(Circulation. 1998;98:2202-2209.)
© 1998 American Heart Association, Inc.
Basic Science Reports |
Importance of Refractoriness Heterogeneity in the Enhanced Vulnerability to Atrial Fibrillation Induction Caused by Tachycardia-Induced Atrial Electrical Remodeling
From the Department of Medicine and Research Center, Montreal Heart Institute and University of Montreal (S.F., C.V., S.N.), and the Department of Pharmacology and Therapeutics (S.N.), McGill University, Montreal, Quebec, Canada.
Correspondence to Dr Stanley Nattel, Research Center, Montreal Heart Institute, 5000 Bélanger St E, Montreal, Quebec H1T 1C8, Canada. E-mail nattel{at}icm.umontreal.ca
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Abstract |
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Background—Rapid atrial activation causes electrical remodeling that promotes the occurrence and the maintenance of atrial fibrillation (AF). Although remodeling has been shown to alter electrophysiological variables, the spatial uniformity of these changes is unknown.
Methods and Results—Dogs subjected to rapid atrial pacing (400 bpm) for 24 hours (n=12) were compared with sham-operated dogs (instrumented but not paced, n=12). Epicardial mapping (240 bipolar electrodes) and extrastimulation at a large number of sites (mean±SEM, 66±4 per dog) were used to evaluate atrial activation and the heterogeneity of the effective refractory period (ERP), respectively. Rapid pacing increased both the percentage of sites at which AF could be induced by single premature stimuli (from 2.6±0.9% to 11.8±2.8%, P=0.007) and AF duration (from 39±28 to 146±49 seconds, P=0.03). Atrial tachycardia decreased atrial ERP (from 120±4 to 103±2 ms, P=0.003), increased the coefficient of variation of ERP (from 14.9±0.9% to 20.7±0.9%, P<0.0001), and accelerated conduction velocity (from 91±2 to 108±3 cm/s, P=0.0004), with no change in the wavelength. The increase in ERP heterogeneity was due both to interregional differences in the extent of ERP remodeling and to increased intersite variability within regions. Stepwise multilinear regression indicated that ERP heterogeneity was an independent determinant of the inducibility (P<0.0001) and duration (P<0.0001) of AF, whereas ERP per se and wavelength were not significant determinants. Combined mapping of AF induction and atrial ERP showed that premature extrastimuli induced AF at sites with short ERP by causing local conduction slowing and/or block in adjacent zones with longer ERP values.
Conclusions—Atrial tachycardia causes nonuniform remodeling of atrial refractoriness that plays an important role in increasing atrial vulnerability to AF induction and the duration of induced AF.
Key Words: fibrillation • remodeling • electrophysiology
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Introduction |
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Atrial fibrillation (AF) is the arrhythmia most frequently encountered in clinical practice and is likely to become more common with the aging of the population.1 2 AF remains a therapeutic challenge, in part because of limitations in our understanding of the pathological and electrophysiological mechanisms underlying AF.3 Over the past few years, rapid atrial activation has been shown to increase the vulnerability to AF induction by premature extrastimuli and to promote sustained AF.4 5 6 7 8 9 10 AF models based on tachycardia-induced remodeling are relevant to the process by which AF alters atrial electrophysiology to favor its own maintenance ("AF begets AF"6 ) and produce ultrastructural abnormalities similar to those seen in patients with AF.4 11
Rapid atrial activation increases the spatial variability in AF cycle length,10 which is an index of atrial refractoriness.12 The SD of AF cycle lengths at different sites correlates with AF duration in dogs subjected to rapid atrial pacing,10 suggesting a potential role for refractoriness heterogeneity in contributing to atrial remodeling due to rapid atrial activation. However, the quantitative relations between AF cycle length and effective refractory period (ERP) are complex,13 so that AF cycle length changes are not necessarily an accurate indicator of ERP alterations.
The potential importance of spatial variability in atrial electrophysiology for the induction and maintenance of AF has long been recognized.14 Initial analyses of AF-induced remodeling showed that AF did not alter the difference between ERPs in the left versus right atrium, suggesting that AF may not alter ERP heterogeneity.6 A recent preliminary report points to increased variability in ERP caused by AF on the basis of ERP measurements at an average of 7 atrial sites per dog.15 The present study was designed to evaluate in detail the spatial distribution of changes in atrial electrophysiological properties, particularly the ERP, caused by 24 hours of rapid atrial pacing in dogs and to relate changes in spatial heterogeneity to the substrate for AF.
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Methods |
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Pacemaker Insertion and Atrial Pacing
Adult mongrel dogs (29.4±0.4 kg, n=24) were anesthetized with sodium pentobarbital (30 mg/kg IV, with additional doses of 4 mg/kg as needed). A pacing lead was inserted into the right atrial appendage with previously described methods,10 and a subcutaneously implanted pacemaker was used to pace the atria for 24 hours at 400 bpm (rapidly paced group, n=12) or left inactivated for 24 hours (sham control group, n=12).
Experimental Protocol
Twenty-four hours after the initial procedure, dogs were
reanesthetized with morphine (2 mg/kg SC) and 
-chloralose
(120 mg/kg IV bolus, followed by a continuous infusion of 29.3 mg
· kg-1 · h-1).
Animals were studied after a median sternotomy, with the same
preparation and instrumentation as previously described in
detail.10 Five thin silicon plaques containing
240 bipolar electrodes for stimulation and/or recording (Figure 1
) were sewn to cover the atrial
epicardial surface. The form and location of the arrays were similar to
those described previously,10 16 17 but the
number of electrodes was increased and their location modified. The
hardware configuration permitted pacing at any of the 240 sites in the
array. The interpolar distance was 1 mm, and the interelectrode
distances were between 3.1 and 4.0 mm for arrays on the right and
left atrial free walls and appendages and Bachmann's bundle and 6
mm for the array between the pulmonary veins.
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Signals were filtered (10 to 900 Hz), digitized (12-bit resolution and a 2-kHz sampling rate), and transmitted into a Silicon Graphics computer for data analysis. Activation data were analyzed off-line with computer-determined peak-amplitude criteria for activation, and data for each electrode were reviewed manually. Double potentials indicating local activation block or a pivot point were taken to represent a single local activation at the time of the largest potential. Electrogram timing was compared with QRS complexes to exclude ventricular electrograms.
Electrophysiological Study
In paced dogs, the pacemaker was deactivated. Activation
maps for conduction velocity (CV) measurement were obtained after 90
seconds at a basic cycle length (BCL) of 300 ms. CV was measured with
the use of 2 parallel sets (4 bipolar electrodes per set) in each of 5
regions: Bachmann's bundle (BB, a in Figure 1
), the left atrial
appendage (LAA, b), the right atrial appendage (RAA, c), the right
superior free wall (d), and the right inferior free wall
(e). Stimulation for the CV measurement was applied at each of the
sites designated by the letters in Figure 1, after it had been
ascertained that stimulation at that site resulted in longitudinal
conduction at the corresponding series of electrodes. Because of
variable contact in the left posterior free wall (LPW), LPW CV
could not be measured accurately in all dogs and was therefore not
included in the analysis.
ERP was determined with the extrastimulus technique at as large a
number of sites as feasible during each experiment, with sites selected
so as to provide representative data from all regions.
All basic and premature stimuli were 2-ms square waves with
twice-threshold current. The pacing threshold was determined separately
at each electrode site, and only sites with a threshold <5 mA were
used. The ERP was defined as the longest
S1S2 interval that failed
to produce a response. A 15-stimulus basic train at a BCL
(S1S1) of 300 ms was
followed by a premature extrastimulus (S2) at a
progressively increasing
S1S2 interval and a
1-second pause to observe the response between trains. This method is
accurate and reproducible and allows the coupling interval of
S2 to be incremented rapidly without altering the
basic rhythm.18 19 The coupling interval of
S2 was increased by 10-ms increments to obtain an
initial estimate of the ERP. The measurement was then repeated with
5-ms increments in the S1S2
interval, and the resulting value was taken as the ERP. In the case of
a 
10-ms difference between the 2 measurements, a third measurement
with 5-ms steps was obtained and the mean of all 3 ERP values was
used.
After the completion of electrophysiological data acquisition, AF was induced by stimulation of the RAA with 10-Hz, 2-ms stimuli at 4 times threshold current. AF was defined as a rapid (>450 bpm), irregular atrial rhythm with varying atrial electrogram morphology. To calculate mean AF duration, AF was induced 10 times for AF duration <10 minutes and twice for AF duration between 10 and 30 minutes. Dogs that developed AF that lasted >30 minutes were eliminated, because such prolonged AF (usually requiring cardioversion for termination) made it impossible to measure ERP at a sufficient number of sites. Two rapidly paced dogs had to be eliminated because of prolonged AF and were replaced by additional animals to maintain the same number of dogs (12) in each group. No control dogs had prolonged AF. The vulnerability to AF induction at each site was determined on the basis of the ability of single S2s to induce, in a reproducible fashion, AF that lasted >1 second. Overall vulnerability in each dog was defined as the percentage of pacing sites at which AF was inducible.
Data Analysis
Regional CV was determined by analyzing activation at each of 2
parallel series of 4 electrodes in each region (Figure 1), with each
series of electrodes oriented along the direction of rapid propagation
(perpendicular to consecutive isochrones). The CV was determined as
previously described10 for each of the 2 series
of parallel electrodes in each region, and the mean of the values
obtained was used for analysis. The same sites were used for CV
measurements for each experiment. The overall CV for each dog was
calculated from the average of each of the 5 regional CV values. An
index of CV heterogeneity in each dog was obtained by
calculating the coefficient of variation (COV CV=SD/meanx100%) of the
5 regional CV values. Similar approaches were used to calculate for
each dog the overall mean ERP, the mean ERP in each region, and the
overall and regional COV in ERP (COV ERP).
Statistical comparisons between only 2 groups were performed by Student's t test or the Mann-Whitney rank sum test when a normal distribution could not be assumed. ANOVA (for parametric data) or a Kruskal-Wallis rank sum test (when data could not be assumed to be normally distributed) was used for multiple-group comparisons, followed by a Bonferroni-corrected t test or a corrected Mann-Whitney rank sum test. Stepwise multilinear regression was used to assess the dependence of a single dependent variable on multiple independent variables and linear regression to analyze single dependent and independent variables. Average results are given as the mean±SEM unless otherwise indicated, and a 2-tailed P<0.05 was considered statistically significant.
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Results |
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Comparability of Groups and Overall Changes Caused by Rapid Pacing
Control and paced dogs were similar in size, study duration, and a number of general variables (Table
).
The number of sites at which ERP was determined and the mean
diastolic current threshold were the same for both
groups.
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Changes in electrophysiological
variables and AF susceptibility are illustrated by measurements
from 1 dog in each group in Figure 2. ERP
was measured at 73 sites in the control dog (A) and averaged 124±16 ms
(mean±SD). The ERP tended to be shorter in the posterior left atrium,
and COV ERP was 13.5%. AF could not be induced by premature stimuli at
any site, and the duration of AF induced by burst pacing averaged 11
seconds. In the paced dog (B), ERP was measured at 94 sites. Mean ERP
was 100±22 ms. Large variations in ERP were seen, from values as great
as maximum values in the control dog (165 ms) to values as short as 60
ms, much shorter than the shortest ERP (95 ms) in the control dog. ERP
heterogeneity was substantial, with a COV ERP of
21.7%. AF could be induced at 19% of sites, indicated by the stars in
Figure 2, and mean AF duration was 240 seconds.
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Overall, rapid pacing significantly enhanced atrial vulnerability
(Table), increasing the percentage of sites per dog at which AF was
induced by a single extrastimulus from 2.6±0.9% to 11.8±2.8%. Five
control dogs (42%) did not exhibit any AF during premature
stimulation, compared with only 1 paced dog (8%). AF duration was also
increased significantly in paced dogs. Pacing decreased mean ERP,
increased ERP heterogeneity, and increased CV. The
offsetting changes in ERP and CV left wavelength unaltered. Rapid
pacing had no effect on CV heterogeneity. Wavelength
was calculated in each region as the product of local CV and mean
ERP and was not altered by pacing in any region. To assess the
stability of ERP values in paced dogs, they were measured at the
beginning and repeated at the end of the study at a total of 20 sites
in 5 dogs. The mean ERP averaged 100.8±3.5 ms at the beginning of the
study and 103.0±3.6 ms at the end of the study (P=NS),
indicating no significant time-dependent changes.
Regional Changes in Electrophysiological Properties
A quantitative analysis of regional differences in the
effect of rapid pacing on ERP is shown in Figure 3. Paced dogs had substantially shorter
ERPs in the atrial appendages and the right free wall but little or no
change in ERPs in the left posterior wall or Bachmann's bundle. Thus,
ERP remodeling induced by pacing was regionally
heterogeneous, accounting (at least in part) for the
increased spatial heterogeneity of ERP in paced dogs
(Table). The increased heterogeneity caused by rapid
pacing was associated with a decrease in the smallest ERP values in
each dog, which averaged 62±2 ms in paced dogs, versus 85±4 ms in
control dogs (P<0.0001). The largest ERP values were not
altered (paced dogs, 162±7 ms; control dogs, 165±7 ms).
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To determine whether increased spatial ERP
heterogeneity in paced dogs was due entirely to
interregional differences in the extent of ERP remodeling or whether
intraregional differences might also contribute, we performed the
analysis illustrated in Figure 4.
The COV in refractoriness was calculated within each region and was
found to be increased significantly by rapid pacing in 3 regions: the
right and left atrial appendages and the right free wall. These are the
same regions in which the greatest absolute change in ERP occurred
(Figure 3), implying that within the regions of greatest ERP
remodeling, there was considerable intersite variability in the extent
of remodeling. Consequently, atrial tachycardia caused
nonuniform shortening in ERP both within and among various atrial
regions.
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Relation Between Electrophysiological
Properties and Atrial Vulnerability
Having examined changes in ERP heterogeneity in
paced dogs, we turned our attention to the factors potentially
accounting for their enhanced vulnerability to AF induction. Figure 5 shows an analysis of the
relations between vulnerability to AF induction in each dog (expressed
as a percentage of sites at which AF could be induced by extrastimuli)
and ERP, ERP heterogeneity (as measured by COV ERP),
and wavelength. There was a strong correlation between vulnerability
and ERP heterogeneity, whereas the relationship with
ERP was weak and that with wavelength was nonsignificant. When stepwise
multilinear regression was applied to select a model relating AF
vulnerability (dependent variable) to ERP, COV ERP, and CV
(independent variables that changed with pacing) in all dogs, the
model selected had a correlation coefficient of 0.82, and the only
independent variable that provided statistically significant
predictive value to the model was COV ERP (P<0.0001).
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, Results for
individual control dogs; 
, results for paced dogs.
Univariate correlation coefficients (r) and
P values at top of each graph are for all dogs studied.
(ERP and wavelength were based on a mean of all measurements in each
dog.)
We next examined in detail the activation sequences for premature
stimuli at S1S2 intervals 5
ms greater than the ERP, at sites at which AF could be induced (n=20)
or at sites without AF inducibility (n=10). Figure 6 shows an example of the activation
pattern of an A2 complex that induced AF. Panels
A and B show atrial activation induced by stimulation in the right
atrial free wall for the last complex of the basic train
(A1) and the atrial premature complex elicited by
an S2 delivered with a coupling interval (90 ms)
5 ms greater than the ERP. Panels C and D are enlarged
representations of activation in the right atrial array
overlying the stimulation site. The extrastimulus captured the region
around the stimulation site (star), with a latency of about 20 ms. The
impulse was blocked in the superior direction, and conduction was
greatly slowed in the inferior direction, leading to marked
slowing of atrial activation. The next cycle (panel E) began close to
the stimulation site, 90 ms after initial activation. Panel F shows ERP
values in the region of the stimulation site. The ERP at the site at
which reentry was induced was 85 ms, and a corridor through which the
S2 was propagated had ERP values of 80 to 90 ms,
similar to the activation-reactivation interval of 90 ms and permitting
reexcitation. At the line of block above the stimulation site, ERPs
were all larger, ranging from 95 to 125 ms.
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Figure 7 shows data from a
different dog, with examples of extrastimulation at adjacent sites, at
1 of which (top) AF could not be induced and at another of which
(bottom) AF was induced by premature stimulation. The last
S1 of the basic train was propagated rapidly and
uniformly during stimulation at either site (left, top and bottom). The
S2 with the shortest
S1S2 interval (110 ms) that
permitted capture at the noninducible site (top, middle) was associated
with an increased latency and some conduction slowing, but conduction
remained relatively uniform. In contrast, the earliest
S2 capturing the inducible site
(S1S2=70 ms) was followed
by substantial local conduction delay and an arc of conduction block
below the site of stimulation (bottom, middle). Slow conduction around
the arc of block led to reactivation in the region of extrastimulation,
as shown in the lower right panel. The distribution of ERPs in the
region of the 2 stimulation sites is shown in the upper right panel,
along with the isochrones of the A2 causing
reentry reproduced from the lower middle panel. The line of block
corresponds to areas with refractory periods between 100 and 105 ms,
substantially greater than the ERP of 65 ms at the site at which
reentry was induced and accounting for the line of block in response to
the extrastimulus. In contrast, the ERP at the site at which reentry
could not be induced was 105 ms, longer than the ERP at almost all
other sites in the area and permitting continuous, if somewhat slowed,
conduction of the complex resulting from the extrastimulus.
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) and bottom (*). Also shown
are activation isochrones of A2 complex that induced
reentry. Insets, Electrogram recordings from right atrial
appendage for cycles mapped.In all 20 cases of AF induction for which activation data were available, reentry was induced at a site of relatively short refractoriness, with 1 or more zones of conduction block corresponding to an adjacent series of sites of greater refractoriness. The conduction block and slowing are reflected by the overall conduction times of A2 complexes at S1S2 intervals 5 ms greater than the ERP, which averaged 128±6 ms for stimulation at sites at which AF could be induced, compared with 93±6 ms (P=0.0005) for stimulation at noninducible sites. In contrast, conduction times of the last A1 complex of the basic train were similar for inducible and noninducible sites (76±2 versus 73±3 ms, respectively, P=NS). These results indicate that the heterogeneous ERP remodeling caused by rapid pacing established the substrate that permitted single extrastimuli to induce AF at many more sites in paced dogs than in control dogs.
Relation Between Electrophysiological
Properties and AF Duration
Figure 8 shows the results of an
analysis of the relationship between AF duration and ERP, ERP
heterogeneity, and wavelength. Only ERP
heterogeneity shows a significant correlation with AF
duration. We also analyzed the relations between minimum or
maximum ERP in each dog and AF duration and found no significant
correlation. When multilinear regression was applied to the relation
between AF duration and ERP, COV ERP, and CV, the best predictive model
(r=0.78) included only 1 independent variable that
contributed significantly: the heterogeneity in ERP
(P<0.0001).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In the present study, we evaluated in detail the spatial distribution of changes in ERP caused by rapid atrial pacing. The results show that tachycardia-induced ERP remodeling is spatially nonuniform, with increased ERP variability both within and among various atrial regions in rapidly paced dogs. Whereas AF duration and vulnerability were not significantly related to ERP per se or to wavelength, they were strongly correlated with ERP heterogeneity. Furthermore, detailed activation mapping showed that local heterogeneities in ERP were central to the ability of premature extrastimuli to induce AF. Reentry was generally initiated at sites with shorter ERP, as a result of the presence of adjacent regions with longer ERP that created arcs of conduction block and other adjacent regions of shorter refractoriness through which conduction occurred. Thus, the spatial nonuniformity of tachycardia-induced ERP remodeling is important in generating a substrate that promotes the occurrence of AF.
Comparison With Previous Studies of Tachycardia-Induced
Atrial Electrical Remodeling
Like previous investigators,4 5 6 7 8 9 10 we found
that electrically induced atrial tachycardia increases the
duration and inducibility of AF and reduces the ERP. Investigators have
observed varying alterations in conduction. Wijffels et
al6 noted an increase in CV after 6 to 24 hours
of sustained AF in the goat, which they attributed to a decrease in
refractory period. In contrast, several groups have reported an
increase in atrial conduction time and/or a decrease in conduction
speed after longer periods of
tachycardia.4 7 10 20 In the
present study, we noted an increase in CV after 24 hours of atrial
tachycardia, consistent with the findings of
Wijffels et al.6 The varying results regarding CV
changes may point to the existence of multiple changes that can affect
CV, with the observed effect depending on the balance. Changes reported
to date that can have opposite effects on CV include decreased ERP and
increased connexin 43 expression,21 which would
tend to increase CV, and decreased
INa,20 which would
have the opposite effect.
Relatively little information is available about the distribution of atrial ERP remodeling. Wijffels et al6 found that the difference between right and left atrial ERP was not altered during atrial remodeling and that the variability of AF cycle length at 12 sites was the same after 1 and 14 days of AF. We have noted an increase in the variability of AF cycle length in dogs subjected to rapid pacing for periods of up to 6 weeks.10 Preliminary results from Tieleman et al15 point to an increase in ERP heterogeneity as measured at an average of 7 sites in the goat, due largely to smaller changes in Bachmann's bundle, consistent with our observations.
Role of Refractoriness Heterogeneity in AF
Variable refractoriness was essential for the generation of AF
in the classic computer model of Moe et al.14
Dogs with AF induced by single extrastimuli after
cardiopulmonary bypass have increased refractoriness
dispersion.22 Dogs with idiopathic AF have
increased ERP dispersion,23 and the ability of
flecainide to terminate idiopathic and vagal AF in dogs is associated
with reductions in ERP dispersion.16 23 Increased
ERP dispersion appears to play a central role in vagally induced
experimental AF.17 24 Patients with AF have an
increased spatial variability in AF cycle
length,12 and atrial tissues from patients with
AF show an increase in ERP
heterogeneity.25 The
leading-circle model and a variety of experimental observations suggest
an important role for the reentry wavelength in determining
susceptibility to reentrant atrial
arrhythmias,26 27 including
AF.16 23 28 Conversely, in some studies, AF
duration was not correlated with wavelength but appeared to be related
to ERP dispersion.17 24 In the present study,
rapid atrial activation did not alter the wavelength but increased ERP
dispersion, and ERP dispersion was a predictor of both AF duration and
inducibility. Recent observations suggest that functional reentry
during AF may correspond to spiral-wave
reentry.29 Further application of the spiral wave
concept may help to explain how interventions that increase
refractoriness dispersion can promote AF maintenance without
altering the reentrant wavelength.
Novel Findings and Potential Significance
The major novel contributions of the present study are
(1) the demonstration that tachycardia-induced remodeling
increases ERP dispersion both within and among atrial regions, implying
spatial variability in the degree of remodeling; (2) the finding that
increased ERP dispersion contributes to the AF-promoting effects of
atrial tachycardia; and (3) the analysis by
epicardial mapping of the relationship between ERP dispersion and the
activation of extrasystoles that cause atrial reentry leading to
AF.
The induction of atrial reentry by premature beats is an important clinical mechanism of AF initiation.30 The ability of single extrastimuli to initiate atrial reentry and AF has been associated with inhomogeneities in conduction31 and refractoriness.17 The present study is the first of which we are aware to relate activation maps of AF induction to detailed maps of ERP. The results suggest that local inhomogeneities in refractoriness can play a significant role in the ability of premature extrastimuli to induce AF and may contribute to the ability of sustained atrial tachycardia to increase atrial vulnerability. Given the probable clinical significance of atrial tachycardia–induced remodeling,32 33 an appreciation of the potential role of spatial heterogeneity in remodeling is important.
Limitations of Our Findings
Electrophysiological variables were
measured at only 1 atrial cycle length. The use of several cycle
lengths would have greatly increased the duration of experiments,
introducing potentially important time-dependent confounding factors
and making the study practically unfeasible. We did not analyze
ERP heterogeneity during AF or at the minimum 1:1 cycle
length, which would have been interesting and relevant but technically
difficult. We cannot exclude the possibility that wavelength during AF
might have been related to AF duration; however, wavelength was not
decreased at a BCL of 300 ms in paced dogs, and ERP rate adaptation is
reduced in tachycardia-remodeled
atria,6 7 10 suggesting that wavelength would not
be reduced at rapid rates in our dogs.
We chose 24 hours of rapid pacing for study because this interval is sufficient for significant atrial remodeling6 8 but is not associated with an excessive prevalence of prolonged AF (>30 minutes). In our experience, prolonged AF due to tachycardia-induced remodeling makes detailed ERP mapping impossible because of the frequent induction of AF, requiring subsequent cardioversion, during ERP determination. Our results are pertinent to the mechanisms of remodeling and AF promotion resulting from recent-onset AF (within 24 hours). Similar mechanisms may be operative during AF of longer duration, but it would be inappropriate to assume that our observations necessarily apply to AF that lasts several days or weeks.
Our mapping system samples the atrial epicardial surfaces extensively
but does not provide information about septal activation or the
activation of subendocardial structures, such as the pectinate muscles.
Such regions may play an important role in atrial reentry, including
AF,34 35 36 and were almost certainly involved in
reentrant excitations (like those shown in Figure 6), for which our
mapping revealed only part of the reentry circuit.
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Acknowledgments |
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This work was supported by grants from the Medical Research Council of Canada, the Heart and Stroke Foundation of Quebec, and the Fonds de Recherche de l'Institut de Cardiologie de Montréal. Dr Fareh is a holder of a fellowship from the Fédération Française de Cardiologie. The authors wish to thank Emma De Blasio and Mirie Levi for their skilled technical assistance and Luce Bégin and Diane Campeau for secretarial help with the manuscript.
Received January 26, 1998; revision received June 17, 1998; accepted June 22, 1998.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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1. Kannel WB, Wolf PA. Epidemiology of atrial fibrillation. In: Falk RH, Podrid PJ, eds. Atrial Fibrillation: Mechanisms and Management. New York, NY: Raven Press Publishers; 1992:81–92.
2. Kannel WB, Abbott RD, Savage DD, McNamara PM. Epidemiologic features of chronic atrial fibrillation: the Framingham study. N Engl J Med. 1982;306:1018–1022.[Abstract]
3. Nattel S. Newer developments in the management of atrial fibrillation. Am Heart J. 1995;130:1094–1106.[Medline] [Order article via Infotrieve]
4.
Morillo CA, Klein GJ, Jones DL, Guiraudon CM. Chronic
rapid atrial pacing: structural, functional, and
electrophysiological characteristics of a
new model of sustained atrial fibrillation. Circulation. 1995;91:1588–1595.
5. Salmon DR, McPherson DD, Augustine DE, Holida MD, White CW. A canine model of chronic atrial fibrillation: echocardiographic and electrocardiographic validation. Circulation. 1985;72(suppl III):III-250. Abstract.
6.
Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA.
Atrial fibrillation begets atrial fibrillation: a study in awake
chronically instrumented goats. Circulation. 1995;92:1954–1968.
7. Elvan A, Wylie K, Zipes DP. Pacing-induced chronic atrial fibrillation impairs sinus node function in dogs: electrophysiological remodeling. Circulation. 1996;94:2954–2960.
8.
Goette A, Honeycutt C, Langberg JL. Electrical
remodeling in atrial fibrillation: time course and mechanisms.
Circulation. 1996;94:2968–2974.
9.
Daoud EG, Bogun F, Goyal R, Harvey M, Man KC,
Strickberger SA, Morady F. Effect of atrial fibrillation on atrial
refractoriness in humans. Circulation. 1996;94:1600–1606.
10.
Gaspo R, Bosch RF, Talajic M, Nattel S. Functional
mechanisms underlying tachycardia-induced sustained atrial
fibrillation in a chronic dog model. Circulation. 1997;96:4027–4035.
11.
Ausma J, Wijffels M, Thoné JF, Wouters L,
Allessie MA, Borgers M. Structural changes of atrial
myocardium due to sustained atrial fibrillation.
Circulation. 1997;96:3157–3163.
12. Ramdat Misier AR, Opthof T, Hemel van NM, Defauw JJAM, de Bakker JMT, Janse MJ, Capelle van FJL. Increased dispersion of "refractoriness" in patients with idiopathic paroxysmal atrial fibrillation. J Am Coll Cardiol. 1992;19:1531–1535.[Abstract]
13.
Kim K-B, Rodefeld MD, Schuessler RB, Cox JL, Boineau
JP. Relationship between local atrial fibrillation interval and
refractory period in the isolated canine atrium.
Circulation. 1996;94:2961–2967.
14. Moe GK, Rheinboldt WC, Abildskov JA. A computer model of atrial fibrillation. Am Heart J. 1964;67:200–220.[Medline] [Order article via Infotrieve]
15. Tieleman RG, De Langen CDJ, Grandjean JG, Van Gelder IC, De Kam PJ, Wijffels MCEF, Crijns HJGM. Regional differences in pacing induced electrical remodeling of the atrium and recovery from electrical remodeling induces increased dispersion of refractoriness. Circulation. 1996;94(suppl I):I-352. Abstract.
16.
Wang Z, Pagé P, Nattel S. The mechanism of
flecainide's antiarrhythmic action in experimental atrial
fibrillation. Circ Res. 1992;71:271–287.
17. Wang J, Liu L, Feng J, Nattel S. Regional and functional factors determining induction and maintenance of atrial fibrillation in dogs. Am J Physiol. 1996;273(Heart Circ Physiol 40):H148–H158.
18. Morady F, Kadish AH, Kushner JA, Toivonen LK, Schmaltz S. Comparison of ventricular refractory periods determined by incremental and decremental scanning of an extrastimulus. Pacing Clin Electrophysiol. 1989;12:546–554.[Medline] [Order article via Infotrieve]
19. Kadish AH, Schmaltz S, Morady F. Variability in the measurement of human ventricular refractoriness. Pacing Clin Electrophysiol. 1991;14:1393–1401.[Medline] [Order article via Infotrieve]
20. Gaspo R, Bosch RF, Bou-Abboud E, Nattel S. Tachycardia-induced changes in Na+ current in a chronic dog model of atrial fibrillation. Circ Res. 1997;97:1045–1052.
21.
Elvan A, Huang XD, Pressler ML, Zipes DP.
Radiofrequency catheter ablation of the atria eliminates pacing-induced
sustained atrial fibrillation and reduces connexin 43 in dogs.
Circulation. 1997;96:1675–1685.
22. Sato S, Yamauchi S, Schuessler RB, Boineau JP, Matsunaga Y, Cox JL. The effect of augmented atrial hypothermia on atrial refractory period, conduction, and atrial flutter/fibrillation in the canine heart. J Thorac Cardiovasc Surg. 1992;104:297–306.[Abstract]
23. Wang Z, Feng J, Nattel S. Idiopathic atrial fibrillation in dogs: electrophysiologic determinants and mechanisms of antiarrhythmic action of flecainide. J Am Coll Cardiol. 1995;26:277–286.[Abstract]
24. Liu L, Nattel S. Differing sympathetic and vagal effects on atrial fibrillation in dogs: role of refractoriness heterogeneity. Am J Physiol. 1997;273(Heart Circ Physiol 42):H805–H816.
25. Boutjdir M, Le Heuzey JY, Lavergne T, Chauvaud S, Guize L, Carpentier A, Peronneau P. Inhomogeneity of cellular refractoriness in human atrium: factor of arrhythmia? Pacing Clin Electrophysiol. 1986;9:1095–1100.[Medline] [Order article via Infotrieve]
26.
Allessie MA, Bonke FIM, Schopman FJG. Circus movement
in rabbit atrial muscle as a mechanism of tachycardia, III:
the "leading circle" concept: a new model of circus movement in
cardiac tissue without the involvement of an anatomical obstacle.
Circ Res. 1977;41:9–18.
27.
Smeets JLRM, Allessie MA, Lammers WJEP, Bonke FIM,
Hollen J. The wavelength of the cardiac impulse and reentrant
arrhythmias in isolated rabbit atrium: the role of heart rate,
autonomic transmitters, temperature, and potassium. Circ
Res. 1986;58:96–108.
28.
Rensma PL, Allessie MA, Lammers WJEP, Bonke FIM,
Schalij MJ. Length of excitation wave and susceptibility to reentrant
atrial arrhythmias in normal conscious dogs. Circ
Res. 1988;62:395–410.
29.
Ikeda T, Uchida T, Hough D, Lee JJ, Fishbein MC, Mandel
WJ, Chen P-S, Karagueuzian HS. Mechanism of spontaneous termination of
functional reentry in isolated canine right atrium: evidence for the
presence of an excitable but nonexcited core. Circulation. 1996;94:1962–1973.
30.
Haft JI, Lau SH, Stein E, Kosowsky BD, Damato AN.
Atrial fibrillation produced by atrial stimulation.
Circulation. 1968;37:70–74.
31. Lammers WIJP, Schalij MJ, Kirchhof HJ, Allessie MA. Quantification of spatial inhomogeneity in conduction and initiation of reentrant atrial arrhythmias. Am J Physiol. 1990;259(Heart Circ Physiol 28):H1254–H1263.
32.
Zipes DP. Atrial fibrillation: a
tachycardia-induced atrial
cardiomyopathy. Circulation. 1997;95:562–564.
33.
Zipes DP. Electrophysiological
remodeling of the heart owing to rate. Circulation. 1997;95:1745–1748.
34.
Schuessler RB, Kawamoto T, Hand DE, Mitsuno M, Bromberg
BI, Cox JL, Boineau JP. Simultaneous epicardial and
endocardial activation sequence mapping in the isolated canine right
atrium. Circulation. 1993;88:250–263.
35.
Kumagai K, Khrestian C, Waldo AL.
Simultaneous multisite mapping studies during induced
atrial fibrillation in the sterile pericarditis model: insights into
the mechanism of its maintenance. Circulation. 1997;95:511–521.
36.
Gray RA, Pertsov AM, Jalife J. Incomplete reentry
and epicardial breakthrough patterns during atrial fibrillation in the
sheep heart. Circulation. 1996;94:2649–2661.We studied
in detail the spatial distribution of
electrophysiological alterations induced in
dogs by 24 hours of atrial pacing at 400 bpm, along with changes in
atrial vulnerability and atrial fibrillation (AF) duration. Atrial
tachycardia reduced effective refractory period (ERP) and
increased conduction velocity, resulting in no net change in the
wavelength for reentry; however, the spatial
heterogeneity of ERP as measured at an average of 66
sites per dog was substantially altered. The vulnerability to AF
induction by premature extrastimuli and the duration of induced AF were
significantly increased in paced dogs, changes that were strongly
correlated with alterations in the heterogeneity of
refractoriness but not with ERP, conduction velocity, or wavelength. We
conclude that tachycardia-induced electrical remodeling
produces spatially heterogeneous alterations in atrial
refractoriness that are important for the initiation and
maintenance of AF.
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|
|
|
|
|
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|
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|
|
|
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|
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|
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|
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|
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|
|
|
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|
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|
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|
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|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
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J. V. Jayachandran, H. J. Sih, W. Winkle, D. P. Zipes, G. D. Hutchins, and J. E. Olgin Atrial Fibrillation Produced by Prolonged Rapid Atrial Pacing Is Associated With Heterogeneous Changes in Atrial Sympathetic Innervation Circulation, March 14, 2000; 101(10): 1185 - 1191. [Abstract] [Full Text] [PDF]
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H. Ramanna, R. N. W. Hauer, F. H. M. Wittkampf, J. M. T. de Bakker, E. F. D. Wever, A. Elvan, and E. O. Robles de Medina Identification of the Substrate of Atrial Vulnerability in Patients With Idiopathic Atrial Fibrillation Circulation, March 7, 2000; 101(9): 995 - 1001. [Abstract] [Full Text] [PDF]
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P. Dorian and D. Newman Rate dependence of the effect of antiarrhythmic drugs delaying cardiac repolarization: an overview Europace, January 1, 2000; 2(4): 277 - 285. [Abstract] [PDF]
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S. Fareh, A. Benardeau, B. Thibault, and S. Nattel The T-Type Ca2+ Channel Blocker Mibefradil Prevents the Development of a Substrate for Atrial Fibrillation by Tachycardia-Induced Atrial Remodeling in Dogs Circulation, November 23, 1999; 100(21): 2191 - 2197. [Abstract] [Full Text] [PDF]
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P. B. Sparks, H. G. Mond, J. K. Vohra, S. Jayaprakash, and J. M. Kalman Electrical Remodeling of the Atria Following Loss of Atrioventricular Synchrony : A Long-Term Study in Humans Circulation, November 2, 1999; 100(18): 1894 - 1900. [Abstract] [Full Text] [PDF]
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S. Nattel Ionic Determinants of Atrial Fibrillation and Ca2+ Channel Abnormalities : Cause, Consequence, or Innocent Bystander? Circ. Res., September 3, 1999; 85(5): 473 - 476. [Full Text] [PDF]
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D. Li, S. Fareh, T. K. Leung, and S. Nattel Promotion of Atrial Fibrillation by Heart Failure in Dogs : Atrial Remodeling of a Different Sort Circulation, July 6, 1999; 100(1): 87 - 95. [Abstract] [Full Text] [PDF]
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R. Gaspo, H. Sun, S. Fareh, M. Levi, L. Yue, B. G. Allen, T. E. Hebert, and S. Nattel Dihydropyridine and beta adrenergic receptor binding in dogs with tachycardia-induced atrial fibrillation Cardiovasc Res, May 1, 1999; 42(2): 434 - 442. [Abstract] [Full Text] [PDF]
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M. Courtemanche, R. J Ramirez, and S. Nattel Ionic targets for drug therapy and atrial fibrillation-induced electrical remodeling: insights from a mathematical model Cardiovasc Res, May 1, 1999; 42(2): 477 - 489. [Abstract] [Full Text] [PDF]
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