168 CATALYZING INQUIRY
Box 5.14
Computational Modeling of the Heart... [Integrative cardiac modelling has sought] to integrate data and theories on the anatomy and structure, hemody-
namics and metabolism, mechanics and electrophysiology, regulation and control of the normal and diseased heart.
The challenge of integrating models of many aspects of such an organ system, including its structure and anatomy,
biochemistry, control systems, hemodynamics, mechanics and electrophysiology, has been the theme of several
workshops over the past decade or so.
Some of the major components of an integrative cardiac model that have been developed include [models of]
ventricular anatomy and fiber structure, coronary network topology and hemodynamics, oxygen transport and sub-
strate delivery, myocyte metabolism, ionic currents, impulse propagation, excitation-contraction coupling, neural
control of heart rate and blood pressure, cross-bridge cycling, tissue mechanics, cardiac fluid dynamics and valve
mechanics, and ventricular growth and remodelling........ [T]hese models can be extended and integrated with others [by considering the role in] several major functional
modules... as shown in the figure below.... They include:
- Coronary artery anatomy and regional myocardial flows for substrate and oxygen delivery.
- Metabolism of the substrate for energy metabolism, fatty acid and glucose, the tricarboxylic acid (TCA) cycle, and
oxidative phosphorylation. - Purine nucleoside and purine nucleotide metabolism, describing the formation of ATP and the regulation of its
degradation to adenosine in endothelial cells and myocytes, and its effects on coronary vascular resistance. - The transmembrane ionic currents and their propagation across the myocardium.
- Excitation-contraction coupling: calcium release and reuptake, and the relationships between these and the
strength and extent of sarcomere shortening. - Sarcomere dynamics of myofilament activation and cross-bridge cycling, and the three-dimensional mechanics
of the ventricular myocardium during the cardiac cycle. - Cell signalling and the autonomic control of cardiac excitation and contraction.
... While [Figure 5.14.1] does show different scales in the structural hierarchy, it emphasizes functional integration, and
thus it is not surprising that the majority of functional interactions take place at the scale of the single cell.... [A
functionally integrated] model of functionally interacting networks in the cell can be viewed as a foundation for structur-
ally coupled models that extend to multicellular networks, tissue, organ and organ system. But it can also be viewed as a
focal point into which feed structurally based models of protein function and subcellular anatomy and physiology.
... Predictive computational models of various processes at almost every individual level of the hierarchy have been
based on physicochemical first principles. Although important insight has been gained from empirical models of
living systems, models become more predictive if the number of adjustable parameters is reduced by making use of
detailed structural data and the laws of physics to constrain the solution. These models, such as molecular dynamics
simulations, spatially coupled cell biophysical simulations, tissue micromechanical models and anatomically based
continuum models are usually computationally intensive in their own right.... This will require a computational
infrastructure that will allow us to integrate physically based biological models that span the hierarchy from the
dynamics of individual protein molecules up to the regional physiological function of the beating heart....
Investigators have developed large-scale numerical methods for ab initio simulation of biophysical processes at the
following levels of organization: molecular dynamics simulations based on the atomic structure of biomolecules;
hierarchical models of the collective motions of large assemblages of monomers in macromolecular structures;
biophysical models of the dynamics of cross-bridge interactions at the level of the cardiac contractile filaments;
whole-cell biophysical models of the regulation of muscle contraction; microstructural constitutive models of the
mechanics of multicellular tissue units; continuum models of myocardial tissue mechanics and electrical impulse
propagation; and anatomically detailed whole organ models.They have also investigated methods to bridge some of the boundaries between the different levels of organization.
We [McCulloch and Huber] and others have developed finite-element models of the whole heart, incorporating
microstructural constitutive laws and the cellular biophysics of thin filament activation. Recently, these mechanics