© 1998 American Heart Association, Inc.
Original Contributions |
Characteristics of the Temporal and Spatial Excitable Gap in Anisotropic Reentrant Circuits Causing Sustained Ventricular Tachycardia
From the Department of Cardiology (N.S.P.), St Mary's Hospital & Imperial College School of Medicine, London, UK; the Departments of Pharmacology (N.S.P., C.C., A.L.W.) and Medicine (J.C.), College of Physicians & Surgeons of Columbia University, New York, NY; the Department of Medicine (M.E.J.), Beth Israel Hospital of Harvard University, Boston, Mass; and the Department of Medicine (M.S.H.), University of Pennsylvania at the Philadelphia VA Medical Center.
Correspondence to Nicholas S. Peters, MD, Department of Cardiology, St. Mary's Hospital, Praed Street, London W2 1NY, UK.
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Abstract |
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Abstract—The excitable gap of a reentrant circuit has both temporal (time during the cycle length that the circuit is excitable) and spatial (length of the circuit that is excitable at a given time) properties. We determined the temporal and spatial properties of the excitable gap in reentrant circuits caused by nonuniform anisotropy. Myocardial infarction was produced in canine hearts by ligation of the left anterior descending coronary artery. Four days later, reentrant circuits were mapped in the epicardial border zone of the infarcts with a multielectrode array during sustained ventricular tachycardia induced by programmed stimulation. During tachycardia, premature impulses were initiated by stimulation at sites around and in the reentrant circuits, and their conduction characteristics in the circuit were mapped. All circuits had a temporal excitable gap in at least part of the circuit, which allowed premature impulses to enter the circuit. Completely and partially excitable segments of the temporal gap were identified by measuring conduction velocity of the premature impulses; conduction was equal to the native reentrant wave front in completely excitable regions and slower than the reentrant wave front in partially excitable regions. In some circuits, a temporal gap existed throughout the circuit, permitting the entire circuit to be reset over a range of premature coupling intervals, although the size of the gap varied at different sites. In other circuits, the gap became so small at local sites that even though premature impulses could enter the circuit, the circuit could not be reset. Premature impulses could terminate reentry in circuits that could be reset or not. We also found a significant spatial gap, which was identified by determining the distance between the head of the circulating wave front, which could be located on the activation map, and its tail, which was the site most distal from the head as located by the site of entry of the premature wave front into the circuit. The spatial gap could also vary in different parts of the circuit. Therefore, nonuniform anisotropic reentrant circuits have both a temporal and spatial excitable gap with fully and partially excitable components that change in different parts of the circuit.
Key Words: anisotropy • reentry • excitable gap
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Introduction |
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The excitable gap in a reentrant circuit, ie, the excitable region that precedes the propagating reentrant wave front,1 has both temporal and spatial properties. It has a time duration at any point in the circuit, the temporal gap, and it has length at any moment in time, the spatial gap. One method that has been used to determine the temporal gap in the in situ heart has been to determine the range of coupling intervals of stimulated premature impulses that can reset the circuit, ie, advance activation at all sites in the circuit (resetting curves).2 3 4 Another method has been to compare the cycle length of reentry with the refractory period in a region of the reentrant circuit determined by the maximum rate at which this site will respond to pacing.5 6 When the cycle length of reentry is longer than the local refractory period, the difference between the two has been designated the (temporal) excitable gap.5 6 7 8 Although these methods have been useful for understanding properties of reentrant circuits, they do not take into consideration the potential heterogeneity of the temporal excitable gap in different regions of the reentrant circuit. For example, the temporal gap would be expected to have different values in different parts of the circuit if there were different refractory periods at different sites in the circuit. Yet the first method described above (resetting curves) shows the minimal excitable gap only at some undefined site in the circuit, whereas the second method gives a measure of the excitable gap only at the site where the refractory period is determined.
In contrast to the temporal gap, the spatial gap of a reentrant circuit is that part of the circuit path length that is excitable at any instant in time. It is the distance between the reentrant wave front and its refractory tail from the previous excitation of the circuit. The spatial gap has not been studied in the in situ heart, although it has been investigated in in vitro models of reentry and isolated perfused hearts.9 10 In regions of the circuit where conduction slows or the refractory period is short, the spatial excitable gap should expand, whereas in regions where there is speeding of conduction or lengthening of the refractory period, the spatial excitable gap should decrease.
In a previous study, we found that anisotropic reentrant circuits in in situ infarcted canine hearts11 12 could be entrained, indicating the presence of an excitable gap.13 However, modification of the reentrant circuit by the repetitive overdrive stimuli used during entrainment limits the usefulness of this stimulation technique for determining the properties of the excitable gap.14 In the present study, we have used single stimulated premature impulses delivered from multiple sites around and within anisotropic reentrant circuits in combination with activation mapping to determine the temporal and spatial properties of the excitable gap. A preliminary report of our results has previously been presented.15
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Materials and Methods |
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Canine Model of Myocardial Infarction
Myocardial infarcts were produced in adult mongrel dogs (weight, 25 to 35 kg) by ligation of the left anterior descending coronary artery (LAD) near its origin.11 13 16 Four days after surgery, the dogs were reanesthetized with sodium pentobarbital (25 to 35 mg/kg) for the electrophysiological study. The left femoral artery was cannulated for constant monitoring of blood pressure, which was displayed along with leads II and III of the surface ECG on an oscillographic recorder (model DR 12, Electronics for Medicine). The left femoral vein was cannulated for administration of fluids. The chest was opened through a median sternotomy. A 9x13-cm flexible polymer sheet, 0.3 mm thick, containing 292 bipolar electrodes was fixed to the left ventricular epicardium over the anterior and lateral aspects of the infarct with 2–0 silk sutures to map impulse propagation in the epicardial border zone of the infarct.13 16 The chest was covered with a clear plastic sheet to maintain body temperature. The epicardial temperature was monitored with a thermistor probe (model 409 A, Yellow Springs Instruments) and maintained at 37°C to 38°C with a heating lamp.
Recording and Stimulating Electrodes and
Instrumentation
The electrodes in the 292 bipolar array were made from silver
disks with a diameter of 1.0 mm. The distance between the centers
of two disks forming a bipolar pair was 2.0 mm. We could
record simultaneously from 196 of the 292 electrodes at
any one time with a computerized mapping system.13 16
Bipolar stimulating electrodes were positioned around the centermost
electrodes, at the basal and lateral margins of the recording
array, and on the right ventricular
epimyocardium adjacent to the LAD margin of the electrode
array.13 16
Experimental Protocol
Ventricular tachycardia was induced by
either single or double premature stimuli (constant current, 2 ms in
duration and 2x diastolic threshold) delivered during
basic drive from one of the stimulating electrodes (central, basal,
LAD, and lateral). Sustained ventricular
tachycardia lasting for at least several minutes (all
tachycardias were monomorphic) was required in order to
study the properties of the excitable gap of the reentrant circuit. In
addition, we only included experiments in which the entire reentrant
circuit could be mapped in the epicardial border zone underlying the
electrode array. Eight complete circuits11 13 16 were
recorded during sustained tachycardia in the seven dogs
that formed the experimental group. In one of these experiments, two
different reentrant circuits occurred.
When a stable reentrant tachycardia was established, single
stimuli (2-ms duration and 2x diastolic threshold) were
introduced from one of the stimulating electrodes at intervals spanning
the full cycle length, approximately every 10 tachycardia
cycles (Fig 1A
). If
tachycardia terminated spontaneously or was terminated by
one of the stimuli (bottom ECG in Fig 1A) before completion of
stimulation throughout the entire cycle length, tachycardia
was reinitiated after several minutes, and the protocol was completed.
We tried to repeat this procedure at each of the four different
stimulation sites, ensuring that the tachycardia had the
same QRS morphology and reentrant circuit, but did not succeed in
completing the entire protocol in all experiments.
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Data Analysis
The magnetic tapes from each experiment were replayed for
off-line data analysis. Our methods for determining local
activation times, drawing isochrones, designating regions of
apparent conduction block, and locating reentrant circuits have been
described in detail.11 13 16
We determined the temporal and spatial excitable gap by mapping the propagation of stimulated premature impulses into the circuit during ventricular tachycardia. We describe these methods in more detail along with the results for greater clarity.
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Results |
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The Temporal Excitable Gap in Anisotropic Reentrant Circuits
Characteristics of the Temporal Excitable Gap
We first describe the results of a representative experiment showing that anisotropic circuits have a temporal excitable gap and that the temporal gap at different sites in the reentrant circuit (local temporal excitable gap) is different, one of the major findings of the present study (Table 1
, experiment 1A). The activation map in
Fig 1B
shows the stable pattern of reentry causing the sustained
tachycardia in Fig 1A. In the time window shown, the
sequence of isochrones (designated by the black arrows) shows a
wave front (the "native" reentrant impulse) initially moving toward
the LAD margin, then dividing in two, and continuing around two lines
of functional block (thick black lines) parallel to the long axis of
the myocardial fiber bundles, which were not present in the absence
of tachycardia, to form a typical figure-of-eight
anisotropic reentrant circuit.11 12 17 The activation
pattern around the left line of block is also shown by the sequence of
electrograms in Fig 1C.
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Fig 2 illustrates the propagation of a
long-coupled premature impulse initiated from the stimulating
electrodes at the LAD site (pulse symbol in Fig 2A) during a complete
scan of the cardiac cycle that was used to determine the properties of
the temporal excitable gap of the reentrant circuit described in Fig 1B. In this and subsequent figures, we focus only on one of the
reentrant loops of the figure-of-eight circuits to keep our description
as brief as possible, but our analysis has shown similar
phenomena occurring in both loops. The time window illustrated by the
activation map in Fig 2A begins at the vertical line in Fig 2B, which
is the time that the stimulus was applied. The long arrows in Fig 2A
represent the stimulated propagating wave front impinging on
and entering the circuit in a region that we call "the zone of
preexcitation." We define the zone of preexcitation as the region
where the stimulated propagating premature impulse enters the circuit
before it becomes the reentrant wave front. The greatest degree of
preexcitation in the circuit, ie, the most orthodromic electrogram
showing the shortest premature coupling interval, defines the limit of
the zone of preexcitation in the orthodromic direction, since it is the
most orthodromic site to be excited by the premature wave front
entering the circuit before it becomes the new reentrant wave front. In
Fig 2, it is electrogram 54 (circled in Fig 2B and shown with a
darkened electrogram trace) with a coupling interval of 250 ms that is
the most premature electrogram, 28 ms earlier than activation of that
site by the native impulse. Electrogram 54 is activated
simultaneously or before electrograms recorded from
sites that precede it in the circuit (electrograms 50 and 52), showing
that it is not activated by an orthodromically propagating
reentrant wave front. The electrogram with the shortest coupling
interval (electrogram 54) is, therefore, the entrance into the circuit
from which the stimulated wave front propagates in the orthodromic
direction through the rest of the circuit, as indicated by the expected
sequence of activation and electrogram morphology of sites in advance
of this site in the circuit (electrograms 82, 96, etc). Electrogram 54
is called the circuit entry electrogram.
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Premature activation at electrode 54 results in an electrogram
morphology similar to that produced by the native reentrant wave front
(Fig 2B), because the directions of propagation of the native and
stimulated wave fronts at that site are similar. However, unlike the
native cycle, the slight alteration in pattern of activation of this
region by the stimulated wave front results in electrogram 54 preceding
electrogram 52. At this stimulated coupling interval, the stimulated
premature wave front enters the circuit when the head of the native
reentrant wave front (represented by the stippled region in
Fig 2A) is somewhere near sites 37 and 50. This conclusion is based on
the observation that electrogram 37 (Fig 2B) is activated at
the native cycle length with a nearly normal morphology; it is not
perturbed by the premature wave front. Electrogram 50 is
activated at a cycle length that is 2 to 3 ms less than the
tachycardia, with a slightly altered morphology, but is
coincident with activation of the preexcited zone just ahead of it.
Therefore, there may be collision of the propagating stimulated wave
front and the native reentrant wave front near electrograms 37 and 50
(diagrammed in Fig 2A). The zone of preexcitation extends from
electrograms 50 to 54.
The premature impulse propagates through the circuit with a pattern
similar to the native reentrant impulse (Fig 2A, curved arrows) but
with slower activation, as indicated by the coupling intervals of the
premature activation increasing with propagation from the circuit entry
electrogram, electrode 54 to the subsequent
representative electrograms around the circuit (Fig 2B). Although much of the circuit is activated prematurely, as
a result of this slowing of activation in the circuit, the premature
impulse falls back on time with respect to the native intervals by the
time it completes a full reentrant cycle. The next, or return, coupling
interval at circuit entry electrogram 54 is 303 ms (Fig 2B), ie, 25 to
26 ms longer than the native cycle length. At this recording
site, the sum of the premature and return cycle lengths is nearly twice
the basic tachycardia cycle length; therefore, the amount
of slowing of activation has balanced the degree of prematurity.
Resetting has not occurred. Similar patterns of activation occurred for
coupling intervals between 250 ms (Fig 2B) and 270 ms; the premature
impulse entered the circuit and preexcited part of it but not all
of it.
Shorter coupled premature impulses stimulated at the LAD margin
(coupling intervals between 250 and 209 ms) during this
tachycardia also entered the circuit at electrode 54
(circuit entry electrogram) but preexcited the entire reentrant
circuit. Fig 3 illustrates the pattern of
propagation of these shorter coupled premature impulses. In Fig 3A, propagation of the stimulated impulse occurred in a broad wave front
(long arrows) that resulted in early and nearly
simultaneous activation of electrograms 37, 50, 52, and 54
(darkened electrogram traces in Fig 3B). Collision of the stimulated
wave front with the native reentrant wave front occurred between
electrodes 37 and 39; electrogram 39 has the cycle length of the
tachycardia and a slightly altered morphology, whereas the
cycle length at electrode 37 is decreased, and the electrogram
morphology is significantly changed (Fig 3B). The greatest degree of
preexcitation in the circuit (ie, the electrogram showing the shortest
premature coupling interval) was at the distal (orthodromic) end of
this zone of preexcitation, still electrogram 54 (coupling interval 209
msec in Fig 3B), which was responsible for propagation of this
premature wave front around the remainder of the circuit. Electrogram
54 remained the circuit entry electrogram. The pattern of activation
remained nearly identical to the native reentrant circuit, although
activation of the circuit by the premature impulse was slower than by
the native reentrant wave front, as shown by coupling intervals that
are decreasingly premature (the coupling intervals lengthen) with
propagation from the entrance point (Fig 3B). For coupling intervals
between 250 and 209 ms (not shown), the premature wave front finished a
complete excursion around the circuit, with the next, or return,
coupling intervals at circuit entry electrogram 54 in advance of where
the native wave front would have been if the circuit had been left
undisturbed, despite the conduction delays. That is, the sum of the
preexcited intervals at electrogram 54 and the return intervals were
less than twice the ventricular tachycardia
cycle length, and the circuit was therefore reset. At the shorter
premature coupling interval of 209 ms shown in Fig 3, the stimulated
premature impulse blocked in the circuit, causing termination of
tachycardia (see Fig 1A, bottom ECG trace).
Recording site 41 was preexcited at a coupling interval of 238
ms (Fig 3B), earlier than it was activated by any other
premature wave front. This resulted in conduction block of the
premature wave front in the region just distal to electrogram 41,
indicated by the horizontal dashed line between sites 41 and 39 in Fig 3A and the solid horizontal line between these electrograms in Fig 3B.
Therefore, the coupling interval of 238 ms at electrogram 41
approximates the effective refractory period of the tissue at the site
where block occurred, just distal to 41, and is the longest local
effective refractory period in the circuit. It represents the
inner boundary of the local temporal excitable gap at that site. The
overall duration of the excitable gap just distal to electrode 41 is
the difference between the native cycle length (278 ms) and the
interval that blocked (238 ms), ie, 40 ms (Table 1, experiment 1A).
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When the full range of coupling intervals of stimulated premature
impulses from the LAD margin, measured at the circuit entry electrogram
(electrogram 54), is plotted (Fig 4), the
curve of premature coupling intervals against return cycle length shows
two phases. There is a phase representing the window of
reset of the circuit, whereby the sum of the premature coupling
interval and the return cycle length is less than twice the
ventricular tachycardia cycle length (the
segment of the curve that falls below the dashed line in Fig 4). Over
this range of coupling intervals, all points in the reentrant circuit
were preexcited by the premature impulse. The window of reset of this
circuit spans 41 ms between coupling intervals of 250 and 209 ms. The
inner boundary of the window is determined by the coupling interval at
which the premature impulse was blocked in the circuit at the site with
the longest refractory period and the shortest excitable gap (site near
electrode 41). Between coupling intervals of 250 ms and the
tachycardia cycle length of 278 ms, despite entrance into
the circuit of the premature impulse, the entire circuit was not reset
because the stimulated wave front propagated prematurely through only
part of the circuit (illustrated in Fig 2). The part of the resetting
curve during these intervals constitutes a second phase of the curve in
Fig 4, the window of compensatory pause, which is indicated by
coincidence between the points on the curve and the dashed line. In
this experiment, the window of reset was 15% of the reentrant cycle
length (Table 1, experiment 1A), and it is the duration of this portion
of the curve that shows resetting, which has been interpreted (in
studies without detailed mapping2 3 4 ) to indicate the
duration of the temporal extent of the excitable gap of the reentrant
circuit. In fact, the present mapping study shows that there is no
one temporal excitable gap but that the gap differs at different sites.
The excitable gap near site 41 was 
40 ms (the difference between the
tachycardia cycle length and the cycle length at which
block occurred) (Table 1, experiment 1A), coinciding with the reset
portion of the curve, but the gap at circuit entry electrogram 54 was
at least 69 ms (25% of the cycle length; Table 1, experiment 1A). That
is, a stimulated wave front was able to enter the circuit at
electrogram 54 over a range of coupling intervals spanning 69 ms from a
premature coupling interval of 209 ms to the tachycardia
cycle length of 278 ms. A gap larger than 69 ms may have existed at
electrode 54, since we did not determine the refractory period of this
site, and a larger gap that we did not measure may have existed at
another region in the circuit.
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We have also found that anisotropic reentrant circuits that cannot be
reset at any premature coupling interval may still have substantial
local temporal excitable gaps, also demonstrating that the gap changes
in different regions of the circuit (Fig 5). Fig 5E shows the curve of premature
coupling intervals versus the return cycle at the circuit entry
electrogram (electrogram 175) for such an experiment on another
figure-of-eight circuit that is diagrammed in Fig 5B. In this circuit,
segments of the lines of block (thick black lines) were oblique or
perpendicular to the long axis of the fibers, a characteristic that
sometimes occurs in anisotropic circuits and may be the result of
unspecified damage caused by infarction. The LAD stimulation site
(pulse symbol) and electrogram recording sites around the
circuit to the left are indicated on the diagram in Fig 5B. The data
points in Fig 5E fall on the line, showing that the sum of the
premature coupling interval and the return cycle equals twice the
ventricular tachycardia cycle, indicating that
the circuit was not reset. Yet the electrograms that were recorded
around the circuit indicate that the stimulated impulses did enter the
circuit. In Fig 5A, 5C, and 5D, the sequence of activation during the
native tachycardia begins at electrogram 65 (asterisk at
the left on the bottom trace in each panel) and progresses to
electrogram 53 (top trace). The vertical lines show the time a
premature stimulus was applied, and the long arrow to the right of the
lines shows propagation of the premature impulse in the circuit.
Despite the failure of the circuit to be reset, part of the circuit was
preexcited. Electrode 175 (circled) is the circuit entry electrogram
and is preexcited (darkened part of the trace) at each of the three
coupling intervals shown (217, 155, and 194), indicating the presence
of an excitable gap at the circuit entry site. However, at all coupling
intervals, slowing of activation of the premature wave front
propagating in the circuit from the circuit entry electrogram caused a
loss of prematurity at subsequent sites in the circuit and failure to
reset. The amount of slowing was proportional to the prematurity of the
reentrant wave front, as shown by the slopes of the long arrows. For
coupling intervals of 217 ms (Fig 5A) and 155 ms (Fig 5C) at electrode
175, activation falls back on time when electrode 56 is reached
(coupling interval of 227 ms, which is the same as the
tachycardia cycle length) because of conduction slowing
that increased with increasing prematurity. Therefore, the region
around the end of the left line of block could not be preexcited,
suggesting that the wave front is propagating in just-recovered
myocardium in this region and that the temporal gap
immediately before electrode 56 is small. However, despite the
inability of premature impulses to reset the circuit, a premature
impulse with a coupling interval of 194 ms, midway through the range of
coupling intervals, was blocked in the circuit, thereby terminating
reentry (Fig 5D). This premature impulse activated electrode 56
five milliseconds earlier than either the later-coupled or the
earlier-coupled premature impulse (coupling interval of 222 ms in Fig 5D), causing block just distal to this site. The cause of the earlier
excitation of electrode 56 appears to be less delay in conduction
around the lower end of the left line of block than with the shorter or
longer coupling intervals; the reason is unknown. Therefore, the
refractory period at the site of block between electrodes 56 and 55 is
222 ms, which is 5 to 7 ms shorter than the tachycardia
cycle length, indicating that the excitable gap was 5 to 7 ms in
this region. In this circuit, therefore, the temporal size of the
excitable gap varied from at least 75 ms at the circuit entry
electrogram (the inner boundary of the gap at this site was not
determined) to 7 ms at this site of block (Table 1, experiment 5).
The inability to reset this circuit with premature stimuli delivered at
5- to 10-ms decrements was the result of the very small duration of the
excitable gap in this region.
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In four other experiments, we determined local temporal excitable gaps
at different entry sites into the circuit, three entry sites in two
experiments (Table 1, experiments 3 and 4) and two entry sites in one
experiment (Table 1, experiment 2), by initiating premature impulses at
different sites outside and within the circuit (see "Materials and
Methods"). We also related the local temporal gaps to the resetting
properties of the circuits in these experiments. Figs 6 and 7
show determination of the temporal gap at two different entry sites in
the same circuit. The native reentrant circuit closely resembled the
one shown in Fig 1B. Although Fig 6A shows the circuit during premature
stimulation (described below), the two parallel lines of functional
block (long, thick, black lines) during the native circuit were located
in the same region. The native reentrant wave front (not shown) moved
around the left line of functional block in a counterclockwise
direction, and the right line of block in a clockwise direction. The
activation sequence around the right line of block during the native
tachycardia is shown in Fig 6B by electrograms recorded
from selected electrodes indicated on the map; beginning at electrode
26 (asterisk in bottom trace), the sequence of activation progresses in
a clockwise direction to electrode 41 (top trace), which completes the
circuit. Fig 6A shows the pattern of activation during stimulation at
the basal electrodes (pulse symbol). Although this earliest stimulated
wave front activated electrode sites 14 to 46 nearly
simultaneously (Fig 6B, darkened electrograms; vertical
line marks the stimulus artifact) when the head of the native wave
front was near electrode 12 (no change in electrogram 12 cycle length
or morphology in Fig 6B), the most distal and prematurely
activated site that constitutes the circuit entry point is
electrode 46 (circled in Fig 6B), which has a premature coupling
interval of 186 ms (53 ms early). From the entry point at electrode 46,
the premature impulse propagated around the circuit with delay but
still resulted in resetting of the circuit by 22 ms (Fig 6A and 6B).
Although the local temporal gap at this circuit entry site (electrode
46) was 53 ms, the circuit was reset over only the shortest 45 ms of
this range (Table 1, experiment 4, base) with no resetting over the
remaining 8 ms of the local gap, similar to Fig 4.
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Fig 7 shows determination of the temporal gap at another entry point in
this circuit, at electrode 41 in the central common pathway. The
illustration is also of the earliest effective stimulated impulse. From
the entry point at electrode 41 (circled in Fig 7B, coupling interval
of 156 ms), the stimulated impulse propagated antidromically to collide
with the native wave front (unfilled arrows) between electrode 43 and
electrode 59; electrode 59 has a normal cycle length and morphology
(Fig 7B). The approximate region of collision is indicated by the
interface of the shaded and unshaded areas on the map in Fig 7A.
Slowing of activation of the premature impulse occurred around the
circuit in the orthodromic (clockwise) direction (arrows in Fig 7A)
with preexcitation of the local site 41 and the resetting of the
circuit over a range of coupling intervals of 88 ms.
The excitable gap was also determined in this experiment from
stimulating at the LAD electrodes (not shown). The circuit entry
electrode was electrode 12. From maps of premature impulses over the
entire cycle length, we determined that the local temporal excitable
gap at electrode 12 was 47 ms (this region was excited over a 47-ms
range of coupling intervals), and the circuit was reset over this
entire range (Table 1, experiment 4, LAD). Therefore, there was
variability in the local temporal excitable gap at three different
locations in this circuit: 53 ms at base electrode 46 (Fig 6), 88 ms at
center electrode 41 (Fig 7), and 47 ms at electrode 12 (Table 1,
experiment 4, EGAP column).
Table 1 summarizes the temporal properties of the excitable gap for the
entire series of eight experiments. A local temporal excitable gap
permitting entry of prematurely stimulated wave fronts existed in all
of the circuits (EGAP column). However, not all sites of premature
stimulation produced wave fronts that were able to enter the circuit.
For example, in experiment 1A, stimuli at the base or lateral
electrodes initiated wave fronts that did not enter the circuit at any
coupling interval. In the experiments in which the local gap was
determined at two to three sites in the circuit, either only at circuit
entry sites (experiments 2, 3, and 4) or at an entry site and a site of
block (experiments 1A and 5), the local gap was different at each site.
Five of the circuits could be reset (experiments 1A, 1B, 2, 3, and 4),
indicating the existence of a temporal excitable gap throughout the
circuit at least as long as the zone of reset, permitting the entire
circuit to be preexcited by the propagating premature impulse. In three
of these five circuits (experiments 1A, 2, and 4), we measured local
temporal excitable gaps that exceeded the window of reset
(reset/EGAP<1), and in the other two, it coincided with the window of
reset (reset/EGAP=1). In three experiments, the reentrant circuit could
not be reset (reset window=0 for experiments 5, 6, and 7). However,
Table 1 shows that a local temporal gap existed in each of these
circuits at the circuit entry site, ranging from 3% to 33% of the
reentrant cycle length. The local temporal excitable gap that we
determined in each of these circuits is, therefore, greater than the
minimal excitable gap in the circuit that limited reset, again
demonstrating variability of the gap in different regions of the
circuit.
Conduction Characteristics During the Temporal Excitable
Gap
Conduction properties of the premature impulse in the circuit can
provide information on excitability characteristics of the temporal
gap. We located the regions of delay in activation and quantified the
slowing of activation by dividing the circuits into four regions: the
two turning points of the wave front through 180° around the ends of
the line of functional block, designated the "entry pathway" and
"exit pathway" with respect to the central common pathway, and the
two conduction pathways between the turning points, one within the
central common pathway and one parallel to the lines of block outside
the central common pathway, designated the outer pathway. Around the
turning points (entry and exit pathways), the reentrant wave front is
moving mostly transverse to the long axis of the myocardial fiber
bundles, whereas in the central common pathway and outer pathway, it is
moving mostly parallel to the long axis in our eight
experiments.11 13 As expected, during the native
tachycardia, the velocity of activation (calculated from
the distance between the recording sites and the time required
for the wave front to move this distance), parallel with the lines of
functional block in the central common pathway and outer pathway (and
therefore along the long fiber axis), was significantly greater for all
experiments (61.4±22 cm/s) than the velocity around the turning points
(entry and exit pathways) of the lines of functional block for all
experiments (24.6±12 cm/s, P<.01). Activation was more
rapid through the outer pathway (75.5±26.1 cm/s) than through the
central common pathway (47.2±22.3, P<.01). Activation
velocities in both the longitudinal and transverse directions were
within the range of normal conduction velocities for
ventricular muscle,18 suggesting that the
reentrant impulse may be conducting in fully excitable
myocardium. Table 2 shows the
ratio of the activation velocities of the native reentrant impulse and
most prematurely stimulated impulse (N/P ratio) in each of the four
regions of the circuit for the eight circuits and 13 sites of
stimulation. A ratio of 1, therefore signifies that the velocity of the
premature wave front is equal to that of the native wave front over
that portion of the circuit, whereas a ratio of >1 indicates that the
velocity of the premature wave front is slower than the native wave
front. Over the range of coupling intervals of premature impulses that
entered the circuit, the shortest coupling interval resulted in the
slowest activation through the entire circuit. For 12 of the 13 sites
of stimulation, the greatest degree of activation slowing of the
premature wave front occurred in the segment immediately after entry
into the circuit (asterisks) (mean N/P ratio, 1.42; n=12). Five of the
eight circuits studied could be reset, indicating that despite this
slowing in the entrance region, there was premature activation of the
remainder of the circuit. This occurred because in the other regions of
the circuit, the premature wave front propagated with a velocity
similar to that of the native wave front with a mean N/P ratio of 1.05.
For the most premature wave front in the three nonentry portions of the
circuit, a ratio of 1 occurred in one or more portions of each of the
circuits, indicating an activation velocity for the most premature wave
front in these regions that was equal to the velocity of the native
reentrant wave front (Table 2). Thus, even though slowing of activation
exists in part of the circuit, indicating that the premature impulse
conducts in relatively refractory tissue and that there is only a
partially excitable gap in these regions, other regions of the circuit
may have a fully or nearly fully excitable gap, since activation by
premature wave fronts occurs at normal velocities, which are the same
as the native wave fronts in these regions. Therefore, the temporal gap
is composed of partially and fully excitable regions.
|
The Spatial Extent of Excitable Gap in Anisotropic Reentrant
Circuits
To measure the spatial extent of the excitable gap (the length of
the circuit that is excitable), we made the initial assumption that all
the myocardium in the circuit in the orthodromic direction
between the head of the circulating reentrant wave front and the end of
its refractory tail is excitable and constitutes the spatial excitable
gap. Since the head of the circulating wave front can be identified
from the activation maps, it was then necessary to identify the end of
the refractory tail to determine the spatial gap. This was done by
identifying the site that was the most orthodromic from the head of the
reentrant wave front and at which the premature wave front could enter
the circuit, ie, the circuit entry electrogram, as previously defined.
Propagation of the most premature wave front into the circuit,
therefore, identified the largest extent of the spatial gap in the
circuit entry regions, because this represents the time that
the tail has just passed the entrance point.
By these criteria, the experiments already illustrated have revealed
information about the spatial extent of the excitable gap. In Fig 3, for a short coupled premature impulse, the distance between the circuit
entry site (electrode 54), which identifies the end of the tail of
refractoriness, and the head of the wave front, which is at electrode
39 (identified by normal morphology and cycle length of the native
tachycardia), is the minimal spatial extent of the gap in
this region in the orthodromic direction of the circuit, a distance of
35 mm. (We use the descriptor "minimal" since the spatial gap
might extend even further orthodromically than electrode 54, but the
prematurely stimulated wave front only reached more orthodromic sites
after entering the circuit and propagating in this direction.) Nearly
simultaneous activation of this region, spanning
electrograms 39 to 54 in the circuit by the premature impulse and
illustrated by the darkened electrograms in Fig 3B, indicates that the
myocardium between these electrodes is in fact excitable;
therefore, all the electrodes lie within the spatial excitable gap. The
spatial gap is 35% of the circuit length, which was estimated to be
101 mm by measuring the distance as close as possible to the
central line of block (Table 3,
experiment 1A). Since in this experiment (and the one illustrated in
Fig 5; see Table 3, experiment 5) there were no other sites of
premature stimulation and no other circuit entry points, we were not
able to determine the spatial extent of the gap in other regions and,
thus, whether it changed size.
|
However, in the experiment previously described in Figs 6 and 7,
premature impulses, initiated from three stimulation sites, enabled us
to determine the spatial extent of the gap at the different circuit
entry points (Table 3, experiment 4). Stimulation at the basal site
revealed a very large spatial extent of the gap. In Fig 6, we described
that the greatest degree of preexcitation of this reentrant circuit
from the basal stimulation site occurred at electrogram 46, which is
the circuit entry electrogram. At this time, the head of the native
reentrant wave front was in the vicinity of electrode 12. Therefore, in
Fig 6 the distance between electrode 46 and electrode 12 is the spatial
extent of the excitable gap in this region, a distance of 42 mm
(42% of the circuit length of 101 mm). Basal stimulation at this
short coupling interval also resulted in a broad wave front that
simultaneously preexcited the entire basal side of the
right-hand line of block between electrodes 14 and 46 (Fig 6B, darkened
electrograms), confirming that this entire region was excitable when
the head of the reentrant wave front was in the vicinity of electrode
12.
Central stimulation at the shortest coupling interval within the common
central pathway of this circuit preexcited the most local electrogram
(electrogram 41) at a coupling interval of 156 ms (Fig 7), when the
head of the native wave front was in the vicinity of electrogram 59
(Fig 7B). Therefore, at this moment, the spatial excitable gap extended
at a minimum from just distal to electrode 41 to the head of the
advancing wave front near electrode 59. Antidromic conduction of the
premature impulse occurred from the stimulus site to the electrodes
between it and the advancing native wave front. Thus, the region of
antidromic propagation was excitable and represents the minimal
spatial extent of the excitable gap in this direction, which measures
26 mm.
However, even at the shortest coupling interval of premature impulses
delivered from the LAD stimulation site in this circuit (not shown),
which should expose the excitable gap in its most counterclockwise
position, electrogram 24 could not be preexcited when the circuit entry
electrogram was electrode 12 (electrode locations in the circuit shown
in Figs 6 and 7). This implies that when the head of the native wave
front was at electrogram 24, the excitable gap at electrode 12 had a
very small spatial extent, which we estimate to be 5 mm in a
circuit with a length of 101 mm (Table 3, experiment 4, LAD).
Therefore, as shown by the extent of the spatial gap at the circuit
entry points in this experiment, the spatial extent of the excitable
gap changed markedly in different locations of the circuit.
The minimum spatial extent of the excitable gaps in one or more regions
of all circuits studied are given in Table 3. The size of the gap
ranged from 5 to 57 mm (mean value, 27.8±1.69 mm), which is
5% to 55% of the circuit length. In some cases, this is likely to be
a significant underestimation of the extent of the gap because of the
methodological shortcomings described above. In the three experiments
in which the spatial extent of the gap was determined at multiple
sites, (experiments 2, 3, and 4), there is clearly variation in the
size of the gap in one (experiment 4) but no clear variation in the
others (experiments 2 and 3).
|
Discussion |
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|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The Excitable Gap in Reentrant Circuits
Traditionally, the properties of the excitable gap have been thought to be different in reentrant circuits caused by anatomic and functional mechanisms.19 20 Reentry caused by the leading circle mechanism, the first mechanism described in detail in heart muscle causing functional reentry, has a very small partially excitable gap,19 whereas some anatomic circuits have a large fully excitable gap.8 21 22 23 24 However, more recently, studies on spiral waves in cardiac muscle have shown that this mechanism of functional reentry is associated with a fully excitable gap,9 25 so such a clear distinction between functional and anatomic reentry can no longer be made. An excitable gap has been shown to occur during atrial5 26 and ventricular6 fibrillation and atrial flutter,27 examples of arrhythmias caused by functional reentrant mechanisms, possibly including spiral waves.28 29 In the present study, we have characterized the properties of the excitable gap of functional reentrant circuits that occur in nonuniform anisotropic myocardium of the infarct epicardial border zone and have found that these circuits also have an excitable gap with a fully excitable component, although the fully excitable component did not exist in all regions of the circuit. In those regions of the circuit where there was a fully excitable gap, propagation of the most premature impulses occurred with conduction velocities that were equal to the conduction velocities of the native impulse (native wave front velocity/premature velocity=1 in Table 2
).
Although it is possible that the native reentrant wave front itself
conducts in relatively refractory myocardium, we do not
think that this is the case, since conduction velocities transverse and
longitudinal to fiber bundle orientation were similar to velocities in
fully excitable normal ventricular muscle.18
However, we did not find a fully excitable gap in all parts of any of
the circuits that we studied, unlike some anatomic
circuits.7 8 23 24
The temporal excitable gap of the circuits that we studied
changed in different parts of the circuit. Although it has been
recognized that the gap can change in reentrant
circuits,7 21 27 30 in many previous studies, the temporal
excitable gap measured at one site has often been treated as a unique
value that is considered to be the same in all parts of the circuit;
therefore, measurement of the gap at a single site in the circuit has
provided the value for the excitable gap of the entire
circuit.2 3 4 31 32 This is particularly relevant for
studies in which resetting response curves have been used to
characterize the properties of the excitable gap in clinical studies of
reentrant ventricular tachycardia in which the
zone of reset is taken as a measurement of the excitable
gap.2 3 4 33 34 However, circuits that we studied that could
not be reset still had excitable gaps in part of the circuit, as also
shown in the study of Boersma et al.7 Reentry could even be
terminated by a blocked premature impulse in a circuit that could not
be reset (Fig 5).
The present study is the first to distinguish the spatial gap from the temporal gap and measure the spatial gap in the in situ heart. Pertsov et al9 have previously described a spatial and temporal gap in spiral wave reentry in isolated superfused epimyocardium, and Girouard et al10 have demonstrated the spatial extent of the gap in reentrant circuits in isolated guinea pig hearts. The spatial gap in both these studies changed in different parts of the circuit; we also noted this change in an experiment in which we were able to measure the spatial gap at three different sites.
Possible Mechanisms for Slow Activation, Functional Lines of Block,
and the Excitable Gap
The characteristics of the temporal and spatial excitable gap in
the present study provide new information concerning the nature of
slow activation and the mechanism for the formation of the lines of
block associated with reentry in the nonuniformly anisotropic
epicardial border zone. Five of the eight circuits that we studied
could be reset over a wide range of coupling intervals, and as
described above, in some regions the premature impulses conducted at
the same velocities as the native reentrant impulse. This property
shows that propagation in just-recovered myocardium of the
refractory tail is not a mechanism for reentry, as is found in the
leading circle mechanism of functional reentry.19 If the
head of the reentrant wave front was conducting in just-recovered,
partially excitable myocardium in any part of the circuit,
premature activation would not be able to preexcite locally or advance
activation throughout the circuit, since premature impulses would
encroach on the effective refractory period of myocardium
in this region and lead to conduction block. In our original
description of this model of reentry, we attributed the slow activation
that enables reentry to occur to slow and discontinuous transverse
propagation in the nonuniformly anisotropic
myocardium.11 In fact, slow activation in these
anisotropic circuits does occur mainly in the transverse direction,
whereas activation in longitudinally oriented segments of the circuit
is more rapid. However, the recent studies on spiral wave reentry in
cardiac muscle9 25 have shown the importance of a convex
wave-front curvature as a cause of slow activation in reentrant
circuits, with the greater the curvature, the slower the
conduction.35 36 These concepts originated in earlier
studies of spiral waves in excitable media.37 38 Wave-front
curvature should also play a role in slow conduction in the circuits in
the epicardial border zone. In the elongated figure-of-eight reentrant
circuits in an anisotropic matrix, the curvature is expected to vary in
different segments of the circuit, with the greatest curvature being
around the pivot points at the ends of the lines of block as the
reentrant wave front emerges from the relatively narrow central common
pathway into a larger mass of myocardium.35
Therefore, changes in curvature can also explain the differences in
conduction velocity in different parts of the circuits that we studied,
and the relative roles of curvature and anisotropy are uncertain.
The characteristics of conduction of premature impulses in anisotropic reentrant circuits also suggest that the functional lines of block that occur during reentry are not solely the result of a refractory barrier, as has been proposed previously.39 A reentrant wave front pivoting around the end of a functional line of block caused solely by a refractory barrier would not be expected to be advanced by a premature impulse without extension of the line of block.21 However, resetting of the anisotropic circuits demonstrates that all points in the circuit, including the pivoting points around the ends of the lines of block, could be activated earlier by premature impulses than by the native tachycardia impulse. The distal end of the line of block and the pivoting point around the line of block remained in a similar region for these premature impulses. Therefore, the distal ends of the lines of block were not the result of refractoriness. The electrophysiological mechanism for the lines of block in this reentrant model still remains unknown. Given that wave-front curvature is a likely important cause of slow activation, what appears to be lines of functional block might be related to the unexcited core caused by spiral waves, which in an anisotropic matrix would be elongated.9 25 35 36 37 38 If the wavelength is significantly larger than the pivoting radius, the trajectory of the tip of the wave front is expected to assume a linear shape similar to the region of functional block observed during reentrant excitation in the epicardial border zone.36 Although we know that the regions where the lines of block form are normally excitable in the absence of ventricular tachycardia,11 13 we do not know whether they remain unexcited during reentry, similar to the core of a spiral wave, because of the lack of the necessary spatial resolution of our mapping electrode array. However, there are likely to be additional factors contributing to the development of lines of block, including an abnormality of distribution of connexin43 in regions correlating with the location of the common central pathway. Lines of block in anisotropic reentrant circuits in this model may be a consequence of alterations in the spatial organization of gap junctions, which impede conduction of the reentrant wave front transversely.40 The region of nonuniformity provided by gap junctional disarray may also serve to "anchor" the reentrant circuit in a fixed location in a medium (epicardial border zone) where there are significant spatial gradients in electrophysiological properties such as refractoriness.9 25 41
Does the nonuniformity of anisotropy in the epicardial border zone contribute to the properties of the excitable gap? If wave-front curvature is an important cause of slow activation, then it is most likely an important determinant of the temporal and spatial excitable gap that we found. Spiral wave reentry has been shown to have a fully excitable temporal and spatial gap that is not dependent on structural discontinuities, because the critical curvature of the wave front prohibits an abrupt turn leaving an unexcited area.9 25 36 A microanatomic factor contributing to defining the ends of the lines of block (gap junctional disarray40 or some other discontinuity in structures) also may contribute to the occurrence of a significant excitable gap, since it can prevent the reentrant wave front from making an abrupt turn and taking a shorter pathway.7 This may also explain why the anisotropic circuits in nonuniform anisotropic myocardium in infarcts have a larger excitable gap than anisotropic circuits in uniform, normal myocardium,7 42 where there is no gap junctional disarray or anatomic discontinuities, and why the excitable gap in the nonuniform anisotropic circuits may have a fully excitable component, whereas it does not in the uniform anisotropic circuits.7 The question of whether the localized anatomic discontinuities (gap junctional disarray), more generalized nonuniform anisotropy, or a combination of the two is crucial for determining properties of the excitable gap remains to be answered.
In considering the cause for changes in the excitable gap in different
parts of anisotropic reentrant circuits, both the temporal and spatial
characteristics of the gap should change if there are changes in
conduction velocity and/or refractory periods in different parts of the
circuit. Changes in the gap are a consequence of changes in the
wavelength of the reentrant impulse (conduction velocityxrefractory
period) in different parts of the circuit. In a computer model of
spiral wave reentry, adding anisotropy to an isotropic matrix expands
the wavelength in the longitudinal direction relative to the transverse
direction.9 Likewise, conduction velocity in the
anisotropic epicardial border zone of the infarcted heart is much more
rapid in the longitudinal direction than in the transverse
direction.11 Therefore, if there were no differences in
refractory periods throughout the circuit, an expansion of the
wavelength during rapid conduction9 10 42 43 should lead to
a decrease in the spatial excitable gap, which would reach a minimum as
the wave front finished its period of rapid conduction in the
longitudinal segments of the circuit. On the other hand, after
propagating slowly around the pivoting point at the ends of the line of
block, the wavelength should reach a minimum,9 10 43
leaving a large part of the circuit time to recover and a large spatial
gap. Because of the limited number of sites in each of the circuits at
which we could measure the excitable gap, we could not precisely test
this hypothesis, although some of our results conform to its
prediction. In the experiment described in Figs 6 and 7, both the
temporal and spatial gaps that occurred on the basal side of the line
of block (outer pathway) as the reentrant impulse finished a period of
slow conduction around the upper end of the line of block were quite
large (Fig 6), whereas the gap at the LAD entrance site (electrode 12)
measured after a period of rapid conduction of the reentrant impulse in
the central common pathway was much smaller. It is also likely that the
refractory periods vary around anisotropic circuits,39 41
contributing to changes in both the spatial and temporal properties of
the excitable gap,30 although this was not found to be an
important contribution to variations of the excitable gap in reentrant
circuits in normal ventricular
myocardium.8 23
Significance
The properties of the excitable gap influence the characteristics
of arrhythmias caused by reentry. Arrhythmias caused by
leading circle reentry, in which the wave front propagates in the
just-recovered myocardium of the refractory tail and in
which there is only a very small partially excitable gap, are
inherently unstable and often terminate after a short period of
time.19 20 On the other hand, we have shown that the
reentrant wave front in nonuniform anisotropic reentrant circuits is,
in general, not propagating in myocardium that has just
recovered excitability and that the gap may be quite large. This
property may contribute to the stability of these reentrant circuits,
which enables anisotropic reentry to cause sustained monomorphic
ventricular tachycardia. In addition, the
presence of a significant temporal and spatial excitable gap in some
anisotropic reentrant circuits, despite the functional nature of the
circuits, enables reentry to be terminated by single premature stimuli
or by overdrive stimulation.13 44 Termination of
arrhythmias by stimulation would be expected to be much more
difficult when the reentrant circuit has only a small partially
excitable gap.
|
Acknowledgments |
|---|
This study was supported by grant R37 HL-31393 and program project grant HL-30557 from the National Heart, Lung, and Blood Institute, National Institutes of Health.
|
Footnotes |
|---|
Previously published as a preliminary report in abstract form (Circulation. 1993;88[pt 2, suppl I]:I-117).
Received June 12, 1997; accepted October 23, 1997.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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 R. J. Barker and R. G. Gourdie JNK Bond Regulation: Why Do Mammalian Hearts Invest in Connexin43? Circ. Res., October 4, 2002; 91(7): 556 - 558. [Full Text] [PDF]
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 E. J. Ciaccio, C. Costeas, J. Coromilas, and A. L. Wit Static Relationship of Cycle Length to Reentrant Circuit Geometry Circulation, October 16, 2001; 104(16): 1946 - 1951. [Abstract] [Full Text] [PDF]
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M. S. Hanna, J. Coromilas, M. E. Josephson, A. L. Wit, and N. S. Peters Mechanisms of Resetting Reentrant Circuits in Canine Ventricular Tachycardia Circulation, February 27, 2001; 103(8): 1148 - 1156. [Abstract] [Full Text] [PDF]
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F. Xie, Z. Qu, A. Garfinkel, and J. N. Weiss Electrophysiological heterogeneity and stability of reentry in simulated cardiac tissue Am J Physiol Heart Circ Physiol, February 1, 2001; 280(2): H535 - H545. [Abstract] [Full Text] [PDF]
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M. J. Schalij, L. Boersma, M. Huijberts, and M. A. Allessie Anisotropic Reentry in a Perfused 2-Dimensional Layer of Rabbit Ventricular Myocardium Circulation, November 21, 2000; 102(21): 2650 - 2658. [Abstract] [Full Text] [PDF]
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