrillation.
TREATMENT STRATEGEMS
Discussion of detailed management of patients with AFib is
beyond the scope of this review. We will instead emphasize
newer therapeutic approaches based largely on newer understanding of mechanisms.
The mainstay of current therapy for patients with AFib
remains drug therapy. Atrioventricular (AV) nodal blocking
agents are used primarily for rate control while antiarrhythmic agents are used to maintain sinus rhythm. The rationale
for the use of antiarrhythmic drug therapy rests primarily on
its ability to prolong atrial refractoriness (34). Even class IC
agents, which are potent Na⫹ channel blockers, have been
shown to exert rate-related prolongation of refractoriness
(35,36). Both experimental and clinical studies have shown
that the use of a calcium channel blocker attenuates both the
abnormal shortening of atrial action potentials and the
abnormal rate response (37). Whether use of a Ca⫹⫹
channel blocker should become standard auxiliary therapy
requires further study.
Another illustration of the way recent laboratory findings
impact medical therapy is the wider use of early cardioversion for treatment of patients with AFib. For patients with
AFib of ⱖ48 h, conventional therapy before planned direct
current cardioversion was a two-to-three-week course of
anticoagulant therapy. Recent prospective studies by Manning et al. (38) have shown that if the patient with AFib has
a normal transesophageal echo, then use of heparin followed
by direct current external cardioversion is safe in terms of
risk of systemic emboli.
CATHETER ABLATION OR MODIFICATION OF THE AV
NODE
Catheter ablation of the AV junction was first introduced in
1982 (39) and has become an accepted treatment modality
for patients with AFib who prove to be refractory to drug
therapy. The advantages of AV junction ablation include
ventricular rate control and improved cardiac function and
quality of life (40). The chief disadvantages are initiation of
a pacemaker-dependent state and continued need for anticoagulant therapy. Death after AV junction ablation has
been reported, and this appears to be due in part to the
relatively slow-paced rates used after ablation (41). With use
of properly paced rates, the incidence of death or sudden
death is identical to that of medically treated patients. More
recently, attempts to modify AV nodal function in order to
obviate the need for permanent pacing were introduced
(42). The chief advantage of this approach is the possibility
of rate control without permanent pacing. Potential problems include failure to prevent the sensation of palpitations,
late onset AV block (16%) (43) and resumption of rapid AV
1689
conduction, and late deaths have been reported (43). In
addition, more than one procedure may be required to
achieve the desired result. Long-term rate control is
achieved in almost 100% of patients after AV junctional
ablation (44), as opposed to approximately 70% after AV
nodal modification.
DEVICE THERAPY
Device therapy has been used in attempts to prevent AFib
or to abort established episodes. Retrospective uncontrolled
studies showed that single-site atrial pacing had a significant
salutary effect, compared with ventricular pacing, in decreasing the incidence of AFib in patients with the bradycardiatachycardia syndromes. More recent prospective controlled
trials have shown conflicting data. Anderson et al. (45)
showed a benefit from single-site atrial pacing, but this
became manifest only after many years of follow-up. A more
recent study (46) showed no benefit from atrial versus
ventricular-based pacing, and the differences between studies may be the result of differences in atrial paced rates used
or length of follow-up.
More recently Saksena et al. (47) have described the use
of dual-site pacing in patients with sick sinus syndrome
(right atrial and coronary sinus) and the impressive decreases in the incidence of AFib for those treated with atrial
pacing. It should be emphasized that recurrences of AFib
were the rule, and the vast majority of these patients
required concomitant drug therapy. Nevertheless, dual-site
pacing may ultimately prove to be a therapeutic option for
patients with bradycardia-tachycardia syndrome, if confirmed by larger studies.
A unique approach to the management of AFib involves
the use of the automatic internal defibrillator. This device
has been extensively tested and shown to accurately detect
AFib and to deliver atrial shocks without eliciting any
ventricular proarrhythmias (48). The chief drawbacks include painful sensations with the delivery of shocks and the
necessity for three intracardiac electrodes, including right
atrial and coronary sinus electrodes for sensing and shock
delivery and a right ventricular sensing electrode in order to
avoid delivery of atrial shocks during the ventricularvulnerable period. The atrial defibrillator would appear to
have a role in patient management, particularly for the
patient with infrequent episodes who wishes to avoid
emergency room visits for treatment of recurrent AFib. In
addition, more rapid conversion of AFib may result in a
situation in which episodes of AFib become less frequent.
In the U.S., the tendency has been for industry to package
the atrial defibrillator with the ventricular defibrillator.
These devices allow for atrial-based pacing and the use of
sophisticated algorithms to distinguish supraventricular
tachycardia (including AFib) from ventricular tachycardia
and thus avoid inappropriate shocks (49). In addition, such
devices can be programmed to deliver therapy and abort
AFib (50). These devices allow for detailed interrogation so
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Scheinman
AFib, Mechanism and Treatment
that the clinician can discern the onset of AFib. For
example, a recent study showed that up to 30% of episodes
of AFib were preceded by bouts of atrial tachycardia (or
atrial flutter) (50).
Of great interest was the finding that antitachycardia
pacing or atrial burst pacing could potentially abort episodes
of atrial fibrillation in over 50% of atrial tachycardia episodes (50).
TECHNIQUES DIRECTED AT CURING AFIB
Guiraudon (51) was the first to describe a procedure that
created a corridor between sinus and AV nodes in patients
with AFib. This ingenious procedure resulted in a regular
rhythm but was essentially abandoned because atrial function was not restored (because the mass of atria were in
fibrillation), and anticoagulant therapy was required. More
recently, Cox et al. (52) described an innovative operation
that involved multiple linear incisions over both atria (maze
procedure), which proved to both restore sinus rhythm and
preserve atrial function (albeit suppressed). These seminal
observations sparked creation of both surgical and catheter
techniques directed at curing atrial fibrillation. Other surgeons have shown that the maze procedure could be
simplified with preservation of efficacy (53–55). It is still
unclear whether the maze procedures are effective specifically because of the lesions created or because of nonspecific effects related to the reduction of atrial mass.
Dr. Swartz et al. (56) were the first to demonstrate that
the maze procedure as described by Cox could be successfully replicated by catheter. More recent collaboratory studies have also validated the concept of AFib cure using long
linear atrial lesions (57). To date, the available experience
suggests that left atrial lesions are necessary for the cure of
most patients with AFib (58). The surgical maze procedure
would appear to be most promising for those patients with
atrial fibrillation who require corrective cardiac procedures
(i.e., mitral valve repair). Use of the maze procedure has not
gained wide general acceptance, because of the need for
cardiopulmonary bypass and the associated postoperative
morbidity and mortality. Similarly, the catheter maze procedures, while appealing (because it obviates the need for
open-heart surgery), have been associated with serious
sequela, including cerebrovascular accidents, pulmonary hypertension owing to occlusion of the pulmonary veins and
cardiac tamponade (59). It would appear that many technical problems need to be solved before widespread application of this technique can be recommended.
An exciting newer approach for cure of AFib was discovered by Haissaguerre et al. (60). They initially reported nine
patients with focal tachycardia that triggered AFib. Ablation of the trigger could cure AFib. More recent studies by
both Haissaguerre et al. (60) and Hsieh et al. (61) have
shown that these arrhythmogenic foci are usually located in
the left or right upper pulmonary veins, although successful
ablation of “focal” AFib has been reported in the lower
JACC Vol. 35, No. 6, 2000
May 2000:1687–92
pulmonary veins or even in the right atrium. This remarkable finding has created great interest in both the electrical
and anatomic relationship of the left atrium and pulmonary
veins. It has been established that tongues of atrial myocardial tissue may extend for several centimeters into the
pulmonary veins. These foci may discharge at very rapid
rates producing AFib. In addition, these arrhythmogenic
foci appear to be poorly coupled, which may allow for local
reentrant arrhythmias caused by anisotropic conduction in
this region. The finding of focal triggers for AFib is an
important finding both conceptually and therapeutically. To
date, it is still unclear how often focal tachycardias are
responsible for atrial fibrillation. The incidence of long-term
successful cures is uncertain. In addition, because the
pulmonary veins have no anastomosis, inadvertent occlusion
of a pulmonary vein may lead to pulmonary insufficiency.
The population with the highest yield for finding “focal”
AFib would appear to be patients with lone atrial fibrillation
who, on Holter recordings, show frequent unifocal atrial
premature complexes and/or bursts of rapid atrial tachycardia that often precede the development of AFib (60,61). We
do not have sufficient data to assess the risks of focal atrial
ablation, and registry data from both very experienced and
less experienced units are needed before making blanket
recommendations.
SUMMARY
Although multiple, very significant, conceptual and practical
advances have been made in both our understanding of and
treatment of AFib, much more remains to be learned. The
history of catheter ablation suggests that true cures occur
only after more complete understanding of the tachycardia
mechanism (i.e., Wolff-Parkinson-White syndrome, AV
node reentrant tachycardia). I do not think that we are
anywhere close to this point for patients with AFib. The
contention that surgical or catheter maze procedures “cure”
AFib is akin to believing that AV junctional ablation cures
all supraventricular arrhythmias. I believe that AFib is a
term that is used to cover a multitude of disordered atrial
rhythms and that, in time, ablative procedures will be
developed for specific abnormal circuits. We need to learn
much more about the basic pathogenesis of this arrhythmia.
Is it related to abnormalities in atrial ionic channels?
Abnormalities of connexon distribution? Ischemia? Or factors unknown (62)? We need to understand the links
between disordered physiology and the triggers, substrate
and modifying factors. Is a cure for AFib at hand? I think
not, but we are much closer today than we were five years
ago.
Reprint requests and correspondence: Dr. Melvin M. Scheinman, 500 Parnassus Avenue, San Francisco, California 941431354. E-mail: [email protected].
Scheinman
AFib, Mechanism and Treatment
JACC Vol. 35, No. 6, 2000
May 2000:1687–92
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