© 1999 American Heart Association, Inc.
Original Contributions |
Spatiotemporal Heterogeneity in the Induction of Ventricular Fibrillation by Rapid Pacing
Importance of Cardiac Restitution Properties
From the Division of Cardiology, Department of Medicine, Cedars-Sinai Medical Center (J.-M.C., Y.-H.K., T.-J.W., H.S.K., P.-S.C.), and the Departments of Medicine (Cardiology), Physiology, and Physiological Science (Z.Q., A.G., J.N.W.), UCLA School of Medicine, Los Angeles, Calif.
Correspondence to Peng-Sheng Chen, MD, Rm 5342, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048-1865. E-mail chenp{at}ucla.edu
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Abstract—The mechanism by which rapid pacing induces ventricular fibrillation (VF) is unclear. We performed computerized epicardial mapping studies in 10 dogs, using 19-beat pacing trains. The pacing interval (PI) of the first train was 300 ms and then was progressively shortened until VF was induced. For each PI, we constructed restitution curves for the effective refractory period (ERP). When the PI was long, the activation cycle length (CL) was constant throughout the mapped region. However, as the PI shortened, there was an increase in the spatiotemporal complexity of the CL variations and an increase in the slope of the ERP restitution curve. In 5 dogs, we documented the initiation of VF by wavebreak at the site of long-short CL variations. Computer simulation studies using the Luo-Rudy I ventricular action potential model in simulated 2-dimensional tissue reproduced the experimental results when normal ERP and conduction velocity (CV) restitution properties were intact. By altering CV and ERP restitutions in this model, we found that CV restitution creates spatial CL variations, whereas ERP restitution underlies temporal, beat-to-beat variations in refractoriness during rapid pacing. Together, the interaction of CV and ERP restitutions produces spatiotemporal oscillations in cardiac activation that increase in amplitude as the PI decreases, ultimately causing wavebreak at the site of intrinsic heterogeneity. This initial wavebreak then leads to the formation of spiral waves and VF. These findings support a key role for both CV and ERP restitutions in the initiation of VF by rapid pacing.
Key Words: chaos • restitution curve • wavebreak • anatomical obstacles • bifurcation
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The mechanisms responsible for ventricular fibrillation (VF) are the subject of continued interest. First, it is generally believed that spatial dispersion of electrophysiological properties such as refractoriness is the chief cause of VF.1 Second, a number of clinical2 and experimental3 studies have correlated VF with the presence of alternans, particularly in the T wave. Other investigators4 5 6 have proposed a causal role for alternans in the genesis of VF and have suggested that the alternans is due in turn to the property known as action potential duration (APD) restitution, which relates an APD (or equivalently, the effective refractory period [ERP]) to the preceding diastolic interval (DI).
This paper investigates the interrelations among these phenomena in the context of VF induced by rapid pacing. We show that, in this model, VF is created by wavebreak, which is in turn caused by spatiotemporal inhomogeneities created by the restitution of ERP and conduction velocity (CV).
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Surgical Preparation
The research protocol was approved by the Institutional Animal Care and Use Committee of Cedars-Sinai Medical Center and followed the guidelines of the American Heart Association. Ten adult mongrel dogs were anesthetized with 25 to 35 mg/kg sodium pentobarbital, intubated, and ventilated with room air by a respirator (Harvard Apparatus). An arterial line was inserted into the right femoral artery to continuously monitor systemic blood pressure. Blood was drawn to determine the pH, PO2, PCO2, base excess, and bicarbonate concentrations. Normal metabolic status was actively maintained throughout the study. A venous line was inserted to infuse saline and to give supplemental doses of pentobarbital. Rectal temperature was monitored and maintained at 36°C to 37°C by heating the table with warm circulating water. The chest was opened through a median sternotomy, and the heart was suspended in a pericardial cradle. In 3 dogs, we performed atrioventricular node ablation with radiofrequency energy under fluoroscopic guidance. The purpose was to decrease the heart rate so that we could determine the restitution curve at slower heart rates, with longer DIs.
Recording Electrodes
For epicardial mapping, a recording sock electrode array
was constructed by fixing stainless steel electrode wires (0.4 mm
in diameter) to the inner surface of a nylon "sock." The
uninsulated ends of the electrode wires served as the recording
electrodes (Figure 1A
and 1B). The
electrode array included 125 bipolar electrodes, with the
interelectrode distance varying from 8 to 10 mm. In addition, 3
channels of surface ECG were also recorded. In all 10 experiments,
the sock was pulled over the ventricular surface for global
epicardial mapping.
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For high-density epicardial mapping over a small region of the
epicardial surface, a recording plaque electrode array was
constructed using similar stainless steel wires. This plaque electrode
array included 478 bipolar electrodes (Figure 1C
) plus 2 ECG leads. The
wires were fully insulated except at the tips, which served as the
tissue contact points. The interelectrode distance was 1.6 mm, and
the interpolar distance was 0.5 mm, measured from center to
center. In 5 of the 10 dogs, mapping studies were performed with both
the plaque electrode array sutured to the right ventricle and septum,
and the sock electrode array pulled over the entire epicardium.
Pacing Protocol
The hearts were paced with cathodal (unipolar) stimuli of 3
times the diastolic threshold current. Unipolar pacing was
used because it is associated with a monotonic strength-interval
curve.7 8 The pacing interval (PI) started at 300 ms and
then was progressively shortened, in 20-ms increments to 200 ms, and
then in 10-ms increments until VF was induced. A PI of 250 ms was also
used for each dog. Each pacing train included 19 beats. There was an
interval of at least 20 seconds between pacing trains. The pacing sites
were at the left ventricular apex and the right
ventricular base. For the 5 dogs in which plaque electrodes
were used, pacing was performed from the left ventricular
apex, the right ventricular base, and the center of the
plaque. If VF was induced, a 25-J shock was delivered to the left and
right ventricles for defibrillation. The heart was allowed to recover
for at least 5 minutes before the resumption of data acquisition.
Construction of the Effective Refractory Period Restitution
Curve
ERPs were measured at the pacing sites, which were either at the
left ventricular apex or at the right
ventricular base. Multiple baseline pacing (S1)
cycle lengths were used. The protocol was as follows. After 8
(S1) stimuli at 600-ms (dogs with complete heart block) or
400-ms (other dogs) cycle lengths (CLs), a premature stimulus
(S2) was given to test the ERP. The current strength for
both S1 and S2 was twice the
diastolic threshold with a pulse duration of 5 ms. If the
S2 captured the ventricle, the
S1–S2 interval was decreased by 10 ms and the
test was repeated. If the S2 failed to capture the
ventricle, the S1–S2 interval was increased by
10 ms, and the test was repeated at 2-ms decrements of
S1–S2 interval until S2 failed to
capture. The longest S1–S2 interval associated
with S2 noncapture was the ERP for that S1 CL.
The DI was estimated by the difference between the S1 CL
and the ERP.
To determine the ERP and the DI at multiple S1 CLs, the S1 CL was progressively decreased by 50-ms increments between 600 and 300 ms, then by 20-ms increments between 300 and 200 ms, and then by 10-ms increments when the CL was <200 ms, until 1:1 capture by S1 was lost or VF was induced. The ERP and DI were determined for each S1 CL. The ERP restitution curve was constructed by plotting ERP against its DI.
Data Analyses
The method of determining the times of activation from the
bipolar electrogram has been reported in detail
elsewhere.9 10 Once the activation times were selected,
the patterns of activation were displayed dynamically10 or
by isochronal activation maps.9
Construction of Isodeviation Maps of Cycle Lengths
The PI is the interval between 2 baseline-pacing outputs. The
activation CL is the interval between 2 consecutive activations
registered by the recording system. The activation time of each
deflection was selected by the computerized mapping system according to
a dV/dt criterion.9 Manual editing was then performed to
eliminate the selection of noise or artifacts. The activation CL was
then calculated as the temporal difference of 2 consecutive
activations. The CL deviation was defined as the difference between the
activation CL registered at each recording channel and the
corresponding PI. A negative value at a given site indicates that the
activation CL is shorter than the PI, whereas a positive value
indicates that the activation CL is longer than the PI. The mean
activation CL during pacing at 300 ms averaged 299.7±3.1 ms
(mean±SD). On the basis of these data, a recording channel was
deemed to have "significant" CL variation if it varied by 
15 ms
(
5xSD of the activation CL at 300-ms PI). We then analyzed
the number of myocardial sites (channels) with significant CL
variations during each pacing episode. The global pattern of CL
variation was estimated by constructing isodeviation maps. The value of
CL deviation registered at each recording site was used by the
computer to generate an isodeviation map. By this method, the
spatiotemporal variation of the CLs could be visualized over the entire
mapped region.
Measurement of Conduction Time (CT)
We calculated the CT of the wave fronts that propagated from the
pacing site in the center of the plaque (channel 180 in Figure 1C)
straight down to the bottom edge of the electrode plaque (channel 474
in Figure 1C), which covers a distance of 22.4 mm. The CT was the
time between activations at channels 180 and 474. However, the distance
that the activation wave front traveled between 2 epicardial points may
be longer than the absolute distance between these 2 points, as the
front may follow alternate route(s), such as the specialized conduction
system.11 Because of this limitation, the conduction
velocity cannot be accurately measured in this study.
Statistical Analysis
All statistical analyses were performed using the
GB-STAT program.12 Results are expressed as mean±SD.
Student t tests were used to compare means. ANOVA and
Newman-Keuls tests were used to compare the percentage of electrodes
showing significant CL variation at different PIs. The null hypothesis
was rejected at a value of P
0.05. For the ERP restitution
curve, the data were fit to an exponential curve, which was then
differentiated to estimate slopes.
Computer Simulations
Our mathematical model begins with the model of the cell, in
Hodgkin-Huxley form:
 | (1) |
 | (2) |
x and y are the transverse and
longitudinal resistivities. We set Cm = 1
µF/cm2, Sv=2000
cm-1, and x=y=0.5k
cm.
(Some sources use Sv=5000 cm-1 and
x=y=0.2kcm.)14 15 16
We simulated a 7.5x7.5-cm tissue, using a 300x300 grid, with
"no-flux" boundary conditions., ie,
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where L=7.5 cm is the length of the side of the square. To match
the experimental data more quantitatively, we altered the relaxation
time constant of the j, d, and f gates, and ion channel conductance, as
discussed in the figure legends. We also changed the maximum
Na+ channel conductance19 from
GNa=23 µS/cm2 to
GNa=16 µS/cm2. These changes yielded an
APD90 of 200 ms and a CV of 0.56 m/s for a planar
wave front, at a PI of 1000 ms. To model a small inhomogeneity in
refractoriness, we chose a 2.5x0.75-cm area near the center of the
tissue and increased APD by 10% in that area by changing the
maximum calcium channel conductance Gsi.
Details of the changes to Gsi are in the
figure legends. APD restitution and CV restitution were obtained by
simulating a 1-dimensional cable equation15 16 with the
pacing site at one end of the cable and a no-flux boundary condition at
the other end. By progressively decreasing the PI, we obtained the
restitution curves.
We integrated Equation 1 numerically, using an operator-splitting
method.17 We then integrated the reaction term using a
second-order Runge-Kutta method with an adaptive time step, which
depended on the derivative of voltage, and integrated the diffusion
term with an alternating-direction implicit method to guarantee
numerical stability. The adaptive time step varied from 0.01 to 0.2 ms.
The diffusion term was integrated with the time step 0.2 ms to keep all
cell synchronized. Numerical simulations showed that the error
introduced by the variable time step was <2% (authors'
unpublished data, 1999). The space step was set at 0.025 cm. All
simulations were carried out on a 433-MHz DEC Alpha workstation. To
ensure that our space step was small enough to prevent artifactual
results, we checked the critical simulations (eg, Figure 10) using a
space step of 0.015 cm; the results differed only slightly.
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Pacing-Induced CL Variability and CL Alternans in Time
In all dogs studied, shortening the PI resulted in a progressive increase in temporal and spatial variability of CL. Whereas the PI that induced VF (the "VF threshold" [VFT]) varied from animal to animal (mean, 174±28 ms; range, 230 to 140 ms), the magnitude of spatiotemporal inhomogeneity needed for VF induction was similar. When the heart was paced at relatively long intervals (
250 ms), little
variation in CL was registered by any of the recording
electrodes, but when the PI was gradually shortened, CL variations
began to increase. Figure 2 shows a
typical example from one bipolar recording electrode in one
animal. VF always occurred with PIs of 180 ms in this dog.
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Note that when the PI shortened to 200 ms, the CL developed alternans.
Further shortening of the PI to 190 ms resulted in more complex
variations. The number of recording electrodes that developed
significant CL variation also increased (see below). In all animals
studied, the longest PIs associated with any significant CL variation
ranged from 240 to 220 ms (mean 226±16 ms). Figure 2B shows the
bipolar electrograms from the same episodes as in Figure 2A. When the
PI was 300 to 250 ms, significant CL and/or morphology variations were
rarely observed. As the PI shortened, both morphology and CL variations
developed. When the PI shortened to 200 and 190 ms, transient
complicated patterns of CL and morphology variations were usually
present in the beginning of the pacing run. The patterns then
settled into stable alternans toward the end of the pacing run. (Figure 2A shows only paced beats 10 to 19.) As the PI further shortened to 180
ms, VF was initiated at the beginning of the pacing train, accompanied
by large variations in CL. There was a significant positive correlation
between the longest PI associated with significant CL variations
(50% of the electrodes showing significant CL variations before the
initiation of VF) and the PI that induced VF (VFT) in each dog
(r=0.83, P<0.01). That is, the longer the PI at
which 50% of the sites showed variability, the longer the VFT
was.
Pacing-Induced Variability in Conduction Time
Figure 3 shows a summary of the CT
variations of one dog (Figure 3A) and of all dogs studied with the
plaque electrode array (Figure 3B). Shortening the PI from 300 to 220
ms was associated with little change in the average CT. However,
temporal (beat-to-beat) variability progressively increased. Before VF
was induced, the CT associated with captured beats showed large
variations. Figure 3B shows the CT deviations for each dog. When the PI
was progressively shortened, there was a slight increase in CT and its
beat-to-beat variability. Further shortening of the PI to <220 ms
resulted in a large increase of CT and an even greater increase of CT
beat-to-beat variability. The PI needed to induce VF varied from 200 to
140 ms. However, a critical increase of CT beat-to-beat variation (as
demonstrated by a large increase of SD) is associated with the
induction of VF. The critical SD associated with the induction of VF in
this case was 20.2±13.7 ms (n=5).
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Spatial Alternans
In addition to temporal variations of CL, rapid pacing also
induced large spatial variations. Figure 4 shows the spatial distribution of CL in
the last 4 paced beats in 1 animal. Note that with a 300-ms PI, there
was little CL variability in space (top row). But as the PI shortened
to 200 ms (second row), CL began to vary significantly in space. CL 16
and 18 show significant negative deviation (red) at the apex near the
pacing site, while CL 17 and 19 show significant positive deviation
(blue) at the same area. Note the remarkably precise alternation
between red and blue areas in successive beats. At a PI of 190 ms, the
amplitude of the spatial alternans increased. Further shortening of the
PI to 180 ms resulted in VF.
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Figure 5 shows the percentage of
electrodes showing significant CL variation. There is a correlation
between the percentage of sites that showed significant CL variation
and the difference between the PI and the VFT (r=0.92,
P<0.001).
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ERP Restitution Curve
The slope of the ERP restitution curve correlated with the
magnitude of the CL variations. Figure 6
shows a representative ERP restitution curve. The DI
was estimated by the difference between the pacing (S1)
interval and the ERP determined at that PI. For each DI, there was a
corresponding PI and an ERP. When the PIs were between 600 to 260 ms,
the restitution curve was relatively flat, with a slope of 0.30±0.25.
When the PIs were <260 ms, the slope became much steeper (1.04±1.38,
P<0.001) and was associated with the development of
significant CL variations. The slope of the restitution curve within 50
ms of the VFT was 2.57±1.68. There was an inverse correlation between
the slope of the ERP restitution curve and the difference between VFT
and PI (r=-0.70, P=0.037). In other words, the
closer the PI is to inducing fibrillation, the steeper the ERP
restitution curve.
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The Development of Wavebreak and VF
The consequences of spatiotemporal CL and CT variations are
the creation of wavebreak and VF. When the PI was 300 ms, the
activation wave front propagated smoothly, with no evidence of
conduction block (Figure 7). When the PI
shortened, there was greater spatial variation in wave propagation.
Figure 8 shows an example in which
spatial variation of conduction time led to wavebreak and VF. Figures 8A and 8B show centrifugal spread of excitation after the pacing
stimulus. Figure 8D, conduction block occurred at the right lower
portion of the panel. The creation of these 2 new waves coincided with
the onset of VF. Figure 8H shows the activation in the center of the
mapped tissue by the 13th pacing stimulus and the independent
activation in the lower portion of the mapped tissue by 2 wavelets most
likely generated by the previous wavebreak. The site of wavebreak in
this example corresponded to the interventricular septum.
The right half of the figure shows bipolar electrograms recorded
during this pacing run. Note that there was little CL variation
immediately next to the pacing site (channels 180 and 201). This was a
consistent finding in all 5 dogs studied with the plaque
electrode array.
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Figure 8 also shows that, as the distance from the pacing site
increased, there was a progressive increase of variability both in
electrogram morphology and in CL. The slanted arrows on channels 348
and 369 point to the time of wavebreak. Note that there was significant
CL alternans before the wavebreak. For channels 390 and 411, which
registered the site of wavebreak, there was a short CL after beat 9 and
a long CL after beat 10. On the basis of the ERP restitution
characteristics, the ERP after paced beat 11 should be long because of
a long recovery interval created by the long preceding CL. When the
paced wave front of beat 12 arrived, it was unable to excite this
region, resulting in conduction block and wavebreak. The area around
electrode 411 was eventually excited 208 ms later. During this delay,
the wave front circled around the site of block and eventually entered
this area. Note that after wavebreak, the activation near the wavebreak
site has a lower amplitude than the activation before the wavebreak.
These fractionated low-amplitude activations are consistent
with extracellular bipolar recordings near the core of
functional reentry.10 The rapid and irregular activity
then gradually spread to the upper part of the mapped region as VF was
initiated.
Among the 5 dogs mapped with the plaque electrode array, we
recorded a total of 7 episodes of VF induction. Among them,
wavebreak was seen within the mapped region in 4 episodes in 3 dogs.
(In 2 dogs, no wavebreak was observed within the mapped area.) The site
of wavebreak was 10 to 14 mm distant from the pacing site. The
line of block in Figure 8 was parallel to the
interventricular septum. In the other 3 episodes, the
recording plaque did not overlie the septum and was limited to
the right ventricular free wall. In these latter episodes,
the line of wavebreak was always parallel to the myocardial fiber
orientation, 10 to 14 mm from the site of pacing.
Figure 9 shows the global
activation patterns at the induction of wavebreak. Panel A shows that
when the heart was paced at 160 ms PI, the initial 6 captured beats had
earliest activation near the pacing site (blue dot). Afterwards, the
complex, nonpaced and rapid activation (Figure 9B) started to develop
from the site marked by a red arrow in Figure 9A. The remainder of the
epicardium continued to be captured by the pacing stimuli, resulting in
fusion. The rapid VF activations took >300 ms (3 cycles) to spread to
the entire epicardial surface (Figure 9B). Figure 9C shows the
isodeviation map. Note that the patterns of spatial CL inhomogeneity
developed as early as paced beat 2, followed by alternans. The site of
wavebreak (blue arrow) was located between regions of long and short
CLs. These findings are compatible with the notion that the initial
wavebreak (shown better in Figure 8) induces reentry, which then
induces VF in the entire ventricle.
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Among 10 dogs mapped with sock electrode array, we recorded a total of 12 episodes of VF induction. In all episodes, the induction of VF was characterized by the induction of complex and rapid activation in a local site. The complex and rapid activation patterns then spread to the entire epicardial surface, leading to the induction of VF.
Computer Simulation Study
In our computer simulations of homogeneous isotropic
tissue, rapid pacing near the center produced a CL alternans in time
and an alternans in space that was spherically symmetrical around the
pacing site. These alternating concentric rings of long and short CLs
did not result in wavebreak and reentry, phenomena that were seen in
the real tissue. To initiate wavebreak, and hence VF, it was necessary
to introduce a heterogeneity into the tissue. We
therefore lengthened the APD (by 10%) in the region indicated by
box A in Figure 10, to simulate a
region of increased refractoriness. As a result of this break in tissue
symmetry, the spatiotemporal complexities and wavebreak induced by
rapid pacing in real tissue were now reproduced. Figure 10 shows the
isodeviation maps generated in the computer model. At a PI of 300 ms,
there was little or no CL variation. When the PI was shortened, the
activation patterns displayed spatiotemporal alternans. These patterns
reproduced the experimental results shown in Figure 4. Note in
particular the crescent-shaped regions of long and short CLs, similar
in shape and location to those seen in the real tissue (Figure 4). As
in the real tissue, further reduction of the PI to 180 ms resulted in
wavebreak and VF-like activity, which continued after terminating the
pacing. When the heterogeneity was removed after the
onset of VF, the VF-like state persisted indefinitely. Thus, the
computer simulations show that spatiotemporal oscillations
in CL (alternans) result directly from the dynamic properties of the
cardiac action potential model without requiring that the tissue have
intrinsically heterogeneous properties. However, a small
heterogeneity is required for these
oscillations to cause wavebreak, since it breaks the radial
symmetry of the activation wave front. Once the radial symmetry is
broken, the maintenance of the VF-like state no longer depends
on the continued presence of the heterogeneity.
We verified that alternans was playing a contributory role in
wavebreak, by removing it (through flattening APD restitution) from the
system. In the case of Figure 10, we flattened APD restitution by
eliminating the Na+ channel contribution to APD restitution
as we did in Reference 1717 . With all settings the same as in Figure 10, except for the flattening of APD restitution, wavebreak was not
observed even with the PI was decreased to 100 ms (compared with the VF
threshold of 180 ms in the control case [Figure 10]). In this case,
wavebreak failed to occur at 100 ms PI, even when
heterogeneity was increased in area A by changing
Gsi to 0.09.
Next, we explored the relationship between CV and ERP restitution and
the development of spatiotemporal CL oscillations (Figure 11 and 12). Flattening CV restitution in the
action potential model eliminated spatial alternans during rapid pacing
(Figure 12), indicating that spatial CL alternans is a direct
consequence of CV restitution. Conversely, in the absence of CV
restitution, increasing the slope of ERP restitution increased the PI
required to induce temporal alternans in ERP, showing that temporal ERP
alternans is sensitive to the steepness of ERP restitution, independent
of CV restitution. When both CV and ERP restitutions were intact,
increasing the ERP restitution slope potentiated both temporal and
spatial alternans (Figure 12D). In the presence of a symmetry-breaking
heterogeneity, this facilitated wavebreak and
development of a VF-like state at longer PIs.
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210 ms. But when CV
restitution was flattened at the relevant DIs (right column), APD
alternans sets in at a PI of
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There are 3 major findings of this study. The first shows that spatiotemporal alternans is created by cardiac restitution properties and emphasizes that both CV and ERP restitution play key roles. The second shows that the presence of an initial heterogeneity is essential in the induction of initial wavebreak by rapid pacing. Indeed, our analysis suggests that the interaction among tissue heterogeneity and cardiac restitution properties is critical for VF induction by rapid pacing. The third shows that the presence of spatiotemporal alternans facilitates the induction of initial wavebreak by heterogeneity.
Spatiotemporal Alternans and Induction of VF
We have documented that rapid pacing in the in situ canine
ventricles induces an uneven spatiotemporal distribution of CL.
Furthermore, we could manipulate the increase of the magnitude of
spatiotemporal heterogeneity by progressively
shortening the PI, until an abrupt transition to wavebreak occurred.
Wavebreak was the physiological event that heralded
the onset of VF and occurred as a result of a progressively increasing
oscillation in the long-short coupling of CLs as the PI
decreased. Because the magnitude of spatiotemporal inhomogeneity can be
controlled with pacing rate, this is a useful model to study the role
of spatiotemporal oscillations in cardiac activation in the
transition to VF in the intact canine ventricles.
Spatiotemporal Alternans and Cardiac Restitution
To relate spatiotemporal oscillations in CL to cardiac
restitution properties in real cardiac tissue is not straightforward.
Whereas ERP restitution can be accurately measured in the in situ
heart, estimates of CV must rely on conduction time differences, which
are subject to error if the conduction pathway changes. Nevertheless,
in our experiments, any deviation of local CL from the PI must reflect
a variation in either CV or conduction pathway from the pacing site to
that location. It has been reported that CV in ventricular
muscle depends on the rate of activation.20 21 22 In one
study,21 reentry was induced in a ring of
ventricular tissue surrounding the canine mitral and aortic
valves. Premature stimuli given during tachycardia resulted
in advancement of tachycardia, but the extent of
advancement was less than the local excitable gap, indicating that
early premature impulses conducted more slowly than the unperturbed
reentrant impulses. In another study,20 the authors showed
a rate dependence of CV in guinea pig ventricles. The conduction was
significantly slower during short PI than during long PI. In rabbit
ventricles, significant CV restitution was demonstrated in both
longitudinal and transverse directions.22 The spatial CL
variation recorded during rapid pacing in this study is compatible
with these known CV restitution properties, especially given that the
variations become larger as the PI decreases. The nearly radially
symmetrical pattern of CL alternation also argues against changes in
conduction pathway, because there is no apparent reason for conduction
block to occur with a symmetrical radial distribution relative to the
pacing site. Finally, the computer simulations show that CV restitution
properties can directly account for the experimentally observed spatial
CL variations, without the need to postulate changes in conduction
pathway. The computer simulations also demonstrate that without CV
restitution, spatial CL variation is eliminated (Fig 11). The
explanation is very intuitive: without CV restitution, CV is
essentially constant throughout the tissue (ignoring the effects of
wave front curvature very close to the pacing site). Therefore, the
arrival time of an impulse at a given distance from the pacing site has
no way to vary between successive beats (assuming the conduction
pathway does not change). From these observations, we conclude that CV
restitution is primarily responsible for producing the spatial
variation in CL.
How does this lead to wavebreak and VF? A key point is that the spatial variation in CL, resulting from CV restitution, will also result in a spatial variation in DI, because CL=APD+DI. This fact directly links CV restitution to ERP restitution. The ERP restitution curve provides the next value of ERP as a function of the previous value of DI. Suppose that, as a consequence of CV restitution, 2 nearby cells develop a slight difference in their DIs during rapid pacing. Because of ERP restitution, these differences in DI will cause the ERP of the next beat to differ at the 2 sites. That is, a functional (spatial) dispersion of refractoriness will be created for the next beat. Those two slightly different ERPs will then generate 2 different next DIs. Whether this difference will be greater or smaller than the preceding difference is determined by the slope of the ERP restitution curve in the region of those DIs. If >1, the next difference will be larger, and if <1, the next difference will be smaller. In this way, a steeply sloped ERP restitution curve is a "difference amplifier," the gain of which is the value of the slope. Thus, any spatial differences in CL and DI resulting from CV restitution will be amplified on the next paced beat by a steeply sloped ERP restitution curve and further increase the functional dispersion of refractoriness. In this way, a steep ERP restitution amplifies over time the spatial differences in DI and ERP produced by CV restitution. That is, CV restitution excites a spatial mode of oscillations in DI, and ERP restitution a temporal mode.
In homogeneous, isotropic tissue, when the growing spatiotemporal oscillations lead to a DI, which is too short to generate an action potential, propagation fails. Because the spatial variations in CL and DI resulting from CV restitution are radially symmetrical in homogeneous tissue, propagation failure occurs everywhere along the wave front at once, leading to extinction of the target wave induced by that pacing stimulus. If a heterogeneity exists in the tissue, however, this radial symmetry is broken. Spatial oscillations in CL and DI resulting from CV restitution will now develop along the same activation wave front. As these differences in DI are translated into differences in ERP and then further amplified temporally by a steep ERP restitution slope, they lead to a break in the wave front at the point where the DI becomes too short to generate an action potential. This wavebreak heralds the onset of the VF-like state. This explanation accounts for the experimental observation that spatiotemporal oscillations in CL increased progressively as the steepness of the ERP restitution increased at shorter PI. Wavebreak presumably occurred because of the normal degree of heterogeneity, which exists in the canine ventricle.
In simulated 2-dimensional cardiac tissue, once wavebreak occurred during rapid pacing, the radial symmetry of the activation was broken. Therefore, the subsequent removal of the heterogeneity from the tissue did not cause the VF-like state to terminate. This observation highlights an important point, which is that, whereas the initiation of the VF-like state depends on the presence of tissue heterogeneity, its maintenance does not. A key but unresolved therapeutic issue is whether modifying ERP and CV restitution can prevent the ability of VF to sustain itself in the presence of heterogeneous tissue properties.
Relationship to Previous Studies
The argument that a steeply sloped APD restitution curve creates
instabilities during rapid pacing was first made by Nolasco and
Dahlen.23 They also showed how a steeply sloped curve
results in alternans, the first time that this phenomenon was
explained. Subsequently, Frame and Simson24 extended this
finding to the study of reentrant excitation (as opposed to external
pacing). They showed that reentry in a ring of cardiac tissue could
give way to an alternans due to APD restitution. They also found that
CV variability gave rise to "more irregular and complex
oscillations" (page 1285). These experimental
results were put in a theoretical context by Courtemanche et
al,15 who studied a mathematical model of a ring of
cardiac tissue like the Frame-Simson preparation and demonstrated that
if the slope of the APD restitution curve is >1, alternans will
develop. They showed that if there is CV restitution, the alternans
will become modulated by another, longer-period
oscillation. This additional modulation frequency makes the
resulting system quasiperiodic. It is interesting to note that the new
modulation frequency arises because of the spatial variation in APD
that is caused by CV restitution.
Previous simulation studies in 2- and 3-dimensional tissue are also
generally consistent with our findings. In 2-dimensional
cardiac simulated tissue, Karma5 showed that a steeply
sloped restitution curve will cause alternans and that if the alternans
is large enough in amplitude, it will result in wavebreak. This is
analogous to a result of Frame and Simon24 with the ring;
an alternans that is mild can be tolerated within the spatial extent of
the ring, but an alternans that is too violent will cause wave
termination by head-tail interactions. In the 1-dimensional ring,
strong head-tail interaction can only result in termination of the
wave, but in 2-dimensional tissue the same phenomenon causes wavebreak.
Our study is compatible with the presence of this mechanism in
pacing-induced VF. Recall that a PI of 190 caused a mild alternans,
which did not result in wavebreak, and hence did not result in the
genesis of reentry. The tissue therefore did not develop VF. But at a
PI of 180, the alternans was larger and resulted directly in the
genesis of wavebreak. Figures 8 and 9 show that when wavebreak was
created, there was a sudden occurrence of more rapid and complicated
activations in the mapped region, starting from the site of wavebreak,
which spread to the entire mapped tissue. These findings support the
notion that the wavebreak created by rapid pacing precedes the onset of
VF.
Thus, our study provides experimental evidence for a causal role for alternans, and shows how alternans caused the wavebreak; ie, long-short couplings create conduction failure, which creates a reentrant spiral wave. We also showed that the formation of the initial spiral wave precedes the sudden transition from paced rhythm to VF. These findings are consistent with the results of Pastore et al,6 who also reported that "discordant alternans" of APD induced by rapid pacing is causally related to the initiation of VF.
Our present findings may also shed light on the mechanism for the quasiperiodic transition to chaos that we hypothesized previously with respect to VF induced by a single extrastimulus.4 In that context, we observed oscillations in CL and APD and conjectured that APD and CV restitutions could be responsible for these additional oscillatory modes. The present study shows that APD and CV restitution do indeed give rise to temporal and spatial oscillations, respectively.
Causal Relationship Between Alternans and VF
Our evidence that CL alternans, which reflects underlying
spatiotemporal DI alternans and therefore also APD alternans, is a
causative factor in the induction of VF by rapid pacing is significant.
Previous studies in both animals and humans have established intriguing
correlations between repolarization alternans and VF, suggesting that
it is not benign. In the canine heart, the induction of repolarization
(APD or T wave) alternans by hypothermia, tachycardia, or
coronary artery ligation has been shown to significantly
facilitate the induction of VF.3 25 In humans, using the T
wave as a surrogate measure of the global repolarization
characteristics,26 Lewis27 first reported
that T wave alternation can occur during tachycardia.
Subsequently, patients with long-QT syndrome,28 Prinzmetal
angina,29 acute ischemia,30 and
electrolyte imbalances31 32 have been found to exhibit a T
wave alternation even during normal sinus rhythm. Rosenbaum et
al2 reported that the beat-to-beat T wave alternans over a
broad range of physiological heart rates (95 to 150
bpm) served as a noninvasive marker of vulnerability to
ventricular arrhythmias. In addition, T wave
alternans was as powerful a predictor of future spontaneous clinical
arrhythmic events as inducibility of ventricular
tachycardia during clinical
electrophysiological studies.
Conclusions
We conclude that during VF induction by rapid pacing, CV and ERP
(or APD) restitution properties underlie the functional dispersion of
refractoriness that leads to wavebreak and VF. CV restitution excites a
spatial mode of oscillations in CL and DI, which through
ERP (or APD) restitution are translated temporally into spatial
differences in refractoriness. If the ERP restitution slope is steep,
its interaction with CV restitution leads to progressively larger
spatial gradients in refractoriness during successive beats,
culminating in wavebreak and VF. In simulated 2-dimensional cardiac
tissue, some pre-existing tissue heterogeneity is
required for wavebreak to occur, but it is not important for the
maintenance of VF once wavebreak is initiated. During rapid
pacing, differences in CL, and hence DI and APD, alternate in both
space and time. Wavebreak occurs when CL alternans reaches a critical
value. Alternans therefore plays a causative role in wavebreak and is a
reliable precursor to VF, accounting for prior experimental and
clinical correlations between alternans and susceptibility to
ventricular arrhythmias. It is possible that drugs
or other interventions that favorably alter CV and ERP (or APD)
restitution to suppress the spatiotemporal oscillations
causing wavebreak could be effective in the prevention of VF and sudden
cardiac death.
|
Acknowledgments |
|---|
This study was done during the tenure of a fellowship grant from the American Heart Association, Greater Los Angeles Affiliate (to J.-M.C. and Z.Q.); a fellowship grant from the Department of Medicine, Korea University (to Y.-H.K.); a Cedars-Sinai ECHO Foundation Award (to H.S.K.); and an AHA Wyeth-Ayerst Established Investigator Award (to P.-S.C.), and was supported in part by NIH Specialized Center of Research Grant in Sudden Death (P50-HL52319), NIH Research Grants HL50259 and HL44880, the Ralph M. Parsons Foundation (Los Angeles, Calif), the Pauline and Harold Price Endowment, Cedars-Sinai Medical Center, and the Kawata and Laubisch Endowments (UCLA). We thank Caroline Kim, Dustan Hough, Avile McCullen, Pei-Li Yan, Meiling Yuan, and Nina Wang for their technical assistance and Eliane Lebowitz for her secretarial assistance.
|
Footnotes |
|---|
1 Both authors contributed equally to this study.
Received February 2, 1999; accepted March 19, 1999.
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References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
1. Han J, Moe GK. Nonuniform recovery of excitability in ventricular muscle. Circ Res. 1964;14:44–60.
2.
Rosenbaum DS, Jackson LE, Smith JM, Garan H, Ruskin
JN, Cohen RJ. Electrical alternans and vulnerability to
ventricular arrhythmias. N Engl J
Med. 1994;330:235–241.
3.
Nearing BD, Huang AH, Verrier RL. Dynamic tracking of
cardiac vulnerability by complex demodulation of the T wave.
Science. 1991;252:437–440.
4. Garfinkel A, Chen P-S, Walter DO, Karagueuzian HS, Kogan B, Evans SJ, Karpoukhin M, Hwang C, Uchida T, Gotoh M, Nwasokwa O, Sager P, Weiss JN. Quasiperiodicity and chaos in cardiac fibrillation. J Clin Invest. 1997;99:305–314.[Medline] [Order article via Infotrieve]
5. Karma A. Electrical alternans and spiral wave breakup in cardiac tissue. Chaos. 1994;4:461–472.[Medline] [Order article via Infotrieve]
6.
Pastore JM, Girouard SD, Laurita KR, Akar FG,
Rosenbaum DS. Mechanism linking T-wave alternans to the genesis of
cardiac fibrillation. Circulation. 1999;99:1385–1394.
7.
Chen P-S. Ventricular fibrillation is not
an anodally induced phenomenon in open-chest dogs. Am J
Physiol. 1992;262:H365–H373.
8. Cranefield PF, Hoffman BF, Siebens AA. Anodal excitation of cardiac muscle. Am J Physiol. 1957:190:383–390.
9.
Bonometti C, Hwang C, Hough D, Lee JJ, Fishbein MC,
Karagueuzian HS, Chen P-S. Interaction between strong electrical
stimulation and reentrant wavefronts in canine ventricular
fibrillation. Circ Res. 1995;77:407–416.
10.
Lee JJ, Kamjoo K, Hough D, Hwang C, Fan W, Fishbein MC,
Bonometti C, Ikeda T, Karagueuzian HS, Chen P-S. Reentrant wave fronts
in Wiggers' stage II ventricular fibrillation:
characteristics, and mechanisms of termination and spontaneous
regeneration. Circ Res. 1996;78:660–675.
11.
Frazier DW, Krassowska W, Chen P-S, Wolf PD, Danieley
ND, Smith WM, Ideker RE. Transmural activations and potentials on
three-dimensional anisotropic canine myocardium. Circ
Res. 1988;63:135–146.
12. Friedman P. GB-Stat [computer program]. Silver Spring, Md: Dynamic Microsystems, Inc; 1995.
13.
Luo CH, Rudy Y. A model of the ventricular
cardiac action potential: depolarization, repolarization, and their
interaction. Circ Res. 1991;68:1501–1526.
14. Courtemanche M, Winfree AT. Re-entrant rotating waves in a Beeler-Reuter based model of two-dimensional cardiac electrical activity. Int J Bif Chaos. 1991;1:431–444.
15. Courtemanche M, Glass L, Keener JP. Instabilities of a propagating pulse in a ring of excitable media. Phys Rev Lett. 1993;70:2182–2185.[Medline] [Order article via Infotrieve]
16. Qu Z, Weiss JN, Garfinkel A. Spatio-temporal chaos in a simulated ring of cardiac cells. Phys Rev Lett. 1997;78:1387–1390.
17.
Qu Z, Weiss JN, Garfinkel A. Cardiac electrical
restitution properties and stability of reentrant spiral waves: a
simulation study. Am J Physiol. 1999;276:H269–H283.
18. Cabo C, Pertsov AM, Davidenko JM, Baxter WT, Gray RA, Jalife J. Vortex shedding as a precursor of turbulent electrical activity in cardiac muscle. Biophys J. 1996;70:1105–1111.[Medline] [Order article via Infotrieve]
19.
Luo CH, Rudy Y. A dynamic model of the cardiac
ventricular action potential, I: simulations of ionic
currents and concentration changes. Circ Res. 1994;74:1071–1096.
20.
Girouard SD, Pastore JM, Laurita KR, Gregory KW,
Rosenbaum DS. Optical mapping in a new guinea pig model of
ventricular tachycardia reveals mechanisms for
multiple wavelengths in a single reentrant circuit.
Circulation. 1996;93:603–613.
21.
Bernstein RC, Frame LH. Ventricular reentry
around a fixed barrier: resetting with advancement in an in vitro
model. Circulation. 1990;81:267–280.
22.
Schalij MJ, Lammers WJEP, Rensma PL, Allessie MA.
Anisotropic conduction and reentry in perfused epicardium of rabbit
left ventricle. Am J Physiol. 1992;263:H1466–H1478.
23.
Nolasco JB, Dahlen RW. A graphic method for the study
of alternation in cardiac action potentials. J Appl
Physiol. 1968;25:191–196.
24.
Frame LH, Simon MB. Oscillations of
conduction, action potential duration, and refractoriness: a mechanism
for spontaneous termination of reentrant tachycardias.
Circulation. 1988;78:1277–1287.
25. Adam DR, Smith JM, Akselrod S, Nyberg S, Powell AO, Cohen RJ. Fluctuations in T-wave morpholoy and susceptibility to ventricular fibrillation. J Electrocardiol. 1984;17:209–218.[Medline] [Order article via Infotrieve]
26.
Chen P-S, Moser KM, Dembitsky WP, Auger WA, Daily PO,
Calisi CM, Feld GK. Epicardial activation and repolarization patterns
in patients with right ventricular hypertrophy.
Circulation. 1991;83:104–118.
27. Lewis T. Notes upon alteration of the heart. Q J Med 1910;4:141–144.
28. Schwartz PJ, Malliani A. Electrical alternation of the T-wave: clinical and experimental evidence of its relationship with the sympathetic nervous system and with the long Q-T syndrome. Am Heart J. 1975;89:45–50.[Medline] [Order article via Infotrieve]
29.
Kleinfeld MJ, Rozanski JJ. Alternans of the ST segment
in Prinzmetal's angina. Circulation. 1977;55:574–577.
30. Dilly SG, Lab MJ. Electrophysiological alternans and restitution during acute regional ischaemia in myocardium of anaesthetized pig. J Physiol (Lond). 1988;402:315–333.
31. Reddy CV, Kiok JP, Khan RG, El-Sherif N. Repolarization alternans associated with alcoholism and hypomagnesemia. Am J Cardiol. 1984;53:390–391.[Medline] [Order article via Infotrieve]
32. Shimoni Z, Flatau E, Schiller D, Barzilay E, Kohn D. Electrical alternans of giant U waves with multiple electrolyte deficits. Am J Cardiol. 1984;54:920–921.[Medline] [Order article via Infotrieve]
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T. Ohara, K. Ohara, J.-M. Cao, M.-H. Lee, M. C. Fishbein, W. J. Mandel, P.-S. Chen, and H. S. Karagueuzian Increased Wave Break During Ventricular Fibrillation in the Epicardial Border Zone of Hearts With Healed Myocardial Infarction Circulation, March 13, 2001; 103(10): 1465 - 1472. [Abstract] [Full Text] [PDF]
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Z. Qu, A. Garfinkel, P.-S. Chen, and J. N. Weiss Mechanisms of Discordant Alternans and Induction of Reentry in Simulated Cardiac Tissue Circulation, October 3, 2000; 102(14): 1664 - 1670. [Abstract] [Full Text] [PDF]
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O. Voroshilovsky, Z. Qu, M.-H. Lee, T. Ohara, G. A. Fishbein, H.-L. A. Huang, C. D. Swerdlow, S.-F. Lin, A. Garfinkel, J. N. Weiss, et al. Mechanisms of Ventricular Fibrillation Induction by 60-Hz Alternating Current in Isolated Swine Right Ventricle Circulation, September 26, 2000; 102(13): 1569 - 1574. [Abstract] [Full Text] [PDF]
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A. Patwardhan, S. Moghe, K. Wang, and F. Leonelli Frequency modulation within electrocardiograms during ventricular fibrillation Am J Physiol Heart Circ Physiol, August 1, 2000; 279(2): H825 - H835. [Abstract] [Full Text] [PDF]
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M. Yashima, T. Ohara, J.-M. Cao, Y.-H. Kim, M. C. Fishbein, W. J. Mandel, P.-S. Chen, and H. S. Karagueuzian Nicotine increases ventricular vulnerability to fibrillation in hearts with healed myocardial infarction Am J Physiol Heart Circ Physiol, June 1, 2000; 278(6): H2124 - H2133. [Abstract] [Full Text] [PDF]
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J.-M. Cao, L. S. Chen, B. H. KenKnight, T. Ohara, M.-H. Lee, J. Tsai, W. W. Lai, H. S. Karagueuzian, P. L. Wolf, M. C. Fishbein, et al. Nerve Sprouting and Sudden Cardiac Death Circ. Res., April 14, 2000; 86(7): 816 - 821. [Abstract] [Full Text] [PDF]
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F. J. Chorro, J. Canoves, J. Guerrero, L. Mainar, J. Sanchis, L. Such, and V. Lopez-Merino Alteration of Ventricular Fibrillation by Flecainide, Verapamil, and Sotalol : An Experimental Study Circulation, April 4, 2000; 101(13): 1606 - 1615. [Abstract] [Full Text] [PDF]
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M. Swissa, T. Ohara, M.-H. Lee, S. Kaul, P. K. Shah, H. Hayashi, P.-S. Chen, and H. S. Karagueuzian Sildenafil-nitric oxide donor combination promotes ventricular tachyarrhythmias in the swine right ventricle Am J Physiol Heart Circ Physiol, May 1, 2002; 282(5): H1787 - H1792. [Abstract] [Full Text] [PDF]
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