Page 66 - Cardiac Electrophysiology | A Modeling and Imaging Approach

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This objective is extremely difficult using experimental techniques, but lends itself to

mathematical modeling. To achieve this goal, we constructed a model of a ventricular myocyte
that contains 10,000 dyads in which Ca release occurs stochastically . 15 LCCs and 100 RyR2s are
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present in each dyad. The sarcolemmal ionic currents, pumps and exchangers were adapted from

the LRd model of the guinea pig ventricular myocyte.

Figure 2.44A displays a schematic diagram of the spatially distributed ventricular myocyte
model and its components. Figure 2.44B shows a simulated Ca spark during myocyte pacing
at 1 Hz. A temporal profile of fluorescent-dye bound Ca (CaF) at 0, 0.1, and 0.5 µm from the spark

center is shown at the top of the right frame. After application of the stimulus, a small foot of Ca
increase due to I is seen before the spark activates. The spatial profile of the Ca spark at the
CaL
times indicated (0 – 50 ms) after spark initiation is shown at the bottom right. The simulated Ca

spark properties are consistent with experiments .
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Figure 2.45 shows Ca currents and Ca concentrations in one of the dyads during steady-
state pacing at 1 Hz. Substantial differences in the peak concentration and time course of Ca exist
among different local Ca compartments within the dyad. Figure 2.46 shows the global whole cell

I cell and SR Ca release flux (J cell ), and compartmental Ca concentrations. The cell is paced at
CaL rel
1 Hz. J cell results from stochastic release of Ca at the local dyads. The duration of J cell and of the
rel rel
average dyadic space transient Ca cell is in the range of 20-30 ms, similar to the duration of local Ca
d
release events. This property reflects high degree of synchrony between dyads. However, the rise
time of the whole-cell parameters is slower, reflecting a slight temporal dispersion in the
occurrence of local Ca release events. The whole cell global SR Ca depletion profile is similar to
that of local SR Ca depletion (compare Ca cell in Figure 2.46 to Ca dyad in Figure 2.45),
SR SR
indicating that SR Ca depletion occurs uniformly throughout the cell. The model reproduces

important properties of Ca cycling , including graded release (the magnitude of SR Ca release
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increases with increasing Ca influx through LCCs) and variable gain (the ratio of Ca released from
the SR to Ca entry into the myocyte is a function of the transmembrane potential). It also

reproduces the rate dependence of myoplasmic Na and Ca .
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