(Circulation. 1999;99:704-712.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Mechanism of Acceleration of Functional Reentry in the Ventricle
Effects of ATP-Sensitive Potassium Channel Opener
From the Division of Cardiology, Burns and Allen Research Institute, Cedars-Sinai Medical Center, and the Department of Medicine, Division of Cardiology, UCLA School of Medicine, Los Angeles, Calif.
Correspondence to Hrayr S. Karagueuzian, PhD, Cedars-Sinai Medical Center, Davis Research Bldg, Room 6066, 8700 Beverly Blvd, Los Angeles, CA 90048. E-mail karagueuzian{at}csmc.edu
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Abstract |
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Background—The effect of effective refractory period (ERP) shortening on the vulnerability and characteristics of induced functional reentry in the ventricle remain poorly defined. We hypothesized that ERP shortening increases ventricular vulnerability to reentry and accelerates its rate, as is the case in the atrium.
Methods and Results—The epicardial surfaces of 19 isolated and superfused canine right ventricular slices (4x4 cm and <2 mm thick) were mapped with 480 bipolar electrodes 1.6 mm apart. Vulnerability was tested during pacing at a cycle length (CL) of 600 ms and with a single premature stimulus of 5-ms duration at increasing current strength of 1 to 100 mA. Cromakalim (10 µmol/L), an ATP-sensitive potassium channel opener, caused a significant (P<0.001) shortening of the ERP but had no effect on conduction velocity. Cromakalim increased (P<0.01) the vulnerability (product of current and the stimulus coupling interval) for reentry induction. Reentry had a significantly shorter CL and lasted for a longer duration (P<0.001). The central core around which the wave front rotated became smaller, which caused shortening of the CL of reentry. A significant (P<0.001) linear correlation was found between core size and reentry CL. These effects of cromakalim were reversible. Two-dimensional simulation studies using the modified Luo-Rudy I model of cardiac action potential, in which the refractory period was variably shortened by a progressive increase of the time-independent potassium conductance, reproduced the experimental findings.
Conclusions—ERP shortening by an ATP-sensitive potassium channel opener increases ventricular vulnerability to reentry and accelerates its rate by decreasing the core size around which the wave front rotates.
Key Words: reentry • tachycardia • potassium • cromakalim • waves
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Introduction |
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The role of ATP-sensitive potassium (K-ATP) channel openers in the genesis (vulnerability) of ventricular reentrant wave fronts remains undefined.1 Although this class of agents shortens action potential duration (APD) and the effective refractory period (ERP),1 2 3 as in myocardial ischemia and hypoxia,4 the influence of these agents on ventricular vulnerability to functional reentry (spiral wave)5 formation by an S2 stimulus remains poorly explored, as do the characteristics of the induced spiral wave. Spiral-wave theory predicts that shortening of the ERP shortens the period of the spiral wave by decreasing the core size around which rotation occurs.6 In accordance with this theory, atrial tissue studies7 8 showed that acetylcholine-induced shortening of the ERP accelerates the rate of functional reentry, increases the vulnerability of the atrium to a premature stimulus, and increases the duration of the induced activity. In the present study, we hypothesized that shortening of the ERP by cromakalim, a K-ATP channel opener, would increase ventricular vulnerability to reentry and accelerate its rate.
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Methods |
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Tissue Preparation
All experiments were performed in accordance with US Public Health Service guidelines for the care and use of laboratory animals. Seventeen mongrel dogs of either sex weighing between 23 and 28 kg were anesthetized with sodium pentobarbital 35 to 40 mg/kg IV. The hearts were removed through a midsternal approach and placed in cold, oxygenated Tyrode's solution.8 9 10 An epicardial "sheet" <2 mm thick and 3.8x3.2 cm wide was taken from the right ventricle as described previously.9 11 The epicardial sheets were then mounted in a tissue bath either face down9 or face up for action potential recordings (see below).9 10
Excitability and Vulnerability Measurements
Bipolar electrodes 2 mm apart (silver–silver chloride)
were used to pace the tissues. Regular stimuli
(S1) at a cycle length of 600 ms and of 5 ms
duration with increasing current strength starting at 0.1 mA were
applied until 1-to-1 capture occurred. This current defined the
diastolic excitability current threshold (DET). To induce
reentry and generate strength-interval plots,8 9 a
premature (S2) stimulus (similar electrode as the
S1) with increasing current strengths (1 to 100
mA) and decreasing coupling intervals was applied 1.5 to 2 cm distal to
the S1 site along the long axis of the fiber
orientation.
Determination of the Excitable Gap
During reentry, trains of stimuli (2 to 5 mA) were given at the
S1 site, and action potentials were recorded
2 to 4 mm away at baseline (n=3) and during cromakalim (n=2).
The difference between the cycle length of the reentry and the shortest
captured interval was taken as the duration of the excitable
gap.8 12
Mapping-Electrode Plaque
The plaque electrode array (3.8x3.2 cm, consisting of 480
bipolar electrodes 1.6 mm apart) was described
previously.8 9 12 13 In 5 tissues, the plaque array was
placed on the epicardial surface with a micromanipulator for action
potential recordings after mapping.9
Action Potential Recordings
Transmembrane action potentials were recorded with glass
capillary electrodes made from the most superficial epicardial cell
layers.9 10 14 Data were stored at 1 kHz by use of Axotape
2.0 software (Axon Instruments, Inc).9 10 14
Construction of Computerized Isochronal Activation
Maps
A custom-made, 509-channel computerized mapping system, EMAP
(Uniservices) was used to construct isochronal activation
maps.8 9 10 12 15 16
Method of Dynamic Display of Activation Wave Fronts
After manual editing of activation times, the pattern of
activation was visualized
dynamically.8 9 10 12 16 An activated site first
illuminates red, then yellow, then green, and then it fades away. Each
illumination was selected to persist for 8 ms.
Method of Measuring the Core of the Reentrant Wave Front
During dynamic display, we traced the trajectory of the tip (ie,
the innermost edge) of the reentry by advancing its motion 10 ms at a
time until the front made a complete rotation. The perimeter traced by
the tip trajectory defined the core of the
reentry.8 12 13 16 The computer then counted the number of
1.6-mm-apart electrodes encircled by the tip and calculated the core
perimeter and its surface.16
Cromakalim Superfusion
At the end of control studies, the effects of 10 µmol/L
cromakalim (Beecham Pharmaceuticals)2 4 on vulnerability
to reentry by an S2 (n=5), action potential, and
reentry characteristics were tested 20 minutes after superfusion
(n=6).
Histological Analysis
At the conclusion of the studies, all tissues were fixed in 10%
formalin and stored in a refrigerator.8 12 Five to 8
different transverse sections within the mapped regions were made and
stained with hematoxylin and eosin.12
Simulation Studies
Computer simulation was performed in 2x2-cm tissues by use of
the following continuous cable equation
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· cm is intracellular
resistance in the longitudinal direction,
Ry=3.125 k · cm is intracellular
resistance in the transverse direction (anisotropic ratio of 2.5), V
(in mV) is the potential, and ILR is the
total ionic current density from the phase I Luo-Rudy (LR)
model.17 The cable equation is integrated by an
algorithm that uses operator splitting and time-adaptive integration
methods developed by us (Z.Q. and A.G., unpublished data, 1998).
The differential equations of the gating variables were integrated
by the method developed by Rush and Lasen.18 The remaining
numerical integrations of the differential equations were done by the
forward Euler method, with a space step equal to 0.02 cm and a
variable time step ranging from 0.01 to 0.1 ms. The tissue was
discretized into 200x200 space units, with "no-flux"
boundary conditions. We found that the following modifications of the
LR model were necessary to make the induced spiral wave stationary to
measure the core size. GNa was made equal to 16
mS/cm2, Gsi=0, and the j gate was
clamped to 1. The effects of different degrees of shortening of the APD
on the spiral-wave period were evaluated by the progressive increase in
the maximum conductance of the time-independent potassium channel (GK1)
from 0.0 to 0.6047 mS/cm2 (Table 2
). A
spiral wave was induced by cross-field stimulation,5
and core size was measured after each increment of GK1, as described
above (n=5).
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Statistical Analysis
Student's t test was used to compare the APD, DET,
ERP, S1-S2 intervals,
current strengths, mean cycle length, and core size before and after
cromakalim.8 10 Linear regression analysis
was done to correlate the length of the linear core to the reentry
cycle length, both in experiments and in simulations with StatView 4.5
and GB-STAT statistical software.8 19 Results are
expressed as mean±SD. A value of P<0.05 was considered
significant.
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Results |
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Effects of Cromakalim on Epicardial Transmembrane Action Potentials
Within 20 minutes, 10 µmol/L cromakalim superfusion shortened the APD from a mean of 158±15 to 48±7 ms (P<0.0001, n=6). Shortening of the APD was associated with a significant (P<0.001) shortening of the ERP from 139±12 to 45±8 ms (n=6)3 4 and no change of the DET (0.4±0.3 versus 0.6±0.4 mA) (Table 1
).
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Effects of Cromakalim on Conduction
Figure 1 shows
simultaneous action potential recordings from 2
epicardial cells before (A) and after (B) cromakalim. Conduction time
between these 2 cells and the total tissue activation time were similar
before and after cromakalim, which is compatible with previous
results.20 In all 7 tissues that we mapped, neither
conduction slowing nor block was observed before or after cromakalim,
which indicates the absence of drug effect and anatomic obstacles. The
propagation, however, was somewhat nonuniform and anisotropic, with
significantly (P<0.01) faster speed along (64±14 cm/s)
than across (26±10 cm/s) the fiber (anisotropic ratio of 2.5).
Cromakalim had no significant effect on conduction velocity during
regular pacing (Figure 1) either along (63±17 cm/s) or across
(24±13 cm/s) the fiber orientation (n=6).
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Cromakalim and Vulnerability to Reentry Induction
The induction of reentry with an S2
stimulus before and after cromakalim critically depended on the
S1-S2 coupling interval and
on the strength of the S2 current. No reentry
could be induced outside these critical time-zone intervals regardless
of the S2 current strength (Table 1
). The
bounded nature (rectangular) of ventricular vulnerability
to S2 is consistent with our previously
published results in canine9 and swine16
isolated and superfused epicardial thin ventricular slices.
Cromakalim significantly (P<0.05) increased the mean
product of the vulnerable period and the current strengths (area of
the rectangle, in mA-ms units) from 1551±1057 to 2597±1159.
Effects of Cromakalim on Induced Reentrant Wave-Front
Characteristics
Cromakalim accelerated the rate of the reentry, decreased its core
size, and maintained its activity longer.
Acceleration
Cromakalim significantly (P<0.001) decreased the cycle
length of induced reentry from 185±31 to 90±24 ms (27 episodes, 11
tissues). Figure 2 shows a dynamic
display of an induced reentrant wave front before and after cromakalim.
The wave front rotated along a line of functional conduction block that
was parallel to the long axis of the fiber orientation during control
and after cromakalim superfusion. Reentry remained stationary for
several consecutive reentrant cycles, as evidenced by the fact that the
tip trajectories of consecutive reentrant activation were
superimposable. Figure 3 is an
isochronal activation map of the same reentry episode shown in
Figure 2. The longer central core (central site of functional
block) during control compared with cromakalim is evident. The
direction of the rotation—clockwise (16 episodes) or counterclockwise
(11 episodes)—had no influence on the reentry cycle length either
before or after cromakalim.
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Core Size
A major difference between the reentry circuit at baseline
compared with that after cromakalim was the size of the central
elliptic core around which the front rotated. Although linear
functional conduction block was present in both cases, the length
of the line of functional conduction block was significantly longer
during control (Figures 2 and 3A) than during cromakalim
(Figures 2 and 3B). In both cases, rotation occurred in an
elliptical pathway that roughly inscribed the perimeter of a rectangle
with a width equal to 1 interelectrode distance or 1.6 mm (Figure 2). The mean length of the line of functional conduction block
was significantly (P<0.01) longer during control
(15.3±4 mm) than after cromakalim (6.9±2.1 mm). Cromakalim
significantly decreased the core area, from 25.2±6.7 to 12.9±2.9
mm2 (P<0.01). A significant
(P<0.01) positive linear correlation (correlation
coefficient of 0.89) was present between the length of the line of
functional block (L, in mm) and the reentry cycle length (CL, in
ms):
CL(ms)=63+7.9xL(mm).
During reentry, cromakalim did not change conduction velocity around the core, measured as the ratio of core perimeter and reentry period (12.2±2.3 versus 13.2±2.1 cm/s; P=NS).
Facilitation and Reproducibility
In 4 tissues, once reentry was induced by an
S2 stimulus, 10 consecutive trials of the same
S2 stimulus were tested for reproducibility to
reinitiate reentry. For this purpose, after reentry was terminated, the
same S2 stimulus was tested for a total of 40
trials before and 40 trials after cromakalim. During control, reentry
was induced in 11 (27%) of the 40 trials, whereas after cromakalim,
reentry was induced in 36 (90%) of the 40 trials
(P<0.001). In 2 tissues exposed to cromakalim, reentry was
induced during regular pacing at a cycle length of 400 ms with twice
diastolic current threshold, a phenomenon never observed at
baseline.
Duration
During control, induced reentry had a short life span. It often
terminated within 10 cycles after its induction, with a mean life span
of 2.5±0.3 seconds. In nearly all episodes, reentry terminated when
the core of an otherwise stationary reentry drifted to the tissue
border. Reentry was stationary in only 2 tissues and lasted for 8 and
12 minutes, respectively. In these 2 episodes, we estimated the
excitable gap duration (see below). In the presence of cromakalim,
reentry lasted significantly (P<0.001) longer in each
tissue studied. The mean duration of reentry after cromakalim was
9±1.2 minutes (range, 30 seconds to 32 minutes).
Excitable Gap
Figure 4 shows action potential
recordings during the induction of reentry by an
S2 stimulus. A distinct phase 4
diastolic interval is present between 2 consecutive
reentrant beats before and after cromakalim. This suggests the presence
of an excitable gap. The introduction of premature stimuli showed early
diastolic capture between 2 reentrant beats. Figure 5 illustrates early capture (34% of the
reentry cycle) in 1 of the 2 long episodes of induced reentry at
baseline and after cromakalim (54% of reentry cycle). A fully
excitable gap was present during reentrant excitation before and
after activation of the K-ATP channels.
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Reversal of the Effect of Cromakalim
No sustained reentry could be induced after 60 to 90 minutes of
superfusion with cromakalim-free Tyrode's solution (n=3)
(Figure 6). Only short runs of reentry (3
to 8 cycles) could be induced within a narrow range of
S2 current strengths, as was the case at baseline
(Figure 6). The APD and ERP lengthened from a mean of 64±13 to
158±22 ms and from 43±8 to 127±12 ms, respectively
(P<0.01; 9 sites tested in 3 tissues) (Figure 6).
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Histology
Histological analysis of the
hematoxylin-and-eosin–stained tissue sections showed no signs of
cellular necrosis or autolysis throughout the entire thickness of the
isolated slices. The lines of functional block occurred across the long
axis of the myocardial fibers.
Computer Simulation: Effects of APD Reduction on Spiral-Wave
Dynamics
Figure 7 shows an induced rotating
spiral wave before (A) and after (B) reduction of the APD by increasing
the GK1 from 0.12094 to 0.6046 mS/cm2. Shortening of
the APD consistently resulted in shortening of the spiral-wave
period, with a concomitant reduction of the central core size around
which the spiral rotated (Table 2). The
core had an ellipsoid shape in accord with the anisotropic
medium.5 A progressive shortening of the APD was achieved
by progressively increasing (7 values) GK1 (Table 2). Simple
linear regression analysis between the length of the major axis
of the ellipse (x axis) and the period (cycle length) of the
spiral (y axis) showed a significant (P<0.001)
correlation, with a 0.98 correlation coefficient: CL=25.98+6.9xL,
where CL is the spiral period in milliseconds and L is the length of
the major axis of the ellipse in millimeters.
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Discussion |
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Acceleration of induced functional reentry with cromakalim and maintenance of the reentry for a longer duration after activation of K-ATP channels constitute the major findings of the present study. Simulation replicated the experimental findings: acceleration of the reentry period was associated with a decrease in the core size.
Increased Vulnerability
The effects of cromakalim on ventricular tissue are
similar to the effects of acetylcholine on atrial
tissue.7 8 21 Whereas the wavelength varies along
different segments of reentrant circuits,22 the overall
shortening of the wavelength increases the chances of incorporating a
reentrant wave front in a given tissue mass, a phenomenon described as
"pharmacologic enlargement" of tissue mass.7 Because
conduction velocity did not change after cromakalim, it is likely that
in our isolated muscles exposed to cromakalim, the shorter wavelengths
led to greater vulnerability to reentry.23 Increased
tissue vulnerability to reentry induced by shortening of the wavelength
has also been suggested to maintain reentry for a longer
duration,23 whereas increasing the wavelength had an
opposite effect.23 24 Chi et al25 showed in
in situ hearts that pinacidil, a K-ATP channel opener, increased
ventricular vulnerability to fibrillation in a canine model
of sudden cardiac death. Similar profibrillatory and increased
vulnerability to reentry by K-ATP channel openers was also reported in
rabbit hearts.20
Mechanism of Acceleration of Reentry
Acceleration of reentry was consistently associated with a
decrease of the central core size, both in tissue and in simulation
studies. The shorter path length needed for completion of a full
rotation while the speed of the propagation remained unchanged led to
reentry acceleration. We could not ascribe reentry acceleration to
cromakalim-induced removal of incomplete recovery of excitability in
the reentrant circuit26 because there was a fully
excitable gap when cromakalim was absent. However, because stimulated
beats during reentry did not advance the return cycle, it is possible
that a partially excitable gap might be present soon after
repolarization. Double-wave reentry27 as a mechanism of
acceleration is refuted because acceleration occurred with a single-
and not a double-arm reentry. Functional reentry in the ventricle is
compatible with a spiral wave of excitation.5 9 11 16 28
The spiral-wave theory predicts that a decrease in the APD or ERP
causes the core size to shrink.6 Simulation studies using
a relatively realistic ventricular cell action potential
model17 reproduced the experimental findings. Although
increasing GK1 is not a realistic representation of cromakalim
effect, it nevertheless provided the desired shortening effect on the
APD and systematic evaluation of its impact on spiral period and core
size. Our simulation studies in an isotropic medium also showed a
positive linear correlation between core size and spiral period with
GK1 changes (data not shown). Faster rotation periods around smaller
cores were observed in normal hearts28 and in the
epicardial border zone of healed myocardial infarcts.29 In
atrial tissues, acetylcholine-induced acceleration of functional
reentry is also consistent with core-size
reduction.10 Although our findings are made essentially
with regard to 2-dimensional spiral waves, the possibility of similar
effects of APD on the 3-dimensional scroll wave is raised by our recent
findings using procainamide.30 We found that
procainamide, while increasing the refractory period, also
increases the core size and prolongs the period of functional reentry
in in situ hearts (scroll wave) during ventricular
fibrillation.30 Although our results show that ERP
shortening accelerates the 2-dimensional spiral-wave period by
core-size reduction, more work is needed to clarify this issue in
3-dimensional scroll waves.
Maintenance of Reentry
Termination of reentry often occurs when the core drifts to the
edge of the tissue and dies out.5 8 12 16 In the presence
of cromakalim, reentry remained stationary, and the core did not drift
toward the edge of the tissue. Core stationarity might explain the
longer maintenance of the reentry. The mechanism of
cromakalim-induced stationarity is unknown. It is possible that the
drug might eliminate the excitability gradient, a driving force that
promotes spiral core drift.5
Study Limitations
It could be argued that in the superfused model, the lack of
adequate perfusion in cells >600 µm thick31 may
cause progressive changes in the deeper cell layers, confounding the
effects of cromakalim. However, the reversibility of the effects of
cromakalim, both with respect to reentry vulnerability and epicardial
cell action potential properties, suggests that superfusion with
oxygenated Tyrode's solution over both surfaces of the
thin epicardial slices kept the tissue viable. The use of the area of a
rectangle (product of current times interval) may be argued to
overestimate vulnerability. However, its substantial increase (40%)
after cromakalim indicates that the method, despite its pitfalls,
provides a useful index for quantitative comparison.8 9
Our method of measuring the excitable gap clearly showed that
functional reentry was not devoid of an excitable gap, because
premature stimuli could capture the tissue. It is, however, possible
that both partially (early after repolarization) and fully (late in
diastole) excitable gaps might be present in the
functional reentrant circuit. Finally, testing our hypothesis required
formation of spirals with stationary cores, a requirement that was met
by modifying the original LR model. Although the maximum conduction
velocity and resting properties did not change in the modified model,
APD restitution and conduction velocity did. A recent
study32 emphasized the need for such changes for the
induction of a stationary core.
Clinical Significance
The ability of cromakalim to accelerate and increase the upper
limit of vulnerability for the induction of reentry might have clinical
relevance. With the increased clinical use of potassium channel openers
in the treatment of angina, hypertension, and asthma, their potential
to accelerate reentry may convert reentrant ventricular
tachycardia to ventricular
fibrillation.25 29 The clinical significance of these
agents in increasing the upper limit of vulnerability remains to be
elucidated.
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Acknowledgments |
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This study was supported in part by a National Institutes of Health (NIH) SCOR grant (HL-52319), an NIH FIRST Award (HL-50259), the Cedars-Sinai ECHO Foundation, the Ralph M. Parsons Foundation (Los Angeles, Calif), an American Heart Association (AHA) National Center Grant-in-Aid (9750623N), an AHA Wyeth-Ayerst Established Investigatorship Award, and the UC Tobacco Related Disease Research Program (6RT-0020). We thank P.K. Shah, MD, for his support, Avile McCullen and Mei Ling Yuan for technical assistance, and Elaine Lebowitz for secretarial assistance.
Received April 15, 1998; revision received September 15, 1998; accepted September 25, 1998.
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