SPECIAL COMMUNICATION
LabHEART: an interactive computer model of
rabbit ventricular myocyte ion channels and Ca transport
José L.
Puglisi1,2 and
Donald M.
Bers2
1 Department of Physiology and Biophysics, University of
Illinois at Chicago, and 2 Department of Physiology, Loyola
University Chicago, Stritch School of Medicine, Maywood, Illinois 60153
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ABSTRACT |
An interactive computer program,
LabHEART, was developed to simulate the action potential (AP), ionic
currents, and Ca handling mechanisms in a rabbit ventricular myocyte.
User-oriented, its design allows switching between voltage and current
clamp and easy on-line manipulation of key parameters to change the
original formulation. The model reproduces normal rabbit ventricular
myocyte currents, Ca transients, and APs. We also changed parameters to simulate data from heart failure (HF) myocytes, including reduced transient outward (Ito) and inward rectifying K
currents (IK1), enhanced Na/Ca exchange
expression, and reduced sarcoplasmic reticulum Ca-ATPase function, but
unaltered Ca current density. These changes caused reduced Ca transient
amplitude and increased AP duration (especially at lower frequency) as
observed experimentally. The model shows that the increased Na/Ca
exchange current (INaCa) in HF lowers the
intracellular [Ca] threshold for a triggered AP from 800 to 540 nM. Similarly, the decrease in IK1
reduces the threshold to 600 nM. Changes in Ito
have no effect. Combining enhanced Na/Ca exchange with reduced
IK1 (as in HF) lowers the threshold to trigger
an AP to 380 nM. These changes reproduce experimental results in
HF, where the contributions of different factors are not
readily distinguishable. We conclude that the triggered APs that
contribute to nonreentrant ventricular tachycardia in HF are due
approximately equally (and nearly additively) to alterations in
INaCa and IK1. A free
copy of this software can be obtained at
http://www.meddean.luc.edu/lumen/DeptWebs/physio/bers.html.
heart failure; excitation-contraction coupling; Na/Ca exchange; mathematical model
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INTRODUCTION |
SINCE THE SEMINAL
WORK of Hodgkin and Huxley (7) describing Na and K
currents mathematically in squid axon, several groups have extended
this sort of modeling to cardiac ionic currents and action potential
(AP) (1, 14, 16-18). The tremendous increase of
experimental work elucidating the behavior of ionic currents in heart
(3) has required the development of new and more
sophisticated models (4, 5, 11-13, 34).
Ca also plays a crucial role in cardiac excitation-contraction coupling
(ECC) (2), and it has become clear that there is a dynamic
interplay between the AP and Ca regulation mechanisms. The membrane
potential (Em) modulates Ca transport, and the
Ca transient also can feedback to alter Em. Thus
cardiac cell models of AP and ionic currents have progressively
incorporated more detailed formulations of the Ca transport systems.
A number of laboratories have made substantial contributions to this
overall development (8, 18, 19, 23, 34, 35). However, the
model of Luo and Rudy (12, 13, 35) has become, perhaps,
the standard through the late 1990s. Unfortunate common features of
most existing models are their limited flexibility and accessibility.
As the model increases in complexity, it is more difficult to modify
parameters, conditions, and equations. The accuracy required to
reproduce a particular physiological observation can hinder the
versatility of the whole model. Accessibility limitations pertain not
only to obtaining the computer code but also to how user-friendly the
interface is. A readily accessible model should be easy enough to use
that 1) students can quickly use it as a learning tool and
2) researchers can use it as a development tool to test its
fidelity in reproducing experimental results and also to explore
potentially new experiments.
To fill this gap, we have created a computer program that combines
current scientific findings with a user-friendly interface. We
developed LabHEART, a program that is very intuitive to use and in
which modifications of key variables, stimulation protocols, and
default conditions can be made with a click on an icon. Standard electrophysiological plots, such as current-voltage relationships (I-V sets) or steady-state activation and inactivation
curves are built-in features. Ionic concentrations and maximal current densities can be altered while the simulation is running, which adds a
dynamic edge to the program.
A second key goal is that the model reproduces faithfully the
electrophysiological and Ca transport characteristics of rabbit ventricular myocytes. Rabbit ventricle is used extensively in experimental studies, but there is no currently available model. A
third goal is to simulate data obtained from control vs. heart failure
(HF) rabbit ventricular myocytes where K currents, Na/Ca exchange, and
sarcoplasmic reticulum (SR) Ca-ATPase function are altered (21,
22). While this study is, in part, a further test of the rabbit
ventricular myocyte model, it also helps to better understand the
cellular basis of changes in AP, Ca transients, and the observed
propensity for triggered arrhythmias that lead to ventricular
tachycardia in HF (23).
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MATERIALS AND METHODS |
We adapted the equations from Luo and Rudy to rabbit ventricular
myocytes using values obtained from the literature and from our
laboratory. The model was implemented by using LabVIEW 5.0 graphical
programming language from National Instruments (Austin, TX). Its
inherent visual capabilities fit perfectly with our aim of intuitive
use. We utilized the Rush and Larsen algorithm (26) to
solve the set of differential equations. The main difference between
our formulation and the one adopted by Luo and Rudy is the inclusion of
transient outward K current (Ito) and
Ca-activated Cl current [ICl(Ca)], as well as
modification of the kinetics of T-type Ca channel
(ICa,T), the rapid component of the delayed rectifier K current (IKr), and rescaling of
several conductances to better match results in rabbit ventricle (see
Table 1).
Transient outward K current.
Ito has been reported in rabbit
ventricular myocytes (6, 9). It is also known as
Ito1 to differentiate it from the Ca-activated Cl current [known as Ito2 or
ICl(Ca)] that is activated at the same time
during the AP (37). Ito can
contribute to ventricular repolarization. We used the
Ito formulation of Winslow et al. (34) for this current
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(1a)
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(1b)
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(1c)
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(1d)
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(1e)
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where Gto is the channel conductance,
Xto and Yto are
activation and inactivation parameters, respectively, and
EK is the reversal potential for K.
Ca-activated Cl current.
ICl(Ca) has been reported in rabbit
Purkinje cells (30) and atrial (36) and
ventricular myocytes (10). It is strongly temperature
dependent, being very small at room temperature but substantial at
35°C (25). ICl(Ca) can be
suppressed by anion blockers such as DIDS or niflumic acid. Because of
its Ca dependence, it also can be eliminated by blocking Ca current
(ICa). We modeled this current as
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(2)
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where GCl is the Cl conductance set to 10 mS/µF, ECl is the reversal potential, and Ca
dependence is incorporated as a Michaelis-Menten factor with
KmCa = 0.10 µM. These values were chosen
to fit experimental records obtained by Puglisi et al.
(25).
T-type Ca current.
Although ICa,T is not generally detectable in
rabbit ventricular myocytes, we have included it to make a more
complete theoretical model. The ICa,T equations
are
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(3a)
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where ECa is the Nernst potential for Ca
and the gating parameters are as follows
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(3b)
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(3c)
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(3d)
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(3e)
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These equations are slightly different from those used by Zeng
et al. (35), but they reproduce more accurately the
I-V relationship for ICa,T.
The kinetics of IKr were modified as follows
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(4a)
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(4b)
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(4c)
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(4d)
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(4e)
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The rest of the parameters follow the same formulation as in Luo
and Rudy, with some rescaling to better fit the rabbit myocyte characteristics (see Table 1).
The general scheme of LabHEART consists of a main menu (Fig.
1) from which the user can choose
different tasks to perform. The main menu screen is a diagram
with the major mechanisms involved in ECC, a series of icons
(left), and a group of command buttons (right).
The self-explanatory icons allow the user to alter the ionic
concentration (top left), choose a voltage or current
protocol (top right), or examine a particular mechanism,
namely, SR, Ca channels, Na/Ca exchanger, sarcolemmal Ca-ATPase, Na and
K channels, Na-K-ATPase, and ICl(Ca). The
command buttons allow the user to access help screens, alter the
cytosolic buffers, run an AP or voltage-clamp simulation, save a
particular set of conditions, or exit the program. During the
generation of an AP, it is also possible to simulate SR Ca release
induced by caffeine application and the effects of some drugs [e.g.,
nifedipine, almokalant, TTX, exchange inhibitory peptide, and
4-aminopyridine to simulate variable block of
ICa, IKr, Na current
(INa), Na/Ca exchange current
(INaCa), and Ito]. One
can choose either current-clamp protocols to simulate APs or
voltage-clamp protocols to study individual current properties.

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Fig. 1.
The MAIN MENU screen shows a schematic diagram of the
different mechanisms involved in cardiac excitation-contraction
coupling (ECC) in a rabbit ventricular myocyte. SL, sarcolemma; Mito,
mitochondrion; MF, myofilaments. By clicking on the icons located on
the left, the user can 1) establish ionic
concentrations, 2) set the stimulus waveforms, and visualize
or alter 3) characteristics of the sarcoplasmic reticulum
(SR) or 4) properties of Ca channels, 5) Na/Ca
exchange, 6) sarcolemmal Ca pump, 7) Na Channel,
8) K channels, 9) Na-K-ATPase, or 10)
Ca-activated Cl channel. By pressing the command buttons on the
right, it is possible to obtain HELP screens, alter amounts
of the Ca BUFFERS, RUN an action potential, SAVE a new set of default
values under a new name, or EXIT the program.
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In every voltage-clamp simulation, typical plots such as I-V
relationship or inactivation curves are built-in features. Also, bearing the novice user in mind, there are help options in each screen
that explain possible choices and include a brief description of the
mechanism under simulation or exploration. The default ionic
concentrations were set as follows (in mM): [Na]o = 140, [Na]i = 10, [K]o = 5.4, [K]i = 145, [Ca]o =1.8, and resting
[Ca]i = 120 nM, where o indicates extracellular and
i indicates intracellular concentration. Currents are expressed in
amperes per farad and voltages in millivolts.
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RESULTS |
Voltage clamp and current characterization.
Under voltage-clamp mode, three protocols are available. The first
protocol generates the I-V relationship of a channel. Figure 2 shows an example of this simulation for
L- and T-type Ca channels. Figure 2A depicts the voltage
waveforms used for this purpose. The protocol is set in a manner
similar to experimental software; that is, the user selects the holding
potential, "step to" voltage, duration of pulse, voltage increment
(Delta V) between pulses, and number of iterations. Figure
2B illustrates the resulting L-type Ca current
(ICa,L) traces. A particular current trace can be chosen with a cursor, and the specific current amplitude, voltage applied, and time of simulation appear on the screen (left).
Some characteristics of the channel such as the conductance or the Km for Ca-induced inactivation can be altered by
directly typing the new value in the corresponding field. The voltage
protocol can be changed on this screen without returning to the
previous one. Default conditions can be restored by a command button
(right); the other command buttons allow the user to toggle
between ICa,L and ICa,T
or to quickly obtain the graph of the I-V set. Figure 2C shows superimposed I-V relationships for
ICa,L and ICa,T and indicates the characteristic differences in amplitudes and
voltage-dependence for those two channels. This plot can be either
directly printed or saved as an ASCII file for further analysis or
presentation. For the normal rabbit ventricular myocyte, the maximum
T-type Ca channel conductance is set to zero, since no
ICa,T is seen in these cells. However, the
option is there to include ICa,T, if it is
observed under other conditions.

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Fig. 2.
Ca current in voltage clamp. A: schematic
representation of the WAVEFORM screen used to control the protocol to
generate current-voltage (I-V) data. The user inputs the
values for holding potential, "step to" voltage, duration of pulse,
voltage increments (Delta V), and the number of iterations. The screens
shown here (and in Figs. 3 and 4) are simplified versions of the actual
computer screen displays. For example, the "knobs" for adjusting
parameters on the actual screen show numbers and units, and the
selected value is also displayed in a box below the knob. The values
also can be changed by either typing in values or nudging a cursor.
B: ICa,L traces obtained in the
simulation. Conductances and affinity constant
(KmCa) values can be altered by typing the new
values in the respective fields (top left). The cursor
allows the user to choose a particular current trace and observe the
corresponding values in boxes (bottom left). One can also
switch protocol parameters by using the controls (bottom),
without returning to the protocol screen. C: I-V
screen showing superimposed ICa,L and
ICa,T I-V
relationships.
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The second protocol under voltage clamp is the steady-state
inactivation, or availability of the channel. Figure
3, A and C, shows
this simulation for INa. Once the
INa traces are obtained (Fig. 3A),
the normalized peak amplitude of the current is plotted against the
holding potential (Fig. 3C).

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Fig. 3.
Availability and recovery from inactivation.
A: INa availability traces for
different holding membrane potentials (Em). The
PLOT command (right) generates the inactivation curve
(C). B: recovery from INa
inactivation traces. Clicking the PLOT (right) command
generates the recovery from inactivation curve (D). All
graphs can be either saved or printed directly.
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Another attribute of some ionic channels is the recovery from
inactivation (assessed by the third voltage-clamp protocol, Fig. 3,
B and D). The standard method to evaluate
recovery is to use a first pulse to produce inactivation and a second
pulse to assess the availability of the current, after rests of
different durations and holding Em. The
time-dependent increase in test pulse INa shows
how the channel recovers from inactivation. The longer the interval
between the pulses and the more negative the holding
Em, the faster the channel recovers. Figure
3B displays the INa traces, and Fig.
3D shows the graph of recovery from inactivation. Like the
I-V plot, this graph can be either directly printed or saved
as an ASCII file for further analysis.
Current clamp and AP simulations.
In current-clamp mode, there are three options: single pulse, double
pulse, and run continuously. In the single pulse mode, an AP is
generated by applying a single current pulse that can be adjusted by
the user (e.g., to study threshold). The currents underlying the AP are
shown in four consecutives screens (Fig. 4). The first screen is a general one
(Fig. 4A) that exhibits AP, Ca transient,
ICa,L, INa, Na-K-ATPase
current (INaK), and INaCa. A second screen (Fig. 4B)
shows all of the K currents included in the model
(Ito, IK1,
IKr, IKs, and
IKp). The third screen (Fig. 4C)
portrays the Ca-related currents: ICa,L and
ICa,T, background Ca current
(ICab), ICl(Ca), and the
sarcolemmal Ca-pump current. Finally, a fourth screen (Fig.
4D) illustrates the amount of Ca that has been transported
across the membrane: the integral of Ca that entered through
ICa,L, ICab, and
INaCa, the amount of Ca extruded by the
sarcolemmal Ca pump and INaCa, and also the net
or total Ca flux. This value helps to show when Ca is being accumulated
into the cell (total >0) or when the cell has been depleted of Ca
(total <0). Figure 4D also shows that the total Ca that
enters the cell is mainly due to ICa,L and that
the principal Ca extrusion mechanism is the Na/Ca exchange. In any of
these four screens, each trace can be toggled on or off to focus on a
particular aspect. Transition between these screens is accomplished by
clicking the arrows on either side of the indicator bar. A particular
trace can be chosen by a cursor, and its value is shown along with the
appropriate units. The chosen traces, with their corresponding labels
and scales, can be saved as an ASCII file. Figure
5 shows traces that have been exported
and plotted using Prism 3.0 software (GraphPad). Figure 5A
shows the AP and [Ca]i. Figure 5B shows
INa with an inset to illustrate the temporal
relationship between Em,
INa, and ICa,L during the
first 10 ms of the AP. Figure 5C displays superimposed
traces of ICa,L, ICa,T,
INaK, and INaCa, a
combination that is not available in the four screens of this simulation. Finally, the five different K currents are presented in
Fig. 5D with an inset of their behavior near the rapid
upstroke of the AP. The single-pulse current-clamp mode also allows one to trigger SR Ca release directly at various times after the AP, thereby simulating spontaneous diastolic SR Ca release (or a
caffeine-induced Ca transient). The second option (two pulses) follows
the same design principles and is useful to study refractoriness. The
third option (run continuously) presents the results as in a chart
recorder, allowing the user to make on-line modifications of the ionic
concentration to visualize the effects of some drugs.

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Fig. 4.
Current clamp simulations: single pulse. A:
simplified general screen of a default action potential (AP)
simulation. This screen shows AP, intracellular Ca concentration
([Ca]i), ICa,
INa, INaK, and
INaCa. Each of these traces can be toggled
"on" or "off" by clicking the buttons below the display
if the user wants to focus on a particular trace(s). B: K
currents during the generation of an AP. C: Ca-related
currents [ICa,L, ICa,T,
ICab, ICl(Ca), and the
sarcolemmal Ca-pump current (SLCa)]. D: integrated amount
of Ca transported by the Ca channels (L-type and background), Na/Ca
exchange, and sarcolemmal Ca-ATPase. Transition between the different
screens is achieved by pressing on the arrows located at the sides of
the bar. Cursors also are on the screen (not shown here) that allow
examination of values (with units) at any time point on any trace. The
time scale also can be altered by overtyping with a new value (e.g., to
expand the early part of the AP). All traces can be printed or saved as
ASCII files.
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Fig. 5.
Example of postprocessed AP traces. Different records
were saved as ASCII files and plotted on selected scales. A:
superimposed AP and [Ca]i. B:
INa plotted alone and on an expanded time scale
(inset) to show the temporal relationship of
Em, INa, and
ICa,L in the first 10 ms. C: AP,
INaK (INaK-ATPase),
ICa,L, and INaCa
(INaCaX). This combination of traces is not
present as a default condition but can be readily achieved this way.
D: K currents, with an inset showing details at
the onset of the AP.
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Heart failure rabbit: a case study.
Current densities or maximal rate of Ca uptake
(Vmax) values can readily be adjusted,
and we took advantage of this feature to simulate
electrophysiological and Ca transport changes that we have measured in
HF, which was induced by combined aortic insufficiency and aortic
stenosis (21, 22). Ventricular myocytes from these HF
rabbits exhibit 100% increase in INaCa, 24%
reduction in SR Ca-ATPase function, 36% reduction in
Ito, and 49% reduction in IK1. Maximum conductance or
Vmax values were changed, and this new HF
parameter set can be saved and recalled at any time.
Figure 6, A and B,
shows how the steady-state Ca transient and AP are modified in HF
compared with control. The mean Ca transient amplitude was reduced by
40% experimentally (Fig. 6, left) and slightly less than
this in the simulation (Fig. 6, right). The prolonged AP
duration in HF (Fig. 6C) also was well reproduced by the
model, as was the shortening with frequency and convergence of AP
duration at higher frequency.

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Fig. 6.
Experimental data (left) and simulated traces
(right) of control (Ctl) and heart failure (HF) myocytes.
Default values for Na/Ca exchanger, IK1,
Ito, and SR Ca-pump rate were replaced with
parameters measured in HF myocytes (see text). A: Ca
transients. B: APs. C: effect of frequency on the
AP duration (APD75). Experimental data are from Ref.
22.
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Figure 7A shows the
Em dependence of INaCa in
HF and control myocytes. Both inward and outward current are increased
twofold in HF (21). The apparent reversal potential is
unchanged and close to the predicted value based on the pipette and
extracellular solutions. Figure 7B illustrates Ca transients
and INaCa induced by a rapid caffeine
application (31). In HF myocytes, a smaller Ca transient
is accompanied by a higher INaCa. Figure
7C displays the Ca dependence of inward
INaCa on [Ca]i. In HF, this
current is much larger, indicating that INaCa is
functionally upregulated during dynamic Ca transient. The enhanced
inward current means that Na/Ca exchange is extruding more Ca in direct
competition with the SR Ca pump. This causes a lower SR Ca content that
contributes to the smaller Ca transient. The experimental data in Fig.
7, B and C, were acquired at 23°C (rather than
at 37°C as in the model data and all of Fig. 7A). This may
largely account for the larger INaCa values in
the model and the more rapid decline of [Ca]i and inward
INaCa in the model (at 37°C) vs. the data at 23°C. Other factors that could impact on the precision of
INaCa predictions with the model are that
1) LabHEART 4.7 uses a common cytosolic Ca pool, whereas
submembrane [Ca]i, in fact, may be higher than average
[Ca]i during the SR Ca release (32), and 2) the expression used for Na/Ca exchange in the model may
not have the correct dependence on [Ca]i
(33). The higher INaCa level in HF implies
that for any given spontaneous SR Ca release [e.g., during a delayed
afterdepolarization (DAD)], a greater inward
INaCa is expected. This could increase the
likelihood that a DAD triggers an AP.

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Fig. 7.
Na/Ca exchange data (left) and simulations
(right). A: INaCa measured
in control and HF myocytes (data from Ref. 21).
B: caffeine (Caff)-induced Ca transient and
INaCa (data from Ref. 22).
C: dynamic relation of INaCa with Ca
transient from B (data from Ref. 22).
Experimental data were recorded at 37°C in A and at 23°C
in B and C. Simulations with LabHEART were all at
37°C.
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K currents also are altered in HF as shown in Fig.
8. Ito is
downregulated by 49% (Fig. 8, A and B). The
faster inactivation kinetics in the simulation apparently result
because the experimental data was recorded at 23°C, rather than at
37°C for the model. The inward rectifier current
(IK1) is also decreased (49%), as plotted in
Fig. 8C. Again, the experimental data are at 23°C vs. the
model at 37°C. Because experimental data have not always been recorded at 37°C, it would be convenient to be able to alter
temperature in the model. Although we hope to include this option in
future versions of LabHEART, this would be a major challenge, because there would be so many required parameters that might have different temperature dependence. Because IK1 is important
in stabilizing the resting Em, the decreased
IK1 may facilitate depolarization during the
initiation of triggered arrhythmias.

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Fig. 8.
K
current alterations in HF. A: current traces of the
Ito for normal (top) and HF
(bottom) myocytes. B: I-V relationship
for Ito. C: I-V
relationship for IK1. Experiments were conducted
at 23°C and simulations at 37°C. Ito and
IK1 amplitudes used in the model were a
compromise between these data (extrapolated to 37°C) and measurements
from other studies and models at 37°C (notably,
Ito kinetics are faster and
IK1 amplitude is larger). NCX, Na/Ca exchange.
Experimental data are from Ref. 22.
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To further examine the role of altered INaCa and
IK1 in triggered arrhythmias like DADs, we
simulated DADs in a manner analogous to our experimental approach (Fig.
9). Pogwizd et al. (22)
applied caffeine pulses at different SR Ca loads to determine the
threshold amount of [Ca]i rise (
[Ca]i)
required to produce a given depolarization (
Em) or trigger an AP. Using different
frequencies to alter the SR Ca content, they determined that there was
a greater depolarization for any give
[Ca]i in HF, and
the threshold
[Ca]i to produce an AP was reduced by
~50% (515 ± 59 nM control, 280 ± 30 nM HF; Fig.
9B, left). In our model (Fig. 9B,
right), caffeine application was simulated by opening the release
channel and setting the Vmax for SR Ca uptake at
zero. Moreover, because we can control the amount of SR Ca release
directly, the model does not require the different conditioning pulses.
Decreasing IK1 by 49% reduced the
[Ca]i threshold by 25% [from 800 nM (control) to 600 nM]. When the Na/Ca exchange (NCX) was increased by 100%, the
threshold value was reduced by 32% (540 nM). If these two changes are
combined (as in HF), the
[Ca]i threshold is reduced by
52% with respect to control (to 380 nM). These values are quite
similar to the experimental observations in HF vs. control. The
simulation also allows us to infer that the two key effects (increased
NCX and reduced IK1) contribute about equally
and additively to the increased propensity for triggered arrhythmias in
HF (24). The reduction of Ito or SR
Ca-ATPase seen in HF did not change DADs appreciably (not shown).

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Fig. 9.
In
the current-clamp single-pulse mode, one can simulate spontaneous SR Ca
release (as in a caffeine application). The amount of Ca released into
the myoplasm is extruded by INaCa, producing a
depolarizing current. A: for larger Ca releases, this
current produces increasing depolarizations (eventually triggering an
AP). B: we measured the delayed afterdepolarizations (DADs)
for given amounts of Ca release for control and HF conditions. The
amount of Ca needed to trigger a given DAD or an AP is significantly
lower in the HF myocytes than in control (800 nM control, 380 nM HF).
Experimental data are from Ref. 22.
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DISCUSSION |
The three goals achieved in this study were to 1)
create a new type of cardiac electrophysiology/Ca model that emphasizes the user interface, 2) create a new model that predicts the
electrophysiological and Ca transport properties of rabbit ventricular
myocytes, and 3) use this model to simulate and analyze
altered function in an experimental model of HF in rabbits.
Computer models of this sort have two major aspects: elaboration and
implementation. Elaboration of the equations that are used to describe
the biological behavior of the channels and how they interact has been
the focal point of most current cardiac AP models. Several excellent
models have been developed for guinea pig, canine, and human ventricle
and rabbit atrium (8, 11-13, 18, 23, 34, 35). Indeed,
this is the context in which important mechanistic innovations in such
models has almost invariably come. However, there is no currently
available model for rabbit ventricular myocyte, a tissue that is widely
used in many types of experimental studies. There are major differences
in Ca transport, ionic currents, and APs among common species and cell
types (2). In particular, rabbit ventricle has a different
balance of K currents and AP shape (compared to rat, dog, human
ventricle, and even rabbit atrium). The competition between the SR
Ca-ATPase and Na/Ca exchange during [Ca]i decline also
differs dramatically among these tissues. Thus it is important to have
a computer model that is tailored to these specific properties.
The second aspect of computer models, implementation, refers to the
computer program itself and, importantly, how the user interacts with
the model. In the present study, we emphasize this aspect by modifying
a widely utilized system of equations to simulate rabbit ventricular
myocyte properties and also by creating a novel and highly
user-friendly interface. LabHEART has several features that may allow
it to have particularly broad utility. First, it is readily accessible.
The program can be downloaded from our lab homepage
(http://www.meddean.luc.edu/lumen/DeptWebs/physio/bers.html). Second, it runs well on a fairly basic personal computer. Some computer
models for biological systems require more sophisticated computer
resources that are not always readily available in the biology
departments where many end users are located. Third, LabHEART is useful
for students at many levels, including those with relatively limited
background in electrophysiology or computer modeling. The help screens
and intuitive layout of Lab-HEART encourage both exploration and
learning. This will help students understand the principles and the
dynamic interactions that occur among the systems considered. Fourth,
LabHEART is valuable for the active scientist working in this field,
where it may be particularly helpful in developing new experimental
hypotheses or insights. Indeed, the user may freely adjust ionic
conditions, pulse protocols, and some ion channel properties. Thus the
experimentalist does not have to independently develop an integrative
model to study the impact of more discretely measured
electrophysiological changes. Fifth, LabHEART is relatively up to date
with respect to ion currents and Ca transport properties.
Using this new program, we were able to both simulate and analyze the
mechanisms underlying the generation of triggered arrhythmias in HF
myocytes. Electrical reentry can contribute to ventricular tachycardia
in many pathophysiological states, but three-dimensional mapping
studies show that most fatal arrhythmias in HF initiate by nonreentrant
mechanisms such as DADs (20). By altering the default
values of the IK1, Ito,
INaCa, and the SR Ca-ATPase in the manner
measured in voltage clamp and Ca transient studies (21,22), we could simulate the changes in AP and Ca
transients. Furthermore, by adjusting these parameters individually in
LabHEART (in a manner that cannot be done readily in experiments), we
could analyze the likely quantitative contributions of different
changes to the size of DADs for a given spontaneous SR Ca release (and the
[Ca]i threshold for triggering an AP). We found
that the reduced IK1 and enhanced
INaCa contribute about equally to shifts in
[Ca]i dependence of DADs and AP threshold (25-32%
shifts of threshold
[Ca]i). Moreover, these two
effects seem to be approximately additive, because when both changes
are instituted together, the threshold
[Ca]i is
reduced by 52% (and this matches the experimental observations where
the two contributions cannot be readily differentiated) (22). This is only one example of the kind of additional
analytical insight that can be gleaned from a computer model of this type.
It should also be acknowledged that this is an ongoing process and that
LabHEART 4.7 as described here is a first major step on this path. We
are actively developing new scientific expressions for modeling the
ventricular AP and Ca transients (e.g., more appropriate equations for
SR Ca transport and Na/Ca exchange) (28, 29, 33). Several
ionic currents also need additional refinement. For example, there are
at least two molecular contributors to Ito
(15) that have different kinetics. Altered functional frameworks also will be necessary. For instance, it is clear that local
[Ca]i near the sarcolemma differs from the bulk
[Ca]i and possibly also from [Ca]i in the
cleft between junctional SR and the sarcolemma (32). We
have begun preliminary incorporation of some of these novel aspects
into the elaboration phase (27) and plan to eventually
transport that much more complex model into the user-friendly LabHEART
format. A long-term challenge is to allow the LabHEART user to readily
simulate different cell types (from stored parameter sets) and also to
be able to easily change the basic equations used for different
channels, transporters, or buffers.
 |
ACKNOWLEDGEMENTS |
We are grateful to Dr. T. R. Shannon for valuable comments on
the manuscript.
 |
FOOTNOTES |
This work was supported in part by American Heart Association
Fellowship 9920452Z (to J. L. Puglisi), National Heart, Lung, and
Blood Institute Grant HL-30077 (to D. M. Bers), and the National Space Biomedical Research Institute (to D. M. Bers).
Address for reprint requests and other correspondence:
D. M. Bers, Dept. of Physiology, Loyola Univ. Chicago, Stritch
School of Medicine, 2160 South First Ave., Maywood, IL 60153 (E-mail dbers{at}lumc.edu).
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 27 April 2001; accepted in final form 20 August 2001.
 |
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