Biomedical Engineering Reference
In-Depth Information
of
I
to1
(39) show that in end-stage HF, current density is reduced by up to 70% in
human and canine tachycardia pacing-induced HF. Human and canine Ca
2+
-
independent transient outward current,
I
to1
, is a combination of currents encoded
by the KCND3 and KCNA4 genes (39,40), and KCND3 expression has been
shown to be reduced in HF (41). There appears to be no change in expression of
the HERG or KCNQ1 gene encoding B-subunits of the
I
Kr
and
I
Ks
channels, re-
spectively, in HF.
Expression of diverse proteins involved in the processes of EC coupling
have also been measured in normal and failing myoyctes. These proteins in-
clude: (a) the SR Ca
2+
-ATPase encoded by the SERCA2 gene; (b) the phos-
pholamban protein encoded by the PLN gene; and (c) the sodium-calcium (Na
+
-
Ca
2+
) exchanger protein encoded by the NCX1 gene. Measurements indicate
there is an approximately 50% reduction of SERCA2 mRNA (37,42,43), ex-
pressed SR Ca
2+
-ATPase protein level, and direct SR Ca
2+
-ATPase uptake rate
(37) during HF. There is a 55% increase in NCX1 mRNA levels, and an ap-
proximate factor of two increase in Na
+
-Ca
2+
exchange activity in human (43-
45) and canine HF (37). There is uncertainty as to whether mRNA and ex-
pressed protein level of phospholamban is decreased (46) or unchanged (47) in
human HF, and evidence that expressed protein level is decreased by a percent-
age equal to that of the SR Ca
2+
-ATPase in the failing canine heart (37).
It is therefore critically important to understand how these changes in gene
expression, protein levels, and current densities measured experimentally impact
on the morphology of the AP and Ca
2+
transient. In particular, it is key to know
which of these changes have the greatest functional effect. To answer this ques-
tion, we developed a computational model of the failing ventricular myocyte
(28). The above data suggest the following
minimal
model of altered repolariza-
tion and Ca
2+
handling in ventricular cells from the failing canine heart: (a) re-
duced expression of
I
K1
and
I
to1
; (b) downregulation of the SR Ca
2+
-ATPase; and
(c) upregulation of the electrogenic Na
+
-Ca
2+
exchanger. Since the density, but
not the kinetic behavior, of each of the four transporters and ion currents com-
prising the minimal model appears altered in HF, we incorporated information
on this altered gene and protein expression in the canine cell model by varying
the density of these four membrane transporters (
I
to1
,
I
K1
, SR Ca
2+
-ATPase, and
Na
+
-Ca
2+
exchanger) within experimentally derived limits (37).
The model has been used to test the hypothesis that this minimal set of heart
failure-induced changes can account for prolongation of AP duration, as well as
decreased peak amplitude and decay rate of the Ca
2+
transient observed in failing
myocytes. Figures 3C and 3D demonstrate the ability of the model to reconstruct
APs and Ca
2+
transients measured in both normal and failing canine mid-
myocardial ventricular myocytes. Figure 3C shows a normal model AP (solid
line), and model APs corresponding to the additive effects of sequential down-
regulation of
I
to1
(by 62%; dot-dashed line),
I
K1
(by 32%; long-dashed line), and
SR Ca
2+
-ATPase (by 62%; rightmost short-dashed bold line), followed by
