(Circulation. 2000;101:1145.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Reversal of Atrial Electrical Remodeling After Cardioversion of Persistent Atrial Fibrillation in Humans
From the Manchester Heart Centre, Manchester Royal Infirmary, Manchester, UK.
Correspondence to Clifford J. Garratt, DM, Manchester Heart Centre, Oxford Rd, Manchester M13 9WL, UK. E-mail Clifford.Garratt{at}mhc.cmht.nwest.nhs.uk
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Abstract |
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Background—Although atrial electrical remodeling has been studied extensively in animal models, the reversibility of this phenomenon after termination of clinical atrial fibrillation (AF) has not been demonstrated. We aimed to examine this important question of reversibility by using AF cycle length (AFCL) and coupling intervals of atrial premature beats after cardioversion as measures of atrial refractoriness.
Methods and Results—We measured AFCL at the right atrial appendage and distal coronary sinus before attempting internal cardioversion in 39 patients with persistent AF. Patients were monitored by daily transtelephonic recordings after discharge and admitted rapidly for repeat internal cardioversion if there was spontaneous AF recurrence. Measurements of AFCL were repeated immediately before repeat cardioversions in the 17 patients who had recurrence of AF. There was an increase in AFCL from the initial cardioversion to that measured at the time of first AF recurrence at both the right atrial appendage (161±22 vs 167±26 ms, P=0.05) and distal coronary sinus (162±20 vs 168±22 ms, P=0.01) sites. The magnitude of increase in AFCL was positively correlated with duration of sinus rhythm before AF recurrence (r=0.524, P=0.001). Other measures of refractoriness (shortest coupling interval of atrial premature beats and directly measured refractory periods after cardioversion) also increased from initial to subsequent cardioversions.
Conclusions—These findings demonstrate that changes in atrial electrophysiology associated with chronic AF in humans are reversible after cardioversion and that the extent of this reversal is dependent on the duration of sinus rhythm after cardioversion.
Key Words: fibrillation • remodeling • cardioversion
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Introduction |
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Atrial fibrillation (AF) has a tendency to become more persistent with time. A large percentage of patients with paroxysmal AF eventually develop chronic AF.1 Recently Wijffels and coworkers2 have demonstrated, in a chronically instrumented conscious goat model, that episodes of AF may be self-perpetuating ("AF begets AF") and have suggested that there may be a purely electrophysiological explanation for the increased persistence of AF with time. The self-perpetuating process in this animal model is associated with a marked shortening of atrial refractoriness and loss of the normal adaptation of atrial refractoriness to heart rate (termed atrial electrical remodeling) that is reproducible in other animal models.3 4 5 These authors suggested that the refractoriness changes would stabilize episodes of AF by decreasing atrial wavelength (wavelength=refractory periodxconduction velocity), leading to an increase in the potential number of electrical reentrant wavelets in the atria and thereby increase AF stability as predicted by Moe’s multiple wavelet hypothesis.6
In the animal model described above, the remodeling process is reversible and atrial refractoriness returns completely to normal within 1 week of cessation of burst pacing (or DC cardioversion) and resumption of sinus rhythm. During this "remodeling reversal" phase the atria are in a state of increased vulnerability, which has been suggested as the mechanism for the markedly increased risk of AF recurrence seen in patients with chronic AF in the first week after cardioversion.7 A logical extension of this suggestion is that if such a patient could be kept in sinus rhythm over this short period, then subsequent likelihood of recurrence would be dramatically lowered. This possibility forms an attractive theoretical basis for the use of repeated early cardioversions in such patients. Alternatively, if atrial remodeling were found to be irreversible in humans, then it would be difficult to support such a strategy in this patient group, at least on the basis of the atrial remodeling hypothesis.
The aim of this study was to examine the hypothesis that atrial electrical remodeling is reversible after DC cardioversion in patients with persistent AF. We compared AF cycle length (AFCL) (as a measure of atrial refractoriness)8 recorded at the time of cardioversion of persistent AF with that recorded at the time of subsequent spontaneous AF recurrences in the same patient group. In addition, we compared the shortest coupling interval of atrial premature beats (as a separate measure of atrial refractoriness) after initial and subsequent cardioversions. Finally, in a subset of patients, atrial effective refractory periods were measured directly after both initial and subsequent cardioversions.
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Methods |
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Patient Selection
Consecutive patients with persistent AF (minimum duration of 3 months) documented by serial ECGs were considered for the study. Written informed consent was obtained through the use of an information sheet and consent form approved by the Central Manchester Research Ethics Committee, which also approved the protocol. Planned exclusion criteria for the study were a contraindication to anticoagulation, pregnancy, and a lack of willingness to undergo repeated cardioversion at short notice in the event of spontaneous AF recurrence. Only 2 patients under consideration were actually excluded from entry into the study, both because of difficulties in traveling rapidly from their homes to the hospital.
Study Protocol
Patients were admitted to the hospital for internal
cardioversion of persistent AF (CV1) after at least 4 weeks of adequate
anticoagulation. Blood was sampled for measurement of International
Normalized Ratio weekly and on the day before the planned procedure.
Transesophageal echocardiography
was performed immediately before cardioversion in any patients with a
measured International Normalized Ratio <2.0 at any time in the 4
weeks before the procedure. Anticoagulation was not stopped before
cardioversion. Antiarrhythmic medication was stopped 3 full days before
the procedure in all patients except those taking amiodarone,
which was continued.
Initial Cardioversion
A TADcath model 8010 temporary transvenous defibrillation
catheter (110 cm, Cournand Curve, ProCath Corp) was inserted into the
coronary sinus through the right internal jugular vein. This is
an 11-electrode catheter, 2 electrodes being used for bipolar
pacing/sensing and 9 comprising the defibrillation electrode. A second
defibrillation catheter was placed in the right atrium through the
right femoral vein, with the tip in the right atrial appendage and
positioned so that the majority of the catheter electrodes had contact
with the right atrial free wall. Before delivery of shock energy,
bipolar electrogram recordings of 1-minute duration were made
at the right atrial appendage by use of the distal electrode pair (2-mm
interelectrode distance) of a quadripolar catheter (Daig) and one at
the most distal coronary sinus position possible by use of the
sensing electrode pair of the defibrillation catheter. A quadripolar
catheter was positioned at the right ventricular apex to
allow synchronization of the defibrillation shock, appropriate
synchronization being confirmed with a Defibrillation Systems Analyser
(DSA, InControl). Immediately before shock delivery, 2 to 12 mg of
midazolam was administered intravenously to ensure adequate
sedation. Defibrillation DC shocks were delivered between the right
atrial and coronary sinus electrodes at an output of 400 V with
a 6/6 ms biphasic truncated exponential waveform. If the first shock
was unsuccessful, the right atrial defibrillation catheter was
repositioned and the procedure repeated.
Postcardioversion Measurements
After successful cardioversion, bipolar recordings of
spontaneous atrial activity were made from the right atrial and distal
coronary sinus electrodes already in place. The coupling
intervals of all atrial premature beats (APBs) occurring in the
immediate postcardioversion period (2 minutes) were measured (shortest
A-A interval in either endocardial signal) with the use of on-screen
calipers at a screen speed of 100 mm/s. Fifteen minutes after
successful cardioversion, right atrial effective refractory periods
were measured (twice diastolic threshold, pacing cycle
lengths 250, 300, 400, 500, 600, and 700 ms) in the subset of patients
who agreed to this part of the protocol.
Patient Follow-Up and Repeat Cardioversions
Patients were discharged the day after the procedure.
Antiarrhythmic therapy was not reinstituted after cardioversion (except
for amiodarone, which, if present before cardioversion was
continued throughout), but anticoagulation was continued for 
6 weeks.
Patients made transtelephonic recordings of their cardiac
rhythm to a central monitoring station on a daily basis for 35 days
after the procedure. Transtelephonic recordings also were made
in the event of symptoms suggestive of return of arrhythmia
during this period. In the event of a confirmed recurrence of
AF, patients were readmitted as rapidly as possible for repeat internal
cardioversion (CV2). Immediately before the repeat cardioversion,
patients underwent intracardiac recordings as described for the
initial procedure. The complete protocol was repeated for up to a
maximum of 2 recurrences.
Data Analysis
The endocardial signals were acquired with the use of a
multichannel Cardiolab system (Pruka Engineering Inc) and stored on
optical disk. Individual atrial electrograms were identified with the
use of predefined criteria and marked manually with the use of a
mouse-driven program. Atrial electrograms with an apparent separation
of <90 ms were considered to be double potentials from a single atrial
activation. AFCLs were calculated automatically with the use of
commercially available software (Pruka Inc). AFCL (mean±SD of
recordings taken over a period of 1 minute) at the initial
cardioversion of persistent AF was compared with that at the time of AF
recurrence in the same patients. The relation between duration
of sinus rhythm after cardioversion and change in AFCL between initial
and subsequent cardioversions was examined for the whole group.
Comparisons also were made between initial and subsequent
cardioversions in terms of postcardioversion measurements, in
particular, (1) shortest APB coupling intervals immediately after
cardioversion and (2) right atrial refractory periods after
cardioversion. Statistical comparisons between the 2 groups were
performed by Student’s t test (2-tailed) 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 was used for multiple group comparisons, followed by a
Bonferroni corrected t test or a corrected Mann-Whitney rank
sum test. Continuous data were expressed as mean±SD, and a value of
P<0.05 was considered statistically significant.
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Results |
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Clinical Characteristics
Thirty-nine patients were entered into the study and underwent attempted internal cardioversion of persistent AF. Mean duration of AF before attempted cardioversion was 38 months (range 3 to 384), and 7 patients had previously failed
1 external cardioversion. Of these 39
patients, sinus rhythm could not be achieved in 5 patients, and in a
further 5 there was repeated recurrence of AF in the
electrophysiology laboratory. Twenty-nine patients left the
electrophysiology laboratory in sinus rhythm. Of these 29, 17 patients
(the study group) had a recurrence of AF within the following
35 days (mean time in sinus rhythm 129 hours, range 1 to 740). Mean
time from AF recurrence to measurement of AFCL and repeat
cardioversion was 17±13.9 hours. The clinical characteristics of the
total patient group, the 29 patients who left the laboratory in sinus
rhythm and the 17 patients who had 1 recurrence of AF, are
detailed in the Table
. Patients leaving the
electrophysiology laboratory in sinus rhythm had a trend toward a
shorter arrhythmia history than those who remained in AF
(26±32 vs 38±66 months, NS), but there were no differences in
clinical characteristics between those patients who had subsequent
arrhythmia recurrence (the study population) and those
who did not.
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Change in AF Cycle Length
Figure 1 shows the change in AFCL
measured at the time of the initial cardioversion (CV1) from that
recorded at the time of first recurrence of AF (CV2) for
all 17 patients with AF recurrence. There is a significant
increase in cycle length at both the right atrial appendage (RAA)
(161±22 vs 167±26 ms, P=0.05) and distal coronary
sinus (DCS) (162±20 vs 168±22 ms, P=0.01) sites. In 7
patients with measurements at the time of a second recurrence
(third cardioversion, CV3) there was a progressive increase in AFCL
with each recurrence. AFCL at the RAA increased from 156±26
(CV1) to 161±20 (CV2) and then 174±27 (CV3) (P=0.02,
ANOVA) in this group. Corresponding values for the DCS were 164±24
(CV1) to 167±20 (CV2) and then 180±27 (CV3) (P=0.03). A
representative example of electrograms recorded
from both sites at the time of 3 successive cardioversions is shown in
Figure 2. In Figure 3, histograms derived from measurement of
individual AFCLs at the time of each of 3 cardioversions in a single
patient are shown.
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Effect of Duration of Sinus Rhythm Before AF Recurrence
Figure 4 shows the relation between
change in AFCL (between CV1 and CV2) and time in sinus rhythm between
cardioversions in all 17 patients with AF recurrences. The
longer the duration of sinus rhythm before recurrence of AF,
the greater the difference in AFCL between chronic AF and
recurrence. The relation is exponential rather than linear,
with time in sinus rhythm plotted on a logarithmic scale
(r=0.524, P=0.001).
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) are obscured in
2 patients because of identical AFCLs measured at DCS (•).
Ventricular Rates During AF
There were no significant differences in mean
ventricular rate measured (at the same time as AFCL
measurement) immediately before CV1, CV2, or CV3 (87±10, 94±25, and
86±16 per minute, respectively).
Coupling Intervals of Atrial Premature Beats After
Cardioversion
Of the 17 patients undergoing repeated internal cardioversion
after a relapse of AF, 12 had atrial premature beats (APBs) present
in the immediate postcardioversion period. In these patients, the
shortest APB coupling interval increased from a mean of 325±59 ms
after cardioversion of persistent AF to 395±124 ms after cardioversion
of the first recurrence (P<0.05). The mean cycle
length of sinus beats immediately before the shortest coupled atrial
premature beat did not change from one cardioversion to the next
(951±232 ms for CV1, 923±232 ms for CV2, 959±193 ms for CV3,
difference not significant), and there was no difference in mean R-R
interval during sinus rhythm after the respective cardioversions.
Figure 5 shows a
representative example of the shortest coupled atrial
premature beats after 3 successive cardioversions in a single
patient.
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Atrial Refractory Periods After Cardioversion
Refractory period measurements at the right atrium were obtained
at both initial and second cardioversions in a subset of 5 patients
(Figure 6). There was a
significant increase in refractory periods at the longer pacing cycle
lengths (500, 600, and 700 ms) from CV1 to CV2.
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Conclusions
Main Findings
This study has demonstrated for the first time that the
electrophysiological characteristics of
acute recurrences of AF differ from those of the corresponding
chronic arrhythmia in the same patient group. Mean cycle length
of AF was significantly longer, when measured at the RAA and DCS,
shortly after the onset of acute AF recurrence than immediately
before the initial cardioversion of chronic AF. This increase is
progressive with repeated spontaneous recurrences of AF. These
findings support the hypothesis that AF-induced changes in atrial
electrophysiology (atrial electrical remodeling) are reversible after
cardioversion of persistent AF in humans. Previous work has shown that
(1) chronic AF in humans is associated with a reduction in
refractoriness9 and (2) there is a strong
correlation between measures of atrial refractoriness and AFCL at any
particular atrial site,8 which suggests that a reversal of
refractoriness change is the most likely underlying mechanism. Further
support for this conclusion is the finding that other measures of
refractoriness examined in this study (shortest coupling interval of
APBs and directly measured refractory periods) also showed an increase
from the initial cardioversion to that of an acute
recurrence.
Correlation Between Change in AFCL and Duration of Sinus
Rhythm
The demonstration of a positive correlation between the magnitude
of increase in AFCL and duration of sinus rhythm between cardioversions
provides strong support for the suggestion that this change is related
to a reversal of AF-induced changes in atrial electrophysiology and
argues against any artifactual change occurring as a result of repeated
sedation or catheterization. Although it could be
argued that patients may be more familiar with the procedure at the
time of the second cardioversion (and that this might have an influence
on refractoriness through autonomic changes), any such effect would be
expected to decrease rather than increase with increasing separation of
the 2 procedures in time. Other arguments against a possible change in
autonomic tone from one cardioversion to another are (1) the lack of
difference in ventricular rate during AF and (2) the lack
of difference in sinus rate after cardioversion from one procedure to
the next observed in this study. The positive correlation between AFCL
change and time in sinus rhythm is evident despite the confounding
factor of differences in durations of AF recurrence before
measurement of AFCL (as a result of differences in proximity of the
patients to the hospital and availability of the electrophysiology
laboratory), which emphasizes the influence of sinus rhythm on atrial
electrophysiology. The logarithmic nature of the relation between
changes in atrial electrophysiology and time in sinus rhythm is
consistent with what has been described previously in animal
models of AF.10
Other Measures of Refractoriness Change
The principal evidence for reversal of refractoriness after
cardioversion in this study relies on indirect measures of
refractoriness such as AFCL and APB coupling interval. Capucci and
coworkers8 have shown that there is a strong correlation
between mean AFCL and the atrial effective or functional effective
refractory period at the same atrial site in patients with lone
paroxysmal AF. Animal studies confirm a strong correlation between
refractoriness and AFCL.11 The use of AFCL as a measure of
atrial refractoriness allowed us to examine reversibility of remodeling
specifically in patients with AF recurrences rather than those
who maintained sinus rhythm in the long term after cardioversion (see
clinical relevance below).
Tieleman and coworkers7 have demonstrated previously that there is a correlation between the shortest coupling interval of APBs after cardioversion of persistent AF and likelihood of early relapse of arrhythmia. They suggest that this is due to the presence of atrial remodeling and shortened refractoriness after cardioversion, that is, shortened refractoriness leads to both shortened APB coupling interval and arrhythmia relapse. In the current study we used the shortest APB coupling interval as a measure of refractoriness and showed that this parameter increased between CV1 and CV2, consistent with the changes in AFCL discussed above.
Direct measurements of atrial effective refractory period after cardioversion were made in only a subset of patients at the time of acute AF recurrence: A number of patients were unwilling to take the risk of reinduction of AF and requirement for further shocks at this time. Nevertheless, the results of these measurements were entirely consistent with those of AFCL and shortest APB coupling interval.
Previous Evidence for Atrial Electrical Remodeling and Its
Reversibility in Humans
Franz and coworkers9 have demonstrated that in
patients after cardioversion of persistent AF or atrial flutter, there
is a marked decrease in the right atrial monophasic action potential
duration during steady-state pacing and extrastimulation relative to
control patients without atrial arrhythmias. In addition, these
workers showed a "flat" response of atrial monophasic action
potential duration to changes in heart rate, similar to the flattened
rate adaption curve seen in the goat model.2 They
interpreted these findings as demonstrating atrial electrical
remodeling occurring in humans as a consequence of persistent clinical
AF. Previous studies had shown that a flat rate adaptation curve is
associated with an increased susceptibility to atrial
arrhythmias in humans.12 The only previous
clinical study that has examined reversibility of remodeling is that of
Daoud and coworkers,13 in which the atrial refractory
period response to very short episodes of induced AF was measured.
Short bursts of AF resulted in reduction of atrial refractory periods
(measured at 350- and 500-ms pacing cycle length) and then, within a
few minutes of sinus rhythm, returned to normal. The current study
extends the findings of these authors in that it demonstrates
reversibility in patients with spontaneously occurring, persistent
clinical AF rather than in subjects with induced, short-lasting,
"nonclinical" episodes. The time courses of increase in
refractoriness after AF termination in these 2 studies are very
different (being much slower in the current study), which suggests that
2 distinct physiological or
pathophysiological processes are involved. The fact
that in the current study these changes are still demonstrable several
hours after onset of AF recurrence indicates that they have a
time course similar to that described in the goat model (ie, lasting
hours rather than minutes).10
Limitations of the Study
It is possible that a number of
electrophysiological variables other
than atrial refractoriness are "remodeled" during persistent AF.
Studies in dog models of atrial fibrillation have shown decreasing
conduction velocity in the atria14 and prolonged surface
P-wave duration4 after prolonged periods of high-rate
atrial pacing. Gaspo and coworkers14 15 have demonstrated
that this atrial pacing–induced conduction slowing in dogs has a
slower time course than that of atrial refractoriness change and
suggest that this effect may constitute an important additional factor
in the self-perpetuation of AF. No attempt was made to assess changes
in conduction velocity in the current study, and further studies are
necessary to address this question.
This study was not designed to address the issue of whether the likelihood of AF recurrence is related to the degree or rate of reversal of remodeling in any particular patient.
Clinical Relevance
The demonstration of reversibility of atrial electrical remodeling
in the current study has important clinical
implications.16 17 It is perhaps the most convincing
evidence to date for the existence of remodeling in humans and provides
a mechanism whereby focal18 or reentrant19
"origins" of AF may degenerate to the typical complex
arrhythmia seen in most patients. It supports the hypothesis
that the persistence of remodeling in the first few days after
cardioversion of persistent AF is the mechanism of the increased rate
of AF recurrence during this period.7 This finding
highlights the potential role of therapies that target the remodeling
process in the management of AF. In addition, it suggests that if these
patients can be kept in sinus rhythm for sufficient time for remodeling
to reverse, the subsequent likelihood of recurrence should be
significantly lowered, forming an attractive theoretical basis for the
use of repeat "acute" cardioversions in the event of early AF
recurrences in such patients. The current study was not
designed to examine the clinical benefit of reversal of remodeling in
patients with AF (repeat cardioversions were limited to 2
recurrences), but preliminary studies of patients with
implanted atrial defibrillators20 suggest that AF
recurrence rate may be reduced after implantation of these
devices.
The electrophysiological differences between chronic AF and acute recurrences in this study suggests that the latter might be more likely to terminate with antiarrhythmic drug therapy. In the study of Capucci and coworkers,8 a progressive increase in mean AFCL interval with time was associated with early termination of AF, and several studies have shown an increase in mean AFCL before termination of AF by drugs. Further clinical studies are required to test this hypothesis formally.
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Acknowledgments |
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Drs Hobbs, Fynn, and Todd are supported by the British Heart Foundation. Dr Todd was supported by a grant from InControl Europe during the pilot phase of the study.
Received April 29, 1999; revision received September 27, 1999; accepted October 8, 1999.
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B. Gorenek, G. Kudaiberdieva, O. Goktekin, Y. Cavusoglu, A. Birdane, A. Unalir, N. Ata, and B. Timuralp Long-short sequence may predict immediate recurrence of atrial fibrillation after external cardioversion Europace, January 1, 2003; 5(1): 11 - 16. [Abstract] [PDF]
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S. P. Fynn and C. J. Garratt The effectiveness of serial cardioversion therapy for recurrence of atrial fibrillation Eur. Heart J., October 1, 2002; 23(19): 1487 - 1489. [Full Text] [PDF]
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 K. Fan, K. L. Lee, W.-H. Chow, E. Chau, and C.-P. Lau Internal Cardioversion of Chronic Atrial Fibrillation During Percutaneous Mitral Commissurotomy: Insight Into Reversal of Chronic Stretch-Induced Atrial Remodeling Circulation, June 11, 2002; 105(23): 2746 - 2752. [Abstract] [Full Text] [PDF]
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K. Shinagawa, Y.-F. Shi, J.-C. Tardif, T.-K. Leung, and S. Nattel Dynamic Nature of Atrial Fibrillation Substrate During Development and Reversal of Heart Failure in Dogs Circulation, June 4, 2002; 105(22): 2672 - 2678. [Abstract] [Full Text] [PDF]
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 M. Allessie, J. Ausma, and U. Schotten Electrical, contractile and structural remodeling during atrial fibrillation Cardiovasc Res, May 1, 2002; 54(2): 230 - 246. [Abstract] [Full Text] [PDF]
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B. J.J.M. Brundel, R. H. Henning, H. H. Kampinga, I. C. Van Gelder, and H. J.G.M. Crijns Molecular mechanisms of remodeling in human atrial fibrillation Cardiovasc Res, May 1, 2002; 54(2): 315 - 324. [Abstract] [Full Text] [PDF]
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S. Nattel Therapeutic implications of atrial fibrillation mechanisms: can mechanistic insights be used to improve AF management? Cardiovasc Res, May 1, 2002; 54(2): 347 - 360. [Abstract] [Full Text] [PDF]
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T. Korte, M. Niehaus, G. Borchert, and J. Tebbenjohanns Significant prolongation of atrial monophasic action potential duration: short-term reverse electrophysiological changes after internal cardioversion of atrial fibrillation Cardiovasc Res, March 1, 2002; 53(4): 944 - 951. [Abstract] [Full Text] [PDF]
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K. Shinagawa, D. Li, T. K. Leung, and S. Nattel Consequences of Atrial Tachycardia-Induced Remodeling Depend on the Preexisting Atrial Substrate Circulation, January 15, 2002; 105(2): 251 - 257. [Abstract] [Full Text] [PDF]
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A. J Workman, K. A Kane, and A. C Rankin The contribution of ionic currents to changes in refractoriness of human atrial myocytes associated with chronic atrial fibrillation Cardiovasc Res, November 1, 2001; 52(2): 226 - 235. [Abstract] [Full Text] [PDF]
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S.P Fynn, D.M Todd, W.J.C Hobbs, K.L Armstrong, and C.J Garratt Role of dispersion of atrial refractoriness in the recurrence of clinical atrial fibrillation. A manifestation of atrial electrical remodelling in humans? Eur. Heart J., October 1, 2001; 22(19): 1822 - 1834. [Abstract] [PDF]
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 R. H. Falk Atrial Fibrillation N. Engl. J. Med., April 5, 2001; 344(14): 1067 - 1078. [Full Text] [PDF]
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H. J. G. M. Crijns Internal cardioversion as a first-line method of cardioversion? Europace, January 1, 2001; 3(1): 2 - 3. [PDF]
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 C.J. Garratt and S.P. Fynn Atrial electrical remodelling and atrial fibrillation QJM, September 1, 2000; 93(9): 563 - 565. [Full Text] [PDF]
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