Published online before print April 13, 2001, doi: 10.1161/hh0801.089259
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© 2001 American Heart Association, Inc.
Article |
Dynamics of Intramural and Transmural Reentry During Ventricular Fibrillation in Isolated Swine Ventricles
From the Division of Cardiology, Department of Medicine (M.V., M.-H.L, T.O., A.C.L., H.S.K., P.-S.C.), Cedars-Sinai Medical Center, and the Department of Pathology and Anatomy (M.C.F.), UCLA School of Medicine, Los Angeles, Calif, and the Department of Physics and Astronomy (S.-F.L.), Vanderbilt University, Nashville, Tenn.
Correspondence to Peng-Sheng Chen, MD, Room 5342, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048. E-mail chenp{at}csmc.edu
Abstract
Abstract—The intramural dynamics of ventricular fibrillation (VF) remain poorly understood. Recent investigations have suggested that stable intramural reentry may underlie the mechanisms of VF. We performed optical mapping studies of VF in isolated swine right ventricles (RVs) and left ventricles (LVs). Nine RV walls were cut obliquely in their distal edge exposing the transmural surface. Six LV wedge preparations were also studied. Results showed that intramural reentry was present. In RV, 28 of 44 VF episodes showed reentry; 15% of the activation pathways were reentrant. Except for 4 episodes, reentry was transmural, involving subendocardial structures as the papillary muscle (PM) or trabeculae. In LV, reentry was observed in 27 of 27 VF episodes; 23% of the activations were part of reentrant pathways (P<0.05 compared with RV). All LV reentrant pathways were truly intramural (confined to the wall) and were frequently located at the PM insertion. In both ventricles, reentry was spatially and temporally unstable. Histological studies showed abrupt changes in fiber orientation at sites of reentry and wave splitting. Connexin 40 immunostaining demonstrated intramyocardial Purkinje fibers at sites of reentry in the PM root and around endocardial trabeculae. Our results confirm that reentry is frequent—but unstable—in the myocardial wall during VF. In RV, reentry is mostly transmural and requires participation of subendocardial structures. The LV has a greater incidence of reentry and is intramural. Anisotropic anatomic structures played key roles in the generation of wave splitting and in the maintenance of reentry.
Key Words: intramural reentry • fibrillation • anisotropy • Purkinje • papillary muscle
Our current knowledge of the activation dynamics that take place during ventricular fibrillation (VF) derives from multiple endocardial and/or epicardial mapping studies.1 2 3 4 5 On the basis of these data, VF has been characterized by spatiotemporal heterogeneity because of the coexistence of both organized reentry and fragmented wavelets.3 4 6 7 However, the intramural dynamics of VF remain largely unexplored because of the lack of an experimental model that allows for intramural mapping of VF. Recent studies8 9 have suggested that rapid and stable intramural reentry might serve as the source of VF. Intramural reentry has been previously demonstrated during ventricular tachycardia or fibrillation,1 10 11 12 13 but whether stable intramural reentry occurs during VF and to what extent is it required to maintain VF are unanswered questions. We have developed an experimental model to study intramural patterns of activation during VF. Our results confirm that reentry is indeed frequently seen in the myocardial wall. Substantial differences are noted between right ventricle (RV) and left ventricle (LV). We also demonstrate that anatomic structures played key roles in the generation of wave splitting and in the maintenance of reentry.
Materials and Methods
RV Preparation
The experimental model has been previously
described.14 Briefly, the
hearts of 9 farm pigs were extracted, and the right coronary
artery was perfused. The RV wall was excised and placed in a tissue
bath, with the endocardium facing up. An oblique cut was performed at
the distal edge, exposing the transmural surface (see online Figure 1
in the data supplement available at http://www.circresaha.org) and
including the papillary muscle (PM). Optical mapping (see below) during
VF was performed in the cut surface as well as in the adjacent
endocardial surface.
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LV Preparation
Our LV wedge preparation was similar to that
described by the laboratory of Yan et
al.15 In 4 hearts, a rim of
tissue surrounding the left circumflex and the second obtuse marginal
artery was excised and perfused, leaving an inverted L-shaped
preparation that contained at least part of the posteromedial PM. The
tissue was placed in the tissue bath with the transmural cut surface up
(see online Figure 1
). In 2 tissues, the left circumflex artery was
ligated proximally and a wedge of tissue surrounding the left anterior
descending artery was cut, exposing the transmural surface of the
interventricular septum. Tyrode’s solution was perfused
via the left coronary artery. These 6 LV wedges developed VF
during manipulation, which persisted for 63 to 79
minutes.
Optical Mapping
The optical mapping system was similar to the one
described previously.16 The
tissues were stained for 20 minutes with 1 to 2 µmol/L di-4-ANEPPS.
Quasimonochromatic light (500±30 nm) was shone on the tissues, and the
fluorescence was collected through a 600-nm long-pass glass
filter with charge-coupled device camera, at 
279 frames per second,
acquiring 96x96 sites simultaneously. Each acquisition
lasted for 4.3 seconds.
Data Analysis
The fluorescent signals were processed to
reduce the noise.16 Each
pixel was assigned a shade of gray between white
(representing a fully depolarized state) and black
(representing a fully repolarized state). The activation
wavefront was colored red, and the repolarization waveback was colored
green. The area between a red and a green line constituted a wavelet. A
wavebreak point in a propagating wavelet is a point at which a red line
and a green line meet. Wave splitting was defined as the generation of
2 daughter wavelets—and 2 wavebreak points—from a single wavelet.
Reentry was defined to be present when a wavefront rotated around a
wavebreak point completing a 360° cycle. Reentry was considered
intramural when the complete rotation occurred within the wall without
invading the adjacent endocardial or epicardial surface. Transmural
reentry was defined as that which involved both the myocardial wall and
the endocardium or subendocardial structures such as the PM or
trabeculae. The fraction of reentrant wavelets was
determined by the ratio of the number of wavelets participating in a
reentrant circuit over the total number of wavelets in the mapping
field.
Data are reported as mean±SD. Linear regression
analysis was used to correlate frequencies. A Student
t test was used to compare
means. A 
2 test was used to compare the
proportion of reentrant episodes in LV versus RV and the proportion of
reentrant episodes located at the PM. A
P value 
0.05 was considered
significant.
Sections of 5 µm parallel to the mapped surface were stained with Masson’s trichrome. We also used connexin 40 (Cx40) immunostaining17 to identify intramyocardial Purkinje fibers.
Electrocardiographic and Frequency
Analysis
Fast Fourier transformation was performed on signals
from the recorded pseudo-ECG and the local fluorescence
signals from each pixel of the optical mapping field. The dominant
frequency was defined as that with the highest power of each frequency
spectrum. Frequency domain maps were constructed as previously
reported.9
An expanded Materials and Methods section can be found in an online data supplement available at http://www.circresaha.org.
Results
Right Ventricle
A total of 44 VF episodes (4.3 seconds each) were
successfully mapped; of these, 28 showed at least 1 episode of reentry
(Table).
A total of 82 episodes of reentry were identified in these 28 episodes
of VF. The fraction of wavelets that participated in a reentrant
circuit was 15% (82 of 563 total number of visualized wavelets). Most
episodes of reentry were short-lived, with a range of 1 to 47
rotations.
Figure 1 shows a histogram with the number of cycles per
episode of reentry. The reentry frequencies and cycle lengths are shown
in the
Table.
Different patterns occurred in the same tissue in different VF
episodes. Visualization of the raw optical mapping data permitted
spatial localization of the sites where reentry occurred. Two episodes
of reentry occurred in the mapped endocardial surface, whereas the
remaining 80 episodes involved the myocardial wall. In most instances
(77 of 80, 96%), reentry in the myocardial wall involved
subendocardial structures (namely, the PM insertion or
trabeculae), and thus was not truly intramural but rather
transmural. This could coexist with intramural reentry (see below) in
figure 8 patterns. All of the 10 episodes that lasted >10 rotations
(Figure 1) involved reentry localized to the PM or
trabeculae.
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Intramural Reentry
Four episodes of intramural reentry were observed.
Figure 2 shows an example of a figure 8 reentry with
1 intramural loop. In the left upper corner of the tissue, 2 wavelets
collided and merged in the endocardial edge of the cut surface in
panels A through C. Then, a division occurred at the takeoff of an
endocardial trabecula (panels D and E, and panel K for the
identification of endocardial trabecula). One wavelet
rotated clockwise toward the endocardium, whereas the other did so
intramurally in a counterclockwise direction. Panel N shows an
isochronal map during 1 rotation. Eighteen rotations were
completed.
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The remaining 3 episodes of true intramural reentry were
isolated and did not involve figure 8 patterns (online Figure 2 in the
data supplement [http://www.circresaha.org] shows an example). They
persisted for 5, 6, and 8 rotations,
respectively.
Transmural Reentry Involving PM and
Endocardial Trabecula
Figure 3 shows, in the same tissue as
Figure 2, an example of transmural reentry in which both the
PM and an endocardial trabecula participated in the
circuit. The dotted line in panel H shows the outline of the PM. In
panel A, 2 wavelets invaded the PM, where they eventually merged (panel
B). This new wavelet traveled toward the PM root, where it split again
(panel C), giving rise to 2 daughter wavelets (panel D). The one on the
right turned clockwise and went back in the endocardial surface using
an endocardial trabecula as its pathway (panels D, E, and
F, and panel I for identification of the trabecula). This
wavelet then reentered the PM (panel G). The other wavelet turned
counterclockwise and similarly went back to the endocardial surface
through a trabecula and then reentered the PM (panels D, E,
and F). Panel K shows an isochronal map during 1 rotation. Seven
rotations were completed.
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Wave Splitting
Wave splitting was more frequent than reentry, and it
was consistently localized to underlying anatomic structures;
of a total of 154 episodes, 102 (66%) were mapped at the PM root, and
52 (34%) at an endocardial trabecula.
Figures 2 and 3 show examples of wave splitting in the same
site but with opposite wave directions, along with the fiber
orientation patterns at the splitting site
(Figure 3).
Left Ventricle
All VF episodes in all 6 tissues showed episodes of
reentry (see
Table).
A total of 85 reentry episodes were mapped in 27 episodes of VF.
Relative to the number of VF episodes, reentry was more common in the
LV than in the RV (85 reentry episodes in 27 VF episodes versus 82 in
44, P=0.001). The fraction of
wavelets participating in a reentrant circuit relative to the total
number of visualized wavelets was 23% (85 of 373), significantly
(P<0.05) higher than the
fraction of reentrant wavelets in the RV. As in the RV, most of these
were unstable and short-lived (see
Figure 1), with the number of cycles ranging from 1 to 54.
There were no significant differences in reentry frequencies or cycle
lengths between RV and LV
(Table).
All of these episodes of reentry in the LV were true intramural
reentry.
Intramural Reentry at the Insertion Site of the
PM
Reentry occurred in the root of the PM in 59% (50 out
of 85 episodes), a similar proportion as in the RV (36 out of 74
episodes, 49%, P=NS).
Figure 4 shows an example of intramural reentry around the
PM insertion. The dotted line in panel I shows the outline of the
intramural PM root. As shown in panel A, a wavelet approached the PM
moving clockwise toward its root. Wave splitting occurred, and 2
wavelets resulted. The one on the bottom rotated clockwise along the PM
root, whereas the one on top did so counterclockwise (panels A through
H). They merged again in panel F, and 5 more rotations were completed.
Interestingly, the upper loop of the figure 8 pattern was only
present in 2 of the 6 total rotations. Panel L shows an
isochronal map of this rotation.
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Reentry Not Involving PM
Reentry outside the PM root occurred in 41% of the
episodes. Most often, the reentry site could not be identified as any
particular macroscopic anatomic structure. In 1 episode, reentry
occurred around a subepicardial artery that had been
ligated.
The septal preparation (N=2) did not include PM but still
showed episodes of reentry.
Figure 5 shows an example. In the right upper
quadrant of the tissue, a wavelet rotated clockwise with the typical
appearance of a spiral wave. Panels A through L show the last 2
rotations (of a total of 12) completed by this spiral wave. Before its
extinction, this spiral seemed to give rise to all of the other
wavelets that activated the tissue. As seen in panel B, a
daughter wavelet arose from the spiral, detached from it (panels E and
F), and proceeded to activate the bottom portion of the tissue
(panels G and H). A second daughter wavelet arose from the side of the
spiral (panels D; E; and, in a subsequent rotation, J) that
activated the left upper portion of the tissue. In both
instances, these daughter wavelets merged with others that arose as
breakthrough activations (left upper corner of the tissue in panels F
and K) or from nonmapped portions of the tissue (bottom part in panel
E). However, the appearance of these other wavelets was, if not
physically connected to the ones arising from the spiral, at least
chronologically synchronized, given that they always appeared
simultaneously. Panel R shows an isochronal map of 1
rotation, suggesting that the wavelets in the left half of the tissue
arise from the spiral (dashed arrows). This pattern eventually
destabilized. Panels J through O show how the spiral annihilated
itself. Up to panel I, the rotation proceeded as previously. As seen in
panels I through M, the progression of the wavelet was slowed and took
61 ms to complete the rightmost part of the rotation (a step that in
the previous cycle—panels D through F—had only taken 33 ms). This
slowing is clearly shown in panel U, in which the activation from
channel 6 to channel 1 is delayed (curved arrow). The result is that,
as shown in panels K, L, and M, the spiral gave rise to another wavelet
(yellow arrows) that collided with the primary one (panels N and O) and
interrupted the reentry. Multiple nonreentrant wavelets were seen
afterward in this episode.
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PM and Wave Splitting
Sixty-eight episodes of wave splitting were mapped. The
PM root served as a site of splitting in 52 of them (the rest were due
to wave collisions).
Figure 4 shows an episode of wave splitting followed by
figure 8 reentry, along with the local histological
pattern (panel K).
Anatomic Correlates of Wavelet Behavior: Fiber
Orientation and Intramyocardial Purkinje Fibers
Histological analyses
were performed with tissue specimens from the mapped surfaces. Similar
patterns of complex fiber architecture, with sharp fiber angulations,
were found in all of the sites of reentry, both in RV and LV (see
Figures 2L, 2M, 3J, 4J, 4K, and 5Q). Transversely cut fibers
were seen in juxtaposition with longitudinally cut fibers, thereby
potentially creating discrete regions of discontinuous anisotropy. The
PM root and the root of endocardial trabecula in the RV
consistently exhibited this pattern, but similar convoluted
patterns were also found at other sites of reentry, even when these
were distant from the trabeculae or the PM (see
Figure 5Q).
Wave splitting, with the generation of wavebreak points in a
propagating wavelet, was localized in the PM root or in
trabeculae in the vast majority of the mapped episodes
(93%, 206 of 222 episodes, adding the RV and LV cases). The
Purkinje–ventricular muscle junction (PVJ) is known to be
a region of low safety factor and potential unidirectional
block.18 19
Because PVJs in the PM are predominantly located at its
base,20 we hypothesized that
PMJs could have played a role in the observed findings. Cx40
immunostaining successfully identified intramyocardial
Purkinje fibers, which were often indistinct from working myocytes on
trichrome staining. These intramyocardial Purkinje fibers ran in 1- or
2-cell columns,21 separating
clearly delimited muscle bundles. Along with abrupt fiber orientation
changes, both the PM root and the endocardial trabeculae in
the RV were remarkable for the presence of intramyocardial Purkinje
fibers that separated them from neighboring myocardial muscle bundles.
This bundle separation was prominent in the case of endocardial
trabeculae in the RV (see online Figure 3 in the data
supplement [http://www.circresaha.org]). In the PM, Purkinje fibers
were located at the root, where single-cell PMJs were present
(Figure 6).
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The association between anisotropy, intramyocardial Purkinje
fiber location, and wavelet behavior was not completely deterministic.
A given tissue could exhibit different reentrant patterns in different
episodes
(Figures 2 and 3). While reentry occurred at these sites, it
was still unstable. The mechanism for this instability was most often
interference by other wavelets. Thus, these anatomic patterns seemed to
play a facilitator role in the occurrence of reentry that was
insufficient to completely stabilize it in our multiple-wavelet VF
model.
Reentry Frequency, VF Frequency, Frequency
Domains, and Anatomic Structure
A significant correlation between reentry frequency and
the dominant frequency of VF was found
(Figure 7).8
Transmural frequency mapping revealed organized regions of similar
frequencies (frequency domains). In contrast with previous
descriptions,9 the spatial
distribution of individual frequencies was unstable over time in a
given tissue over different acquisitions. However, the specific
activation patterns, including the occurrence of reentry, impacted
significantly on the specific domain localization.
Figure 7 shows how, for a given tissue, the domains’
spatial location changed over time. Different reentrant patterns
occurred in a given tissue in different VF episodes (isochronal
maps in panels B and D for the same RV tissue as in
Figures 2 and 3 and in panels F and H for the same tissue as
in
Figure 4). The dominant frequency maps were completely
different each episode. The frequency domains existed irrespective of
the presence or absence of detectable reentry (panel K). The location
of some frequency domain boundaries was stationary over time. This was
most obvious in the PM insertion; in 82% (36 of 44) and 78% (21 of
27) of the VF episodes in RV and LV, respectively, a frequency domain
boundary could be localized to the PM.
Figure 7 shows examples (dotted red line in panels A, C, E,
G, I, K, and L). Stationary boundaries were also seen at sites of
tissue heterogeneity (such as those where reentry
localized), as shown in
Figures 5S and 5T. No significant consistent
epicardial-to-endocardial frequency gradient was
found.
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Discussion
The major findings of this study are the following: (1) the demonstration and characterization of both intramural and transmural reentry during VF in isolated swine ventricles and (2) the demonstration of the impact of anatomic structures on wavelet behavior. Reentry was mostly short-lived, but it could also last for a long time (47 cycles in RV and 54 cycles in LV). In the RV, transmural reentry was common, and the reentrant pathway often included subendocardial structures such as the PM root and trabeculae. True intramural reentry was rare in the RV. In contrast, all reentrant episodes in LV were intramural. Reentry and wave splitting tended to occur around the PM or in areas with anisotropy (abrupt changes in fiber orientation). The intramyocardial Purkinje system may play a role in the generation of reentry.
Intramural Reentry and the Mechanism of
VF
On the basis of frequency analysis, recent
investigations have suggested the presence of high-frequency periodic
sources underlying VF.8 The
nature of these sources has been hypothesized to be reentrant on the
basis of the facts that the few visualized episodes of reentry had the
same frequency as the dominant frequency and that such high frequencies
cannot be accounted for by the known mechanisms of
automaticity.8 9
Because the dominant frequency is also present in cases of
repetitive breakthrough activations, which are the most frequent form
of
periodicity,6 7 8
it has been inferred that intramural reentry underlies most of these
cases. Further conceptual support for this hypothesis is provided by
theoretical studies in which 3-dimensional reentry inside the
myocardial wall seems to be organized so that it rotates around the
long axis of the myocardial
fibers.22 Moreover, it has
been demonstrated that the spatial distribution of the dominant
frequencies is relatively simple and stationary over
time.9 These considerations
would suggest that continuous, spatiotemporally stable intramural
reentry underlies VF and therefore should be necessary for VF to be
sustained. Although demonstration of intramural reentry has been
reported,12 13 it
is unclear whether or not intramural reentry is required to sustain
VF.
Our results show that intramural or transmural reentry is indeed present. Because some of these episodes might last >40 cycles, it is possible that these reentrant wavelets could serve as a source of rapid activation during VF. However, the vast majority of these reentrant wavelets were spatiotemporally unstable. Long-lasting intramural reentry was an exception rather than a rule. Occasionally we observed VF in the absence of any transmural or intramural reentry. These episodes suggest that either we have failed to detect the focal source (the mother rotor) or sustained reentry is not important to the mechanisms of VF. Therefore, the observations of the present study are compatible with both the focal-source hypothesis23 and the multiple-wavelet hypothesis24 of cardiac fibrillation.
Many previous studies1 4 6 7 8 25 have documented the presence of epicardial or endocardial reentry during VF. The overall incidence of transmural reentry reported in the present study only slightly exceeded the incidence of epicardial or endocardial reentry reported in those communications. Lee et al4 reported that per 4 seconds of VF, there were on average 1.2 episodes of reentry, with a cycle length of 111 ms and lasting 3.4 rotations. Therefore, in 452 ms out of the 4 seconds (11.3%), organized reentry was present on the epicardium in canine VF. Rogers et al25 reported that 2.3% of the activation pathways during epicardial VF mapping were unequivocally reentrant and suggested that an additional 28% could also have been so by scaling analysis. We found that 15% and 23% of the visualized wavelets were reentrant in the RV and the LV, respectively.
Tissue Heterogeneity,
Intramyocardial Purkinje Fibers, and Wavelet Behavior
In accord with previous work, remarkable relationship
between tissue structure and wavelet behavior was found in this study.
Microscopic26 and
macroscopic2 27 28 29 30 31
heterogeneities, whether they are
natural,2 27 29 30
artificially
created,28 31 32
or the result of a pathological
process,33 significantly
affect wavelet behavior, creating conduction delays or blocks and
facilitating wavelet anchoring. Their impact in multiple-wavelet VF is
not completely deterministic, but transient anchoring can be
induced.31 Nonrandom spatial
localization of reentry has been described in epicardial VF
mapping,25 but no attempts
were made to anatomically characterize the sites of reentry. Our
results suggest that certain anatomic patterns—associated or not with
macroscopic structures—can increase the likelihood of reentry at their
locations.
We also describe wave splitting as a frequent consequence of anisotropy that could have arisen from fiber orientation heterogeneities. Areas of excessive curvature can lead to conduction failure,34 but at the same time, adjacent areas with lesser curvature could also lead to wavelet attachment,28 which could explain the occurrence of both phenomena, given the dynamic nature of VF.
The Purkinje system could have contributed significantly to
our results. The localization of PVJ at the base of the PM has been
documented functionally.20
We extend these findings with the description of intramyocardial PVJs
deep into the root of the PM
(Figure 6). A propensity for unidirectional conduction block
at the PVJs has been well described in pacing
studies.18 19 35
This block sets the stage for Purkinje-muscle reentrant
excitation,36 which has been
recently implicated as a mechanism of polymorphic
ventricular arrhythmias in simulation
studies.37 Our data suggest
that both conduction block (leading to wave splitting) and reentry at
the PM root could have had the participation of PVJ, further confirming
the relevance of the Purkinje system during VF. Furthermore, the
localization of intramyocardial or transitional Purkinje fibers in
between muscle bundles (specifically endocardial
trabeculae; see online Figure 3 in the data supplement
[http://www.circresaha.org]) may potentially have impaired conduction
leading to wave splitting at other locations as well.
Anatomic heterogeneities have been speculated to underlie
the complex spatial distribution of excitation
frequencies.9 We show a
direct spatial correlation between some domain boundaries and anatomic
heterogeneities
(Figures 5 and 7), confirming this hypothesis. However, in
contrast with recent
observations,9 we found no
temporal stability of the frequency domains during
VF.
Technical Limitations
Both our in vitro models are isolated, cut portions of
ventricular tissue, and our results may not apply directly
to the behavior of VF in vivo. By cutting and exposing the myocardial
wall, new boundaries were generated that might have impacted on wavelet
behavior. Although our study provides insight into the 3-dimensional
dynamics of VF, our methods are still 2-dimensional and therefore
limited to the mapped transmural surface.
Implications
In this study we show that anatomic structures and
myocardial anisotropy played key roles in the generation of wave
splitting and in the maintenance of intramural and transmural
reentry in normal swine ventricles. Disease states, such as myocardial
infarction, may further increase structural abnormality and promote
arrhythmogenesis through similar
mechanisms.33
Acknowledgments
This study was supported by a Postdoctoral Fellowship Award from the American Heart Association, Western States Affiliate (to M.V.), a Cedars-Sinai ECHO Foundation Award (to H.S.K.), a Pauline and Harold Price Endowment (to P.-S.C), an NIH Specialized Center of Research Grant in Sudden Death (Grant P50-HL-52319), NIH Grant R01 HL-66389, AHA National Center Grants-in-Aid (Grants 9750623N and 9950464N), and the Ralph M. Parsons Foundation. We thank Dr Ali Hamzei, Elaine Lebowitz, and Avile McCullen for assistance.
Footnotes
Original received October 27, 2000; resubmission received January 30, 2001; revised resubmission received February 26, 2001; accepted February 26, 2001.
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