COMPUTER-SIMULATION OF LOW-DENSITY-LIPOPROTEIN REMOVAL IN THE PRESENCE OF A BIOREACTOR CONTAINING PHOSPHOLIPASE A(2)

High concentrations of low-density lipoproteins (LDL) in the blood can lead to coronary heart disease, the primary cause of death in the Wes tern hemisphere. A new treatment to reduce LDL levels is now being tes ted on rabbits, which are model animals for hypercholesteremia. The tr eatment involves using an immobilized enzyme within a bioreactor that is incorporated in an extracorporeal circuit. The enzyme modifies LDL to a form that is much more rapidly removed from the circulation. A ma thematical model to describe LDL metabolism in the presence of the bio reactor was developed to give a better understanding of the biodistrib ution of modified LDL during and following treatment. A four-compartme nt model was developed on the basis of previous studies on human lipid metabolism, with the specific values of the constants taken from the experimental data on rabbits. A Macintosh II computer with a Stella II modeling program was used to simulate the treatment and to predict LD L levels over time given different values for initial enzyme activity, length of treatment, rate of enzyme denaturation, and other relevant parameters. The model provided a close fit with the experimental resul ts for the change in total cholesterol. It confirmed the observed dela y in the plasma cholesterol rebound level after the end of the extraco rporeal treatment. One conclusion derived from both the experimental d ata and the model is that during the first 1.5 h, the limiting step fo r LDL removal is the rate at which modified LDL is taken up by the liv er. However, bioreactor cessation becomes the limiting step in maintai ning low LDL levels for an extended term. The study suggests that cont inuous modification of LDL, possibly using an implantable device, is r equired to maintain low levels of plasma LDL.