Biophysical Models of the Cardiovascular System - Systems Biology: Networks, Models, and Applications - page 268

component serving to prevent overloading of the SR with Ca 2+ at rest.
An additional Ca 2+ extrusion mechanism is the sarcolemmal Ca 2+ -
ATPase. This Ca 2+ pump hydrolyzes ATP to transport Ca 2+ out of the cell.
However, it contributes a sarcolemmal current that is small relative
to that of the Na + -Ca 2+ exchanger, with estimates indicating that
perhaps as little as 3% of Ca 2+ extrusion from the myocyte is mediated
by this pump.

COMPUTATIONAL MODELS OF THE VENTRICULAR MYOCYTE

Development of myocyte models began in the early 1960s with publi-
cation of Purkinje fiber AP models. Subsequent elaboration of these
models led to development of the first biophysically based cell model
describing interactions between voltage-gated membrane currents,
membrane pumps, and exchangers that regulate Ca 2+ , Na + , and K +
levels, and additional intracellular Ca 2+ cycling processes in the car-
diac myocyte: the DiFrancesco-Noble model of the Purkinje fiber [7].
This important model established the conceptual framework from
which all subsequent models of the myocyte have been derived (ven-
tricular myocytes [8-11], SA node cells [12-15], and atrial myocytes
[16,17]). These models have proven reproductive and predictive
properties and have been applied to advance our understanding of
myocyte function in both health and disease.
The chief distinction between models of the ventricular myocyte
in use today concerns the representation of the CICR process. In all
present-day models, CICR is described either phenomenologically or
through use of a formulation known as the “common pool.” Common
pool models are ones in which Ca 2+ flux through all LCCs is lumped
into a single trigger flux, Ca 2+ flux through all RyRs is lumped into a
single release flux, and both the trigger and release flux are directed
into a common Ca 2+ compartment (the “subspace”) with volume equal
to the sum of the volume of all dyads in the cell. In such models,
activation of the JSR release mechanism is controlled by Ca 2+ concen-

tration in this common pool.
A consequence of this physical arrangement is that once RyR
Ca 2+ release is initiated, the resulting increase of Ca 2+ concentration in
the common pool stimulates regenerative, all-or-none rather than
graded Ca 2+ release from the JSR. Graded release refers to a distinctive
feature of cardiac CICR, originally observed by Fabiato [18-20], that
Ca 2+ release from JSR is a smooth and continuous function of trigger
Ca 2+ entering the cell via LCCs. Common pool models therefore fail to
capture one of the most important properties of CICR observed exper-
imentally. This “latch up” of Ca 2+ release can be avoided and graded
JSR release can be achieved using phenomenological models in which
Ca 2+ release flux is an explicit function of only Ca 2+ flux through LCCs,