© 2000 American Heart Association, Inc.
Integrative Physiology |
A Mechanism of Transition From Ventricular Fibrillation to Tachycardia
Effect of Calcium Channel Blockade on the Dynamics of Rotating Waves
From the Department of Pharmacology (F.H.S., R.M., C.Z., J.B., J.J.) and Pediatrics (Cardiology) (R.M.), SUNY Upstate Medical University, Syracuse, NY; Department of Biomedical Engineering (R.A.G.), University of Alabama, Birmingham, Ala; and Cardiovascular Institute (Y.W.), Fujita Health University, Japan.
Correspondence to José Jalife, Department of Pharmacology, SUNY Upstate Medical University, 766 Irving Ave, Syracuse, NY 13210. E-mail jalifej{at}mail.upstate.edu
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Abstract |
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Abstract—Abbreviation of the action potential duration and/or effective refractory period (ERP) is thought to decrease the cycle length of reentrant arrhythmias. Verapamil, however, paradoxically converts ventricular fibrillation (VF) to ventricular tachycardia (VT), despite reducing the ERP. This mechanism remains unclear. We hypothesize that the size and the dynamics of the core of rotating waves, in addition to the ERP, influence the arrhythmia manifestation (ie, VF or VT). The objectives of this study were (1) to demonstrate functional reentry as a mechanism of VF and VT in the isolated Langendorff-perfused rabbit heart in the absence of an electromechanical uncoupler and (2) to elucidate the mechanism of verapamil-induced conversion of VF to VT. We used high-resolution video imaging with a fluorescent dye, ECG, frequency and 2-dimensional phase analysis, and computer simulations. Activation patterns in 10 hearts were studied during control, verapamil perfusion (2x10-6 mol/L), and washout. The dominant frequency of VF decreased from 16.2±0.7 to 13.5±0.6 Hz at 20 minutes of verapamil perfusion (P<0.007). Concomitantly, phase analysis revealed that wavefront fragmentation was reduced, as demonstrated by a 3-fold reduction in the density of phase singularities (PSs) on the ventricular epicardial surface (PS density: control, 1.04±0.12 PSs/cm2; verapamil, 0.32±0.06 PSs/cm2 [P=0.0008]). On washout, the dominant frequency and the PS density increased, and the arrhythmia reverted to VF. The core area of transiently appearing rotors significantly increased during verapamil perfusion (control, 4.5±0.6 mm2; verapamil, 9.2±0.5 mm2 [P=0.0002]). In computer simulations, blockade of slow inward current also caused an increase in the core size. Rotating waves underlie VF and VT in the isolated rabbit heart. Verapamil-induced VF-to-VT conversion is most likely due to a reduction in the frequency of rotors and a decrease in wavefront fragmentation that lessens fibrillatory propagation away from the rotor.
Key Words: arrhythmia • fibrillation • tachycardia • verapamil • optical mapping
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Introduction |
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Ventricular tachycardia (VT) and ventricular fibrillation (VF) are the leading causes of sudden cardiac death.1 However, despite 100 years of research, the mechanisms responsible for their initiation, maintenance, and interconversion are not well understood. Our laboratory2 3 4 and others5 6 have shown that VF is not random, but rather a complex sequence of ventricular excitation that is organized in space and time. Theories regarding the mechanisms of fibrillation include (1) multiple wavelet reentry,7 (2) fibrillatory conduction,8 9 and (3) spiral wave(s)2 3 4 or 3-dimensional scroll waves10 and their breakup.11 12 Irrespective of the proposed theory, functional reentrant circuits are likely to underlie VF and most cases of VT. However, the mechanisms that determine whether the arrhythmia manifests as fibrillation or tachycardia are poorly understood.
Recently, several studies addressed VF-to-VT transitions by studying the role of action potential duration (APD) and/or effective refractory period (ERP) on fibrillatory dynamics. Studies with potassium channel openers, cromakalim and acetylcholine respectively,13 14 showed that ERP shortening increases the vulnerability to reentry and accelerates its rate. In contrast, APD prolongation by tedisamil, an Ito and IK blocker, increases both the spatial coherence and temporal regularity of VF.15 Similarly, dofetilide, an IK blocker, increased the APD and ERP while slowing or suppressing VT.16
Previously, Watanabe and Uchida17 and Watanabe et al18 reported that rapid ventricular stimulation in isolated rabbit hearts in the presence of verapamil, a calcium channel blocker, resulted in the induction of sustained monomorphic VT (MVT). The induction of VT rather than fibrillation despite a reduction of ERP by verapamil19 seemed paradoxical, suggesting that parameters besides tissue refractoriness may play a role. We hypothesized that the size and dynamics of the core around which reentrant waves rotate, as well as refractoriness, may determine whether the arrhythmia manifests as VF or MVT. Our objectives were to (1) demonstrate functional reentry as a mechanism of VF and MVT in the isolated Langendorff-perfused rabbit heart in the absence of an electromechanical uncoupler and (2) elucidate the mechanism of verapamil-induced conversion of VF to MVT.
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Materials and Methods |
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Langendorff-Perfused Rabbit Heart and Experimental Setup
Isolated rabbit hearts were immersed in a chamber and perfused via a cannula in the aorta with warm (36.5±1°C), oxygenated Tyrode’s solution3 (control) or Tyrode’s solution containing 2x10-6 mol/L verapamil. During VF, motion was eliminated by an adjustable glass wall, which gently restrained the heart against the chamber. Electromechanical uncouplers were not used. A volume-conducted ECG was recorded from 2 leads in the chamber. A bolus of 15 mL of the dye, di-4-ANEPPS (10 µg/mL), was injected into the aorta. Light (535 nm) was shone on the epicardial surface of the heart; the emitted fluorescence (590 nm) was acquired by a charge-coupled device camera at 120 frames per second.3 The background fluorescence was subtracted from each frame, and low-pass spatial filtering was applied.20 Optical recordings were 3 to 4 seconds in duration.3
Phase Analysis and the Measurement of Core Area
Phase analysis4 was used to quantify the
extent of wavefront fragmentation by determining the number of phase
singularities (PSs). PSs are easily identified as sites where all
phases converge, and the continuous spatial phase change reflects the
processes of excitation, recovery, and diffusion.
Reentrant spiral waves were identified, and the sizes of their cores were measured by tracing the path of the "pivoting point" where the front and tail meet.21 22 23 The trajectory of this point is a closed loop, and the region within this loop is equivalent to the area of the core.21
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Experimental Protocols |
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VF and MVT
In 10 normal hearts, VF was induced by burst pacing of the left ventricular epicardium. Verapamil perfusion was initiated after 5 minutes of control recordings. After 30 minutes of verapamil, the heart was perfused and superfused with control solution once again (washout).
ERP and Conduction Velocity (CV)
The ERP was determined in 8 additional hearts via programmed
stimulation (2 times diastolic threshold) at several cycle
lengths (CLs) during control and verapamil
perfusion.24
In 4 hearts, local CV was determined at pacing CL of 300 ms during control and verapamil perfusion.20 25 The fastest velocity was considered CVmax; the slowest velocity was considered CVmin.
VF and MVT Analysis
For PS analysis, 10 control VF recordings
(obtained 5 minutes after induction) and 10 MVT recordings
(obtained 20 minutes after verapamil perfusion) were
identified. For determination of core areas, all recordings
obtained during the first 5 minutes of VF and within 20 to 30 minutes
of verapamil perfusion were analyzed, and all
spirals were identified and their cores measured.
Statistics
The data are presented as mean±SEM. Comparisons were
performed using individual Student t tests or
ANOVA.
Computer Simulations
Two-Dimensional Luo and Rudy Model. Simulations were
performed using a modification of phase I of the Luo and
Rudy26 model of the ventricular
cell.27 28 The model was a uniform anisotropic cardiac
sheet (3x3 cm) that incorporated 7 ionic currents. To approximate the
effect of verapamil on reentry, we reduced the slow inward
current (Isi).
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Results |
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Analysis of Frequency Changes
Verapamil perfusion during VF resulted in the rapid conversion of the arrhythmia to sustained MVT in all 10 hearts within 10 to 20 minutes. Figure 1A
is an
example of ECG recordings and their frequency spectra from an
experiment. The ECGs during control and washout are irregular, with
characteristic VF-like frequency spectra. Verapamil
converted VF to MVT, as indicated by the change in pattern of the ECG
and the transformation of the frequency spectrum from multiple peaks
(VF) to a single peak with its harmonic (MVT). Frequency
analysis also demonstrated that VF-to-MVT transition was
accompanied by a decrease in the dominant frequency (DF) (ie, the
frequency at which maximum power occurred) from 17.01 Hz (control) to
11.64 Hz (verapamil) and an increase during washout to
16.08 Hz. Quantification of the frequency changes in the 10 hearts is
illustrated in Figure 1B. With the VF-to-VT conversion, the DF
in the power spectrum decreased from 16.2±0.7 to 13.5±0.6 Hz
(P<0.007). Washout of verapamil resulted in the
conversion of VT to VF and an increase in the DF to near control values
(15.9±0.9 Hz after 10 minutes of washout, P=NS versus
control).
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Imaging of Verapamil-Induced Changes in Dynamics
of VF
Video imaging of the anterior surface of the ventricles elucidated
the effects of verapamil on wave dynamics during VF. Figure 2 shows ECGs, isochrone, and phase
maps from 1 heart. The VF dynamics during both control and washout
conditions were complex. Isochrone maps of VF (Figure 2B)
show a short-lived high-frequency rotor during control (rotation
period, 54.6 ms, corresponding to 18.3 Hz) and washout (rotation
period, 65.4 ms, corresponding to 15.3 Hz). Propagation during VF was
inhomogeneous, suggesting that breakup of waves propagating
away from the rotors resulted in disorganized activity that is
characteristic of VF. During verapamil, a slower rotor
(rotation period, 84.0 ms, corresponding to 11.9 Hz) is present at
the base of the heart. In contrast to VF, propagation during MVT was
less fragmented and more repetitive. These data strongly suggest that
with the reduction of the rotor frequency, propagation becomes less
fragmented, thus manifesting as MVT.
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This notion is further supported through the quantification of PSs.
Figure 2C
shows phase maps depicting the phase at an instant in
time during the rotation of the rotors in Figure 2B. The
asterisks represent PSs that are formed when breaks occur in
the propagating waves after collisions with refractory tails of other
waves or obstacles.4 PSs occasionally represent a
center of rotation (white circles). However, more often they indicate
the fragmentation of the mother waves into daughter wavelets. The
daughter wavelets may be bound on each end by a PS, a PS and a
boundary, or 2 boundaries.4 The phase maps in this episode
demonstrate that during control VF, 6 PSs coexist on the anterior
surface of the ventricles that give rise to at least 3 daughter
wavelets. However, during verapamil, only 1 PS is observed,
clearly demonstrating that propagation was less fragmented. During
washout, once again 6 PSs are present, suggesting that the dynamics
were complex and similar to those of control VF.
Figure 2D shows the quantification of PS density in all 10
experiments. For each experiment, a 500-ms episode of
arrhythmia during control (5 minutes after VF induction), after
20 minutes of verapamil perfusion, and during washout was
chosen at random and analyzed. There was a significant decrease
in the PS density during verapamil perfusion. During VF, in
control conditions and washout, the mean PS density was 1.04±0.12 and
0.96±0.15 PSs/cm2, respectively (P=NS
versus control), whereas during MVT the mean decreased to 0.32±0.06
PSs/cm2 (P=0.0008). These data clearly
suggest that the decreased breakup of activity is likely the result of
the slower rate of the arrhythmia, further supporting the idea
that the spatially and temporally periodic activity during MVT is the
result of more homogeneous and less fragmented
propagation.
Functional Reentry: Mechanism of VT
Additional support for the notion that MVT, with
verapamil, resulted from functional reentry was obtained
from a heart in which different ECG morphologies were observed during
MVT (Figure 3). In Figure 3A and 3B, reentrant waves rotate around cores located in different regions of
the anterior surface of the ventricles. In Figure 3C, the core
is outside the viewing area, but the waves emanating from the apex are
likely to be from a reentrant circuit. The transition to a different
QRS pattern, with minimal change in the CL, may be attributed to a
change in the position of the core with respect to the fixed position
of the ECG lead.
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It has been shown that the rotation period of a reentrant source
determines the DF of the ECG.21 Consequently, to further
confirm that functional reentry is the underlying mechanism for VT, the
rotation periods of 5 spirals identified during MVT were correlated
with the inverse of the DF of the power spectrum of the
volume-conducted ECG (Figure 3D). As expected, a strong
correlation (R2=0.997, slope=0.98) is
found between the 2 parameters, suggesting that the
periodicity of the rotating spiral wave is the main contributor to the
DF in the ECG during MVT. These data further support the idea that MVT,
in this episode, resulted from a functional reentrant source.
Conduction Velocity
Frequency analysis shows that conversion of VF to VT was
accompanied by a decrease in the DF of the arrhythmia. Possible
mechanisms for such a decrease include (1) the rotating waves traveling
along a longer trajectory, ie, increase in core size, or (2) a decrease
in the CV of rotating waves. Previous reports show that in addition to
blocking L-type calcium current, verapamil also partially
blocks sodium currents and reduces CV.18 To determine the
effect of verapamil in our system, local CVs were measured
in a group of 4 hearts. During pacing (CL=300 ms),
verapamil had a minor effect on CV.
CVmax decreased slightly from 54.4±2.2 cm/second
during control to 49.2±2.8 cm/second at 20 minutes of
verapamil perfusion, but this difference was not
statistically significant. Similarly, CVmin
decreased from 35.5±2.1 to 30.8±2.0 cm/second (P=ns).
Measurement of Core Dimensions
Without a reduction in CV, the most probable mechanism for
verapamil-induced decrease in the arrhythmia
frequency is an increase in core size.21 29 Thus, we
measured the core dimensions of several rotors during the first 5
minutes of control and after 20 minutes of verapamil
perfusion. Figure 4A shows 2
representative ECG traces and their corresponding
isochrone maps delineating the core of a spiral during control and
verapamil perfusion. In this example, in control, the core
is small (4.58 mm2), but during
verapamil perfusion the core area increases by >2-fold
(9.56 mm2). To illustrate the reliability of
the core delineation criteria, we show optical action potentials in
Figure 4B. Clearly, the amplitude of the optical action
potentials within the cores (Figure 4B-I) when the spiral is
present (represented by the solid black line) is <50%
of maximum (50% line is the dashed thin line), whereas, in the
perimeter of the core (Figure 4B-II), the amplitude is slightly
more than 50%, and at a distance from the core (Figure 4B-III),
it is significantly larger than 50% of maximum.
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The quantification of the core area is shown in Figure 5. Significant increases in core area
were seen with verapamil perfusion. During VF, in control
conditions, the cores had a mean area of 4.5±0.6
mm2 (n=7). After 20 minutes of
verapamil perfusion, the mean core area more than doubled
and measured 9.2±0.5 mm2 (n=5;
P=0.0002). Consistently, with the increase in core
area, we observed a lengthening of the rotation period from 60.5±1.5
(control) to 79.7±5.6 ms (verapamil) (P=0.003).
These data demonstrate that the slowing of the VF frequency during
verapamil perfusion most likely is the result of the
pivoting point of the spiral traveling a longer distance to complete a
rotation due to an increased core size.
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Effective Refractory Period
Verapamil decreases the ERP and
APD.19 30 Therefore, the conversion of VF to VT seemed
paradoxical. To confirm that verapamil has a similar effect
in our experimental model, in a group of 8 hearts, we studied its
effect on ERP. Figure 6 shows a plot of
ERP versus CL (S1-S1 interval). At every CL tested,
verapamil reduced the ERP (P=0.012) by 
7% to
9% from control values. Specifically, at the CLs of 250, 200, and 180
ms, the ERP changed from 161.3±4.8, 152.5±2.5, and 142.5±4.9 ms to
150±5.6 (P=0.026), 142.5±4.8 (P=0.025), and
130±4.1 ms (P=0.008), respectively.
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Computer Simulations
To further demonstrate that calcium channel blockade is
responsible for the increase in core size and the subsequent increase
in the rotation period, we carried out computer simulations of
sustained spiral wave reentry. Figure 7
shows 3-dimensional representation of 2 stable spiral waves
rotating around an elliptical core. Data are presented under
control conditions (Figure 7A;
Isi=100%) and during 75% reduction of
Isi (Figure 7B) simulating the
effect of verapamil. Isi
blockade reduces the APD (42%) and increases the rotation period of
the spiral (10%) by increasing the core size (26%) (Figure 7C). Additionally, we investigated the role of
Isi on curvature-related failure of
propagation toward the center of the core. In accordance with the
theory, the reentrant wavefront forms a spiral shape and exhibits
increasing curvature until a pronounced curvature is developed close to
the spiral tip. Here the wavefront fails to activate tissue
ahead. In this manner propagation toward the center of the spiral fails
(ie, conduction block). Therefore, to determine the effect of
Isi on propagation toward the center of the
spiral, we measured curvature at the site of maximum curvature. We
found that Isi blockade results in the
earlier development of conduction block (ie, propagation toward the
center of the core fails earlier), as indicated by the reduction of
curvature (9% along and across fibers, respectively) at this site.
Thus, the simulations show that the block of
Isi reduces the APD and increases the
rotation period of the spiral through an increase in the core size. The
measured electrophysiological
parameters are summarized in the Table.
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Discussion |
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This study demonstrates that verapamil in the isolated Langendorff-perfused rabbit heart transforms VF to MVT despite a decrease in the ERP. We have, for the first time, shown that verapamil-induced increase in the size of the core of rotating waves is a likely mechanism underlying such a transformation. The resultant lowering of the rotor frequency decreases fibrillatory propagation emanating from reentrant sources and is ultimately responsible for transforming the arrhythmia. Thus, the results demonstrate that, in addition to tissue refractoriness, the size of the core of rotating waves is likely an important factor that determines whether the arrhythmia is VF or MVT.
Rotors During Fibrillation and Tachycardia
The study of wave propagation in the heart has explained VF
in terms of self-organized 3-dimensional electrical
rotors11 that may destabilize (ie, break up) and give rise
to fibrillation.10 12 Recently, however, it has been
proposed that fibrillation, at least in the atria, may depend on the
uninterrupted periodic activity of discrete reentrant
sites.8 9 The shorter reentrant circuits act as sources
that maintain the overall activity. Chen et al9 provided
further support for the notion that fibrillatory conduction may be also
underlying VF in the isolated rabbit heart. They demonstrated that the
rapidly succeeding wavefronts emanating from periodic sources propagate
throughout the ventricles and interact with anatomic and functional
obstacles, leading to fragmentation and wavelet formation. In the
present study, we provide additional evidence that disordered
activation sequences, characteristic of VF, may be the result of
fibrillatory conduction. Furthermore, we show that frequency of the
source is an important determinant of the overall manifestation of the
arrhythmia.
VF-to-VT Transitions
One possible mechanism for the VF-to-VT conversion is the
anchoring of a rotor to a discontinuity or defect in the cardiac muscle
(eg, blood vessel).22 However, Figures 2 and 3 demonstrate that functional reentry is underlying both VF and
MVT. Furthermore, the VT-to-VF transition (Figure 2) during
washout further supports our contention that reentry was functional
rather than anatomic. In a functional reentrant circuit, the frequency
of the source to a large extent determines whether the overall
manifestation is disorganized fibrillation or organized
tachycardia. VF results when the cardiac tissue is unable
to keep up with the source and there is breakup of activity, ie,
fibrillatory conduction. However, if the source frequency is
sufficiently slow, then the emanating wave will not break up, in which
case tachycardia rather than fibrillation may be
observed.
Increase in Core Size May Result in VF-to-VT Transition
We demonstrated that the dominant frequency of VF decreases
from 16.2 Hz during control to 13.5 Hz after 20 minutes of
verapamil perfusion (Figure 1).
Simultaneously, there was a significant increase in the
core area from 4.5 mm2 (control) to 9.2
mm2 (verapamil) (Figure 5).
These data suggest that during verapamil perfusion, the
pivoting point of the spiral wave traveled a longer distance to
complete a rotation, which led to an increase in its period and a
slowing in the rate of VF. To ensure that the decrease in frequency is
due to a longer path length and not to slowing of propagation, we
measured local CVs during control and verapamil and found
that verapamil does not alter propagation velocity.
Therefore, this suggests that the lower frequency is the result of the
longer trajectory followed by the tip of the rotor rather than slower
propagation.
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Verapamil-Induced Increase in Core Size: Mechanisms |
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Sodium Currents and Core Size
The core of a rotating wave is formed under conditions determined by the kinetics of the sodium current and curvature-related block of conduction.31 32 Experimental and numeric studies in isolated cardiac muscle31 and other excitable media32 show that when excitability is normal, the critical radius of curvature is small; thus, reentrant circuits manifest as rotors moving rapidly around small cores. However, when excitability is lowered (eg, decreased conductance), the critical radius is large, thus resulting in the increase in the core size and rotation period. Our data suggest that verapamil does not significantly alter CV. Nevertheless, we cannot discount a minor blocking action of verapamil on sodium channels at high frequencies that can result in the block of conduction at a lesser curvature (ie, larger critical radius),31 thus contributing to an increase in the size of the core.
Calcium Current and Core Size
Our simulation demonstrates that by blocking
Isi, the core of the spiral wave is
altered. This suggests that calcium currents also influence the core
dynamics. Rohr et al33 showed that in the presence of
reduced electrical coupling, the calcium current is necessary for
sustained propagation. Similarly, a modeling study analyzing the
currents involved in intercellular communication presented
additional evidence for the role of the calcium current during such
conditions.34 Recently, Laurita et al35 used
imaging techniques that concurrently measured calcium transients and
transmembrane potentials and demonstrated that calcium is a major
contributor to transmembrane potential at sites of slow propagation
(eg, site of steep wavefront curvature). We suggest that curvature
effects at the core produce a load similar to those observed during
reduced coupling. Therefore, verapamil-induced block of
calcium current causes conduction to block at a lesser curvature
resulting in the increase in core size.21 We have
confirmed the effect of calcium channel blockade on curvature through
computer simulations and have shown that in our model, 75% block of
the Isi resulted in reduction of curvature
at the core by 10% along and across fibers, respectively. Therefore,
the mechanism for the increase in the size of the core may be the block
of conduction at a lesser curvature.
Effect of Wavelength/APD on Reentry
Wavelength shortening is believed to increase the vulnerability to
reentry15 16 36 and accelerate its rate, whereas an
increase in wavelength has the opposite effect.13 14
Therefore, induction of high-frequency VF would be expected with
verapamil. However, measurements of wavelength are not the
only predictors of the behavior of the system once reentry has been
established.37 38 Recent computer
simulations39 show that during functional reentry both APD
and wavelength change as functions of distance from the core.
Similarly, experiments demonstrate that both APD and wavelength change
dynamically depending on the orientation of propagation with respect to
the fiber axis.40 Hence, what finally determines the
arrhythmia expression (ie, VF or VT) is not simply APD or
wavelength. Rather, it depends on the intricate interplay among the
curvature effects, dynamics of the core, and the APD or ERP.
Can a Decrease in APD Organize Fibrillatory Activity?
On the basis of long-held views,13 14 36 it is
expected that APD shortening leads to more rapid and disorganized
reentrant activity. However, if the core of a rotating wave becomes
larger and the arrhythmia frequency decreases, then the
reduction of APD enables increased organization. Previous studies show
that spiral wave drift is a contributor to the complexity of the ECG
patterns during VF.2 In such a case, as predicted by
theory,41 increasing the wavelength causes a spiral wave
to drift secondary to the collision of the wavefront with the
refractory tissue ahead. The opposite effect is expected if the APD
shrinks; that is, the spiral drift decreases as a result of decreased
wavefront interactions with fully or partially refractory tissue. Our
experimental results and computer simulations demonstrate that
verapamil abbreviates the ERP, thereby decreases the chance
of waves interacting with refractory tails of previously propagating
waves, and thus slows the speed of drift and gives rise to a more
uniform ECG pattern. In addition to causing drift, inhomogeneities in
electrophysiological properties may also
result in the formation of wavebreaks when collisions occur. Using a
new technique4 (phase analysis), we have
quantified the formation of new wavebreaks (Figure 2) that
result when collisions occur. Our experiments show that there are 3
times as many PSs formed during VF as compared with MVT. This does not
necessarily imply that these new wavebreaks are the "sources" that
maintain fibrillation.4 However, it does strongly suggest
that the complex spatiotemporal patterns of excitation in the heart
evident during VF are the consequence of more fragmented propagation,
whereas MVT is the result of more uniform propagation.
It is also probable, as speculated by Riccio et al,30 that verapamil-induced changes in the restitution kinetics may play a role in preventing spiral wave breakup and thereby prevent induction of VF in the presence of verapamil and also convert VF to MVT. Such mechanisms, however, do not account for the frequency reduction that is accompanied by VF-to-MVT transition in our study.
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Technical Aspects and Limitations |
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Experimental. The high spatial resolution and the large field of view of the video camera provide an invaluable tool for the study of arrhythmias in the isolated heart. However, there are limitations to this approach that should be noted.3 20 22 Mechanical artifacts are among the major limitations of video-imaging systems. However, during VF, contraction is uncoordinated and weak, and with minimal restraining these artifacts can be eliminated; this alleviates the need to use electromechanical uncouplers. Therefore, in these experiments, we placed the heart between 2 glass plates and applied moderate levels of pressure and nearly eliminated motion. Another limitation is that the video imaging system has low signal-to-noise ratio, which requires spatial filtering, resulting in a reduced effective spatial resolution of the system.20
Computer Simulations
Computer simulations of 2-dimensional reentry were performed using
the 1991 version I of the Luo-Rudy model.26 This model is
limited in that Isi is not an accurate
description of calcium current in ventricular myocytes.
Furthermore, version I of the model does not incorporate mechanisms for
the regulation of the intracellular concentrations of ions. Newer and
more elaborate ionic models of cardiac excitation
exist.42 However, these models require large amounts
of computation time and are mostly empirical. Thus, our approach
represents a good tradeoff between computational expense and
description of ionic mechanisms.
Conclusions
Here, we demonstrated that functional reentry underlies VF
and MVT in the isolated Langendorff-perfused rabbit heart. Furthermore,
verapamil-induced VF-to-MVT conversion likely occurs as the
result of an increase in the size of the core of rotating waves that
may lead to a decrease in the rotor frequency and a reduction in
fragmentation of the excitation wavefronts.
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Acknowledgments |
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This work was supported by Grant PO1 HL 39707 from the National Heart, Lung, and Blood Institute; grants from the Whitaker Foundation (to J.B. and R.A.G.); and an American Heart Association New York State Affiliate Fellowship (to R.M.). Computational resources were provided by the National Partnership for Advanced Computational Infrastructure. We are grateful to Jiang Jiang, Fan Yang, and Li Gao for technical assistance, as well as Janet Jackson, Clara Wu, and late Laverne Gilbert for excellent secretarial support. Y.W. is the originator of the idea in this manuscript.
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Footnotes |
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1 Both authors contributed equally to this study.
Received July 21, 1999; accepted December 27, 1999.
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References |
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