Myocardial energy metabolism: a therapeutic target in cardiac ischemia B.S. Kalra and V. Roy. Efficacy of metabolic modulators in ischemic heart disease: an overview. J Clin Pharmacol. 2011. Published online 7 March 2011. H. Tuunanen and J. Knuuti. Metabolic remodelling in human heart failure. Cardiovasc Res. 2011. Advance online access published March 3, 2011.

Energy: a vital need for the heart Each day, the heart beats about 100 000 times and pumps approximately 10 metric tonnes of blood through the body. Cardiac muscle uses 1 mM ATP per second Energy reserves: 20mM of Pi (ATP and PCr) >90% of energy is produced as PCr >90% energy comes from mitochondrial respiration During intense exercise the heart uses >90% of oxidative capacity In order for the heart to properly ensure its role, cardiac cells have very high and fluctuating energy demands. Each day, the heart beats about 100 000 times and pumps approximately 10 metric tonnes of blood through the body. To achieve this, the heart needs more energy than any other organ in the body. As a result, it cycles through about 6 kg of ATP every day - 20 to 30 times its own weight. Mitochondria are the site of energy production, their volume represents 30% of myocardial cell volume. There is a linear relationship between oxygen consumption and cardiac work, meaning that the cardiac cell is able to adapt mitochondrial respiration to work. However, storage of energy in the heart is very limited with regard to the organ’s needs. Reserves can only ensure approximately 20 seconds of normal activity. Thus the heart should permanently adjust energy production to energy utilization. Moreover, for a muscle such as myocardium with such sustained and prolonged and cyclic activity, only oxidative phosphorylation can provide enough energy for contraction. This provider is limited, as the cardiac cell utilizes 90% of its oxidative capacity at maximal exercise. All of this explains why any significant diturbance in energy production in the heart can have deleterious consequences.

The heart mainly produces ATP through oxidative pathways Fatty Acid -oxidation Provides 60% to 90% of energy. Requires more 02 than glucose. ATP/02=2.6 Glucose oxidation Provides 10% to 40% of energy. More 02 efficient pathway. ATP/02=3 Glucose Fatty acids Acyl coA Pyruvate In normal conditions, to acquire the energy necessary to carry out its function, the heart mainly relies on oxidative metabolic pathways and converts the chemical energy stored in fatty acids and glucose into ATP that provides the mechanical energy for the actin-myosin interaction of myofibrils. The heart also derives its energy from other sources such as lactate, pyruvate, and ketone bodies, but to a much lower extent. Free fatty acids are the major source of energy for the heart, generating 60% to 90% of ATP while glucose metabolism produces the rest of 10% to 40% of ATP depending on physiological conditions. Energy yield per gram of substrate metabolized is more with fatty acids, 37kJ/g versus only 16kJ/g with carbohydrates. However, this is at the cost of much greater amount of oxygen consumed, 2.016L/g with fats versus 0.829L/g with carbohydrates. This results in a higher ATP/oxygen ratio for glucose. Acetyl coA Energy (ATP)

Cardiac disease is closely linked to impairments in cardiac energy metabolism Fatty acid oxidation Glucose Fatty acids Anaerobic glycolysis Acyl coA Pyruvate Acetyl coA Cell acidosis Calcium overload Whether it is during acute or chronic ischemia, or in situations of altered cardiac function, characteristic alterations of cardiac energy metabolism have been described. In situations of ischemia, fatty acid oxidation and glucose oxidation both diminish due to oxygen shortage, and anaerobic glycolysis becomes a more important source of energy as it is the only process capable of producing ATP in the absence of oxygen. However, ATP generated by glycolysis is not sufficient to meet the energy needs of the beating heart, resulting in a concomitant decline in total ATP and energy production of the heart. Moreover, in response to catecholamine release, FFA levels increase and free fatty acid oxidation becomes the preponderant residual oxidative pathway. The resulting high rate of fatty acid oxidation produces high levels of acetyl-coenzyme A, which negatively feedback PDH activity and thus inhibit pyruvate oxidation. The nonoxidized pyruvate is converted into lactate and protons (H+), which gradually induce cellular acidosis (a fall in pH) and calcium overload inducing an increase in ATP expenditure in order to sustain cellular homeostasis. In situations of heart failure, similar metabolic alterations have been described mainly explained by the development of a significant increase in insulin resistance. This results in a significant reduction in energy production, leading to a decrease in efficiency of the failing heart. Cell damage Increase need of ATP for homeostasis. Energy (ATP) Contractile dysfunction

Therapeutic perspectives for agents modulating cardiac energy metabolism It therefore appears that shifting of cardiac metabolism from free fatty acids to glucose might be beneficial since fatty acid oxidation requires more oxygen; also because accumulation of products of fatty acid metabolims during ischemia contributes to the ischemic injury. Hence, any approach that stimulates myocardial glucose oxidation and suppresses or inhibits fatty acid oxidation may optimize energy metabolism in the heart, relieve ischemic symptoms, and improve cardiac efficiency/function. Metabolic interventions shifting the source of energy toward carbohydrate utilization can be directed to 3 different goals: Modulate free fatty acid oxidation, which indirectly increases carbohydrate oxidation: Trimetazidine, CPT-1 inhibitors (oxfenicine, etomoxir and perhexiline), PPAR agonists, nicotinic acid and ranolazine (?) Increase glycolysis or carbohydrate utilization: increase in glycogen load or glucose-insulin-potassium infusion Direct increase in carbohydrate oxidation: dichloroacetate, L-Carnitine Among these different molecules, three are widely used in clinical practice. β-adrenergic receptor antagonists have been shown to somehow influence substrate utilization in the heart, but this activity has not been shown to be linked to their therapeutic properties. Ranolazine has established evidence of antianginal efficacy. However, it seems that the therapeutic benefits of the molecule are mainly due to a late sodium current inhibition. Trimetazidine (available in a large number of countries under the brand name of Vastarel) is used in over 100 countries to treat stable angina. Trimetazidine also has extensive clinical evidence showing its ensures a significant improvement of cardiac function in heart-failure patients. Heart Metab. 2008;38:5-14,