© 2001 American Heart Association, Inc.
UltraRapid Communication |
Fluorescent Imaging of a Dual-Pathway Atrioventricular-Nodal Conduction System
Presented in part at the 73rd Scientific Sessions of the American Heart Association, New Orleans, La, November 12–15, 2000, and published in abstract form (Circulation. 2000;102[suppl II]:II-3).
From the Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio.
Correspondence to Igor R. Efimov, PhD, Department of Biomedical Engineering, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH 44106-7207. E-mail ire{at}cwru.edu
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Abstract |
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Abstract—A dual-pathway theory to explain atrioventricular-nodal (AVN) reentry has been proposed previously. However, the exact anatomical and functional correlates of the fast pathway (FP) and slow pathway (SP) have not yet been elucidated. We used optical mapping to reconstruct patterns of activation during retrograde conduction through the AVN and during AVN reentry in the triangles of Koch of 12 rabbits. Reentry was inducible by a premature stimulation of the bundle of His in 6 preparations (50%). A functional FP and SP appear to be anatomically correlated with posterior and posterolateral extensions of the AVN, which were recently described. Retrograde breakthrough points in 6 noninducible preparations were clustered near the apex of the triangle of Koch (FP), whereas 6 inducible preparations had either cycle length–dependent FP and SP exits (n=3) or only SP exits located near the coronary sinus orifice. The shift of breakthrough points from FP to SP during progressive shortening of the coupling interval was accompanied by a discontinuity in the conduction curve. We observed a transmural reentrant circuit involving the AVN, FP, SP, and the superficial endocardial layer of atrial and transitional cells. The presence of a functional SP during retrograde conduction was associated with inducibility of AVN reentry. The full text of this article is available at http://www.circresaha.org.
Key Words: ablation • electrophysiology • arrhythmia • imaging
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Introduction |
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On the basis of functional studies using microelectrodes, Moe et al1 formulated a theory of a dual-pathway conduction system of the atrioventricular node (AVN) to explain AV-nodal reentry. Yet, the exact anatomical substrate of these functionally described pathways remains unclear. This is due to the difficulties of interpretation of microelectrode and macroelectrode recordings conducted from a small and profoundly complex 3-dimensional structure of the triangle of Koch, which contains the AVN.
The first morphological evidence of extensions in the AVN was presented by Tawara2 in his seminal study published in 1906. Janse et al3 later provided an additional description and electrophysiological interpretation of these "blind ending extensions." Recent morphological studies by Inoue and Becker4 and Waki et al5 presented a detailed 3-dimensional morphological reconstruction of the two posterior extensions originating in the AVN of the adult and developing human heart. Elegant electrophysiological studies by Medkour et al6 and Khalife et al7 demonstrated functional evidence of unique properties of the posterior extension in the rabbit heart and suggested that it constitutes an anatomical substratum of the slow pathway (SP).
We8 9 have recently suggested that potentiometric dye and fluorescent imaging may prove to be valuable tools in tracking the trajectories of impulse propagation within a complex 3-dimensional structure of the AVN. Unlike microelectrograms, fluorescent signals carry composite information about many layers of cells even if there are no electrotonic interactions between them. Therefore, signatures of several wavefronts propagating asynchronously across different anatomical layers could be deciphered from fluorescent signals.8 This allows the tracking of the trajectory of impulse propagation during AVN reentry.9 We applied stimulation at the bundle of His to reveal the points of electric conduction between the AVN and the atrium and to simplify the interpretation of the optical signals from the posterior extension(s).
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Materials and Methods |
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This study conformed to the guidelines of the American Heart Association. We used isolated AVN preparations (see Figure 1A
) from 12 rabbit hearts. Preparations were superfused with
37°C Tyrode’s solution containing 15 mmol/L 2,3-butanedione monoxime
(BDM).8 10
Preparations were paced with a bipolar electrode at the bundle of His.
Programmed stimulation was applied, including 20 basic beats with a
cycle length of 300 ms followed by a test premature stimulus applied at
progressively shorter coupling intervals (300 to 50 ms). Bipolar
electrodes at the crista terminalis (CrT), interatrial septum (IAS),
and AVN (see Figure 1) were used to construct conduction curves.
Preparations were stained by adding to the perfusate di-4-ANEPPS at a
final concentration of 1 µmol/L for 40 to 60 minutes. Optical
fluorescent signals (F) were recorded from a 5x5- to 8x8-mm area at
the triangle of Koch at a rate of 1894 frames/second using a 16x16
photodiode array. A final spatial resolution was 300 to 500 µm per
photodiode. The signals were low-pass-filtered at 50 Hz, differentiated
(dF/dt), normalized by the basic beat recordings, and plotted as
two-dimensional intensity graphs or as animation. Moving bright bands
of dF/dt on the animations were considered as a visualization of the
propagating action potential wavefronts (see Figures 4 and 6). Using
IDL software (Research Systems, Boulder, Colo), we reconstructed
3-dimensional stack-plots,11
which allowed the visualization of the direction and speed of wavefront
propagation in the triangle of Koch as spatiotemporal patterns (see
Figure 10). In all preparations, we identified the location of
breakthrough points12 at
different coupling intervals of pacing. Isochronal maps of activation
were built as described
before,9 based on the
maximums of the first derivatives (dF/dt)max.
All quantitative data are expressed as
mean±SD.
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Results |
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Voltage-Sensitive Dye Staining
We have previously shown that optical recordings collected at the triangle of Koch during anterograde conduction had two distinct components.8 9 The first component corresponded to an atrial-transitional layer of cells and the second component corresponded to the nodal cells. During retrograde conduction, we also observed two components, yet with a reverse sequence, which followed from the reversed temporal sequence of activation. Furthermore, the cellular origin of the two components was revealed during slow staining by superfusion. Figure 1B
illustrates the changes in the optical signal
morphology recorded during a steady-state pacing at a cycle length of
300 ms at the AV-nodal region (black square dot on
Figure 1A) during staining by superfusion. We used 1
µmol/L solution of di-4-ANEPPS, which is 10 to 20 times lower than
the previously used
concentration.8 In the first
minutes, only the superficial layer of tissue was stained because of
the slow diffusion of the dye into deeper layers. As a result, the
first component ("hump") of the optical trace, which is supposed to
represent the deeper AVN structure during retrograde conduction, became
distinguishable only after 20 minutes, whereas the second component
appeared after 5 to 10 minutes.
Figure 1C shows the time graph of conduction delays measured
with bipolar electrodes and amplitudes of the two humps of the optical
signal during and after staining. The delivery of the dye was stopped
at 40 minutes. The amplitude of the first hump continued to grow
because of the maintained diffusion of the dye from the superficial to
deeper layers. Meanwhile, the difference between the second and the
first hump started to decrease, reflecting dye washout from the
surface.
Optical Signal Morphology
Figure 2 illustrates signal morphology during retrograde
conduction. Pacing stimuli were applied at the bundle of His, which was
within a few millimeters from the right edge of the 6x6-mm field of
view.
Figure 2A shows a schematic of the entire preparation, field
of view (box) and 4 recording sites selected along the hypothetical
main axis of the AVN. Signals from these sites are shown in
Figure 2B. Site 1 is posterior to the AVN. Sites 2 through 4
are presumably within the nodal area.
Figure 2B illustrates the last beat, H1A1, in a sequence of
a basic pulses with a 300-ms interval and a premature beat, H2A2,
evoked at a coupling interval of 100 ms. Two electrograms recorded at
the bundle of His and the crista terminalis are shown. Four optical
traces are superimposed. With the exception of trace 1, all traces
clearly contain double-component action potentials recorded during both
the basic and the premature beats. The delay between the two components
was increased during propagation of the premature beat compared with
the basic beat.
Figure 2C shows a likely interpretation of these data. The
scheme represents a vertical cross section of the AVN along the long
axis, which connects the location of the four chosen recording sites
illustrated in
Figure 2A. Each photodiode recorded the average electrical
activity from two (AVN and transitional region) or one (transitional
region) layers of tissue. Thus, records 2 through 4 had a first
component corresponding to the AVN (white structure) and then a second
component corresponding to the activation of the superficial layer of
atrial and transitional cells (gray structure). The black structure
represents the connective tissue separating the atrium from the distal
node and the bundle of His.
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Figure 3 illustrates the optical signals
(Figure 3A) and derivatives
(Figure 3B) recorded during a basic beat from the entire
field of view, which is shown in
Figure 2A. Area, which has two humps in
Figure 3B, is selected with shades of gray. More dark
regions show the locations where the ratio between amplitudes of the
derivatives of the first and the second humps is greater. This area may
represent the projection of the AVN and a part of the extension on the
surface.
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Maps of Retrograde Activation of the
AVN
Figure 4 illustrates the activation pattern reconstructed
from these data. The maps in
Figure 4A are conventional isochronal maps of the
conduction. The left map represents the conduction within the AVN and a
part of the posterior nodal extension. It was constructed using the
first peaks of the derivatives from only dual-humped signals. The right
map shows the conduction after the breakthrough, which activated the
endocardial surface layer of the AVN region and the rest of the atrium.
This map was built using the second peaks of derivatives in dual-humped
signals and the only peaks in single-humped signals. This map
illustrates that the activation first spread along the elongated
structure, hypothetically located below the surface, until it reached a
breakthrough point. The wavefront then emerged at the surface of the
preparation and rapidly spread out across its entire surface in a
radial fashion. The breakthrough point is located in the middle of the
triangle of Koch. Unfortunately, this approach has an important
limitation. The method does not permit the visualization of the entire
posterior nodal extension in most cases, because the optical signals
originating from the posterior extension of the AVN are typically
buried under a much stronger signal originating from the superficial
layer of transitional and atrial cells.
We used an alternative method to obtain additional
information.
Figure 4D shows snapshots of the first derivative dF/dt of
inverted optical signals. Frames are separated by 10 ms. The first two
rows of frames illustrate the impulse conduction across the AVN as
shown in conventional isochronal maps in
Figure 4A. The two left frames of the lower row show the
takeoff of the derivative posterior to the AVN. The geometry of this
pattern is consistent with the reported posterior extension anatomy.
Comparison of these two frames with subsequent frames shows why the
posterior bundle could not be visualized with the conventional
isochronal map. The presence of an overwhelming wavefront, which
originated later at the point of breakthrough but spread much faster
and buried the optical signature of the bundle before it reached
(dF/dt)max, made it impossible to resolve in a
conventional isochronal map.
Figure 5 summarizes the images of the AVN and extensions
obtained in this example.
Figure 5A shows the image of the AVN obtained by averaging
the ratio between the two peaks, as in
Figure 3. It represents an area of the triangle of Koch in
which clear dual-humped signals were observed.
Figure 5B shows the location of a wavefront just before the
breakthrough, which is presumably located within the posterior
extension.
Figure 5C shows the sum of the two images and the direction
of conduction before breakthrough. It represents a surface projection
of a subsurface structure, which provided an anatomical substrate for
conduction from the bundle of His until the breakthrough.
Hypothetically, this is an image of AVN and its
extensions.
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Anterograde Conduction
For comparison,
Figure 6 illustrates anterograde conduction in the same
preparation in response to a single premature stimulus applied at the
crista terminalis at a coupling interval of 120 ms.
Figure 6A shows traditional isochronal maps, which
illustrate the conduction in the atrium activating the entire field of
view, followed by the conduction in a well-defined channel.
Figure 6C shows the same propagation as a sequence of
snapshots of dF/dt, 20 ms apart. The first 3 frames show rapid
activation of the atrial layer. Subsequent frames show the formation
and propagation of the wavefront within the posterior extension and the
AVN itself. The comparison between the retrograde and anterograde
conduction illustrates the difficulty in resolving the signature of the
posterior extensions during anterograde conduction. The signal from the
extensions was sometimes buried in the signal, corresponding to the
activation of atrial and transitional layers of tissue. This especially
presents a problem during anterograde conduction. Alternatively, such
signature could be missed because of the relatively low amplitude
compared with the level of noise.
Cycle Length–Independent Breakthrough Points
at the Anterior and Middle of the Triangle of Koch
Six preparations (50%) had only the fast-pathway (FP)
exit from the AVN during retrograde conduction. The breakthrough points
were in the middle or at the apex of the triangle of Koch (see
Figure 7A). Their conduction curves were relatively smooth
and even flat
(Figure 7B). No reentry was induced in these preparations.
Figure 8 illustrates an example of a stationary breakthrough
point, which was located in the middle of the triangle of Koch.
Shortening of the coupling interval resulted in widening of the
breakthrough region, although no obvious shift was
observed.
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In 3 other preparations (25% of total), the stationary
breakthrough point was observed near the coronary sinus orifice
(Figure 7A), which means that there were SP exit points.
Reentry was inducible in all 3 of these preparations, in contrast to
the 6 preparations described above, which had only FP exit points.
Apparently, the FP in these 3 preparations was functional only in the
anterograde direction and nonfunctional in the retrograde
direction.
Shift of Breakthrough Points From the Anterior
to Posterior of the Triangle of Koch
In 3 other preparations, we observed a significant and
easily defined shift of the breakthrough point from the anterior
triangle of Koch to the coronary sinus orifice, which was accompanied
by a prominent jump in the conduction curve. In all of these
preparations, AVN reentry was inducible.
Figure 9 illustrates one of the preparations, where the
location of the breakthrough point moved from the FP exit point (areas
near the anterior corner of the triangle of Koch in
Figure 9A) to the SP exit point (area near the coronary
sinus orifice).
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Summary of the Breakthrough Points
Figure 7 shows the summary of breakthrough points and the
conduction curves recorded in all 12 studied preparations. In 3
preparations, the breakthrough points (circles) clearly shifted from
the anterior area of the triangle of Koch, or the FP exit, to the
posterior, or the SP exit on shortening of the premature coupling
interval. This shift of the exit point at the coupling interval of
199±25 ms caused a jump of 64±15 ms in the conduction curve, as seen
in
Figure 7B (dotted lines). In all of these preparations,
reentry was inducible (1 to 2 reentrant beats). Exit sites marked with
stars show the breakthrough points during reentry. In one preparation,
reentry was inducible in both directions (FP and SP exits
points), whereas in the remaining two preparations, the reentrant
circuits were only unidirectional. Intranodal and SP conduction was
retrograde, and extranodal conduction across the superficial layer of
atrial and transitional cells and FP was anterograde.
In the remaining 9 preparations, there was no apparent shift
in the location of the breakthrough points, which are shown with
squares
(Figure 7B). Yet, there was a difference among them with
respect to inducibility of reentry. In 3 preparations (boxes with
stars), breakthrough points were closer to the SP compared with the FP.
These were inducible preparations with the same exit points during
reentry (stars). In contrast, the remaining 6 preparations had
stationary breakthrough points near the FP or the middle of the
triangle of Koch (empty boxes). AVN reentry could be induced in none of
these 6 preparations at any coupling interval of retrograde
pacing.
Furthermore, in 7 of these 9 preparations with stationary
breakthrough points, the conduction curves appeared smooth and flat
(solid
lines in Figure 7B). In the remaining 2 of 9
preparations, the curves (dashed lines in Figure 7B) had an apparent
jump just before the block of conduction. Yet, no plateau at the
shortest coupling intervals was observed after the jump at short
prematurities, as it was seen in the 3 preparations with shifted
breakthrough points. Analysis of the conduction patterns in these two
preparations revealed that this jump resulted from a significant
increase of the conduction delay between the pacing site and the apex
of the triangle of Koch. The mechanism of this increase in the
conduction delay in these two preparations remains
unknown.
Stack-Plot Visualization of AVN Reentry
In 6 of 12 (50%) preparations, we observed reentry in
response to retrograde premature stimulation. Fluorescent imaging
revealed the reentrant circuit involved in this arrhythmia. We used two
methods to visualize the reentry: animation and 3-dimensional
stack-plots.
Figures 10 and 11 and the online-only movie (data supplement
available at http://www.circresaha.org) illustrate reentry in one of
the preparations. The 3-dimensional stack-plots A-B-C-D in
Figure 10 show impulse propagation during the corresponding
time intervals shown in
Figure 11.
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During the basic beat
(Figures 10A and 11A) an impulse entered the AVN from the His
bundle and split into two wavelets. One propagated rightward, toward
the tendon of Todaro (FP exit), whereas the other propagated leftward,
along the posterior nodal extension. Conduction via the FP reached the
breakthrough point earlier and rapidly activated the atrium, which
annihilated the SP impulse.
During a premature beat
(Figures 10B and 11B) applied at a coupling interval of 160
ms, the FP was still refractory, and as a result, conduction went
through the SP and rapidly activated the atrium. Reduced amplitude of
the FP bipolar electrogram during a premature beat (response 7 in
Figure 11B) relative to the basic beat (response 3 in
Figure 11A) is consistent with the idea of decremental
conduction, which provided reduced and apparently insufficient driving
force to activate the atrial layer of cells.
During slow propagation along the SP, the blocked FP was
able to fully recover. Therefore, after breakthrough from the SP exit
and activation of the entire atrial surface layer, excitation reentered
the AVN through the FP (see white ellipse at the top plane of
Figure 10C). It then split into two wavelets. One wavelet
went rightward through the AVN and left the field of view toward the
bundle of His (another white ellipse in
Figure 10C). The optical signature of His activation was
synchronous (see the online-only movie in the data supplement) with a
bipolar response (10 in
Figure 11C). At the same time, the other leftward wavelet
spread across the SP, again reaching the SP breakthrough point on the
surface of the atrium. After rapid activation of the atrium, the wave
again reentered the FP (white ellipse in
Figure 10D) and split into two. Once again, one wavelet
crossed the AVN and exited toward the bundle of His (ellipse in
Figure 10D) synchronously with the bipolar waveform (13 in
Figure 11D). The other wavelet that reentered the SP
terminated quickly. Therefore, the reentry was self-terminated. Unlike
human or canine hearts, the rabbit heart rarely supports sustained AVN
reentrant tachycardia. In our experiments, we never observed more than
two reentry beats.
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Discussion |
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AV-nodal conduction has fascinated both basic and clinical electrophysiologists for nearly a century. A large body of literature has been accumulated by several generations of investigators. Recent clinical success in treatment of AV-nodal reentrant tachycardia by radiofrequency ablation of the SP has rejuvenated interest in the structural-functional relationship of the AVN and the triangle of Koch. Yet, despite the efforts of many investigators, the mechanisms of conduction through the AVN remain unclear. A recent comprehensive work by Mazgalev and Tchou13 provides an update in the field. The main obstacle impeding the efforts of investigators is the lack of experimental techniques capable of measuring a 3-dimensional pattern of activation in the AVN. Novel imaging techniques may prove to be a key to unlock this century-old puzzle. Application of fluorescent imaging with voltage-sensitive dyes represents the first step in this direction.8 14
Our study presents the first functional fluorescent visualization of the dual-pathway conduction in the AVN of the rabbit heart during retrograde activation and AV-nodal reentry/ventricular echo. In the present study, we show that AVN reentry, observed during ventricular echo beat, involves the AVN itself, the FP and the SP, as well as the superficial layer of atrial and transitional cells enveloping the AVN and its posterior and posterolateral approaches.4
Visualization of the activation propagation as a sequence of dF/dt intensity plots or animations helps to clarify the dual-hump signal in the AV-nodal area. We consistently detected separate moving waves of activation corresponding to the different "humps" in the optical signals. This supports "the concept of asynchronous propagation of activation in poorly coupled sheets or bundles of transitional cells or asynchronous arrival of converging wave fronts," thoroughly justified by de Bakker et al.15
It is interesting that we observed an apparently greater rate of inducibility of ventricular echo (50%) compared with that reported previously.16 This difference could be due to the side effects of BDM and/or di-4-ANEPPS. BDM is known to block sodium and calcium ionic channels and therefore may result in slowing of the conduction, which could be proarrhythmic. Similarly, di-4-ANEPPS has been implicated in photodynamic damage and arrhythmia.17
Our data show that AVN reentry was inducible in preparations with a functional retrograde SP, which is anatomically supported by the posterior nodal extension.4 5 6 7 Therefore, such a pathway could be required to sustain AVN reentry in the rabbit heart. Khalife et al7 have recently presented strong experimental support for such a hypothesis. In their study, ablation of the posterior nodal extension abolished reentry. This finding is consistent with conventional clinical ablation therapy of AVN reentrant tachycardia and may explain why the SP approach ablation site below the coronary sinus orifice is the most preferable site of radio-frequency ablation of the AVN reentrant tachycardia in humans,18 19 with a success rate of 99%.20
Our imaging data are in agreement with recent histological findings,4 5 6 7 which identified two posterior bundles in humans and suggested that these bundles provide the anatomical substrate for the dual-pathway electrophysiology of the AVN.
Limitations
The technique used in our study was unable to fully
resolve the depth of origin of the signals. The data recorded were a
weighted average from the multiple cell layers. Newer, advanced methods
such as two-photon
fluorescence21 or optical
coherent tomography22 could
potentially resolve the signals collected from the different depths of
the preparation.
To eliminate the movement artifact during optical recording, we had to use BDM, which could affect AV-nodal conduction and ventricular echo inducibility. Preparation staining with di-4-ANEPPS could also potentially produce similar side effects.
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Acknowledgments |
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This project was supported by Grant HL58808 from the National Institutes of Health, National Heart, Lung, and Blood Institute.
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Footnotes |
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Original received August 10, 2000; resubmission received December 18, 2000; revised resubmission received January 19, 2001; accepted January 25, 2001.
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References |
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