REVIEW ARTICLE
Stanley Nattel*, MD Montreal Heart
Institute Research Center, Department of Medicine,
Montreal Heart Institute and University of Montreal,
Montreal, Quebec, Canada
Atrial fibrillation is a condition in which
control of heart rhythm is taken away from the
normal sinus node pacemaker by rapid activity
in different areas within the atria. This results
in rapid and irregular atrial activity and, instead
of contracting, the atria only quiver. It is the
most common cardiac rhythm disturbance and contributes
substantially to cardiac morbidity and mortality.
For over 50 years, the prevailing model of atrial
fibrillation involved multiple simultaneous re-entrant
waves, but in light of new discoveries this hypothesis
is now undergoing re-evaluation. Atrial fibrillation
(AF) is characterized by rapid and irregular activation
of the atrium, for example, 400–600 pulses of
the atrium muscular wall per minute in humans.
The occurrence of AF increases with age, with
a prevalence rising from 0.5% of people in their
50s to nearly 10% of the octogenarian population1,
2. Several cardiac disorders predispose to AF,
including coronary artery disease, pericarditis,
mitral valve disease, congenital heart disease,
congestive heart failure (CHF), thyrotoxic heart
disease and hypertension. Many of these are thought
to promote AF by increasing atrial pressure and/or
by causing atrial dilation; however, the precise
mechanisms linking the various diseases to AF
genesis are incompletely defined. AF also occurs
in individuals without any other evidence of heart
or systemic disease, a condition known as “lone
AF.”
Normally, heart rate is finely attuned to
the body’s metabolic needs through physiological
control of the cardiac pacemaker function of the
sinoatrial node (Fig. 1a), which maintains a rate
of about 60 beats per minute at rest and can fire
as rapidly as 180–200 times per minute at peak
exercise. During AF, atrial cells fire at rates
of 400–600 times per minute. If each atrial impulse
were conducted to the ventricles, the extremely
rapid ventricular rate would lead to ineffective
cardiac contraction and rapid death. This is prevented
by the filtering function of the atrioventricular
(AV) node (Fig. 1b), which has a limited impulse-carrying
capacity and through which atrial impulses must
pass before activating the ventricles.
The ventricular
rate during AF (the effective ‘heart rate’) is
thus no longer under physiological control of
the sinus node, but instead is determined by interaction
between the atrial rate and the filtering function
of the AV node. The ventricular rate during AF
is typically in the region of 150 pulses per minute
in the absence of drug therapy. In normal individuals,
a brief period of AF may cause palpitations, chest
discomfort and light-headedness. Sustained AF
with an uncontrolled ventricular response rate
can, by itself, cause severe CHF after several
weeks to months, but this is reversible with proper
rate and/or rhythm control 3.
Owing to the loss
of effective atrial contraction, and the irregular
and excessively rapid ventricular rhythms that
can be caused by AF, acute and sometimes life-threatening
decompensation of otherwise compensated cardiac
disease may occur. The loss of atrial contraction
also leads to stasis of blood in the atria, which
promotes clot formation and the occurrence of
thromboemboli. These thromboemboli tend to propagate,
particularly to the brain but also to other organs
(including the kidneys, mesenteric circulation
and the heart itself), potentially leading to
infarction. The thromboembolic risk is reduced
by administration of oral anticoagulant drugs,
but at the price of an increased risk of bleeding
complications. These considerations probably account
for the significant role of AF in the occurrence
of stroke: AF is the single most important cause
of ischaemic stroke in people older than 75 years4.
Fig. 1. Diagram of electrical activity during
atrial fibrillation. a, Normal rhythm; b, atrial
fibrillation. Representative action potentials
are shown from the sinoatrial node (SAN), atrium,
AV node and ventricles. The vertical line on each
action potential recording corresponds to a common
time reference. LA, left atrium; LV, left ventricle;
RA, right atrium; RV, right ventricle.
Cardiac arrhythmias have been treated traditionally
with antiarrhythmic drugs that control the rhythm
by altering cardiac electrical properties. However,
the available drugs are not specific for atrial
electrical activity and can have profound effects
on ventricular electrophysiology. For example,
K+-channel-blocking drugs that are used to treat
AF can mimic potentially lethal congenital disorders
of cardiac repolarization, as discussed by Marban
(Nature 2002;415:213-218). It has become apparent
over the past 15 years that the effects of antiarrhythmic
drugs on the electrophysiology of the ventricles
can themselves paradoxically lead to life-threatening
rhythm disorders (so-called ‘proarrhythmia’) and
increase mortality5. There has been, therefore,
a shift towards non-pharmacological therapies
for cardiac arrhythmias, including controlled
destruction of arrhythmia-generating tissue (‘ablation
therapy’) and implantable devices that can sense
arrhythmias and terminate them with controlled
electrical discharges. In contrast to a wide range
of other cardiac arrhythmias, for which safe and
highly effectivenon-pharmacological therapies
have been developed,AF continues to be a challenge
for both pharmacological and non-pharmacological
approachesto treatment6, which has motivated a
search for improved treatment modalities. One
hope is thatabetter understanding of the fundamental
mechanisms underlying AF will lead to safer and
moreeffective mechanism-based therapeutic approaches.
Here I review the recent evolutionofour understanding
of the mechanisms of AF, highlighting experimental
findings that have produced new insights and questions
about the theory of the arrhythmia. In addition,
I discuss the potential implications of this knowledge
for therapeutic innovation.
To aid in the comprehension of
AF mechanisms, the basic electrophysiological
mechanisms of arrhythmia are presented in Fig.
2. Abnormal impulse formation can lead to focal
ectopic (that is, arising from an area other than
the sinus node) arrhythmia generators (Fig. 2a,b).
Figure 2a illustrates the mechanism of ‘automaticity’,
which is the basis of cardiac pacemaker function.
Various areas of the heart can show automaticity,
but cardiac rhythmicity is normally controlled
by the sinus node, which is intrinsically the
fastest pacemaker.
Inward currents (positive ions
entering the cell)
Fig.2. Cellular mechanisms of atrial arrhythmia
generation. a, Normal ‘automaticity’ occurs when
a spontaneously depolarizing cell reaches threshold
potential and fires (1). When the rate of depolarization
increases, abnormally rapid firing will occur
(2). b, Afterdepolarizations are depolarizations
caused by excessively large inward currents carried
by the Na+/Ca2+ exchanger (2). If afterdepolarizations
are large enough to reach threshold, premature
ectopic action potentials result (3) before the
next expected normal action potential (1). c,
Re-entry occurring between two tissue zones, I
and II, which are connected as shown on the right.
A premature activation (2) in zone II, which fails
to initiate firing in zone I because zone I is
still refractory, may conduct back (red dashed
line) to zone I at a time when it can respond
with an action potential (3). This action potential
may propagate to initiate (4) in zone II, and
the process can continue indefinitely. RP, refractory
period; TP, threshold potential.
depolarize the cell membrane (making
the cell interior more positive), and outward
currents repolarize it (making the cell interior
more negative). Pacemaker activity results from
a change in the balance of cardiac currents in
the resting (diastolic) phase of the action potential,
such that inward currents predominate and lead
to progressive diastolic depolarization. When
the membrane potential reaches a critical value,
called the ‘threshold potential’, the cell fires
(Fig. 2a, 1). If the slope of diastolic depolarization
is increased in a region outside the sinus node
(for example, by acute myocardial ischaemia; Fig.
2a, dashed line), the cell will reach threshold
earlier and generate ectopic action potentials
(Fig. 2a, 2) at a rapid rate.
Abnormal focal activity
can also arise from ‘afterdepolarizations’ (Fig.
2b). As discussed in detail by Bers (Nature 2002;415:198
– 205), the free intracellular Ca2+ concentration
rises sharply during the depolarized (systolic)
phase of the action potential, and diastolic relaxation
ensues when cytosolic Ca2+ is reduced by uptake
into the sarcoplasmic reticulum and by extrusion
from the cell through transmembrane Na+/Ca2+ exchange
(NCX). The latter process is electrogenic, exchanging
three Na+ ions for each Ca2+ (one net positive
charge moves in the direction of Na+ transport
in each cycle), and produces an inward current
during Ca2+ extrusion. This inward current can
depolarize the cell, generating an afterdepolarization(Fig.2b,2).If
afterdepolarizations reach the threshold potential
(Fig. 2b, 3), spontaneous action potentials will
result, producing ectopic firing if they arise
in tissues outside the sinus node. This form of
afterdepolarization is favoured by conditions
that increase NCX current, such as excessive intracellular
concentrations of Ca2+ and enhanced NCX activity.
Re-entry arises from abnormal impulse propagation
between different zones of tissue (Fig. 2c, I
and II). After initial depolarization of an action
potential, Na+ channels are inactivated and the
cell cannot be re-fired until the cell repolarizes
to a potential (about –60 mV) at which Na+ channels
recover from inactivation — a time referred to
as the ‘refractory period’. An ectopic complex
(Fig. 2c, 2) arising in zone II during the refractory
period of action potential 1 in zone I will initially
fail to activate zone I, but may propagate through
an alternative pathway to return to zone I when
its refractory period is over, causing reactivation
at this site (Fig. 2c, 3). The impulse will now
leave zone I and move towards zone II and, if
the time to return to zone II is sufficiently
long, then zone II will be reactivated (Fig. 2c,
4). If the conditions are correct (that is, there
is an appropriate substrate for re-entry), zones
I and II can repeatedly reactivate each other
once re-activation has been initiated, resulting
in persistent re-entrant activity. Re-entry can
occur in a single circuit, producing rapid regular
firing, or multiple unstable re-entry circuits
can coexist simultaneously, producing more irregular
(fibrillatory) activity. The refractory period
is clearly a key determinant of re-entry — long
refractory periods make it more likely that the
circulating impulse will encounter tissue that
is still refractory and will die out.
fibrillation The conceptual framework
for understanding AF mechanisms has been grounded
in ideas developed in the early twentieth century7.
The principal competing notions at the time were
that AF is caused by rapidly discharging, spontaneously
active, atrial ectopic foci (Fig. 3a), by a single
re-entry circuit (Fig. 3b), or by multiple functional
re-entrant circuits (Fig. 3c). For multiple-circuit
re-entry excitation (Fig. 3c), irregular atrial
activity is a consequence of the primary arrhythmia
mechanism. For the rapid focal and single-circuit
mechanisms, irregularity is presumed to result
from interactions between high-frequency wavefronts
produced by the primary generator (the ectopic
focus or primary re-entrant circuit) and the spatially
variable refractory properties of atrial tissue
(‘fibrillatory conduction’). These mechanisms
have significant implications for potential therapies.
Multiple-circuit re-entry should be amenable to
interventions that interfere with the ability
of the re-entering circuits to perpetuate themselves.
Such interventions include drugs that increase
the refractory period and surgical division of
the atria into electrically isolated areas, as
exemplified by the ‘Maze’ procedure8. Ectopic
mechanisms would be susceptible to drugs that
suppress automaticity and to targeted destruction
of ectopic foci by surgery or catheter-based approaches.
Single-circuit re-entry should be suppressed by
drugs that prolong the refractory period and inhibit
re-entry, and by ablating key components of the
re-entrant pathway. Over the past 50 years, multiple-circuit
re-entry has been the dominant conceptual model
of AF. The ectopic focus and single-circuit concepts
fell largely into disfavour. Particularly influential
has been the work of Moe and co-workers9, who
emphasized the role of multiple re-entrant wavelets
in the perpetuation of AF. An important component
of this theoretical framework is the concept of
the ‘wavelength of re-entry’, as developed by
Allessie and colleagues10,11. The wavelength is
the distance travelled by the electrical impulse
in one refractory period, which is the product
of the refractory period and the conduction velocity.
If the pathlength of the potential circuit is
smaller than the wavelength, the impulse will
traverse the circuit and return to its starting
point in a time shorter than the refractory period,
forcing it to impinge on still-refractory tissue
and die out. Thus, the wavelength is the shortest
pathlength that can sustain re-entry. According
to the ‘leading circle’ hypothesis of Allessie
et al.10 (Fig. 4a), functional re-entry
Fig. 3. Conceptual models of atrial
fibrillation in the early twentieth century, along
with therapeutic implications. Ectopic foci (a)
and single re-entrant circuits (b) generating
atrial fibrillation can be located in either atrium,
but are shown here as arising in the right atrium.
In c, atrial fibrillation is maintained by multiple
re-entry circuits with spatial and temporal variability.
LA, left atrium; RA, right atrium; RP, refractory
period.
Fig.4. Models of re-entry and implications
for atrial fibrillation. a) Mechanism of functional
re-entry in the leading circle model10. b) Spiral
wave model of re-entry. c) Role of wavelength
in the stability of atrial fibrillation according
to the leading circle model. The size of functional
re-entry circuits depends on the wavelength. Short
wavelengths allow several simultaneous circuits
to be maintained, favouring continuation of atrial
fibrillation. Drugs that increase the wavelength
reduce the number of circuits that can be accommodated,
favouring termination of atrial fibrillation.
CV, conduction velocity; PL, path length; RP,
refractory period; WL, wavelength.
naturally establishes itself in
a pathlength the size of the wavelength. The number
of re-excitation waves that can be accommodated
is then a simple function of atrial size and the
wavelength: decreased wavelength decreases the
minimum circuit size, which increases the number
of circuits that can be accommodated, which in
turn favours multiple-circuit re-entry and tends
to perpetuate AF (Fig. 4c). Traditionally, therefore,
the primary approach to AF has been to increase
the refractory period (and thereby the wavelength),
which limits the number of functional circuits
that can be maintained so that AF cannot sustain
itself. An observation incompatible with leading
circle theory is the response of AF to antiarrhythmic
drugs that block Na+ channels. Such agents are
effective in terminating AF, but according to
leading circle theory should promote AF because
they decrease conduction velocity and thereby
decrease the wavelength.
Observations obtained over the
past 5 years have challenged the previously prevailing
notion that all AF is caused by multiple-circuit
re-entry. Optical mapping studies of AF in sheep
hearts point to a primary local generator, consisting
of either a single small re-entry circuit or an
ectopic focus12, 13. Left atrial sources of activity
seem to be particularly important12-14. Left atrial
predominance may be related to the location of
the pulmonary veins in the left atrium, which
seem to have a highly significant role15 (see
below), or to ionic differences that lead to shorter
left atrial refractory periods that favour re-entry16.
There is also evidence to show that single-circuit
re-entry maintains AF in experimental CHF17, 18.
Thus, the recently evolving evidence has thrown
us back to the debates of the early twentieth
century, suggesting that ectopic activity, single-circuit
re-entry and multiple circuit re-entry may all
be involved in AF.
Evolving clinical evidence shows that AF almost
invariably occurs in a setting of atrial electrical
dysfunction that provides a favourable substrate
for the arrhythmia. Transmembrane ionic currents
are key determinants of the arrhythmia mechanisms
shown in Fig. 2. Figure 5a shows a representative
human atrial action potential.
Fig.5. Ionic determinants of atrial fibrillation.
a) Action potential showing the principal currents
that flow in each phase, with the corresponding
subunit clones shown in parentheses. b) The substrate
for re-entry is governed by the refractory period
and the conduction velocity. The refractory period
depends on the action potential duration (APD),
which is governed by the intrinsic ionic current
properties of atrial tissue. Conduction properties
are determined by the function of Na+ channels
and connexins. Reductions in outward currents
increase the refractory period, prevent re-entry
and oppose atrial fibrillation. Reductions in
inward current and increases in outward current
reduce the refractory period and promote atrial
fibrillation. Increased Na+/Ca2+ exchange promotes
afterdepolarization-related ectopic activity,
which can trigger re-entry in the presence of
an appropriate substrate or cause atrial tachycardias
that induce electrical remodelling and produce
a re-entry substrate. Activation of stretch-induced
channels can promote both ectopic activity and
re-entry. Cx40, connexin 40; CHF, congestive heart
failure.
Inward (depolarizing) currents are indicated
by a downward arrow and outward (repolarizing)
currents by an upward arrow. IK1 is the background
current responsible for the considerable resting
K+ conductance that sets the resting potential
to between -70 and -80 mV. Cell firing is caused
by rapid depolarization through a large Na+ current
(INa) that brings the cell from its resting potential
to a value in the region of +40 mV, providing
the electrical energy for cardiac conduction.
The cell then partially repolarizes through a
transient outward K+ current (Ito), inactivation
of which produces a notch in the action potential.
This is followed by a relatively flat portion
of the action potential (the ‘plateau’), which
is maintained by an inward L-type Ca2+ current
(ICa). A series of K+ currents that activate in
a time-dependent way and show little inactivation
— the so-called ‘delayed rectifiers’ (IK) — leads
to cellular repolarization. In human atrium, IK
has three components: an ‘ultra-rapid’ component
(IKur), a ‘rapid’ component (IKr) and a ‘slow’
component (IKs). Spontaneously automatic cells
are depolarized by an inward pacemaker current
(If). NCX also carries an inward current during
terminal repolarization and for a short time thereafter.
The balance between plateau inward and outward
currents determines the action potential duration
(APD): increased inward current prolongs the action
potential, and increased outward current abbreviates
it. APD governs the time from cellular depolarization
to recovery of excitability at about -60 mV; the
ionic current balance therefore determines the
refractory period and the likelihood of re-entry.
Alterations in ionic currents that increase APD
and thereby the refractory period can be used
to prevent AF. For example, many clinically used
drugs prolong APD and refractoriness by inhibiting
IKr. They are effective in preventing AF, but
can produce dangerous ventricular arrhythmias
by interfering with ventricular repolarization
(Marban. Nature 2002;415:213 – 218). IKs and IKur
are under strong adrenergic control19, and their
stimulation might contribute to AF that occurs
in situations of increased adrenergic tone. IKur
is carried by Kv1.5 channels that are expressed
functionally in human atrium but not ventricle
— inhibiting these channels may provide a means
of preventing AF without the risk of ventricular
proarrhythmia20-22. An important advance in our
understanding of AF was made with the recognition
that AF, once initiated, alters atrial electrophysiological
properties in a manner that favours the ease of
Fig. 6. Changes in cell Ca2+ loading caused
by atrial fibrillation and consequent adaptive
responses. Adaptations to atrial tachycardia decrease
Ca2+ loading by reducing ICa, but at the expense
of a shorter action potential duration (APD) and
a greater propensity for atrial fibrillation.
RP, refractory period.
inducing and maintaining the arrhythmia — a process
called "electrical remodeling"23. The principal
mechanisms involved are shown in Fig.6. The roughly
tenfold atrial rate increase caused by AF is the
primary stimulus to remodelling, and similar changes
are produced by any form of sufficiently rapid
atrial tachycardia24. Ca2+ enters the cells through
ICa with each action potential, so a tenfold increase
in atrial rate substantially increases cellular
Ca2+ loading25.
Progressive Ca2+ loading threatens
cell viability, and the cells respond to minimize
the impact of increased rate on intracellular
Ca2+ load. Short-term defence mechanisms include
voltage-dependent and intracellular Ca2+-concentration-dependent
inactivation of ICa26. Over the longer term, the
concentration of messenger RNA encoding the pore-forming
subunit27-29 decreases, which in turn decreases
ICa30–32. Both short- and long-term decreases
in ICa reduce Ca2+ entry and help to prevent Ca2+
overload; however, because ICa is a key contributor
to the action potential plateau (Fig. 5), reduced
ICa decreases APD, reduces the refractory period,
and promotes the induction and maintenance of
AF by multiple-circuit re-entry33. AF that begins
by any mechanism causes electrical remodelling,
which by promoting multiple-circuit re-entry will
make this a “final common pathway" of AF irrespective
of the initial mechanism (Fig. 7).
In addition
to downregulating ICa, AF induces many other changes,
consistent with a substantial cellular insult
caused by excessively rapid activation. Cellular
Ca2+ handlingisaltered, decreasing the release
of systolic Ca2+(ref 34)in association with altered
concentrationsof intracellular Ca2+-handling proteins29,
35. Cellular myolysis occurs, along with changes
that suggest a return to a more fetalphenotype36.
Decreased release of systolic Ca2+ and myolysisimpairatrial
contractility, contributing to the occurrence
of atrial blood stasis and thromboembolic events
after termination of AF37. INa seems to be decreased,
possibly contributing to a slowly developing decrease
in atrial conduction that may help to promote
AF33, 38. Ito is decreased30, 32, 39 and IK1 may
be altered32, 39; however, the physiological significance
of these changes in K+ current are currently unclear.
Finally, AF has been associated with altered expression
of connexin channel proteins that govern intercellular
electrical communication40-42. There is evidence
for spatially heterogeneous reductions in expression
of connexin 40 (ref. 41), but the results of available
studies have been inconsistent40-42 and the significance
of these changes in connexin remains unclear.
Experimental CHF also promotes AF and produces
atrial ionic remodelling43. In CHF, inward ICa
is reduced much less than in atrial tachycardia
remodelling. Outward IKs, which is unaffected
by atrial tachycardia, is decreased by about 30%
and inward NCX is increased43. Thus, unlike atrial-tachycardia-induced
ionic remodelling, CHF-induced remodelling does
not reduce APD and does not in itself favour re-entry.
By contrast, CHF changes the architecture of atrial
tissue, causing a substantial increase in fibrous
tissue content (fibrosis) within and between muscle
bundles, which interferes with electrical conduction
and causes AF that often seems to be due to single-
Fig. 7. A synthesis of recent advances in our
knowledge of the substrates for atrial fibrillation.
Although the competing mechanisms postulated in
the early twentieth century (Fig. 1) remain at
the centre of our understanding of atrial fibrillation
mechanisms, we have begun to appreciate better
the determinants of their occurrence and the extent
to which the various mechanisms interact with
one another. APD, action potential duration; LA,
left atrium; NCX, Na+/Ca2+ exchange; RA, right
atrium; WL, wavelength; RP, refractory period.
circuit re-entry17,18,44. In addition, the increased
NCX promotes afterdepolarization-related atrial
ectopic firing and AF45. Figure 5 summarizes the
ionic determinants of AF, including both intrinsic
and extrinsic determinants.
Alt hough electrical remodelling
accounts for the self-promoting nature of AF once
it has begun, other factors must lead to the initial
occurrence of AF. Individuals affected with AF
are known to have upregulated levels of atrial
extracellular signal-related kinase (ERK) and
angiotensin-converting enzyme (ACE)46, but a decreased
density of angiotensin-II type 1 receptors and
an increased density of angiotensin-II type 2
receptors47. Carboxypeptidase activity and protein
levels are also decreased in chronic AF48. Atrial
tissue from AF-affected individuals shows both
nuclei that are positive for TUNEL (terminal deoxyribonucleotide
transferase-mediated dUTP nick end labelling)
and increased concentrations of the apoptotic
enzyme caspase-3, which suggests that apoptosis
is occurring49. In experimental CHF, the promotion
of AF is preceded by increased atrial concentrations
of angiotensin-II and by activation of mitogen-activated
protein kinases including ERK50. A rise in atrial
caspase-3 concentration, associated with infiltration
of white blood cells, apoptosis and cell death,
is seen early in experimental CHF and is followed
by progressive fibrosis51.
These results suggest that,
in CHF, atrial cell death pathways are activated,
followed by replacement fibrosis, which promotes
intra-atrial re-entry. Inhibition of ACE reduces
CHF-induced activation of ERK and fibrosis, and
also decreases the AF-promoting effects of CHF50.
The effectiveness of ACE inhibition shows that
interrupting signalling pathways can prevent development
of the AF substrate — a process that might potentially
be used in new therapeutic approaches. A recent
study supporting this notion showed that ACE inhibition
reduces the incidence of AF after myocardial infarction
in people with left ventricular dysfunction52.
Atrial fibrillation can occur on
a familial basis, pointing to a genetic cause
of the arrhythmia in some individuals53. Linkage
analyses have identified possible loci on chromosome
10 in two kindreds54. Identifying the gene of
susceptibility, coupled with defining the sequence
and function of the protein that it encodes, has
the potential to provide both insight into the
pathophysiology of the arrhythmia and diagnostic
tools with which to identify susceptible individuals.
Studies of transgenic mouse
models of AF are still in their infancy but promise
to advance our understanding of the role of defined
genes in the pathophysiology of the arrhythmia.
Mice with a homozygous deficiency in the gene
encoding connexin 40 have slowed intra-atrial
and AV nodal conduction, along with inducible
atrial tachyarrhythmias55. Mice overexpressing
cardiac RhoA, a low molecular-weight GTPase, develop
atrial fibrillation and AV block, and show progressive
deterioration of ventricular function56. Mice
with cardiac overexpression of a constitutively
activated form of transforming growth have atrial
but not ventricular fibrosis57. In addition, preliminary
data suggest that these mice are susceptible to
AF58, compatible with the notion that atrial fibrosis
is an important AF-promoting factor.
The molecular events leading to ionic
remodelling remain incompletely understood. On
the basis of evidence indicating that Ca2+ overload
has a central role in AF, the efficacy of ICa
blockers in atrial tachycardia remodelling has
been studied. L-type Ca2+-channel blockers are
effective in short-term remodelling59-61, but
are ineffective in remodelling caused by longer
periods of atrial tachycardia62, 63. Mibefradil,
a drug that blocks both L-type Ca2+ channels and
the high-threshold T-type Ca2+ channels, prevents
atrial tachycardia remodelling effectively, but
it remains uncertain whether this action is due
to inhibition of ICa or to collateral drug actions63,
64. The T-type Ca2+ current has been difficult
to demonstrate in human atrial myocytes65. Recent
work has suggested that oxidant stress may be
involved in atrial tachycardia remodelling, and
that ascorbic acid may be beneficial in preventing
AF that occurs after cardiac surgery66.
Another important advance in our
understanding of the pathophysiology of AF has
been the demonstration by Haissaguerre et al.15
of the importance of pulmonary vein foci in initiating
arrhythmia. AF may begin as a rapid atrial tachycardia
from the pulmonary veins, with tachycardia remodelling
promoting the transition to multiple-circuit re-entry
AF67. Ectopic foci from other sources, such as
the ligament of Marshall (a venous remnant in
the left atrium)68 and the superior vena cava69,
may also be important in initiating AF, although
pulmonary veins remain the most common source
of focal activity. More recently, rapid pulmonary
vein activity has been shown to be promoted by
atrial tachycardia remodelling70, and to have
a role in maintaining (and not just initiating)
AF71, 72.
The underlying basis of pulmonary
vein activity remains poorly understood. In 1981,
Cheung73 showed that cardiac tissue in the sleeves
around the proximal ends of pulmonary veins can
generate action potentials and shows slow spontaneous
activity. The rate of pulmonary vein activity
can be greatly accelerated by adrenergic stimulation74.
It is not yet clear whether the pulmonary veins
have a role that is limited to action potential
generation, or whether (owing to the geometric
arrangement of cardiac fibres around the veins
or because of strands of poorly coupled cardiac
tissue overlying vascular smooth muscle) they
provide preferential zones for re-entry.
The pulmonary veins are subjected
to stretch from pulsatile blood flow. The stretch-induced
non-selective cation current (Ins-st) can carry
Na+ into the cell or K+ out. It depolarizes the
cell at the resting potential (favouring ectopic
activity) and repolarizes it during the depolarized
phase positive to 0 mV, decreasing APD and promoting
re-entry. Ins-st may have a role in AF initiation
in the pulmonary veins or other atrial tissues
subjected to stretch. A tarantula toxin that specifically
inhibits Ins-st suppresses AF related to acute
stretch in rabbit hearts75. The toxin may prove
useful as an experimental tool, as well as a lead
for antiarrhythmic agents that specifically antagonize
stretch-related electrophysiological perturbations.
There is a clinical association
between abnormalities of sinoatrial (SA) node
function and AF. At one time, this observation
and the characteristic slow conduction within
the sinus node led investigators to speculate
that the sinus node might be involved in maintaining
the arrhythmia. The data available at present
suggest that the sinus node is probably passive
during AF, with atrial impulses invading the SA
node at a rate much faster than its intrinsic
frequency (Fig. 1). The association between sinus
node dysfunction and AF is probably due to diseases
that affect both the SA node and atria simultaneously,
rather than participation of SA node pathology
per se in AF.
Recent work has provided exciting
insights into the molecular basis of the pacemaker
current If. A family of cyclic-nucleotide-binding
subunits, called the HCN family, underlies If
function in the sinus node and other cardiac regions76.
Further work on HCN channels may provide interesting
insights into the molecular basis of normal and
abnormal cardiac pacemaker function, and may provide
important knowledge regarding the pathophysiology
of AF and other cardiac arrhythmias.
The development of ‘spiral wave’
theory has provided a new model for the fundamental
properties of cardiac re-entry 77 (Fig. 4b). According
to this theory, re-entry is maintained through
the ability of circulating spiral waves to perpetuate
in media with sufficient excitability to support
the angle of spiral curvature. Evidence has been
provided for a non-activated, excitable core at
the centre of re-entry circuits during AF78 —
as predicted by spiral wave theory — in contrast
to the constantly excited and refractory tissue
predicted by leading circle theory (Fig. 2a).
Recent work using a two-dimensional
computer model of AF that is based on realistic
atrial cellular ionic properties suggests that
Na+ blockade may terminate AF by reducing excitability,
thereby causing the spiral wave activity that
maintains AF to die out despite a decrease in
the wavelength79. This theoretical work can account
for recent experimental observations of the action
of class I antiarrhythmic drugs in AF80.
The sole, multiple-circuit re-entry
mechanism for AF, which was the predominant notion
for about 50 years until the mid-1990s, has been
challenged by more recent work showing the complexity
of AF mechanisms and the validity of competing
concepts proposed in the early twentieth century.
Furthermore, the inter-relationships among AF
mechanisms and the determinants of their occurrence
have been highlighted (Fig. 7), raising several
new questions. What are the molecular signals
leading from atrial tachycardia to electrical
remodelling? By what signalling mechanisms does
CHF lead to atrial fibrosis and atrial ionic remodelling?
What are the mechanisms of AF associated with
hypertension, coronary artery disease, thyrotoxicosis
and senescence? Why do the pulmonary veins seem
to be so important in initiating, and possibly
maintaining, AF? How does atrial tachycardia affect
pulmonary vein activity? What are the precise,
relative roles of ectopic activity, single-circuit
re-entry and multiple-circuit re-entry in maintaining
clinical AF? What are the genes responsible for
familial AF, and how do they lead to the arrhythmia?
Can improved knowledge of the dynamical basis
of AF lead to pacing modalities that can prevent
or stop the arrhythmia? Can interventions against
remodelling safely and effectively prevent the
development of the substrate for AF?
In the near future, the answers
to these and related questions are likely to increase
our understanding of the mechanisms underlying
AF and to lead to new and improved possibilities
in prevention and therapy.®
Reprinted by permission. Nature 2002;415:219-226.
©2002 Macmillan Publishers Ltd.
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*Director, Cardiac Catheterization Laboratory, Cardiology & Cardiovascular Surgery Dept., Hamad Medical Corporation, Doha, Qatar
Correspondence to: Dr. Stanley Nattel, Montreal Heart Institute Research Center 5000 Belanger St. East Montreal, Quebec H1T 1C8, Canada.
Email: nattel@icm.umontreal.ca
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