As a part of a multi‐university, multi‐investigator program on integrated function of the heart, we are targeting the metabolism and regulation of the endothelial cell (EC) and the cardiomyocyte (CM) and the interactions between these two cell types. Models for blood flow, glucose, fatty acid and for oxygen are essential steps. Initial models are “eternal” in that there is no protein anabolism or catabolism, thus all enzymes remain at fixed concentrations. The emphasis is on the physico‐chemical balances (charge, ionic regulation, mass, volume, energy, reducing equivalents, carbon, oxygen, phosphorus and so on), on the limitations to the kinetics imposed by the energetics, and the responses to transients rather than steady state analysis. Fatty acid, the prime substrate for cardiac metabolism, is tightly bound to as many as 12 sites on plasma albumin, yet is about 1/3 extracted during a single capillary passage. The modeling of palmitate (a 16:0 fatty acid) flux starts with the release from these sites, the rebinding at multiple sites, diffusion in the plasma, and uptake across the capillary endothelial plasmalemma by a fatty acid transporter, e.g. CD36, facilitated diffusion by fatty acid binding protein (FABP) across the 1 micron thick EC, then facilitated or diffusive transport into the interstitial fluid space to the CM surface and transmembrane passage. The next stage, acylCoA formation, leads 2 ways. One is to di‐ and tri‐acyl glycerol (TAG) and lipid vacuole formation and the reverse, a storage and buffering system. The other is for acyl‐CoA to cross the mitochondrial membrane, undergo beta‐oxidation and insert the two‐carbon products into the tricarboxylic acid (TCA) cycle to provide energy for ATP generation through oxidative phosphorylation, thereby setting the balance between oxygen delivery by flow and ATP generation. The models serve for data analysis and hypothesis testing, account for the kinetics of enzyme binding and the resultant concentration‐dependent substrate capacitance (cellular volume of distribution), and provide mass balance. They serve as working hypotheses until disproven, and are “open source” on our website (www.physiome.org), so that they can be tested and improved by the scientific community. Such models will serve as tools to link overall cellular function to the underlying physiology and its regulation at the proteomic and genetic levels.Support or Funding InformationThese efforts are a part of the Physiome Project sponsored by NIH/NHLBI U01‐HL122199 Cardiac Energy Grid and our Simulation Resource (http://www.physiome.org).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.