Regulation of cardiac energetics: role of redox state and cellular compartmentation during ischemia.

The heart is capable of altering its metabolic rate during exercise or ischemia. Under most state transitions, the heart maintains the concentration of adenosine triphosphate (ATP) at relatively constant values, in spite of large fluctuations in metabolic rate or in the delivery of fuels and oxygen. However, the mechanisms responsible for the regulation of cardiac energetics under conditions of increased demand or reduced supply are still under debate. To improve quantitative understanding of the regulation of glycolysis and oxidative phosphorylation under physiological and pathological conditions, it is essential to assess the dynamics of cytosolic and mitochondrial nicotinamide adenine dinucleotide (NAD(+)) and its reduced form (NADH) during stress (e.g., ischemia, exercise). However, at present there are no reliable methods to measure the dynamics of redox state in vivo in these subcellular compartments. In the present study, computer simulations with a mathematical model of myocardial energy metabolism are used to investigate the role of cytosolic and mitochondrial redox states in regulating cardiac energetics during reduced myocardial blood flow.