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Keener 1999
Keener 1999
We demonstrate that a biphasic shock is more e!ective than a monophasic shock at eliminat-
ing reentrant electrical activity in an ionic model of cardiac ventricular electrical activity. This
e!ectiveness results from early hyperpolarization that enhances the recovery of sodium
inactivation, thereby enabling earlier activation of recovering cells. The e!ect can be seen easily
in a model of a single cell and also in a cable model with a ring of excitable cells. Finally, we
demonstrate the phenomenon in a two-dimensional model of cardiac tissue.
1999 Academic Press
The purpose of this paper is to demonstrate represented by the conductivity tensors, p and
G
that biphasic shocks are usually more e$cient p , which represent average, or e!ective, conduc-
C
than monophasic shocks at de"brillation, and to tances of the media. Since current is conserved,
describe the ionic mechanism for this di!erence. Kirchhof 's laws imply that
In what follows, we describe a mathematical
model for de"brillation, explore the e!ect of *<
monophasic and biphasic stimuli on single cells, s C #I "
) (p
), (2)
K *t GML G G
and then demonstrate the e!ect of these stimuli
on one- and two-dimensional collections of cells.
) (p
#p
)"0. (3)
Indeed we demonstrate that, as suggested by G G C C
single-cell studies, the "rst phase of the bipolar
waveform acts as a conditioning prepulse that Equation (2) implies that current can leave the
reestablishes sodium current excitability, thereby intracellular space only as a transmembrane cur-
reducing the activation threshold for the second rent, and that the transmembrane current has
phase of the waveform. This is turn leads to an two components, namely the capacitive current
improved activation of partially refractory tissue and the ionic current I . Equation (3) states that
GML
and enables the wavefront to be pushed further the total of intracellular and extracellular current
into the refractory tail of the preceding action I "!p
!p
, i "!p
and
. In the case of one spatial dimension right-half of the cell. [This is equivalent to a rep-
C resentation of = (z) and = (z) in terms of the
with the intracellular conductance idealized as G C
a constant base level plus delta function jumps orthogonal Walsh functions (Keener, 1988)].
(representing gap junctions) and the extracellular With this simpli"cation and the assumption that
= (z )"!=(z ) (e.g. symmetric cells), the
conductance approximated by a constant, \ >
= "0 and = "!b [z (mod 1)!], where b is transmembrane potential becomes <#A on half
C G of the cell membrane and <!A on the other half,
a constant involving a combination of the con-
where A"e= (z ) ¹\
!e= (z ) ¹\
,
ductivities of the gap junction and the intracellu- G > G C > C
lar and extracellular #uid. Notice that = , and a function of x alone. While it is possible to
G determine A as part of the solution of the bido-
thus H, accounts for the sawtooth variation in
potentials mentioned earlier. main equations in response to boundary condi-
These modi"cations of the electrical potential tions with an applied current, for this paper, we
simply take A"cI (t), where I (t) is the ex-
average to zero over the length of the cell every-
where in eqns (2) and (3) except in the ionic ternally applied current, and c (independent of x)
current term (the only nonlinear term). Therefore, is some constant relating the applied current to
the ionic current used in eqn (2) must be taken the amplitude of the de#ection of the transmem-
to be brane potential. The parameter c depends in im-
portant ways on the nature of the tissue (Keener,
1998), but its actual numerical value is of little
1
I " f (<#eH (z, x), w(x, z)) dz, (10) consequence to this study (provided it is not
GML S *X
zero).
On the two di!erent regions of cell membrane,
i.e. the average of f with respect to the variable there are two di!erent values of the gating vari-
z over the surface of a single cell, *X, with total ables, governed by
surface area S. This modi"cation of the trans-
membrane current is signi"cant only when there w$"g (<$A, w$), (12)
R
THE BIPHASIC MYSTERY 5
where w> are the gating variables on that region In this and all remaining sections, we use the
of the cell where t"<#A, and w\ are the Beeler}Reuter model (Beeler & Reuter, 1977) to
gating variables on that region of the cell where represent the ionic current of a cardiac myocyte,
t"<!A. With this simpli"cation, the average I . The Beeler}Reuter model describes I as the
GML GML
ionic current (10) simpli"es to sum of four separate ionic currents: a sodium
current, a time-independent and a time-activated
I " ( f (<#A, w>)#f (<!A, w\)). (13) potassium current and a calcium current. These
GML currents are controlled by six gating variables, m,
h, j, d, f and x , and the intracellular calcium
The version of the bidomain model that is
concentration ([Ca>] ), which are governed by
studied in this paper consists of eqn (4) with ionic G
current speci"ed by eqn (13) and gating variables ordinary di!erential equations. The equations for
governed by eqn (12). This model was originally the gating variables are of the form
derived by Biktashev et al. (1997).
The most important feature of this model (and dw 1
" [w (<)!w]. (15)
principle di!erence from the models of de"brilla- dt q (<)
tion discussed in Keener (1996, 1998; Keener U
& Pan"lov (1996), Krinsky & Pumir (1998 and This equation implies that as the transmembrane
Pumir & Krinsky 1996, 1997) is that it keeps potential, <, changes at a rate associated with the
track of the possible di!erences of the gating time constant, C R (where R is the instan-
variables in di!erent regions of a cell during the K K K
taneous membrane resistivity), w tracks < by
time that a stimulus is applied. It is precisely this moving toward its instantaneous steady-state
feature that leads to di!erences in the e!ects of value w (<) with an instantaneous time constant
monophasic and biphasic stimuli, and the feature
q (<).
that is the subject of the discussion that follows. U
For this discussion, the most important cur-
We emphasize that it is not necessary to numer- rent is the sodium current, which is represented
ically resolve this model at the spatial resolution by
of cells. Rather, this model represents a variation I "(4m hj#0.003) (<!50). (16)
on the idea of the bidomain model, that at ,
every point of physical space there are two
potentials. Here, we are assuming that at every The product mhj can be thought of as the
point of physical space there are two sets of fraction of the time-dependent sodium current
gating variables, corresponding to the two sides that is recruited. The variable m is a fast activa-
(or compartments) of each cell, that must be tion variable. It increases with depolarization of
tracked. the membrane and its associated time constant is
small enough to keep m quite close to its steady-
state value m (<). The variables h and j are
3. The Response of a Single Cell inactivation variables, because their steady-state
values decrease when the membrane is de-
Before discussing how de"brillation takes
polarized. The variable h represents &&fast'' so-
place and why a biphasic shock is more e!ective
dium current inactivation (although h is slower
for de"brillation, it is necessary to understand the
than m) and j represents &&slow'' inactivation (al-
response of a single cell to stimuli.
though it is generally faster than other gating
Because current di!usion is rapid on the length
variables, i.e. d, f, x ). Figure 1 depicts the time
scale of the cell, the di!usion term on the right-
constants and steady-state value of m, h and j as
hand side in eqn (2) can be ignored for a single
a function of <. It should be noted that there is
cell, hence the transmembrane potential for an
disagreement in the literature about the necessity
isolated myocyte is governed by
of the slow inactivation variable j. For example,
the Ebihara-Johnson model (Ebihara & Johnson,
*< 1980) does not include j, while the Luo}Rudy
C "!I . (14)
K *t GML model (Luo & Rudy, 1994a, b) does. Some recent
6 J. P. KEENER AND T. J. LEWIS
FIG. 1. The time constants (top) and the steady-state values (bottom) of m, h, and j as functions of transmembrane potential.
m (**); h (- - - - ); j (} ) } ) }).
data suggests that the slow inactivation has increasing the sodium current inactivation
a typical time constant on the order of seconds (decreasing h and j). If the stimulus is large and
(Richmond et al., 1998), which is far too slow to rapid, the membrane depolarizes rapidly to thre-
have an e!ect on de"brillatory processes lasting shold and activates the sodium current rapidly,
only 10 ms. before h and j can substantially change. However,
To understand the response of a single cell to if the stimulus is longer but of smaller amplitude,
an extracellular stimulus, it is valuable to "rst then the membrane potential changes more slow-
review the simpler scenario of the response of ly and the inactivation variables can decrease
a cell to an applied intracellular current. It is well substantially therefore shutting o! the sodium
known that if the applied inward current is of current (m hj+0) before an action potential up-
small amplitude and duration, the membrane stroke can be evoked.
acts as a capacitor and depolarizes, but the mem- One of the ways that the activation threshold is
brane potential quickly returns to rest after the controlled is through the level of sodium current
stimulus ends. On the other hand, if the stimulus inactivation at the beginning of the depolarizing
has su$cient amplitude and duration, then the stimulus. In particular, a hyperpolarizing pre-
initial capacitive depolarization brings < to pulse has the e!ect of reducing inactivation (note
a threshold potential and triggers the autocata- that there is a non-zero resting level of inactiva-
lytic activation of the sodium current. This fur- tion) thereby temporarily lowering the threshold
ther depolarizes the membrane potential and for action potential generation (Jones et al.,
generates the rapid upstroke of an action poten- 1987). This is the key to understanding the in-
tial. It is important that the depolarizing stimulus creased e$cacy of a biphasic extracellular stimu-
be both su$ciently large and rapid. This is be- lus over a monophasic one.
cause, besides activating the sodium current (in- A cell that is stimulated via an extracellular
creasing m), depolarization also has the e!ect of "eld experiences depolarization at one side of the
THE BIPHASIC MYSTERY 7
in Fig. 3, the corresponding gating variables m, h, depolarization cannot increase m rapidly enough
and j are shown. In each of these "gures there are to overcome the decrease in h and j. The biphasic
four curves, two representing the response to stimulus, in contrast, exploits the e!ect of hyper-
a monophasic stimulus and two for a biphasic polarization by activating the sodium current on
stimulus. The curves labeled &&#'' correspond to the side of the cell that was initially hyperpolariz-
dynamics in that part of the cell that is initially ation and thereby rendered more excitable.
depolarized (with <#A) and similarly, curves The behavior of all remaining variables shows
labeled &&!'' correspond to dynamics in that part no signi"cant di!erence between the depolarized
of the cell that is initially hyperpolarized (with and hyperpolarized sides (not shown here). The
<!A). For the monophasic stimulus, the &&#'' reason for this is that either the variables are too
side remains relatively depolarized and the &&!'' slow to signi"cantly respond directly to the 10 ms
side remains relatively hyperpolarized through- stimulus of the particular amplitude given here
out the stimulus, but for the biphasic stimulus, (x , f ), the steady-state value does not change
the &&#'' side becomes relatively hyperpolarized signi"cantly in the interval of transmembrane
and the &&!'' side becomes relatively depolarized potential that is important here (d ), or the vari-
after the polarity of the stimulus is reversed. Prior able directly or indirectly has no major e!ect on
to the stimulus, monophasic and biphasic, as well activation threshold ([Ca>] ).
G
as &&#'' and &&!'', curves are identical. During the This di!erence between monophasic and bi-
"rst half of the stimulus interval, &&#'' and &&!'' phasic stimuli is qualitatively similar but varies
curves diverge, however, the monophasic and bi- quantitatively for di!erent parameter values. For
phasic curves remain identical. Once the polarity example, the dependence of the activation thre-
#ips during the biphasic stimulus, the mono- shold (in units of A) is shown in Fig. 4 plotted as
phasic and biphasic curves diverge. a function of coupling interval. Notice that
The m curves show the di!erence in transmem- biphasic stimulation has a lower activation
brane potential response but do not show the threshold than monophasic stimulation for all
reason for the di!erence. As expected, m is depress- coupling intervals, but the di!erence increases
ed in the hyperpolarized part of the cell and elev- drastically for the small coupling intervals (below
ated in the depolarized part of the cell. For the about 325 ms). This is critical in the mechanism
monophasic stimulus, the depolarization is insu$- for de"brillation. The previous "gures used a
cient to activate the cell, but for the biphasic coupling interval of 360 ms, which is close to the
stimulus, the cell is activated almost immediately minimal threshold for both stimulus protocols
following reversal of the stimulus polarity. according to this plot.
The h and j curves are much more revealing of The di!erence between monophasic and bi-
the mechanism underlying this di!erence. As phasic stimuli depends on the length of the stimu-
expected, both h and j are reduced (hence lus. If the stimulus is of extremely short duration,
inactivated) by depolarization and increased there is insu$cient time for the inactivation vari-
(hence inactivation is reduced) by hyperpolariz- ables h and j to respond signi"cantly to the hy-
ation. With the monophasic stimulus, the de- perpolarizing pulse, and so there is no advantage
polarization cannot activate the cell, because the for a biphasic stimulus. However, as the pulse
&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&
FIG. 3. The response of a single Beeler}Reuter cell subject to monophasic and biphasic "eld stimuli. The curves from top to
bottom represent the transmembrane potential <, the activation variable m, the inactivation variable h, the inactivation
variable j. The stimuli are as described in Fig. 1. Of the four curves in each sub"gure, two correspond to the monophasic
stimulus and two to the biphasic stimulus; Of the two curves for each type of stimulus, one is for the &&#'' side of the cell and
one each for the &&!'' side of the cell. The mechanism for the increased e!ectiveness of the biphasic stimulus reveals itself in the
dynamics of the sodium current inactivation variables h and j. Both h and j are reduced (hence inactivated) by depolarization
and increased (hence inactivation is reduced) by hyperpolarization. With the monophasic stimulus, the depolarization cannot
activate the cell, because the depolarization cannot increase m rapidly enough to overcome the decrease in h and j.
The biphasic stimulus, in contrast, exploits the e!ect of hyperpolarization by activating the sodium current on the side
of the cell that was initially hyperpolarized and thereby rendered more excitable. Mono! (**); mono# (} } } );
bi! (} ) } ) }); bi# () ) ) ) )).
10 J. P. KEENER AND T. J. LEWIS
FIG. 6. The transmembrane potential < (mV) in a one- FIG. 7. The transmembrane potential < (mV) in a one-
dimensional ring (¸"15.8 cm) of Beeler}Reuter tissue dur- dimensional ring (¸"15.8 cm) of Beeler}Reuter tissue dur-
ing and following the application of a monophasic stimulus ing and following the application of a biphasic stimulus. As
of duration 10 ms and amplitude A"17.5. Prestimulus in the simulation shown in the previous "gure, the stimulus
dynamics correspond to a circulating pulse. Each curve is had a duration of 10 ms and an amplitude A"17.5, and the
the solution at a "xed time and as time progresses the curves prestimulus dynamics correspond to a circulating pulse.
are lifted slightly. The output time step is 0.5 ms. The mono- Each curve is the solution at a "xed time and as time
phasic shock has the e!ect of exciting the partially recovered progresses the curves are lifted slightly. The output time step
medium directly ahead of the action potential, and hence the is 0.5 ms. Again the shock has the e!ect of exciting the
wavefront is e!ectively pushed ahead into less recovered partially recovered medium directly ahead of the action
media that is closer to the tail of the &&preceding'' action potential, and hence the wavefront is e!ectively pushed
potential. However, the monophasic shock pushes the ahead into less recovered media that is closer to the tail of
wavefront into a region where it is slowed but not halted and the &&preceding'' action potential. However, the biphasic
the reentry persists. shock is able to activate media that is less recovered than the
monophasic shock does. In fact, the wavefront is pushed so
far forward that it is in a region that cannot support propa-
gation. The result is that the wave collapses and the reen-
trant behavior is annihilated.
the other hand, is able to activate media that is
less recovered and thus pushes the wavefront so
far forward that it is in a region that cannot monophasic shock is due to propagation because
support propagation. As a result, the wave col- it occurs after the new position of the wavefront
lapses and the reentrant behavior is annihilated. is established following the termination of the
The ionic mechanism underlying this di!er- shock.
ence is the same as seen in single-cell simulations. At position x"9.450 cm (see Fig. 9), the di!er-
Figures 8 and 9 show the potential < and inac- ence in response is more dramatic. Here, the
tivation variables h and j as functions of time monophasic shock has virtually no e!ect on the
during and following the application of the action potential, while the biphasic shock pro-
stimulus, at two di!erent positions on the ring. In duces direct activation. The mechanism for this
Fig. 8, for position x"7.875 cm, the medium is di!erence is similar to that described previously
activated by the shock, but much more quickly for the response of a single cell. The important
with the biphasic shock than with the mono- di!erence, however, is that following the biphasic
phasic shock. As with single cells, the biphasic shock the modi"ed action potential wavefront is
shock eliminates inactivation in the hyper- unable to sustain propagation and fails, whereas
polarized portion of the cell with the "rst phase of following the monophasic shock, action potential
the shock, and activates the cell when the polarity propagation is slowed slightly but not halted.
of the shock is reversed. At this position Also, in this case, the e!ect on j is more signi"cant
(x"7.875 cm), the activation following the than in the case shown for the single cell. During
12 J. P. KEENER AND T. J. LEWIS
FIG. 8. The transmembrane potential < (in mV) and inactivation variables h and j at position x"7.785 cm on a periodic
ring described in the previous "gures. The monophasic shock has little e!ect on the action potential, while the biphasic shock
produces direct activation. Notice that the same ionic mechanisms are at work here as in the single cell. The biphasic shock
eliminates inactivation in the hyperpolarized portion of the cell with the "rst phase of the shock, and then activates the cell
when the polarity of the shock is reversed. (a) Mono (**); bi (- . - . -). (b) and (c) Mono! (**); mono# (} } });
bi! (} ) } ) }); bi# () ) ) ) ) )).
the "rst half of the pulse at x"9.450 cm, j in- sional simulations, the Euler integration method
creases from below 0.5 to above 0.7, whereas was used with a time-step of 0.025 ms and
there is little change in h. a space-step of 0.025 cm (Courtemanche & Win-
The e!ectiveness of monophasic and biphasic free, 1991; Xu & Guevara, 1998).
shocks for annihilating spiral wave reentry was Figures 10 and 11 show the membrane poten-
also studied in two-dimensional collections of tial during and following the application of a
cells. For this portion of the study, we used monophasic stimulus and a biphasic stimulus,
a modi"ed Beeler}Reuter model with the time respectively. The stimuli were both of duration
constants of calcium current activation and 10 ms and amplitude A"17.5. We see that the
inactivation (d and f ) halved (Courtemanche results here are similar to those for the ring
& Winfree, 1991). The change in time constants dynamics. The monophasic stimulus pushes the
allows the formation of a stable spiral wave on wavefront of the spiral wave forward; however it
a computationally reasonable domain (10 cm; only manages to shift the phase of the spiral wave
10 cm). This stable spiral wave is used as the and is unable to annihilate it. The biphasic stimu-
initial conditions for simulations where external lus, on the other hand, is able to push the wave-
shocks are given. Parameters are the same as for front of the spiral wave much further into its
the ring simulations, however for the two-dimen- waveback and activate more of the core than the
THE BIPHASIC MYSTERY 13
FIG. 9. The transmembrane potential < (in mV) and inactivation variables h and j at position x"9.450 cm on a periodic
ring described in the previous "gures. Here, the di!erence between monophasic and biphasic stimuli can be seen even better
than in the previous "gure. The monophasic shock has almost no e!ect on the action potential, while the biphasic shock
produces direct activation. Notice that the same ionic mechanisms are at work here as in the single cell. The biphasic shock
eliminates inactivation in the hyperpolarized portion of the cell with the "rst phase of the shock, and then activates the cell
when the polarity of the shock is reversed. The major facillatory e!ect of the initial phase of the biphasic stimulus is on j.
(a) Mono (**); bi (- . - . -). (b) and (c) Mono! (**); mono# (} } }); bi! (} ) } ) }); bi# () ) ) ) ) )).
monophasic stimulus. This is seen best by com- accelerating its recovery, and thereby lowering
paring the t"10 ms panels of Figs 10 and 11. the activation threshold prior to the subsequent
The ionic mechanism responsible for the success polarity reversal.
here appears to be identical to that described in This mechanism is robust, meaning that it can
the cases of the single cell and ring dynamics (not be observed in a variety of ionic models under
shown). varying conditions and parameter values. How-
ever, the quantitative details of this phenomenon
can vary greatly depending on the detailed struc-
5. Discussion ture of the sodium channel and its associated
There is a substantial di!erence in the response time constants of inactivation. In fact, we have
of ionic models between monophasic and bi- observed as great as a three-fold di!erence in
phasic shocks. This di!erence occurs because of activation threshold for a particular modi"cation
the relatively fast response time of the sodium to the Beeler}Reuter model (in which j was
inactivation variables. The fundamental mecha- increased) between biphasic and monophasic
nism for this di!erence is that the hyperpolariz- stimulus protocols. The latest model for sodium
ation phase of the biphasic pulse acts as a inactivation is yet to be incorporated into a full
pre-pulse to remove inactivation from the cell, ionic model (Richmond et al., 1998). It should
14 J. P. KEENER AND T. J. LEWIS
FIG. 10. The transmembrane potential < in a two-dimensional sheet of modi"ed Beeler}Reuter tissue during and following
the application of a monophasic stimulus of duration 10 ms and amplitude A"17.5. Prestimulus dynamics correspond to
a spiral wave. The monophasic stimulus shifts the phase of the spiral wave, but is unable to annihilate it.
also be noted that the quantitative details in- cally, there is need for a convergence study to
volved in determining both monophasic and bi- determine the dependence of these results on the
phasic activation thresholds depend greatly on number of cellular compartments. As noted
currents responsible for recovery as well as above, di!erent sample numbers have been used
excitation currents. A complete quantitative to discretize single cells [2 points here, 3 points in
study of de"brillation thresholds, therefore, must Tung & Borderies (1992), 4 points per cell in
include a detailed comparison of di!erent ionic Fishler et al. (1996b), 11 points in Fishler et al.
models. (1996b) and 48 points in Leon & Roberge (1993)],
There are several other concerns relating to the although the qualitative results are identical in all
quantitative reliability of these results. Speci"- of these studies.
THE BIPHASIC MYSTERY 15
FIG. 11. The transmembrane potential < in a two-dimensional sheet of modi"ed Beeler}Reuter tissue during and following
the application of a biphasic stimulus of duration 10 ms and amplitude A"17.5. Prestimulus dynamics correspond to a spiral
wave (as in the previous "gure). Unlike the monophasic stimulus of the same amplitude and duration, the biphasic stimulus is
able to annihilate the spiral wave.
We also do not currently know how to accu- failed (Gillis et al., 1996; Zhou et al., 1998) leading
rately relate the stimulus threshold at the cellular some investigators to dispute the validity of this
level to tissue level thresholds (although rough model. It should be noted, however, that there is
estimates give reasonable agreement with experi- no doubt that resistive inhomogeneities play an
mental results (Keener, 1996, 1998). This is be- important role in the distribution of transmem-
cause the functions = and = , which give brane currents during a stimulus (Fishler, 1998;
G C
a measure of small scale resistive inhomogenei- Fishler & Vepa, 1998; White et al., 1998), nor can
ties, are not known. In fact, to date, attempts to one dispute the existence of small-scale resistive
directly observe the &&sawtooth'' potential have inhomogeneities, only whether or not the e!ect of
16 J. P. KEENER AND T. J. LEWIS
FIG. 12. The transmembrane potential < (mV) of a single cell (top) in respose to the application of two di!erent biphasic
stimuli of equal energy and duration (shown in the bottom two traces). The non-symmetric biphasic stimulus is successful in
activating the cell, whereas the symmetric one is not. This suggests that there are even more e!ective stimulus protocols for
de"brillation than a symmetric biphasic shock. Stimulus 1 (**); stimulus 2 (} ) } ) }).
these is su$cient to a!ect transmembrane cur- is not optimal, since there is no symmetry that
rent #ow at de"brillation strength current levels. would demand this. Figure 12 shows the results
There are also numerous technical di$culties of two biphasic stimuli with identical total energy
with directly observing the sawtooth potential, so (squared area"2560 mV ms) and duration
that we do not view the current experimental (10 ms) but with di!ering consequences. The bi-
mismatch as de"nitive or fatal to this theory. phasic pulse with a 50}50 temporal split between
There are other features of de"brillation that phases and equal amplitude (A"16) in the two
this theory does not explain. For example, Strick- phases is unsuccessful at evoking a stimulus,
berger et al. (1994) reported a di!erence in de"b- while a biphasic stimulus with unequal ampli-
rillation threshold between anodal and cathodal tudes (A "10, A "26.46) and unequal dura-
monophasic shocks during transvenous de"bril- tions (t "7.5 ms, t "2.5 ms) is successful.
lation. The model presented here is symmetrical Thus, there are ways to redistribute the energy
with respect to the direction of current #ow. that improve the likelihood of successful de"bril-
Termination of ventricular tachycardia is lation.
generally considered to require less energy than Most de"brillators used clinically use trun-
termination of ventricular "brillation (AMA cated exponential waveforms rather than the
Standards, 1986). There is currently no theoret- square waveform used here. The optimal wave-
ical explanation of this di!erence. form, whether square or a truncated exponential,
The obvious question that remains is to deter- and its biphasic distribution, is not yet known,
mine the optimal biphasic protocol. It is certain although the results presented here provide a way
that the 50}50 temporal split of polarity phases to search for the optimal waveform.
THE BIPHASIC MYSTERY 17
This research was supported in part by NSF Grant KEENER, J. P. & PANFILOV, A. V. (1996). A biophysical
DMS 9626334. model for de"brillation of cardiac tissue. Biophys. J. 71,
1335}1345.
KEENER, J. P. & SNEYD, J. (1998). Mathematical Physiology.
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