Computational studies of the effects of myocardial blood flow reductions on cardiac metabolism

BACKGROUND: A computational model of myocardial energy metabolism was used to assess the metabolic responses to normal and reduced myocardial blood flow. The goal was to examine to what extent glycolysis and lactate formation are controlled by the supply of glycolytic substrate and/or the cellular redox (NADH/NAD+) and phosphorylation (ATP/ADP) states. METHODS: Flow was reduced over a wide range and for a sufficient duration in order to investigate the sequence of events that occur during the transition to a new metabolic steady state. RESULTS: Simulation results indicated multiple time-dependent controls over both glycolysis and lactate formation. CONCLUSIONS: Changes in phosphorylation state and glucose uptake only significantly affect the initial phase of the glycolytic response to ischemia, while glycogen breakdown exerts control over glycolysis during the entire duration of ischemia. Similarly, changes in the redox state affect the rates of lactate formation and release primarily during the initial transient phase of the response to the reductions in blood flow, while the rate of glycolysis controls the rate of lactate formation throughout the entire period of adaptation.