Biomedical Engineering Reference
In-Depth Information
upregulation of Na
+
-Ca
2+
exchanger (by 75%; dotted line). Changes of trans-
porter amplitude were based on average values derived from experiments using
mid-myocardial failing canine ventricular myocytes. Model simulations indicate
that downregulation of
I
to1
produces a modest
shortening
, not lengthening, of AP
duration. On first consideration, this seems an anomalous effect since
I
to1
is an
outward K current, but is one which agrees with the experimental results of
Zygmunt et al. (48) in canine myocytes (see their Fig. 2). The mechanism of this
AP duration shortening has been investigated in detail using computational
models (33), and results show that reduction of the Phase 1 notch depth through
downregulation of
I
to1
reduces the electrical driving force on inward Ca
2+
current
and hence shortens AP duration. The additional downregulation of
I
K1
(long-
dashed line) produces modest AP prolongation, consistent with the fact that
outward current through
I
K1
is activated primarily at potentials which are hyper-
polarized relative to the plateau potential. The most striking result is shown by
the short-dashed line in Figure 3C—significant AP prolongation occurs follow-
ing downregulation of SR Ca
2+
-ATPase. This downregulation results in a near
doubling of AP duration that is similar to that observed experimentally (Figure
3A). Finally, the model predicts that upregulation of Na
+
-Ca
2+
exchanger, when
superimposed on these other changes, contributes to modest APD
shortening
due to reverse mode Na
+
-Ca
2+
exchange and generation of a net outward current
during the plateau phase of the AP.
This modeling has provided important insights into the mechanism of AP
prolongation and altered Ca
2+
transients in heart failure. Prior to this work, the
consensus was that downregulation of the genes encoding the
I
to1
and
I
K1
outward
K currents was responsible for AP prolongation—a very intuitive and reasonable
hypothesis. The model indicates that this is not likely to be the case. Rather, the
main contributor to AP prolongation involves downregulation of the gene en-
coding the SR Ca
2+
-ATPase. Subsequent model simulations have shown that
downregulation of this transport process alone has a severe effect on prolonga-
tion of the AP, a prediction confirmed by experiments in which cyclopiazonic
acid is used to block SR Ca
2+
-ATPase transport (49). This modeling illustrates
the value of using quantitative models to interpret the consequences of changes
in gene and protein expression on cell function. It also points out how prediction
of a cellular phenotype using knowledge of underlying molecular changes
must
be based on interpretations derived from quantitative experimentally based
models.
2.7. A New Class of Myocyte Models
While common pool models are able to reconstruct APs with high fidelity,
they are unable to reproduce a very fundamental behavior of cardiac myo-
cytes—SR Ca
2+
release that is smoothly and continuously graded with influx of
