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

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.Simulation results indicated multiple time-dependent controls over both glycolysis and lactate formation.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.The primary effect of reduced myocardial blood flow is a decrease in the rate of aerobic ATP resynthesis, an increase in the cellular redox state (NADH/NAD+), acceleration of glycogenolysis and glycolysis, accumulation of lactate, and a switch from net lactate uptake to net lactate release by the myocardium. Studies in pigs and dogs have shown that the extent of the metabolic derangement (e.g., increased glycolytic rate and lactate production) during reduced myocardial blood flow is dependent upon the severity and duration of flow reduction [1-6]. Glucose uptake increases during moderate ischemia, but decreases in severely ischemic myocardium due to limited glucose delivery [7,8], causing a greater reliance on glycogen for glycolytic substrate. The classic switch to net lactate release with the onset of reduced myocardial blood flow (30–50% reduction) gradually reverses back to no net lactate exchange after 40 to 120 minutes [9]. The control mechanisms responsible for the gradual reduction in lactate release are unclear.At a given demand, O2 delivery to the myocardium determines the rate of oxidative phosphorylation, which sets the cellular NADH/NAD+ and ATP/ADP ratios, both