Biophysical Models of the Cardiovascular System - Systems Biology: Networks, Models, and Applications - page 288

the tricarboxylic acid (TCA) cycle, oxidative phosphorylation, and
mitochondrial Ca 2+ handling has been formulated [91]. The model is
able to reproduce experimental data concerning mitochondrial bioen-
ergetics, 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 myocyte, 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 a- and b-adrenergic
signaling pathways acting through G-protein-coupled membrane
receptors to modulate properties of LCCs, various K + channels, and
Ca 2+ transporters such as the SR Ca 2+ -ATPase. The addition of these
modulatory mechanisms to the cell models remains an important goal
for the future.
As demonstrated, magnetic resonance imaging now offers a relatively
rapid way to measure ventricular fiber structure at high spatial resolu-
tion. The ability to rapidly acquire fiber orientation data throughout
the ventricles in large populations of normal and diseased hearts will
enable quantitative statistical comparison of normal and abnormal
cardiac structure, and will provide insights into the possible structural
basis of arrhythmia in heart disease. Unfortunately, a detailed under-
standing of the spatial heterogeneities within the heart, such as variation
of intercellular coupling, regional expression of ionic currents, and
Ca 2+ -handling proteins, is still unavailable, although significant progress
has certainly been made. Understanding and modeling of these spatial
heterogeneities remains a challenge for the future.
These are exciting times for cardiovascular biology. A national
infrastructure supporting the acquisition, distribution, and analysis
of cardiovascular genomic and proteomic data is now in place (in
particular, the Programs for Genomic Applications and Innovative
Proteomics Centers supported by the National Heart, Lung, and
Blood Institute of the National Institutes of Health). The data and
models produced from these efforts will without question enhance
our understanding of the systems biology of the heart in both health
and disease. Major challenges in data collection, representation, storage,
dissemination, and modeling remain. Meeting these challenges
will contribute to the creation of a truly integrated cardiovascular
research community, the whole of which is far greater than the sum
of its parts.