Gary D. Lopaschuk

Fatty Acid Oxidation in the Reperfused Ischemic Heart

Myocardial ATP production is dependent chiefly on the oxidative decarboxylation of glucose and fatty acids. The co-utilization of these and other substrates is determined by both the amount of any given substrate supplied to the heart as well as by complex intracellular regulatory mechanisms. This regulated balance is altered during and after ischemia. During aerobic reperfusion of ischemic myocardium, a rapid recovery of energy production is desirable for the complete recovery of muscle contractile function. It is now clear that the type of energy substrate used by the heart during reperfusion will directly influence this contractile recovery. By increasing the relative proportion of glucose oxidized to that of fatty acids, the mechanical function of the reperfused heart can be improved. However, fatty acid oxidation recovers quickly during reperfusion and dominates as a source of oxygen consumption. These high rates of fatty acid oxidation occur at the expense of glucose oxidation, resulting in a decreased recovery of both cardiac function and efficiency during reperfusion. One contributory factor to these high rates of fatty acid oxidation is a decrease in myocardial malonyl-coenzyme A (CoA) levels. Malonyl-CoA, which is synthesized by acetyl-CoA carboxylase, is an essential metabolic intermediary in the regulation of fatty acid oxidation. A decrease in malonyl-CoA level results in an increase of carnitine palmitoyl transferase-1 mediated fatty acid uptake into the mitochondria. This mechanism seems important in the regulation of fatty acid oxidation in the postischemic heart and is discussed in detail in this review, with reference to specific clinical scenarios of ischemia and reperfusion and options for modulating cardiac energy metabolism.

CHAPTER 32 – Myocardial Energy Metabolism

This chapter presents an overview of the process and regulation of myocardial energy metabolism. ATP provides the energy for contractile function, membrane homeostasis, and cellular functions, and interruption in the supply of substrate and/or oxygen results in significant changes in myocardial energy metabolism and contractile function. High rates of myocardial energy production are required to maintain the constant demand of the working heart for ATP. A constant supply of oxygen and at least one of the major exogenous substrates such as fatty acids, lactate, and glucose, are required for normal metabolic function and for ATP production to continue. Glucose has an inducible transporter, GLUT-4, which is regulated chiefly by insulin, and which responds well to the level of myocardial oxygenation and the workload of the myocardium. Glucose is activated to glucose 6-phosphate by hexokinase and can be diverted into either glycogen synthesis or glycolysis. Glycolysis transforms glucose into two three-carbon units (pyruvate), with the net production of ATP and the reducing equivalents (NADH 2 ) without any oxygen requirement. Pyruvate can be oxidized to lactate and released or activated to form acetyl-CoA, which then enters the citrate cycle. Fatty acids provide the major component of myocardial oxidative energy under both conditions of normal oxygen supply and moderate impairment of oxygenation (ischemia). The uptake and transport of fatty acids require fatty acid-binding proteins and intracellular fatty acid transport protein.