© 1999 American Heart Association, Inc.
Integrative Physiology |
Shock-Induced Figure
-of-Eight Reentry in the Isolated Rabbit Heart
From the Departments of Biomedical Engineering (I.B., R.A.G., R.E.I., W.M.S.) and Medicine (R.E.I., W.M.S.), Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, Ala.
Correspondence to Richard A. Gray, Cardiac Rhythm Management Laboratory, B140 Volker Hall, 1670 University Blvd, Birmingham, AL 35294-0019. E-mail rag{at}crml.uab.edu
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Abstract—The patterns of transmembrane potential on the whole heart during and immediately after fibrillation-inducing shocks are unknown. To study arrhythmia induction, we recorded transmembrane activity from the anterior and posterior epicardial surface of the isolated rabbit heart simultaneously using 2 charge-coupled device cameras (32,512 pixels, 480 frames/second). Isolated hearts were paced from the apex at a cycle length of 250 ms. Two shock coils positioned inside the right ventricle (-) and atop the left atrium (+) delivered shocks at 3 strengths (0.75, 1.5, and 2.25 A) and 6 coupling intervals (130 to 230 ms). The patterns of depolarization and repolarization were similar, as is evident in the uniformity of action potential duration at 75% repolarization (131.4±8.3 ms). At short coupling intervals (<180 ms), shocks hyperpolarized a large portion of the ventricles and produced a pair of counterrotating waves, one on each side of the heart. The first beat after the shock was reentrant in 90% of short coupling interval episodes. At long coupling intervals (>180 ms), increasingly stronger shocks depolarized an increasingly larger portion of the heart. The first beat after the shock was reentrant in 18% of long coupling interval episodes. Arrhythmias were most often induced at short coupling intervals (98%) than at long coupling intervals (35%). The effect and outcome of the shock were related to the refractory state of the heart at the time of the shock. Hyperpolarization occurred at short coupling intervals, whereas depolarization occurred at long coupling intervals. Consistent with the "critical point" hypothesis, increasing shock strength and coupling interval moved the location where reentry formed (away from the shock electrode and pacing electrode, respectively).
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Key Words: action potential • electrical stimulation • arrhythmia • fibrillation • optical mapping
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Introduction |
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Understanding the underlying mechanisms of ventricular fibrillation (VF) is crucial in a society in which sudden cardiac death is the leading cause of mortality.1 VF can be induced in healthy hearts when an electrical stimulus occurs during ventricular repolarization (ie, the "vulnerable period").2 3 4 Only certain shock strengths induce fibrillation during the vulnerable period3 5 6 7 8 ; the highest shock strength to induce fibrillation is called the upper limit of vulnerability (ULV).9 It has been shown that the ULV correlates with the defibrillation threshold, which suggests a mechanistic link between fibrillation induction and defibrillation.8 10 The earliest proposed mechanisms of defibrillation and VF induction suggested that a strong electric shock results in the depolarization of cardiac tissue by direct activation followed by propagating activation fronts,11 12 13 but recent data suggest that shock-induced hyperpolarization also plays a role.14 15 16 17 18
Among the first proposed mechanisms for the induction of fibrillation was the dispersion of refractoriness hypothesis,4 19 which suggests that reentry forms when a wave propagates into a region of cardiac tissue with a nonuniform dispersion of refractoriness. Conduction block occurs in the more refractory area while propagation continues in the less refractory area, giving rise to unidirectional block. Rapid pacing or shock-induced accelerating beats have been shown to increase the dispersion of refractoriness and cause wavefronts to break down into reentry.4 Similarly, Dillon and Kwaku20 suggest that a progressively stronger shock will increasingly depolarize recovered tissue and also progressively increase the synchronization of repolarization. During the vulnerable period, if a shock is not strong enough to synchronize the repolarization of the refractory tissue, the shock-induced wavefront may encounter a dispersion of refractoriness leading to reentry.20
Another proposed hypothesis of fibrillation induction is the "critical point" (CP) mechanism. Introduced by Wiener and Rosenbleuth21 and later extended by Winfree,22 this hypothesis states that a CP will form where a critical degree of refractoriness intersects a critical strength stimulus.12 A shock-induced wavefront will propagate into recovering tissue but block in regions exhibiting residual refractoriness or stimulus-induced prolongation of refractoriness. The location of the CPs on the heart depends on the state of refractoriness at the time of the shock. Therefore, applying a stimulus at different coupling intervals within the vulnerable period will affect the location of the CPs. Similarly, varying the shock strength will also modify the extracellular potential distribution and the portion of the heart subjected to the critical stimulus strength, therefore moving the location of the CPs. According to the CP mechanism, ULV is the shock strength that will create a potential gradient greater than the critical value throughout the ventricular myocardium at all coupling intervals.9 If no CPs are formed in the heart, there will be no induction of fibrillation.
Recent experiments using optical mapping18 23 24 and simulations incorporating anisotropic bidomain models25 26 have demonstrated that electrical stimulation simultaneously depolarizes and hyperpolarizes cardiac tissue. The spatial patterns of the change in transmembrane potential (Vm) in anisotropic cardiac tissue during stimulation are usually composed of a "dog bone" shape of one polarity under the electrode and 2 regions of the opposite polarity, one on each side of the electrode along the fiber direction.17 New mechanisms of fibrillation induction27 28 and defibrillation29 have been proposed on the basis of the spatial distribution of Vm. One hypothesis suggests that the location where reentry occurs is at the intersection of shock-induced areas of positive, negative, and no polarization.27 28
The characterization of Vm from the whole heart during and after fibrillation-inducing shocks has not been accomplished. The purpose of this study is to investigate how coupling interval and shock strength influence the outcome of a shock during pacing. By recording Vm before, during, and after shocks, we seek to improve our understanding of the mechanisms responsible for fibrillation induction.
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Materials and Methods |
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Isolated Rabbit Heart
The excised heart was connected to the perfusion system and continuously perfused via the aorta with oxygenated warm (36°C to 38°C) Tyrode solution at a constant flow (50 mL/min). The excitation-contraction decoupler 2,3-butanedione monoxime (diacetyl monoxime; DAM) was added to the perfusate (
15
mmol/L).30 Subsequently, the heart was immersed in a
chamber filled with warm Tyrode solution and stained with the
voltage-sensitive dye di-4-ANEPPS31 (Molecular Probes) at
a concentration of 10.4 µmol/L (first dose, 10 mL; additional
injections, 5 mL).
Stimulation Protocol
A bipolar lead (Guidant) paced the heart from the apex at twice
the diastolic threshold. An unfiltered pacing sequence of
20 beats was used to compute an ensemble average beat, reducing the
noise by 
20. A pulse train of 10 S1 pacing stimuli (10-ms duration,
250-ms intervals) was followed by a 10-ms monophasic S2 square wave
delivered via the cathodal coil (inside the right ventricle, RV) and
the anodal coil (atop the left atrium posterior to the aorta) (Figure 1
).
(Coils were 1 cm long and 2 mm in diameter.)
S2 shocks were randomly delivered at 3 strengths, 0.75, 1.5, and 2.25 A and 6 coupling intervals, as follows: 130, 150, 170, 190, 210, and 230 ms. The outcomes of the premature stimuli were classified into the following 3 categories: (1) sustained arrhythmia (>2 seconds), (2) nonsustained arrhythmia, and (3) single beat (followed by sinus rhythm). The epicardial patterns after shocks were classified among the following 4 categories: reentrant, focal, global depolarization, and undetermined. Reentrant beats were characterized by curving isochrones around a point or line. Focal patterns were characterized by concentric isochrone lines. Global depolarization waves propagate throughout the heart without reentry or foci within the field of view. Episodes in which both a focal and a reentrant pattern were observed were classified as undetermined.
High-Resolution Optical Mapping
The components used for the optical mapping system were as
follows32 : Light sources, 450- and 250-W Xenon arc lamps
(anterior and posterior, respectively); excitation filters, 520±60 nm;
dichroic mirrors, reflection bandwidth, 400 to 560 nm, and transmission
bandwidth, 590 to 800 nm; emission filters, 610-nm long pass; and
cameras, 128x128 charge-coupled device cameras (480 frames per
second).
Image and Signal Processing
Briefly, a 5-point median temporal filter was followed by a
spatiotemporal (x, y, t) conical
filter (3x3x3 mask).
Definitions of Terms
"Activation time" refers to the time at which the action
potential (AP) upstroke reaches 50% of the maximal
amplitude33 (Figure 1C). "Repolarization time"
is the time at which the AP is 75% recovered. "AP duration"
(APD75) is the time difference between the
repolarization time and the activation time.
"Hyperpolarization/depolarization" refers to a
decrease/increase of Vm' at the end of an S2
shock compared with the Vm' of the ninth S1 at
the same time relative to the onset of the (ninth and tenth) pacing
stimulus. "Coupling interval" refers to the time interval from the
onset of the tenth S1 to the onset of the shock. Values are
presented as mean±SD, unless otherwise indicated.
An expanded Materials and Methods section is available online at http://www.circresaha.org.
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Results |
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Overview
Hearts from 7 rabbits (3.8±0.5 kg) were studied. The diastolic threshold was 0.5±0.36 mA. All hearts were mapped from both the posterior and the anterior surfaces. For all 7 hearts, the resolution for both the anterior and the posterior surfaces was 304±10 µm/pixel (size of the field of view, 3.9x3.9 cm). The portion of the ventricles projected to both cameras was estimated to be 81.5±2.7% (n=4) by using fiduciary markers every 5 mm. The total number of shocks (including defibrillation shocks) given to each heart was 23±2. The energy delivered for 0.75-, 1.5-, and 2.25-A shocks was 0.25±0.02, 1.01±0.07, and 2.28±0.18 J, respectively. The shock impedance calculated from the mean of all shocks measured in 6 hearts was 59.7±3.6
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The signal-to-noise ratio (SNR) of the raw data was 8.7±1.0 (n=7) at
the beginning of the experiment and decreased by 50% by the last
recording. After the 5-point median filter, the SNR increased
to 9.2±1.3. The spatiotemporal conical filter increased the SNR to
24.6±4.6. Fluorescence magnitude (
F/F) for all hearts was
8.5±0.7%.
Depolarization and Repolarization During Pacing
The spatial distribution of depolarization and repolarization was
studied using the ensemble average pacing episodes. The pacing
activation sequence followed an apex-to-base pattern. All rabbit hearts
had a very similar spatial pattern of activation and repolarization
during pacing. An example is shown in Figure 1; the earliest activity appeared on the
anterior apical portion of the epicardium 29.2 ms after the onset of
the S1 pulse (panel A, left). The earliest activity on the posterior
side occurred 33.3 ms after the onset of S1 (panel A, right). The
earliest recovery time on the heart surface was 150 ms after the onset
of the pacing stimulus on the posterior side (panel B). For all hearts,
the mean APD75 for all sites was 131.4±8.3 ms
with a mean spatial SD of 9.0±2.5 ms.
The dispersion of Vm', quantified as the spatial
SD of Vm' on the epicardium for all ensemble
average episodes, is plotted in Figure 1D along with the
percentages of induced arrhythmias for each coupling interval
(circles). The first peak occurred 50 ms after the onset of the pacing
stimulus when the heart is depolarizing. The second peak occurred 170
ms after the onset of the pacing stimulus and coincides with the
repolarization of the heart. The dispersion is greatest during
depolarization. It is the dispersion of repolarization that is normally
associated with arrhythmia induction. The tracing in Figure 1D
can be compared with an ECG, with the second peak
representing the T wave. In this protocol, short coupling
intervals were associated with a high probability of arrhythmia
induction, whereas episodes with long coupling intervals mostly
resulted in a shock-induced wave that propagated throughout the heart
(single beat). At late coupling intervals, inducibility decreased to
0.
Effect of the Shock on Vm'
Figure 2 shows the effect of
coupling interval and shock strength on Vm' at
one site, located on the anterior RV near the apex and close to the
cathode. The effect of the shock on Vm' varied
nonlinearly with coupling interval. For strong shocks and short
coupling intervals, shock-induced hyperpolarization
occurred, immediately followed by depolarization. The
hyperpolarization magnitude occurring during the
shock was greatest at the shortest coupling intervals examined. The AP
for 1.5 A/150 ms is typical of a pixel located near the line of block
of a reentrant circuit (see below). The effect of the shock on
Vm' also varied nonlinearly with shock strength.
At coupling intervals >190 ms, no
hyperpolarization was observed during the shock;
however, depolarization occurred during or shortly after the shock.
Variations in shock strength did not produce a proportional variation
in the magnitude of Vm' changes. A 3-fold
increase in shock strength (from 0.75 to 2.25 A) did not produce a
3-fold change in Vm' during the shock at any
site. (For all coupling intervals, shocks depolarized the entire atrial
epicardium in the field of view.)
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Vm' at the End of the Shock
Vm' at the end of the shock was dependent on
the refractory state of the heart at the time of the shock (ie,
coupling interval). At the shortest coupling interval studied (130 ms),
the ventricles were mostly depolarized at the time of the shock, with
the basal region at high Vm' and the apical
region at lower Vm' (Figure 3A, top). At the longest coupling
interval (230 ms), the entire ventricle surface was recovered (Figure 3A, bottom).
To allow a comparison between
Vm' and activation patterns, Figures 3, 4, and 5
were generated from the same heart, which we considered
representative of the population studied. This heart
was selected because it presented good signals throughout the
18 episodes. Figure 3B is a map of Vm' at
different times for different shock applications. To facilitate the
comparison between the state of the heart without a shock (Figure 3A) and the state of the heart after a shock (Figure 3B),
each row of Figure 3A displays Vm' 10 ms
after the coupling interval indicated (the equivalent of a 0-A-strength
S2 shock) for an ensemble average episode.
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By comparing panel B with panel A, one can identify regions of
shock-induced hyperpolarization and depolarization.
At short coupling intervals, the region near the RV cathode and the
apical region of the ventricles were hyperpolarized by the shock. For
coupling intervals <190 ms, the size of the region hyperpolarized by
the shock decreased with decreasing shock strength and increasing
coupling interval (Figure 3). Figure 3B (from 130 to 170
ms) shows an increase in the size of the recovered region (blue and
purple colors), yet the size of the hyperpolarized region decreased
because of the increased recovery (panel A) as a result of the later
application of the shock (ie, increasing coupling interval). At
coupling intervals >190 ms, the shock depolarized the heart near the
RV cathode. The size of the region depolarized by the cathodal shock
increased with increasing shock strength and increasing coupling
interval.
First Beat After the Shock
Figure 4 shows isochrones of the beat starting at the
onset of the shock. In Panel A, 3 episodes are presented in
detail for the region near the electrode. At a coupling interval of 150
ms (Figure 4A, top), the shock produced
hyperpolarization in the apical RV region, whereas
basal regions were not affected. The first sites to activate
were in the region most hyperpolarized by the shock (near the RV
cathode). Because the sites basal to the area hyperpolarized were
refractory, no activation propagated toward the base on the RV. The
activation propagated through recovered sites from the apical RV to the
LV. While the sites at the apex were being activated, the basal
sites repolarized and the wavefront moved from the LV apex toward the
base and eventually returned where it started, forming a closed
reentrant loop. At a coupling interval of 190 ms (Figure 4A, middle), most sites in the apical half of the heart had repolarized
before the shock was applied. The shock initiated a wavefront that
rapidly activated the apical half of the heart. The basal
portion of the heart was more refractory than the apical, causing slow
propagation on the RV toward the base. The part of the wavefront
propagating through the LV reached the basal RV at the same time,
allowing propagation toward the base. Propagation on the RV was not
slow enough to qualify as block,12 and reentry was not
initiated, resulting in a nonsustained arrhythmia. At a
coupling interval of 230 ms, the shock depolarized a large portion of
the heart very rapidly, producing a single beat (Figure 4A, bottom).
For coupling intervals of 130 to 170 ms, all strengths (Figure 4B, top 9 panels), the earliest region to activate in
the field of view was near the RV cathode. The wavefront moved from the
RV cathode first toward the apex and then up toward the base through
the left ventricle and finally came back down the RV to complete the
reentry loop. The reentrant circuits on the anterior and posterior
views had opposite rotation direction when viewed from the epicardium,
counterclockwise and clockwise, respectively. For shocks of coupling
intervals <190 ms, increasing the shock strength from 0.75 to 2.25 A
increased the extent of the line of block away from the RV toward the
LV because of faster propagation at the apex after stronger shocks. The
wavefront started to curve in the basal direction 30 ms after the
end of the shock. At 2.25 A (coupling interval<190 ms), both ends of
the line of blocks were located on the left ventricle (LV), whereas at
0.75 A, they were both on the RV. At a coupling interval of 190 ms,
slow propagation was observed near the RV cathode at the same location
where block occurred at shorter coupling intervals; however, reentry
did not occur. For coupling intervals >190 ms, the shock depolarized a
large portion of the ventricles during the shock, and the entire heart
was depolarized within 60 ms after the onset of the shock.
Second Beat After the Shock
Figure 5 shows isochrones for the second beat of
activation after the S2 shock. Activation times are continuous with the
previous beat (Figure 4), and plus signs and asterisks mark the
first isochrone of beat 2. Isochrones of sinus rhythm for the
230-ms coupling intervals were omitted. For coupling intervals of 130
to 170 ms at all shock strengths (top 9 episodes), propagation followed
a pattern similar to that of the first beat. For coupling intervals of
190 and 210 ms, focal beats were characterized by breakthrough patterns
on the ventricular epicardium (concentric isochronal
lines).
Sustained Versus Nonsustained Arrhythmias
The numbers of both sustained and nonsustained arrhythmia
episodes for each coupling interval at all strengths combined are shown
in the Table. The Table presents the number of
episodes for each outcome by coupling interval. The first 2 beats of
sustained and nonsustained arrhythmia episodes were separated
into 4 categories: reentrant, focal, global depolarization, and
undetermined. Patterns that we could not classify presumably because of
a missing portion of reentrant circuit (wavefronts arising from the
lateral boundary of the heart within the field of view) were labeled
undetermined. Relatively short coupling intervals were associated with
the induction of arrhythmias, whereas episodes with long
coupling intervals mostly resulted in a shock-induced wave that
propagated throughout the heart (single beat). Many arrhythmia
induction episodes were associated with reentrant patterns immediately
after the shock (Table, first beat) and later (Table,
second beat). At short coupling intervals, reentrant patterns formed
immediately after the shock. At a coupling interval of 230 ms, all
shocks directly activated a portion of the ventricles resulting
in single beats followed by sinus rhythm (no reentry was observed).
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Reentrant patterns were observed during the first beat after the shock in 90% of episodes for sustained arrhythmias compared with 48% for nonsustained arrhythmias (P<0.01). During the second beat after the shock, 91.7% of sustained episodes were reentrant compared with 48% of nonsustained episodes (P<0.01). The probability of an episode being sustained given that the second beat was reentrant was 73.3% (33/45). Similarly, the probability of an episode being nonsustained given that the second beat was focal was 83.3% (15/18). The undetermined episodes were excluded from the above percentages.
Reproducibility of Shocks
Three episodes of the same coupling interval/strength (190/1.5,
150/0.75, and 210/0.75) were repeated on the same hearts at the end of
the protocol. The first 2 resulted in reentrant and focal nonsustained
arrhythmias, and the last in a single beat. For all duplicated
episodes (n=3), the beat sequence was nearly identical. In one case,
all duplicate episodes of the nonsustained arrhythmias lasted 6
beats. The similarity of pattern for all 6 beats suggests that
activation patterns are deterministic and repeatable up to 500 ms after
the shock.
Uniformity Index and Phase Singularities
To quantify the sign of the polarization resulting from the shock,
we have measured the uniformity index34 for all animals at
all shock strengths and coupling intervals (Figure 7A). At short
coupling intervals (130 to 150 ms), the major effect of the shock was
to hyperpolarize Vm', whereas at longer coupling
intervals (190 to 230 ms), the effect was depolarization.
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Phase singularities were selected for every episode in which the
isochrone maps demonstrated a reentrant pattern immediately after
the shock. Figure 6 displays the spatial
distribution of phase35 for the examples shown in Figure 4A. Phase singularities are defined as sites around which all
phase values (–
to ) converge.36 For a coupling
interval of 150 ms, 2 phase singularities formed immediately after the
shock (one on each side of the heart, Figure 6A, top) and 33 ms
later (Figure 6B, top) were established and moved toward the tip
of the line of block (shown on the isochrones of Figure 4B;
2.25 A, 150 ms). For a coupling interval of 190 ms, the phase pattern
at the end of the shock did not demonstrate the formation of phase
singularities (Figure 6A, middle), and 33 ms later (Figure 6B, middle) the phase gradient had almost disappeared,
demonstrating a global pattern of depolarization. For a coupling
interval of 230 ms, the shock did not produce much phase variation
throughout the ventricles (Figure 6A, bottom), and 33 ms after
the shock, the phase was synchronized over the whole heart (Figure 6B, bottom).
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The location of the phase singularity was manually selected from phase
maps35 at 33 ms after the onset of the shock. The
distances (dy) in mm between the apex
and the phase singularities for all 3 strengths were fitted to a linear
regression (dy=-3.9xcoupling
interval+0.1, P<0.0001, Figure 7B). The distance
(dx) in mm between the edge of the RV
and the phase singularities for all coupling intervals was fitted to a
linear regression (dx=1.4xS+8.1,
P<0.0001, Figure 7C), where S is the shock strength.
Overall means and SEs of phase singularity location are plotted in
panels B and C of Figure 7. These equations suggest that by
applying the shock at later coupling intervals, the location of phase
singularities moved further away from the apex. Similarly, by applying
a stronger shock, the location of phase singularities moved further
away from the RV edge. The distribution of Vm'
before the shock for all sites identified as phase singularities is
plotted in Figure 7D. Vm' before the
shock, for sites identified as phase singularities, was –23.5±13.8,
whereas Vm' at all other sites was –36.7±26.0.
Both the mean and variance were significantly different
(P<0.0001). The distribution of Vm'
before the shock is affected by the pacing site, the portion of the
heart contained in the field of view, and the range of coupling
intervals studied.
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Discussion |
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Spatial Distribution of Vm
For a long time, investigators have related the outcome of an electrical stimulus or the vulnerability of the heart to the dispersion of repolarization.19 Traditionally, dispersion has been measured as the maximum difference between repolarization times at several sites. Such measurements have provided evidence that a critical dispersion of repolarization times is required to induce fibrillation for localized stimulus.37 38 Kirchof et al39 have shown that the dispersion of repolarization times is a better predictor of the vulnerable period than T-wave parameters obtained from the ECG. Laurita et al40 have recently reported that the dispersion of repolarization can be influenced by a premature stimulus and that a decrease in dispersion results in a decrease in vulnerability. Because our experimental approach renders such a high spatial resolution with tens of thousands of sites, we were able to calculate the spatial dispersion over the majority of the epicardium (measured as the spatial SD of Vm') during every recorded frame (every 2.1 ms). By comparison, the traditional measure of dispersion estimates the width (in time) of the second peak of the curve, occurring during repolarization (Figure 1D
).
According to our study, arrhythmia induction
occurred when the spatial dispersion of repolarization was high, but
the spatial dispersion of Vm' at the time of the
shock was not linearly related to inducibility. The highest probability
of inducing arrhythmias (Figure 1D, coupling intervals
of 130 and 150 ms) did not occur at the peak of repolarization
dispersion, but before the peak.41 42 The relationship
between dispersion of repolarization and vulnerability to induce
arrhythmias in the normal heart is consistent with the
CP hypothesis. Figure 1D shows a decrease of inducibility
starting at the peak of the dispersion of Vm'
during repolarization. This suggests that other factors such as reentry
through the Purkinje system or rapid firing, and shock-induced
hyperpolarization and depolarization, as predicted
by the virtual electrode hypothesis, may contribute to heart
vulnerability.
Outcome
The 6 coupling intervals studied resulted in outcomes ranging from
VF induction to single shock-induced activations. The number of
episodes that induced arrhythmias in the Table suggests
that our strength/coupling interval pairs were focused in the lower
right corner of the area of vulnerability.7 Therefore, our
shocks were below the ULV and longer than the shortest coupling
interval that induces VF.
The difference between sustained and nonsustained arrhythmias
cannot be discerned from isochrones of the first beat after the
shock, although our results suggest that the first beat of sustained
rhythms is most often reentrant. But episodes in which the second beat
was focal were most often nonsustained (P<0.01). For
episodes in which reentry occurred, the phase maps (Figure 6)
after the shock all contained phase singularities 33 ms after the
shock. We have observed that at short coupling intervals, the most
common outcome was a pair of counterrotating waves, one on each side of
the heart (anterior and posterior). For episodes of nonsustained
arrhythmias, reentry was not always present and the phase
distribution was mostly uniform. We observed that phase singularities
did not always form during the shock, but developed after the shock.
Phase singularities moved with time along the line of block
represented on the isochrones (Figures 4 and 6). Although isochrone maps are helpful in describing the
propagation of the wavefront, phase maps are localized in time and
therefore can describe the state of the heart at any
time.36
Critical Point
We have observed the formation of a pair of counterrotating
wavefronts (Figure 4) for many of the episodes that induced
arrhythmias. Consistent with the CP
hypothesis,8 12 increasing the coupling interval moved the
phase singularities toward the base of the heart following the movement
of the 43% repolarization isorecovery line
(Vm'=-23.5 mV', Figure 7D). By increasing
shock strength, the phase singularities moved away from the edge of the
RV, which is also consistent with the CP mechanism. Although we
did not measure the extracellular potential gradient caused by the
shocks, models43 44 and experimental
evidence8 45 46 suggest that increasing shock strength
will move the critical gradient further away from the electrodes. Our
results enable us to extend the explanation of the CP
mechanism8 12 to include the effects of
hyperpolarization. Originally, CP suggested that
shocks producing depolarization cause direct excitation to a larger
region when increasing shock strength. The shock-induced
hyperpolarization observed presumably caused
all-or-nothing repolarization,47 therefore resetting the
sodium channels in certain areas and restoring excitability. We believe
that in our experiments, the movement in phase singularity location is
caused by the fact that the apical region was hyperpolarized by the
shock, enabling faster propagation toward the residually refractory
area in which block occurred. At sites where phase singularities
occurred, Vm' was –23.5 mV' immediately
preceding the shock. This value is similar to the value of
Vm' at the center of reentry (2405 or -21.3 mV';
see Materials and Methods) during arrhythmias. The occurrence
of phase singularities in the center of reentrant patterns suggests
that the threshold for propagation and block in this preparation may be
-20 mV'. The complex patterns of
hyperpolarization and depolarization (such as
virtual electrodes) throughout the wall may provide an alternate
explanation to the influence of shock strength on the location of phase
singularities.48
Shock-Induced Changes in Vm
By using optical methods to record the electrical activity
during a shock, we observed hyperpolarization
occurring near the RV cathode followed by rapid conduction causing the
wavefront to propagate into recovered regions and block in regions
exhibiting residual refractoriness or shock-induced prolongation of
refractoriness. In earlier studies,8 12 investigators were
unable to map during the shock because of the amplifier-switching delay
of the mapping system. The first activations that could be detected
were away from the shock location, which led to the assumption that the
region between the new activation and the electrode was directly
excited by the shock.
Electrical mapping studies such as the ones leading to the CP mechanism could not address the issue of shock-induced hyperpolarization/depolarization because of the limitations of the technique. Studies using microelectrodes, optical mapping, and monophasic AP recordings (MAPs) have measured the effects of shocks on Vm from a limited area. The magnitude of change of Vm is related to strength and polarity; anodal shocks cause greater changes in Vm than cathodal shocks. Conversely, passive models predict that a greater shock will induce a proportionally greater change in Vm. The shock-induced depolarization has been shown to prolong the APD, therefore extending the refractory period.13 15 49 50 51 52 This suggests that the spatial effects of the shock on Vm (such as virtual electrodes) influence the outcome of the shock.
The mechanism of origination of the new activation wavefronts arising during or after the shock cannot be determined by our experiment. Several hypotheses have been proposed. The anode-break excitation mechanism predicts new wavefronts originating where a sufficiently large gradient in Vm causes diffusion between depolarized and hyperpolarized regions.18 53 Recent simulations and experiments by Ranjan et al54 55 propose that excitation can originate at the site of stimulation-induced hyperpolarization (cellular anode break) because of the combined effect of the If and IK1 currents driving Vm toward threshold and initiating an AP.
Many researchers have published experimental data of shock-induced
virtual electrode patterns near electrodes14 17 18 23 24
similar to the ones obtained with the anisotropic bidomain model by
Sepulveda et al25 and Roth.56 We did
not observe the depolarization and
hyperpolarization in a dog bone shape. We have only
observed hyperpolarization of
Vm' in refractory tissue near the cathode. Our
experimental protocol was not designed to study virtual electrodes. It
is possible that virtual electrodes were present outside the field
of view (eg, transmurally, at the boundary of the field of view on the
RV and/or LV free walls). Several differences in experimental procedure
may explain why we did not observe the same patterns as Efimov et
al.18 27 We did not press the heart against a window, and
the electrode geometry and placement (9-mm coil inside the RV and 6-cm
coil above the heart) are different. Recent modeling
simulations48 57 58 predict a difference in epicardial
measurements of Vm when experimental conditions
such as conductivity of the medium surrounding the heart are changed.
Entcheva et al48 predict that the dog bone pattern of
virtual electrodes will not be observed on the epicardium when
conductive fluid is present in the ventricular chambers
and surrounding the heart. By restricting the fluid layer, the virtual
electrodes become visible from the epicardium. According to this
hypothesis, our data may be consistent with the virtual
electrode mechanism, except that the pattern driving the epicardial
layer is below the epicardium. In this case, increasing the shock
strength will also increase the size of the virtual electrodes
produced,18 24 therefore affecting the location of phase
singularities, as observed.27 The prediction that large
polarization occurs in the midwall48 may explain the large
epicardial RV area depolarized by the shock at long coupling intervals
(Figure 3B, 210 and 230 ms) in contrast to the smaller apical
area hyperpolarized at shorter coupling intervals (Figure 3B, 130 to 170 ms). The virtual electrode mechanism also predicts that
changing the time of application of the shock from the plateau to the
resting phase of the AP will not reverse the sign of the shock-induced
changes in Vm,17 25 56 as we have
observed. The magnitude of shock-induced polarization is affected
by coupling interval because of the nonlinear properties of cardiac
tissue.15 This will affect the spatial pattern of
shock-induced polarization due to the preshock repolarization gradient.
It is possible that at long coupling intervals, the sites that we
report as being depolarized by the shock were initially hyperpolarized,
but propagation from depolarized sites in deeper layers of the
myocardial wall occurred so rapidly (in <2 ms) that we were unable to
record it. At short coupling intervals (ie, during the refractory
period), the shock fails to hyperpolarize all sites sufficiently to
restore excitability, leading to slow conduction or block.
Although many studies suggest that 2 CPs will produce a figure-of-eight reentry pattern,8 59 some have suggested that 4 CPs can induce quatrefoil reentry by applying S1 and S2 stimuli from the same location of an anisotropic medium.28 60 We did not observe quatrefoil reentry patterns but only figure-of-eight reentry patterns. We believe that both cathodal make and break excitations are involved in the induction of fibrillation in our experiment; at short coupling intervals (<130 ms; ie, in refractory tissue), cathodal break occurs, whereas at long coupling intervals (>190 ms; ie, in recovered tissue), cathodal make is responsible for the rapid depolarization. At intermediate coupling intervals, break may occur in the basal portion of the heart that is refractory, whereas make will occur in the apical portion of the heart that is recovered.60 Accordingly, we believe that residual refractoriness plays an important role in the pattern of activation ensuing from the shock. In this study, the shock did not seem to prolong the APD of sites that did not hyperpolarize during the shock (at short coupling intervals), but these sites remained refractory long enough to support reentry. Additional studies using reversed polarity are necessary to generalize our findings and to further distinguish whether the CP or the virtual electrode mechanism is responsible for inducing fibrillation.
Limitations
Because of the decrease in SNR caused by dye bleaching, we limited
our experiments to the use of one waveform, which produced 20
episodes per heart. The RV cathode/simulated superior vena cava anode
electrode configuration was selected because of its clinical relevance.
The polarity chosen is reported to induce reentry more
easily.59 Similar electrode configurations have been shown
to produce a nonuniform shock field of complex spatial
distribution.46 The RV cathode/simulated superior vena
cava configuration increased the complexity of the analysis and
limited detailed comparisons with the CP12 and virtual
electrode18 24 experiments, which were observed with a
more specific electrode configuration. We did not measure the
extracellular field during the shock.
To allow spatial measurements of Vm', we assumed all sites to have the same AP amplitude.61 Although the effects of the drug DAM have not been characterized in the rabbit ventricles, it has been shown to have some effect in sheep and guinea pig on electrical activity, such as shortened APD and refractory period.62 63 DAM reversibly blocks cardiac contraction without causing damage to the cardiac cells. Other factors such as pacing cycle length and species also affect APD and refractoriness. The reported outcomes should not be strictly associated with the reported coupling intervals, because these factors influence the timing of the vulnerability window within the cardiac cycle. For example, Fabritz et al7 have reported vulnerability on the isolated rabbit heart to occur at coupling intervals ranging from 170 to 210 ms when pacing at 600 ms. Our pacing rate was 250 ms, yet the vulnerability window remained in a similar range from 130 to 190 ms. This difference in vulnerability window is probably a result of the slower pacing rate as well as the use of DAM. Comparisons with structurally diseased human hearts must be made with caution because of differences in size and electrophysiological properties. The hearts studied here were not diseased or ischemic and were much smaller than typical human hearts.
In this study, we identified the CP as the location where phase
singularities occurred. For several reentrant episodes, the phase
singularities did not form immediately after the shock, whereas in all
episodes, they were clearly established 33 ms after the onset of the
shock (Figure 6B, 150 ms). The effect of shock strength and
coupling interval on the location of phase singularities identified
immediately at the end of the shock and at the end of the first
reentrant cycle showed relationships similar to the ones shown in
Figure 7B and 7C.
The activations we measured are averages of a cluster of cells that
extend 300 µm wide and at a depth of 300 to 500 µm;
our high spatial resolution combined with our temporal resolution (2.1
ms) is adequate to measure activation times.14 64 Because
the recordings are from the epicardium and the heart is a
3-dimensional structure, the patterns observed were influenced by
regions within the deeper layers of the myocardium.
Therefore, we cannot exclude the possibility that patterns that were
classified as focal were produced by intramural reentry. It is also
possible that the Purkinje system provided a pathway for transmural
reentry or a rapid firing trigger.65 The temporal
continuity of the activation patterns observed on the epicardium in
most instances (see Figures 1, 4, 5, and 6)
suggests that we accurately captured the dynamics of events. Lee et
al66 reported that chemical ablation of subendocardial
layers of myocardium did not affect the incidence, life
span, cycle length, or core size of reentrant wavefronts.
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Acknowledgments |
|---|
This research was supported by grants from the Whitaker Foundation and the Cardiac Arrhythmia Research and Education Foundation and by NIH Grant HL-28429. We thank Frederick G. Evans for his technical assistance during the experiments and also R. Kyle Justice for developing the graphical user interface of the data analysis software. We also thank Anthony L. Sims and Angelo D. Hinkle for their assistance in building electrodes and parts of our experimental setup and Windy Jones for caring for and preparing the rabbits for surgery.
Received March 30, 1999; accepted August 10, 1999.
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References |
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