Circulation Research. 2000;87:440-447
(Circulation Research. 2000;87:440.)
© 2000 American Heart Association, Inc.
Ionic Remodeling in the Heart
Pathophysiological Significance and New Therapeutic Opportunities for Atrial Fibrillation
Stanley Nattel,
Danshi Li
From the Department of Medicine and Research Center, Montreal Heart
Institute (S.N., D.L.), Department of Medicine, University of Montreal, and
Department of Pharmacology and Therapeutics, McGill University (S.N.),
Montreal, Quebec, Canada.
Correspondence to Stanley Nattel, MD, Research Center, Montreal Heart Institute, 5000 Belanger St East, Montreal, Quebec, H1T 1C8, Canada. E-mail nattel{at}icm.umontreal.ca
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Abstract
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AbstractHeart disease has long
been recognized to alter
cardiac electrical function. Detailed studies
of disease-induced
remodeling of ionic transport processes that
underlie ventricular
electrophysiological
alterations have been
performed over the past 10 years, but
our knowledge of atrial ionic
remodeling is more limited and
has emerged much more recently. The
present review focuses on
recent findings regarding ionic
remodeling at the atrial level,
particularly with respect to two
conditions that promote atrial
fibrillation (AF) in well-developed
clinically relevant animal
models: (1) sustained atrial
tachycardia and (2) ventricular
tachypacinginduced
congestive heart failure. Complementary data from
experimental
models and from observations in atrial tissue samples from
patients
are examined critically and integrated. Consideration is also
given
to potential molecular mechanisms underlying remodeling, the
relationship
between atrial and ventricular ionic
remodeling in response
to similar stimuli, and the potential relevance
of insights
into ionic remodeling for understanding the pathophysiology
of
AF and developing improved therapeutic approaches.
Key Words: ion channels heart arrhythmia mechanisms cardiac electrophysiology heart disease congestive heart failure
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Introduction
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As early as 1930, it was noted that cardiac
K
+ content is altered
in patients with congestive
heart failure (CHF), pointing to
disease-induced changes in ionic
transport mechanisms.
1 In
1961, van Dam and
Durrer
2 recorded electrical activity from
left atrial
appendages of patients with mitral valve disease,
noting functional
abnormalities in patients with sinus rhythm
and an inability to
record activity in patients with grossly
dilated atria and atrial
fibrillation (AF) before surgery. Action
potential abnormalities in
patients with heart disease were
described by Trautwein et al in
1962.
3 The first description
of action potential
abnormalities (including decreased resting
potential and
dV/dt
max and increased action potential duration)
in
an experimental model of heart failure was provided by Gelband
and
Bassett in 1973.
4 The abnormalities in cardiac electrical
activity
associated with heart disease pointed toward changes in ion
channel
function, and in the early 1980s, Ten Eick et
al
5 6 described
alterations in both outward
K
+ currents (decreased inward and
delayed
rectifiers) and inward Ca
2+ currents in diseased
hearts.
Over the past 10 years, great progress has been made in understanding
the ionic remodeling caused by various cardiac pathologies. A
particularly large amount of work has been performed to study ionic
remodeling in the ventricles, with respect to which the interested
reader is invited to consult two recent thorough
reviews.7 8 Less work has been directed to the study of
atrial ionic remodeling. The ionic properties of the atria play an
important role in determining the occurrence and properties of atrial
arrhythmias, particularly AF. The present work reviews the
information available regarding ionic remodeling in the atria under a
variety of pathological conditions. Although ventricular
ionic remodeling is not discussed in detail, attempts are made to
relate atrial remodeling to that in the ventricles under comparable
conditions. Finally, we endeavor to assess the role of atrial ionic
remodeling in the pathophysiology of AF and in the context of possible
new approaches to treating the arrhythmia.
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Ionic Remodeling Induced by AF and Atrial Tachycardia
in Experimental Models
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The possibility that AF might itself produce ionic remodeling
was
suggested by the ingenious work of Wijffels et al.
9 These
authors
maintained AF in chronically instrumented goats with the use
of
a computer algorithm that sensed sinus rhythm and then promptly
applied
a burst of rapid atrial pacing to induce AF. In this
fashion, they were
able to maintain virtually continuous AF
while
simultaneously tracking over time the duration that induced
AF
continued spontaneously until sinus rhythm supervened. AF was
found
to produce rapid decreases in atrial refractory period
(reaching near
maximum within 24 hours) and progressive increases
in spontaneous AF
maintenance, with AF generally becoming persistent
within 1 to
2 weeks. Other studies showed that atrial tachycardia
is a
sufficient stimulus to induce the changes typical of AF-induced
remodeling.
10 11 12
Subsequent work has revealed that many of the AF-promoting effects of
atrial tachycardiainduced remodeling are mediated by
alterations in ion channel function (as schematically summarized in
Figure 1
). Rapid atrial pacing (400 bpm)
in dogs leads to progressive decreases of
Ca2+-independent transient outward current
(Ito) and L-type Ca2+
current (ICa.L) density, by
70% after 6
weeks of tachycardia.13 The dependencies of
current on voltage and time are unaffected. A variety of other
currents, including the inward rectifier
(IK1), ultrarapid
(IKur.d), rapid
(IKr) and slow
(IKs) delayed rectifiers, T-type
Ca2+ current (ICa.T),
and Ca2+-dependent Cl-
current, are unaffected by atrial
tachycardia.13 Inhibiting
ICa.L of a control cell with 10
µmol/L nifedipine mimics many of the action
potential changes produced by atrial tachycardia, whereas
increasing ICa with Bay K 8644 reverses
action potential abnormalities in tachycardia-remodeled
myocytes.13 Mimicking Ito
inhibition with 4-aminopyridine fails to reproduce the
repolarization abnormalities caused by atrial
tachycardia.13

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Figure 1. Role of atrial ionic remodeling in AF promotion by
atrial tachycardia. Note that mibefradil has been shown to
prevent electrophysiological changes (ERP
reduction, AF promotion) caused by tachycardia-induced
remodeling. The level at which mibefradil acts has not been
established. In this Figure , mibefradil action is indicated as proximal
to mRNA downregulation, but this remains to be established. At. Tach.
indicates atrial tachycardia; ERP, effective refractory
period; CV, conduction velocity; and APD, action potential
duration.
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The results of pharmacological studies, as well as those provided by
mathematical models of the action potential,14 15 suggest
that ICa.L suppression is an important
determinant of the action potential duration and refractoriness changes
observed in response to atrial tachycardia. On the other
hand, changes in other ion transport mechanisms have been reported that
may be significant in other areas of atrial function.
There is evidence that rapid Na+ current
(INa) may be downregulated by atrial
tachycardia, with changes that are slower to develop and
quantitatively less important than those in
ICa.L.16 Alterations in
INa correlate with changes in atrial
conduction velocity occurring with maintained atrial
tachycardia,16 and
INa downregulation may therefore contribute
to the decreased atrial conduction velocity commonly associated with
AF. By decreasing wavelength, conduction velocity slowing may also
favor multiple-circuit reentry.
In addition to a decrease in ICa.L, there
is evidence for more extensive abnormalities in cellular
Ca2+ handling with
tachycardia-induced atrial remodeling.
Microfluorescent studies with Indo 1-AM show a decrease in the
amplitude, as well as a change in the kinetics, of
Ca2+ transients in atrial myocytes from dogs
subjected to long-term (7 days or more) atrial
tachycardia.17 These abnormalities
correlate with decreases in cell shortening17 and likely
play a role in the transient hypocontractility (atrial
stunning) observed when persistent AF is converted to sinus rhythm.
Furthermore, the dynamic behavior of action potential duration in
atrial tissues of dogs with atrial tachycardiainduced
remodeling is quite different from the behavior of control action
potentials, but in the presence of the sarcoplasmic reticulum
Ca2+ release inhibitor ryanodine,
control and remodeled action potentials behave more
similarly.18 These findings suggest that
Ca2+ handling abnormalities may contribute to
abnormal dynamic behaviors of tachycardia-remodeled atrial
action potentials.
Connexins are integral membrane ion channel proteins that govern
cell-to-cell communication and conduction. There are conflicting data
regarding changes in connexins in experimental models of AF. Elvan et
al19 showed upregulation of connexin43 expression in dogs
with AF maintained for 10 to 14 weeks by electrical stimulation. van
der Velden et al, 20 on the other hand, found no change in
connexin43 mRNA or protein expression in dogs with AF. Although
connexin40 mRNA and protein levels were similarly unchanged, there were
patchy areas involving
25% of the atria in which connexin40 protein
expression was substantially decreased.20 The same group
subsequently showed evidence for decreases in the ratio between atrial
connexin40 and connexin43 protein that correlate with cellular
myolysis, without any change in connexin40 mRNA levels.21
Transgenic mice completely lacking connexin40 are susceptible to the
induction of atrial tachyarrhythmias, but mice
heterozygous for connexin40 do not show an increased atrial
arrhythmia susceptibility.22 23 The notion that
alterations in connexins contribute to arrhythmogenic ionic remodeling
in AF is thus attractive, but although presently available data are
consistent with such a possibility, they are insufficient to
establish it.
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Ionic Remodeling in Other Experimental Models of Pathology
Associated With AF
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CHF is one of the clinical conditions most commonly associated
with
AF. Atrial action potentials are little changed in animals with
atrial
enlargement due to tricuspid or mitral valve abnormalities
causing
atrial disease.
24 25 In cats with
cardiomyopathies and atrial
arrhythmias,
including AF, right atrial action potentials are
unaltered, but action
potentials tend to be prolonged in tissue
from more severely dilated
left atria.
26 In a recent study
of dogs with a substrate
for AF produced by ventricular tachypacinginduced
CHF,
action potential duration in right atrial cells was unchanged
at low
activation frequencies and increased at higher
frequencies.
27 Membrane resting potential was unaltered.
Several atrial ionic
currents were altered by CHF in the latter study:
IKs and
ICa.L
were
decreased by

30% and
Ito by

50%. The density of
Na
+Ca
2+ exchanger (NCX)
current was substantially increased, as was
the expression of NCX
protein,
27 in contrast to the atrial
tachycardiainduced
substrate in which NCX expression is
unchanged.
28 A variety
of other currents, including
IK1,
IKur.d,
IKr, and
ICa.T,
were
unaltered by ventricular tachypacinginduced
CHF.
27
Hyperthyroidism is a significant clinical cause of AF, but relatively
little is known about the underlying cellular and ionic mechanisms.
Atrial action potential duration is decreased by
hyperthyroidism,29 a change that would be expected to
promote AF. Hyperthyroidism strongly increases
Ito and enhances its temperature dependence
in rabbit ventricle but does not affect rabbit atrial
Ito.30 31
Ventricular ICa appears to be
increased by hyperthyroidism in guinea pigs,32 33 and
atrial tissue samples from patients with latent hyperthyroidism show
increased ICa due to increased
single-channel availability, along with increased
1c subunit protein expression on Western
blot.34
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Ionic Alterations in Patients With Atrial Disease or
Arrhythmias
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Data from animal models of heart disease are crucial for
understanding
the effects of defined cardiac pathologies on atrial
cellular
and ionic electrophysiology; however, extrapolation to humans
must
be cautious. Studies on clinical samples are therefore crucial
but
have the limitation that the results obtained never reflect
the effects
of any single variable: the contributions of organic
heart disease,
rhythm disorders, varying age, and concomitant
drug therapy all need to
be considered. In addition, clinical
samples are almost never of the
size and quality possible in
animal experimentation, and handling
conditions (from excision
to laboratory processing) are often
suboptimal. Thus, experiments
with clinical samples and studies with
experimental animals
provide important complementary information.
Fine-tipped microelectrode action potential recordings in the
1970s showed that diseased human atria have decreased resting membrane
potentials.35 Subsequent work indicated that atrial
specimens from patients with atrial disease have a reduced resting
potential response to
[K+]o,36 37
pointing to decreased resting K+ conductance as
the mechanism of depolarization. The addition of acetylcholine and the
reduction of [Na+]o
improve the resting potential,37 further pointing to
abnormalities in the basal
Na+/K+ conductance ratio.
Koumi et al38 subsequently showed that atrial myocytes of
patients with advanced CHF have reduced IK1
and acetylcholine-dependent K+ current
(IKACh) densities, confirming the
mechanisms inferred previously on the basis of indirect evidence. On
the other hand, Le Grand et al39 found that the
resting potential and IK1 density were not
altered in cells from dilated, compared with nondilated, human atria,
pointing to variability in the IK1 response
in different populations of patients with atrial disease.
Ito is reduced in myocytes of dilated human
atria,39 40 as is the sustained current
(Isus) at the end of a depolarizing
pulse39 carried predominantly by Kv1.5
K+-channel subunits.41 42 Results
regarding ICa.L changes are discrepant,
with two studies showing a decrease39 43 and one no
change44 in patients with severe CHF and/or atrial
dilatation.
A variety of ionic abnormalities have been reported in atrial myocytes
from patients with AF. Van Wagoner et al45 reported a
decrease in atrial Ito and
Isus (along with Kv1.5 subunit protein) in
patients with AF. They also noted an increase in left, but not right,
atrial IK1 density. Bosch et
al46 observed a decreased
Ito and an increase in both
IK1 and IKACh
densities in right atrial myocytes of patients with AF. Two studies
have reported that ICa.L is decreased by
70% in atrial myocytes of patients with persistent
AF,46 47 and that, as in previous experimental
work,13 action potential duration abnormalities typical of
AF can be reproduced by exposing normal myocytes to
ICa.L blockers. A recent study by Grammer
et al48 found Isus to be
unaltered in patients with AF, with the discrepancy from the earlier
study of Van Wagoner et al45 possibly attributable to
differences in patient populations. (Grammer et al48
studied cells from patients undergoing aortocoronary bypass
surgery, whereas the patients in the Van Wagoner et al45
study were undergoing Maze procedures and mitral valve replacement and
generally had quite dilated atria.) In their study of
ICa.L in human atrium, Van Wagoner et
al47 also noted that patients in sinus rhythm at the
time of surgery who subsequently developed AF had larger
ICa density than those that maintained
sinus rhythm throughout their course. This difference could not be
explained by discrepancies in patient age or the degree of cellular
hypertrophy between groups.
 |
Synthesis of Data Regarding Ionic Remodeling and AF From
Studies of Patients and Experimental Animals
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As mentioned above, studies of cells isolated from atrial tissues
of
experimental animals and of patients provide complementary
information.
Both clinical
46 47 and
experimental
13 studies consistently
point to an
important downregulating effect of AF on
ICa.L and
to an important role of
ICa.L downregulation in arrhythmogenic
action
potential abnormalities associated with AF. Decreases in
Ito are also consistently
seen,
13 45 46 although their functional
consequences
for action potential changes and arrhythmia promotion
are
unclear. Changes in inward rectifier currents are inconsistent:
increased
inward rectifier currents in cells from left but not
right atrium
of patients with AF were seen in one
study
45 and from right
atrium in another,
46
whereas
IK1 density was unaltered in an
experimental
study of atrial tachycardiainduced
remodeling.
13 Increased
inward rectifier currents
could contribute to action potential
shortening by AF, so this issue
merits resolution by further
investigation. Observations regarding
ultrarapid delayed rectifier
currents and
Isus are also inconsistent. One
clinical study
found a decrease in
Isus in
AF,
45 whereas another found no
change
48
and
IKur.d was not altered in the canine
model.
13 Differences in patient populations and/or in
the molecular
basis of ultrarapid relayed rectifiers between dogs and
humans
49 may be responsible for the discrepancies
noted.
With respect to the effects of CHF and/or atrial dilation, several
clinical and experimental studies indicate decreases in
ICa.L and
Ito,27 39 40 43 although
individual clinical studies report no change or even an
increase.44 50 Advanced CHF decreases
IK1,38 but this may not
occur with less severe clinical disease39 and is not
observed in an animal model of CHF predisposing to AF.27
NCX upregulation is a prominent feature of atrial ionic remodeling in
the experimental CHF model27 and is typically observed in
failing human hearts,51 although specific data for atrial
NCX expression in patients with heart failure appear to be lacking.
 |
Potential Underlying Molecular Mechanisms
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Atrial tachycardiainduced decreases in
ICa.L,
Ito, and
INa in the dog model of atrial
tachycardiarelated AF quantitatively
parallel changes in
mRNA levels for corresponding pore-forming

subunits,
28 suggesting that transcriptional
downregulation
is a central mechanism of AF-induced ionic remodeling.
Clinical
studies also show a decrease in
1c
Ca
2+ channel subunit mRNA
concentrations in
patients with AF, particularly those with
long-standing (>6 months)
arrhythmia.
52 53 54 55 Substantial
decreases in Kv4.3
mRNA, paralleling changes in
Ito, have also
been
reported in patients with AF, along with unchanged expression
of
Kv1.5 mRNA and the corresponding current
Isus.
48 Few data
are
available regarding other subunits of the L-type
Ca
2+ channel,
but one report suggests that mRNA
encoding
ICa.L ß subunits
may be
downregulated to an extent quantitatively greater than
that of the

subunit.
55 Consistent with transcriptional
downregulation
of channel protein production in AF, decreased
quantities of
Kv4.3 and Na
+ channel

subunits
have been demonstrated in dogs
with atrial-tachycardia
remodeling by Western blot
28 and decreased
ICa channels by
dihydropyridine receptor binding
assays.
56 Protein
measurements in clinical samples
include the demonstration of
decreased
1c
protein by slot blot assay in the Brundel et al
study
53
and in the Van Wagoner et al
45 study of patients
undergoing
the Maze procedure for AF, decreased Kv1.5 subunit protein
expression.
There are presently no data available regarding changes
in ion
channel mRNA or protein expression produced at the atrial level
by
CHF.
There is very little solid information available about the
sequence of signaling events that mediate
tachycardia-dependent atrial remodeling. Indirect evidence
points to a role for Ca2+ overload in short-term
(minutes to hours) remodeling.57 58 Short-term AF (5 to 15
minutes in humans) is associated with refractoriness abbreviation and
promotion of AF induction, effects that can be prevented by the
ICa.L antagonist
verapamil.59 60 The changes induced by
such short-term AF are too rapid to be due to decreased membrane
expression of ion channel proteins and are likely caused by
rate-related changes in ICa.L availability,
largely via Ca2+i-induced
ICa.L inactivation.61
Verapamil reduces refractory period abbreviation caused by
24 hours of rapid pacing in the goat but has minimal effect on
concomitant tachycardia-induced AF
promotion.62 Remodeling induced by longer-duration
tachycardia is not reduced by the L-type
Ca2+ channel blockers diltiazem63 or
verapamil64 but is substantially attenuated by
mibefradil.63 65 Mibefradil blocks T-type
Ca2+ channels in a relatively selective
fashion,66 which may indicate that T-type channels play a
particularly important signaling role in atrial
tachycardiainduced remodeling. On the other hand, the
protection provided by mibefradil could be related in whole or in part
to other actions of the drug, such as collateral
ICa.L blockade,66 effects
on K+ channels,67 or cytochrome
inhibition.68 The
Na+-H+ exchange
inhibitor cariporide,69 the
angiotensin II receptor antagonist
candesartan,70 and the angiotensin-converting
enzyme inhibitor captopril70 reduce short-term
atrial tachycardiainduced remodeling, but their precise
mechanism of action on remodeling and their effects on longer-term
remodeling are unknown.
The effects of drug interventions on tachycardia-induced
remodeling are consistent with an important role for
Ca2+ overload as an early and common signaling
mechanism,71 but this concept remains to be proven. In the
dog model of atrial tachycardiainduced remodeling,
changes in mRNA expression are slow to develop and parallel changes in
ion channel function and protein expression.13 A more
recent study of tachycardia-induced atrial remodeling in
the rat showed rather rapid increases in Kv1.5 mRNA concentration (as
early as 30 minutes after the onset of atrial tachycardia),
with slightly slower decreases in Kv4.2 and 4.3 expression (substantial
after 3 to 4 hours).72 Much additional work needs to be
performed to establish the precise signaling pathways and the
respective roles of changes in transcription, translation, and
posttranslational protein modification in the ion channel alterations
involved in atrial ionic remodeling.
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Relationship of Atrial to Ventricular
Ionic Remodeling
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One might expect ion channels in the atria and ventricles to
respond
to corresponding stimuli in comparable fashions. In the case
of
CHF-related remodeling, there are indeed many similarities.
Ventricular
Ito is strongly
reduced by ventricular tachycardiainduced
CHF,
and
IK1 density is decreased as
well.
73 A recent study shows
that
ventricular
IK is reduced in a
rabbit tachycardiainduced
heart failure
model
74 but suggests that unlike atrial remodeling
in
CHF,
27 IKr may be affected as
well as
IKs. Changes in
ventricular
ICa.L have been
inconsistent across studies, with some investigators
finding
ICa.L to be unchanged in failing
ventricles
73 75 and
others reporting a moderate
decrease.
74 76 77 78 Ventricular
NCX
overexpression is quite striking in CHF.
51 79 80 Overall,
therefore,
the ventricular ionic remodeling caused by CHF
is quite similar
to that occurring at the atrial level,
27
pointing to common
underlying mechanisms. Comparison of
tachycardia-induced remodeling
between atrium and ventricle
is greatly limited by the fact
that ventricular
tachycardia causes substantial CHF, which produces
strong
ionic remodeling (making it virtually impossible to study
the effects
of tachycardia alone), whereas atrial
tachycardia
does not cause CHF unless the
ventricular response is extremely
rapid.
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Pathophysiological Relevance of
Ionic Remodeling
|
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The pathophysiological role of ionic
remodeling in AF promotion
by atrial tachycardia is
illustrated in Figure 1

. Refractory
period changes appear to be
central to the AF-promoting properties
of atrial
tachycardia
9 10 11 12 and are largely attributable
to
downregulation of
ICa.L.
13 Spatial
heterogeneity of atrial
refractoriness changes seem
important,
81 pointing to spatially
heterogeneous
ion channel modifications, but the latter
have not been directly
evaluated.
INa
downregulation may contribute by causing conduction
slowing,
16 which reduces the reentrant wavelength and
thereby promotes
reentry. Spatially heterogeneous
connexin40 loss may also contribute
to spatially
heterogeneous conduction abnormalities.
21
Thus,
ionic remodeling appears to play a very important role in the
AF-promoting
properties of atrial tachycardia and such
clinically important
phenomena as the transition from paroxysmal to
persistent AF,
9 the early recurrence of AF after
cardioversion,
82 and the
transition from focal atrial
tachycardias to AF.
83 Changes
in cellular
Ca
2+ handling caused by atrial
tachycardia likely
contribute importantly to the reduced
atrial contractility observed
after termination of
persistent AF,
17 an important determinant
of
thromboembolic complications after electrical
cardioversion.
84
Experimental CHF clearly promotes AF
maintenance,27 but the relationship between
CHF-induced AF promotion and ionic remodeling (Figure 2
) is much less clear than for atrial
tachycardia. Unlike atrial tachycardia, the
cellular remodeling in CHF does not reduce action potential duration,
atrial refractoriness, or wavelength.27 85 The mechanism
of AF maintenance in the presence of CHF-induced atrial
remodeling appears related to structural remodeling that causes
prominent local conduction abnormalities and stabilizes atrial
macroreentry.85 86 Ionic remodeling sets the conditions
under which reentry occurs, without per se facilitating reentry. In
addition, the increased atrial NCX current caused by CHF27
may well contribute to atrial tachycardias caused by
CHF,87 in light of the ability of the NCX to cause
arrhythmogenic delayed afterdepolarizations in atrial
tissue.88 Atrial tachycardias caused by
delayed afterdepolarizationrelated triggered activity may act as
initiators in the setting of a vulnerable substrate for AF and could
also contribute by causing tachycardia-induced
remodeling.

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Figure 2. CHF-induced atrial ionic remodeling and the
mechanisms by which CHF promotes AF. The net result of ionic remodeling
is no change (-) or an increase ( ) in wavelength, which does not
promote AF per se but sets the
electrophysiological environment for AF
initiation and antiarrhythmic drug action.
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It appears paradoxical that some conditions that promote AF (such as
tachycardia-induced remodeling) act by decreasing
ICa.L,13 whereas others
(such as postoperative AF47 and
hyperthyroidism34 ) appear to increase
ICa.L. This apparent paradox likely
reflects the pathophysiological
heterogeneity of AF. Increased
ICa.L could promote AF by increasing
Ca2+ loading and favoring
afterdepolarization-mediated atrial tachyarrhythmias.
Decreased ICa.L promotes AF by a very
different mechanism, the occurrence of multiple-circuit reentry in
relation to reduced refractoriness and wavelength. Additional work is
needed, however, to determine more precisely the mechanisms of AF in
the postoperative setting and in thyrotoxic subjects, as well as to
define better the mechanistic role of changes in
ICa.L in various forms of the
arrhythmia.
 |
Potential Therapeutic Significance
|
|---|
The central role of ionic remodeling in atrial
tachycardiainduced
AF promotion has significant potential
relevance for AF therapy.
If the signal transduction mechanisms leading
to channel downregulation
were determined, effective therapy to prevent
atrial tachycardiainduced
ionic remodeling could be
developed, potentially making the
arrhythmia much more
tractable. At least one drug (mibefradil)
has been identified that
substantially reduces atrial remodeling
caused by long-term
tachycardias.
63 65 Understanding ionic
remodeling
may also have important implications for improving
antiarrhythmic
drug therapy. The antiarrhythmic response to the
selective
IKr blocker dofetilide is
categorically different between the atrial
tachycardia and
CHF models of AF,
86 suggesting that differences
in
ionic remodeling may have a determinant effect in the response
to
antiarrhythmic drugs. The ionic remodeling that occurs on
the
ventricular level may explain the proarrhythmic diathesis
seen
in response to drugs used to treat AF among patients with
CHF.
89 Much more work needs to be done regarding the
specific effects
of the remodeling of individual ion channels on the
response
to various categories of antiarrhythmic agents.
An important question relevant to potential therapeutic relevance of
manipulating ionic remodeling is whether the latter fulfills an
important adaptive function, in which case interfering with remodeling
could have negative consequences. For instance, increased NCX
expression appears to improve diastolic function in
patients with CHF.90 K+ channel
downregulation and consequent action potential prolongation increase
Ca2+ influx and Ca2+
transient amplitude after myocardial infarction in rats,91
potentially helping to maintain contractility. On the
other hand, a long-term reduction of Ito in
transgenic mice may lead to a heart failure
phenotype.92 Much more work needs to be
performed to understand the positive and negative consequences of ionic
remodeling and to evaluate the therapeutic implications for the primary
disease.
 |
Conclusions
|
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A great deal has recently been learned regarding ionic remodeling.
An
understanding of the atrial ionic changes caused by AF-promoting
pathologies
has already provided important new insights into mechanisms
of
arrhythmogenesis and has opened up interesting new therapeutic
avenues.
Much more work needs to be done, particularly in the area of
understanding
the signal transduction mechanisms that lead from the
stimuli
to remodeling to the final changes in ion channel function and
in
the translation of improved mechanistic understanding to new
therapeutic
approaches.
 |
Acknowledgments
|
|---|
This work was supported by grants from the Medical Research
Council
of Canada and the Quebec Heart Foundation. Dr Li is a Heart
and
Stroke Foundation of Canada/Astra Zeneca Research Scholar.
The authors
thank France Thériault for expert secretarial
assistance and
Sylvie Bolduc for help in preparing the figures.
Received July 17, 2000;
revision received July 28, 2000;
accepted July 31, 2000.
 |
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