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(Circulation. 2001;103:1157.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Pulmonary Veins and Ligament of Marshall as Sources of Rapid Activations in a Canine Model of Sustained Atrial Fibrillation
From the Division of Cardiology (T.-J.W., C.-T.T.), Department of Medicine, Taichung Veterans General Hospital and Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; and the Division of Cardiology (J.J.C.O., C.-M.C., R.N.D., M.Y., H.-L.A.H., H.S.K., P.-S.C.), Department of Medicine, Cedars-Sinai Medical Center and the Department of Pathology and Laboratory Medicine (M.C.F.), UCLA School of Medicine, Los Angeles, Calif.
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionReferences |
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Background—In dogs, chronic rapid pacing may result in sustained atrial fibrillation (AF). However, activation patterns in pacing-induced sustained AF are unclear.
Methods and Results—We induced sustained AF (>48 hours) in 6 dogs by rapid pacing for 139±84 days. We then performed computerized atrial epicardial mappings and recorded the activations in the ligament of Marshall (LOM) and the pulmonary veins (PVs). During AF, mean activation cycle length in the right atrial free wall (126±17 ms) was significantly longer than that in the left atrial free wall (96±5 ms, P=0.006). In addition, mean activation cycle length in the left atrial free wall was significantly longer than that in the LOM (84±5 ms, P<0.001), the left inferior PV (81±4 ms, P=0.001), and the left superior PV (85±7 ms, P=0.003). Similarly, the dominant frequency was highest in the LOM and the PVs (range 11.2 to 13.3 Hz), followed by the left and right atria (P<0.001). In all dogs studied, rapid and complicated electrograms were consistently observed at the LOM and the PVs. During AF, both wandering wavelets and organized reentry were present. There were more wave fronts in the left atrium than in the right atrium (P<0.001).
Conclusions—In chronic pacing-induced sustained AF, the LOM and the PVs are the sources of rapid activations. The mechanism by which the left atrium activates faster and has more wave fronts than the right atrium may relate to the fact that the left atrium is closer to the sources of rapid activations.
Key Words: arrhythmia • fibrillation • mapping • pacing • pathology
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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It has been demonstrated in animal models that chronic rapid pacing may induce sustained atrial fibrillation (AF).1 2 3 The mechanisms by which sustained AF occurred were usually attributed to atrial electrical remodeling, as evidenced by the progressive shortening of the atrial effective refractory period (AERP).1 2 3 Because AERP has been reported to be shorter in the left atrium (LA) than in the right atrium (RA),3 4 the LA would have more reentrant wave fronts and more complex activation patterns than the RA. However, because the activation patterns in chronic pacing-induced sustained AF are not well defined, it is unclear whether reentry is present in pacing-induced AF. In addition to the LA and the RA, other structures such as the pulmonary veins (PVs)5 and the ligament of Marshall (LOM)6 also contain muscle fibers that are electrically active. Rapid activations from these structures are known to be responsible for paroxysmal AF in humans.7 8 9 We10 have previously demonstrated that the LOM in dogs with long-term rapid pacing serves as a source of rapid activations and may contribute to the development of AF in vitro. On the basis of these results, we hypothesize that rapid activations from these structures may also play roles in the formation of sustained AF in vivo. In the present study, we used chronic rapid pacing to induce sustained AF in dogs. During AF, the entire epicardial surfaces of both atria, the LOM, and the PVs were mapped with densely spaced bipolar electrodes. The purpose of this study was to test the following hypotheses: (1) chronic pacing-induced sustained AF is characterized by the presence of both wandering wavelets and organized reentry; and (2) there is an activation rate gradient during sustained AF, with the faster rate in the LOM and the PVs, followed by the LA and the RA.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Chronic Pacing-Induced Sustained AF
The method used to induce sustained AF has been described previously.10 Briefly, 6 mongrel dogs (weight 17 to 25 kg) were used. Under general anesthesia, a bipolar pacing lead was inserted via a right jugular vein into the RA appendage. The pulse generator (Medtronic Itrel neurostimulator) was programmed to burst pace at a pacing interval of 50 ms for 5 seconds, followed by a 2-second period without pacing. Digoxin (0.125 to 0.25 mg/d) was given to control ventricular rate. The pacemaker was then turned off periodically so that the animals could be checked for the presence of sustained AF (>48 hours in duration). When sustained AF was documented, the dogs were ready for the mapping study.
Computerized Mappings
In dogs 1 to 5, we performed high-density
computerized mapping studies using 480 bipolar electrodes. As shown in
Figure 1A
, 4 large plaque electrodes with 2.5-mm
interelectrode distance were used to cover the entire epicardial
surfaces of the LA (1 and 2) and the RA (3 and 4) free walls. The
electrodes were connected to a computerized mapping system for data
acquisition.11 To
simultaneously record the activations in the LOM, a small plaque
(4.5x1.0 cm, marked "LOM" in
Figure 1A) containing 30 bipolar electrodes with 5.0-mm
interelectrode distance was used to map the posterolateral LA. In
addition, 1 pair of hook bipolar recording electrodes was inserted into
each PV within 1 cm of the atrial free wall. We also inserted a basket
electrode catheter (Webster) via the femoral vein into the RA to
register the activations in the interatrial septum using 5 bipolar
recording electrodes.
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In 1 dog (dog 6), 4 pairs of hook bipolar recording electrodes were evenly placed in each of the atrial free walls. Similarly, activations in the LOM (2 pairs of hook bipolar electrodes) and in the PVs (1 pair of hook bipolar electrodes for each) were also registered. Both the epicardial bipolar electrograms and the surface ECG were acquired continuously.10 This dog (dog 6) served as a control to rule out the possibility that large plaque electrodes used in dogs 1 to 5 might alter the activation rates in the areas mapped.
Cardioversions
In dogs 1 to 5, after sustained AF was mapped,
synchronized cardioversions (25 to 50 J) were attempted to convert the
rhythm from AF to sinus rhythm. Computerized mappings of sinus rhythm
and during the spontaneous recurrence of AF were then
performed.
Histological Examination
At the conclusion of each study, the hearts were
fixed and processed routinely. The sections were stained with
hematoxylin-eosin and trichrome. The areas with slow conduction and
conduction block were correlated with the anatomic
findings.
Data Analysis
We analyzed 3 runs of AF (8 seconds per run) in each
dog according to the methods reported
previously.11 Briefly, the
computer selected a time as the local activation if the dV/dt exceeded
20% of the maximal dV/dt in that channel and if an interval of 50 ms
had passed since a previous activation.
Figure 1C
shows an example. The activations selected by the
computer were marked by vertical lines. Manual editing was then
performed to select the activations (vertical arrows) with the dV/dt
<20% of the maximum. The deflections within 50 ms of a
computer-selected activation were not selected manually (asterisks).
Once the times of activation were determined, they were displayed
dynamically.11 The patterns
of activation were then studied. For analysis of organized reentry and
lines of conduction block, we focused on 1 plaque at a time by repeated
displays.
We also performed fast Fourier transforms (FFTs) on bipolar
electrograms from different
regions.12 The relative
amplitudes of peaks in each FFT were compared to determine the dominant
peak and the dominant frequency
(Figure 1D).
ANOVAs with repeated measures were performed to determine
whether there were differences in the activation cycle lengths among
different regions. If ANOVA showed significant differences, we then
used paired t tests to compare
the means of activation cycle lengths. The interatrial septum and the
right PVs were not included in analyses because of missing data
(Table).
ANOVA was also used to compare the dominant frequency among different
regions. Students’ t tests
were used to compare the mapping data (such as the number of wave
fronts and the length of line of block) between the LA and the RA. A
P value 
0.05 was considered
significant. In case of multiple comparisons, Bonferroni adjusted
probability values were used to determine
significance.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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After 139±84 days of rapid pacing, sustained AF was induced in all 6 dogs. These dogs were studied 27±25 days after sustained AF was documented. All dogs arrived at the laboratory in AF with a mean ventricular cycle length of 508±46 ms. All dogs continued to fibrillate throughout the experiments or until successful cardioversion. There was no clinical evidence of heart failure in any dog studied.
Activation Rate Gradient During Sustained
AF
The time between the first and third runs of AF
analyzed averaged 12±2.7 minutes. The variability of activation cycle
lengths, estimated by the difference between the fastest and the
slowest runs, was 4.2±1.7 ms.
During sustained AF, there was an activation rate gradient
in all 6 dogs studied. As shown in
Figure 1B and the
Table,
activation was faster in the PVs and the LOM, followed by the LA and
the RA free walls. There were no differences among the LOM and the left
inferior or left superior PVs. Mean activation cycle length at the RA
free wall was significantly
(P=0.006) longer than that at
the LA free wall. Furthermore, mean activation cycle length in the LA
free wall was significantly longer than that in the LOM
(P<0.001), the left inferior
PV (P=0.001), and the left
superior PV (P=0.003).
Complicated activations, defined as frequent occurrences of deflections
separated by intervals of <50 ms, were consistently observed at the
LOM and the PVs in all dogs studied
(Figures 1B and 1C).
FFT analyses also showed a gradient of dominant frequency
distribution, with the higher frequency in the LOM (12.1±1.0 Hz) and
the PVs (left superior PV 11.7±0.8 Hz, left inferior PV 12.0±0.4 Hz),
followed by the left (10.2±0.6 Hz) and the right (8.0±1.0 Hz) atria
(P<0.001). Examples are shown
in
Figure 1D. The site with the highest dominant frequency
(range 11.2 to 13.3 Hz) was located at the LOM in 4 and the left
inferior PV in 2 dogs.
Spontaneous Recurrence of AF After
Successful Cardioversion
Successful cardioversion was achieved in dogs 1, 2, and
3. Among these dogs, dogs 1 (6 episodes) and 2 (2 episodes) had
spontaneous recurrence of AF within 10 minutes after successful
cardioversion. In dog 3, however, there was no atrial ectopic beat or
recurrent AF after successful cardioversion.
These AF episodes were initiated by a single ectopic beat
arising either from the high RA (dog 1) or from the LA free wall (dog
2). The single ectopic beat first induced a short period (788±333 ms)
of more organized activity (atrial tachycardia). It was then followed
by rapid activations (cycle lengths, range 65 to 120 ms) converting
atrial tachycardia to AF. Both the earliest activations during atrial
tachycardia and the rapid activations during transition to AF were
consistently recorded by the electrodes overlying the LOM.
Figure 2 shows an example, suggesting the possible
importance of the LOM for AF recurrence.
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Characteristics of Wave Fronts
During Sustained AF
As described
previously,13 multiple wave
fronts were observed in each episode of sustained AF. In addition, both
wandering wavelets and organized reentry were present. The mean number
of wave fronts in the LA free wall was significantly more than that in
the RA free walls (11.8±1.1 versus 8.7±1.3 per second in each plaque,
P<0.001). Similarly, the
maximum number of wave fronts in the LA free wall (range 2 to 4 in each
plaque) was more than in the RA free wall (range 1 to 3 in each plaque)
(2.9±0.5 versus 1.8±0.7 in each plaque,
P<0.001).
Reentrant Wave Fronts During AF
Macroreentry was present in each run of AF. In the LA,
reentrant wave fronts (76 episodes in 15 runs of AF) always had
complete rotations. Among 17 episodes in 2 dogs, reentry appeared near
the Bachmann’s bundle (pattern a in
Figure 3). However, most of reentry (59 of 76 episodes,
78%) occurred at plaque 2 (pattern b in
Figure 3) in 5 dogs. The life span of reentry was short
(2.4±1.1 rotations, range 1 to 5), and the mean cycle length was 89±9
ms. In contrast, complete reentry (only 2 episodes in 15 runs of AF)
was rare in the RA. Most (61 episodes in 15 runs of AF) showed
incomplete reentry. They originated either from the Bachmann’s bundle
(n=45, pattern c in
Figure 3) in 5 dogs or from the medial side of plaque 4
(n=16, pattern d in
Figure 3) in 2 dogs. Compared with reentry in the LA,
incomplete reentry in the RA persisted longer in each episode (5.9±3.2
rotations, range 2 to 20,
P<0.001), and the mean
activation interval was also longer (122±22 ms,
P<0.001).
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Although multiple wave fronts were observed in all runs of
AF analyzed, the activation patterns in the RA contained more large and
organized wave fronts than in the LA.
Figure 4 shows an example. During each run of AF, the mean
duration of the presence of organized wave fronts (patterns c and d in
Figure 3) in the RA was significantly longer than that in
the LA (patterns a and b in
Figure 3; percent of the recording time 40±14% versus
15±9.1%,
P<0.001).
Lines of Conduction Block and
Endocardial Structures
As shown in
Figures 3 and 4, there were lines of conduction block
observed in both atria during AF. These lines always occurred over the
same regions in each dog but varied in length from beat to beat (as
shown in
Figures 4F, 4H, 4J, and 4L).
Furthermore, the fully extended lines observed in the RA (n=10) were
longer than those in the LA (n=8; 14.2±1.1 versus 8.5±0.7 mm,
P<0.001). Verified
anatomically, these lines always occurred along the long axis of atrial
endocardial structures, including the crista terminalis in 2 dogs and
large pectinate muscles in 5. In both atria, these rotating wave fronts
were usually initiated by conduction block along these structures,
leading to wave break (an asterisk in
Figure 4B) and the initiation of complete reentry
(Figures 4A through
4F)
or incomplete circuits
(Figures 4F and 4G
through
4L).
Figure 5 shows the actual activations registered in
Figure 4.
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Histological Examination
In all dogs studied, increased fibrosis and organized
thrombi occurred around the pacemaker lead insertion site. However,
remote from the lead insertion site, there was only a focal and mild
increase in fibrous tissue in either atrium. These findings are similar
to those reported by others.1
Figure 6A shows a typical example. In
Figure 6B, trichrome stain shows that there was a thick
intimal layer in the PVs. The intimal layer was composed of collagen
and smooth muscle cells arranged individually and in small bundles.
These smooth muscle cells were embedded within the collagenous tissue
and were isolated from the atrial myocardium by the collagenous stroma
of the intima.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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This study has the following major findings: (1) In chronic pacing-induced sustained AF, there is an activation rate gradient, with the LOM and the PVs activating consistently faster than the LA and the RA free walls. (2) Both wandering wavelets and organized reentry are present during sustained AF. (3) The LA has more wave fronts than the RA. (4) Atrial endocardial structures are important in modulating the wave-front dynamics.
Mechanisms of Chronic AF
Prinzmetal et
al14 proposed that rapid
focal activations could result in AF (the focal-source hypothesis of
AF). Recently, this hypothesis was supported by radiofrequency ablation
of AF by energy application inside the PVs in
humans.7 The PVs were also
found to be the sources of rapid activations of AF in isolated sheep
hearts.12 In addition to the
PVs, we9 recently
demonstrated that the LOM could be a source of rapid activations in
patients with paroxysmal AF. Results of the present study indicate that
similarly to paroxysmal AF, the LOM and the PVs are also the sources of
rapid activations in chronic pacing-induced sustained AF. These
findings provide a potential implication that ablation or isolation of
all the PVs and the LOM may result in cure of AF.
Many investigators have demonstrated that during sustained AF in humans15 and in dogs,1 16 the LA activates faster than the RA. Small areas of particularly rapid activations can be identified in the PV orifice region in humans15 and in the posterior LA in dogs. A combination of mitral valve surgery, cryoablation of the PV orifice, and resection of the LA appendage cured 10 of 12 patients with chronic AF and mitral valve diseases.15 Although the authors did not specifically test the hypothesis that PV or LOM ablation terminates chronic AF, their findings are encouraging.
Explanation for Activation Rate
Gradient Between LA and RA
According to the focal-source hypothesis of
AF,14 rapid activation foci
could drive the atria into fibrillation. Because of the high-rate
activations, conduction block might occur between the source and the
target. Therefore, tissues (the RA and the septum) that are further
away from these focal sources have slower activation rates than tissues
closer to the source, such as the LA free wall.
A second possible explanation is the anatomic differences between the LA and the RA. The presence of large anatomic barriers (the crista terminalis and large pectinate muscles) in the RA might facilitate the formation of large reentry with long activation cycle lengths.17 In comparison, the PVs and the LOM in the LA might also provide areas of conduction block, creating anatomically preferred circuits for reentry. However, because the anatomic barriers in the LA are smaller than those in the RA, the reentrant cycle lengths in the LA are shorter.
A third possible explanation is the development of differential AERP after chronic rapid pacing. As demonstrated previously,1 local AERP correlated well with local activation cycle length in AF. Differential electrical remodeling may be induced by chronic rapid pacing, resulting in shorter AERP in the LA than in the RA.3 4
A fourth possible factor is that chronic pacing induces differential autonomic remodeling. Jayachandran et al16 recently reported that rapid atrial pacing could result in a heterogeneous increase in atrial sympathetic innervation. These changes parallel the changes on atrial electrophysiology, including the activation cycle length.
Study Limitations
The demonstration of rapid activations from the
LOM and the PVs in the present study does not necessarily rule out the
importance of multiple-wavelet
reentry13 as a mechanism of
AF. A limitation of this study was that we did not perform ablations of
all the PVs and the LOM to determine whether these ablations would
terminate AF. Also, our data cannot completely rule out the possibility
that fibrillatory conduction from a slower source into the highly
anisotropic regions could produce faster and more disorganized
electrograms.
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Acknowledgments |
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This study was supported by grants from the American Heart Association (1114-G12, 9750623N, and 9950464N), the National Institutes of Health (HL-03611 and HL-52319), the University of California Tobacco-Related Disease Research Program (UC-TRDRP 9RT-0041), a Piansky Family Endowment, a Cedars-Sinai ECHO Foundation Award, a Pauline and Harold Price Endowment, and the Ralph M. Parsons Foundation, Los Angeles, Calif. We thank Dr Rahul Mehra and Medtronics Inc for providing Itrel neurostimulator, and Avile McCullen, Meiling Yuan, and Elaine Lebowitz for assistance.
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Footnotes |
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Corresondence to Tsu-Juey Wu, MD, Division of Cardiology, Department of Medicine, Taichung Veterans General Hospital, 160, Section 3, Chung-Kang Road, Taichung, Taiwan.
Received June 6, 2000; revision received August 21, 2000; accepted September 12, 2000.
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A. M. Park, C.-C. Chou, P. C. Drury, Y. Okuyama, A. Peter, A. Hamabe, Y. Miyauchi, R. M. Kass, H. S. Karagueuzian, M. C. Fishbein, et al. Thoracic vein ablation terminates chronic atrial fibrillation in dogs Am J Physiol Heart Circ Physiol, June 1, 2004; 286(6): H2072 - H2077. [Abstract] [Full Text] [PDF]
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C.-C. Chou, S. Zhou, Y. Miyauchi, H.-N. Pak, Y. Okuyama, M. C. Fishbein, H. S. Karagueuzian, and P.-S. Chen Effects of procainamide on electrical activity in thoracic veins and atria in canine model of sustained atrial fibrillation Am J Physiol Heart Circ Physiol, May 1, 2004; 286(5): H1936 - H1945. [Abstract] [Full Text] [PDF]
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L.-F. Hsu, P. Jais, D. Keane, J. M. Wharton, I. Deisenhofer, M. Hocini, D. C. Shah, P. Sanders, C. Scavee, R. Weerasooriya, et al. Atrial Fibrillation Originating From Persistent Left Superior Vena Cava Circulation, February 24, 2004; 109(7): 828 - 832. [Abstract] [Full Text] [PDF]
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D. M. Todd, A. C. Skanes, G. Guiraudon, C. Guiraudon, A. D. Krahn, R. Yee, and G. J. Klein Role of the Posterior Left Atrium and Pulmonary Veins in Human Lone Atrial Fibrillation: Electrophysiological and Pathological Data From Patients Undergoing Atrial Fibrillation Surgery Circulation, December 23, 2003; 108(25): 3108 - 3114. [Abstract] [Full Text] [PDF]
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H. Hayashi, C. Omichi, Y. Miyauchi, W. J. Mandel, S.-F. Lin, P.-S. Chen, and H. S. Karagueuzian Age-related sensitivity to nicotine for inducible atrial tachycardia and atrial fibrillation Am J Physiol Heart Circ Physiol, November 1, 2003; 285(5): H2091 - H2098. [Abstract] [Full Text] [PDF]
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J. R Ehrlich, T.-J. Cha, L. Zhang, D. Chartier, P. Melnyk, S. H Hohnloser, and S. Nattel Cellular electrophysiology of canine pulmonary vein cardiomyocytes: action potential and ionic current properties J. Physiol., September 15, 2003; 551(3): 801 - 813. [Abstract] [Full Text] [PDF]
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Y. Miyauchi, S. Zhou, Y. Okuyama, M. Miyauchi, H. Hayashi, A. Hamabe, M. C. Fishbein, W. J. Mandel, L. S. Chen, P.-S. Chen, et al. Altered Atrial Electrical Restitution and Heterogeneous Sympathetic Hyperinnervation in Hearts With Chronic Left Ventricular Myocardial Infarction: Implications for Atrial Fibrillation Circulation, July 22, 2003; 108(3): 360 - 366. [Abstract] [Full Text] [PDF]
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Y. Okuyama, Y. Miyauchi, A. M. Park, A. Hamabe, S. Zhou, H. Hayashi, M. Miyauchi, C. Omichi, H.-N. Pak, L. A. Brodsky, et al. High resolution mapping of the pulmonary vein and the vein of marshall during induced atrial fibrillation and atrial tachycardia in a canine model of pacing-induced congestive heart failure J. Am. Coll. Cardiol., July 16, 2003; 42(2): 348 - 360. [Abstract] [Full Text] [PDF]
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A. Hamabe, Y. Okuyama, Y. Miyauchi, S. Zhou, H.-N. Pak, H. S. Karagueuzian, M. C. Fishbein, and P.-S. Chen Correlation Between Anatomy and Electrical Activation in Canine Pulmonary Veins Circulation, March 25, 2003; 107(11): 1550 - 1555. [Abstract] [Full Text] [PDF]
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H. Oral, B. P. Knight, M. Ozaydin, A. Chugh, S. W.K. Lai, C. Scharf, S. Hassan, R. Greenstein, J. D. Han, F. Pelosi Jr, et al. Segmental Ostial Ablation to Isolate the Pulmonary Veins During Atrial Fibrillation: Feasibility and Mechanistic Insights Circulation, September 3, 2002; 106(10): 1256 - 1262. [Abstract] [Full Text] [PDF]
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S. Zhou, C.-M. Chang, T.-J. Wu, Y. Miyauchi, Y. Okuyama, A. M. Park, A. Hamabe, C. Omichi, H. Hayashi, L. A. Brodsky, et al. Nonreentrant focal activations in pulmonary veins in canine model of sustained atrial fibrillation Am J Physiol Heart Circ Physiol, September 1, 2002; 283(3): H1244 - H1252. [Abstract] [Full Text] [PDF]
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O. Berenfeld, A. V. Zaitsev, S. F. Mironov, A. M. Pertsov, and J. Jalife Frequency-Dependent Breakdown of Wave Propagation Into Fibrillatory Conduction Across the Pectinate Muscle Network in the Isolated Sheep Right Atrium Circ. Res., June 14, 2002; 90(11): 1173 - 1180. [Abstract] [Full Text] [PDF]
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J. Jalife, O. Berenfeld, and M. Mansour Mother rotors and fibrillatory conduction: a mechanism of atrial fibrillation Cardiovasc Res, May 1, 2002; 54(2): 204 - 216. [Abstract] [Full Text] [PDF]
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J. M.T. de Bakker, S. Y. Ho, and M. Hocini Basic and clinical electrophysiology of pulmonary vein ectopy Cardiovasc Res, May 1, 2002; 54(2): 287 - 294. [Abstract] [Full Text] [PDF]
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P.-S. Chen, T.-J. Wu, C. Hwang, S. Zhou, Y. Okuyama, A. Hamabe, Y. Miyauchi, C.-M. Chang, L. S. Chen, M. C. Fishbein, et al. Thoracic veins and the mechanisms of non-paroxysmal atrial fibrillation Cardiovasc Res, May 1, 2002; 54(2): 295 - 301. [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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