(Circulation. 1998;98:2774-2780.)
© 1998 American Heart Association, Inc.
Basic Science Reports |
Modulated Dispersion Explains Changes in Arrhythmia Vulnerability During Premature Stimulation of the Heart
Presented in part as the NASPE Young Investigator Award presentation, Seattle, Wash, May 1996.
From the Departments of Medicine and Biomedical Engineering and The Cardiac Bioelectricity Research and Training Center, Case Western Reserve University, Cleveland, Ohio, and The Veterans Affairs Medical Center, Cleveland, Ohio.
Correspondence to Kenneth R. Laurita, PhD, Case Western Reserve University, Department of Biomedical Engineering, Wickenden Bldg, Room 504, Cleveland, OH 44106-7207. E-mail KLR2{at}po.cwru.edu
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Abstract |
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Background—Previously, we have shown that a premature stimulus can significantly modulate spatial gradients of ventricular repolarization (ie, modulated dispersion), which result from heterogeneous electrophysiological properties between cells. The role modulated dispersion may play in determining electrical instability in the heart is unknown.
Methods and Results—To determine if premature stimulus–induced changes in repolarization are a mechanism that governs susceptibility to cardiac arrhythmias, optical action potentials were recorded simultaneously from 128 ventricular sites (1 cm2) in 8 Langendorff-perfused guinea pig hearts. After baseline pacing (S1), a single premature stimulus (S2) was introduced over a range of S1S2 coupling intervals. Arrhythmia vulnerability after each premature stimulus was determined by measurement of a modified ventricular fibrillation threshold (VFT) during the T wave of each S2 beat (ie, S2-VFT). As the S1S2 interval was shortened to an intermediate value, spatial gradients of repolarization and vulnerability to fibrillation decreased by 51±9% (mean±SEM) and 73±45%, respectively, compared with baseline levels. As the S1S2 interval was further shortened, repolarization gradients increased above baseline levels by 54±30%, which was paralleled by a corresponding increase (37±8%) in vulnerability.
Conclusions—These data demonstrate that modulation of repolarization gradients by a single premature stimulus significantly influences vulnerability to ventricular fibrillation. This may represent a novel mechanism for the formation of arrhythmogenic substrates during premature stimulation of the heart.
Key Words: action potentials • arrhythmia • reentry • mapping • pacing
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Introduction |
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A premature impulse is traditionally viewed as a "trigger" for reentrant arrhythmias that, in the presence of a suitable arrhythmogenic "substrate,"1 can provoke reentry. The essential components of the substrate, such as nonuniformities of recovery2 3 4 and tissue anisotropy,5 6 are thought to remain unchanged during a premature beat. Accordingly, the increase in arrhythmia vulnerability associated with multiple premature stimuli delivered at progressively shorter coupling intervals is thought to result from shortening (ie, similar to "peeling back"7) of refractoriness at the pacing site, allowing capture of subsequent stimuli at increasing degrees of prematurity.8 Although this paradigm is based on the well-established dependence of cellular repolarization/refractoriness on stimulus prematurity,9 10 it only considers what happens to repolarization at one ventricular site and does not account for spatial variations in the response of cellular repolarization to a premature stimulus. Such a response would suggest that a premature stimulus may not only serve as a trigger for arrhythmias but may also produce significant changes in dispersion of refractoriness that forms the underlying electrophysiological substrate for reentry.
There is now considerable evidence that membrane ionic processes that govern the extent of action potential duration (APD) shortening after a premature stimulus (ie, APD restitution11) vary substantially throughout the heart.12 13 14 15 16 In particular, we have shown previously17 that systematic heterogeneities of APD restitution between cells across the epicardial surface govern, in a coupling-interval–dependent fashion, premature stimulus–induced modulation of spatial gradients of repolarization. Because spatial gradients of repolarization are closely associated with reentrant arrhythmogenesis,3 18 modulation of such gradients may play an important role in the mechanisms of cardiac arrhythmias.
Therefore, an alternative hypothesis is that a premature stimulus also alters the underlying arrhythmogenic substrate by modulating spatial gradients of repolarization in a coupling-interval–dependent manner, ie, modulated-dispersion hypothesis. However, because of limitations of conventional recording techniques, dynamic changes in the spatial pattern and organization of repolarization during a premature stimulus are poorly understood. To test the modulated-dispersion hypothesis, high-resolution action potential mapping with voltage-sensitive dye was used to measure spatial gradients of cellular repolarization during a premature stimulus delivered over a broad range of coupling intervals. We found that a premature stimulus not only serves to "trigger" arrhythmias but also importantly modulates spatial gradients of repolarization and, as a result, the electrophysiological substrate for ventricular fibrillation (VF).
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Methods |
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Experimental Preparation
All experiments were performed in accordance with Public Health Service guidelines for the care and use of laboratory animals. Guinea pigs (n=8) were anesthetized (pentobarbital sodium 30 mg/kg IP) and their hearts rapidly excised and perfused as Langendorff preparations (perfusion pressure, 70 mm Hg) with oxygenated (95% O2, 5% CO2) Tyrode's solution containing (in mmol/L) NaCl 130, NaHCO3 25.0, MgSO4 1.2, KCl 4.75, dextrose 5.0, and CaCl2 1.25 (pH 7.40, 31°C to 33°C). The right atrium was excised to avoid competitive stimulation from the sinoatrial node. Hearts were stained with voltage-sensitive dye di-4-ANEPPS (10 µmol/L) by direct coronary perfusion for 10 minutes.
Beating and perfused hearts were immersed in a Tyrode's
solution–filled, custom-built acrylic plastic chamber that was
attached to a micromanipulator so that the mapping field could be
centered over the left anterior descending coronary artery
6 mm below its bifurcation with the diagonal coronary
artery (Figure 1
). Gentle pressure was
applied with a movable piston to the posterior surface of the heart to
stabilize the anterior surface of the ventricle against an imaging
window, which reduced motion artifacts. This design permitted the heart
to contract freely during action potential recordings except
for the 1-cm2 area within the mapping field,
while the electrophysiological side effects
associated with pharmacological suppression of cardiac motion were
avoided.19 20 21 22 Cardiac rhythm was monitored with
3 silver disk electrodes fixed to the chamber in positions
corresponding to ECG limb leads I, II, and III. The ECG signals were
filtered (0.3 to 300 Hz), amplified (1000x), and displayed on a
digital recorder (Windograf, Gould Inc). Although all
experiments were typically completed within 1 to 2 hours, these
preparations were stable and exhibited normal action potential
characteristics for 
3 hours of Langendorff perfusion.
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Experimental Protocol
The ventricular epicardial surface was stimulated at
2x diastolic threshold with Teflon-coated silver bipolar
electrodes (0.1 mm diameter, interelectrode spacing of 1.0
mm). Drivetrain (S1) and the first premature
stimulus (S2) were always delivered from the same
stimulus electrode by a programmable stimulator (DTU 101, Bloom
Associates Ltd). Action potentials were recorded from each of 128
ventricular recording sites during the last 3 beats
of a 50-beat drivetrain and during premature stimulation. Premature
coupling intervals (S1S2)
were decreased progressively by a minimum of 5 ms until
ventricular refractoriness was reached. To ensure that our
results were independent of the order of coupling intervals tested,
S1S2 was progressively
increased from ventricular refractoriness to the baseline
cycle length in several experiments.
Experiments were designed to establish a relationship between
coupling-interval–dependent modulation of repolarization gradients and
susceptibility to VF. In all hearts, the dependence of
arrhythmia vulnerability on
S1S2 coupling interval was
measured by use of a modified VF threshold test (ie,
S2-VFT). S2-VFT was used as
a measure of vulnerability of the heart to VF after a single
(S2) premature stimulus. The
S2-VFT test stimulus was delivered by use of a
Teflon-coated silver bipolar electrode (0.1 mm diameter,
interelectrode spacing of 1.0 mm) connected to a second
programmable stimulator (DCI-1114, Digital
Cardiovascular Instruments Inc). Baseline pacing
(S1S1 ranging from 300 to
400 ms) and a single premature stimulus (S2) were
delivered from the same site near the center of the mapping field
(Figure 1
). The site of S2-VFT stimulation was
always positioned near (<4 mm) the
S1S2 stimulation site. To
determine S2-VFT, a burst pulse train (100 Hz)
was applied during the T wave of the S2 beat
(Figure 1). Because the pacing protocol required shortening of the
S1S2 coupling interval over
a broad range, we adjusted the timing of burst stimulation to account
for shortening in the QT interval of the ECG. For each coupling
interval tested, QT interval was measured and the timing of the burst
train adjusted to span the entire T wave of the
S2 beat. To verify its onset and termination
relative to the T wave, a test burst train was delivered below
threshold. The number of pulses that extended beyond the end of the T
wave was kept constant throughout the experiment. This ensured that for
every coupling interval tested, an equal number of pulses traversed the
vulnerable period and, if present, the protective zone of the
S2 beat.23 The
S2-VFT burst stimulus was repeated for the same
S1S2 coupling interval at
increasing current strengths until sustained VF occurred.
S2-VFT was defined by the minimum current
strength that initiated VF. After induction of fibrillation, the heart
was defibrillated (0.8 J) and allowed to equilibrate at the baseline
pacing rate for 3 minutes. To assure reproducibility, the
S2-VFT measurement was repeated 2 to 3 times for
each S1S2 coupling interval
tested.
Optical Mapping System
The action potential mapping system used in the present
study was described in detail elsewhere.17 19 24
Briefly, to make quantitative measurements of action potential
characteristics, including depolarization and repolarization, our
optical mapping system was designed to record high-fidelity action
potentials simultaneously from 128 sites on the intact
heart. In the present study, an optical magnification of 1.8x was
used, corresponding to a mapping field of 1 cm2
and 0.83-mm spatial resolution between recording sites. Action
potentials recorded from each photodiode element and the ECG
signals were multiplexed, digitized with 12-bit precision, and sampled
at 2000 Hz/channel to the hard disk of a UNIX workstation (Concurrent
5450S, Concurrent Computer Corp). The signal-to-noise ratio and dynamic
range of these recordings allowed detection of voltage changes
as small as 1 mV (based on a 100-mV action potential). Data acquisition
software was used to control the onset and duration of
recordings and display data for on-line inspection by the
investigators. Data were analyzed off-line with the use of UNIX
workstations (Sun Sparcstation, Sun Microsystems) connected to the data
acquisition computer through a fiber optic network.
Action Potential Analysis
In all experiments and for each
S1S2 coupling interval
tested, the spatial patterns and gradients of depolarization,
repolarization, and APD were represented as contour maps.
Both depolarization time and repolarization time were measured relative
to a single fiducial point (ie, the stimulus) and were determined by
use of previously validated computer
algorithms.19 25 Depolarization time was defined
as the point of maximum positive derivative in the action potential
upstroke (dV/dtmax). Repolarization time was
calculated for the S2 beat and was defined by the
maximum positive curvature (maximum positive second derivative) during
repolarization. APD was defined as the difference between
repolarization time and depolarization time. Software was written to
display action potentials and computer-assigned depolarization and
repolarization times for review by the investigator. The dependence of
repolarization time on S1S2
coupling interval was estimated by calculation of the mean
repolarization time over all 128 mapping sites (ie,
S2-RT). To quantify spatial dispersion of
repolarization caused by repolarization gradients, the variance of
repolarization times over all sites was calculated for each
S2 beat (ie, S2-DISP).
For each experiment, arrhythmia vulnerability (ie, S2-VFT), mean repolarization time (ie, S2-RT), and dispersion of repolarization (ie, S2-DISP) were compared at 3 predefined S1S2 coupling intervals: a coupling interval equal to or near the baseline drivetrain (S1S1), an intermediate coupling interval, and a short coupling interval just beyond the effective refractory period of the S1 beat. The intermediate coupling interval was defined as the coupling interval when dispersion of repolarization of the S2 beat (ie, S2-DISP) reached a minimum. Levels of significance were determined by the Wilcoxon matched-pairs test. All values shown are mean±SD unless otherwise indicated.
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Results |
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Gradients of Repolarization and Modulated Dispersion During a Premature Stimulus
Figure 2
illustrates a
representative example of spatial gradients of
depolarization and repolarization measured during a premature beat
(S2) delivered at a coupling interval equal to
the drivetrain (400 ms, Figure 2A), at an intermediate coupling
interval (220 ms, Figure 2B), and at a short coupling interval near
refractoriness (205 ms, Figure 2C). For an
S1S2 coupling interval
equal to the drivetrain (Figure 2A), the prematurely stimulated
(S2) impulse propagated anisotropically from the
site of pacing. Significant gradients of APD were present across
the epicardial surface (not shown), as evidenced by gradients of
repolarization that produced a spatial dispersion of repolarization
times (46 ms2). A premature stimulus introduced
at an intermediate coupling interval (Figure 2B) produced no change in
the pattern of depolarization compared with baseline pacing. In
contrast, repolarization gradients were substantially reduced,
minimizing dispersion of repolarization to 10
ms2. The significant reduction of repolarization
gradients is also evident in the ECG by the diminished T-wave amplitude
during the S2 beat. When a premature stimulus was
introduced at a short coupling interval near refractoriness (Figure 2C), conduction slowed somewhat, but the overall pattern of
depolarization was unchanged. In contrast, repolarization gradients
reappeared. The gradients of repolarization increased dispersion to
levels (38 ms2) comparable to that during
baseline pacing. In addition, the orientation of the repolarization
gradients (arrows in Figure 2) was reversed; ie, where repolarization
was latest during baseline pacing, it became earliest during the short
premature coupling interval and vice versa. The reversal of
repolarization gradients was also evidenced by inversion of the ECG T
wave of the S2 beat relative to the drivetrain
beat. The changes observed in T-wave morphology suggest that modulation
of repolarization gradients was not limited to the optical mapping
field but was most likely occurring throughout the heart.
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The spatial dispersion of repolarization observed during baseline
pacing and during premature stimulation is summarized for all
experiments in the Table. The initial
decrease and subsequent increase (ie, biphasic modulation) in
dispersion of repolarization as the coupling interval was shortened
were observed in all experiments. In general, dispersion changed more
rapidly at short coupling intervals than at long coupling intervals. As
the S1S2 coupling interval
was shortened from baseline to an intermediate value, dispersion
decreased by 27 ms2; however, as
S1S2 was further reduced
from intermediate to short coupling intervals, dispersion increased by
54 ms2. With the exception of 2 experiments
(experiments 7 and 8), dispersion of repolarization was always greater
at short coupling intervals than at baseline. These data indicate that
dispersion of repolarization was predictably and significantly
modulated by simply changing the timing of a single premature
stimulus.
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Vulnerability to Fibrillation
To determine vulnerability to VF in the wake of repolarization
gradients induced by a premature stimulus, we initiated VF by applying
a burst train of stimuli during the vulnerable period of the premature
beat (S2-VFT). Figure 3 demonstrates the initiation of VF after
a premature beat delivered at a coupling interval equal to the
drivetrain (400 ms, Figure 3A), at an intermediate coupling interval
(210 ms, Figure 3B), and at a short coupling interval near
refractoriness (185 ms, Figure 3C). The ECG and transmembrane potential
recorded from 1 ventricular site are shown for each
coupling interval. For an
S1S2 coupling interval
equal to the drivetrain (Figure 3A), APD of the
S2 beat (192 ms) was unchanged compared with the
drivetrain, and the average S2-VFT was 12±5 mA.
When S1S2 coupling interval
was shortened to an intermediate value of 210 ms (Figure 3B), APD of
the S2 beat decreased significantly (138 ms)
compared with the drivetrain; however, the average
S2-VFT increased to 24±3 mA, indicating a
paradoxical 50% decrease in arrhythmia vulnerability. As the
S1S2 coupling interval was
further shortened (185 ms), APD continued to decrease (107 ms), and
S2-VFT (11±7 mA) decreased to levels observed
during drivetrain pacing (Figure 3C). Therefore, despite the fact that
APD shortened monotonically as the
S1S2 coupling interval was
shortened, arrhythmia vulnerability first decreased markedly
(ie, S2-VFT increased) with shortening of the
S1S2 coupling interval and
then increased only at very short
S1S2 intervals.
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Because optically recorded action potentials are immune to stimulus
artifacts, it was possible to clearly identify the beats captured by
the burst train. The transmembrane potentials shown in Figure 3
demonstrate that for each coupling interval tested, only 1 beat was
captured by the burst train, as evidenced by the initiation of only a
single action potential upstroke between the dashed lines. Similar
results were observed for all experiments. This indicates that in the
wake of S2 repolarization, only a single beat was
captured by the burst train. Hence, modulation of the
electrophysiological substrate (ie,
repolarization gradients) by the S2 beat directly
influenced the response of the beat subsequently captured by the burst
train that initiated VF.
Modulated Dispersion and Vulnerability to Fibrillation
To quantitatively determine the relationship between
S1S2 coupling interval and
repolarization properties of the ventricle, mean repolarization time
(ie, S2-RT) and dispersion of repolarization time
(ie, S2-DISP) were calculated over a broad range
of S1S2 coupling intervals.
Figure 4A shows the mean and dispersion
of repolarization times generated during each prematurely stimulated
beat from a representative experiment.
S2-RT decreased monotonically from 221 to 145 ms
as the S1S2 coupling
interval was shortened from 300 to 230 ms. These changes were
attributed to coupling-interval–dependent changes in APD, which were
most marked at short S1S2
coupling intervals, as predicted from restitution properties of cardiac
myocytes.9 In contrast,
S2-DISP was modulated in a biphasic fashion as
coupling interval was shortened. For
S1S2 coupling intervals
near the baseline pacing rate, dispersion of repolarization was
relatively high; however, as
S1S2 coupling interval was
shortened, dispersion of repolarization decreased until a critical
coupling interval was reached (255 ms; dashed arrow in Figure 4). With
additional shortening of the
S1S2 coupling interval,
dispersion of repolarization rose sharply to a level slightly higher
than that measured during baseline pacing.
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To examine the relationship between repolarization gradients and
arrhythmia vulnerability, the VF threshold after the premature
beat (ie, S2-VFT) was measured for all
S1S2 coupling intervals
tested. Figure 4B shows S2-VFT measured from the
same experiment as in Figure 4A. It is evident that vulnerability was
modulated in a biphasic fashion in parallel with dispersion of
repolarization (filled circles, Figure 4A). As the
S1S2 coupling interval was
shortened to a critical value (dashed arrow),
S2-VFT increased (ie, vulnerability decreased).
With additional shortening of
S1S2,
S2-VFT decreased (ie, vulnerability increased) to
levels below those present at baseline pacing. Therefore, during
premature stimulation of the heart, biphasic changes in vulnerability
to fibrillation coincided exactly with coupling-interval–dependent
changes in dispersion of repolarization but not with changes in mean
repolarization time.
The results from all 8 experiments are summarized in Figure 5, which shows mean repolarization time
(Figure 5A), dispersion of repolarization (Figure 5B), and
arrhythmia vulnerability (Figure 5C) after a single premature
stimulus. Values are shown for coupling intervals near baseline pacing
rates (344±50 ms), intermediate coupling intervals (244±16 ms), and
short coupling intervals just beyond refractoriness of the
S1 beat (217±12 ms). In all experiments,
mean repolarization time decreased significantly in a monotonic fashion
as the S1S2 coupling
interval was progressively shortened (Figure 5A). However, dispersion
of repolarization was modulated in a biphasic fashion, as evidenced by
a significant reduction as
S1S2 coupling interval was
shortened and then a sharp increase in dispersion as
S1S2 approached
refractoriness (Figure 5B). In general, there was a trend for
dispersion of repolarization at short
S1S2 coupling intervals to
be greater than that at baseline pacing rates. Arrhythmia
vulnerability was also modulated in a biphasic fashion as the
S1S2 coupling interval was
shortened (Figure 5C). At short
S1S2 coupling intervals,
arrhythmia vulnerability was always greater than that at
baseline pacing rates. The biphasic coupling-interval dependence
exhibited by S2-VFT supports a mechanistic
relationship between arrhythmia vulnerability and modulated
dispersion, more so than changes in mean refractoriness.
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Discussion |
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In this study, we report a potentially important mechanism of initiation of VF based on the direct effect of a premature stimulus on the electrophysiological substrate for reentry. We found that vulnerability to fibrillation was modulated in a coupling-interval–dependent manner by pacing-induced modulation of repolarization gradients. Such modulation of repolarization gradients explained a paradoxical reduction of arrhythmia vulnerability after premature stimulation at intermediate coupling intervals, followed by a sharp increase in vulnerability at coupling intervals approaching refractoriness. Our results suggest that the "trigger" and the "substrate" for reentry are not independent, and the manner in which the electrophysiological substrate is modulated by a premature stimulus can strongly influence the state of cardiac electrical instability.
Previously, we17 have shown that a premature
stimulus can systematically modulate spatial gradients of APD in a
coupling-interval–dependent manner, which was explained on the basis
of heterogeneities of APD restitution kinetics between
ventricular cells. Although repolarization was dependent on
the combined influence of APD and propagation, our data indicate that
modulation of repolarization gradients was primarily due to
coupling-interval–dependent changes in APD. For example, as the
S1S2 coupling interval was
shortened to an intermediate value, the pattern of depolarization was
unchanged (Figure 2), whereas gradients of repolarization were
essentially eradicated because of a significant reduction of APD
gradients. As the S1S2
coupling interval was further shortened, conduction slowed slightly and
APD gradients reappeared, both of which combined to increase the
magnitude (ie, dispersion) of repolarization gradients. In general,
dispersion of repolarization at the shortest
S1S2 coupling intervals was
greater than at baseline pacing. It is possible that slow conduction at
short S1S2 coupling
intervals preferentially delayed repolarization away from the site of
stimulation and further enhanced dispersion of repolarization. In any
case, biphasic modulation of APD gradients played a dominant role in
determining repolarization gradients created by a premature
stimulus.
In the present study, we found that stimulus-induced changes in
repolarization gradients directly influenced vulnerability to
fibrillation. As the S1S2
coupling interval was shortened to an intermediate value, dispersion of
repolarization and arrhythmia vulnerability decreased in
parallel (Figure 5). From a teleological standpoint, it is possible
that such attenuation of repolarization gradients observed at
intermediate premature coupling intervals serves as a protective
mechanism against arrhythmias during premature stimuli. On the
other hand, in some pathological conditions, this mechanism may be
lost, which can explain why under such circumstances, less aggressive
pacing protocols (ie, intermediate
S1S2 coupling intervals)
are capable of inducing arrhythmias.26
Additional shortening of the
S1S2 coupling interval to a
value just longer than the effective refractory period markedly
accentuated repolarization gradients, which in turn produced conditions
necessary for the development of fibrillation. For all experiments,
arrhythmia vulnerability was higher (ie, smaller VFT) at the
shortest S1S2 coupling
intervals than with baseline pacing (Figure 5C). This may be explained
by conduction slowing and reduced refractoriness at very short
S1S2 coupling intervals,
both of which (in addition to increased dispersion of repolarization)
are expected to promote reentrant excitation. The rapid increase in
vulnerability at very short coupling intervals is consistent
with the common observation that the initiation of VF in normal hearts
typically required multiple closely coupled premature
stimuli.26
Relatively little attention has been given to how a premature stimulus alters the electrophysiological substrate for reentry in general and gradients of repolarization in particular throughout the heart. It is generally assumed that the effect of shortening the premature stimulus coupling interval is to increase the likelihood of inducing reentry by shortening refractoriness (ie, wavelength). However, this notion is somewhat limited because it does not account for spatial heterogeneities in cellular responses to a premature stimulus and, thus, changes in the spatial pattern of refractoriness during premature stimulation. Accordingly, we hypothesized that a premature stimulus influenced arrhythmia vulnerability by altering gradients of refractoriness. Early studies supported this concept by showing that tightly coupled premature stimuli increased dispersion of repolarization.27 However, those studies were limited in their ability to resolve spatial gradients of repolarization, and dispersion of repolarization was only measured for S1S2 coupling intervals near the effective refractory period. This may explain why the paradoxical decrease in arrhythmia vulnerability and repolarization gradients we observed as the coupling interval was initially shortened may have been unrecognized previously. The growing awareness of heterogeneities throughout the heart (ie, from epicardium to endocardium14) raises the possibility that in the intact heart, repolarization gradients are modulated across deeper subepicardial layers as well as across the epicardial surface. We made no attempt to account for transmural heterogeneities of cellular repolarization. However, studies from limited transmural recording sites across the ventricular wall of canine hearts16 have revealed mechanisms of repolarization similar to those we have observed.17 Therefore, the principles set forth in the present study may apply to other situations in which a heterogeneity of membrane repolarization properties exists.
Modulation of the electrophysiological substrate by a premature stimulus in a coupling-interval–dependent manner (ie, modulated dispersion), as demonstrated in the present report, may have important implications for the mechanism of arrhythmias initiated by premature stimuli. In patients with ischemic heart disease, tachycardia is preceded by pairs or multiple ventricular ectopic beats in 55% of all spontaneous events.28 Moreover, during programmed stimulation, the likelihood of inducing reentry increased as the number of extrastimuli increased.29 30 It is possible that a premature stimulus preconditioned the electrophysiological substrate and, accordingly, altered the likelihood of inducing reentry by a second (S3) and possibly a third (S4) premature stimulus. The results of the present study also suggested that in some circumstances, suitable conditions for reentry may not exist during baseline pacing but can form dynamically during premature stimulation of the heart.
Using the S2-VFT test, we were able to quantify
arrhythmia vulnerability and demonstrate a significant
correlation with repolarization gradients induced by a single premature
stimulus (Figure 5). On the basis of these data, it is likely that the
presence or absence of steep repolarization gradients directly
influenced the initiation of VF. However, even though the VFT test is
an established experimental technique that has been used extensively to
quantify arrhythmia
vulnerability,18 31 32 the precise mechanism of
arrhythmia initiation is not completely understood. For
example, it is possible that >1 stimuli in the burst train captured
the tissue (ie, S3 and S4)
before the initiation of fibrillation. However, the optically
recorded transmembrane potentials confirmed that for all coupling
intervals tested, only 1 beat was captured by the burst train before
the onset of fibrillation (Figure 3). It is also possible that before
capture, stimuli in the burst train altered transmembrane potential.
Strong, shock-strength stimuli have been associated with virtual
electrode effects33 and graded
responses,34 both of which can directly influence
arrhythmia initiation independently of repolarization
gradients. However, we did not observe any significant change in
transmembrane potential during the burst train before capture. This is
not surprising because the average S2-VFT (17±7
mA, 1 ms in duration) in the present study was relatively small
compared with shock-strength impulses. Most likely, modulation of
repolarization gradients that we observed in the present study
directly influenced the occurrence of unidirectional
block.35 However, additional studies are required
to determine the precise mechanisms by which modulation of
repolarization gradients alters the
electrophysiological requirements for
reentry.
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Acknowledgments |
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This work was supported by the Medical Research Service of the Department of Veterans Affairs, NIH grant HL-54807, the American Heart Association (Dr Rosenbaum), and the Whitaker Foundation (Dr Laurita and Dr Rosenbaum).
Received February 16, 1998; revision received July 15, 1998; accepted August 13, 1998.
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