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James B Bassingthwaighte

Publications and source records attributed to James B Bassingthwaighte.

15 recordsLinked to original sources
PubMed2006

Coupling of a 3D finite element model of cardiac ventricular mechanics to lumped systems models of the systemic and pulmonic circulation.

In this study we present a novel, robust method to couple finite element (FE) models of cardiac mechanics to systems models of the circulation (CIRC), independent of cardiac phase. For each time step through a cardiac cycle, left and right ventricular pressures were calculated using ventricular compliances from the FE and CIRC models. These pressures served as boundary conditions in the FE and CIRC models. In succeeding steps, pressures were updated to minimize cavity volume error (FE minus CIRC volume) using Newton iterations. Coupling was achieved when a predefined criterion for the volume error was satisfied. Initial conditions for the multi-scale model were obtained by replacing the FE model with a varying elastance model, which takes into account direct ventricular interactions. Applying the coupling, a novel multi-scale model of the canine cardiovascular system was developed. Global hemodynamics and regional mechanics were calculated for multiple beats in two separate simulations with a left ventricular ischemic region and pulmonary artery constriction, respectively. After the interventions, global hemodynamics changed due to direct and indirect ventricular interactions, in agreement with previously published experimental results. The coupling method allows for simulations of multiple cardiac cycles for normal and pathophysiology, encompassing levels from cell to system.

Animals↗
PubMed2006

GENTEX, a general multiscale model for in vivo tissue exchanges and intraorgan metabolism.

Endothelial cells lining myocardial capillaries not only impede transport of blood solutes to the contractile cells, but also take up and release substrates, competing with myocytes. Solutes permeating this barrier exhibit concentration gradients along the capillary. This paper introduces a generic model, GENTEX, to characterize blood-tissue exchanges. GENTEX is a whole organ model of the vascular network providing intraorgan flow heterogeneity and accounts for substrate transmembrane transport, binding and metabolism in erythrocytes, plasma, endothelial cells, interstitial space and cardiomyocytes. The model is tested here for the analysis of multiple tracer indicator dilution data on purine nucleoside metabolism in the isolated Krebs-Henseleit-perfused non-working hearts. It has been also used for analysing NMR contrast data for regional myocardial flows and for positron emission tomographic studies of cardiac receptor kinetics. The facilitating transporters, binding sites and enzymatic reactions are nonlinear elements and allow competition between substrates and a reaction sequence of up to five substrate-product reactions in a metabolic network. Strategies for application start with experiment designs incorporating inert reference tracers. For the estimation of endothelial and sarcolemmal permeability-surface area products and metabolism of the substrates and products, model solutions were optimized to fit the data from pairs of tracer injections (of either inosine or adenosine, plus the reference tracers) injected under the same circumstances a few minutes later. The results provide a self-consistent description of nucleoside metabolism in a beating well-perfused rabbit heart, and illustrate the power of the model to fit multiple datasets simultaneously.

Animals↗
PubMed2006

Simultaneous blood-tissue exchange of oxygen, carbon dioxide, bicarbonate, and hydrogen ion.

A detailed nonlinear four-region (red blood cell, plasma, interstitial fluid, and parenchymal cell) axially distributed convection-diffusion-permeation-reaction-binding computational model is developed to study the simultaneous transport and exchange of oxygen (O2) and carbon dioxide (CO2) in the blood-tissue exchange system of the heart. Since the pH variation in blood and tissue influences the transport and exchange of O2 and CO2 (Bohr and Haldane effects), and since most CO2 is transported as HCO3(-) (bicarbonate) via the CO2 hydration (buffering) reaction, the transport and exchange of HCO3(-) and H+ are also simulated along with that of O2 and CO2. Furthermore, the model accounts for the competitive nonlinear binding of O2 and CO2 with the hemoglobin inside the red blood cells (nonlinear O2-CO2 interactions, Bohr and Haldane effects), and myoglobin-facilitated transport of O2 inside the parenchymal cells. The consumption of O2 through cytochrome-c oxidase reaction inside the parenchymal cells is based on Michaelis-Menten kinetics. The corresponding production of CO2 is determined by respiratory quotient (RQ), depending on the relative consumption of carbohydrate, protein, and fat. The model gives a physiologically realistic description of O2 transport and metabolism in the microcirculation of the heart. Furthermore, because model solutions for tracer transients and steady states can be computed highly efficiently, this model may be the preferred vehicle for routine data analysis where repetitive solutions and parameter optimization are required, as is the case in PET imaging for estimating myocardial O2 consumption.

Animals↗
PubMed2006

Computational evidence for protein-mediated fatty acid transport across the sarcolemma.

Long-chain fatty acids (FAs) are important substrates used by the heart to fulfil its energy requirements. Prior to mitochondrial oxidation, blood-borne FAs must pass through the cell membrane of the cardiac myocyte (sarcolemma). The mechanism underlying the sarcolemmal transport of FAs is incompletely understood. The aim of the present study was to estimate the trans-sarcolemmal FA uptake rate using a comprehensive computer model, in which the most relevant mechanisms proposed for cardiac FA uptake were incorporated. Our in silico findings show that diffusion of FA, present in its unbound form (uFA) in close proximity to the outer leaflet of the sarcolemma and serving as sole FA source, is insufficient to account for the physiological FA uptake rate. The inclusion of a hypothetical membrane-associated FA-TFPC (FA-transport-facilitating protein complex) in the model calculations substantially increased the FA uptake rate across the sarcolemma. The model requires that the biological properties of the FA-TFPC allow for increasing the rate of absorption of FA into the outer leaflet and the 'flip-flop' rate of FA from the outer to the inner leaflet of the sarcolemma. Experimental studies have identified various sarcolemma-associated proteins promoting cardiac FA uptake. It remains to be established whether these proteins possess the properties predicted by our model. Our findings also indicate that albumin receptors located on the outer leaflet of the sarcolemma facilitate the transfer of FA across the membrane to a significant extent. The outcomes of the computer simulations were verified with physiologically relevant FA uptake rates as assessed in the intact, beating heart in experimental studies.

Biological Transport, Active↗
PubMed2006

A practical extension of hydrodynamic theory of porous transport for hydrophilic solutes.

OBJECTIVE: The equations for transport of hydrophilic solutes through aqueous pores provide a fundamental basis for examining capillary-tissue exchange and water and solute flux through transmembrane channels, but the theory remains incomplete for ratios, alpha, of sphere diameters to pore diameters greater than 0.4. Values for permeabilities, P, and reflection coefficients, sigma, from Lewellen, working with Lightfoot et al., at alpha = 0.5 and 0.95, were combined with earlier values for alpha < 0.4, and the physically required values at alpha = 1.0, to provide accurate expressions over the whole range of 0 < alpha < 1. METHODS: The "data" were the long-accepted theory for alpha < 0.2 and the computational results from Lewellen and Lightfoot et al. on hard spheres (of 5 different alpha's) moving by convection and diffusion through a tight cylindrical pore, accounting for molecular exclusion, viscous forces, pressure drop, torque and rotation of spheres off the center line (averaging across all accessible radial positions), and the asymptotic values at alpha = 1.0. Coefficients for frictional hindrance to diffusion, F(alpha), and drag, G(alpha), and functions for sigma(alpha) and P(alpha), were represented by power law functions and the parameters optimized to give best fits to the combined "data." RESULTS: The reflection coefficient sigma = {1 - [1 - (1 - phi)2]G'(alpha)} + 2alpha2 phi F'(alpha), and the relative permeability P/Pmax = phi F '(alpha)[1 + 9alpha5.5 x (1.0 - alpha5)0.02], where phi is the partition coefficient or volume fraction of the pore available to solute. The new expression for the diffusive hindrance is F'(alpha) = (1 - alpha2)(3/2) phi/[1 + 0.2 x alpha2 x (1 - alpha2)16], and for the drag factor is G'(alpha) = (1 - 2alpha(2)/3 - 0.20217 alpha5)/(1 - 0.75851 alpha5) - 0.0431[1 - (1 - alpha10)]. All of these converge monotonically to the correct limits at alpha = 1. CONCLUSIONS: These are the first expressions providing hydrodynamically based estimates of sigma(alpha) and P(alpha) over 0 < alpha < 1 They should be accurate to within 1-2%.

Animals↗
PubMed2005

Multiscale modeling of cardiac cellular energetics.

Multiscale modeling is essential to integrating knowledge of human physiology starting from genomics, molecular biology, and the environment through the levels of cells, tissues, and organs all the way to integrated systems behavior. The lowest levels concern biophysical and biochemical events. The higher levels of organization in tissues, organs, and organism are complex, representing the dynamically varying behavior of billions of cells interacting together. Models integrating cellular events into tissue and organ behavior are forced to resort to simplifications to minimize computational complexity, thus reducing the model's ability to respond correctly to dynamic changes in external conditions. Adjustments at protein and gene regulatory levels shortchange the simplified higher-level representations. Our cell primitive is composed of a set of subcellular modules, each defining an intracellular function (action potential, tricarboxylic acid cycle, oxidative phosphorylation, glycolysis, calcium cycling, contraction, etc.), composing what we call the "eternal cell," which assumes that there is neither proteolysis nor protein synthesis. Within the modules are elements describing each particular component (i.e., enzymatic reactions of assorted types, transporters, ionic channels, binding sites, etc.). Cell subregions are stirred tanks, linked by diffusional or transporter-mediated exchange. The modeling uses ordinary differential equations rather than stochastic or partial differential equations. This basic model is regarded as a primitive upon which to build models encompassing gene regulation, signaling, and long-term adaptations in structure and function. During simulation, simpler forms of the model are used, when possible, to reduce computation. However, when this results in error, the more complex and detailed modules and elements need to be employed to improve model realism. The processes of error recognition and of mapping between different levels of model form complexity are challenging but are essential for successful modeling of large-scale systems in reasonable time. Currently there is to this end no established methodology from computational sciences.

Algorithms↗
PubMed2004

Blood HbO2 and HbCO2 dissociation curves at varied O2, CO2, pH, 2,3-DPG and temperature levels.

New mathematical model equations for O2 and CO2 saturations of hemoglobin (S(HbO2) and S(HbCO2)) are developed here from the equilibrium binding of O2 and CO2 with hemoglobin inside RBCs. They are in the form of an invertible Hill-type equation with the apparent Hill coefficients K(HbO2) and K(HbCO2) in the expressions for S(HbO2) and S(HbCO2) dependent on the levels of O2 and CO2 partial pressures (P(O2) and P(CO2), pH, 2,3-DPG concentration, and temperature in blood. The invertibility of these new equations allows P(O2) and P(CO2) to be computed efficiently from S(HbO2) and S(Hbco2) and vice-versa. The oxyhemoglobin (HbO2) and carbamino-hemoglobin (HbCO2) dissociation curves computed from these equations are in good agreement with the published experimental and theoretical curves in the literature. The model solutions describe that, at standard physiological conditions, the hemoglobin is about 97.2% saturated by O2 and the amino group of hemoglobin is about 13.1% saturated by CO2. The O2 and CO2 content in whole blood are also calculated here from the gas solubilities, hematocrits, and the new formulas for S(HbO2) and S(HbCO2). Because of the mathematical simplicity and invertibility, these new formulas can be conveniently used in the modeling of simultaneous transport and exchange of O2 and CO2 in the alveoli-blood and blood-tissue exchange systems.

2,3-Diphosphoglycerate↗
PubMed2004

The computational integrated myocyte: a view into the virtual heart.

The presentation outlines an integrative approach for developing a computational model of cardiomyocytes. A modular approach is proposed, and strategies of linking the modules (intermediary metabolism, electrophysiology, and mechanics) of the model are presented. A strong recommendation is given toward an integrated system approach backed by experimental validation.

Computational Biology↗
PubMed2003

Myocardial density and composition: a basis for calculating intracellular metabolite concentrations.

Systems for describing myocardial cellular metabolism with appropriate thermodynamic constraints on reactions have to be on the basis of estimates of intracellular and mitochondrial concentrations of metabolites as driving forces for reactions. This requires that tissue composition itself must be modeled, but there is marked inconsistency in the literature and no full data set on hearts of any species. To formulate a self-consistent set of information on the densities, contents, or concentrations of chemical components and volumes of tissue spaces, we drew on information mostly on rats. From the data on densities, volumes, volume fractions, and mass fractions observed mainly on left ventricular myocardium, cytoplasm, and mitochondria and from morphometric data on cellular components and the vasculature, we constructed a matrix based on conservation laws for density, volume, and constituent composition. The four constituents were water, protein, fat, and solutes (or ash). To take into account the variances in the observed data sets, we used a constrained nonlinear least squares optimization to minimize the differences between the final results and the data sets. The results provide a detailed estimate of cardiac tissue composition, previously unavailable, for the translation of whole tissue concentrations or concentrations per gram protein into estimated local concentrations that are relevant to reaction processes. An example is that the concentrations of phosphocreatine and ATP in cytosolic water space are twice as high as their mean tissue concentrations. This conservation optimization method is applicable to any tissue or organ.

Animals↗
PubMed2003

Transient transcapillary exchange of water driven by osmotic forces in the heart.

Osmotic transient responses in organ weight after changes in perfusate osmolarity have implied steric hindrance to small-molecule transcapillary exchange, but tracer methods do not. We obtained osmotic weight transient data in isolated, Ringer-perfused rabbit hearts with NaCl, urea, glucose, sucrose, raffinose, inulin, and albumin and analyzed the data with a new anatomically and physicochemically based model accounting for 1) transendothelial water flux, 2) two sizes of porous passages across the capillary wall, 3) axial intracapillary concentration gradients, and 4) water fluxes between myocytes and interstitium. During steady-state conditions approximately 28% of the transcapillary water flux going to form lymph was through the endothelial cell membranes [capillary hydraulic conductivity (Lp) = 1.8 +/- 0.6 x 10-8 cm. s-1. mmHg-1], presumably mainly through aquaporin channels. The interendothelial clefts (with Lp = 4.4 +/- 1.3 x 10-8 cm. s-1. mmHg-1) account for 67% of the water flux; clefts are so wide (equivalent pore radius was 7 +/- 0.2 nm, covering approximately 0.02% of the capillary surface area) that there is no apparent hindrance for molecules as large as raffinose. Infrequent large pores account for the remaining 5% of the flux. During osmotic transients due to 30 mM increases in concentrations of small solutes, the transendothelial water flux was in the opposite direction and almost 800 times as large and was entirely transendothelial because no solute gradient forms across the pores. During albumin transients, gradients persisted for long times because albumin does not permeate small pores; the water fluxes per milliosmolar osmolarity change were 200 times larger than steady-state water flux. The analysis completely reconciles data from osmotic transient, tracer dilution, and lymph sampling techniques.

Animals↗
PubMed2002

An integrative model of coupled water and solute exchange in the heart.

Physiologists have devised many models for interpreting water and solute exchange data in whole organs, but the models have typically neglected key aspects of the underlying physiology to present the simplest possible model for a given experimental situation. We have developed a physiologically realistic model of microcirculatory water and solute exchange and applied it to diverse observations of water and solute exchange in the heart. Model simulations are consistent with the results of osmotic weight transient, tracer indicator dilution, and steady-state lymph sampling experiments. The key model features that permit this unification are the use of an axially distributed blood-tissue exchange region, inclusion of a lymphatic drain in the interstitium, and the independent computation of transcapillary solute and solvent fluxes through three different pathways.

Animals↗
PubMed2002

Relation between local myocardial growth and blood flow during chronic ventricular pacing.

UNLABELLED: Several studies have shown that, per unit mass, myocardial blood flow (MBF) and oxygen consumption are similar in hypertrophic and non-hypertrophic ventricles. This observation may be explained by the degree of myocardial growth matching the increase in oxygen demand. Such matching may, however, not be perfect at the local level, because substantial heterogeneity of MBF exists within the ventricular wall. We investigated to what extent local growth and MBF are matched after redistribution of workload within the left ventricular (LV) wall. Redistribution of workload was established by ventricular pacing at physiological heart rate, which induces asynchronous activation and contraction. Local wall mass (2D-echocardiography) and MBF (fluorescent microspheres) were determined in the canine LV wall before (t=0) and after 6 months of normal sinus rhythm (SHAM group, n=5) or 6 months of pacing at the LV free wall (PACE group, n=8). During acute pacing MBF (ml/min/g) increased with increasing distance to the pacing site. Local relative MBF (rMBF, local MBF normalized to mean MBF in the LV wall) varied from 0.8 adjacent to the pacing site to 1.2 in remote regions. After 6 months of pacing these regional differences had disappeared, probably due to changes in wall mass, which increased with increasing distance to the pacing site (by up to 39+/-13%). In SHAM animals rMBF at t=0 correlated well with rMBF 6 months later (r=0.71). In PACE animals, however, this correlation was poor (r=0.33), because rMBF increased in regions close to the pacing site with initial rMBF<1 and rMBF decreased in regions remote from the pacing site with initial rMBF>1. CONCLUSIONS: After redistribution of workload within the LV wall as induced by ventricular pacing, local load-regulated growth tends to equalize MBF distribution, but local adaptation of MBF also depends on initial MBF.

Animals↗
PubMed2002

A computational model of oxygen transport from red blood cells to mitochondria.

A computational model of oxygen transport from red blood cells to mitochondria with subsequent reaction to water is presented. This computational model consists of a five region convection-diffusion-reaction mathematical model which is solved using a standard numerical time-split method. The unique feature of this mathematical model is the treatment of the red blood cells and the plasma as two separate flows. The numerical method is second order accurate overall. This computational model is useful for analyzing residue data from positron emission tomography or data from multiple indicator dilution curves.

Biological Transport↗
PubMedDate not supplied

The macro-ethics of genomics to health: the physiome project.

Advances in pharmacology and genomics, and their intervention in human biology are beyond our abilities to understand their consequences. Therapeutic intervention in highly complex, non-linear, adaptive biological systems results in some unforeseen and undesirable consequences. To do the most good with the least harm, the information on biological systems should be gathered into databases, and into comprehensive quantitative models that can help to predict the long-range effects of proposed interventions. This is a societal or professional macro-ethical imperative. The Physiome Project helps to meet this imperative via databasing and creating models and tools for large-scale integration.

Computational Biology↗