Current Pharmaceutical Design, 2009, 15, 000-000 1 1381-6128/09 $55.00+.00 © 2009 Bentham Science Publishers Ltd. The Heart Metabolism: Pathophysiological Aspects in Ischaemia and Heart Failure K. Abozguia * , G. Nallur Shivu, I. Ahmed 1 , T.T. Phan and M.P. Frenneaux Department of Cardiovascular Medicine, Medical School, University of Birmingham, Edgbaston, Birmingham, B15 2TT, United Kingdom Abstract: The morbidity and mortality of coronary heart disease and of heart failure remain unacceptably high despite major advances in their management. The main focus of treatment has been revascularisation for ischaemic heart disease and neuro-humoral modification for heart failure. There is an urgent need for new modalities of treatment to improve mor- tality and morbidity. Recently, there has been a great deal of interest in the role of disturbances in cardiac energetics and myocardial metabolism in the pathophysiology of both ischaemic heart disease and heart failure and of therapeutic poten- tial of metabolic modulation. The myocardium is a metabolic omnivore, but mainly uses fatty acids and glucose for gen- eration of Adenosine-5'-triphosphate (ATP). This review focuses on the key changes that occur to the metabolism of the heart in ischaemia and in heart failure and its effects on cardiac energetics. Key Words: Heart failure, ischaemia, myocardial metabolism, pathophysiology. BURDEN OF ISCHAEMIC HEART DISEASE AND HEART FAILURE The global burden of coronary artery disease is ever in- creasing. Around 18 million people die worldwide every year from cardiovascular disease (CVD) [1] out of which 4.3 million are from Europe, accounting for nearly half of all deaths in Europe [2]. It is the main cause of disease burden in the western world. The economic costs are alarming: CVD cost the EU around 192 billion Euro in 2006 and this figure is increasing every year [2]. The prevalence of heart failure has dramatically increased throughout the western world. The incidence and prevalence of heart failure increases with increasing age [3,4] and ageing of the population accounts in part for the increasing prevalence of heart failure. Increased survival rates in patients suffering acute myocardial infarc- tion [5] (associated with revascularisation) has also been proposed to contribute. It has been estimated that there are currently 6.5 million chronic heart failure (CHF) patients in Europe and 5 million in the USA [6]. Heart failure has a poor prognosis with nearly 50% of the patients dying in the first four years of diagnosis and nearly half of those with severe heart failure dying within 1 year [7-9]. These dismal figures are in spite of the dramatic improvements in the treatment of heart failure over the past 20 years or so. These have focused on the blockade of maladaptive neurohormonal activation [10,11]. Recently, there has been increasing inter- est in metabolic agents (which alter the fuel usage of the heart) as treatment for both ischaemic heart disease and heart failure [12,13]. This review focuses on metabolic changes that occur in the heart in ischaemia and in heart failure and how this understanding could be of potential therapeutic benefit. *Address correspondence to this author at the Department of Cardiovascular Medicine, Medical School, University of Birmingham, Edgbaston, Bir- mingham, B15 2TT, UK; Tel: +44 121 414 5916; Fax: +44 121414 3713; E-mail: abozguia@gmail.com *Joint first Authors. MYOCARDIAL METABOLISM IN NORMAL HEARTS The human heart is a relentless pump that never stops working during life. It beats for approximately 100,000 times a day and hence requires vast amount of energy to fulfil its function. Therefore, it is not a surprise that cardiac energetics play a key role in the pathogenesis and progression of ischaemic heart disease and heart failure. The myocardium is a metabolic omnivore and is able to metabolise glucose, Free Fatty Acids (FFAs), amino acids, ketones and lactate for energy production. In normal circumstances, 60-90% of the acetyl Co-A, which enters the Krebs cycle comes from beta- oxidation of FFAs and 10-40% from oxidation of pyruvate [14,15] (Fig. (1)). Glucose metabolism consists of two im- portant components, glycolysis and glucose oxidation. Gly- colysis which occurs in the cytosol involves conversion of glucose to pyruvate, while glucose oxidation involves the subsequent mitochondrial oxidation of pyruvate. Pyruvate derived from glucose and lactate enters the krebs cycle via the Pyruvate Dehydrogenase Complex (PDC) that catalyses the conversion of pyruvate to acetyl Co-A [16,17]. Glycoly- sis only contributes approximately 5% of the total ATP gen- erated by the heart during aerobic conditions. During ischaemia, glycolysis is accelerated, producing a greater pro- portion of the heart’s ATP supply. However, this may result in accumulation of protons and lactate if glucose oxidation does not increase in parallel. Ischaemia also inhibits the PDH complex and results in anaerobic glycolysis. Therefore, ac- celerated glycolysis during ischaemia can have detrimental consequences. Unlike glucose metabolism, fatty acid me- tabolism produces all of the ATP via beta oxidation in the mitochondria. Fatty acid oxidation consumes more oxygen to produce an equivalent amount of ATP compared to glucose oxidation. Also increased fatty acid metabolism results in a concomitant decrease in glucose oxidation due to Co-A me- diated inhibition of PDH. This can lead to an uncoupling of