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1.  Multiscale modeling of metabolism, flows, and exchanges in heterogeneous organs 
Large-scale models accounting for the processes supporting metabolism and function in an organ or tissue with a marked heterogeneity of flows and metabolic rates are computationally complex and tedious to compute. Their use in the analysis of data from positron emission tomography (PET) and magnetic resonance imaging (MRI) requires model reduction since the data are composed of concentration–time curves from hundreds of regions of interest (ROI) within the organ. Within each ROI, one must account for blood flow, intracapillary gradients in concentrations, transmembrane transport, and intracellular reactions. Using modular design, we configured a whole organ model, GENTEX, to allow adaptive usage for multiple reacting molecular species while omitting computation of unused components. The temporal and spatial resolution and the number of species are adaptable and the numerical accuracy and computational speed is adjustable during optimization runs, which increases accuracy and spatial resolution as convergence approaches. An application to the interpretation of PET image sequences after intravenous injection of 13NH3 provides functional image maps of regional myocardial blood flows.
PMCID: PMC2849657  PMID: 20201893
multiscale modeling; cardiovascular system; myocardial blood flows; computational biology; capillary–tissue exchange; JSim simulation analysis; optimization; positron emission tomography; magnetic resonance imaging
2.  Linking Cellular Energetics to Local Flow Regulation in the Heart 
A mathematical model has been developed to explain the metabolic and energetic responses induced by abnormal routes of cardiac excitation. For example, in left bundle branch block (LBBB), both glucose uptake and flow are reduced in the septal region, similar to the situation in dogs paced at the right ventricular outflow tract. In these conditions the septum is activated early, the sarcomere lengths shorten rapidly against low left ventricular (LV) pressure, and the blood flow to the interventricular septum diminishes. In contrast, the work load and the blood flow increases in the later-activated LV free wall. To provide a logical, quantitatively appropriate representation, the model links: (1) the processes of excitation–contraction coupling; (2) regional ATP utilization for force development at the cross-bridge, for ion pumping, and for cell maintenance; (3) the regulation of demands on local fatty acid and glucose metabolism for ATP generation by glycolysis and oxidative phosphorylation; and (4) feedback regulation of blood flow to supply substrate and oxygen. The heart is considered as a cylinder composed of two parts: an early-activated region and a late-activated region in tandem, but activated separately with the time delay representing the time for excitation to spread from septum to free wall. The same model equations and parameter sets are used for the two regions. The contraction of the early-activated region stretches the other region, with the result that the early-stimulated region has diminished oxygen requirements compared to those found with simultaneous stimulation. The late-activated region has increased work and increased oxygen consumption, as seen in the intact heart. Integrating the modeling of cardiac energy metabolism with local blood flow regulation and capillary–tissue substrate exchange provides a quantitative description, an hypothesis formulated to stimulate further experimentation to test its validity. The hypothesis “explains” observations of contraction and metabolism in LBBB, but whether this concept can be extended to explain the normal flow heterogeneity in the heart remains unknown.
PMCID: PMC2854143  PMID: 18375585
myocardial blood flow; heterogeneity; cardiac pacing; excitation–contraction coupling; cellular energetics; cardiac cell model; bundle branch block; shortening deactivation; ionic regulation; smooth muscle receptors; branch point competition; apparent cooperativity

Results 1-2 (2)