Circulation. 2001;103:769-777
(Circulation. 2001;103:769.)
© 2001 American Heart Association, Inc.
Pathophysiology and Prevention of Atrial Fibrillation
Maurits A. Allessie, MD, PhD;
Penelope A. Boyden, PhD;
A. John Camm, MD;
André G. Kléber, MD;
Max J. Lab, MD, PhD;
Marianne J. Legato, MD;
Michael R. Rosen, MD;
Peter J. Schwartz, MD;
Peter M. Spooner, PhD;
David R. Van Wagoner, PhD;
Albert L. Waldo, MD
From the University of Limberg, Maastricht, the Netherlands (M.A.A.); the
College of Physicians and Surgeons of Columbia University, Department of
Pharmacology, New York, NY (P.A.B., M.J. Legato, M.R.R.); St Georges
Hospital, London, England (A.J.C.); University of Bern, Bern, Switzerland
(A.G.K.); Imperial College School of Medicine, London, England (M.J. Lab);
University of Pavia, Pavia, Italy (P.J.S.); National Heart, Lung, and Blood
Institute, Bethesda, Md (P.M.S.); Cleveland Clinic Foundation, Cleveland, Ohio
(D.R.V.W.); and Case Western Reserve University, Cleveland, Ohio (A.L.W.).
Correspondence to Michael R. Rosen, MD, Gustavus A. Pfeiffer Professor of Pharmacology, Professor of Pediatrics, College of Physicians & Surgeons of Columbia University, Department of Pharmacology, 630 W 168 St, PH7W-321, New York, NY 10032. E-mail mrr1{at}columbia.edu
Key Words: risk factors atrial fibrillation prevention
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Introduction
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Atrial
fibrillation (AF) is a ubiquitous yet diverse cardiac
arrhythmia
whose incidence increases with age; with most forms
of cardiac and some
pulmonary diseases; and with a number of
metabolic, toxic, endocrine,
or genetic
abnormalities.
1 2
Classification
of clinical AF subtypes can be achieved on the basis of
the
ease by which episodes of the arrhythmia terminate as
follows
3 : "Paroxysmal" AF
refers to episodes that generally stop spontaneously
after no more than
a few days. "Persistent" AF occurs less frequently
than paroxysmal
AF and, rather than self-terminating, requires
cardioversion to restore
sinus rhythm. "Permanent" AF cannot
be converted to sinus rhythm.
These terms apply strictly to
chronic AF, because a single episode of
the arrhythmia cannot
be fully categorized. Although there are some
mixed patterns,
they generally derive from physician impatience for
early cardioversion
or from pragmatic clinical considerations (eg, to
avoid thrombus
formation or hemodynamic decompensation).
Patients initially presenting with paroxysmal AF often
progress to longer, nonself-terminating bouts. An exception may be
paroxysmal AF during intense vagotonia. Moreover, AF initially
responsive to pharmacological or electrical cardioversion tends to
become resistant and cannot then be converted to sinus rhythm. To some
extent, the failure of the physician to suggest or the patient to
accept further cardioversion attempts may lead to diagnosis of
"permanent" AF. Thus, the "point of no return" may be
determined by true pathophysiological abnormalities or may merely be an
artifact of clinical pragmatism.
Effective prevention is essential in managing this
arrhythmia whose occurrence is widespread, progression is relentless,
and morbidity and mortality are significant. To focus on means for
prevention necessitates considering both clinical risk factors and
pathophysiology.
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Clinical Risk Factors Predisposing to
AF
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AF derives from a complex continuum predisposing
factors, summarized
in
Table 1

. In the West, about 5% of the population
>65 years
of age is afflicted with
AF.
4 5 The most
frequent causes of
acute AF are myocardial infarction (5% to 10% of
patients with
infarct)
6 7 and
cardiothoracic surgery (up to 40% of
patients).
8 The
most common
clinical settings for permanent AF are hypertension
and ischemic heart
disease, with that subset of patients having
congestive failure being
most likely to experience the arrhythmia.
In the developing world,
hypertension and rheumatic valvular
(usually mitral) and congenital
heart diseases are also common
associations.
9 10 11
Adrenergic and vagotonic forms of paroxysmal AF are
uncommon.12 Nonetheless,
lone fibrillators often have attacks against the background of
parasympathetic
predominance,13 whereas
paroxysms in patients with structural heart disease more usually occur
in a sympathetic setting. About half of the patients with paroxysmal AF
have no obvious clinical cause (lone or idiopathic AF). This proportion
falls to <20% in patients with persistent or permanent
forms.14 These observations
are disquieting because, in the absence of identifiable predisposing
factors, targeting preventive therapy is difficult.
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Pathophysiology of AF
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Onset of AF
We consider the factors responsible for onset of AF to
include
triggers that induce the arrhythmia and the substrate that
sustains
it. The triggers are diverse yet do not cause AF in the
absence
of other contributors. Triggers include sympathetic or
parasympathetic
stimulation, bradycardia, atrial premature beats or
tachycardia,
accessory AV pathways, and acute atrial stretch. Recently
identified
as triggers are ectopic foci occurring in "sleeves" of
atrial
tissue within the pulmonary veins or vena caval junctions. These
regions
likely resemble the juxtaposed islets of atrial myocardium and
vascular
smooth muscle in coronary sinus and AV valves that, under
normal
circumstances, manifest synchronous electrical activity but
develop
delayed afterdepolarizations and triggered activity on rapid
pacing
or acute stretch.
15
Supporting this idea are clinical studies
of impulses generated by
single foci propagating from individual
pulmonary veins or other atrial
regions to the remainder of
the atria as fibrillatory
waves
16 and abolition of AF
by radiofrequency
ablation to isolate the venous
foci.
17
Triggers propagating into atrial myocardium may initiate
reentering wavelets if the wavelength is sufficiently short. Wavelength
shortening can occur even in normal atria if the effective refractory
period (ERP) or conduction velocity is decreased. Initiation and
maintenance of AF may depend on uninterrupted periodic activity of a
few discrete reentrant sources localized to the left atrium, emanating
from such sources to propagate through both atria and interact with
anatomical and/or functional obstacles, leading to fragmentation and
wavelet
formation.18 19
Factors such as wavefront
curvature,20 sink-source
relationships,21 and spatial
and temporal
organization22 23
all are relevant to our understanding of the initiation of AF by the
interaction of the propagating wave fronts with such anatomic or
functional obstacles. Indeed, all these factors, which differ from
triggers, may be considered initiators of AF.
Having been initiated, AF may be brief. A variety of factors
may act as perpetuators, ensuring the persistence of AF for longer
periods. One is persistence of the triggers and initiators that induce
AF,24 but at some point, AF
persists even in their
absence.25 26 27
Persistence here may result from electrical and structural remodeling,
characterized by atrial dilatation and shortening of the atrial ERP.
This combination, along with other remodeling changes, likely
facilitates the appearance of multiple reentrant wavelets (a final
common pathway for AF).
The longer AF persists, the more difficult it is to restore
sinus rhythm and prevent recurrence. Whether this temporal factor is
explained by atrial remodeling is not known, but clearly, time is a
factor for perpetuation. It is likely associated with increased
dispersion in atrial ERP and increased and inhomogeneous dispersion of
conduction abnormalities, including block, slow conduction, and
uncoupling of muscle bundles. The extent to which gap junctional
alterations contribute to the conduction changes is not yet understood.
Certainly, disorganization and fragmentation of gap junctions are
described as accompanying permanent
AF.28 However, human and
animal studies of connexins, the proteins that form the gap junctional
channels, give inconsistent
results,29 30 31
although all suggest that anomalies are present. Finally, factors
determining the point of no return to sinus rhythm are not yet
characterized. Investigation of the determinants of this milestone in
the road to permanent AF is important to devising strategies for
prevention.
Recurrence of AF
If paroxysmal or persistent AF is not only to occur but
to recur, factors facilitating this sequence should be present for some
interval after reversion to sinus rhythm. Therefore, we must understand
whether AF-induced electrophysiological remodeling is reversible. In
goats fibrillating for about 3 weeks, interposed periods of sinus
rhythm prevent further AF-induced remodeling, so that subsequent AF
episodes do not become
chronic.32 A day after
cardioversion to sinus rhythm, the atrial ERP remains short, but it
returns to normal within a week. The course can be complicated by
depressed sinoatrial automaticity, which requires a week or more in
sinus rhythm to recover from AF-induced
remodeling.33 The time for
recovery of ERP after reversion to sinus rhythm also varies regionally,
being slower in canine left atrium than in right atrium and Bachmanns
bundle.34
Prompt cardioversion progressively reduces the total time
that patients are in AF and progressively increases the time between
cardioverted episodes.35 The
latter result is attributable to prevention of long-lasting AF
paroxysms and attendant
remodeling,35 suggesting
that prompt restoration of sinus rhythm will forestall progressive
remodeling and the increase in duration and frequency of arrhythmic
episodes. Because the time course of tachycardia-induced remodeling and
the subsequent reverse remodeling of the atrial ERP and action
potential (AP) duration requires only 2
days,25 36 it is
likely that not only electrophysiological but other mechanisms, like
reverse mechanical and/or structural remodeling, are involved in the
prevention of AF by prompt cardioversion.
Structure, Mechanics, and Signal
Transduction
Attractive as it is to seek uniquely
electrophysiological causes and therapeutic strategies for AF, reality
imposes greater complexity, integrating mechanical, structural, and
signaling processes. Incorporated in this mix are atrial architecture,
including the extracellular matrix and cytoskeleton, which provide a
source for transatrial force and stretch distribution
(Figure 1
). Yet given the microarchitecture of normal atrium,
with marked regional variation in the pattern of packing of cells
within their connective tissue
envelopes,37 it is likely
that dilatation and/or altered stretch affect some groups of myocytes
differently than others. Uneven distribution of stretch on myocyte
groups derives from variations in the collagen network and nonuniform
excitation-contraction coupling. An example is the extensive
interstitial fibrosis associated with macroreentry and fibrillatory
conduction described in dogs with congestive failureinduced
AF.38 Age and atrial disease
also are associated with increases in connective tissue
elements39 and/or scarring
in atrium. Resultant changes in patterns of myocyte apposition may
contribute to altered cell-cell interaction and redistribute the
stretch that occurs
(Figure 1A
). However, fibrotic restructuring of the atrial
wall may also be protective by shielding myocytes from abnormal stress
and strain, depending on geometrical arrangement.

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Figure 1. Mechanoelectric feedback/coupling (mechanosensitivity) and heterogeneity as possible contributors to AF. A, Altered stress/strain patterns on myocyte either directly or via cytoskeletal linkages to integrins open stretch-activated channels (SACs) and ICa, L and stimulate muscarinic receptors (M2). Catecholamine release, which may be cause and/or effect of altered stress/strain, results in binding of - and ß-adrenergic agonists to their respective receptors (recp). Additionally, angiotensin II (AII) synthesis is increased, which agonist binds to the angiotensin II (AT-1) receptor. These agonists, in binding to their respective receptors, initiate G-proteincoupled pathways, with ß-adrenergic and muscarinic pathways opposing one another in activating adenylyl cyclase and turning on cAMP synthesis, and -agonist and angiotensin II triggering phosphatidylinositol second messenger system that, via phospholipase C (PLC) action, synthesizes IP3 and diacylglycerol (DAG). Protein kinases A (PKA) and C (PKC), activated by cAMP and PI pathways, respectively, modulate Cai level, via opening of ICa, L and sarcoplasmic reticulum (SR) calcium release. In addition, PKC activates mitogen-activated protein kinase (MAPK), which turns on immediate early gene (IEG) program to initiate hypertrophy. B, Simplified depiction of mechanical aspects of A, with prevailing explanations for mechanoelectric transduction or coupling. Starting from mechanical force-length (F/L) changes on left, transducers reside in force transmission, directly or indirectly via the focal proteins on cytoskeleton, to SACs or mechanosensitive channels. Force transduction may also be via myofibrillar proteins. Calcium and cell signal transduction (see A) play central roles. Ach indicates acetylcholine; actomyo, actomyosin; and ET, endothelin.
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One starting point for considering the interactions of these
factors is hemodynamic load, which, when chronically increased in
diseases such as mitral valvulitis, hypertension, or congestive
failure, is frequently associated with AF. Altered load is often
accompanied by changes in myocardial segment length that, acutely, can
result in decreased resting potential, AP amplitude and duration, and
occurrence of afterdepolarizations causing extrasystoles that originate
in the region of greatest
stretch.40
The effects of changes in stretch are many; even in normal
hearts, regional stretch for <30 minutes turns on the immediate early
gene program, initiating hypertrophy and altering AP duration in
affected areas.41 Moreover,
acutely altered stress/strain patterns augment the synthesis of
angiotensin II, which induces myocyte
hypertrophy.42 By regionally
increasing L-type Ca current (ICa, L) and
decreasing the transient outward potassium current,
Ito,43
angiotensin II can contribute to arrhythmogenic electrical dispersion.
These observations suggest that benefit might derive from preventing
the remodeling effects of angiotensin II.
The effects of altered stretch on myocytes influence the
internal machinery of the cell in part via stretch-activated channels
(SACs)44 as follows: Force
transmits directly to SACs in the membrane or indirectly to them via
cytoskeletal linkages to the integrins, resulting in channel opening
(Figure 1A
and 1B
).45 Stress and strain not
only activate
SACs44 46 but may
modify activity of other ion channels, receptors, and enzymes with
cytoskeletal connections. For example, ICa, L
density increases in response to positive pressure or hypotonic
swelling in rabbit atrial
myocytes,47 providing a
potential mechanism linking the cytoskeleton and this calcium channel.
Moreover, ICa, L in neonatal mouse cardiac
myocytes is sensitive to agents that modulate the actin filament
network.48 Because
ICa, L is a critical regulator of atrial
excitation-contraction coupling, it is quite conceivable that stretch
in atrial myocardium contributes to its
modulation.47
Not only do acute mechanical changes produce
electrophysiological alterations and
arrhythmia,49 but once AF is
induced, rapidly and inhomogeneously contracting and interacting atrial
segments would tend to perpetuate electrophysiological dispersion. It
is not difficult to visualize a geometry in which contractile
dispersion (an earlier-activated segment stretching another) in the
scarred matrix induces electrophysiological
dispersion50
(Figure 1B
). In addition, fibroblasts manifest
mechanoelectric coupling in human
atrium,51 and
electrophysiological interactions between fibroblasts and myocytes are
likely.52 Hence,
stretch-induced depolarization of fibroblasts would facilitate
depolarization of the myocytes, depending on the extent of
fibroblast-myocyte coupling.
Changes in AF characteristics during evolving fibrosis also
have a direct impact on why electrical and/or drug treatment ultimately
fails to achieve conversion to sinus rhythm. The characteristics of
fibrosis in infarct scars are a helpful paradigm here. Fibrotic
myocardium exhibits slow conduction, whose low macroscopic propagation
velocities are explained by microscopically zigzagging
circuits53 or by the special
conduction characteristics of tissues with discontinuous, branching
architecture.54 Reentrant
circuits can be only a few millimeters in diameter in discontinuously
conducting tissue.55 Thus,
atrial regions with advanced fibrosis can be local "sources" for
AF. Such a hypothesis would not preclude the remainder of the atria
from showing fibrillatory conduction and/or intact, functional
reentrant waves. A highly fibrotic atrial region or regions would
explain the refractoriness of AF to therapeutic interventions as
follows.
- In any
markedly discontinuous tissue (discontinuous anisotropy, marked degree
of gap junctional uncoupling, branching), the safety-factor for
propagation is even higher than in normal
tissue.56 Thus, blocking
INa to the same degree as is necessary for the
termination of functional reentry might not terminate reentry caused by
slow and fractionated conduction in fibrotic scars of remodeled
atria.
- That conduction in discontinuous tissue is mostly
structurally determined will lead to excitable gaps behind the wave
fronts. If a gap is of critical size, the effectiveness of
ERP-prolonging drugs will be
limited.57
- Scar tissue is likely to exhibit multiple entry and
exit points and multiple sites at which unidirectional block
occurs.20 This may lead to
activity whose appearance in local extracellular electrograms changes
from beat to beat, as well as beat-to-beat cycle length variability.
Although such regions may be expected to respond to defibrillation, AF
might resume after extrasystoles or normal sinus beats immediately
after conversion, with unidirectional block recurring as a result of
the presence of scar.
Apoptosis (programmed cell death) is
another likely contributor to the structural substrate of AF. Apoptosis
normally controls expression of specific cell types, but under
pathophysiological conditions, it may occur inappropriately. When this
happens in heart, myocytes die and contractile capacity and electrical
activity are permanently altered. Although there is no apoptosis in the
goat model after 19 to 23 weeks of
AF,58 small numbers of
apoptotic cells are identifiable in chronically fibrillating human
atria.59 These cells are
likely to be lost structurally and functionally when apoptosis is
complete, causing irreversible atrial damage.
The Cellular Electrophysiological and
Molecular Substrate
The cellular electrophysiological changes typifying AF
are a decrease in AP duration and depression of the AP plateau
(Figure 2
). These occur in pacing-induced AF in
animals60 61 and
in AF in patients.62 A
critical component of the cellular electrophysiological changes is
altered restitution of AP duration, so that the response to rapid
changes in rate is attenuated and vulnerability to the propagation of
premature depolarizations is
increased.61 Abnormalities
in calcium handling as described above are important contributors to
this altered restitution. In the setting of chronically diseased and
dilated atria, decreases in resting potential and in AP upstroke
velocity occur as
well.28

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Figure 2. AF and cardiac AP. A, AP at cycle lengths of 2000 and 500 ms in normal right atrial endocardium (left) and that from chronically fibrillating dog (right). Note shorter AP duration (APD) in latter and failure to see any change in AP duration with changes in rate. B, APD to 50% repolarization in endocardium from normal ( ) and fibrillating ( ) canine atria. Left, cycle length is changed abruptly from 500 to 1500 ms. Note initial prolongation of APD, secondary shortening, and then gradual prolongation. At all times, APD for AF is shorter than control. Right, cycle length is shortened abruptly from 1500 to 500 ms. Note again markedly shorter and attenuated APD in AF. Hence, there is abnormal rate adaptation in setting of AF. C, Same population but after treatment with the SR calcium release blocker ryanodine. Note that at both ranges of cycle lengths, early portion of rate adaptation is blocked by ryanodine. Later portion remains intact. This demonstrates importance of calcium release mechanisms in determining the rate adaptation in both normal and fibrillating atria. Modified from Hara et al.61
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Explanations for these AP changes have been sought at the
level of ion channels; those changes thus far identified as
accompanying and/or predisposing to AF in human subjects are summarized
in
Table 2
. Reductions in Ito and in
the sustained outward current, IK, sus, which
includes IKur as a major
component,63 64 65
are seen in human tissues and animal models. However, reduction in
these currents would tend to prolong AP duration, a change opposite
that which typifies rapid atrial pacing or
AF.61 In light of this, it
is important that ICa, L, which maintains a
positive plateau voltage and sustains AP duration, decreases within 24
hours of rapid atrial
pacing66 and in
long-standing
AF67 68 and that
the outward currents IK1 and IK,
ACh increase in myocytes from chronically fibrillating
human atria.69 The sum of
these changes in inward and outward currents likely explains the
depressed AP plateau and accelerated AP repolarization.
Although such changes in inward and outward ionic currents
appear to provide a key to the AP alterations characteristic of AF,
there are concerns about overinterpreting the roles of these currents.
We state this because similar current changes occur in rapidly paced
yet nonfibrillating atria, dilated and nonfibrillating atria, and atria
that are chronically fibrillating. In other words, these ion channel
changes are a response to a variety of stresses that, while
contributing to the milieu favoring fibrillation, may not in and of
themselves be the root cause. This observation may partially explain
the limited success attained with the use of ion channelblocking
drugs in AF.
Channel function is partially controlled by metabolic
changes. During rapid pacing or AF, atria are likely to reach a
negative metabolic balance, characterized by diminished energy reserves
and altered oxidative state. Under these conditions, several components
of the cytosolic and interstitial milieu are altered, including
pH86 and PO2.
Interestingly, the
1c subunit of human
cardiac ICa, L is reversibly inhibited at
clinically relevant, reduced PO2.87
The importance of this observation to AF is seen in patients after
cardiac surgery in whom monophasic AP recordings demonstrate decreased
atrial AP duration minutes to hours before AF
onset.88 This period is one
of increased metabolic demand, elevated sympathetic tone, and increased
levels of circulating cytokines. These factors provoke hypoxia and/or
ischemia and can suppress ICa, L, thus playing
important roles as initiators or triggers of AF. Also noteworthy is
that the redox state is age dependent. Hence, decreased metabolic
reserve may contribute to the age-related propensity to occurrence of
AF.
Regulation of channels is also genetically determined. This
is important because in families in which a high incidence of AF occurs
in young people of one or more generations, genetic linkage indicates
familial elements of
susceptibility.2 As we learn
more regarding the significance of specific DNA changes associated with
AF, we may increasingly appreciate some of its fundamental
determinants. Very importantly, the value of genetic information may
not be restricted to family members of those individuals in whom
inherited AF is expressed. Rather, it may extend to a significant
subset of that 5% of the population that develops the arrhythmia
during and after the seventh decade of life, thereby providing further
clues regarding susceptibility to AF.
To sum up our consideration of pathophysiology,
electrophysiological research, complemented by cellular
electrophysiology and biophysics, has provided a detailed picture of AF
and some of its determinants. Now being added to this information is
literature incorporating mechanical and structural data, with a major
focus on the molecular and genetic mechanisms associated with ongoing
changes in cardiac
function.67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 The overall picture incorporates a variety of disease entities, as well
as age and autonomic influences, individually and together altering the
extracellular matrix and cytoskeleton and affecting individual myocytes
at the multiple levels depicted in
Figures 1
and 2
and
Table 2
. The resultant fundamental reorientation of atrial
structure and function provides the groundwork for AF. Given the
profound changes that determine the likely progression from paroxysmal
to persistent to permanent AF, it would appear that early detection and
early prevention are the soundest strategies for combating the
arrhythmia.
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Prevention of AF
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Given that AF is the final arrhythmic expression of a
diverse
family of diseases, preventive measures ideally must reflect
the
root causes of AF and be explored and administered in ways
reflecting
that diversity. High priority should be given to
understanding
epidemiological risk factors and diseases predisposing to
AF
and to managing them aggressively. Immediate goals are to recognize,
and
if possible prevent, the evolution of age-related, structural,
and
electrophysiological substrates favoring the progression
of AF. Hence,
preventive strategies should ideally focus on
the comorbidity factors
contributing to AF. These factors appear
to involve disease processes
that (1) contribute to the triggering
of AF (eg, sympathetic and
parasympathetic nervous systems,
predisposing arrhythmias, ectopic foci
in pulmonary veins);
(2) increase atrial distension (eg, valvular heart
disease,
hypertension and heart failure); (3) decrease the ratio of
atrial
myocyte to fibrotic tissue, possibly including an increased
rate
of apoptotic cell death (hypertension and ischemic heart
disease); (4)
disrupt transmyocyte communications (pericarditis
and edema); (5)
increase inflammatory mediators (pericarditis
and myocarditis); and (6)
alter energy and redox states that
modulate the function of ion
channels and gap junctions.
To optimize recognition of comorbidity factors, standard
tests like ECG, echocardiography, clinical electrophysiological
studies, and x-ray or ventriculography should be used. Of these,
clinical electrophysiological techniques are rightfully receiving
increased attention, given their success in diagnosing and treating
conditions such as pulmonary venous
ectopy.16 17 In
addition, more widespread application of techniques like
signal-averaged ECG, fast Fourier transforms, high-resolution mapping,
and autonomic testing should be
explored.
- Fast Fourier transforms. Digital analysis
of surface, endocardial, or epicardial electrograms recorded during AF
has already provided useful clinical information in some patients.
Fibrillatory oscillations can be analyzed in detail, especially after
the QRS-T deflections have been eliminated by subtraction techniques.
Frequency and morphology analyses can demonstrate the origin of the
most rapid atrial activity, information that can then guide assessment
of the mechanisms of the initiation and maintenance of
AF.
- High-resolution mapping. Activation maps
can be constructed during sinus rhythm or AF. Maps during sinus rhythm
may reveal areas of abnormal conduction or refractoriness that might
point to the need for a specific therapy, eg, ablation or pacing.
During ongoing AF, activation maps might demonstrate areas of rapid
focal activity, frequently engaged reentrant pathways, or areas of
consistent activation and organization that give clues to mechanism of
the arrhythmia and its therapy. Increasingly detailed high-resolution
technologies are now being deployed to map the atrial endocardium
rapidly. Epicardial mapping from the right pulmonary artery, esophagus,
and pericardial space is now being
developed.
- Autonomic testing. Autonomic tone can be
investigated by baroreceptor sensitivity testing, analysis of heart
rate variability, and posture- or exercise-induced or spontaneous
changes in heart rate. Considering autonomic input is important,
because it may contribute significantly as a trigger as well as to
alteration of the atrial substrate.
Importantly, each comorbidity factor does not
specifically target ion channel, gap junctional, or
electrophysiological substrates but diversely affects myocardial
structure and contractile function. Hence, exploration of potential
interventions needs to become more far ranging and should take into
account the observation that different interventions are of varying
effectiveness at different times in the evolution of AF. Therefore, we
make the following
suggestions.
- More active investigation is needed of the role of
angiotensin II as a possible signal transduction factor and of ACE
inhibition and angiotensin II receptor blockade in delaying onset and
preventing recurrences of
AF.90 That ACE inhibition
appears to reduce the incidence of
AF90 91 may
result from actions on the cardiac signal transduction cascades of
angiotensin II but also could occur via effects on hemodynamic load. If
ACE inhibitors slow or reverse mechanical remodeling and create more
homogeneous contraction patterns, this would promote homogeneous
mechanoelectric coupling and reduce electrophysiological dispersion.
Other hypertrophic and arrhythmogenic hormones (eg, endothelin,
catecholamines) also need study in greater
detail.
- More information is needed regarding why calcium
blockade shows mixed results as a preventive
measure.92 93 In
an animal model, verapamil delays the shortening of the atrial ERP
during the first 24 hours of rapid atrial
pacing.92 However, after a
longer period of rapid pacing or AF, verapamil no longer has a
preventive effect.94
Nonetheless, clinically, calcium-lowering drugs may reduce the number
of early recurrences of AF after
cardioversion.92 Increasing
the complexity here is that the shortened AP of remodeling atria is
restored to normal by an ICa, L
agonist.66 Although this
might suggest the use of calcium agonists as a preventive intervention,
these agents can induce early afterdepolarizations and torsade de
pointes.95 Clearly, the
complex changes in calcium handling in AF constitute one of the keys to
formulating new approaches to prevention.
- Metabolic status before AF onset may influence the
propensity of atrium to undergo electrophysiological remodeling once AF
begins. Interventions that alter the redox state of fibrillating atria
may prevent the short-term electrophysiological remodeling that
accompanies AF initiation and decrease the propensity of AF to
reinitiate after cardioversion. Moreover, the time required to recover
normal electrophysiological function on termination of AF may relate to
its metabolic state at that time, as well as to factors such as
autonomic
remodeling.96
- The basis for the initial success and ultimate
failure of antiarrhythmic drugs and their inconsistencies in
prevention93 97
must be better understood. Do channel changes evolve to a point beyond
the range at which antiarrhythmic drugs can be expected to be
effective, or is there excess fibrosis and/or uncoupling of gap
junctions? It is possible that AF prevention may be achieved with
better ion channeltargeted drugs. Not only might new drugs like
ibutilide, dofetilide, and azimilide effectively supplement the
existing armamentarium, but given the important downregulation of
IKur and ICa, L in
remodeled
atria,62 63
development of atrium-selective drugs that upregulate or open these
channels might be appropriate.
- As the role of mechanoelectric coupling in AF is
defined, additional targets can be identified. One is the transducer
residing in SACs, although extensive drug discovery is required to
permit clinically rational approaches. The cytoskeleton may be an
opportune target, given its mechanical linkage to SACs and other
mechanosensitive signal sources. Because depolymerization of
cytoskeletal F-actin filaments promotes stretch-induced
AF,98 cytoskeletal
stabilizers may curtail AF.
- We must learn whether molecular genetic information
from families with congenital AF characterizes only those who are
biallelic for genes that confer susceptibility and whether and to what
extent genetic heterogeneity may contribute to acquired disease. It is
likely that information gained from studying such families will provide
leads for discovering more widespread DNA alterations detectable in the
general population via soon-to-be-available screening techniques.
Potential genetic associations with age, sex, disease, and other
determinants of AF may provide highly sensitive identifiers of risk and
new means for prevention.
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Conclusions
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Modalities selected for prevention ultimately depend on
risk
stratification.
Table 3

overviews approaches currently used
and being
explored clinically. Primary prevention of AF is difficult
to comment
on, because it requires stratification of risk factors
with better
selectivity and sensitivity than are now the case.
It calls for
preventive measures for patients in whom risk factors
are present but
AF has not been documented. When a causative
disease is diagnosed,
primary prevention rests largely on treatment
of that disease. When no
disease is identifiable but a risk
factor is present and evolving (eg,
pulmonary venous foci inducing
paroxysmal AF), novel means for
prevention based on some of
the approaches discussed above need be
identified and tested
for therapeutic potential.
Secondary prevention of AF incorporates approaches that
maintain patients with paroxysmal or persistent AF in sinus rhythm.
Most of the approaches in
Table 3
are used clinically today. Those not explored or
not sufficiently explored include ACE inhibitors and angiotensin II
receptor blockers, calcium blockers, and pacing, as well as some of the
experimental approaches mentioned above. With respect to permanent AF,
the only methods currently in use or on the horizon involve surgical or
catheter maze procedures to restore regular atrial rhythms.
Finally, it is equally important to understand when
preventive measures no longer can be expected to succeed and a point of
no return has been reached. Ideally, this point of no return should be
identified by objective pathophysiological markers supplementing
clinical judgment. With this in mind, studies focusing on the time
course and extent of structural change, fibrosis, and apoptosis may be
valuable in determining when efforts to restore sinus rhythm have no
expectation of
success.
 |
Acknowledgments
|
|---|
This work was supported by an
educational grant from Procter
and Gamble to the Partnership for
Womens Health at Columbia
University. This article summarizes results
from a meeting held
on Ile de Porquerolles, France, September 27,
1999, cosponsored
by the Council on Basic Cardiovascular Sciences of
the American
Heart Association and the Partnership for Womens Health
at
Columbia University. The meeting was chaired and the manuscript
preparation
was coordinated by Dr Rosen. Discussion sections were
headed
by Drs Allessie, Boyden, Camm, Kléber, and Schwartz.
We
acknowledge with gratitude the contributions of Dr Douglas
Zipes to the
organization of the meeting and the content of
the manuscript, as well
as the critical commentary on the manuscript
provided by Drs Jose
Jalife and Stanley Nattel. We also express
thanks to Eileen Franey for
her attention to detail in administration
of the meeting and
preparation of the manuscript and to Dr Roger
Karam for facilitating
support of the meeting.
 |
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