NONLINEAR MODELING OF MYOCARDIAL HIGH ENERGY PHOSPHATE SYSTEM

控制ATP合成和水解速率的过程

The processes governing the rates of ATP synthesis and hydrolysis are of critical importance during coronary underperfusion, since myocardial energy metabolism plays a primary role in the death or survival of myocardial tissue. Analysis of myocardial phosphoenergetics is dominated by the thermodynamic view of a closed system, since high energy phosphate compounds have low membrane permeability. However, data on the timecourse of myocardial phosphocreatine (PCr) and ATP (NMR spectroscopy) during coronary underperfusion can only be described by an open phosphoenergetic system, in which ATP breakdown during ischemia causes the production of adenosine, which is membrane permeable and effluxes from the system. By accounting for novel open system kinetics using a preliminary model, we obtained the surprising result that even when coronary flow was reduced by 95% from baseline, the matching of the rates of ATP synthesis and hydrolysis was just as precise as under control conditions. To confir m this finding and explore the metabolic pathways that regulate energy metabolism during ischemia, we propose a more complete nonlinear open system model, linking the myocardial high energy phosphate system with the metabolic pathways producing membrane permeable adenosine. First, an ODE solver will be used to describe intracellular metabolism, an interstitial region, and a uniform vascular space. Next, the cell model will be embedded in the axially distributed convection-diffusion blood-tissue exchange (BTEX) architecture, to include vascular transport of oxygen and nucleosides. Finally, the model will be extended for a more complete description of adenosine pathways, including adenosine uptake in capillary endothelial cells. The combination of an accurate model and high resolution kinetic data will provide completely new insight on the regulation of myocardial energy metabolism during ischemia.