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To meet its high-energy demand, the heart is very flexible in its choice of energy substrates. It can use a variety of energy substrates which include fatty acids, glucose, lactate, pyruvate, ketones, and amino acids. In the failing heart, significant changes in cardiac energy substrate metabolism occur, although there is no consensus as to exactly what these changes are. Energy starvation in heart failure has been extensively discussed, where reduced oxygen and energy substrate delivery to the heart, reduced cardiac energy substrate uptake, reduced mitochondrial oxidative phosphorylation, and decreased metabolic flexibility have been implicated as contributing factors to the declining mechanical function in heart failure. In addition to energy starvation, there is also the possibility of inefficient energy utilization in the failing heart. This inefficiency can occur at the level of ATP production where the preferential dependence on fatty acids consumes more oxygen per unit ATP and/or the overexpression of uncoupling proteins can increase energy loss as heat rather than ATP production. Increased ATP utilization for non-contractile purposes, such as ionic homeostasis and futile cycling of fatty acids, can also contribute to inefficiency in the failing heart. Impaired phosphocreatine/creatine kinase shuttle activity may also contribute to inefficient transport of ATP from the mitochondria to the contractile myofibrils. The degree and type of energy inefficiency in the failing heart are likely dependent on the pathogenesis and severity of heart failure. In this chapter, we review the various contributors to energy inefficiency in heart failure and discuss the potential to optimize cardiac energy metabolism as a potential treatment for heart failure.

The passage of adenosine and other nucleosides across plasma membranes may occur by simple diffusion, or may be mediated by nucleoside-specific transport systems that are intrinsic components of the plasma membrane. Both facilitated diffusion and sodium-dependent nucleoside transport (NT) systems have been described and each of these classes may possess several subtypes. It should be noted that, in some cells, adenosine fluxes are rapid. Consequently rapid sampling assays are required to measure initial rates of uptake that are representative of transport rates (see reviews by Paterson et al., 1985; Gati et al., 1989a). Interpretation of inhibition of nucleoside entry as transport inhibition requires that uptake rates be demonstrably initial rates. Thus, accurate assessment of NT and its inhibition can best be obtained using cells in culture or in fresh cells that have been dispersed enzymatically. This report will review mechanisms of adenosine transport and summarize the evidence in support of NT system heterogeneity, with particular emphasis on NT systems in cells and tissues likely to be involved in the modulation of the physiological and pharmacological actions of adenosine.