Vol. 281, Issue 2, H490-H505, August 2001
Purkinje and ventricular contributions to
endocardial activation sequence in perfused rabbit right
ventricle
Adam W.
Cates1,3,
William M.
Smith1,
Raymond
E.
Ideker1,2, and
Andrew E.
Pollard1
Cardiac Rhythm Management Laboratory, 1 Department of
Biomedical Engineering and 2 Departments of Medicine and
Physiology, University of Alabama at Birmingham, Birmingham,
Alabama 35294; and 3 Guidant Corporation, St. Paul, Minnesota
55112-5798
 |
ABSTRACT |
Interactions
between peripheral conduction system and myocardial wave fronts control
the ventricular endocardial activation sequence. To assess those
interactions during sinus and paced ventricular beats, we recorded
unipolar electrograms from 528 electrodes spaced 0.5 mm apart and
placed over most of the perfused rabbit right ventricular free wall
endocardium. Left ventricular contributions to electrograms were
eliminated by cryoablating that tissue. Electrograms were
systematically processed to identify fast (P) deflections separated by
>2 ms from slow (V) deflections to measure P-V latencies. By using
this criterion during sinus mapping (n = 5), we found P
deflections in 22% of electrograms. They preceded V deflections at
91% of sites. Peripheral conduction system wave fronts preceded
myocardial wave fronts by an overall P-V latency magnitude that
measured 6.7 ± 3.9 ms. During endocardial pacing
(n = 8) at 500 ms cycle length, P deflections were
identified on 15% of electrodes and preceded V deflections at only
38% of sites, and wave fronts were separated by a P-V latency
magnitude of 5.6 ± 2.3 ms. The findings were independent of
apical, basal, or septal drive site. Modest changes in P-V latency
accompanied cycle length accommodation to 125-ms pacing (6.8 ± 2.6 ms), although more pronounced separation between wave fronts
followed premature stimulation (11.7 ± 10.4 ms). These results
suggested peripheral conduction system and myocardial wave fronts
became functionally more dissociated after premature stimulation.
Furthermore, our analysis of the first ectopic beats that followed 12 of 24 premature stimuli revealed comparable separation between wave
fronts (10.7 ± 5.5 ms), suggesting the dissociation observed
during the premature cycles persisted during the initiating cycles of
the resulting arrhythmias.
extracellular mapping; premature stimulation; cycle length
accommodation; specialized conduction system
| |
INTRODUCTION |
AN UNDERSTANDING OF
ELECTRICAL interactions between the peripheral conduction system
and ventricular myocardium is important because those interactions
dictate the endocardial activation sequence. Most investigations to
date have focused on interactions across the discrete
Purkinje-ventricular junction (PVJ) in superfused canine papillary
muscles. This preparation is attractive because there are relatively
few PVJs. Furthermore, PVJs are confined to the base of the muscle,
which allows antegrade (Purkinje-to-ventricular) conduction to be
established by stimulating Purkinje strands attached to the muscle and
retrograde (ventricular-to-Purkinje) conduction to be established by
stimulating the apex of the muscle. By using this preparation,
investigators (22, 26, 27, 32, 35, 40) have demonstrated
that PVJ conduction is highly discontinuous because the sparse
electrical coupling between Purkinje and ventricular tissue types forms
a resistive barrier (35) and that retrograde PVJ
conduction is preferential to antegrade PVJ conduction because of the
impedance mismatch between tissue types.
These two characteristics ensure the peripheral conduction system
dictates the endocardial activation sequence during sinus rhythm and
ventricular drives in the canine ventricle, where the distribution of
PVJs is relatively coarse compared with other mammalian preparations
because of the size of the heart. Long antegrade PVJ conduction delays
allow peripheral conduction system wave fronts to remain ahead
of myocardial wave fronts during sinus beats. For example, Nagao et al.
(31) paced right bundle branches of superfused canine
right ventricular (RV) free wall-septum preparations and showed local
Purkinje deflections that consistently preceded ventricular deflections
throughout the free wall. By using similar preparations, Rawling et al.
(35) showed that coarse PVJ distribution was advantageous
in this regard because it limited the electrical load imposed by the
myocardium on the peripheral conduction system, which allowed high
Purkinje conduction velocities to be maintained. During ventricular
drives, short retrograde PVJ conduction delays prevent myocardial wave
fronts from moving ahead of peripheral conduction system wave fronts
and the coarse PVJ distribution allows peripheral conduction system
wave fronts to move ahead of myocardial wave fronts once Purkinje cells
excite. For example, Ben-Haim et al. (5) found consistent
activation sequences with endocardial or atrial stimulation of in situ
canine hearts. Pollard et al. (33) frequently saw islands
of early activity, suggesting antegrade PVJ conduction in close
proximity to endocardial pacing sites in isolated canine hearts.
Similarly, Arisi et al. (1) demonstrated independence of
epicardial breakthrough sites during epicardial pacing of in situ
canine hearts, consistent with the emergence of epicardial wave fronts
after transmural expansion from fixed antegrade PVJ conduction sites.
We undertook the present study to assess interactions between
peripheral conduction system and myocardial wave fronts in preparations with more densely distributed PVJs. In the rabbit RV free wall, the
peripheral conduction system forms a web of Purkinje strands that cover
anastomosing trabeculae, which in turn cover the compact myocardium.
This anatomic arrangement is consistent with a representation for the
peripheral conduction system as a sheet of Purkinje myocytes coupled
strongly to the ventricular mass with relatively high PVJ density
compared with canine preparations and with papillary muscle
preparations from other species. The size of this preparation allowed
mapping from the majority of viable tissue during activation sequences
resulting from sinus rhythm and endocardial drives. Consistent with the
approach used in canine papillary muscle studies, rapid (P) and slow
(V) deflections were identified in the electrograms to assess local
Purkinje and myocardial activation, respectively. P-V latencies then
quantified the extent to which wave fronts separated. We found
peripheral conduction system wave fronts that preceded myocardial wave
fronts during sinus rhythm but lagged behind those wave fronts during
endocardial drives. Separation between wave fronts was comparable
during sinus beats and endocardial drives with nominal cycle lengths or
with rapid pacing. During premature stimulation and the ectopic cycles
that followed many premature responses, myocardial wave fronts also
preceded peripheral conduction system wave fronts, suggesting
functional uncoupling between the myocardium and the peripheral
conduction system despite the dense distribution of PVJs.
| |
MATERIALS AND METHODS |
Experimental methods.
We studied hearts from 13 New Zealand White rabbits (3-5 kg)
anesthetized with intramuscular ketamine (44 mg/kg) and xylazine (20 mg/kg), followed by intraveneous pentobarbital sodium (2.5 ml) and
heparin (2.0 ml). The hearts were rapidly excised after a medial
sternotomy and retrogradely perfused through the aorta with
recirculating, oxygenated (95% O2-5% CO2)
normal solution containing (in mmol/l) 126 NaCl, 22 dextrose, 1 MgCl2, 4.4 KCl, 20 taurine, 5 creatine, 5 sodium pyruvate,
1 NaH2PO4, 30.1 NaHCO3, and 1.08 CaCl2 (pH 7.3-7.4). We maintained temperature at 37° ± 1°C and flow rate at 45-50 ml/min. Each heart settled for 10 min before dissection for endocardial electrode placement and protocol initiation.
We mapped responses to endocardial drives in 8 of 13 experiments. In
these hearts, the right atria (RA) and left (LA) atria were removed,
and the right coronary artery was tied off just proximal to the
posterior descending artery to ensure continuous perfusion of the RV
free wall. A base-to-apex cut along the posterior descending artery
distal to the suture separated the free wall from the septum on one
side of the ventricle, forming an RV flap. Chordae tendinae were
severed to allow papillary muscles to contract freely. The perfused
heart lay horizontally and the RV flap was pinned in place at basal and
apical ends to a rubber pad with the endocardial side facing up. Figure
1A shows a schematic of the
preparation, including the location for the plaque on the free wall
adjacent to the septum and positions for all stimulating electrodes.
Figure 1B shows the plaque, which contained 528 Ag/AgCl tips
(102-µm diameter), spaced 0.5-mm apart.
View larger version (40K):
[in this window]
[in a new window]
|
Fig. 1.
A: schematic of the preparation including the
position for the recording array and the approximate locations for
stimulus sites on the septum (i), apex (ii), and
base (iii) during the endocardial pacing experiments.
B: recording array used for all experiments. The image in
B was inverted so that its shape coincided with the diagram
in A. RV and LV, right and left ventricles, respectively.
|
|
Before placing the plaque on the preparation with a micromanipulator,
we cryoablated the left ventricular (LV) free wall, septum, and apex by
administering liquid nitrogen for ~2 min via a metal cryoprobe placed
inside the LV. This procedure eliminated LV contributions to the
electrograms and controlled the amount of viable tissue outside the
mapped region while facilitating collateral perfusion of the RV. A
rubber nipple was placed on the end of the probe to prolong the time
between epicardial breakthrough of the ablation lesion on the LV free
wall and its apical migration to the RV. During cryoablation, the
migration of the lesion was carefully monitored to ensure that apical
and medial portions of the RV septum remained viable for experimental
study, although the basal septum was consistently ablated to destroy
the His bundle. Electrograms were recorded with the reference electrode
located inside the cryoablated LV. Each signal was amplified (×50),
band-pass filtered (0.5-1,000 Hz), and digitized at 2,000 samples/s with 14-bit resolution (42).
Stimulating electrodes were located outside the plaque region on
1) the septum, just inferior to the anterior papillary
muscle, 2) the apex, away from the septum, and 3)
the base, away from the RV outflow tract. Hearts were driven with the
use of 1.2-1.5× threshold strength, constant-current square
pulses of 2 ms duration, applied by a Bloom Electrophysiology (Fischer
Imaging; Denver, CO) stimulator from bipolar electrodes with 1-mm tip
separation. Preparations were initially driven at 500-ms cycle length
from sites 1-3. The cycle length was then reduced to
125 ms, and the measurements were repeated. To ensure cycle length
accommodation to the faster rate, we analyzed signals recorded at least
40 beats after the reduction and after each change in drive site. Cycle length was then increased back to 500 ms to acquire baseline
measurements in advance of premature stimulation. Premature stimulation
intervals started at 100 ms and were incremented in 5-ms steps until
global capture. In this way, we were able to analyze 24 activation
sequences to quantify responses to baseline drive, cycle length
accommodation, and premature stimulation.
We mapped sinus beats in 5 of 13 experiments. The dissection steps were
modified so that the RA was left on the heart when the LA was removed
to allow insertion of the cryoprobe into the LV. Cryoablation was
performed with a rubber sleeve placed over the probe that included a
5-mm-wide slit along the shaft of the probe. Before being ablated, the
slit was directed toward the medial LV free wall to focus the
epicardial breakthrough of the lesion distant from the septum. This
arrangement prevented migration of the lesion onto the septal crest,
where the His bundle courses before its proximal connection to the
right bundle branch, which ensured that this tissue was preserved.
Electrogram processing.
All of the electrograms were processed to identify P and V deflections
by using the steps shown in Fig. 2.
First, we differentiated each raw signal, which allowed straightforward
identification of the rapid P deflection. Derivatives were thresholded
to 
2 V/s for automatic identification and then reviewed manually to ensure deflections with characteristics that clearly indicated peripheral conduction system activation were included in the analysis. P deflections were not identified on all electrograms. Second, we
digitally filtered each raw signal by using a ninth-order Chebychev Type II low-pass filter (MATLAB, The Mathworks; Natick, MA) with a
stop-band edge frequency of 100 Hz and a stop-band ripple of 25 dB.
Because filtering removed the P deflection, it was then straightforward
to identify the V deflection automatically as the time of the minimum
derivative (37). Each derivative was thresholded to 0.3
V/s for determination. Finally, we measured the latency between the P
and V deflections when both were identified. For P-V latency below 2 ms, the electrogram was excluded from analysis because it was
impractical to distinguish the V deflection in the filtered electrogram
from the P deflection in the raw signal. P-V latencies above 2 ms were
recorded. When P deflections preceded V deflections, P-V latencies were
positive, and sites were termed "P-led," whereas "V-led" sites
where the V deflections preceded P deflections had negative P-V
latencies. Mean P-V latency magnitude was taken as a global measure for
the separation between peripheral conduction system and myocardial wave
fronts for each activation sequence. Differences in mean P-V latency
magnitude between activation sequences were quantified by using paired
Student's t-tests.
View larger version (15K):
[in this window]
[in a new window]
|
Fig. 2.
Processing steps to identify fast (P) and slow (V)
deflections from the endocardial electrograms.
|
|
Partial validation of this processing scheme is presented in Fig.
3, which shows raw and digitally filtered
electrograms recorded before and after dilute Lugol mixed with normal
solution (LNT; in a 1:9 ratio) application in one experiment. Because
Lugol binds to the rich glycogen stores in Purkinje cells, it has been
used extensively as a stain to visualize the specialized conduction system. It has also been used in electrical mapping studies (11, 15, 28, 33) with isolated or in situ canine hearts for selective inhibition of the conduction system. At the end of our initial experiments, the plaque was raised, LNT was applied, and mapping was
attempted again. In most experiments, signal degradation suggesting tissue damage to overlying myocardium accompanied inhibition of the
peripheral conduction system. In one experiment, however, LNT
application eliminated rapid P deflections at many sites where these
deflections were evident. That elimination established a closer match
between the raw and filtered electrograms, as shown in the post-LNT
traces from Fig. 3A. In addition, the post-LNT electrograms
(raw and filtered) matched closely at the sites where no P deflections
were evident in the pre-LNT recordings, as shown in Fig. 3B.
View larger version (18K):
[in this window]
[in a new window]
|
Fig. 3.
Electrograms recorded from different 3 × 3 regions in the
plaque before and after Lugol with normal solution (LNT) application.
Two pairs of waveforms are shown for each site, with the top of each
pair recorded pre-LNT application and the bottom of each pair recorded
post-LNT application. In each group, the solid and dashed lines show
the raw and filtered electrograms, respectively. A:
electrograms were recorded from a region where multiple P deflections
separated from V deflections were observed pre-LNT. B:
electrograms were recorded from a region with no obvious P deflections
pre-LNT.
|
|
The extent to which P deflections were attenuated by 2,000 samples/s
mapping is shown in the electrograms and derivatives from a site with a
P deflection in Fig. 4. During this
experiment, sampling rate was increased from 2,000 to 4,000, 8,000 to
12,000 samples/s, with accompanying increases in low-pass cutoff
frequencies from 1 to 2 kHz and 4 kHz. The 4-kHz cutoff was the
mapping system upper limit. As sampling rate increased, the P
deflection amplitude increased (2.5-6.9 mV), whereas the minimum
derivative decreased (2.2 to 10.0 V/s). Nevertheless, the timing
for P and V deflections was consistent and P-V latency exceeded 2 ms at
each sampling rate.
View larger version (19K):
[in this window]
[in a new window]
|
Fig. 4.
Electrograms (left) and derivatives (right)
after increases in sampling rate. Numbers accompanying each P
deflection in the electrograms are peak-to-peak voltages for that
deflection. Numbers accompanying each derivative trace are peak
negative values.
|
|
Activation sequence reconstruction.
Activation sequences were assessed in three ways. First, we used the
raw electrograms to determine the spatial distribution of active
samples and identify the peripheral conduction system and myocardial
wave fronts that crossed the mapped region. For every experiment and
activation sequence, electrodes were drawn on a schematic as small
squares. Those squares were placed into the shape of the recording
array. At electrodes where the raw signal derivative fell below 0.5
V/s, those squares were filled to indicate active tissue
(24). As described previously, this approach avoided many
of the ambiguities associated with accurate identification of unique
activation times that complicate traditional isochrone map construction
(6). This approach facilitated identification of active
sites that collected into thin bands corresponding with peripheral
conduction system wave fronts, and active samples that collected
into broad regions corresponding with myocardial wave fronts. Second,
we assembled isochrone maps with the use of V deflection times from the
filtered electrograms to assess myocardial wave front expansion
independent of peripheral conduction system wave front expansion.
Isochrones were assembled with 1-ms intervals. Third, we quantified
activation sequence differences after pacing adjustments with sample
Pearson correlation coefficients (CCF) by using V deflection times.
| |
RESULTS |
Incidence of P deflections during sinus rhythm and 500 ms pacing.
By using the electrogram processing criteria, we found P deflections in
22% of recordings from the sinus mapping experiments and 15% of
recordings from the endocardial pacing experiments (500-ms cycle
length). In both the sinus and paced activation sequences, we found
P-led and V-led sites. Figure
5A shows means ± SD for
the number of P-led and V-led sites from both sets of experiments. For
the paced activation sequences, the entries marked overall were
obtained by combining data from septal, apical, and basal drives.
During sinus mapping, we found 117 ± 51 sites with unique P and V
deflections. P deflections preceded V deflections in 91% of the
electrograms. During 500-ms pacing, the overall mean ± SD for the
number of sites with P deflections was 81 ± 59 (range
13-226). P-led sites accounted for 38% of electrograms with P
deflections, and V-led sites accounted for 62%. Septal stimulation
produced the most sites (113 ± 61) with P deflections, with 40%
P-led and 60% V-led sites. Apical stimulation produced the fewest
sites (42 ± 29), with 63% P-led and 37% V-led sites. Figure
5B shows P-V latency magnitudes grouped as in Fig.
5A. Mean PV latency magnitude measured 6.7 ± 3.9 ms
during sinus rhythm and 5.7 ± 3.1 ms during 500-ms pacing.
Latencies measured 5.7 ± 2.0 ms during septal pacing, 5.1 ± 3.3 ms during apical pacing, and 6.3 ± 3.8 ms during basal
pacing. Differences with pacing site were not statistically
significant. We therefore combined latencies resulting from
all stimulus sites for the analyses in subsequent sections.
View larger version (14K):
[in this window]
[in a new window]
|
Fig. 5.
A: means ± SD for the number of sites
with P deflections during sinus mapping and endocardial pacing
experiments. For the endocardial pacing experiments, septum, apex, and
base responses were averaged for the overall group. B:
means ± SD for P-V latency magnitudes with endocardial pacing
responses grouped as in A.
|
|
Sinus and paced activation sequences.
Consistent with the relatively small P-V latency magnitudes, activation
sequences during sinus rhythm and 500-ms pacing showed peripheral
conduction system and myocardial wave fronts that remained close to one
another throughout rabbit RV free wall. During sinus mapping,
peripheral conduction system wave fronts barely preceded myocardial
wave fronts. Figure 6A shows
the spatial distribution of active samples determined from the raw
electrograms during an experiment, in which there were 190 sites with
unique P deflections, 170 of which were P-led. P-V latency magnitude
averaged 5.4 ± 3.2 ms for this experiment. Figure 6B
shows isochrone maps assembled from the filtered electrograms. Frames
were aligned between panels to visualize the combined expansion of the
peripheral conduction system and myocardial wave fronts (Fig.
6A) alongside the expansion of the myocardial wave front
alone (Fig. 6B). The earliest activity resulted from one or
more peripheral conduction system wave fronts, as active samples in the
0-ms frame from Fig. 6A were unaccompanied by activity in
Fig. 6B. Peripheral conduction system wave fronts expanded
during the 2-, 4-, and 6-ms frames, with the first evidence of a
myocardial wave front (W1) in the apicoseptal portion of the 6-ms
frame. W1 expanded in the 8-, 10-, and 12-ms frames. Its position was
evident in Fig. 6A as the broad collection of active
samples. At 14 ms, a second myocardial wave front (W2) originated in
the conus and coalesced with W1 over the 16- and 18-ms frames. A third
myocardial wave front (W3) originated in the lateral free wall at 20 ms. It was overtaken by W1 at 22 ms. The last region to excite was in
the basolateral corner. All wave fronts moved out of the measurement
region by 28 ms.
View larger version (31K):
[in this window]
[in a new window]
|
Fig. 6.
Activation sequence during a sinus mapping experiment.
A: spatial distribution of active samples determined from
the raw electrograms. Black boxes indicate active electrodes and gray
boxes indicate inactive electrodes. Frames were drawn at 2-ms
intervals, with 0 ms as the time at which the first active samples were
observed. B: isochrones determined from the V deflections in
the filtered electrograms. Each frame shows the isochrone corresponding
to the V deflections at the frame time. W1, W2, and W3 show regions
where new myocardial wave fronts were observed.
|
|
The extent to which peripheral conduction system wave fronts preceded
myocardial wave fronts in different locations is shown in Fig.
7A. The separation between
wave fronts was highly variable. For example, in the apicoseptal region
where the initial peripheral conduction system and myocardial activity
was observed, P-V latencies exceeded 10 ms at most sites on the septal
edge of the plaque but were considerably smaller on the apical edge of
the plaque. Figure 7B shows electrograms recorded on a
septum-to-free wall line of electrodes from this region. P deflections
were separated by more than 2 ms from V deflections at 4 of 6 electrodes on this row. P deflection timing indicated sequential
activation at sites i-iv. V deflections were largely
aligned, consistent with the entry of W1 into these sites as a broad
wave front. Figure 7C shows electrograms from an
intersecting column of electrodes in the path of W1 expansion. V
deflection timing in these electrograms indicated sequential activation
from the most apical (site i) to most basal (site
vi) electrodes.
View larger version (38K):
[in this window]
[in a new window]
|
Fig. 7.
A: spatial distribution of P-V latencies in
milliseconds from the sinus mapping experiment (see Fig. 6 for the
activation sequence). Electrograms extracted from
B-E are shown below A. For each
row and column, the electrodes selected as sites i and
vi for display in B-E are
indicated. In B, raw electrograms are shown as solid lines
and filtered electrograms are shown as dashed lines.  ,
P deflections.  , V deflections. P-V latencies for
electrograms with P deflections separated by >2 ms from V deflections
are in milliseconds. Thin and thick lines through P and V deflections,
respectively, indicate directions for wave front expansion. Formats for
C-E follow B.
|
|
Because electrograms were recorded in unipolar mode, we were unable to
apply the criterion of Veenstra et al. (40) to establish whether P-V latencies decreased because antegrade PVJ conduction occurred in the apicoseptal region. By using a reference electrode retracted 1-2 mm from the tissue surface and directly above the recording electrode, those investigators identified discrete PVJs based
on the rapid biphasic P deflection that preceded the uniphasic, completely negative V deflection. By using the filtered electrograms, however, we were able to detect some islands of early myocardial activity that suggested antegrade PVJ conduction, although the close
proximity of the peripheral conduction system and myocardial wave
fronts throughout the mapped region limited that detection. One
exception was in the lateral free wall region, where W3 (Fig. 6B, 18 ms) emerged. Figure 7D shows electrograms
recorded on a septum-to-free wall line of electrodes that spanned the
W3 island. The timing for prominent P deflections at sites i
and ii indicated peripheral conduction system wave fronts
approached this region in advance of W3 initiation. V deflection timing
indicated myocardial wave front initiation near sites iii
and iv with components expanding toward the septum (through
sites i and ii) and the free wall (through sites v and vi). Electrograms from sites on the
orthogonal axis shown in Fig. 7E showed V deflection timing
that indicated W3 components expanded toward the apex (through
sites i and ii) and the base (through sites
v and vi) as well.
During paced activation sequences, the peripheral conduction system
wave fronts generally lagged behind the myocardial wave fronts,
although the extent to which wave fronts separated was comparable to
that of the sinus activation sequences. Figure
8 shows the spatial distribution of
active samples and selected electrograms after septal stimulation in an
experiment in which there were 159 V-led sites and no P-led sites. From
Fig. 8A, the broad myocardial wave front that emerged from
the septum 50 ms after stimulation expanded toward the flap in between
53 and 80 ms during this activation sequence. Small bands of electrodes that formed the peripheral conduction system wave front were scattered throughout the 62- to 80-ms frames. From Fig. 8, B and
C, slower V deflections preceded the faster P deflections at
all sites where P deflections were evident. P-V latencies at these
sites ranged between 3.9 ms and 12.3 ms. The P-V latency magnitude
from this experiment measured 7.5 ± 2.8 ms.
View larger version (32K):
[in this window]
[in a new window]
|
Fig. 8.
A: activation sequence. B and C:
selected electrograms from an endocardial pacing experiment with 500 ms
cycle length drive. In A, times are relative to the stimulus
in milliseconds. In B and C, site ix
was at the intersection between traces B and C.
|
|
Pacing adjustments.
After reduction in the steady-state cycle length from 500 to 125 ms,
myocardial wave fronts still preceded peripheral conduction system wave
fronts, and there was a modest increase in their separation. Across all
experiments, P deflections were evident at 57 ± 36 sites with
74% of those sites being V-led. P-V latency magnitude increased from
5.7 ± 3.1 to 6.8 ± 2.6 ms (P = 0.02).
Figure 9, A and B,
shows activation sequences during 500 and 125 ms (respectively) pacing
from the septum in one experiment. Both activation sequences showed
peripheral conduction system wave fronts in advance of and in the wake
of the myocardial wave front in different parts of the mapped region.
The main difference between the two activation sequences was in their
timing, as wave front expansion during 125-ms pacing was slower than
that during 500 ms pacing. CCF between these two activation sequences
measured 0.92. Across all 24 activation sequences, CCF measured
0.79 ± 0.18.
View larger version (26K):
[in this window]
[in a new window]
|
Fig. 9.
Activation sequences during 500-ms pacing (A), 125-ms
pacing (B), and premature stimulation (C) from an
endocardial pacing experiment. All times are relative to the preceding
stimulus.
|
|
By comparison, premature stimulation caused more pronounced separation
between peripheral conduction system and myocardial wave fronts and
larger changes to the activation sequence. P-V latency magnitude
increased from 5.6 ± 2.3 to 11.7 ± 10.4 ms
(P = 0.005), although the number of sites with P
deflections only decreased from 85 ± 54 to 72 ± 51. The
percentage of V-led sites was 61%. Figure 9C shows the
activation sequence after premature stimulation from the same
preparation and septal pacing site as Fig. 9, A and
B. During premature stimulation, initial activity within the
measurement region was located in the conus. The activation sequence
during premature stimulation was poorly correlated to the 500-ms pacing
sequence at CCF = 0.04. This example was consistent with
correlations between activation sequences during premature stimulation
and 500-ms pacing across all experiments (CCF = 0.63 ± 0.37).
A consistent feature that highlights the functional nature of coupling
between the peripheral conduction system and myocardium that we
observed with cycle length accommodation and premature stimulation was
a dynamic shifting of P-V latencies at individual recording sites.
Figure 10 shows electrograms recorded
in the conus during 500-ms pacing, 125-ms pacing, and premature
stimulation from the experiment presented in Fig. 9. In the septum to
flap direction, P-V latencies that measured 7.4 ms (site
ii), 6.9 ms (site iii), and 5.5 ms (site iv)
were observed during 500-ms pacing. Those delays shortened during cycle
length accommodation, with a P-V latency exceeding 2 ms limited to
site iii (2.3 ms). During premature stimulation, we only
observed V deflections that preceded P deflections along this line of
electrodes. In the base-to-apex direction, no P-V latencies were
measured during 500-ms pacing or premature stimulation. During cycle
length accommodation, however, P-V latencies of 2.5 ms (site
ii), 2.1 ms (site iii), and 2.3 ms (site v)
were observed. Across all experiments, rapid pacing shifted 81% of the
P-led sites to V-led sites and 61% of V-led sites to P-led sites. With
premature stimulation, 70% of P-led sites became V-led and 60% of
V-led sites became P-led sites.
View larger version (35K):
[in this window]
[in a new window]
|
Fig. 10.
Electrograms recorded on septum-to-flap (A) and
base-to-apex lines (B) grouped with the top trace showing
the response to 500-ms pacing, the middle trace showing the response to
125-ms pacing, and the bottom trace showing the response to premature
stimulation. Numbers are P-V latencies in milliseconds. Site
i is the same in A and B.
|
|
Initiating ectopic cycles.
Ectopic beats were observed after 12 of the 24 premature stimuli.
Cycles persisted for <1 s in 2 of 12 cases, between 1 and 2 s in
4 of the 12 cases, and between 5 and 24 s in 6 of the 12 cases.
The initiating ectopic cycles showed comparable separation between
peripheral conduction system and myocardial wave fronts to that
measured during premature stimulation, as mean P-V latency magnitude
measured 10.7 ± 5.5 ms. There were 60 ± 37 sites with P
deflections, and the percentage of sites that were V-led (69%) exceeded the percentage of sites that were P-led (31%). Overall, initiating ectopic activation sequences were poorly correlated to the
paced (CCF = 0.32 ± 0.45) and premature (CCF = 0.49 ± 0.29) sequences.
The distinguishing characteristic of these cycles compared with
the sinus and paced sequences was the presence of several slow moving
wave fronts that appeared and disappeared in different portions of the
measurement region. In many instances, it appeared as if the peripheral
conduction system and myocardium were functionally uncoupled. For
example, Fig. 11 shows the initiating
ectopic activation sequence from an experiment in which first activity
was observed in the conus. Electrograms recorded from this region are
denoted as a, b, and c, and the
responses during 500-ms pacing, premature stimulation, and the ectopic
cycle are included. Note that all three sites were V-led (6.0-7.0
ms) during 500-ms pacing and switched to P-led (2.5 ms) during
premature stimulation. During the ectopic cycle, separation between
peripheral conduction system and myocardial wave fronts was
pronounced at these sites, as the P-V latencies measured 19.0-22.0
ms. Comparable separation between wave fronts was also observed at the
basal sites marked d, e, and f. However, these
sites were P-led during 500-ms pacing (2.0-2.5 ms) but became V-led during premature stimulation (6.5-7.0 ms) and the ectopic cycle (18.0-24.0 ms).
View larger version (26K):
[in this window]
[in a new window]
|
Fig. 11.
Activation sequence during the initiating ectopic cycle
from one experiment shown alongside selected electrograms that include
the paced, premature, and ectopic cycles. P-V latencies in milliseconds
are included for each cycle.
|
|
| |
DISCUSSION |
We used 528-channel mapping of perfused rabbit RV endocardium to
measure the relative timing for P and V deflections during sinus rhythm
and during endocardial pacing at basic cycle length, cycle length
accommodation, and premature stimulation. Because premature responses
were followed by ectopic beats in 50% of the activation sequences
analyzed, we were further able to compare the timing of P and V
deflections during arrhythmia formation to that during pacing. New
findings that arose from the study include demonstration of
1) comparable P-V latency magnitudes during sinus rhythm and
500-ms pacing, 2) a consistent preference for V deflections
that preceded P deflections during endocardial pacing, and
3) pronounced separation between peripheral conduction system and myocardial wave fronts during premature stimulation and
ectopic beats. These findings are important because they highlight the
dynamic nature of electrical interactions between the peripheral conduction system and myocardium in preparations with relatively strong
PVJ coupling between layers.
528-Channel mapping of perfused RV endocardium.
We established these relationships by using an integrated methodology
that overcame limitations commonly associated with endocardial mapping.
We used high spatial and temporal resolution during simultaneous recording with fixed electrode geometry in continually perfused preparations. This approach differed from endocardial mapping studies
that used monophasic action potential (19) or
transmembrane potential-dependent fluorescence (3, 18, 23)
recordings in that it provided information on both P and V
deflections. P deflections have been reported in studies with
intramural needles for three-dimensional mapping of in situ (2,
5) and Langendorff-perfused (17) hearts. However,
such studies typically focused on intramural contributions to
activation sequence and presented less detail regarding endocardial
contributions than we present.
Details regarding the separate expansion of peripheral conduction
system and myocardial wave fronts have been presented in previous
studies (30, 31, 40) using sequential recordings from
superfused canine septum-free wall preparations. We recognize an
advantage of such studies is their unambiguous demonstration of
Purkinje cell upstrokes from impalements. However, maintenance of
midwall and epicardial myocardium distinguished our study from their
work because midwall uncoupling resulting from healing over for spared
subendocardium likely reduces the electrical load imposed by the
ventricular layer on the peripheral conduction system layer. Load is an
important determinant of antegrade PVJ conduction delay (21,
32). Therefore, maintenance of midwall myocardium is an
important factor in the use of P-V latencies to assess peripheral conduction system and myocardial wave front expansion.
We were able to establish relationships between peripheral conduction
system and myocardial wave fronts by applying criteria from experiments
with superfused preparations. Specifically, we analyzed timing for P
and V deflections that represented peripheral conduction system and
ventricular layer activation, respectively. This approach is
specifically supported by Nagao et al. (31), who analyzed
their sequentially recorded electrograms for rapid P deflections (1- to
3-ms duration) that preceded slower V deflections (6- to 10-ms
duration) because accompanying microelectrode impalements showed those
deflections corresponded to Purkinje and ventricular cell upstrokes,
and by other investigators who have used similar approaches (25,
31, 32, 35). Consistent with these reports, we found that the
rapid deflections most likely resulted from peripheral conduction
system activation because they were eliminated during LNT application
(Fig. 3).
Rabbit RV free wall.
Rawling et al. (35) suggested that limited PVJ coupling is
advantageous for endocardial excitation. Those investigators simulated
action potential propagation with a fast conducting Purkinje cable
connected to a slow conducting myocardial cable at 7-mm intervals. Such
spacing was advantageous because the distribution of early sites for
action potential initiation in the myocardium established multiple wave
fronts that coalesced to achieve rapid ventricular excitation.
Furthermore, the limited coupling lowered the electrical load imposed
by the myocardial cable on the Purkinje cable, which allowed the
Purkinje cable to maintain high conduction velocity. Such sparse PVJ
coupling is typical of superfused canine papillary muscle and free wall
preparations and is also consistent with our observations during
endocardial mapping from 14 × 14-mm regions of Langendorff-perfused
canine hearts (33). In those experiments, we identified
2-3 early sites from which secondary myocardial wave fronts were
initiated in advance of the primary wave front established by pacing on
the periphery of the region. Our limited ability to routinely identify
early sites during sinus mapping or 500-ms pacing in the present
experiments supports a much higher degree of PVJ coupling in the rabbit
RV free wall than in canine hearts. In this regard, it is also
important to distinguish our preparation from previous studies that
used rabbits. Overholt et al. (32) used rabbit LV
papillary muscles and showed the basal halves of the rabbit
preparations were devoid of peripheral conduction system, consistent
with canine preparations. Stimulation of free running Purkinje strands
attached to the muscle established distinct peripheral conduction
system and myocardial wave fronts that allowed early site
identification and assembly of separate activation maps for the
peripheral conduction system and myocardial components. Tranum-Jensen
et al. (38) studied superfused rabbit LV preparations in
which free running strands were driven to facilitate PVJ identification
with electrical recordings in advance of fixation to allow histologic
reconstruction of the junctional region.
In contrast to the rabbit LV preparations that share similarities with
canine preparations, the rabbit RV free wall includes a web of Purkinje
strands that overlie a network of anastomosing trabeculae. Although
relatively long (6-10 mm) free running strands course from the
septum to the apical free wall in most preparations, numerous short
strands course between trabeculae. Furthermore, LNT staining shows
significant Purkinje cell distribution along trabeculae. Assuming that
PVJs are more densely distributed over these trabeculae than in other
preparations provides a plausible explanation for our observation that
comparable P-V latency magnitudes were measured during sinus rhythm and
500-ms pacing. A high degree of coupling would prevent either the
peripheral conduction system or the myocardial wave front from becoming
unsynchronized. In this regard, use of either the proximal conduction
system during a sinus beat or a myocardial wave front during
endocardial pacing would be expected to establish synchronous wave
front expansion between peripheral conduction system and ventricular
layers in approach to the measurement region, consistent with our findings.
Preference for V-led sites during endocardial pacing.
By analyzing separate P and V deflections, we did not expect to find
the preference for V-led sites that we observed during 500-ms pacing.
Our 500-ms pacing protocol was designed to promote Purkinje-mediated
activation in the measurement region. We used bipolar stimulation of
septal, apical, and basal tissue because we anticipated such placement
would provide sufficient time for action potential propagation from the
myocardium to the peripheral conduction system in advance of both wave
fronts reaching the plaque. We believe the V-led preference relates
both to the developmental similarities between the trabecular component
of the ventricular layer and the specialized conduction system, and to
electrical loading of the peripheral conduction system by the
myocardium. Studies (29) of specialized conduction system
development suggest that trabecular tissue may be more closely related
to the conduction system than to the free wall myocardium and may in
fact be the precursor to the entire conduction system. The genetic and
molecular similarities between cells in the trabecular component and
the conduction system correspond to similar functions in the activation sequences of developing hearts. For example, De Jong et al.
(16) found that endocardial electrograms recorded from
4-day-old embryonic chicken hearts before conduction system development
revealed earlier activation near the apex than near the
atrioventricular canal. This result was similar to the pattern of
activation spread after conduction system development. In subsequent
simultaneous endocardial and epicardial electrogram recordings, those
investigators found that activation occurred earlier on trabeculae than
at corresponding epicardial sites, suggesting that activation spread
preferentially through the ventricular trabeculae. In addition to
producing a similar pattern of ventricular activation to that produced
by the fully developed conduction system, trabeculae display a
conduction velocity intermediate to Purkinje and myocardial fibers due
to their higher connexin43 expression than myocardium.
These developmental links suggest refinement to the interpretation of
Rawling et al. (35) for Purkinje-mediated activation sequence. In that interpretation, PVJ conduction delays minimally influenced the activation sequence because Purkinje conduction velocity
was much higher than myocardial conduction velocity and PVJs were
separated from one another. During myocardial stimulation, overall
activation was similarly enhanced because retrograde PVJ conduction
near the stimulus site initiated a Purkinje wave front that established
antegrade conduction at the distant PVJ. In canine preparations,
both sinus and endocardially paced activation sequences show antegrade
conduction across most PVJs. This occurs during ventricular drives
because the high Purkinje conduction velocity and the coarse PVJ
distribution allow peripheral conduction system wave fronts to
accelerate past myocardial wave fronts and establish antegrade
conduction at distant PVJs. In contrast, we believe coordinated
development with enhanced gap junction expression along trabeculae
(29) led to conditions in which the discrepancy between
conduction velocities in the rabbit peripheral conduction system and
trabecular layers was much smaller than in canine papillary muscles.
More continuous PVJ coupling, with accompanying retrograde PVJ
conduction delays during propagation initiated in the ventricular layer, would necessarily result in V deflections that preceded P deflections.
Cycle length accommodation.
Further evidence for this interpretation is provided by the relatively
modest changes to endocardial activation sequence and mean P-V latency
magnitudes that we observed during cycle length reduction. The spatial
characteristics of activation sequences were maintained because the
sequences during 125-ms pacing were highly correlated to sequences
during 500-ms pacing. The sequences slowed, however, which was
consistent with reports demonstrating steady-state accommodation to
fast rates included conduction velocity slowing in isolated Purkinje
strands (8, 9) and papillary muscle preparations (9,
12). Also, V-led sites remained preferential to P-led sites.
This likely occurred because retrograde PVJ conduction delays were
minimally influenced by the rapid rate. In isolated guinea pig
papillary muscle preparations, Chen and Gettes (12) showed
that cycle length reduction from 333 to 160 ms reduced upstroke
velocity by only 10%. Such a small change would have negligible effect
on source charge available for Purkinje cell activation via retrograde
PVJ conduction, especially because downstream sink charge requirements
for maintenance of such conduction are relatively modest due to the
high membrane resistance that establishes high excitability of Purkinje
cells (10, 13, 14, 21, 34). By comparison, antegrade PVJ
conduction time likely increased with rate acceleration. In isolated
canine Purkinje strands, Bigger et al. (8) reported that
cycle length reduction from 500 to 200 ms reduced upstroke velocity by
20%. Such reduction places increased importance on the maintenance of
a depolarized action potential plateau for antegrade PVJ conduction.
That importance is highlighted by prolongation of delays in canine
Purkinje-papillary muscle preparations exposed to cadmium by Wiedmann
et al. (41). Cadmium partially blocks L-type calcium
current, which maintains the action potential plateau. A plausible
explanation for our observation that P-led sites were still observed
relates to the prominent transient outward current of rabbit Purkinje
cells (14). At slow rates, that current dramatically
repolarizes the early plateau of the Purkinje cell action potential
(21). Rate acceleration markedly inhibits transient
outward current with a concomitant depolarization of the plateau, which
would in turn facilitate antegrade PVJ conduction.
Premature stimulation.
Our finding that endocardial activation sequences were altered by
premature stimulation is seemingly contradictory to findings by Van Dam
and Janse (39). By completing multiple needle electrode mapping studies with isolated canine hearts, those investigators showed
similar transmural activation sequences occurred during premature
stimulation and during epicardial stimulation at basic drive cycle
lengths. However, the premature sequence was slower, and the lack of
clearly defined Purkinje potentials (i.e., rapid deflections) on the
endocardial electrodes led those investigators to conclude that the
peripheral conduction system contributed minimally to activation
sequence. Whereas our finding that endocardial activation sequence
slowed is consistent with this earlier report, we note important
differences that suggest the peripheral conduction system contributed
to the response to premature stimulation. For example, we found that
the activation sequence changed considerably, as evidenced by the low
correlation coefficient between the paced and premature sequences
(0.63 ± 0.37). This occurred despite the existence of more sites
where P deflections were detected than during cycle length
accommodation. We believe the explanation for these collective changes
is related to the marked increase in P-V latency. That increase
suggests that delayed or failed PVJ conduction allowed peripheral
conduction system and myocardium to functionally uncouple. Failed PVJ
conduction is consistent with measurements by Gilmour and Watanabe
(20), who used canine Purkinje-papillary muscle
preparations to show that premature papillary muscle excitation
prolonged retrograde conduction time, and with measurements by Sasyniuk
and Mendez (36), who used canine papillary muscle-false
tendon preparations to show that false tendon premature stimulation
produced conduction block at PVJs proximal to the stimulus site. This
interpretation is also consistent with the report of Ben-Haim et al.
(5), who used multiple needles arranged in an apex-to-base
line in the LV of in situ canine hearts to study relationships
among Purkinje, endocardial, and epicardial activation sequences. Those
investigators found conduction delays in the peripheral conduction
system with premature stimulation changed activation sequence by
allowing remote epicardium to be activated by alternate routes.
Ectopic beats.
Our finding regarding the pronounced separation between peripheral
conduction system and myocardial wave fronts during the initiating
ectopic cycles is consistent with the suggested contribution of the
conduction system to arrhythmia formation by Berenfeld and Jalife
(7). Those investigators assembled a three-dimensional model of the mammalian ventricles and attached a representative conduction system to 1-mm3 ventricular elements at 214 PVJ
sites. Reentry was initiated by initial conditions in the
FitzHugh-Nagumo equations that were intended to represent triggered
Purkinje activity in elemental excitation and recovery processes.
Initiation gave rise to polymorphic ventricular tachycardia with
drifting epicardial breakthrough sites and endocardial foci that
originated at PVJs. Evolution of separate reentrant activation
sequences in specialized conduction system and ventricular elements was
essential to the formation of intramural reentrant circuits. Once these
latter circuits formed, complete uncoupling at PVJs had no effect on
activation sequence. Although our methodology prevented reconstruction
of separate activation sequences during ectopic beats, we consistently
observed P-V latencies exceeding 10 ms. Latencies of such magnitude are well beyond reported measures for PVJ conduction times. This asynchrony of P and V deflections in the present study supports the concept that
separate activation sequences in the peripheral conduction system and
overlying ventricular layer precede arrhythmia formation.
Limitations.
In assessing our findings, it is important to recognize certain
limitations. To facilitate endocardial access and plaque positioning with electrodes covering most of the RV free wall, preparations were
pinned in a chamber during aortic perfusion. The horizontal orientation
may have deformed the aortic valve annulus and could potentially have
caused valvular insufficiency. Although signal characteristics were
maintained through the protocols and we did not observe marked the S-T
segment elevation that suggests ischemia, the possibility that
perfusion was incomplete cannot be excluded. In this regard, horizontal
positioning, the process of cryoablation, and the free wall dissection
required for endocardial access may all have contributed to the
relatively high incidence of ectopy that we observed in response to
single premature stimuli.
It would have been advantageous to complete all protocols after LNT
application to eliminate contributions of the specialized conduction
system to the endocardial activation sequences. This information would
have been especially beneficial in analyzing the transition from
premature to ectopic responses, because a demonstration that
endocardial-programmed pacing following LNT application failed to
establish nonsustained arrhythmias of the type observed pre-LNT would
have been compelling evidence for a contribution of the peripheral
conduction system to endocardial arrhythmia formation. Unfortunately,
we had limited success with maintaining preparations after LNT
application because there was marked signal degradation despite the
relatively small amounts (0.2-0.4 ml) used in our applications.
This finding was in contrast to experiments with isolated and in situ
canine hearts (11, 15, 28, 33), where LNT has been used to
effectively ablate specialized conduction system. Our observation
suggests some destruction of endocardial myocytes accompanies Purkinje
cell ablation during LNT application. Because the rabbit RV free wall
is so thin compared with the canine heart, accompanying myocyte damage
would necessarily be expected to have a more pronounced influence in
rabbit RV free wall than in preparations from larger hearts. The use of
an animal model with larger heart size may therefore have been
advantageous to facilitate the completion of pacing protocols pre- and
post-LNT.
We used a 2-ms threshold for the separation between P and V deflections
to measure P-V latencies. Although antegrade PVJ conduction delays on
the order of 2 ms were reported by Tranum-Jensen et al.
(38) in experiments using superfused rabbit LV
preparations, it was not our intent to relate conduction delay to this
threshold. The threshold was selected on practical grounds, because we
were unable to identify unique deflections without ambiguity when they were spaced closer than 2 ms. One consequence of this selection is that
we potentially underreported the number of sites with P deflections.
Sites at which peripheral conduction system and myocardium excited
within 2 ms of one another were treated in the same way as sites at
which no peripheral conduction system was present. Likewise, sampling
at a higher rate may also have allowed the identification of more P
deflections. By using isolated canine Purkinje strands, Barr and Spach
(4) found a rate of 15,000 samples/s was necessary for
complete reconstruction of unipolar electrograms.
Although our use of a plaque recording array was advantageous in terms
of completing the experiments because simultaneous data acquisition
with fixed-electrode geometry was achieved, the array itself imposed
certain limitations that potentially influenced our analyses. Because
the Ag/AgCl electrodes were embedded in epoxy, it was not practical to
integrate a 1-2 mm retracted reference for each electrode. As
described by Veenstra et al. (40), the primary advantage
to using such a reference is that discrete PVJs can be identified from
characteristic signal components, without the need to analyze those
components alongside the myocardial activation sequence. As confirmed
by the detailed electrophysiological and histological measurements by
Tranum-Jensen et al. (38), a rapid biphasic P deflection
that precedes a uniphasic, completely negative V deflection corresponds
with underlying Purkinje and ventricular cell depolarization in such
electrograms. If we had been able to integrate such electrode pairs
into our recording array, it may have been possible to identify more
sites with P deflections and to label more regions as antegrade PVJ
conduction sites. Additionally, the use of a plaque prevented direct
electrode contact at all sites on the RV free wall because of the
trabeculation that is characteristic of this preparation. Local signal
attenuation associated with differences in contact likely contributed
to the relatively low percentage of P deflections we measured in all experiments.
It would also have been advantageous to complete sinus mapping in
advance of endocardial pacing protocols using the same preparations. This was a practical limitation that resulted from our goal of limiting
viable tissue to the measurement region in the pacing experiments,
which was especially important for mapping of the initiating ectopic
cycles to ensure the arrhythmias did not simply result from
atrioventricular conduction. Mapping of sinus beats in advance of
endocardial pacing would have allowed measurements of the change in P-V
latencies at individual sites and might additionally have allowed
identification of more early sites suggesting discrete PVJs as
described for larger hearts.
| |
ACKNOWLEDGEMENTS |
The authors acknowledge the editorial comments of Dr. Delilah Huelsing.
| |
FOOTNOTES |
This work was supported by National Science Foundation Awards
BES-9457212 and BES-9903466, American Heart Association Southeast Affiliate Award 0051196B, and National Heart, Lung, and Blood Institute
Grants HL-54024, HL-33637, and HL-28429.
Address for reprint requests and other correspondence: A. E. Pollard, Cardiac Rhythm Management Laboratory, Univ. of Alabama at
Birmingham, Volker Hall B140, 1670 University Blvd., Birmingham, AL
35294 (E-mail: pollard{at}crml.uab.edu).
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 7 April 2000; accepted in final form 5 April 2001.
| |
REFERENCES |
1.
Arisi, G,
Macchi E,
Corradi C,
Lux RL,
and
Taccardi B.
Epicardial excitation during ventricular pacing. Relative independence of breakthrough sites from excitation sequence in canine right ventricle.
Circ Res
71:
840-849,
1992[Abstract/Free Full Text].
2.
Arnar, DO,
Bullinga JR,
and
Martins JB.
Role of the Purkinje system in spontaneous ventricular tachycardia during acute ischemia in a canine model.
Circulation
96:
2421-2429,
1997[Abstract/Free Full Text].
3.
Asano, Y,
Davidenko JM,
Baxter WT,
Gray RA,
and
Jalife J.
Optical mapping of drug-induced polymorphic arrhythmias and Torsades de Pointes in the isolated rabbit heart.
J Am Coll Cardiol
29:
831-842,
1997[Abstract].
4.
Barr, RC,
and
Spach MS.
Sampling rates required for digital recording of intracellular and extracellular cardiac potentials.
Circulation
55:
40-48,
1977[Abstract/Free Full Text].
5.
Ben-Haim, SA,
Cable DG,
Rath TE,
Carmen L,
and
Martins JB.
Impulse propagation in the Purkinje system and myocardium of intact dogs.
Am J Physiol Heart Circ Physiol
265:
H1588-H1595,
1993[Abstract/Free Full Text].
6.
Berbari, EJ,
Lander P,
Scherlag BJ,
Lazzara R,
and
Geselowitz DB.
Ambiguities of epicardial mapping.
J Electrocardiol
24:
16-20,
1991.
7.
Berenfeld, O,
and
Jalife J.
Purkinje-muscle reentry as a mechanism of polymorphic ventricular arrhythmias in a three-dimensional model of the ventricles.
Circ Res
82:
1063-1077,
1998[Abstract/Free Full Text].
8.
Bigger, JT,
Bassett AL,
and
Hoffman BF.
Electrophysiological effects of diphenylhydantoin on canine Purkinje fibers.
Circ Res
22:
221-236,
1968[Abstract/Free Full Text].
9.
Boyett, MR,
and
Jewell BR.
Analysis of the effects of changes in rate and rhythm upon electrical activity in the heart.
Prog Biophys Mol Biol
36:
1-52,
1980[Web of Science][Medline].
10.
Callewaert, G,
Carmeliet E,
and
Vereecke J.
Single cardiac Purkinje cells: general electrophysiology and voltage-clamp analysis of the pacemaker current.
J Physiol (Lond)
349:
643-661,
1984[Abstract/Free Full Text].
11.
Cha, YM,
Birgersdotter-Green U,
Wolf PL,
and
Chen PS.
The mechanism of termination of reentrant activity in ventricular fibrillation.
Circ Res
74:
495-506,
1994[Abstract/Free Full Text].
12.
Chen, CM,
and
Gettes LS.
Combined effects of rate, membrane potential, and drugs on maximum rate of rise of action potential upstroke of guinea pig papillary muscle.
Circ Res
38:
464-469,
1976[Abstract/Free Full Text].
13.
Colatsky, TJ,
and
Tsien RW.
Electrical properties associated with the wide intercellular clefts in rabbit Purkinje fibres.
J Physiol (Lond)
290:
227-252,
1979[Abstract/Free Full Text].
14.
Cordeiro, JM,
Spitzer KW,
and
Giles WR.
Repolarizing potassium currents in rabbit heart Purkinje cells.
J Physiol (Lond)
508:
811-823,
1998[Abstract/Free Full Text].
15.
Damiano, RJ,
Smith PK,
Tripp HF,
Asano T,
Small KW,
Lowe JE,
Ideker RE,
and
Cox JL.
The effect of chemical ablation of the endocardium on ventricular fibrillation threshold.
Circulation
74:
645-652,
1986[Abstract/Free Full Text].
16.
De Jong, F,
Opthof T,
Wilde AAM,
Janse MJ,
Charles R,
Lamers WH,
and
Moorman AFM
Persisting zones of slow impulse conduction in developing chicken hearts.
Circ Res
71:
240-250,
1992[Abstract/Free Full Text].
17.
Durrer, D,
Van Dam RT,
Freud GE,
Janse MJ,
Meigler F,
and
Arzbaecher R.
Total excitation of the isolated human heart.
Circulation
41:
899-912,
1970[Abstract/Free Full Text].
18.
Efimov, IR,
Ermentrout B,
Huang DT,
and
Salama G.
Activation and repolarization patterns are governed by different structural characteristics of ventricular myocardium: experimental study with voltage-sensitive dyes and numerical simulations.
J Cardiovasc Electrophysiol
7:
512-530,
1996[Web of Science][Medline].
19.
Franz, MR,
Bargheer K,
Rafflenbeul W,
Haverich A,
and
Lichtlen PR.
Monophasic action potential mapping in human subjects with normal electrocardiograms. Direct evidence for the genesis of the T wave.
Circulation
75:
379-386,
1987[Abstract/Free Full Text].
20.
Gilmour, RF,
and
Watanabe M.
Dynamics of circus movement reentry across canine Purkinje fibre-muscle junctions.
J Physiol (Lond)
476:
473-485,
1994[Abstract/Free Full Text].
21.
Huelsing, DJ,
Spitzer KW,
Cordeiro JM,
and
Pollard AE.
Conduction between isolated rabbit Purkinje and ventricular myocytes coupled by a variable resistance.
Am J Physiol Heart Circ Physiol
274:
H1163-H1173,
1998[Abstract/Free Full Text].
22.
Joyner, RW,
and
Overholt ED.
Effects of octanol on canine subendocardial Purkinje-to-ventricular transmission.
Am J Physiol Heart Circ Physiol
249:
H1228-H1231,
1985.
23.
Kanai, A,
and
Salama G.
Optical mapping reveals that repolarization spreads anisotropically and is guided by fiber orientation in guinea pig hearts.
Circ Res
77:
784-802,
1995[Abstract/Free Full Text].
24.
Laxer, C,
Ideker RE,
Smith WM,
Wolf PD,
and
Simpson EV.
A graphical display system for animating mapped cardiac potentials.
In: Proceedings of the Third Annual IEEE Symposium on Computer-Based Medical Systems. New York: IEEE Computer Society, 1990, p. 197-204.
25.
Lazzara, R,
Yeh BK,
and
Samet P.
Functional anatomy of the canine left bundle branch.
Am J Cardiol
33:
623-632,
1974[Web of Science][Medline].
26.
Mendez, C,
Mueller WJ,
Merideth J,
and
Moe GK.
Interaction of transmembrane potentials in canine Purkinje fibers and at Purkinje fiber-muscle junctions.
Circ Res
24:
361-372,
1969[Abstract/Free Full Text].
27.
Mendez, C,
Mueller WJ,
and
Urguiaga X.
Propagation of impulses across the Purkinje fiber-muscle junction in the dog heart.
Circ Res
26:
135,
1970[Abstract/Free Full Text].
28.
Millar, K,
Burgess MJ,
Abildskov JAA,
and
Eich RH.
Dependence of intraventricular pressures on activation order before and after experimental Purkinje net block.
J Electrocardiol
3:
51-56,
1970[Medline].
29.
Moorman, AFM,
DeJong F,
Denyn MMFJ,
and
Lamers WH.
Development of the cardiac conduction system.
Circ Res
82:
629-644,
1998[Free Full Text].
30.
Myerburg, RJ,
Gelband H,
Nilsson K,
Castellanos A,
Morales AR,
and
Bassett AL.
The role of canine superficial ventricular muscle fibers in endocardial impulse distribution.
Circ Res
42:
27-35,
1978[Abstract/Free Full Text].
31.
Nagao, K,
Toyama J,
Kodama I,
and
Yamada K.
Role of the conduction system in the endocardial excitation spread in the right ventricle (Abstract).
Am J Cardiol
48:
864-870,
1981[Web of Science][Medline].
32.
Overholt, ED,
Joyner RW,
Veenstra RD,
Rawling DA,
and
Wiedmann R.
Unidirectional block between Purkinje and ventricular layers of papillary muscles.
Am J Physiol Heart Circ Physiol
247:
H584-H595,
1984.
33.
Pollard, AE,
Spitzer KW,
and
Burgess MJ.
Contributions of the specialized conduction system to the activation sequence in the canine pulmonary conus.
Am J Physiol Heart Circ Physiol
273:
H446-H463,
1997[Abstract/Free Full Text].
34.
Pressler, ML.
Cable analysis in quiescent and active sheep Purkinje fibers.
J Physiol (Lond)
352:
739-757,
1984[Abstract/Free Full Text].
35.
Rawling, DA,
Joyner RW,
and
Overholt ED.
Variations in the functional electrical coupling between the subendocardial Purkinje and ventricular layers.
Circ Res
57:
252-261,
1985[Abstract/Free Full Text].
36.
Sasyniuk, BI,
and
Mendez C.
A mechanism for reentry in canine ventricular tissue.
Circ Res
28:
252-261,
1971.
37.
Simpson, EV,
Ideker RE,
Cabo C,
Yabo S,
Zhou X,
Melnick SB,
and
Smith WM.
Evaluation of an automatic cardiac activation detector for bipolar electrograms.
Med Biol Eng Comput
31:
118-128,
1993[Web of Science][Medline].
38.
Tranum-Jensen, J,
Wilde AAM,
Vermeulen JT,
and
Janse MJ.
Morphology of electrophysiologically identified junctions between Purkinje fibers and ventricular muscle in rabbit and pig hearts.
Circ Res
69:
429-437,
1991[Abstract/Free Full Text].
39.
Van Dam, RT,
and
Janse MJ.
The effect of changes in rate and rhythm on the refractory period of the ventricular myocardium and the specialized conducting system of the canine heart.
In: Cardiac Electrophysiology and Arrhythmias, edited by Kao FF,
Koizumi K,
and Vassalle M.., 1971, p. 161-175.
40.
Veenstra, RD,
Joyner RW,
and
Rawling DA.
Purkinje and ventricular activation sequences of canine papillary muscle. Effects of quinidine and calcium on the Purkinje-ventricular conduction delay.
Circ Res
54:
500-515,
1984[Abstract/Free Full Text].
41.
Wiedmann, RT,
Tan RC,
and
Joyner RW.
Discontinuous conduction at Purkinje-ventricular muscle junction.
Am J Physiol Heart Circ Physiol
271:
H1507-H1516,
1996[Abstract/Free Full Text].
42.
Wolf, PD,
Rollins D,
Simpson E,
Smith WM,
and
Ideker RE.
A 528 channel system for the acquisition and display of defibrillation and electrocardiographic potentials.
In: Proceedings of Computers in Cardiology. New York: IEEE Computer Society, 1993, p. 125-128.
Am J Physiol Heart Circ Physiol 281(2):H490-H505
0363-6135/01 $5.00
Copyright © 2001 the American Physiological Society
TOP
ABSTRACT
INTRODUCTION
