© 1999 American Heart Association, Inc.
Integrative Physiology |
Virtual Electrode–Induced Reexcitation
A Mechanism of Defibrillation
From the Department of Cardiology, Cleveland Clinic Foundation, Cleveland, Ohio.
Correspondence to Igor R. Efimov, PhD, Department of Cardiology, Desk FF1, Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195. E-mail efimov{at}ieee.org
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Abstract—Mechanisms of defibrillation remain poorly understood. Defibrillation success depends on the elimination of fibrillation without shock-induced arrhythmogenesis. We optically mapped selected epicardial regions of rabbit hearts (n=20) during shocks applied with the use of implantable defibrillator electrodes during the refractory period. Monophasic shocks resulted in virtual electrode polarization (VEP). Positive values of VEP resulted in a prolongation of the action potential duration, whereas negative polarization shortened the action potential duration, resulting in partial or complete recovery of the excitability. After a shock, new propagated wavefronts emerged at the boundary between the 2 regions and reexcited negatively polarized regions. Conduction velocity and maximum action potential upstroke rate of rise dV/dt max of shock-induced activation depended on the transmembrane potential at the end of the shock. Linear regression analysis showed that dV/dtmax of postshock activation reached 50% of that of normal action potential at a Vm value of -56.7±0.6 mV postshock voltage (n=9257). Less negative potentials resulted in slow conduction and blocks, whereas more negative potentials resulted in faster conduction. Although wavebreaks were produced in either condition, they degenerated into arrhythmias only when conduction was slow. Shock-induced VEP is essential in extinguishing fibrillation but can reinduce arrhythmias by producing excitable gaps. Reexcitation of these gaps through progressive increase in shock strength may provide the basis for the lower and upper limits of vulnerability. The former may correspond to the origination of slow wavefronts of reexcitation and phase singularities. The latter corresponds to fast conduction during which wavebreaks no longer produce sustained arrhythmias.
Key Words: conduction • fibrillation • polarization • mapping • defibrillation
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The goal of defibrillation shocks is to resynchronize electrical activity to restore contractile function. Although the exact mechanisms of defibrillation are still poorly understood, it is clear that 2 main processes determine the success of a defibrillation shock. First, the defibrillation shock must extinguish irregular electrical activity. Second, the shock itself must not produce a new arrhythmia. Several theories have been proposed in an attempt to explain the mechanisms of defibrillation, but recent studies using high-resolution imaging of electrical activity during defibrillation shocks1 provide evidence of several inconsistencies in these theories.
One theory2 3 proposes the commonly accepted mechanism of extinguishing fibrillatory activity. According to this theory, resynchronization occurs through shock-induced prolongation of refractory periods (RPs) or action potential (AP) durations (APDs). However, our recent data suggest1 that due to the virtual electrode (VE) effect,4 APDs and RPs will be prolonged in some areas of myocardium while they shortened in other areas. These are areas of positive and negative polarization, respectively. Therefore, VEs may create a dispersion of repolarization.
There is no commonly accepted theory regarding the mechanisms of postshock arrhythmias that underlie defibrillation failure. Two alternative ideas are often considered: (1) persistent fibrillatory activity due to unextinguished wavelets or due to focal activity and (2) shock-induced new wavefronts and reentry. The first appears to be commonly accepted,5 whereas the second remains debatable.6 The upper limit of vulnerability theory, and specifically its critical point hypothesis,7 suggests that new reentrant wavefronts develop when a low-voltage gradient occurs in excitable gaps in the fibrillation. However, others have suggested8 that new wavefronts can be induced in fully refractory tissue. The mechanisms of this excitation remain unclear.
As suggested in our previous study,1 the VE effect may be responsible for at least 2 apparently proarrhythmic effects: (1) simultaneous prolongation and shortening of APDs may create significant dispersion of repolarization, and (2) new shock-induced wavefronts can interact with this APD dispersion and develop block of conduction that results in wavebreaks and reentrant arrhythmias. A wavebreak is a critical point between propagating wavefront and the line of block.
The role of VEs in successful monophasic defibrillation is controversial. Any monophasic shock will produce VEs. Therefore, why do some VEs result in phase singularity and arrhythmia and others do not? We hypothesized that the shortening of APD produced by the negative polarization is the key. Shortening of APD by an intracellular stimulus applied during the RP is a well known effect that has been demonstrated in isolated cells, fibers, and tissue strips.9 10 11 12 This effect has been termed "deexcitation," "immediate repolarization," "forced repolarization," "regenerative repolarization," and "all-or-nothing repolarization." It is also referred to as "hyperpolarization" when the transmembrane voltage is more negative than the resting potential.
Until our recent study,1 the effect of deexcitation had not been observed in the intact heart during extracellular stimulation. We hypothesized that this effect not only is present during defibrillation shocks but also may play a major role in the success and failure of defibrillation therapy. We quantitatively investigated the genesis and conduction of shock-induced wavefronts and wavebreaks and their relation to deexcitation. Our data provide mechanistic insights into defibrillation, as well as the lower and upper limits of vulnerability.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Detailed protocols have been previously published.1 13 Langendorff-perfused rabbit hearts (n=20) were paced at the apex at a 300-ms cycle length with 2-ms pulses. Hearts were stained with 20-µmol/L di-4-ANEPPS (Molecular Probes) during 5 to 10 minutes. Temperature and pH were maintained at 36±0.5°C and 7.35±0.05, respectively. 2,3-Butanedione monoxime (BDM; 15 mmol/L; Fisher Chemical) was added. Monophasic shocks (150 µF, 8 ms, ±20 to 300 V) were delivered 100 ms after the average activation time with the use of a defibrillator (HVS-02; Ventritex) between the 2 coil electrodes.13
Fluorescence was excited at 520±45 nm and collected above 610 nm with the use of a photodiode array (C4675; Hamamatsu). Spatial and temporal resolution of optical recordings was 375 to 970 µm and 528 µs, respectively. The signal-to-noise ratio (SNRRMS) was 250±80. Transmembrane voltage was calculated from fluorescent recordings with the use of a pseudo-mV calibration.14 We assumed that the normal AP has a 100-mV amplitude and a -85-mV resting potential.
Optical recordings represent the average electrical activity of a large number of cells. The observed dF/dt during optical AP upstroke depends on the conduction velocity, spatial resolution, and optical depth of field.15 Therefore, the absolute rate of rise during cellular AP upstroke cannot be measured from optical recordings. We estimated the rate of rise during shock-induced responses (postshock dF/dt) with respect to that of the normal AP upstroke dF/dt by calculating their ratio. Here, we refer to this ratio as the upstroke rate of rise dV/dtmax of postshock activation.
To correlate the rate of postshock excitation with the degree of deexcitation produced by negative polarization, we measured the dV/dtmax of upstrokes of optical postshock responses. We hypothesized that this rate would depend on the excitability of deexcited cells. Excitability is determined by 2 factors: the degree of deexcitation produced by negative polarization, and the time lapsed after the shock withdrawal. The latter component does not depend on shock-induced VE polarization (VEP) and thus was considered to be a contamination of the studied phenomenon. Therefore, we designed inclusion criteria that would automatically remove this contamination. We included in our analysis only the records of postshock excitation that were excited between 5 and 30 ms after the shock withdrawal. Furthermore, the rate of excitation depends on the driving force, which is especially important at the boundary between areas of positive and negative polarization. Although the process at the boundary is an important phenomenon in the genesis of wavefront via break excitation, this effect would also contaminate the studied correlation between the deexcitation and the rate of postshock excitation that occur at a distance from the boundary. Therefore, we also excluded this effect by considering only the sites that were deexcited by >-20 mV from the preshock transmembrane voltage. Such criterion effectively excluded areas at the boundary between the oppositely polarized regions.
To automatically process the large amounts of data, a program was developed with the use of C++. This program used a 5-point boxcar filter and automatically calculated postshock transmembrane voltage, dV/dtmax, and APD as described earlier. No manual correction was required except in APD measurements. Data are expressed as mean±SD.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
VEs Simultaneously Prolong and Shorten APD
Conventional electrode and optical recordings provided evidence that a strong electric shock prolongs APD and RP.2 16 This effect became a key element of the theory of defibrillation; however, with this theory, we could not explain how shocks of either polarity could both prolong APDs. We investigated this apparent paradox.
The first striking finding was the observation that the APD may be both
prolonged and shortened at the same time in different areas of the
epicardium due to the VE effect. Figure 1A
shows a postshock map of transmembrane
voltage at the end of -100-V shock applied during the RP of a normal
AP. Positive polarization was produced next to the right
ventricular (RV) electrode (not shown) in the left half of
the field of view. Negative polarization was observed in the adjacent
left ventricular (LV) area (right half of the field of
view). Figure 1B shows a map of postshock activation. The sites
of the origin of the wavefront of postshock activation are shown in
white and located at both sides of the positively polarized areas
(compare with panel A). Activation spread along an arrow, forming
reentry. Figure 1C shows 15 raw traces recorded sequentially
along this arrow. As seen from these traces, shortening and
prolongation of APD was produced by negative and positive polarization,
respectively. Figure 1D further illustrates these observations
in all 256 unfiltered traces recorded during this shock-induced
arrhythmia.
|
We investigated the simultaneous prolongation and
shortening of APD in 5 experiments in which the shock electrode was
placed in the LV. This electrode position was chosen because it was
less likely to result in an arrhythmia compared with an RV
shock. As shown in Figure 1C
and 1D, the onset of an
arrhythmia would make it impossible to measure the APD of the
postshock response. The top panels of Figure 2 show maps of transmembrane voltage at
the end of an anodal monophasic (+200 V) shock (left) and the
APD90 of normal (middle) and a shock-altered
(right) responses. These data were recorded from a 15.5x15.5-mm
area of the LV epicardium. The bottom panel of Figure 2 shows
representative traces recorded from the areas
selected with black boxes in the top panels. Two superimposed maps of
optical recordings are shown: APs recorded during the last
basic beat and during a shock at the boundary between the positively
(red traces) and negatively (blue traces) polarized areas. Notice that
APDs were shortened in the area of negative polarization. In contrast,
APDs were prolonged in the area of positive polarization. This resulted
in a significant dispersion of repolarization.
|
In contrast, Figure 3 shows responses
that appear as APD prolongation in all areas. These data were
recorded when the shock strength was increased to +300 V. As
evident from the representative traces shown in the
bottom panel and the maps of APDs in the top panels, there was little
difference in the areas of positive polarization (red traces) but a
dramatic change in the areas of negative polarization (blue traces)
compared with Figure 2. Repolarization times in the positively
polarized areas were progressively prolonged with increases in shock
strength from +100 (not shown) to +300 V. On the contrary, in the area
of negative polarization, repolarization times were first shortened and
then prolonged with shocks ranging from +100 to +300 V. Is this bimodal
response caused by shock-induced prolongation of APD or by a new
response? And if it is caused by a new response, what is the origin of
this response?
|
Figure 4 illustrates the
transmembrane voltage distribution at the end of shocks (+100, +200,
and +300 V) along a horizontal line shown in the top left panels of
Figures 2 and 3. The voltage gradient between positively
and negatively polarized areas progressively increased with increasing
in shock intensity. Areas of negative polarization reached -23.8,
-41.9, and -52.8 mV, for +100-, +200-, and +300-V shocks,
respectively. As evident from Figures 2 and 3, only the
+300-V shock produced an extension of recovery time in the negatively
polarized area. The Table summarizes the average extension of APD
(
APD90) that resulted from shocks of different
amplitude and either polarity (7950 analyzed
recordings, 5 hearts). Asterisks in the Table indicate
data that contained both shortening and prolongation of APD in
different channels; daggers indicate that data were measured when no
shortening was observed. Averaging of APD90
was done across the entire field of view, including both positive
(prolongation) and negative (shortening) polarizations.
|
|
Modulation of Negative Polarization and Rate of Rise of Postshock
Excitation by Shock Intensity
Analysis of the transition from APD shortening to APD
prolongation is complicated due to the spatial
heterogeneity of the polarization and due to the rapid
postshock excitation that usually follows the shock withdrawal (Figure 5). Therefore, we chose to evaluate the
degree of shock-induced deexcitation and the recovery of excitability
based on the rate of rise of postshock activation. Figure 5
summarizes the results of 1 experiment. Figure 5A shows a
typical VEP pattern produced by a cathodal shock (-100 V). Figure 5B shows 7 superimposed optical traces recorded from the
same site during shocks with different amplitudes (-60 to -260 V). As
seen from the red trace in this figure, the weakest shock (-60 V)
resulted in deexcitation and shortening of APD. An increase in shock
intensity to -80 V (green trace) resulted in stronger negative
polarization and a slowly rising postshock response, which was absent
after the -60-V shock. Further increases in shock intensity resulted
in stronger negative polarizations and faster postshock responses.
Figure 5C summarizes the data from all 7 shocks. This figure
includes data from a total of 656 recording sites that were
negatively polarized by the shock to >-20 mV relative to preshock
value and that were activated between 5 and 30 ms after the
shock withdrawal. There is a clear correlation between postshock
transmembrane voltage and the rate of rise of postshock upstroke.
|
A linear regression analysis was used as the simplest possible
approximation to quantitatively analyze this distribution. It
resulted in the following equation:
dV/dtrelative=A+B*Vm,
where A is -0.833±0.047 and B is -0.024±0.001
mV-1. dV/dtrelative refers
to the ratio between the postshock dF/dtmax and
that of the normal AP. dV/dtrelative reached 50%
at a Vm value of -55.5±2.0 mV in this
case. Figure 6 shows 8 additional
individual experiments and a summary for 9 hearts. Linear regression
analysis conducted on data from the 9 hearts with a total of
9257 recordings showed that dV/dtmax of
reexcitation reached 50% of that of normal AP at a
Vm value of -56.7±0.6 mV. The remaining 6
experiments were qualitatively analyzed, and similar phenomena
were observed. Thus, these observations were reproduced in all 15
hearts studied.
|
Shock-Induced Reexcitation and Propagated Activation
Wavefronts
As follows, recovered regions may be subsequently excited and
support an active, propagated response. Figure 7 demonstrates 1 such example. The top
panel shows 8 optical recordings from a line of photodiodes
identified in the diagram as 1 to 8. As evident from the activation map
(bottom), recording sites were chosen along the conduction
velocity vector (black arrow). All of these sites were negatively
polarized at the end of a -100-V monophasic shock. As seen in the top
panel of Figure 7, all 8 recording sites were
sequentially reexcited. Excitation started from a site near the shock
electrode and then spread away from the electrode. The sequence of
reexcitation cannot be explained by the passive discharge of the
membrane due to its propagative nature. A purely electrotonic response
also fails to explain this sequential depolarization, because distant
recordings sites are located more than several space constants
away. Lower maps in Figure 7 show the pattern of transmembrane
voltage at the end of the shock and a 5-ms isochrone map of
postshock activation. These maps further support the earlier
conclusions regarding the propagating nature of the postshock response.
The arrows in these maps show the location and direction of the
recording sites illustrated in the top panel.
|
These data are consistent with the idea that excitability may be recovered in refractory tissue if sufficiently negative polarization is produced. As a result, it can be subsequently reexcited if sufficient driving force is provided. What are the possible sources of this driving force, and how it is transmitted?
Relation Between the Postshock Propagation and VE Polarization
Amplitude
We previously demonstrated that the VE effect may result in the
genesis of new wavefronts of activation.1 The conduction
velocity of a new wavefront depends on both the degree of excitability
in the negatively polarized regions and the driving force provided by
the positively polarized regions. To investigate this dependence, we
analyzed activation maps and maps of transmembrane voltage at
the end of shocks of different intensity.
Figures 8 and 9 illustrate a typical finding. Figure 8A shows that a -80-V shock resulted in VEP with
Vm ranging from -4 to -68 mV in
positively and negatively polarized regions, respectively. Deexcitation
to a transmembrane voltage of 
-60 mV occurred in the most negatively
polarized region at the bottom right of the field of view (dark-blue
area). As illustrated in the activation map of Figure 8A, this
region was subsequently slowly excited. Incomplete deexcitation (-40
to -60 mV) in the upper right (light blue) precluded the genesis of a
wavefront of reexcitation. This region was also subsequently excited,
pending its recovery. The wavefront then turned around and produced a
reentrant circuit, which resulted in an arrhythmia.
|
|
Increasing the shock intensity to -160 V resulted in an increase in
both the amplitude and the area of positive and negative polarization.
Complete deexcitation (dark-blue area) was now achieved in a
significant area occupying the bottom right of the field of view. Thus,
a wavefront of reexcitation was produced in a larger area and promptly
propagated across the entire deexcited region, reaching the right edge
of the field of view only 20 ms after shock withdrawal. Such prompt
excitation did not provide sufficient time for recovery of the
incompletely deexcited regions; therefore, no reentry was induced by
this wavefront. Interestingly, the small area of complete deexcitation
in the upper right of Figure 8B (small dark-blue region) was not
activated. This was presumably due to the lack of adequate
electrotonic interaction between this region and the positively
polarized region, which is necessary for wavefront generation. Thus,
deexcitation is a required, but not a sufficient, condition for
postshock reexcitation. A certain gradient between the positively and
negatively polarized regions is also required for the genesis of a
postshock wavefront.
Further increase in shock intensity to -220 V (Figure 8C)
resulted in complete deexcitation in nearly the entire negatively
polarized region (dark-blue area). Such strong deexcitation provided
conditions for the genesis of a new wavefront along the entire border
between the areas of positive and negative polarization. As in the
previous case, no reentry could be produced.
Thus, the conduction velocity of postshock excitation depended on the transmembrane voltage at the end of shock (ie, degree of shock-induced deexcitation).
Figure 9 illustrates the genesis of a VE-induced wavefront with
optical recordings taken along the gradient between the
positive and negative polarizations. Recording sites are shown
with the thick green arrows in Vm maps of
Figure 8. Figure 9A shows that -60 mV was barely reached
at the end of shock in the area of negative polarization. Nevertheless,
due to the strong electrotonic driving force provided from the
positively polarized region, a slowly rising and slowly propagating
wavefront was generated. Two distal recording sites shown near
the arrowhead could not be reached through electrotonus from the
positively polarized region due to the great distance. Therefore, they
were presumably activated by an active, slowly propagated
response. Due to the slow propagation, these sites had more time to
repolarize, reaching well below -60 mV. Better recovery resulted in
larger amplitudes of the postshock responses and
dV/dtmax.
Figure 9B illustrates that an increase of shock intensity to
-160 V resulted in deexcitation with transmembrane voltages reaching
well below -60 mV at the end of shock in all distal sites. In
addition, stronger positive polarization provided a stronger driving
force, as can be estimated from the magnitude of the transmembrane
voltage gradient at the end of shock between positively and negatively
polarized sites. As a result, a vigorous wavefront of reexcitation with
nearly normal AP amplitude was generated and rapidly propagated in
these sites. A further increase of shock intensity to -220 V (Figure 9C) resulted in stronger negative polarization, a stronger
gradient between the 2 opposite polarizations, and faster conduction of
the postshock wave of reexcitation.
Correlation Between Negative Polarization and Postshock
Activation
Figure 10 summarizes an
analysis of the reproducibility of these findings, in which we
analyzed the relationship between shock intensity and the rate
of rise of postshock activations and transmembrane voltage at the end
of shock. As described in Materials and Methods, a fully automated,
exhaustively tested computer algorithm was developed to analyze
tens of thousands of optical records. Figure 10 shows
transmembrane voltage at the end of shocks (last 528 µs) and the rate
of rise of postshock excitation as a function of shock intensity. With
the criteria described in Materials and Methods, the computer algorithm
selected an average of 101.9±29.0 of 256 recording sites per
shock, represented as a single data point. The data shown
in 9 panels varied with respect to sample size, due to the differences
in polarization pattern. The average numbers of recording sites
per data point in experiments 1 to 9 were 93.7±6.1, 77.2±16.7,
63.2±7.7, 78.8±22.5, 116.6±10.3, 109.3±21.8, 122.4±15.3,
119.1±11.5, and 141.8±21.4, respectively. Data from a total of 9257
of 23 296 analyzed recordings met the criteria
described in Materials and Methods and were included in this figure.
The data clearly show progressively more negative
Vm values and stronger
dV/dtmax values with increasing shock
intensity.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Fibrillation and defibrillation are profoundly complex and poorly understood processes. No known experimental technique can be used to fully assess the electrical activity during these processes with adequate resolution in 3 dimensions. The recent application of voltage-sensitive dyes17 and imaging techniques18 to defibrillation research has made it possible to measure electrical activity free of electric field artifacts3 13 19 with high spatiotemporal resolution.
VE Effect
Using this technology, we demonstrated both that the VE effect is
present and that it is likely to play an important role during
defibrillation.1 This was previously theoretically
predicted for point stimulation4 and experimentally
demonstrated during epicardial pacing.20
The VE effect can occur at macroscopic and microscopic scales due to intramyocardial and extramyocardial heterogeneities and discontinuities. Sepulveda et al4 predicted that in a two-dimensional bidomain model, areas of opposite polarizations would be induced by epicardial stimuli due to the unequal anisotropic properties of intracellular and extracellular spaces in the myocardium. Roth21 also predicted that this effect might produce transient wavebreaks, which, however, could not result in sustained reentry. These VEPs were experimentally observed during epicardial pacing by several groups.20 22 23 A similar, but much stronger, effect was found during defibrillation shocks.13 Fast et al24 demonstrated that positive and negative polarizations might be produced by electric shocks at opposite sides of microscopic tissue clefts. These VEs were induced on tissue discontinuities and may produce propagated responses.24 White et al25 observed similar effects on a macroscopic scale. Trayanova26 predicted, using a bidomain model, that areas of opposite polarizations can occur at any tissue/bath interface.
Despite apparent differences in the exact mechanism of VE effect, it appears to be produced primarily by passive structural heterogeneities/discontinuities. These modulate and redistribute extracellularly applied fields, producing an inward or outward activating current in different parts of the myocardium. This current produces positive or negative polarizations, respectively. The general nature of the mechanism was best expressed by Sobie et al.27 One might argue that during extracellularly applied fields, no net current flow across the membrane would occur. Thus, the presence of areas of opposite polarization next to each other is a consequence of the redistribution of charges between neighboring regions of the syncytium, next to the discontinuity/heterogeneity. Therefore, a single myocyte, being a part of the syncytium, may undergo transmembrane polarization due to macroscopic charge redistribution within intracellular or extracellular domains without actual transmembrane current injection.
Relation Between Break Excitation and Reexcitation Wavefront
Mechanisms
Break excitation has been proposed to explain the mechanisms of
pacing based on VE effect.20 According to this mechanism,
negatively polarized areas will be simultaneously
activated after the withdrawal of a long stimulus by an
electrotonically transmitted driving force from neighboring positively
polarized area. During defibrillation, this may not be exactly the same
because of scale differences. Indeed, negatively polarized areas,
although fully excitable, can extend to large distances, comparable
with the size of the entire ventricle.13 Clearly,
electrotonic transmission cannot reach such remote areas. Break
excitation can only initiate new wavefronts at the boundary between
positively and negatively polarized areas, which then propagate across
the negatively polarized region, as demonstrated in this study.
Alternative theory of break excitation suggested that the postshock depolarization may result from hyperpolarization-activated IF current.28 Unfortunately, our data do not provide direct verification of this hypothesis, because the degree of negative polarization observed in our study was insufficient to open IF current. Additional studies are required to evaluate the contribution of the mechanism of break excitation of Ranjan et al28 to defibrillation.
VE-Induced Reexcitation: Mechanism of Defibrillation
The VE effect has dual roles in defibrillation. Due to this
effect, a monophasic defibrillation shock of any polarity can erase
preexisting fibrillatory activity by rapidly resetting the phase and
inducing positive and negative polarization in neighboring areas.
However, at the same time, this effect may create a new
arrhythmia via induction of VE-induced phase
singularities.1
This report shows that conduction velocity and AP rate of rise of a
postshock reexcitation wavefront depends on the transmembrane voltage
in negatively polarized areas (see Figures 5 through 10). Conduction can be very slow
and discontinuous with unidirectional blocks when deexcitation is
insufficient. Perhaps such slow, discontinuous conduction is supported
when polarization resulted in recovery from inactivation of calcium but
not sodium channels (see Figure 8A). In this case, phase
singularities and arrhythmias are induced, leading to
defibrillation failure.1
As we recently demonstrated, optimal biphasic defibrillation shocks can cancel the VEs and the phase singularity resulting from it.1 Effective second phases of optimal defibrillation waveforms cancel the VE effect produced by the first phase. This may be the best scenario for successful defibrillation, because no dispersion of repolarization or new propagated wavefronts will be induced by the shock. This mechanism is likely to underlie type A defibrillation with no postshock responses.
Alternatively, successful defibrillation may result from shocks
producing strong VE polarizations. In this case, negatively polarized
areas will be rapidly reexcited by break excitation–induced propagated
responses. Reexcitation can be completed within milliseconds after the
shock (Figure 8C). Although wavebreaks may be induced, they do
not result in sustained arrhythmias, because of the rapid
conduction velocity and the long wavelength of the shock-induced
response. This mechanism may underlie type B defibrillation,
characterized by the occurrence of a few extra beats induced by
wavebreaks.
Implications to Lower and Upper Limits of Vulnerability
Chen et al29 was first to point out that the
proarrhythmic and antiarrhythmic effects of strong electric shocks are
in a causal relationship, proposing the upper limit of vulnerability
theory. Our data indicate that progressive increases in shock intensity
will result in passing 2 distinct thresholds, with the separation of
fundamentally different proarrhythmic responses produced by VEs. First,
the weakest shocks will produce prolongation and shortening of APs in
areas of positive and negative polarization, respectively. This will
produce a dispersion of repolarization but will not result in
shock-induced wavefronts and therefore cannot be proarrhythmic (Figure 2). Further increases in shock intensity will result in recovery
from inactivation in some areas and will result in the creation of both
dispersion of repolarization and reexcitation wavefronts (Figures 1 and 3). VE-induced phase singularity and slow
conduction will result in the genesis of arrhythmias. The
threshold in shock intensity between these 2 types of responses may
correspond to the lower limit of vulnerability. Further gradual
increases in shock intensity will result in a gradually stronger
negative polarization and more rapid reexcitation. At some shock
voltage, the reexcitation wavelength will be too long to sustain the
reentrant circuit (Figure 8B and 8C); therefore, no sustained
arrhythmia will be induced, and the upper limit of
vulnerability will be reached.
Study Limitations
We recently demonstrated that the VE phenomenon is essentially
3-dimensional.30 Therefore, the 2-dimensional mapping
technique used in this study provides somewhat limited insights into
the mechanism. For instance, the driving force may come from deeper
layers of the myocardium, which may introduce a distortion
in the spatial correlation between postshock transmembrane
polarizations and resulting propagation. Nevertheless, our data
strongly indicate that the observed phenomenon of shock-induced
reexcitation by propagated wavefronts can be easily extended to the
3-dimensional situation. Unfortunately, no experimental technique is
available at present to assess the 3-dimensional map of electrical
activity. Computer simulations may provide the missing link between
passive bidomain predictions of VE effects and the resulting
3-dimensional pattern of electrical activity.
The possible impact of BDM has been previously addressed.13 BDM has limited effects on the APD of rabbit atrioventricular nodal cells31 and ventricular cells.32 However, the effects of BDM on shock-induced responses remain to be investigated.
|
Acknowledgments |
|---|
This work was supported by NIH grants R01-HL59464 and R01-HL58808 and American Heart Association, Northeast Ohio Affiliate, Grant-in-Aid 9806201. We thank Dr D. W. Wallick for careful review of the manuscript.
Received July 9, 1999; accepted September 21, 1999.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
1. Efimov IR, Cheng Y, Van Wagoner DR, Mazgalev T, Tchou PJ. Virtual electrode-induced phase singularity: a basic mechanism of failure to defibrillate. Circ Res. 1998;82:918–925.
2.
Witkowski FX, Penkoske PA. Refractoriness prolongation
by defibrillation shocks. Circulation. 1990;82:1064–1066.
3.
Dillon SM. Synchronized repolarization after
defibrillation shocks: a possible component of the defibrillation
process demonstrated by optical recordings in rabbit heart.
Circulation. 1992;85:1865–1878.
4. Sepulveda NG, Roth BJ, Wikswo JP Jr. Current injection into a two-dimensional anisotropic bidomain. Biophys J. 1989;55:987–999.[Medline] [Order article via Infotrieve]
5. Walcott GP, Knisley SB, Zhou X, Newton JC, Ideker RE. On the mechanism of ventricular defibrillation. Pacing Clin Electrophysiol. 1997;20:422–431.[Medline] [Order article via Infotrieve]
6.
Chen PS, Wolf PD, Ideker RE. Mechanism of cardiac
defibrillation: a different point of view. Circulation. 1991;84:913–919.
7. Frazier DW, Wolf PD, Wharton JM, Tang AS, Smith WM, Ideker RE. Stimulus-induced critical point: mechanism for electrical initiation of reentry in normal canine myocardium. J Clin Invest. 1989;83:1039–1052.
8.
Kwaku KF, Dillon SM. Shock-induced depolarization of
refractory myocardium prevents wave-front propagation in
defibrillation. Circ Res. 1996;79:957–973.
9. Weidmann S. Effect of current flow on the membrane potential of cardiac muscle. J Physiol. 1951;115:227–236.
10. Chang JJ, Schmidt, RF. Prolonged action potentials and regenerative repolarization responses in Purkinje fibers of mammalian heart. Arch Physiol. 1960;272:127–140.
11. Hall AE, Noble D. Transient responses of Purkinje fibers to non-uniform currents. Nature. 1963;199:1294–1295.[Medline] [Order article via Infotrieve]
12. Vassale M. Analysis of cardiac pacemaker potential using a "voltage clamp" technique. Am J Physiol. 1966;210:1335–1341.
13. Efimov IR, Cheng YN, Biermann M, Van Wagoner DR, Mazgalev T, Tchou PJ. Transmembrane voltage changes produced by real and virtual electrodes during monophasic defibrillation shock delivered by an implantable electrode. J Cardiovasc Electrophysiol. 1997;8:1031–1045.[Medline] [Order article via Infotrieve]
14.
Gray RA, Ayers G, Jalife J. Video imaging of atrial
defibrillation in the sheep heart. Circulation. 1997;95:1038–1047.
15. Girouard SD, Laurita KR, Rosenbaum, DS. Unique properties of cardiac action potentials recorded with voltage-sensitive dyes. J Cardiovasc Electrophysiol. 1996;7:1024–1038.[Medline] [Order article via Infotrieve]
16. Dillon SM, Mehra R. Prolongation of ventricular refractoriness by defibrillaion shocks may be due to additional depolarization of the action potential. J Cardiovasc Electrophysiol. 1992;3:442–456.
17. Davila HV, Salzberg BM, Cohen LB, Waggoner AS. A large change in axon fluorescence that provides a promising method for measuring membrane potential. Nat New Biol. 1973;241:159–160.[Medline] [Order article via Infotrieve]
18.
Grinvald A, Cohen LB, Lesher S, Boyle MB.
Simultaneous optical monitoring of activity of many neurons
in invertebrate ganglia using a 124-element photodiode array.
J Neurophysiol. 1981;45:829–840.
19.
Zhou X, Ideker RE, Blitchington TF, Smith WM, Knisley
SB. Optical transmembrane potential measurements during
defibrillation-strength shocks in perfused rabbit hearts. Circ
Res. 1995;77:593–602.
20. Wikswo JP, Lin S-F, Abbas RA. Virtual electrodes in cardiac tissue: a common mechanism for anodal and cathodal stimulation. Biophys J. 1995;69:2195–2210.[Medline] [Order article via Infotrieve]
21. Roth BJ. A mathematical model of make and break electrical stimulation of cardiac tissue by a unipolar anode or cathode. IEEE Trans Biomed Eng. 1995;42:1174–1184.[Medline] [Order article via Infotrieve]
22. Knisley SB, Hill BC, Ideker RE. Virtual electrode effects in myocardial fibers. Biophys J. 1994;66:719–728.[Medline] [Order article via Infotrieve]
23. Neunlist M, Tung L. Spatial distribution of cardiac transmembrane potentials around an extracellular electrode: dependence on fiber orientation. Biophys J. 1995;68:2310–2322.[Medline] [Order article via Infotrieve]
24.
Fast VG, Rohr S, Gillis AM, Kleber AG. Activation of
cardiac tissue by extracellular electrical shocks: formation of
"secondary sources" at intercellular clefts in monolayers of
cultured myocytes. Circ Res. 1998;82:375–385.
25.
White JB, Walcott GP, Pollard AE, Ideker RE. Myocardial
discontinuities: a substrate for producing virtual electrodes that
directly excite the myocardium by shocks. Circ. 1998;97:1738–1745.
26. Trayanova NA. Effects of the tissue-bath interface on the induced transmembrane potential: a modeling study in cardiac stimulation. Ann Biomed Eng. 1997;25:783–792.[Medline] [Order article via Infotrieve]
27. Sobie EA, Susil RC, Tung L. A generalized activating function for predicting virtual electrodes in cardiac tissue. Biophys J. 1997;73:1410–1423.[Medline] [Order article via Infotrieve]
28. Ranjan R, Chiamvimonvat N, Thakor NV, Tomaselli GF, Marban E. Mechanism of anode break stimulation in the heart. Biophys J. 1998;74:1850–1863.[Medline] [Order article via Infotrieve]
29.
Chen PS, Shibata N, Dixon EG, Martin RO, Ideker RE.
Comparison of the defibrillation threshold and the upper limit of
ventricular vulnerability. Circulation. 1986;73:1022–1028.
30. Entcheva E, Eason J, Efimov IR, Cheng Y, Malkin RA, Claydon F. Virtual electrode effects in transvenous defibrillation: modulation by structure and interface: evidence from bidomain simulations and optical mapping. J Cardiovasc Electrophysiol. 1998;9:949–961.[Medline] [Order article via Infotrieve]
31. Cheng Y, Mowrey KA, Efimov IR, Van Wagoner DR, Tchou PJ, Mazgalev TN. Effects of 2,3-butanedione monoxime on the atrial-atrioventricular nodal conduction in isolated rabbit heart. J Cardiovasc Electrophysiol. 1997;8:790–802.[Medline] [Order article via Infotrieve]
32. Tovar O, Amanna A, Milne K, Krauthamer V, Jones J. Effects of diacetyl monoxime on cardiac action potential duration and fibrillation cycle length. Pacing Clin Electrophysiol. 1994;17(II):824. Abstract.
This article has been cited by other articles:
 |
|
 |
|
  V. Raman, A. E. Pollard, and V. G. Fast Shock-induced changes of Cai2+ and Vm in myocyte cultures and computer model: Dependence on the timing of shock application Cardiovasc Res, January 1, 2007; 73(1): 101 - 110. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G.-S. Hwang, H. Hayashi, L. Tang, M. Ogawa, H. Hernandez, A. Y. Tan, H. Li, H. S. Karagueuzian, J. N. Weiss, S.-F. Lin, et al. Intracellular Calcium and Vulnerability to Fibrillation and Defibrillation in Langendorff-Perfused Rabbit Ventricles Circulation, December 12, 2006; 114(24): 2595 - 2603. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Trayanova Defibrillation of the heart: insights into mechanisms from modelling studies Exp Physiol, March 1, 2006; 91(2): 323 - 337. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Li, V. Nikolski, D. W. Wallick, I. R. Efimov, and Y. Cheng Mechanisms of enhanced shock-induced arrhythmogenesis in the rabbit heart with healed myocardial infarction Am J Physiol Heart Circ Physiol, September 1, 2005; 289(3): H1054 - H1068. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Qu, L. Li, V. P. Nikolski, V. Sharma, and I. R. Efimov Mechanisms of superiority of ascending ramp waveforms: new insights into mechanisms of shock-induced vulnerability and defibrillation Am J Physiol Heart Circ Physiol, August 1, 2005; 289(2): H569 - H577. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Rodriguez, L. Li, J. C. Eason, I. R. Efimov, and N. A. Trayanova Differences Between Left and Right Ventricular Chamber Geometry Affect Cardiac Vulnerability to Electric Shocks Circ. Res., July 22, 2005; 97(2): 168 - 175. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Ashihara and N. A. Trayanova Cell and tissue responses to electric shocks Europace, January 1, 2005; 7(s2): S155 - S165. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Rodriguez, B. M. Tice, J. C. Eason, F. Aguel, J. M. Ferrero Jr., and N. Trayanova Effect of acute global ischemia on the upper limit of vulnerability: a simulation study Am J Physiol Heart Circ Physiol, June 1, 2004; 286(6): H2078 - H2088. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. T. Sambelashvili, V. P. Nikolski, and I. R. Efimov Virtual electrode theory explains pacing threshold increase caused by cardiac tissue damage Am J Physiol Heart Circ Physiol, June 1, 2004; 286(6): H2183 - H2194. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Ashihara, T. Namba, T. Ikeda, M. Ito, K. Nakazawa, and N. Trayanova Mechanisms of Myocardial Capture and Temporal Excitable Gap During Spiral Wave Reentry in a Bidomain Model Circulation, February 24, 2004; 109(7): 920 - 925. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Cheng, L. Li, V. Nikolski, D. W. Wallick, and I. R. Efimov Shock-induced arrhythmogenesis is enhanced by 2,3-butanedione monoxime compared with cytochalasin D Am J Physiol Heart Circ Physiol, January 1, 2004; 286(1): H310 - H318. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. P. Nikolski, A. T. Sambelashvili, V. I. Krinsky, and I. R. Efimov Effects of electroporation on optically recorded transmembrane potential responses to high-intensity electrical shocks Am J Physiol Heart Circ Physiol, January 1, 2004; 286(1): H412 - H418. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Chattipakorn, I. Banville, R. A Gray, and R. E Ideker Effects of shock strengths on ventricular defibrillation failure Cardiovasc Res, January 1, 2004; 61(1): 39 - 44. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. T. Sambelashvili, V. P. Nikolski, and I. R. Efimov Nonlinear effects in subthreshold virtual electrode polarization Am J Physiol Heart Circ Physiol, June 1, 2003; 284(6): H2368 - H2374. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. R. Efimov, K. A. Mowrey, Y. Cheng, and P. J. Tchou Reply Europace, January 1, 2003; 5(3): 243 - 244. [Full Text] [PDF]
|
|
|
|
|
|
Y. Cheng, K. A. Mowrey, V. Nikolski, P. J. Tchou, and I. R. Efimov Mechanisms of shock-induced arrhythmogenesis during acute global ischemia Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2141 - H2151. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. P. Nikolski, A. T. Sambelashvili, and I. R. Efimov Mechanisms of make and break excitation revisited: paradoxical break excitation during diastolic stimulation Am J Physiol Heart Circ Physiol, February 1, 2002; 282(2): H565 - H575. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. A. Mowrey, Y. Cheng, P. J. Tchou, and I. R. Efimov Kinetics of defibrillation shock-induced response: design implications for the optimal defibrillation waveform Europace, January 1, 2002; 4(1): 27 - 39. [Full Text] [PDF]
|
|
|
|
|
|
H. S Karagueuzian and P.-S. Chen Cellular mechanism of reentry induced by a strong electrical stimulus: Implications for fibrillation and defibrillation Cardiovasc Res, May 1, 2001; 50(2): 251 - 262. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Al-Khadra, V. Nikolski, and I. R. Efimov The Role of Electroporation in Defibrillation Circ. Res., October 27, 2000; 87(9): 797 - 804. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. R. Efimov A Shocking Experience : Ionic Modulation of Virtual Electrodes in Defibrillation Circ. Res., September 15, 2000; 87(6): 429 - 430. [Full Text] [PDF]
|
|
|
|
|
|
I. R. Efimov, F. Aguel, Y. Cheng, B. Wollenzier, and N. Trayanova Virtual electrode polarization in the far field: implications for external defibrillation Am J Physiol Heart Circ Physiol, September 1, 2000; 279(3): H1055 - H1070. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Cheng, K. A. Mowrey, V. Nikolski, P. J. Tchou, and I. R. Efimov Mechanisms of shock-induced arrhythmogenesis during acute global ischemia Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2141 - H2151. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||