170 CATALYZING INQUIRY
(^95) R.L. Winslow, D.F. Scollan, A. Holmes, C.K. Yung, J. Zhang, and M.S. Jafri, “Electrophysiological Modeling of Cardiac
Ventricular Function: From Cell to Organ,” Annual Reviews of Biomedical Engineering 2:119-155, 2002.
(^96) P.J. Hunter, “The IUPS Physiome Project: A Framework for Computational Physiology,” Progress in Biophysics and Molecular
Biology 85(2-3):551-569, 2004.
Box 5.15
Illustrations of Functional Models of Cellular Behavior
Example 1: Results from Single-cell Modeling
Winslow et al. have developed and applied a model of the normal and failing canine ventricular myocyte to
analysis of the functional significance of changes in gene expression during tachycardia pacing-induced heart
failure. Using the data on mRNA and protein expression levels cited above, these investigators defined a minimal
model of end-stage heart failure as (1) 33 percent reduction of IK1; (2) 66 percent reduction of Ito1; (3) 68 percent
reduction of the SR [sacroplasmic reticulum] Ca2+-ATPase; and (4) 75 percent upregulation of the Na+-Ca2+
exchanger. They incorporated these changes sequentially into the computational model and used the model to
predict the functional consequences of each alteration of gene expression in this disease. Results show that the
minimal HF [heart failure] model can reproduce the increased APD [action potential duration] observed in
failing myocytes relative to normal myocytes. The minimal model can also account for the reduced amplitude
and slowed relaxation of the Ca2+ transients observed in failing versus normal myocytes. Most importantly,
model simulations reveal that reduced expression of the outward potassium currents Ito1 and IK1 have relatively
little impact on APD, whereas altered expression of the Ca2+ handling proteins has a profound impact on APD.
These results suggested a strong interplay between APD and the properties of Ca2+ handling in canine myo-
cytes. The nature of this interplay was examined in the model. The model indicated that reductions in expres-
sion level of the SR Ca2+-ATPase and increased expression of the Na+-Ca2+ exchanger both contribute to a
reduction of JSR Ca2+ load. This reduction in the junctional SR (JSR) Ca2+ load in turn produces a smaller Ca2+
release from SR, reduced subspace Ca2+ levels, and therefore reduced Ca2+-mediated inactivation of the Ca2+
current. The enhanced Ca2+ current then contributes to prolongation of APD. This is an important insight,
because identifies the heart failure-induced reduction in JSR Ca2+ load as a critical factor in APD prolongation
and in the accompanying increased risk of arrhythmias related to repolarization abnormalities.
Analyses of the type described above are likely to become increasingly important in determining the function-
al role of altered gene and protein expression in various disease states as more comprehensive large-scale data
on genome and protein expression in disease become available.
its contractile behavior.^95 In particular, Winslow has used this model to show that the reduced contrac-
tility (i.e., reduction in the strength with which a ventricular muscle contracts, which is associated with
heart failure) is caused largely by changes in the calcium ion currents in those cells, rather than changes
in potassium ion currents as was widely speculated before this work (Example 1 in Box 5.15). Such an
insight suggests that the development of drugs to cope with heart failure would thus be better focused
on those that can regulate calcium flow. Examples 2 and 3 in Box 5.15 illustrate some of the scientific
insights that can be gained with a computational model integrated across functional and structural
lines.
Integrating these various perspectives on the heart (and other organs as well) is the mission of the
Physiome Project, which seeks to construct models that incorporate the detailed anatomy and tissue
structure of an organ in a way that allows the inclusion of cell-based models and spatial structure and
distribution of proteins. The Physiome project has developed a computational framework for integrat-
ing the electrical, mechanical, and biochemical functions of the heart:^96