Biomedical Engineering Reference
In-Depth Information
these results demonstrate the feasibility of combined experimentation and mod-
eling of electrical conduction in specific imaged and reconstructed hearts.
4.
DISCUSSION AND CONCLUSIONS
This chapter has reviewed modeling research in three broad areas: (1) mod-
els of single ventricular myocytes; (2) methods for the reconstruction and mod-
eling of ventricular geometry and microanatomy; and (3) integrative modeling
of the cardiac ventricles. We have seen that the level of biophysical detail, and
hence the accuracy and predictability of current ventricular myocyte models, is
considerable. Nonetheless, much remains to be done.
One emerging area of research is modeling of mitochondrial energy produc-
tion. Approximately 2% of cellular ATP is consumed on each heartbeat. The
major processes consuming ATP in the myocyte are muscle contraction, activity
of the SR Ca
2+
-ATPase, and Na-K pumping. Cellular ATP levels also influence
ion channel function including the sarcolemmal ATP-modulated K channel (71).
Recently, we have formulated an integrated thermokinetic model of cardiac mi-
tochondrial energetics comprising the tricarboxylic acid (TCA) cycle, oxidative
phosphorylation and mitochondrial Ca
2+
handling (72). This model describes the
dynamics of the key regulatory effectors of TCA cycle enzymes and the produc-
tion of NADH and FADH
2
. These molecules are used by the electron transport
chain to establish a proton motive force (
N
H
), which then drives the
F
1
F
0
-
ATPase. Mitochondrial matrix Ca
2+
is also a model state variable. Mitochondrial
Ca
2+
concentration is determined by the Ca
2+
uniporter and Na
+
/Ca
2+
exchanger
activities, and regulates activity of the TCA cycle enzymes isocitrate dehydro-
genase (IDH) and B-ketoglutarate dehydrogenase (KGDH). The model is de-
scribed by twelve ordinary differential equations that represent %:
m
(mito-
chondrial membrane potential) and matrix concentrations of Ca
2+
, NADH, ADP,
and TCA cycle intermediates. The model is able to reproduce experimental data
concerning mitochondrial bioenergetics, Ca
2+
dynamics and respiratory control,
relying only on the fundamental properties of the system. The time-dependent
behavior of the model, under conditions simulating an increase in workload,
closely reproduce the experimentally observed mitochondrial NADH dynamics
in heart trabeculae subjected to changes in pacing frequency. The steady-state
and time-dependent behavior of the model support the role of mitochondrial
matrix Ca
2+
in matching energy supply with demand in cardiac cells. Further
development and testing of this model, its integration into models of the myo-
cyte, and the use of these models to investigate myocyte responses to ischemia,
are required.
In real cardiac myocytes, there exist a diversity of mechanisms that act to
modulate cellular excitability. This includes B- and C-adrenergic signaling
pathways acting through G protein-coupled membrane receptors to modulate the
