(Circulation. 1997;96:4027-4035.)
© 1997 American Heart Association, Inc.
Articles |
Functional Mechanisms Underlying Tachycardia-Induced Sustained Atrial Fibrillation in a Chronic Dog Model
From the Department of Medicine and Research Center, Montreal (Quebec) Heart Institute and University of Montreal (R.G., R.F.B., M.T., S.N.), and the Department of Pharmacology and Therapeutics (S.N.), McGill University, Montreal, Quebec, Canada.
Correspondence to Stanley Nattel, MD, 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 atrial fibrillation (AF), but underlying mechanisms are incompletely understood. We applied epicardial mapping to evaluate atrial electrophysiology and AF duration in dogs subjected to rapid atrial pacing (400/min).
Methods and Results Dogs paced for 1 (P1, n=7), 7 (P7, n=13), or 42 (P42, n=7) days were compared with sham dogs (P0, n=13). Atrial pacing progressively increased AF duration. Atrial effective refractory period (ERP) and ERP accommodation to rate were significantly decreased by pacing, with near-maximal changes within 7 days. Atrial conduction velocity decreased more slowly, with maximum changes at 42 days, contributing to increases in AF duration after ERP stabilized. Stepwise multilinear regression indicated that both wavelength (P=.02) and duration of pacing (P=.0001) were independent determinants of changes in AF duration. Mean atrial fibrillation cycle length (AFCL) at 112 recording sites decreased with increased duration of rapid pacing (P<.001), and the SD of AFCL increased progressively (P<.0001), together accounting for 72% of the variance in AF duration. Increases in AFCL variability were due to regionally determined differences in AFCL changes caused by rapid pacing. The number of zones of reactivation per cycle of AF increased as AF became more sustained, consistent with multiple-wavelet reentry.
Conclusions Rapid atrial activation causes time-dependent decreases in ERP, conduction velocity, and wavelength, which, along with increased regional heterogeneity, provide a substrate for AF. The conduction abnormalities and increased regional heterogeneity previously noted in patients with AF may be a consequence, as well as a cause, of the tachyarrhythmia.
Key Words: atrial fibrillation • pacing • conduction • electrocardiography • arrhythmia
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Introduction |
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Atrial fibrillation is the most frequently encountered arrhythmia in clinical practice and is likely to become more common with the aging of the population.1–3 Major limitations remain in our knowledge of the pathological and electrophysiological mechanisms underlying AF. Experimental AF has been studied in normal animal hearts,4–9 with or without acute interventions like topical aconitine4 or vagal nerve stimulation7–9 to promote AF maintenance. Most clinical AF occurs in patients with chronic atrial pathology, which is absent in the short-term AF models described above, limiting their applicability to clinical AF.
Over the past few years, investigators have developed new animal models of AF associated with atrial dilation and ultrastructural changes that resemble those of clinical AF.10,11 These models generally involve rapid atrial activation, induced by either rapid 1:1 atrial pacing11 or electrically maintained AF,10,12 mimicking the "domestication of AF," a process by which AF causes electrophysiological remodeling that favors its own maintenance ("AF begets AF").12
Limited information is available on the mechanisms of AF in the rapid activation models. Whereas Wijffels et al12 showed that electrically maintained AF results in a decrease in atrial ERP and in ERP adaptation to rate change,12 ERP changes were near-maximal within 24 hours, while the duration of AF increased more slowly to approach steady-state values over 7 days.12 This implies that additional factors are altered to promote the maintenance of AF. Morillo et al11 showed that 1:1 atrial pacing at 400/min for 6 weeks led to reductions in atrial ERP and to sustained AF in about 85% of dogs, but they did not study the time course of electrophysiological changes or directly measure conduction velocity.
The present study was designed to assess the electrophysiological changes that provide a substrate for sustained AF among dogs subjected to atrial pacing at 400/min for periods of up to 6 weeks. We wished to determine (1) whether the ERP changes produced by rapid 1:1 atrial pacing resemble those previously described during electrically maintained AF, (2) whether atrial conduction is altered, (3) whether the time course of changes in electrophysiological variables can account for the time course of changes in the duration of AF, and (4) whether epicardial mapping of atrial activation during AF can provide clues about the mechanisms of the arrhythmia and the role of underlying electrophysiological alterations.
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Methods |
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Pacemaker Insertion and Atrial Pacing
Adult mongrel dogs (weight, 28.2±2.0 kg; n=40) were anesthetized with sodium pentobarbital (30 mg/kg IV, additional doses of 4 mg/kg as needed). Respiration was maintained via an endotracheal tube and a mechanical ventilator. Under sterile conditions, a unipolar screw-in pacing lead (Medtronic Inc) was inserted via the right external jugular vein and fixed in the right atrial appendage under fluoroscopic guidance. The lead was then connected to a Medtronic pacemaker unit (model 8084) in a subcutaneous pocket in the neck.
Twenty-four hours later, the pacemaker was programmed to capture the atrium at 400/min with 4-ms pulses at twice-threshold current. The atrium was stimulated at this rate for a period of 1 (group designated "P1," n=7), 7 ("P7," n=13), or 42 ("P42," n=7) days. The surface ECG was verified after 24 hours and then weekly. Rapidly paced dogs were compared with sham dogs ("P0," n=13), similarly instrumented but maintained without pacemaker activation for 1 (n=5), 7 (n=5), or 42 (n=3) days. The results of P0 dogs were the same regardless of observation period, so they were grouped together for all analyses.
Electrophysiological Study
On study days, dogs were reanesthetized with morphine (2
mg/kg SC) and 
-chloralose (120 mg/kg IV bolus,
continuous infusion of 29.25 mg ·
kg-1 · h-1) and
ventilated with oxygen-enriched air. Respiratory parameters
were adjusted to maintain physiological
arterial blood gases. Body temperature was maintained
(37°C) with a circulating-water system. Polyethylene catheters were
inserted into the left femoral artery and both femoral veins. A median
sternotomy was performed, and a pericardial cradle was created. Two
bipolar Teflon-coated stainless steel electrodes were inserted into the
right atrial appendage for recording and stimulation. A
programmable stimulator (Digital Cardiovascular
Instruments) was used to deliver 2-ms pulses at twice-threshold
current. A P23 1D transducer (Statham Medical Instruments),
electrophysiological amplifiers (Bloom
Ltd), and a paper recorder (Astromed MT-95000) were used to
record blood pressure, surface ECG leads, a right atrial
electrogram, and stimulus artifacts.
Experimental Protocol
In paced dogs, the implanted pacemaker was deactivated.
Activation maps for CV measurements were obtained after 2 minutes of
pacing at the right atrial appendage at each of four BCLs from 150 to
400 ms. The ERP was measured with 15 basic (S1)
stimuli followed by a premature (S2) stimulus at
an S1S2 interval that was
decreased by 10-ms decrements from the BCL, with the ERP defined as the
longest S1S2 interval
failing to produce a response. The ERP was determined twice at each
BCL, and the mean of the ERP values was used for data analysis.
If AF occurred during ERP testing, it was cardioverted, and the dog was
allowed to rest for 30 minutes. In such cases, incremental
S1S2 from below the ERP
were used to obtain an initial ERP estimate and minimize the number of
S1S2 trials needed.
AF was then induced with 10-Hz, 2-ms stimuli at four times the threshold current. AF was defined as a rapid (>450/min), irregular atrial rhythm with varying atrial electrogram morphology. AF lasting >45 minutes was considered sustained. An 8-second window of activation data was acquired during AF to analyze activation patterns. To estimate mean AF duration, AF was induced 15 times for AF duration <10 minutes and twice for AF duration between 10 and 45 minutes. If AF lasted >45 minutes, no further AF induction was attempted to avoid excessive prolongation of the experiment. AF lasting >45 minutes was terminated by direct current electrical cardioversion. AF inducibility was also assessed with single premature S2 stimuli at a 400-ms BCL. AF was considered to be inducible if induced reproducibly at a given coupling interval.
Activation Mapping
Five thin silicon plaques containing 112-bipolar electrodes with
1-mm interpolar and 6-mm interelectrode distances were sewn into
position to cover the atrial epicardial surface as previously
described.7–9 Each electrogram signal was
filtered (30 to 400 Hz), digitized (12-bit resolution and 1-kHz
sampling rate), and transmitted into an IBM-compatible microcomputer.
Software routines were used to amplify, display, and analyze
each electrogram signal and to generate activation
maps.7–9 Each electrogram was analyzed
with computer-determined peak-amplitude criteria and was reviewed
manually. Electrogram timing was compared to QRS complexes to exclude
ventricular electrograms.
Data Analysis
CV was determined by analyzing activation at four electrode
sites in the direction of rapid propagation (perpendicular to
consecutive isochrones) in the right atrial free wall. Distance
from the proximal site was plotted against activation time, and CV was
determined from the slope of the best-fit regression line. Activation
maps were reviewed to ensure continuous longitudinal propagation, and
only data with correlation coefficients >.99 were accepted for
analysis. The same sites were used for CV measurements for each
experiment. Fig 1
illustrates CV
measurements under P0, P1, P7, and P42 conditions. Two other indexes of
conduction speed were analyzed. First, CV along Bachmann's
bundle was measured in a fashion similar to that used to calculate CV
in the right atrial free wall. Second, total conduction time was
assessed by subtracting the mean earliest activation time (average of
the three earliest activation times) from the mean latest activation
time (average of the three latest atrial activation times during the
atrial complex). The wavelength for reentry was calculated as the
product of conduction velocity and ERP.13
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AFCL was calculated at each recording site by calculating the mean of 10 consecutive activation intervals. The results at all sites were averaged to obtain the overall mean AFCL under each condition. Regional variability of AFCL was assessed two ways. First, overall intersite variability was evaluated by calculating the SD in AFCL at all 112 recording sites. Second, regional differences were assessed by calculating mean AFCL at all sites within each of six zones: the left and right atrial appendage, Bachmann's bundle in the left and right atria, and right and left atrial free walls.
The activation pattern during AF was studied by constructing sequential atrial activation maps. Zones of reactivation were defined as zones activated early in one cycle that were reactivated at the beginning of the next cycle. The number of reactivation zones was determined for each of three successive AF cycles in each dog by an individual blinded to study group.
Statistical Analysis
Statistical comparisons of multiple group means were obtained by
ANOVA with Dunnett's test. The Kruskal-Wallis test was used for
nonparametric comparisons of unpaired measures. Stepwise
multilinear regression was used to assess the dependence of a single
dependent variable on multiple independent variables, and
linear regression was used to analyze single dependent and
independent variables. Average results are given as mean±SEM, and
a two-tailed value of P<.05 was considered statistically
significant.
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Results |
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Changes in AF Duration and Electrophysiological Properties
The duration of AF induced by burst pacing increased progressively with increased duration of rapid atrial stimulation (the Table
), increasing from 7.4±1.8 seconds (P0) to
2486±497 seconds after 6 weeks of rapid pacing (P42,
P<.0001). The number of dogs in which sustained AF was
induced increased progressively, from none under control conditions to
86% of P42 dogs. Pacing decreased ERP, CV, wavelength for reentry, and
rate-dependent ERP accommodation.
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Fig 2 shows the BCL-dependent changes in
atrial ERP, CV, and wavelength produced by rapid atrial pacing. Under
control conditions, ERP decreased in response to increased rate,
showing typical rate-dependent accommodation (Fig 2, top). Mean ERP
values (particularly at longer cycle lengths) and ERP accommodation to
rate were strongly diminished by rapid pacing, with decreases in
accommodation apparent within 1 day of the onset of pacing and near
maximal at 7 days. Rapid stimulation also reduced atrial CV; however,
the changes in CV were slower to develop than those in ERP, with
relatively small changes after 1 and 7 days of pacing and much more
pronounced alterations at 42 days (Fig 2, middle). Alterations in
wavelength reflect the time course of changes in both ERP and CV, with
a progressive reduction that becomes significant at longer cycle
lengths after 7 days and at all cycle lengths at 42 days (Fig 2, bottom).
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To confirm the effects of rapid pacing on atrial CV, we obtained two
other measures reflecting conduction speed (Fig 3). Pacing led to highly significant
decreases (P<.01) in CV over Bachmann's bundle and
increases (P<.01) in atrial conduction time under P42
conditions (Fig 3). These changes were highly correlated with right
atrial CV (r2=.94, P<.05 for
correlation between CV in Bachmann's bundle and right atrial free
wall; r2=.99, P<.01 for right
atrial CV versus conduction time).
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AF occurred spontaneously within 1 week in 3 of 13 P7 dogs (23%) and 2 of 7 P42 dogs (29%); by the end of the 6-week observation period, spontaneous and persistent AF had occurred in 4 of 7 P42 dogs (67%). When AF occurred spontaneously, the dog was not cardioverted and was left in the arrhythmia until the scheduled study day. There were no significant differences at electrophysiological study between dogs without spontaneous AF and those with AF: at a cycle length of 150 ms, ERP averaged 87±4 and 76±7 ms, CV averaged 92±4 and 86±7 cm/s, and wavelength was 7.8±0.5 and 7.0±0.6 cm in dogs without and with AF, respectively.
Relation Between Electrophysiological Changes and AF
Duration
Fig 4 shows the results of an
analysis of the relationship between AF duration and ERP, CV,
and wavelength. Individual symbols show results for each dog, and
symbols with error bars are the mean±SEM for each group. The
correlation was weak between individual values of ERP and AF duration
(r2=.136, P=.019), stronger for
AF duration as a function of CV (r2=.211,
P=.003), and strongest for AF duration as a function of
wavelength (r2=.277, P=.0005,
n=40 for each comparison). When ERP, CV, wavelength, and duration of
pacing were included as covariates in stepwise multilinear regression,
the correlation was best explained by a model including wavelength
(P=.018) and duration of pacing (P=.0001). These
results suggest that both ERP and CV changes contribute to the
progressive tendency to maintain AF, that alterations in wavelength
appear to reflect well their combined effects, and that pacing duration
affects AF duration independently of changes in ERP, CV, and
wavelength.
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Changes in Atrial Activation During AF
Fig 5 shows an analysis of
mean AFCL as a function of pacing interval. AFCL decreased
progressively with increased duration of rapid pacing, with significant
changes after 7 and 42 days (P<.01 for each). The SD of
AFCL (an index of AFCL variability) increased progressively during
rapid pacing (Fig 6, left). When the SD
of AFCL was expressed as a ratio of mean AFCL in each dog, to determine
the variation in AF interval relative to the interval itself, the
increases in variability became even more apparent (Fig 6, right). We
performed stepwise multilinear regression of AF duration on the
duration of rapid pacing, the mean AFCL, and the SD of AFCL in each dog
(n=40). Both AFCL and SD of AFCL were highly significant determinants
of AF duration (P<.0001 for each), and the model including
them accounted for 72% of the variance in AF duration
(R2=.721). The duration of rapid pacing did
not provide significant information in predicting AF duration
independently of mean AFCL and SD of AFCL.
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The increase in AFCL variability caused by rapid pacing could be due to
a random or highly localized (eg, site by site) increase in variability
or could be organized at a regional level. To address the latter
possibility, we analyzed the mean AFCL in six different atrial
regions, as illustrated in Fig 7. AFCL
was first determined at multiple electrode sites in the left atrial
appendage, the right atrial appendage, the left and right sides of
Bachmann's bundle, and the right and left atrial free walls. Data from
a total of four to nine (mean, seven) electrode sites were available
for analysis in each region. Values of AFCL at individual sites
are shown for representative dogs in each group in Fig 7. The AF interval decreased in dogs subjected to longer durations of
rapid pacing and appeared to decrease to a greater extent in some
zones, particularly in the left atrium, than in others. Fig 8 shows the mean (±SEM) AFCL in each of
the six regions for each group. In sham dogs, there were no
statistically significant regional differences in mean AFCL. After 7
and 42 days of rapid pacing, mean AFCL decreased from control values in
all regions, but decreases were larger in some regions than in others,
resulting in highly significant regional variability in AFCL. These
observations suggest that a substantial proportion of the increased
variability in AFCL resulting from sustained rapid pacing is due to
regionally determined differences in electrical remodeling.
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The final set of analyses addressed the pattern of epicardial
activation during AF. Fig 9 shows
activation data during three consecutive cycles of AF in a P0 dog (top)
and a P42 dog (bottom). In the P0 dog, the first cycle (top left) shows
one zone of early activation with a figure-eight pattern of
propagation. Electrograms from six sites show consecutive activation to
site f. Site a (asterisk) was reactivated from the region of
site f (dashed arrow), initiating the next cycle (top middle). The
overall activation pattern of this cycle was similar to the preceding
one, resulting in initiation of the next cycle by reactivation near
site a. In all P0 dogs, AF was characterized by one or two sites of
early activation per cycle and a fairly organized pattern of
activation. In paced dogs, activation became progressively more
complex. For the P42 dog shown in Fig 9 (bottom), the first cycle had
early-activating zones at the middle of Bachmann's bundle, the lateral
left atrium, and the medial left atrium. Reactivation of these zones
(asterisks, dashed arrows) initiated the next cycle (bottom middle).
Three early-activating zones in the middle cycle were also
reactivated (dashed arrows) to initiate the third cycle (bottom
right). Pacing dogs with sustained AF were characterized by multiple
spatially distinct regions initiating each cycle and complex activation
patterns. To quantify these activation changes, we calculated the mean
number of zones of reactivation per cycle during AF in each dog. For
example, the P0 dog illustrated in Fig 9 showed one reactivation zone
between cycles 1 and 2 and one between cycles 2 and 3 (asterisks in top
left and middle), whereas the P42 dog had three reactivation zones for
each cycle. As shown in Fig 10, rapid
pacing caused a progressive increase in the number of reactivation
zones per cycle of AF.
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Discussion |
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In the present study, we evaluated the time course of changes in atrial electrophysiology and activation during AF in dogs subjected to rapid atrial pacing. The results suggest that chronic atrial tachycardia causes progressive decreases in atrial ERP, in ERP adaptation to rate and in CV, along with progressive increases in the ability of single atrial extrasystoles to induce AF and in the duration of AF induced by burst pacing. The time course of changes in CV is slower than that of ERP alterations, contributing to increases in AF susceptibility after ERP changes are maximal. Activation studies indicate regional variability in the extent of electrophysiological remodeling (as reflected by the local AFCL), and point toward increases in the number of functional reentry zones during AF as the latter becomes more sustained.
Electrophysiological Changes Related to
AF
The present studies provide the first direct evidence (to our
knowledge) that chronic rapid atrial activation may lead to
abnormalities in atrial conduction. Increases in CV that occurred after
ERP changes stabilized likely contributed to delayed changes in AF
duration in our dogs and could account for the discrepancies between
the time courses of ERP changes and AF duration in the work of Wijffels
et al12 (although preliminary reports from the
same laboratory argue against conduction slowing in the goat
model14). Abnormalities of intra-atrial
conduction are known to be associated with clinical
AF,15–17 and it has long been known that
patients with AF have prolonged P waves when in sinus rhythm.
Conduction abnormalities favor AF by reducing the wavelength for
reentry5 and are usually considered to be
secondary to underlying atrial disease. Our findings raise the
interesting possibility that atrial conduction abnormalities can be due
to the arrhythmia itself, with AF being both a potential cause
and a consequence of atrial conduction abnormalities.
Tachycardia-induced conduction slowing may well have
contributed to the increases in P-wave duration noted in rapidly paced
dogs by Morillo et al11 and more recently by
Elvan et al.18
We found evidence for a role of regional differences in electrical remodeling in refractory properties during AF as reflected by local values of the AFCL. The most important changes occurred in the inferoposterior left atrial free wall, implying that regionally variable remodeling may contribute to the reduced left atrial refractoriness suggested by a variety of observations. In patients with AF, complex atrial activity is found during AF more often in the left compared with right atrium.19 Morillo et al11 found that in dogs subjected to 6 weeks of rapid atrial pacing, the inferoposterior left atrium shows particularly rapid activation during AF and is important in arrhythmia perpetuation. Li et al20 also found that rapidly paced dogs have shorter refractory periods in the left atrium, differences not observed in dogs with chronic pericarditis.20,21
The statistical importance of AFCL variability as an independent determinant of AF duration supports the importance of remodeling-induced electrical heterogeneity in the substrate for AF. This finding agrees with published observations supporting a role for atrial electrical heterogeneity in experimental AF.22–24 Heterogeneity in atrial repolarization also appears to be prominent in clinical AF25,26 and is associated with increased variability in AFCL at multiple atrial recording sites.27 Initial analyses did not provide evidence of increased refractoriness heterogeneity in the goat AF model of Wijjffels et al,12 but recently presented data from additional studies point toward increases in regional heterogeneity of refractoriness.28
Increased atrial vulnerability in humans is associated with a reduced atrial ERP adaptation to rate change,29 which resembles the ERP changes in our dogs. We have previously shown that atrial ERP is a major determinant of the ability of single extrasystoles to induce AF, with short local refractory periods facilitating AF induction.30 A loss of ERP adaptation to rate resulted in substantial ERP abbreviation at longer cycle lengths in both our dogs and previous studies,12,29 a factor that may be an important contributor to vulnerability to AF induction by premature beats.
Although multiple wavelet reentry is believed to underlie tachycardia-dependent AF,12 direct evidence from epicardial mapping studies has been lacking. In the present study, we observed changes in activation during AF compatible with multiple wavelet reentry and with an increased number of reentrant wave fronts stabilizing AF in rapidly paced dogs.
Possible Mechanisms Underlying Electrophysiological
Changes
The ionic mechanism of ERP alterations in patients with AF is
poorly understood. We have found that ERP alterations in dogs subjected
to rapid atrial pacing are probably due to alterations in action
potential duration caused by decreases in L-type
Ca2+ current.31 Action
potential duration changes in patients with
AF25,26 are similar to those we have noted in the
present model,31 and L-type
Ca2+ current is reduced in atrial cells from
patients with atrial dilation.32,33 We have also
obtained data that suggest that atrial myocytes of rapidly paced dogs
have reduced INa, possibly accounting for
conduction changes.34 There is evidence for
reduced connexin 40 expression in goats with AF-induced
remodeling,14 suggesting a potential role for
intercellular coupling changes in altering conduction.
Potential Clinical Relevance
The ability of AF to alter atrial electrophysiology means
that in patients with AF, the atrial substrate contains two elements:
the factors that permit the initial occurrence of AF and the changes
caused by AF per se. The latter component will vary in importance in
any given patient, depending on the duration and incidence of AF
episodes. The present study suggests that increased regional
heterogeneity in AFCL and the occurrence of conduction
slowing, common in patients with AF,27,35 may be
caused by rapid atrial activation during AF. The AF-promoting effect of
rapid pacing may also be relevant to the known predilection to AF of
patients with the Wolff-Parkinson-White syndrome in whom sustained
atrial tachycardias may create a substrate that can support
AF.36 To date, the therapy of AF has targeted the
electrophysiological properties promoting
maintenance of the arrhythmia; however, with improved
knowledge of the mechanisms underlying development of the substrate for
AF, it may become possible to target the substrate directly.
Limitations of Our Findings
The mapping system we used has a variety of limitations that must
be considered. The number of electrograms available (maximum, 112)
limits spatial resolution. Much better resolution can be obtained with
visual imaging systems based on voltage-sensitive
dyes.37 Dye-based techniques also have drawbacks,
including possible toxic effects of voltage-sensitive dyes and
chemicals needed to arrest cardiac contractility, a
need for ex vivo perfusion with crystalloid solutions, and a limited
field of vision. Possibly because of the limitations of our
system, we were unable to define complete reentry circuits at the
origin of many activation wave fronts during AF. On the other hand, we
were able to identify clear changes in the pattern of activation during
AF as a function of the period of atrial pacing. These changes are
consistent with an increased number of reentry circuits, in
keeping with the observed decreases in the wavelength for atrial
reentry, and support the concept that an increased number of
simultaneous circuits made possible by decreases in the
reentrant wavelength stabilize AF in dogs exposed to chronic atrial
tachycardia. Our observations are compatible with those of
Gray et al,37 who applied optical mapping with
voltage-sensitive dyes to record transmembrane potentials from
20 000 right atrial sites during AF in Langendorff-perfused sheep
hearts. These workers observed incomplete reentry circuits,
breakthrough patterns, and wave-front collision on the epicardial
surface, in agreement with earlier in vitro studies suggesting that
reentry can occur in a three-dimensional fashion and that the right
atrium cannot be treated fully as a two-dimensional
structure.38
We measured CV in the direction of rapid atrial propagation. Fiber orientation is an important determinant of CV in cardiac tissue, with lower junctional resistance in the longitudinal direction (parallel to the long axis of fibers) resulting in much more rapid longitudinal conduction compared with conduction transverse to fiber orientation.39,40 This property (referred to as tissue anisotropy) is particularly important in the atria and can vary at the microcospic level.40 Atrial geometry is complex, and issues of anisotropy, transmural conduction, and structural determinants (like the pectinate muscles and crista terminalis) are undoubtedly relevant to mechanisms underlying AF.37,39,40 These issues, while of great importance, are beyond the scope of the present study.
We considered AFCL to be an index of atrial refractoriness during AF in our AFCL heterogeneity studies. Previous studies have shown a good correlation between AFCL and ERP and have used AFCL as an index of refractory period during AF.27 However, refractory period may not be the only determinant of AFCL, and because of excitable gaps during AF, the true refractory period is likely to be less than the AFCL. Recent in vitro studies suggest that the minimum AF interval correlates well with local ERP and that the latter is less than the mean AFCL.41
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by grants from the Medical Research Council of Canada, the Quebec Heart Foundation, and the Fonds de Recherche de l'Institut de Cardiologie de Montréal. Dr Gaspo is a research fellow from the Medical Research Council of Canada. Dr Bosch is a holder of a fellowship from the Deutsche Forschungsgemeinschaft. The authors wish to thank Emma De Blasio and Mirie Levi for their skilled technical assistance.
Received June 10, 1997; revision received August 14, 1997; accepted August 27, 1997.
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Y.-g. Wang, M. B. Wagner, R. W. Joyner, and R. Kumar cGMP-dependent protein kinase mediates stimulation of L-type calcium current by cGMP in rabbit atrial cells Cardiovasc Res, November 1, 2000; 48(2): 310 - 322. [Abstract] [Full Text] [PDF]
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 H. S. Friedman, M. Win, A. Hussain, and A. Sinha Effects of Cardiac Glycosides on Atrial Contractile Dysfunction After Short-term Atrial Fibrillation Chest, October 1, 2000; 118(4): 1116 - 1126. [Abstract] [Full Text] [PDF]
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R. J. Ramirez, S. Nattel, and M. Courtemanche Mathematical analysis of canine atrial action potentials: rate, regional factors, and electrical remodeling Am J Physiol Heart Circ Physiol, October 1, 2000; 279(4): H1767 - H1785. [Abstract] [Full Text] [PDF]
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T. H. Everett IV, H. Li, J. M. Mangrum, I. D. McRury, M. A. Mitchell, J. A. Redick, and D. E. Haines Electrical, Morphological, and Ultrastructural Remodeling and Reverse Remodeling in a Canine Model of Chronic Atrial Fibrillation Circulation, September 19, 2000; 102(12): 1454 - 1460. [Abstract] [Full Text] [PDF]
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S. Nattel and D. Li Ionic Remodeling in the Heart : Pathophysiological Significance and New Therapeutic Opportunities for Atrial Fibrillation Circ. Res., September 15, 2000; 87(6): 440 - 447. [Abstract] [Full Text] [PDF]
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H. J. Sih, D. P. Zipes, E. J. Berbari, D. E. Adams, and J. E. Olgin Differences in organization between acute and chronic atrial fibrillation in dogs J. Am. Coll. Cardiol., September 1, 2000; 36(3): 924 - 931. [Abstract] [Full Text] [PDF]
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E. G. Manios, E. M. Kanoupakis, G. I. Chlouverakis, M. D. Kaleboubas, H. E. Mavrakis, and P. E. Vardas Changes in atrial electrical properties following cardioversion of chronic atrial fibrillation: relation with recurrence Cardiovasc Res, August 1, 2000; 47(2): 244 - 253. [Abstract] [Full Text] [PDF]
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D. Li, A. Benardeau, and S. Nattel Contrasting Efficacy of Dofetilide in Differing Experimental Models of Atrial Fibrillation Circulation, July 4, 2000; 102(1): 104 - 112. [Abstract] [Full Text] [PDF]
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R. G. Tieleman and H. J.G.M. Crijns The 'Second Factor' of tachycardia-induced atrial remodeling Cardiovasc Res, June 1, 2000; 46(3): 364 - 366. [Full Text] [PDF]
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H. M.W. van der Velden, J. Ausma, M. B. Rook, A. J.C.G.M. Hellemons, T. A.A.B. van Veen, M. A. Allessie, and H. J. Jongsma Gap junctional remodeling in relation to stabilization of atrial fibrillation in the goat Cardiovasc Res, June 1, 2000; 46(3): 476 - 486. [Abstract] [Full Text] [PDF]
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W. J. C. Hobbs, S. Fynn, D. M. Todd, P. Wolfson, M. Galloway, and C. J. Garratt Reversal of Atrial Electrical Remodeling After Cardioversion of Persistent Atrial Fibrillation in Humans Circulation, March 14, 2000; 101(10): 1145 - 1151. [Abstract] [Full Text] [PDF]
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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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 S. K. Doshi and B. N. Singh Reviews: Pure Class III Antiarrhythmic Drugs: Focus on Dofetilide Journal of Cardiovascular Pharmacology and Therapeutics, January 1, 2000; 5(4): 237 - 247. [PDF]
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 C. W. Hogue Jr and M. L. Hyder Atrial fibrillation after cardiac operation: risks, mechanisms, and treatment Ann. Thorac. Surg., January 1, 2000; 69(1): 300 - 306. [Abstract] [Full Text] [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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R. F. Bosch, X. Zeng, J. B. Grammer, K. Popovic, C. Mewis, and V. Kuhlkamp Ionic mechanisms of electrical remodeling in human atrial fibrillation Cardiovasc Res, October 1, 1999; 44(1): 121 - 131. [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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A. M. Gillis, D. G. Wyse, S. J. Connolly, M. Dubuc, F. Philippon, R. Yee, P. Lacombe, M. S. Rose, and C. D. Kerr Atrial Pacing Periablation for Prevention of Paroxysmal Atrial Fibrillation Circulation, May 18, 1999; 99(19): 2553 - 2558. [Abstract] [Full Text] [PDF]
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S. Nattel Atrial electrophysiological remodeling caused by rapid atrial activation: underlying mechanisms and clinical relevance to atrial fibrillation Cardiovasc Res, May 1, 1999; 42(2): 298 - 308. [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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W.-C. Yu, S.-H. Lee, C.-T. Tai, C.-F. Tsai, M.-H. Hsieh, C.-C. Chen, Y.-A. Ding, M.-S. Chang, and S.-A. Chen Reversal of atrial electrical remodeling following cardioversion of long-standing atrial fibrillation in man Cardiovasc Res, May 1, 1999; 42(2): 470 - 476. [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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L. Yue, P. Melnyk, R. Gaspo, Z. Wang, and S. Nattel Molecular Mechanisms Underlying Ionic Remodeling in a Dog Model of Atrial Fibrillation Circ. Res., April 16, 1999; 84(7): 776 - 784. [Abstract] [Full Text] [PDF]
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L.-P. Lai, M.-J. Su, J.-L. Lin, F.-Y. Lin, C.-H. Tsai, Y.-S. Chen, S. K. S. Huang, Y.-Z. Tseng, and W.-P. Lien Down-regulation of L-type calcium channel and sarcoplasmic reticular Ca2+-ATPase mRNA in human atrial fibrillation without significant change in the mRNA of ryanodine receptor, calsequestrin and phospholamban: An insight into the mechanism of atrial electrical remodeling J. Am. Coll. Cardiol., April 1, 1999; 33(5): 1231 - 1237. [Abstract] [Full Text] [PDF]
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S.-H. Lee, F.-Y. Lin, W.-C. Yu, J.-J. Cheng, P. Kuan, C.-R. Hung, M.-S. Chang, and S.-A. Chen Regional Differences in the Recovery Course of Tachycardia-Induced Changes of Atrial Electrophysiological Properties Circulation, March 9, 1999; 99(9): 1255 - 1264. [Abstract] [Full Text] [PDF]
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S. Fareh, C. Villemaire, and S. Nattel Importance of Refractoriness Heterogeneity in the Enhanced Vulnerability to Atrial Fibrillation Induction Caused by Tachycardia-Induced Atrial Electrical Remodeling Circulation, November 17, 1998; 98(20): 2202 - 2209. [Abstract] [Full Text] [PDF]
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J. Feng, L. Yue, Z. Wang, and S. Nattel Ionic Mechanisms of Regional Action Potential Heterogeneity in the Canine Right Atrium Circ. Res., September 7, 1998; 83(5): 541 - 551. [Abstract] [Full Text] [PDF]
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R. Gaspo, R. F. Bosch, E. Bou-Abboud, and S. Nattel Tachycardia-Induced Changes in Na+ Current in a Chronic Dog Model of Atrial Fibrillation Circ. Res., December 19, 1997; 81(6): 1045 - 1052. [Abstract] [Full Text]
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