(Circulation. 1996;93:603-613.)
© 1996 American Heart Association, Inc.
Articles |
Optical Mapping in a New Guinea Pig Model of Ventricular Tachycardia Reveals Mechanisms for Multiple Wavelengths in a Single Reentrant Circuit
Presented in part at the North American Society of Pacing and Electrophysiology Young Investigator Awards, May 6, 1995, Boston, Mass, and published in abstract form (Pace. 1995;18[pt II]:II-858).
From the Departments of Medicine and Biomedical Engineering and the Cardiac Bioelectricity Research and Training Center, Case Western Reserve University, Cleveland, Ohio.
Correspondence to David S. Rosenbaum, MD, Case Western Reserve University, Department of Biomedical Engineering, Wickenden Bldg, Room 504, Cleveland, OH 44106-7207. E-mail dsr@pace.cwru.edu.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion Appendix References |
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Background Although the relationship between cardiac wavelength (
) and path length importantly determines the stability
of reentrant arrhythmias, the physiological
determinants of are poorly understood. To investigate the cellular
mechanisms that control during reentry, we developed an
experimental system for continuously monitoring within a reentrant
circuit with the use of voltage-sensitive dyes and a new guinea pig
model of ventricular tachycardia (VT).
Methods and Results Action potentials were recorded
simultaneously from 128 ventricular sites in
Langendorff-perfused hearts (n=15) in which propagation was
confined to a two-dimensional rim of epicardium by an endocardial
cryoablating procedure. The reentrant path was precisely controlled by
creating an epicardial obstacle (2x10 mm) with an argon laser. To
control for fiber orientation and rate-dependent membrane
properties, during reentry was compared with during plane wave
propagation transverse and longitudinal to cardiac fibers at a stimulus
cycle length (CL) comparable to the VT CL. Reentrant VT
(CL=97.0±6.2
ms) was reproducibly induced by programmed stimulation in 93% of
preparations. varied considerably within the reentrant circuit
(range, 10.6 to 22.5 mm), because of heterogeneities of conduction
rather than action potential duration. was significantly shorter
during reentrant propagation (ie, with pivoting) parallel to fibers
(10.6±4.2 mm) compared with plane wave propagation (ie, without
pivoting) parallel to fibers (32.8±6.5 mm, P<.02),
indicating that wave-front pivoting was primarily responsible for
shortening of during reentry. The mechanism of shortening was
conduction slowing from increased current load experienced by the
pivoting wave front.
Conclusions We provide direct experimental evidence that
multiple wavelengths are present even within a relatively simple
reentrant circuit. Abrupt changes in loading during wave-front
pivoting, rather than membrane ionic properties or fiber structure,
were a major determinant of and, therefore, may play an important
role in the stability of reentry.
Key Words: reentry • tachycardia • mapping • action potentials • electrophysiology
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Introduction |
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TopAbstractIntroductionMethods Results Discussion Appendix References |
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The cardiac impulse was first described in terms of its
by Mines in 1913, whose classic
experiments led him to hypothesize that reentrant excitation is
possible only if the reentrant path length is longer than the of
the propagating impulse.1 More recently, the concept of
has been widely applied to the analysis of
experimental2 3 and
theoretical4 5 models of
reentry, to the evaluation of antiarrhythmic drug
mechanisms,6 7 and to the clinical assessment of VT
during
electrophysiological
testing.8
The hypothesis has been criticized because the reentrant wave
is classically assumed to have constant length as it traverses the
reentrant circuit; ie, a reentrant circuit is characterized by a single
. Consequently, this description of fails to account for
electrophysiological and structural
heterogeneities known to exist within reentrant
circuits.9 10 Electrophysiological
heterogeneities in ventricular myocardium may
be caused by spatial dispersion of ionic membrane properties, which
produces regional differences in APD and
refractoriness.11 12 Structural heterogeneities, such
as
tissue anisotropy13 14 or changes in the geometry of
a
propagating reentrant wave front produced by conduction through a
narrow isthmus,15 16 17 or pivoting
around
obstacles18 19 may introduce changes in conduction
and
refractoriness that are expected to additionally influence .
Due to limitations of conventional recording techniques,
it has been difficult to simultaneously measure
propagation, membrane repolarization, and details of wave-front
geometry during reentrant excitation. Previously, has been
estimated from the product of conduction velocity and
refractoriness measured at a single recording site. An inherent
limitation to this approach is that it cannot account for the presence
of the aforementioned heterogeneities of conduction or refractoriness
known to exist in reentrant circuits. Therefore, although is
thought to underlie the functional characteristics and stability of
most forms of reentry, it has been difficult to measure
experimentally. Hence, the application of has been largely
restricted to one of a useful theoretical construct.
In our study, we applied high-resolution optical action potential
mapping with voltage-sensitive dyes to a new intact guinea pig
heart model of reentrant VT to investigate mechanisms of reentry at the
cellular level. This approach allowed us to measure quantitatively
in electrophysiologically and structurally
heterogeneous tissue in which cardiac fiber orientation was
known and the geometry of the circuit was precisely controlled with an
argon laser. We provide experimental evidence demonstrating that
cannot be assumed to be constant during reentry; instead multiple
wavelengths exist in a single reentrant circuit. Moreover, the
predominant mechanism responsible for heterogeneity of
during reentry is conduction velocity slowing that resulted from
the dissipation of excitatory current at the pivot points of the
reentrant circuit rather than tissue anisotropy or heterogeneities of
membrane repolarization.
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Methods |
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TopAbstractIntroductionMethods Results Discussion Appendix References |
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Experimental Preparation
All experiments were carried out in accordance with the guidelines of the American Physiological Society. Retired male breeder guinea pigs weighing 750 to 1200 g were anesthetized intraperitoneally with 30 mg/kg sodium pentobarbital, and their hearts (weight, 3.1 to 4.2 g) were rapidly excised and perfused as Langendorff preparations with oxygenated (95% O2/5% CO2) Tyrode's solution containing (mmol/L): NaCl 130, NaHCO3 25, MgSO4 1.20, KCl 4.75, dextrose 5.0, and CaCl2 1.25 (pH 7.40, 37°C). Perfusion pressure was maintained at 80 mm Hg by adjusting the height of the perfusion reservoir relative to the height of the preparation. Hearts were stained with the voltage-sensitive dye di-4-ANEPPS (10 µmol/L; Molecular Probes) by direct coronary perfusion for 5 minutes.
Beating and perfused hearts were immersed in a custom-built chamber made of acrylic plastic mounted onto a micromanipulator such that the mapping field could be positioned behind an imaging window located on the front of the chamber. Tyrode's solution in the chamber was maintained at 37°C with a heat exchanger to prevent intramyocardial temperature gradients. Gentle compression applied to the posterior surface of the heart with a movable piston was used to stabilize the anterior surface of the ventricle against the imaging window to ensure that the mapping surface and optical focal plane were coplanar, thus avoiding distortion of action potential signals. Previously, we have confirmed that this procedure does not alter the electrophysiological properties of this preparation.20 21 Cardiac rhythm was monitored using three Ag/AgCl disk electrodes fixed to the chamber in positions corresponding to ECG limb leads I, II, and III. ECG signals were filtered (0.05 to 1000 Hz), amplified (1000x), and displayed on a digital oscilloscope (Gould DRO 1604). ECG tracings were printed on paper (100 mm/s) with a strip-chart recorder (Gould WindoGraf, model 40-8474).
Experimental Model of Reentrant VT
To create essentially
two-dimensional anisotropic
myocardium free from the confounding influences of
rotational anisotropy22 or His-Purkinje breakthrough, a
"frozen heart" preparation was created by ablating the
endocardial three fourths of the LV wall using a modification of a
cryoablation technique previously described in rabbits.23
Langendorff-perfused hearts were immersed in a rapidly stirred,
oxygenated, and temperature-controlled (30°C)
Tyrode's bath. A cylindrical (4-mm diameter) brass tube, tapered at
its tip to conform to the guinea pig LV apex, was then inserted through
the mitral annulus into the LV. Coronary perfusion was
interrupted for 7 minutes while liquid nitrogen (-196°C) was
injected into the tube. To prevent reentry from occurring around the
circumference of the heart,24 the posterior RV was
cryoablated transmurally. As a result of ablating the entire
intraventricular septum, the endocardial and
intramural layers of the LV, and the posterior RV, a thin (810±220
µm) viable rim of LV and anterior RV epicardia remained (Fig
1
). The electrophysiological
properties of the viable epicardial rim were not altered by the
cryoablation procedure, since conduction velocity, refractoriness, and
action potential characteristics were found to remain normal in each
preparation.
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Previous investigators have created an anatomic obstacle
for reentry by
applying a cryoprobe to the epicardial surface of rabbit
hearts.25 26 In a series of pilot studies
(unpublished
observations), we found that epicardial cryoablation was not suitable
for these studies since path length and geometry of the reentrant
circuit could not be precisely controlled (eg, the area of necrosis was
typically broad and irregular). Furthermore, since working distances
are relatively small in the guinea pig, the epicardial cryoablation
often impaired coronary blood flow, resulting in regional
ischemia and depressed action potentials within the reentrant
circuit. To circumvent these problems, we developed a system to produce
epicardial reentry around an anatomic obstacle in which the geometry of
the reentrant circuit is precisely controlled with a 5-W argon ion
laser (model 2020-05, Spectra-Physics). Laser light was coupled into a
200-µm diameter fiber-optic cable and focused (200 µm spot)
with a gradient index lens through the imaging window so that the
obstacle could be "etched" onto the LV epicardium without moving
the heart. A 2x10-mm linear obstacle (1-mm depth), oriented
perpendicular to cardiac fibers and parallel to the left anterior
descending coronary artery (Fig 2), was created
such that a thin zone of necrosis extended transmurally from the
epicardial surface to the boundary of the endocardial cryoablation
lesion. The position and translational velocity of the laser beam were
precisely controlled (±0.1 µm) with three micropositioners
(UT100-75, Klinger Corp) driven by a microprocessor with a software
interface developed in our laboratory. The extent of the lesion was
histologically confirmed after each experiment by
2,3,5-triphenyltetrazolium chloride
staining27 and light microscopy.
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Stimulation Protocol: Initiation of Sustained
VT
The stimulation protocol was initiated no sooner than 30 minutes
after completion of the cryoablation and laser ablation procedures to
allow the preparation to equilibrate. Although these preparations
exhibited stable action potential properties over the course of a
3-hour experiment, action potential maps reported in this study were
recorded within 1 hour of establishing the Langendorff
preparations. The epicardial surface was stimulated at 5x
diastolic threshold current using a synthetic
resin–coated (except at the tip) silver bipolar electrode
(diameter, 0.1 mm; interelectrode spacing, 1 mm) and a programmable
stimulator. We attempted to induce sustained monomorphic VT in 15
hearts using programmed ventricular stimulation. After a
10-beat constant CL drive train (CL=250 ms), single, double, and triple
extrastimuli were introduced starting at 30 ms above the refractory
period and then at intervals that scanned diastole by 5-ms
decrements. When refractoriness to the last extrastimulus
(SN) was reached, the SN-1 coupling interval
was decreased by 5 ms and SN was further decremented until
refractoriness was again reached. If VT was not induced by
extrastimulus technique, bursts of up to 25 consecutive stimuli were
introduced. Every episode of VT was terminated with burst pacing and
then reinitiated with programmed stimulation to confirm reproducibility
of VT in this model.
Stimulation Protocol: Plane Wave Stimulation
In five separate
experiments, steady-state stimulation was
carried out in the frozen heart preparation, without the epicardial
obstacle, to investigate the dependence of on fiber orientation and
rate in the absence of wave-front pivoting. With the use of a
custom-built orthogonal plane wave electrode consisting of two
bipolar pairs of platinum wires (0.5-mm diameter, 1-mm interelectrode
spacing, 10-mm length) oriented perpendicular to one another, one
electrode was used to stimulate a plane wave parallel to the cardiac
fibers and the other stimulated a plane wave transverse to fibers.
Action potentials were recorded from LV epicardium (Fig 2
)
during
steady-state (>1 min) plane wave stimulation along one fiber axis
at CLs ranging from 1000 to 100 ms. The identical stimulation protocol
was repeated for plane wave propagation parallel and perpendicular to
fibers.
Optical Mapping With Voltage-Sensitive Dyes
We have developed
an optical mapping system capable of
recording high-fidelity action potentials
simultaneously from 128 sites of an intact and beating
heart (Fig 3). Voltage-sensitive dye was excited
using quasimonochromatic light (540±10 nm) from a 250-W
tungsten-halogen lamp. Excitation light was directed toward the
heart using a liquid light guide. Fluoresced and scattered light
was collected using a high numerical aperture lens (50 mm, F1.8),
long-pass filtered (610 nm), and focused onto a 12x12 element
photodiode array (MD144-5T, Centronic Ltd). The camera design allowed
optical magnification to be rapidly varied during an experiment. We
used two magnifications in the present study. Low magnification
(1.5x) yielded a 12x12-mm mapping area and 1.0-mm spatial
resolution
between recording pixels. High magnification (3.6x) yielded a
5x5-mm mapping area with 0.4-mm spatial resolution. A
charge-coupled device video detector mounted coaxially on the
camera housing was used to image the heart surface so that the mapping
sites could be determined relative to the epicardial obstacle and
coronary arteries. Photocurrent from each photodiode was
converted to a voltage with the use of low-noise
current-to-voltage amplifiers and then underwent
postamplification (1x, 50x, 200x, and 1000x) with AC
coupling
(
=10 s) and low-pass anti-alias filtering (1000 Hz). Action
potential waveforms and ECGs were multiplexed and digitized directly to
the disk of a UNIX workstation (Concurrent 5450S, Concurrent Computer
Corp) with a 1-MHz 12-bit analog-to-digital converter at a
sampling rate of 2000 Hz per channel (Fig 3).
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This
system was designed to optimize action potential fidelity to allow
quantitative analysis of APD, conduction velocity, and in
the intact heart. We have shown previously that optical action
potentials recorded with this system closely mimic the time course
and morphology of action potentials recorded with microelectrode
techniques.20 28 In these studies, action potentials
could
be recorded from the intact heart without motion artifact because
endocardial cryoablation anchored the epicardial surface and thus
obviated the need for suppressing cardiac contraction with drugs known
to influence action potential characteristics21 29
and
reentrant arrhythmias.30 Action potentials were
not distorted by this recording system since the bandwidth of
the amplifiers was set well outside the frequency content of optical
action potentials. The sampling rate used in these studies was
approximately 10 times the highest frequency content of optical action
potentials,20 28 therefore cardiac action potentials
could
be accurately reconstructed from digitized waveforms. To optimize
dynamic range, the large offset caused by background
fluorescence of di-4-ANEPPS was removed without filtering out
low-frequency components (eg, the plateau) of the action potential
waveform by discharging the AC coupling capacitor just before each data
acquisition. The high signal-to-noise ratio of the system made
it possible to detect action potential amplitude changes as small as 1
mV (based on a 100-mV action potential).
Measurement of Cardiac Wavelength From Optical Action
Potential Maps
Optical action potentials were analyzed using a
previously validated computer algorithm to automate the detection of
activation and recovery times.31 Activation time was
defined as the point of maximum upstroke velocity, and recovery was
defined as the point of maximum second derivative during
repolarization. This corresponds to recovery measured at 
95%
repolarization32 (ie, APD95%). All
computer-assigned times were verified by the investigators. was
determined from the product of mean APD and mean conduction
velocity measured within the region of depolarized tissue such that
was not dependent on APD or conduction velocity at any single point.
For further confirmation, was also measured directly from
isopotential maps as the extent of depolarized tissue (ie, distance
from the depolarizing head of the wave to the point of recovery at the
tail) surrounding the laser obstacle at any point in time. was not
assumed to be stationary in time (ie, from beat to beat) or space (ie,
throughout the reentrant circuit) but was measured as a continuously
changing function of the cardiac cycle. For the purpose of statistical
analysis, the VT circuit was divided into four zones (L1, L2,
T1, and T2; Fig 2, inset) based on direction of reentrant
propagation
relative to the cardiac fiber orientation. Zones L1 and L2 were near
pivot points of the circuit where the wave front turns in the
longitudinal fiber direction. Zones T1 and T2 were located on either
side of the long axis of the linear obstacle where propagation is
transverse to cardiac fibers.
Statistical Analysis
Statistical comparisons of APD,
conduction velocity, and
during plane wave propagation parallel and perpendicular to fibers were
made using a Student's paired t test. APD, conduction
velocity and in various zones (L1, L2, T1, and T2) of the reentrant
circuit were also compared using a Student's t test. A
value of P<.05 was considered to be statistically
significant, and a Bonferroni correction for multiple comparisons was
applied when appropriate.
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Results |
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TopAbstractIntroductionMethods Results Discussion Appendix References |
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Characteristics of Experimental VT Model
Computer-driven laser ablation proved effective for producing precisely controlled reentrant circuits. The dimensions of the epicardial obstacle were nearly identical in all experiments, resulting in a consistent reentrant path length (range, 23.0 to 26.5 mm). The epicardial obstacle had sharply demarcated borders as normal action potentials were recorded from sites as close as 400 µm from the obstacle border.
Reentrant VT was initiated with programmed stimulation
in 14 of 15
(93%) hearts (VT CL=97.0±6.2 ms). In every experiment, VT was
pace-terminated and reinitiated to ensure reproducibility of the
model. In several cases, burst pacing at one CL produced classic
entrainment of VT (in 8 of 14 experiments) or acceleration to
polymorphic VT (in 2 of 14 experiments), while pacing at other CLs
terminated VT. A reentrant mechanism was confirmed by direct action
potential mapping of the entire circuit. Fig 4
illustrates a representative isochrone activation
map of VT. Conduction proceeds clockwise around the linear obstacle,
and conduction velocity is most rapid along the long axis of the lesion
where propagation is transverse to myocardial fibers. In contrast,
conduction slows near each pivot point where propagation turns parallel
to fibers. Despite the relatively fast CL of VT, action potentials
recorded from the reentrant circuit exhibited well-defined
upstrokes, plateaus, repolarization, and diastolic
intervals (Fig 4). In this model, VT remained stable and
persisted for
more than 2 hours unless actively terminated by pacing.
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Cardiac Wavelength During Plane Wave
Stimulation
To determine the dependence of on rate-dependent
membrane
properties and fiber orientation independent of the effects of
pivoting, was measured during steady-state plane wave
stimulation over a wide range of stimulus CLs. APD, conduction
velocity, and are plotted in Fig 5 as a function of
stimulus CL. APD decreased exponentially at faster CLs, but APD did not
differ significantly during propagation longitudinally (Fig 5,
filled
circles) compared with transversely (Fig 5, open circles) to
myocardial
fibers. Conduction velocity also fell sharply at rapid CLs (<200 ms),
but unlike APD, conduction velocity was significantly influenced by
fiber direction. However, as stimulus CL approached 100 ms (ie, near
the VT CL ), the differences in conduction velocity between the two
orthogonal fiber directions decreased owing to preferential conduction
velocity slowing longitudinal to fibers (Fig 5). Due to these
rate-dependent changes in conduction velocity, at relatively slow
CLs there was a large difference in the magnitude of in the
longitudinal and transverse directions (Fig 5,
L-T40 mm), whereas at rapid CLs
fiber orientation had less influence on (Fig 5,
L-T10 mm).
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)
and transverse (
) to cardiac fibers. Mean APD (top), conduction
velocity (middle), and
Cardiac Wavelength During Reentry
In Fig 6,
APD, conduction velocity, and
measured during reentrant VT (shaded bars) are compared in four
predefined zones (T1, T2, L1, and L2 in Fig 2) of the circuit.
To
determine the influence of wave-front pivoting independent of fiber
orientation and rate, Fig 6 also shows measured during
plane wave
propagation longitudinal and transverse to cardiac fibers using a
stimulus CL equivalent to the VT CL. During reentry, APD did not vary
significantly around the circuit (Fig 6, left, compare L1, L2,
T1, and T2) and was not significantly different from APD measured
during plane wave stimulation (Fig 6, left, compare L1 and L2
to Lp).
Although subtle variations of APD (typically <10 ms) were observed
within the VT circuit, dispersion of APD did not contribute
significantly to the heterogeneity of .
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In contrast to APD,
conduction velocity (Fig 6, center) differed
markedly in the four zones of the circuit. During reentry, when
propagation was transverse to cardiac fiber orientation (T1, T2),
conduction was faster than in zones in which the wave front was
pivoting parallel to fibers (L1, L2). In zones T1 and T2, velocity was
not significantly different than would be expected from anisotropic
conduction during plane wave stimulation (Fig 6, center, T1,T2
Tp).
However, within zones L1 and L2, conduction velocity was significantly
slower than would be expected from anisotropy (Fig 6 center,
L1,L2<Lp). Consequently, the relation between longitudinal (L1, L2)
and transverse (T1, T2) conduction velocities during reentrant
propagation was reversed from their relationship during plane wave
propagation.
With the use of optical action potential mapping, it was
possible to
measure directly by plotting the extent of depolarized tissue
within the reentrant circuit at any time. The isopotential contour maps
in Fig 7 demonstrate how dynamically expands and
contracts within a single reentrant VT cycle. These maps depict the
voltage distribution in the reentrant circuit at two time points (A and
B) separated by 27 ms. The white arrow in each map extends from the
tail of recovery to the leading edge of depolarization and therefore
corresponds to . At time A (Fig 7, left), the leading edge
of
depolarization has passed through an area of slow conduction around a
pivot point; hence, contracts as the repolarizing tail of the wave
front begins to "catch up" with the slowly propagating head. At
time B (Fig 7, right), the leading edge has just conducted
rapidly down
the long axis of the obstacle; hence, expands. In these
experiments, varied by 20% to 50% during an individual cycle of
reentrant VT. Also note that there is corresponding variation of the
"excitable gap" (Fig 7, black region) as indicated
by changes in
the area of fully repolarized tissue at time A versus time B. The
pattern of changes during the VT cycle (Fig 7, inset) was
identical
from beat to beat.
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Mechanism for Multiple Wavelengths During
Reentry
We found that conduction velocity slowing near pivot points of
the
reentrant circuit was the most important factor that caused to vary
during VT. To investigate the mechanisms of conduction velocity
slowing, high-magnification action potential maps (400-µm
interpixel resolution) were recorded at each pivot point during
reentrant VT and were compared with action potentials obtained from the
similar site during plane wave propagation. An example of propagation
around a pivot point is shown in Fig 8. As the impulse
begins to rotate, there is profound conduction slowing (ie, crowding of
isochrones) at the pivot point fulcrum, whereas more rapid
conduction occurs at sites distant from the pivoting fulcrum. As the
wave front exits the pivot point, uniform conduction is restored across
the wave front.
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Alterations of conduction velocity were associated with
marked slowing
in the time course of action potential upstrokes at each pivot point.
Action potential upstrokes recorded from five uniformly spaced
sites around the pivot point are shown in Fig 8. As the wave
front
approaches the pivot point, action potential upstroke velocity is rapid
(Fig 8, right, potentials A and B) and is no different than
upstrokes
observed in other nonpivoting areas of the circuit. However, as the
propagating wave pivots, action potential upstrokes become
progressively slowed and contain irregularities and multiple notches
not observed at nonpivoting sites (Fig 8, right, potentials C
and D).
During plane wave stimulation (ie, in the absence of pivoting), the
potentials recorded from sites C and D exhibited normal upstrokes,
indicating that action potential upstroke delays and conduction slowing
during reentry were caused by altered loading of the pivoting wave
front and not because these cells were intrinsically depressed or
injured. Finally, upstroke slowing could not be attributed to
artifactual blurring of optical action potentials within a
recording pixel (see "Appendix").
To investigate the extent
to which the natural isthmus formed by the AV
groove and the basal tip of the laser lesion may affect conduction, an
additional lesion was created using the argon laser in a stepwise
fashion starting from the AV groove and extending toward the obstacle.
Isthmus width was narrowed progressively during VT, and VT CL was
measured as a function of isthmus width. Fig 9 shows that VT CL
did not
vary with decreasing isthmus width. In three hearts tested, there was
no significant change in the VT CL until a critical width was reached,
at which time VT terminated and could no longer be initiated. These
data suggest that the isthmus width affected refractoriness without
altering conduction velocity and hence was not expected to have
influenced significantly during steady-state VT.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion Appendix References |
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A variety of experimental techniques have been used previously to investigate arrhythmia mechanisms, including multisite extracellular mapping and single-cell microelectrode and patch-clamp recordings. Extracellular techniques offer reasonable spatial resolution but limited information on the time course of membrane potential change. On the other hand, microelectrode and patch-clamp recordings provide detailed and quantitative information concerning membrane events but only from one cell. It has been suggested that "[an understanding of] the interaction of ionic currents and the means by which electrical activity is propagated between cells requires a more integrated approach."33 Accordingly, in the present study, we used high-resolution optical action potential mapping to study reentry at the cellular level in the intact and beating heart.
Optical mapping provided direct experimental evidence that is not a
static property of reentry; rather, varies continuously within a
reentrant circuit. Although fiber structure and rate-dependent
ionic membrane properties influenced , during established reentry
these properties did not cause heterogeneity of
within the reentrant circuit. In contrast, we found that dissipation of
excitatory current caused by changes in the geometry of the reentrant
wave front at the pivot points of the circuit was primarily responsible
for heterogeneity of observed during reentry.
Characteristics of the Guinea Pig VT Model
We have developed
a unique experimental system that allowed us to
record high-fidelity action potentials from the intact heart
and therefore to monitor continuously throughout the entire
reentrant circuit. This was possible because our guinea pig model of VT
was designed so that the reentrant circuit could be confined to
essentially two dimensions, and the geometry of the reentrant path was
precisely controlled with an argon ion laser. Conduction within the
thin epicardial rim simulated chronic myocardial infarct
models34 while eliminating the confounding effects of
ischemia35 and nonuniform
anisotropy.36 Reentrant VT in this model shared many of
the characteristics of clinically encountered VT. For example, VT was
reproducibly initiated using a clinically relevant stimulation protocol
and could be terminated, entrained, and accelerated with pacing.
Although the VT CL was relatively fast, action potentials recorded
during VT demonstrated sharp upstrokes and normal plateaus, indicating
that reentry did not require the presence of depressed tissue within
the circuit.
Dependence of Wavelength on Rate-Dependent Membrane Properties and
Fiber Structure
To date, cardiac has not been well characterized
in
ventricular myocardium. In the present
study, measured during plane wave stimulation was dependent on both
stimulation rate and fiber structure (Fig 5). We found that
shortened exponentially with increased stimulation frequency. This was
an expected result since is dependent on conduction velocity and
APD, both of which decrease at faster stimulation rates. Dynamic
shortening of with increased rate has also been observed in
rabbit2 and canine37 atria, reaffirming that
is not a static property of cardiac muscle. Although fiber
structure did not affect APD, was consistently longer
during propagation in the longitudinal direction compared with the
transverse direction due to anisotropic conduction. These data suggest
that the of a propagating impulse adapts to the local
electrophysiological environment and thus
can contract or expand dynamically as conditions change.
Dynamic
adaptation of , and specifically the capacity of to
contract at rapid heart rates, was critical to the formation of
reentrant VT in our model. As shown in Fig 5, at
physiological heart rates (CL=300 to 400 ms)
was much longer than the circumference of the entire heart. Therefore,
reentry could not be initiated (since >> path length) had
not contracted to the dimensions of the reentrant circuit at more
rapid CLs. Data presented in Fig 5 also provide insight into
mechanisms that control during reentrant VT. If were governed
exclusively by fiber orientation and the rate-dependent ionic
processes that govern depolarization and repolarization, the
observed during VT would be expected to be identical to measured
during plane wave stimulation at the VT CL. This was not the case,
because the range of observed during reentrant VT (Fig 5,
shaded
bar) was significantly less than measured during plane wave
stimulation at the VT CL (100 ms). Therefore, the degree to which
shortened during reentrant VT cannot be attributed to anisotropic
conduction or rate-dependent changes in APD or conduction velocity
but was explained by the presence of wave-front pivoting, since
this was the only difference between reentrant propagation and plane
wave propagation in these experiments. In fact, one would predict from
Fig 5 that in the absence of pivoting (ie, during plane wave
propagation), would be longer than the reentrant path length, thus
precluding the initiation of reentry. Therefore, in this experimental
model, pivoting was critical to the development of reentry.
Multiple Wavelengths During Reentry
A major finding of this
study was that even in a relatively simple
reentrant circuit, and in the absence of regional tissue injury, the
of a reentrant impulse varies considerably as it traverses a
circuit. It should be emphasized that our result does not diminish the
importance of to the mechanism of reentry. Rather, our data
indicate that the relationship between , path length, and the
stability of reentry is more complex than many earlier investigations
suggested. This was predicted from recent computer simulations by
Rudy,38 who concluded that "one should use caution when
using a single value of wavelength or excitable gap as an index of
stability of reentry."
Reiter et al26 estimated
and excitable gap from
four discrete zones of a reentrant circuit in rabbit ventricle and also
found that and excitable gap varied throughout the circuit.
Moreover, they found that conduction velocity varied by 66% (range, 20
to 59 cm/s), whereas refractoriness varied by 12% throughout the
reentrant circuit, supporting our finding that
heterogeneous conduction influences regional changes in
more than do heterogeneities of refractoriness or APD. It was somewhat
surprising to find that membrane repolarization was so
homogeneous during VT in our model, particularly since we
previously observed considerable APD gradients in guinea pig epicardium
at physiological heart rates,31 and
since there is ample evidence that ion channels that govern
repolarization are heterogeneously distributed throughout
the ventricle. However, regional variations in transient outward
current39 as well as variations in the components of
delayed rectifier current, IKr and
IKs,40 have been observed predominantly
at slow heart rates and not during tachycardia; hence,
variability in the activity of these currents may be more important to
the initiation than maintenance of reentry.
Cardiac is
classically described as a homogeneous
property of a reentrant impulse such that a single characterizes an
entire circuit.1 41 42 Consequently,
investigators have
estimated from the product of conduction velocity and APD (or
refractoriness) measured at a single recording site. An
inherent limitation to this approach is that it assumes that
electrophysiological properties, including
, are homogeneous throughout the circuit. Our data
demonstrate that this approach is oversimplified and is probably only
valid under ideal conditions such as plane wave propagation in
structurally and electrophysiologically
homogeneous tissue. Investigators10 26 have
also used the local effective refractory period (ERP) to estimate
(ie, the length of time myocardium at one site is
refractory rather than the length of refractory tissue at any point in
time) and similarly have estimated excitable gap by subtracting ERP
from the tachycardia CL (ie, the length of time
myocardium at one site is excitable rather than the length
of excitable tissue at any point of time). Had we calculated and
excitable gap in this manner, we would have failed to observe
heterogeneities of and excitable gap during reentry, since APD was
relatively homogeneous throughout the VT circuit. However,
as shown in Fig 7, our direct measurement of as the
extent of
depolarized tissue in space revealed 50% variation of during a
single reentrant cycle. Although the results from our experimental
model should be extrapolated cautiously to VT in patients, these
findings may explain why responses of clinical VT to artificial
stimulation (ie, entrainment, termination) are so highly dependent on
the region of the reentrant circuit in which stimuli are
delivered.43 44
A more complete description of
and excitable gap requires that
these parameters be viewed with regard to how they vary in
both time and space. The of a reentrant impulse should be
determined from the difference between conduction velocity at the head
of the impulse and repolarization velocity at the tail of the impulse.
Whenever the head is propagating faster than the tail, will
lengthen; conversely, when the velocity of the head is slower than the
tail, will shorten. Since the depolarizing head and repolarizing
tail of a reentrant wave front are located simultaneously
in different regions of the circuit, and typically propagate at
different velocities, it is not possible to accurately measure
without measuring conduction and repolarization at the head and tail of
the impulse simultaneously. Spinelli and
Hoffman10 have previously emphasized the limitations of
measuring from a single recording site. In contrast to
optical action potential maps in which APD can be monitored
continuously over time from multiple sites in space, ERP is measured
from one site during a relatively long period of time. Therefore, it is
not possible to monitor using extracellular techniques during
important transient events such as the initiation and termination of
reentry. Techniques similar to those used in this study may also help
to elucidate the role of in the mechanism of drug-induced
termination of reentry.
Mechanisms of Wavelength Heterogeneity and the Role
of Wave-Front Pivoting
All forms of reentrant excitation, whether due
to
functional42 45 or anatomic46 block or
tissue
anisotropy,47 require that wave fronts rotate and pivot so
that a complete circuit is established. Little information is available
on the electrophysiological effects of
wave-front pivoting and their relationship to the geometry of
reentrant circuits. Heterogeneity of in our
experimental VT model was primarily due to conduction slowing at the
pivot points of the reentrant circuit rather than regional
heterogeneities of membrane repolarization or anisotropic fiber
structure. During plane wave propagation, action potential
characteristics were normal at pivot points, ruling out the possibility
that this tissue was intrinsically depressed. In contrast, during VT,
action potentials (Fig 8, right) exhibited markedly slowed
upstrokes
close to but not remote from the pivoting fulcrum, indicating that
conduction slowing at the pivoting fulcrum was related to the curvature
of the rotating wave front. This can be explained by increased current
load, as the excitatory current of a curved wave front is dissipated
over a larger cross-sectional area producing a current
sink.17 38 Experimental13 48
and computer
modeling5 studies have confirmed that an abrupt increase
in axial current load produced by branching points or a sudden change
in the direction of propagation will impair conduction. Also
consistent with this mechanism is the fact that conduction
slowing could not be explained by rate-dependent membrane
properties, fiber structure (Fig 5, center), local prolongation
of APD
at the pivot points (Fig 6, left), or conduction through an
isthmus
(Fig 9).
The fact that conduction was slowest at the pivot points at which propagation turned parallel to cardiac fibers indicates that the influence of pivoting on conduction was far stronger than the influence of anisotropy. This apparent paradox can also be explained on the basis of source-sink relationships at the pivot points of the reentrant circuit. Pivoting from the transverse to the longitudinal fiber direction results in an abrupt change in the electrotonic load experienced by cells at the pivoting fulcrum. As the wave front turns, there is increased current load owing to reduced axial resistance in the longitudinal direction. Thus, tissue anisotropy may have created an additional current sink that further depressed conduction of the pivoting wave front. It is not possible from our data to distinguish the relative contributions of wave-front curvature and tissue anisotropy to altered current loading at the pivot points. However, previous experimental studies have demonstrated that a close, inverse correlation exists between the curvature of a pivoting wave front and local membrane response17 and that these source-sink changes are not dependent on a specific fiber orientation.49
Pivoting may influence the stability of
reentry in two opposing ways.
In our experimental model, conduction slowing at the pivot points
shortened sufficiently to prevent the head of the reentrant impulse
from colliding with its tail, thus allowing stable reentry to persist.
On the other hand, pivoting may produce a "weak link" in the
reentrant circuit by imposing a local current load that may cause
propagation to fail. This may be an important mechanism of
arrhythmia termination in circumstances in which the reentrant
path length is much longer than and in which head-tail
interactions are less likely to occur. For example, during functional
reentry in the sterile pericarditis model of atrial flutter, the pivot
points of the reentrant circuit are consistently the sites of
slow conduction and termination of reentry by either antiarrhythmic
drugs or pacing.18 These findings support the notion that
the pivot point of a circuit can be a site of impaired propagation of
excitatory current and therefore the component of the circuit that is
most susceptible to the actions of antiarrhythmic drugs that
depress excitability.
Study Limitations
Multisite high-resolution action potential
recordings
made with voltage-sensitive dyes were critical to the measurement
of in this study. The basis for our measurement of lies in the
close quantitative relation between APD and refractory
period.32 50 Measurement of APD near complete
repolarization, as used in this study, has been shown to closely
parallel changes in refractoriness of ventricular
myocardium.32 This relation may not hold in
slow fibers (eg, nodal cells) and in ischemic
myocardium in which membrane recovery may outlast
repolarization.51 52
Unlike reentrant VT in
chronically healed myocardial infarction, our VT
model is relatively simple. We made no attempt to incorporate several
factors that may have an important influence on the arrhythmogenic
substrate in patients, such as sympathetic stimulation,53
nonuniform anisotropy,36 and
endocardial-to-epicardial heterogeneities of repolarizing
currents.11 54 Our experimental model was
intentionally
designed to eliminate these confounding influences so that it would be
possible to study the independent effects of fiber orientation, circuit
geometry, and membrane repolarization on in a controlled fashion.
The effects of wave-front pivoting may be even more important in
reentrant VT after myocardial infarction in which the reentrant path is
tortuous and includes multiple pivot points. Further studies of
experimental systems such as ours that also incorporate these
additional complexities are required to provide a more complete
understanding of the mechanisms of VT in humans.
|
Selected Abbreviations and Acronyms |
|---|
|
|
Acknowledgments |
|---|
This work was supported by NIH grant HL-54807, the Whitaker Foundation, the Medical Research Service of the Department of Veterans Affairs, and a Grant-in-Aid from the American Heart Association, Northeast Ohio Affiliate. The authors thank Mark Cohen, MD, for his assistance with the preparation and interpretation of the histological specimens. Also, we thank M.A. Allessie, MD, for his helpful suggestions in the development of the guinea pig VT model.
|
Appendix |
|---|
|
TopAbstractIntroductionMethods Results Discussion Appendix References |
|---|
Since an optical action potential arises from an average of single cell potentials within a recording pixel, prolongation of optical action potential upstroke rise time can theoretically be caused by conduction slowing (ie, "blurring" of the upstroke within a pixel) and may not necessarily indicate depressed excitability or altered loading at the level of the single cell. To rule out this possibility, one can express the rise time measured from an optical action potential upstroke (RTop) in terms of the single-cell rise time (RTcell) and the conduction velocity (
) at a recording pixel of length (l) as
follows:
 |
Therefore, the single-cell rise time can be estimated from
 |
The
RTop measured at the pivot point of the
reentrant circuit (eg, site D in Fig 8,
RTop=14.5 ms) thus
corresponds to a single-cell rise time, RTcell=10 ms,
which is substantially longer than RTcell measured at
nonpivoting sites (eg, site A in Fig 8,
RTcell=2.0 ms).
Therefore, the upstroke slowing observed at the pivot points was not an
artifact of the optical recording technique but indeed
represented the membrane response at the level of the
single cell.
Received June 19, 1995; revision received September 1, 1995; accepted September 11, 1995.
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References |
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K. R. Laurita and A. Singal Mapping action potentials and calcium transients simultaneously from the intact heart Am J Physiol Heart Circ Physiol, May 1, 2001; 280(5): H2053 - H2060. [Abstract] [Full Text] [PDF]
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M. A. Allessie, P. A. Boyden, A. J. Camm, A. G. Kleber, M. J. Lab, M. J. Legato, M. R. Rosen, P. J. Schwartz, P. M. Spooner, D. R. Van Wagoner, et al. Pathophysiology and Prevention of Atrial Fibrillation Circulation, February 6, 2001; 103(5): 769 - 777. [Full Text] [PDF]
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J. M. Pastore and D. S. Rosenbaum Role of Structural Barriers in the Mechanism of Alternans-Induced Reentry Circ. Res., December 8, 2000; 87(12): 1157 - 1163. [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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 M. Valderrabano, Y.-H. Kim, M. Yashima, T.-J. Wu, H. S. Karagueuzian, and P.-S. Chen Obstacle-induced transition from ventricular fibrillation to tachycardia in isolated swine right ventricles: Insights into the transition dynamics and implications for the critical mass J. Am. Coll. Cardiol., November 15, 2000; 36(6): 2000 - 2008. [Abstract] [Full Text] [PDF]
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K. R. Laurita and D. S. Rosenbaum Interdependence of Modulated Dispersion and Tissue Structure in the Mechanism of Unidirectional Block Circ. Res., November 10, 2000; 87(10): 922 - 928. [Abstract] [Full Text] [PDF]
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S. B. Knisley, R. K. Justice, W. Kong, and P. L. Johnson Ratiometry of transmembrane voltage-sensitive fluorescent dye emission in hearts Am J Physiol Heart Circ Physiol, September 1, 2000; 279(3): H1421 - H1433. [Abstract] [Full Text] [PDF]
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F. H. Samie, R. Mandapati, R. A. Gray, Y. Watanabe, C. Zuur, J. Beaumont, and J. Jalife A Mechanism of Transition From Ventricular Fibrillation to Tachycardia : Effect of Calcium Channel Blockade on the Dynamics of Rotating Waves Circ. Res., March 31, 2000; 86(6): 684 - 691. [Abstract] [Full Text] [PDF]
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J.-M. Cao, Z. Qu, Y.-H. Kim, T.-J. Wu, A. Garfinkel, J. N. Weiss, H. S. Karagueuzian, and P.-S. Chen Spatiotemporal Heterogeneity in the Induction of Ventricular Fibrillation by Rapid Pacing : Importance of Cardiac Restitution Properties Circ. Res., June 11, 1999; 84(11): 1318 - 1331. [Abstract] [Full Text] [PDF]
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J. M. Pastore, S. D. Girouard, K. R. Laurita, F. G. Akar, and D. S. Rosenbaum Mechanism Linking T-Wave Alternans to the Genesis of Cardiac Fibrillation Circulation, March 16, 1999; 99(10): 1385 - 1394. [Abstract] [Full Text] [PDF]
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T. Uchida, M. Yashima, M. Gotoh, Z. Qu, A. Garfinkel, J. N. Weiss, M. C. Fishbein, W. J. Mandel, P.-S. Chen, and H. S. Karagueuzian Mechanism of Acceleration of Functional Reentry in the Ventricle : Effects of ATP-Sensitive Potassium Channel Opener Circulation, February 9, 1999; 99(5): 704 - 712. [Abstract] [Full Text] [PDF]
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E. Robert, A. G. M. Aya, J. E. de la Coussaye, P. Peray, J.-M. Juan, J. Brugada, J.-M. Davy, and J.-J. Eledjam Dispersion-based reentry: mechanism of initiation of ventricular tachycardia in isolated rabbit hearts Am J Physiol Heart Circ Physiol, February 1, 1999; 276(2): H413 - H423. [Abstract] [Full Text] [PDF]
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K. R. Laurita, S. D. Girouard, F. G. Akar, and D. S. Rosenbaum Modulated Dispersion Explains Changes in Arrhythmia Vulnerability During Premature Stimulation of the Heart Circulation, December 15, 1998; 98(24): 2774 - 2780. [Abstract] [Full Text] [PDF]
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T.-J. Wu, M. Yashima, F. Xie, C. A. Athill, Y.-H. Kim, M. C. Fishbein, Z. Qu, A. Garfinkel, J. N. Weiss, H. S. Karagueuzian, et al. Role of Pectinate Muscle Bundles in the Generation and Maintenance of Intra-atrial Reentry : Potential Implications for the Mechanism of Conversion Between Atrial Fibrillation and Atrial Flutter Circ. Res., August 24, 1998; 83(4): 448 - 462. [Abstract] [Full Text] [PDF]
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Y. Y. Kwan, W. Fan, D. Hough, J. J. Lee, M. C. Fishbein, H. S. Karagueuzian, and P.-S. Chen Effects of Procainamide on Wave-Front Dynamics During Ventricular Fibrillation in Open-Chest Dogs Circulation, May 12, 1998; 97(18): 1828 - 1836. [Abstract] [Full Text] [PDF]
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N. S. Peters, J. Coromilas, M. S. Hanna, M. E. Josephson, C. Costeas, and A. L. Wit Characteristics of the Temporal and Spatial Excitable Gap in Anisotropic Reentrant Circuits Causing Sustained Ventricular Tachycardia Circ. Res., February 9, 1998; 82(2): 279 - 293. [Abstract] [Full Text] [PDF]
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T. Ikeda, M. Yashima, T. Uchida, D. Hough, M. C. Fishbein, W. J. Mandel, P.-S. Chen, and H. S. Karagueuzian Attachment of Meandering Reentrant Wave Fronts to Anatomic Obstacles in the Atrium : Role of the Obstacle Size Circ. Res., November 19, 1997; 81(5): 753 - 764. [Abstract] [Full Text]
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K. R. Laurita, S. D. Girouard, and D. S. Rosenbaum Modulation of Ventricular Repolarization by a Premature Stimulus: Role of Epicardial Dispersion of Repolarization Kinetics Demonstrated by Optical Mapping of the Intact Guinea Pig Heart Circ. Res., September 1, 1996; 79(3): 493 - 503. [Abstract] [Full Text]
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A. W.C. Chow, R. J. Schilling, D. W. Davies, and N. S. Peters Characteristics of Wavefront Propagation in Reentrant Circuits Causing Human Ventricular Tachycardia Circulation, May 7, 2002; 105(18): 2172 - 2178. [Abstract] [Full Text] [PDF]
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