Energy metabolism in heart failure

Abstract

Heart failure (HF) is a syndrome resulting from the inability of the cardiac pump to meet the energy requirements of the body. Despite intensive work, the pathogenesis of the cardiac intracellular abnormalities that result from HF remains incompletely understood. Factors that lead to abnormal contraction and relaxation in the failing heart include metabolic pathway abnormalities that result in decreased energy production, energy transfer and energy utilization. Heart failure also affects the periphery. Patients suffering from heart failure always complain of early muscular fatigue and exercise intolerance. This is linked in part to intrinsic alterations of skeletal muscle, among which decreases in the mitochondrial ATP production and in the transfer of energy through the phosphotransfer kinases play an important role. Alterations in energy metabolism that affect both cardiac and skeletal muscles argue for a generalized metabolic myopathy in heart failure. Recent evidence shows that decreased expression of mitochondrial transcription factors and mitochondrial proteins are involved in mechanisms causing the energy starvation in heart failure. This review will focus on energy metabolism alterations in long-term chronic heart failure with only a few references to compensated hypertrophy when necessary. It will briefly describe the energy metabolism of normal heart and skeletal muscles and their alterations in chronic heart failure. It is beyond the scope of this review to address the metabolic switches occurring in compensated hypertrophy; readers could refer to well-documented reviews on this subject. Metabolic alterations in the heartSpecificity of cardiac metabolism. Myocardial function depends on a fine equilibrium between the work the heart has to perform to meet the requirements of the body and the energy that it is able to synthesize and transfer in the form of energy-rich phosphate bonds to sustain excitation-contraction coupling. Heart muscle is a highly oxidative tissue that produces more than 90% of its energy from mitochondrial respiration. Mitochondria occupy ≈30% of cardiomyocyte space and are well organized under the sarcolemma and in rows between myofilaments such that a constant diffusion distance exists between mitochondria and the core of myofilaments. During maximal exercise the heart uses more than 90% of its oxidative capacity, showing that there is no excess capacity of energy production over energy utilization (Mootha et al. 1997). There is a strict relationship in vitro and in vivo between oxygen consumption and cardiac work that occurs at constant global cellular ATP and phosphocreatine (PCr) concentrations. Therefore, a strong energy signalling pathways should exist to ensure a close matching between oxygen consumption and energy utilization. At present, the nature and function of such signals are still under debate. Oxygen availability, substrate limitation, ATP, ADP and PCr changes, inorganic phosphate, calcium, redox state and phosphotransfer systems have all been considered to play a ...

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